Pharm test 1

PHARMACODYNAMIC

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The mechanisms by which drugs interact, on a molecular level, with constituents of cells or cellular environments to produce biochemical and/or physiological changes in cells, tissues, organs, and ultimately patients.

A study of the mechanisms by which drug molecules influence target cells, or cellular environments, that result in physiological or biochemical alterations recognized as the pharmacologic action of the drug.

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PHARMACODYNAMIC

Non-Specific Physio-Chemical Drug Actions

Drugs which work by non-specific physiochemical actions produce pharmacodynamic effects by influencing the environment of cells, and thus altering extracellular body compartments. They do not produce any direct effect on cells but can alter the functioning of cells by indirectly affecting the cell's environment. Their actions do not require any interaction between the drug and any component of the cell.

five mechanisms by which drugs can alter the physical or chemical environment of cells

1)ALTERATION OF BODY CHEMISTRY
2)ADSORPTION OF TOXINS, ELECTROLYTES, BILE SALTS, AND OTHER DRUGS IN THE INTESTINAL TRACT
3) IMPOSITION OF A PHYSICAL BARRIER
4) LUBRICATION
5) ALTERATION OF SURFACE TENSION

ALTERATION OF BODY CHEMISTRY

Drugs can be used to alter gastric or extracellular pH, extracellular osmotic pressure, or composition of extracellular electrolytes.

Examples:

1. Antacids are used to alter gastric pH.
2. Mannitol alters osmotic pressure of extracellular fluids
3. Electrolyte solutions alter the composition of serum electrolytes

ADSORPTION OF TOXINS, ELECTROLYTES, BILE SALTS, AND OTHER DRUGS IN THE INTESTINAL TRACT

Drugs can be used to form an irreversible chemical bond between themselves and some other molecular substance in the intestinal tract. By binding to these substances, their absorption is prevented because the drugs to which they are bound cannot be absorbed.

Examples:

1. Kaopectate adsorbs orally ingested microbial enteric toxins
2. Cholestyramine (Questran) adsorbs bile salts, thereby preventing absorption of dietary fat. It can also bind to other orally ingested medications, preventing their absorption
3. Activated Charcoal binds to (adsorbs) other orally ingested drugs and toxins, preventing their absorption

IMPOSITION OF A PHYSICAL BARRIER

These drugs, by interposing themselves between cells and some other injurious environmental substance, can block injury to cells from their exterior.

Examples:

1. Sunscreens coat the skin cells blocking ultraviolet radiation injury from the sun
2. Sulcralfate (Carafate) forms an insoluble paste with hydrochloric acid, coating the base of a peptic ulcer blocking additional injury to the gastric wall from the acid

LUBRICATION

These drugs coat the surface of cells (or tissues) decreasing the abrasive forces (friction) that cells are subjected to from their external environment. By decreasing mechanical injury to the cells, the lubricant drugs perform a protective function.

Examples:

1. Mineral Oil (ingested orally or taken rectally) decreases friction between colonic wall and stool, allowing easier defecation
2. Talcum Powder, applied to the inframammary surfaces, decreases close apposition of skin surfaces and friction between these surfaces

ALTERATION OF SURFACE TENSION

These drugs alter the physical forces that exist between two different states of matter (i.e., solids and liquids). In general, they decrease the natural resistance of the two states of matter to mix allowing the liquid phase of matter to "enter" the solid phase.

Examples:

1. Stool softeners alter the surface of hard stool allowing water from the colonic lumen to enter the stool, making it softer

Direct Interaction Between Drug Molecules and Molecular Target Enzymes

Many drugs work by interacting directly with a specific enzyme molecular target in a cell or in a body fluid. This interaction typically causes the action of the enzyme to become decreased. Drug-enzyme interaction can take one of two forms.

Drug-enzyme interaction 2 forms

(1) A drug may bind to the same physical location on the enzyme that is normally occupied by the substrate of that enzyme. In doing so, the drug competes with the substrate for the active site on the enzyme, preventing the enzyme from functioning normally.

(2) A drug may interact with an enzyme target changing the physical structure of the enzyme and disrupting its integrity.

Examples:

1. Digoxin binds to and blocks the action of the enzyme Na/K ATPase which inhibits the movement of sodium ions from within the cardiac muscle cells to the extracellular fluid. This, in turn, enhances the entry of calcium ions into the cells, making the cardiac muscle contract more forcefully and, thereby, improving cardiac output.
2. ACE inhibitor drugs bind to and block the action of angiotensin-converting enzyme which inhibits the formation of angiotensin II. This enzyme-blocking action thereby results in an inhibition of peripheral vasoconstriction that would normally occur with angiotensin II. The ultimate result is a lowering of blood pressure.
3. Sildenifil (Viagra) binds to and blocks the action of phosphodiesterase V which prevents the degradation of a naturally occuring compound called cGMP. The "build-up" of cGMP results in vasodilatation of the penile arteries and increased blood flow into the penis.

Drug ReceptorsThe complimentary structural and electromagnetic interaction between a drug molecule and its specific molecular docking site attached to a membrane located on or in a target cell.Characteristics of ReceptorsCOMPOSITION, FUNCTION LOCATION NATURAL HISTORY RECEPTOR NOMENCLATURECOMPOSITIONReceptors are complex molecules consisting primarily of very large and complex protein molecules arranged in a long chain and folded into very specific three-dimensional structures. Some receptors are pure proteins but others are mixtures of carbohydrates and protein (glycoproteins) or proteins and fat (proteolipids). The precise structure of each receptor is pre-programmed within the genetic codes of each cell in which the receptor is located. Different cells have many different types of receptors but many different cells share common genetic codes which allows them to have many of the same types of receptors. (For example, nerve cells have many different types of receptors when compared to muscle cells. However, some of the same types of receptors are found on both nerve and muscle cells.)FUNCTIONReceptors are normal body structures synthesized as a normal part of cellular metabolism whose function is to interact with the body's own normal physiologically active substances such as hormones, neurotransmitters, biomediators, etc. The long folded chain typically has components that span the width of the cell's plasma membrane with extensions both to the outside of the cell and also to the inside of the cell. In this way, the natural substances (or drug molecules) can fit into a three-dimensional compartment on the receptor's external extension, react with other atoms at that site, change the electromagnetic forces of the entire receptor molecule, and influence the electromagnetic forces on the receptor's internal extension. This change of the receptor's electromagnetic forces (and sometimes its structure) inside the cell then signals other, secondary changes inside the cell that ultimately results in an alteration in the cell's biochemistry or physiology. Receptors are not created by drugs; drugs simply "borrow" them for a time from the body's own natural physiologically active substances. The interaction of the drug with the active site on the receptor's external extension has the same or similar effect as the body's own natural substances.LOCATIONThe great majority of receptors are located on the surface of cells, intimately associated with the cell's plasma membrane. Some receptors are located on the cell's nuclear membrane and others are located inside the nucleus or attached to some other constituent of the cell's cytoplasm.NATURAL HISTORYReceptors are transient in structure and in function. The repeated interactions that occur with natural substances or with drugs eventually "damage" the receptor, decreasing its ability to perform its functions. This damage can be structural in which the precise three-dimensional structure becomes so altered that it will no longer fit its activator substances. Alternatively, the damage can be functional in which the receptor can no longer interact chemically with its activator substances. In either event, the receptor becomes worn out. The cell's repair machinery recognizes this and "pulls" the receptor to the inside of the cell, breaks it apart, and synthesizes a new receptor to take its place. In other words, the damaged receptors are continuously being replaced with undamaged receptors. When receptors become damaged or decreased in number, they are said to be "down-regulated". Occasionally cells can be induced to increase the synthesis of receptors. When receptor number or level of functioning is increased above that which is normal, they are said to be "up-regulated".RECEPTOR NOMENCLATUREReceptors are typically named for the natural substance (hormone, biomediator,etc.) with which they normally interact. For example: histamine receptor, insulin receptor, estrogen receptor. Many receptors exist naturally in a variety of forms called subtypes. For example: H1 (for histamine-1) receptor or Beta 2 receptor (a type of epinephrine or adrenergic receptor). All cells have tens of thousands of receptors of various types but not all cells have the same types of receptors in the same proportions. The number and type of receptors that each cell has is determined by the specific genetic codes for receptor synthesis in the nucleus of each cell.Drug-Receptor BindingThe interaction between a drug and its specific receptor is referred to as drug-receptor binding. It is only when this binding is occuring that a drug can exert its pharmacologic action on its target cell. This binding between drug and receptor is only temporary; the drug molecule, after temporarily binding to a receptor, will separate from it. The drug may come back to bind again or it may drift too far away from the receptor to interact with it a second time. When the drug molecule can no longer bind to the receptor, the pharmacologic activity of that drug molecule is ended. This phenomenon explains how drug molecules produce their pharmacologic effects but it seems to indicate that drug-receptor binding is an all-or-none phenomenon; in other words, when the receptor is occupied and activated by a drug, expect the full effect of drug and when the receptor is not occupied by a drug, expect no effect. In practice, this "occupancy theory" of drug-receptor interaction fails to explain how similar drugs which activate the same receptor can have markedly different effects on the cell. It also fails to explain how different dosages of the same drug can have markedly different effects. Certain features of drug-receptor interaction have been recognized to explain the varying intensities of action of different drugs. These features are collectively referred to as the Modified Occupancy Theory of Drug-Receptor Interaction and are the explanation for the magnitude of a drug's effect.features of drug-receptor interactionReceptor Occupancy Drug-Receptor Affinity Drug's Intrinsic Activity on the ReceptorReceptor Occupancythe actual number of receptor molecules occupied by drug molecules at any one point in time. Since each cell has thousands of receptors, any number or all of them can be physically occupied at any one point in time. How many receptors are occupied is, in turn, dependent on how many drug molecules are in the vicinity of the target cell at any point in time. The number of drug molecules present is usually determined by the amount of drug actually administered (i.e., the dose).Drug-Receptor Affinitythe degree of attraction (electromagnetic force) between a drug molecule and its receptor molecule. Because each type of drug is a different molecule, it is composed of different atoms with varying degrees of electromagnetic forces. Each has a different ability to interact chemically with other chemical molecules. Receptors, being chemical molecules, have the ability to interact chemically with other molecules (like drugs) but the intensity of the interaction will differ depending on the molecular make-up of the two interacting substances. Drugs and receptors that are "pulled" together with very strong electromagnetic forces spend more time together; in other words, the receptor is occupied by the drug for a longer period of time. This translates into a greater pharmacologic effect. Drug-receptor affinity bears a very close relationship to drug potency. When we say that a particular drug is potent it is because that drug occupies the receptor for a longer period of time than does a similar drug that is not as potent. This is the explanation why Demerol has a greater magnitude of analgesic effect when compared to Codeine. They both interact with the same receptor but Demerol has the greater affinity for the receptor, occupies the receptor longer, and produces a greater degree of pain relief.Drug's Intrinsic Activity on the Receptor.the ability of a drug to influence receptor functioning once binding and interaction has occurred. It is not enough for a drug to simply bind to a receptor in order to produce a pharmacologic effect. This binding must produce an interaction between the drug and the receptor which changes the electromagnetic forces of the structure of the receptor enough to transmit a "signal" into the inside of the target cell. This "signal" then triggers other secondary changes in the internal environment of the target cell which are recognized as the biochemical or physiological effects of the drug. These secondary changes are often mediated by secondary messengers (enzymes, G-proteins, cAMP, etc.) that are responsible for the internal effects of the drug on the cell.Categories of Drugs-Drugs which act through drug-receptor interaction mechanisms, can be categorized into two basic types. Which areagonist drugs and antagonist drugsAGONIST DRUGSDrugs which mimic the actions of the body's endogenous biomediators on their receptors. They have both affinity for and intrinsic activity on these receptors.There are two basic types of agonist drugs:two basic types of agonist drugsAgonist I Agonist IIAgonist IAgonist drugs which bind to the same molecular extracellular site on the receptor as the endogenous biomediator. Examples of agonist I drugs are epinephrine, Beta 2 bronchodilators, and opiates. Each of these types of drugs bind to the very same spot on the receptor as the body's own natural epinephrine, norepinephrine, or opiate compounds.Agonist IIAgonist drugs which bind to a different molecular extracellular site on the receptor than the endogenous biomediator but, by binding to the receptor, enhance the effect of the endogenous biomediator on its own receptor. In other words, the agonist II drugs increase the natural intrinsic activity of the biomediator on its own target cells. Examples are thyroid hormone drugs and the benzodiazepines. Thyroid hormone binds to a different spot on the epinephrine and norepinephrine receptor but can potentiate the actions of the body's endogenous adrenergic hormones (epinephrine and norepinephrine) on their receptors. In a similar manner, the benzodiazepines bind to a different spot on the GABA (gamma aminobutyric acid) receptor but can potentiate the actions of the natural inhibitory neurotransmitter, GABA, on its receptors.ANTAGONIST DRUGSDrugs which prevent (or block) the actions of the body's endogenous biomediators (or other agonist drugs) on their receptors. Antagonist drugs have affinity for receptors but lack intrinsic activity on them. They work by occupying the receptor, having no action of their own, but prevent occupancy of the receptor by the natural endogenous biomediator. (Alternate names for antagonist drugs are inhibitors or blockers.) There are three basic typesthree basic types of ANTAGONIST DRUGSAntagonist I, Antagonist II, Antagonist IIIAntagonist IDrugs which bind to the same molecular extracellular site on the receptor as the natural biomediator and diminish (inhibit) or prevent (block) the action of the natural compound. Examples are atropine and the H 2 receptor blockers.Antagonist IIDrugs which bind to a different molecular extracellular site from the endogenous biomediator and partially inhibit the action of the natural compound. Examples are calcium channel blockers.Antagonist IIIDrugs which translocate through the plasma membrane and inhibit the receptor's signal on the inside of the cell, either at the internal part of the receptor or some other secondary messenger mechanism inside the cell. Examples are milrinone (Primacor), phosphodiesterase inhibitors (theophylline), and Viagra.Continuous, sustained agonist drug administration results indown-regulation of receptors and continuous, sustained administration of antagonist drugs results in up-regulation of receptorsDefining the Relationship Between a Drug's Dosage and its EffectsBecause of the marked variability in drug dosages, receptor occupancy, degrees of affinity, variable intrinsic activities, receptor up-regulation and down-regulation, and numerous patient variables, it is no wonder that there is great variability in the responses that are observed when administering drugs to patients. It is clear, however, that there is not always a direct linear relationship between the dose of a drug and its pharmacologic effect. In other words, simply doubling the dose of a drug does not always result in twice the effect. There is, however, a relationship between the dose of a drug and its effect and this relationship is expressed graphically by plotting the logarithm of the dose of a drug against the magnitude of its effect. Called the log dose-response curve, it demonstrates the dosage range that will most likely produce the desired degree of response for each drug. The curve is an S-shaped curve which depicts minimal response with low doses of a drug, a sharp rise in response with mid-range doses, and a lack of additional response with higher doses of a drug.log dose-response curveit demonstrates the dosage range that will most likely produce the desired degree of response for each drug. The curve is an S-shaped curve which depicts minimal response with low doses of a drug, a sharp rise in response with mid-range doses, and a lack of additional response with higher doses of a drug.steep part of the of Log Dose-Response curvedepicts a range of dosages that produce a clinical responsepart of the Log Dose-Response curve where the sharp rise just beginsrepresents the lowest dosages of the drug which are capable of producing only minimal therapeutic responsesThe upper part of the Log Dose-Response curve just before it begins to flatten out againrepresents those dosages where the maximal response is produced.the Log Dose-Response curve flattens out at 100%.When a drug dosage has been reached that produces 100% of the possible therapeutic effect, further increases in dosage cannot increase the drugs effect any more. In other words, the curve flattens out at 100%.What can we learn from examining a log dose-response curve?Focusing on the steep part of the curve, we can read a range of doses that produce clinically useful effects ranging from minimal to maximal. Dosages less than the lowest dose in this range are too low to produce a clinically useful effect. Put another way, dosages below the clinically useful range have too few drug molecules occupying too few receptors to exert any significant pharmacologic effect on target cells. On the other end of the range, when 100% of a drug's clinically useful effect has been reached, all available receptors are occupied. Any additional drug molecules put into the area (i.e., giving a larger dose) will not have any receptors to occupy, therefore they would be unable to increase the pharmacologic actions of the drug any further. The dosages in the steep part of the curve are the clinically useful dosages that could conceivably be used for pharmacologic effect in patients.EFFECTIVE DOSE50%ED50For convenience, the dose exactly in the center of this clinically useful range is defined as that dose which produces one half of the clinically desired effect. This is the dose typically recommended by the pharmaceutical company that developed the drug as the average (or most effective) dose of that drug for most patients. Called the effective dose-50% or the ED50, it is defined in two different ways depending on the clinical action of the drug.For objective measurements such as lowering of blood pressure, ED50 is defined asthat dose of a drug which produces one half of the desired effect in the patient. For example, the ED50 of an antihypertensive drug might be defined as that dose which reduces a patient's elevated blood pressure one half of the number of mm of Hg above normal. This is the type of measurement that can be made in a single patient-For subjective symptom relief such as nausea or painit is impossible to measure when one half of a patient's nausea has been relieved or one half of the pain has been relieved. Log dose-response curves for these types of subjective measurements must utilize many patients. In these situations, ED50 is defined differently. The ED50 is that dose which produces effective relief of nausea or effective pain relief in one half of the test subjects. The varying dosages of the drug are used in hundreds of patients with a given symptom in order to determine the dose that is most useful clinically. The ED50, then, is a starting place for dosage selection. For any given patient, a clinician may have to go up or down from the ED50 but at least the acceptable dosage range is known for any given drug and lies somewhere on the steep part of the log dose-response curve.THERAPEUTIC INDEX Why not use a dose that would produce 80-90% of the desired therapeutic response? Why limit the effectiveness of a drug to only 50% of its clinical usefulness?some of the higher doses in the therapeutic range are identical to some of the lower doses in the toxic effect dose range. Use of a dosage that would produce an 80-90% therapeutic effectiveness for some patients may cause toxic effects for others. The problem for the clinician is which of these two patients is the one being treated now. By using the ED50 dose, the clinician is assured of a dose that will be fairly effective therapeutically in a good number of patients without being unduly dangerous to others.toxic dose ranges of drugsoften measured as the number of deaths that occur with a given drug. Since this is not something that can be studied in humans, these data are usually extrapolated from animal experiments. Plotted side-by-side with the therapeutic dose range is the lethal dose range of the drug. Also an S-shaped curve, it parallels and may also partially overlap the therapeutic dosages curve. In a similar way, the dose in the center of the curve can be identified and is labeled as the lethal dose - 50% or the LD50.LD50defined as that dose of a drug which produces death in one half of the test animals to which it is administered (and theoretically to one half of the patients to whom it is given).referred to as a drug's therapeutic indexDividing the LD50 by the ED50 results in a number that reflects the size of the difference between the average effective therapeutic dose for a drug and the average lethal dose of the drug. It is a measurement of a drug's safety/toxicity and can be used to compare one drug's safety/toxicity to another's. Often referred to as the margin of safety of a drug, the therapeutic index is the width of separation of the two curves. The wider apart the two curves, the less the overlap of the two and the safer the drug. A low number for a therapeutic index indicates that the two curves are very close together, have a narrow margin of safety, and have a comparatively high risk for toxicity (or lethalityCOMPARATIVE POTENCIES OF TWO DRUGSAnother use of the log dose-response curve is to compare the relative potencies of two different drugs. This is accomplished by plotting the log dose-response curves of the therapeutic dosage ranges of two different drugs on the same set of coordinates. In this way, the ED50's of the two drugs are depicted on the same graph and a comparison between these two dosages is made. Because potency is the measurement of the amount of active ingredient of the drug in the preparation, the drug with the least amount of active ingredient producing its ED50 is the most potentCOMPARATIVE EFFICACIES OF TWO DRUGSAgain by plotting the therapeutic log dose-response curves of two similar drugs on the same set of coordinates, a comparison of their relative efficacies can be made. Because efficacy is the ability of a drug to produce an effect, by plotting the two separate curves on the same set of coordinates, even though each drug will be noted to produce 100% of its effect, the maximum effect of one drug will usually be less than the maximal effect of the other. Each drug can be compared to the other in terms of the magnitude of its effect. The drug with the greatest maximum magnitude of effect is the most efficacious.pharmacokineticsThe mechanisms by which the body handles (processes) drugs. It embraces the principles of the relationship between the administered dose of a drug and its eventual serum (or tissue) concentration. It involves the four processes of absorption, distribution, metabolism, and excretion.drug clearanceprocesses of metabolism and excretion. It is the disappearance of the administered drug (the parent drug) from the patient's serum.The eventual pharmacologic effect of any drug will depend onhow much of the administered dose of the drug actually gains entry into the patient's body (absorption), how many drug molecules reach their target cell receptors (distribution), how long the drug remains in the body in its active form (metabolism), and how long before it is removed from the body and is no longer able to interact with its receptors or target enzymes or other body constituents (excretion). The processes of pharmacokinetics determine the magnitude and the timing of all of these events in each individual patient and ultimately determines the pharmacologic activity of each drug in question. Because there is great variability in all of these parameters, it is essential that each practitioner understand the unique pharmacokinetic features of each drug and the unique pharmacokinetic differences of each patient in order to rationally select the best drug for every situation.ABSORPTIONThe process by which drug molecules move from their site of administration, across one or more cell membranes, in order to gain entry into the blood. By definition, this process involves drug movement from the patient's external environment into the patient's blood. In order to do this, drug molecules must cross cell membranes at the absorbing surface (e.g., intestinal mucosa, subcutaneous fat cells, etc.), several layers of cells beneath the absorbing surface, and eventually the vascular endothelial cells of the capillary. For the great majority of drugs, the driving force for this movement is the difference in drug concentration on either side of the membranes involved. The magnitude of the concentration gradient (the difference in drug concentrations on either side of a membrane) determines both the speed and the extent of movement of drug molecules between and among the various body compartments. Movement of drug molecules "down their concentration gradient" does not require any energy expenditure on the part of the body and is referred to as passive diffusion. (See Figure 2-5, p. 17 in our textbook) The only routes of drug administration that do not involve the absorption process are the intravenous and intra-arterial drug routes of administration in which the drug molecules are administered directly into the blood stream and, therefore, do not have to cross any cell membranes in order to enter the blood stream.factors that determine the rate and the extent of drug absorption are:THE SOLUBILITY (OR DISSOLVABILITY) OF THE DRUG PHYSICAL PROPERTIES OF THE DRUG THE AREA OF THE ABSORPTIVE SURFACE BLOOD SUPPLY AT THE ABSORPTIVE SURFACE THE LENGTH OF TIME THE DRUG IS IN CONTACT WITH THE ABSORBING SURFACETHE SOLUBILITY (OR DISSOLVABILITY) OF THE DRUGMany medications are administered orally as solid tablets, capsules, lozenges, etc. They must first undergo dissolution into liquid forms (i.e., individual drug molecules in solution) before they can be absorbed. The length of time (rate of dissolution) it takes for drugs to dissolve will vary greatly from drug to drug and from patient to patient. It will be influenced by the form of the medication and the pH of the patient's gastric fluid. If medications are administered in liquid form initially, because they require no dissolution, they will undergo faster absorption and will reach their sites of action more quickly.The following is a list of drug formulations and the relative speeds of their absorption from fastest to slowestFASTEST 1. Liquids (elixirs, syrups, mists, aerosols) 2. Suspensions 3. Powders 4. Capsules 5. Tablets 6. Enteric-coated tablets 7. Sustained-release tablets SLOWESTPHYSICAL PROPERTIES OF THE DRUGBecause cell membranes are composed of lipids, drug molecules that are fat- soluble are readily able to enter and cross the lipid content of the cell membrane. In addition, small drug molecules are able to squeeze through holes in a cell's membrane more easily than large drug molecules. These "holes" in a cell's membranes are called "aqueous pores" in endothelial (blood vessel lining) cells and "tight junctions" in epithelial cells such as mucosal cells. A basic tenet of chemistry is that molecules which have no net positive or negative charge and which have an equal distribution of positive and negative charges throughout the molecule are said to be non-ionized and non-polarized respectively and are, therefore, fat soluble. (The molecules of fat that compose the lipid bi-layer of cell membranes are themselves non-polarized and are compatible with other non-polarized molecules.) Drug molecules that fit this description (i.e., non-ionized or non-polarized) are said to be fat-soluble and are able to easily cross the lipid cell membranes. On the other hand, drug molecules that are ionized, or polarized are said to be water soluble and do not readily enter the fat layer. (The water molecule itself is polarized and any drug molecules that have polarization of electrical charges are compatible with water.) They take a longer time to cross the fat layers of the cell's membranes and, therefore, are absorbed more slowly. (Remember, fat and water do not mix.) The degree of ionization (or polarization) of a drug is determined by the chemistry of the drug itself but also by the pH of the solution (i.e., gastric juice, intestinal fluid, etc.) in which the drug is dissolved. Acidic drugs remain non-ionized (and more fat soluble) in the acidic environment of the stomach and alkaline drugs remain non-ionized in the alkaline environment of the small intestine. On the other hand, acidic drug molecules become more ionized (and more water soluble) in an alkaline environment like the small intestinal tract and alkaline drug molecules become more ionized in an acidic environment like the gastric lumen. Many drugs used in clinical medicine are classified as weak acids or as weak bases. Examples of weak acid drugs include phenobarbital, pentobarbital, acetaminophen, and aspirin. Examples of weak bases include cocaine, ephedrine, chlordiazepoxide, and morphine. [Note: Drugs which are highly ionized (i.e., have large positive or negative charges or a high degree of polarization) are said to be highly hydrophilic (water-loving) and cannot cross the lipid bi-layer of a cell membrane very easily. Drugs which are highly lipophilic (fat-loving) also have difficulty being absorbed because they have difficulty crossing the thin water layer that lies adjacent to a cell membrane.]THE AREA OF THE ABSORPTIVE SURFACEBecause individual drug molecules must come in contact with cell membranes in order to enter and eventually cross them, it stands to reason that the more absorptive surface available to the drug, the faster will be the absorption of all the drug molecules. Drugs administered into the GI tract for absorption by the small intestine take advantage of this fact. The small intestinal mucosa has a large surface area available for contact with individual drug molecules. With all other factors considered, absorption through the GI mucosa is relatively fast. The same can be said for administration of medication as an inhalant through the lung. The "unfolded" alveolar surface is enormous; medications administered directly into the lung have a very fast absorption and, therefore, a fast onset to their pharmacologic actions.BLOOD SUPPLY AT THE ABSORPTIVE SURFACEBecause the process of absorption involves entry into the blood, the amount of blood flow at the absorptive surface will be a major factor in the degree and the speed of absorption of drug molecules. The proximity of blood flow to the absorptive surface will impact the absorptive process. Sites of administration that have good blood flow in proximity to the absorbing surface are the intestinal tract, the lung, and skeletal muscle. Administration of drugs in these areas usually results in fairly rapid absorption. Adipose tissue and edematous tissues have poor blood flow and are sites where drug molecules are absorbed more slowly. A medication that is administered I.M. will be absorbed faster than the same dose of the same medication administered subcutaneously. The difference is the magnitude of the blood supply at the absorbing surface in these two different types of tissue.THE LENGTH OF TIME THE DRUG IS IN CONTACT WITH THE ABSORBING SURFACEIt also stands to reason that if drugs must contact and then cross cell membranes in order to be absorbed, that the length of time that the two are in direct contact will be a determinant in how quickly and effectively they will be absorbed. The opposite is also true. The shorter the contact time, the less opportunity drug molecules will have for effective absorption. Patients who have vomiting or diarrhea will demonstrate this point well. Medications that do not remain in contact with the intestinal mucosa long enough will be absorbed poorly or not at all.Relationships Between Absorption and Sites of Drug AdministrationThe process of absorption can be influenced by the route of administration of a drug. In selecting drugs for inclusion in a pharmacotherapeutic plan, there are several important points to consider in terms of ensuring that the desired amount of the administered drug will actually be absorbed.INTRAVENOUS AND INTRA-ARTERIAL ROUTESAdvantages: - Any drug administered directly into the blood stream (either venous or arterial) need not cross any lipid cell membranes in order to be absorbed. Therefore, there is no mechanism of absorption involved with their entry into the blood. With the determinants of absorption not playing a role in these routes, the speed with which the pharmacologic effects of drugs administered by these routes is seen is entirely determined by how much of the drug is administered and how fast it is delivered into the blood by the person administering the drug (i.e., the speed of I.V. push administration or the I.V. or I.A. flow rates). - With this route, the exact amount of drug "absorbed" is known. Disadvantages: - Requires specialized equipment and trained individuals to administer; generally not easily done on an out-patient basis - Drugs in their I.V. (or I.A.) formulations are generally more expensive than other formulations of the same drug - Many drugs administered I.V. generally have very rapid onset of action but frequently have shorter durations of action requiring either continuous or frequent dosing to maintain clinically effective serum drug levels.ORAL INGESTION (ENTERAL) ROUTEAdvantages: - This route is generally considered the most convenient, the most economical, and the simplest for patient compliance. Disadvantages: - Nausea and vomiting made preclude the oral route entirely or, if oral administration is attempted, any vomiting of drug leaves the clinician or the patient uncertain as to how much of the drug was actually absorbed. - Gastric and/or intestinal pH will greatly affect the degree of ionization of orally administered drugs which, in turn, affects their fat/water solubility and their absorption. Any artificial change in the gastric or the intestinal pH (like from other administered drugs) will alter the absorption of any other orally administered drugs. This leads to inconsistent degrees of absorption. - Many drugs are acid-labile which means that they are degraded (inactivated totally) by acidic gastric pH. In a similar manner, some drugs are degraded in the intestinal tract by intestinal mucosal enzymes before they can be absorbed. - The absorption of many drugs is delayed by the presence of food in the intestinal tract. In addition, several drugs are chemically altered or bound by food items concurrently present in the intestinal tract. (Example: Inhibition/prevention of absorption of tetracycline antibiotics by calcium-containing food items.) Administration of drugs by the oral route frequently requires sequencing of doses around mealtime so as to ensure optimal absorption. - Absorption of drugs from the intestinal tract is influenced by the length of time the drug remains in contact with the surface at which it is optimally absorbed. Therefore, gastric emptying time will influence the amount and the rate of absorption of drugs that are typically absorbed from the stomach. If gastric emptying time is faster than normal, drugs typically absorbed from the stomach will be absorbed less efficiently but drugs typically absorbed from the small intestinal may be absorbed faster than expected. The opposite is true if gastric emptying time is slower than normal. These same principles apply if intestinal transit is either faster than normal or delayed for some reason. Several conditions or mechanisms may be responsible for altering gastric emptying time and intestinal transit time, including other drugs. - Because blood flow at the absorbing surface is a critical component of drug absorption, conditions in which intestinal blood flow is compromised will decrease the amount and the rate of intestinal drug absorption. This is especially true in older adults who have vascular diseases that include deficient intestinal blood flow. - The presence of intestinal edema impairs intestinal drug absorption. Edema is the accumulation of excessive amounts of water in the interstitial spaces between cells and this increases the distance between the absorbing surface and the blood and it also increases the water content of the space that drugs must cross in order to gain access to cells membranes. Some drugs are fat-soluble and are impeded by having to cross a waterlogged space. - Many drugs administered by the oral (enteral) route undergo "first-pass" metabolism. From the intestinal absorption site, drug molecules are absorbed into the portal circulation and pass directly to the liver. For drugs that are highly metabolized in the liver, extensive metabolic conversion to forms that are less active pharmacologically takes place before the "pharmacologically active" drug molecules can reach their sites of action. [Note: This accounts for the commonly noted marked differences in doses for the oral and I.V. preparations of the same drug with the recommended dose for the oral formulations frequently being ten times the dose recommended for the same drug administered I.V. - Some drugs are structurally altered by being metabolized in the intestinal lumen by intestinal microorganisms. This change in structure may alter the chemical nature of the drug or change its degree of ionization. Both of these may inhibit or enhance the absorption of the drug.PERCUTANEOUS (TRANSDERMAL) ROUTEAdvantages: - Only lipid soluble substances are capable of crossing the normally "water-proof" intact skin. As a rule, absorption of these fat-soluble drugs occurs better through hairy skin (better blood supply) than hairless skin. Absorption is also faster and more efficient through thin skin than through thick skin, through abraded skin than through intact skin, and through skin that has been massaged immediately before or immediately after the application of the drug (improves the blood supply temporarily). - Application of drugs to the skin allows for steady and sustained rates of absorption and consistent and predictable serum drug concentrations. This decreases the need for determining the peak and trough drug levels. - This is a basic and simple technique that allows for better patient compliance. Disadvantages: - Generally the transdermal delivery systems required for the administration of drugs by this route add considerable cost to the drugs. - Location of the transdermal patches requires application to a different anatomical site each time the medication is re-dosed. Long-term administration can result in running out of appropriate sites. - Some medications or the adhesive on the patches can produce skin irritation.INTRAMUSCULAR ROUTEAdvantages: - Absorption is better through large, active muscle than through small, inactive, paretic, or paralyzed muscle. Active muscle has a richer blood supply. Adults generally have bigger and more vascular muscles than small children. Very young children, especially newborns, have very small muscles with minimal blood supply. Drugs administered intramuscularly in these individuals will be absorbed at a much slower rate than the same drugs administered to patients with large, active muscles well-supplied with blood. - Onset of action by this route can be relatively rapid. - Useful route to use in uncooperative or unconscious patients. - Ensures accurate assessment of the amount of drug that enters the body. - There is no first-pass metabolism; this allows a smaller dose of the drug than is generally administered enterally. Disadvantages: - Requires special equipment (syringe and needle) and trained individuals (or patient training for self-administration) which adds to the expense. - Can be painful and may cause damage to tissues at the sites of the administration.SUBCUTANEOUS ROUTEAdvantages: - Again, massage immediately before or immediately after the administration of a drug subcutaneously will improve the efficiency of its absorption by temporarily increasing the local blood supply. The rate of absorption subcutaneously is generally slower than the same drug administered by the intramuscular route. - Same as for intramuscular (above). Disadvantages: - Same as for intramuscular (above).TRANSRECTALAdvantages: - Relatively easy route of administration - Most medications administered by this route are inexpensive Disadvantages: - Rate and extent of absorption and pharmacologic effect can be variable. If rectal suppository is placed high in the rectum, the medication is absorbed into the superior hemorrhoidal veins that drain into the portal system. These drugs may undergo significant first-pass metabolism, decreasing their pharmacologic effect (see metabolism). If suppository is placed low in the rectum, the drug is absorbed into the systemic venous system, by-passing the first-pass metabolic effect.Enterohepatic Circulation as a Mechanism of AbsorptionA special type of drug absorption, or actually reabsorption occurs during the process of enterohepatic circulation. This process is actually a combination of drug excretion and absorption. Some drugs, after metabolism in the liver (see below), are excreted in the bile as conjugates. The metabolites of the drugs are attached to a variety or other compounds which make them more water-soluble and readily excreted in the "water" of the bile. Being highly polar compounds, they travel down the intestinal tract with the bile and are not reabsorbed as long as they remain conjugates. When these compounds reach the lower ileum, they encounter increased numbers of intestinal microflora. The microflora interact with these compounds, cleaving the drug from the conjugate. The drug now separated from the conjugate, becomes fat soluble and much of it is readily reabsorbed back into the blood. The blood brings it back to its receptors and also back to the liver to once again undergo the same process. This process of recirculation continues until all of the drug is eventually excreted in the stool. See Figure 2-8, p. 17 in our textbook.DISTRIBUTIONThat component of pharmacokinetics by which an absorbed drug is dispersed throughout the body in order to gain access to its target cells. Distribution occurs in two phases.Distribution occurs in two phases:RAPID DISTRIBUTION REDISTRIBUTIONRAPID DISTRIBUTIONThe dispersal of drug throughout the central circulating blood volume (heart, large arteries, and veins). This process occurs almost immediately with drug molecules reaching first the central portion of the circulation receiving the greatest amount of blood flow (i.e., heart, major arteries, brain, kidney and lungs) and then to the more peripheral parts of the circulation (i.e., fatty tissues and skin).REDISTRIBUTIONThe second phase of distribution is much slower and is the dispersal of drug molecules to the extravascular body compartments (i.e., the interstitial compartment and the intracellular compartment). As drug is redistributed, some of it leaves the blood but does not leave the body.Preference of drug distributionWhen drugs are distributed, they are preferentially distributed to the type of compartment in which they are chemically best suited. For example, fat-soluble drugs are preferentially distributed to adipose tissues and water-soluble drugs are distributed into the various water-containing compartments of the body. Eventually, however, all drugs can enter all compartments despite their individual fat/water solubilities.4 Determinants of Distribution1)THE ADEQUACY OF SYSTEMIC BLOOD FLOW 2)SERUM PROTEIN BINDING 3)TISSUE TRAPPING 4)PHYSIOLOGICAL BARRIERSTHE ADEQUACY OF SYSTEMIC BLOOD FLOWBecause drugs are generally distributed by the blood to the various body compartments, it stands to reason that the amount of perfusion to any given area in the body will directly impact both the amount and the speed with which a drug reaches that area. Poor perfusion is associated with diseases and conditions such as shock, hypotension, peripheral vascular diseases, vasoconstrictor drugs, abscesses, and large neoplasms. The poor blood flow associated with these conditions can deny full access of the drugs to the affected areas.SERUM PROTEIN BINDINGDrugs circulating in the blood stream can exist in two forms: (1) as free drugs unattached to any other blood constituent or (2) as protein bound drugs physically attached to a non-specific drug binding site on serum protein. Whether a drug can exist free or bound is determined by the chemistry of the drug. The degree of protein binding of a drug can range from zero to nearly 100% and is determined entirely by its molecular structure, its fat/water solubility, and its electromagnetic make-up. For example, if a drug is said to be 80% protein bound, for however many drug molecules of that drug are present in the blood stream at any one point in time, that percentage (80%) of the drug molecules are physically linked to the protein with the remaining (20%) existing as free drug. This percentage remains constant as long as the drug is present in the blood. In general, the more fat soluble a drug molecule is the more likely it is to be highly protein bound. The protein that binds most of the protein-bound drug molecules is albumin with a small number of drugs also binding to alpha-1-acid glycoprotein and some binding to special globulins (like sex-hormone-binding gobulin, transcortin, etc.). The amount of drug that albumin can hold at any one time is limited because the number of drug molecule binding sites is limited and can become saturated; when saturated, any drug normally bound would have to exist as free drug. The albumin binding sites are non-specific; any drug that requires protein binding can link up with any available albumin binding site. Drugs can compete with each other and with other normally bound body constituents (like bilirubin, fatty acids, etc.) for these limited number of binding sites with the more highly protein-bound drugs (80-100% bound) displacing the more weakly protein-bound drugs (20-30% bound) from the albumin. Conditions that can reduce the availability of albumin-binding sites include hypoalbuminemia, hyperbilirubinemia, excessive high serum fatty acid levels, and occasionally renal failure. [Note: In some patients with renal failure, an unknown metabolic products accumulates in the blood and apparently attaches to the albumin-binding sites, eliminating them from providing binding capability for highly protein-bound drugs.] It is important to remember that it is only the free drug molecules that are able to leave the blood through redistribution and can come in contact with their target cell receptors. As long as drug molecules are bound to albumin, they are (temporarily) pharmacologically inactive. As more and more drug molecules leave the blood stream by redistribution or by clearance (metabolism and excretion), the previously protein-bound portion of the drug will become free to reestablish the normal percentage of bound-to-free drug. Eventually, all bound drug will become free and will be cleared from the blood and the body.TISSUE TRAPPINGCertain tissue types have the ability to preferentially capture circulating drugs from the circulation, preventing their free and equal distribution to all perfused parts of the body. This ability is inherent in the tissue doing the trapping and the chemistry of the particular drug that is trapped. Examples of this phenomenon are: (1) lipid soluble drugs being preferentially "trapped" in the adipose tissue deposits of the body, (2) tetracyclines becoming trapped by calcium in bone tissue and in developing teeth, (3) B-vitamins and fat soluble vitamins becoming trapped in the liver cells, and (4) iodine-containing drugs becoming trapped by thyroid tissue.PHYSIOLOGICAL BARRIERSThere are two areas in the body that, despite being well-perfused, have special anatomic configurations which prevent the free and equal distribution of drugs to the tissues and organs they protect. These two areas are the brain (protected by the blood-brain-barrier) and the developing fetus (protected by the placenta). Thus, the blood-brain-barrier and the placenta represent physiological barriers to the passage of drugs which are presumably identified by the body as potentially harmful substances that may do damage to brain and fetus. Of these two, the most efficient is the blood-brain-barrier that allows some fat-soluble drugs to pass but denies access to the brain of many water-soluble drugs. The placenta is much less efficient in this regard; although drugs may be delayed in crossing, eventually almost all drugs can get across the placenta.METABOLISM/BIOTRANSFORMATION.The conversion of the administered drug (parent drug) into one or more totally different chemical compounds (metabolites of the parent drug).Mechanisms of Drug Metabolismthe main organ of drug metabolism is the liver but other sites at which drugs can be metabolized include the kidney, lungs, gastrointestinal mucosa, and nerve endings. There are even enzyme systems circulating in the blood at all times that can participate in drug biotransformation. The liver processes drugs (and drug metabolites) through a series of enzyme systems that are capable of altering the physical (three dimensional) structure of the drug. It does this in two clearly defined phases, each utilizing its own enzyme system. THese are Phase I and phase IIPHASE IPhase I reactions are mediated in the liver (and some other organs) by the P-450 enzyme systems (also referred to as the mixed function oxidase system or the cytochrome oxidase system). These are several different enzyme pathways labeled by a series of numbers and letters (i.e., CYP1A2, CYP2A6, CYP3A4, etc.). Collectively referred to as the Phase I reactions, they are the main pathways for the metabolism of most of the drugs used in clinical medicine. They function to alter the molecular structure of the parent drug so as to deactivate its pharmacologic effect and to render it more water-soluble. (See Purposes of Drug Metabolism below.) These reactions consist of such chemical reactions as oxidation, reduction, hydrolysis, hydroxylation, deamination, and dealkylation. In other words, these changes simply add or remove oxygen atoms, add or remove hydrogen atoms, remove amino groups or methyl groups, or do some other modification of the structure of the molecule that drastically alters the drug's ability to interact with its target receptors. Phase I reactions are performed on parent drugs to produce metabolites of the parent drugs but they can also do further enzymatic metabolism on some of the metabolites of the parent drugs if they require it. Many drugs require only Phase I reactions for complete metabolism. Others require a second step for sufficient structural change to occur.PHASE IIPhase II reactions are mediated by a different series of enzymes called conjugases or transferases. These reactions are more complex and convert drug metabolites and occasionally a parent drug itself into a radically different compound by adding an entire endogenous chemical substrate (i.e., glucuronic acid, a sulfate, an acetate, a glycine molecule, or a glutathione molecule) to the drug (or metabolite) being metabolized. By this chemical addition, the drug is rendered more water-soluble and will be more readily excreted in the urine (see Purposes of Metabolism - Enhancement of Excretion below). Some drugs only require a Phase I reaction to produce a metabolite that is deactivated and excretable. Other drugs require a Phase I reaction on the parent drug and then a Phase II reaction on the metabolite. In some instances, some parent drugs are metabolized by a phase II reaction only. It should be remembered that many drugs that are used in clinical medicine do not require any degree of metabolism or biotransformation; they enter the body, perform their pharmacologic activity, and are then excreted unchanged in the water of the urine.Purposes of Drug Metabolism(1) Reduction in the pharmacologic activity of the drug (2) Enhancement of the pharmacologic activity of the drug (3) Activation of a prodrug (4) Enhancement of excretion (5) Detoxification of foreign substancesReduction in the pharmacologic activity of the drugMetabolism or biotransformation is performed on a drug molecule in order to alter the drug's three-dimensional structure so that it no longer has a complimentary geometric spatial relationship with its receptor or its target enzyme. In the absence of this three dimensional relationship, affinity and intrinsic activity of a drug for its targets is radically altered. This, in turn, results in marked reduction or even elimination of the normal pharmacologic (pharmacodynamic) activity of the drug.Enhancement of the pharmacologic activity of the drugOccasionally, the first action in the metabolism of a drug actually changes the three dimensional structure in such a way as to make it more spatially compatible with the target receptors or enzyme. In other words, the drug's metabolite has even greater affinity and/or intrinsic activity than the parent drug. This seems contrary to the usual purpose of metabolism (i.e., decreasing the drug-induced alterations) but this is not the complete story. This metabolite is further metabolized (e.g. by phase II reactions); these additional changes in the drug's structure do reduce the drug's pharmacological effects.Activation of a prodrugThere are some medications called prodrugs that, in the form in which they are administered, have no pharmacological activity (i.e. they lack both affinity and intrinsic activity). The metabolic activity which the body performs on them actually changes the three dimensional structure to the point that they acquire pharmacological activity. Many of the drugs administered in clinical medicine are actually prodrugs. The reasons for administering a drug as a prodrug include inability to administer the active metabolite orally and insufficiently short shelf life of the active metabolite. Pharmaceutical companies understand how the body will metabolize the parent prodrug and plan on using these metabolic processes to convert their product into the active form of the drug.Enhancement of excretionThe two components of drug clearance from the body are metabolism and excretion. Both of these mechanisms work in concert to eliminate the "unwanted foreign substance" (i.e., drug). Because most drugs are eliminated from the body by way of renal excretion, any parent drug or metabolite which is fat soluble or minimally water soluble can be restructured by either phase I or phase II enzyme reactions to become more water soluble and more likely to be excreted in the water of the urine.Detoxification of foreign substancesA main activity of the liver is to decrease the very harmful effects that any substance can cause after its entry into the body. All drugs, if given in large enough dose sizes, have the potential to produce toxic effects on one or more body constituents. As part of its general mission of detoxifying any foreign agent, detoxification of toxic drug effects is a major purpose of drug metabolism.Determinants of Drug MetabolismAlthough drug metabolism takes place in many different areas in the body and by many different mechanisms, the great majority of drugs that require metabolism (and not all do) are biotransformed in the liver by one or more of the mechanisms noted above. Because of its unique anatomy and physiology, many conditions that affect the liver will have an effect on the metabolism of drugs. 1) First-Pass Effect (2) Physiologic Status of the Liver (3) Hepatic Enzyme Induction and InhibitionFirst-Pass EffectAs hepatic blood flow brings drug molecules to the liver cells, they are "extracted" from the blood by these hepatic cells. Once inside the cells, the drug molecules undergo varying degrees of biotransformation into their metabolites. As blood leaves the liver and enters the systemic circulation, the drug molecules are capable of interacting with their receptors and exerting their pharmacological effects. Each time the drug molecules are again carried to the liver by hepatic blood flow, additional drug metabolism takes place, each time reducing the drug's pharmacologically active forms. When drugs are administered enterally (by the mouth and swallowed), the drugs molecules are absorbed into the intestinal veins (and therefore the portal venous system) and carried directly to the liver first before they can enter the systemic circulation. These drug molecules undergo some degree of metabolism and reduction in their pharmacologically active forms before they ever have a chance to reach their receptors. For drugs that are highly metabolized in the liver, this "first-pass effect" can significantly reduce the pharmacological activity of the drug when administered by mouth compared to the same drug administered by another route. This explains why recommended dose of some drugs is much higher when they are administered by mouth.Physiologic Status of the LiverOptimal drug metabolism by the liver requires that the liver cells are in an optimal state of health. Diseases such as cirrhosis, acute hepatitis, acute alcoholic damage (from severe binge drinking), and others can significantly damage liver cells including the hepatic drug metabolizing enzyme systems resulting in often significant reduction in drug metabolic rates. A reduction in drug metabolic rates delays the clearance of the pharmacologically active forms of the drugs, prolonging their pharmacological activity. This may require a reduction in dosage and/or frequency compared to that usually recommended for a drug.(3) Hepatic Enzyme Induction and InhibitionHepatic enzyme systems are not stable systems with a fixed amount of molecules and activity. Liver cells which synthesize these systems can be induced to synthesize more of the enzymes and, conversely, can be inhibited from synthesizing them. Their are many drugs themselves (called enzyme inducers) that are capable of stimulating the liver cells to synthesize more of the enzymes, increasing the metabolic rates of themselves and any other drugs that are metabolized by the same enzymes. On the other hand, some drugs function as enzyme inhibitors, reducing the metabolic rates of themselves and any other drugs metabolized by these systems. Knowing that these phenomena take place requires clinicians to alter the dose and/or frequency of some drugs possibly affected by these alterations in metabolic activity. See Table 2-3, p.19 in our textbook, Common Drugs that Cause Drug Interactions Through the Effect on Metabolism.dietary factors will affect drug metabolic ratesSubstances in cruciferous vegetables (brussel sprouts, cabbage, cauliflower) and hydrocarbons found in charcoal broiled meats can act as hepatic drug metabolizing enzyme inducers. It is doubtful that this has much effect on drug dosing unless the patient in question consumes large amounts of these substances.EXCRETIONThe process by which a drug or its metabolites are eliminated from the body. The great majority of the drugs and the drug metabolites that result from biotransformation are eliminated by renal excretory mechanisms. Other routes by which drugs are excreted include the bile, the stool, breast milk, the lungs, saliva, and sweat.Mechanisms of Excretion(1) GLOMERULAR FILTRATION (2) RENAL TUBULAR SECRETION (3) DISTAL RENAL TUBULAR REABSORPTIONGLOMERULAR FILTRATIONDrugs and metabolites are filtered through the pores in Bowman's Capsule in the renal glomerulus and enter the lumen of the nephron at this level. This is a totally passive process not requiring any energy expenditure on the part of the renal epithelial cells. Only free drug and free metabolites are capable of being filtered by this mechanism; any drug or metabolite that is bound to serum albumin cannot be filtered because the albumin molecule is too large to fit through the pores in the capsule. Therefore anything attached to the albumin will not pass. This process of filtration is a timed event and the amount of drug (and metabolite) that is excreted in this way is dependent on the total number of functioning glomeruli and, especially, the renal blood flow (i.e., the glomerular filtration rate [GFR]).RENAL TUBULAR SECRETIONIn the proximal convoluted tubule of the renal nephron there are excretory channels capable of actively pumping drugs and metabolites from the blood against a concentration gradient into the lumen of the nephron. This active process does require energy expenditure on the part of the renal epithelial cells. The energy is in the form of ATP (adenosine triphosphate). The movement of drugs from an area of relatively low concentration in the circulating blood into the continuously increasing concentration in the lumen of the nephron is accomplished through many of the same portals that are utilized by the kidney in excreting normal waste products. Drugs actually have to compete for these excretory pathways with waste products. Free drug (i.e., not bound to protein) is excreted by this mechanism. Albumin bound drug is also excreted by this pathway because the renal epithelial cell possesses enzyme systems which are capable of cleaving drug molecules from the drug binding sites on the albumin molecule. The amount and the rate by which drugs are excreted by this mechanism are not dependent on renal blood flow but rather are determined by the drug's serum concentration.DISTAL RENAL TUBULAR REABSORPTIONAfter drugs (or metabolites) have been successfully excreted into the lumen of the renal nephron, they can be handled in two different ways. They may remain in the water of the urine and are consequently passed out of the body with the urine. They may also be passively reabsorbed in the distal convoluted tubule and re-enter the blood and may resume their pharmacologic activity. Whether drug molecules remain in the urine or re-enter the blood is dependent on the relative water or fat solubility of the drug itself. Drugs, which are highly water-soluble, will remain in the water of the urine and will not be appreciably reabsorbed. Drugs which are fat soluble or with only slight water solubility can be reabsorbed if they come in contact with the lipid membranes of the renal epithelial cells. To enter the urine, drug (or metabolite) molecules are, for the most part, water-soluble. The degree of water solubility is dependent on whether the drug has an electrical charge or is ionized or polarized. The degree of ionization / polarization can change after a drug enters the urine because of the pH of the urine. Acidic drugs become less ionized (i.e., more fat soluble) in acid urine but alkaline drugs become more ionized (i.e., more water soluble) in acid urine. The opposite is true for alkaline drugs entering acid urine. If the urine is alkaline, then the converse is true (i.e., acidic drugs become more ionized in alkaline urine and alkaline drugs become less ionized in alkaline urine). Therefore the pH of the urine is a main determinant of drug reabsorption. Urinary pH can be altered by other drugs. An example of this concept is the treatment of aspirin overdose. In those patients who accidentally or intentionally take an overdose of aspirin, toxic effects from the drug can be minimized by enhancing the rate of elimination of the drug from the blood. Aspirin is an acidic drug. Administering to the patient sodium bicarbonate that is itself excreted in the urine can increase its renal excretion. As the sodium bicarbonate enters the urine it changes the pH of the urine to alkaline (or at least less acidic). The aspirin (acidic) drug becomes more ionized in the alkaline urine; the now more ionized aspirin drug molecules become more water-soluble and pass through the renal nephron without being reabsorbed. They are eliminated more quickly. This accelerates the clearance of aspirin from the patient's blood.Principles of Drug Action in Specialized Patient PopulationsMuch of the information about specific drugs contained in standard drug references refers to the typical actions of the drug that was gathered when the drug was studied in adult populations prior to its release for general usage. Many times this information is derived from studies done during the initial stages of drug development when it is administered to normal healthy adult volunteers. Drug companies are usually prevented from "experimenting" on certain special populations and the information about the drug in these populations is usually discovered after the drug has been tried by clinicians in these groups. Many of the indications for the use of a given drug will be seen in patients other than healthy adults and it is essential that clinicians understand the physiological differences between normal healthy adults and these special populations. The special populations most often encountered in clinical practice are the pregnant patient, the fetus, the lactating patient, the pediatric patient, and the older adult. These special patients have significant difference in their physiology that result in significant differences in the pharmacokinetics of the drugs they are taking. Pharmacokinetic variations in these groups may require deviations from the recommended drug selections, dosing requirements, dosing intervals or routes of administration of a given drug. A proper pharmacotherapeutic plan must take these pharmacokinetic variations into account for safe and effective drug therapy. An examination of each of the phases of pharmacokinetics in these groups will reveal the considerations that must be made.The Pregnant Patient - Variations in PharmacokineticsWhen considering the pregnant patient, there are three major areas of concern: (1) drug action in the mother, (2) drug transfer across the placenta, and (3) drug action in the fetus.The Pregnant Patient, ABSORPTION- Nausea and Vomiting of the First Trimester - In many pregnant women, the emesis of pregnancy often precludes the oral ingestion route for drug administration. Any attempt to administer drugs may fail entirely or may result in vomiting of some undetermined part of the administered dose leaving the clinician with uncertainty as to how much of the administered dose was actually absorbed. The clinician then must decide whether to readminister the medication. - Decreased Gastric Emptying - Pregnancy induces a slowing of peristalsis in the stomach and in the remainder of the GI tract. This is presumed to be an effect of the increased serum level of progesterone that is known to decrease the contraction of smooth muscle cells in many parts of the body. This slowing of peristalsis results in delay in gastric emptying and will, in turn, result in a delay in the absorption of any drugs that are usually absorbed from the small intestine. Pregnant patients often have a slower onset of action of intestinally-absorbed drugs. - Increased (Gastric) HCl Secretion - The normally increased serum levels of estrogen always present in pregnancy are thought to be responsible for an increased secretion of HCl in the stomach. This can result in a reduction in the pH of gastric juice that, in turn, alters the ionization of drug molecules in the stomach. If drug molecules become more ionized in a more acid environment (as occurs with alkaline drugs), they become more water-soluble and will be absorbed more slowly, delaying their onset of action. If they become less ionized in an acid environment (as occurs with acidic drugs), they will become more fat soluble, increasing the rate of absorption and possibly speeding their onset of action.The Pregnant Patient, DISTRIBUTION- Increased Total Body Water - Pregnancy results in an increase in total body water. With more water in all of the patient's body compartments, any drug that is water-soluble will have a wider distribution and be "more diluted". - Increased Total Body Fat - Pregnancy is typically associated with gaining weight, much of which is adipose tissue. Any drug which is fat-soluble will have a larger volume of fat in which to become dispersed and will probably remain in the body longer than it otherwise would. - Increased Plasma Volume - The fluid retention typical of pregnancy not only results in a gain of total body water but also much of that water is contained in the vascular space adding to plasma volume. This, in turn, results in increased cardiac output. Because blood flow patterns are a major component of distribution, any alteration of blood volume and cardiac output could theoretically affect drug distribution. - Increased Competition for Protein-Binding Sites - Estrogen molecules in the circulating blood typically prefer to be bound to specific proteins called sex-hormone binding globulin. Some estrogen binds to albumin and can theoretically compete with any drug molecules that are normally highly protein-bound. If this competition is significant, estrogen can displace some drugs from their serum albumin binding sites that will result in higher free drug serum levels of these drugs and their greater pharmacological activity. To compound this phenomenon, pregnancy is typically associated with a lower overall serum albumin level. There are already fewer albumin drug binding sites available for the usually highly protein bound drugs. - Pregnancy-Associated Hyperdynamic Circulation - The increased circulating blood volume is one of the features of the usually hyperdynamic cardiovascular functioning of the state of pregnancy. Because of the already stimulated state of the circulation, pregnant patients are often more susceptible to the pharmacologic effects of other cardiovascular stimulants and may be at greater risk for adverse effects of these types of medicationThe Pregnant Patient-METABOLISM- Hepatic Enzyme Induction by Estrogen - The increased serum levels of estrogen during pregnancy usually result in a stimulation of protein synthesis in many areas. One of these areas is hepatic synthesis of the enzymes that the liver (and other organs) uses to metabolize drugs (i.e, P-450, conjugases, and transferases). Theoretically, this would result in an increase in the rate of drug metabolism (and drug clearance) and undoubtedly does in some patients. At the same time, however, estrogen itself requires metabolism by some of these same enzyme systems and will compete with drugs for these metabolic pathways. This may have the effect of decreasing the rate of metabolism of some drugs. Drug metabolic rate in pregnancy is, therefore, variable. - Placental Drug Metabolism - There is a slight additional drug metabolic pathway in pregnancy provided by the placenta. The placental tissues possess a complement of P-450 enzymes and as pregnancy progresses, some of the mother's drug metabolizing will be accomplished by the placenta. How much this adds to the total drug clearance in the mother is debatable.The Pregnant Patient, EXCRETION- Increased Glomerular Filtration Rate - One of the mechanisms responsible for the renal excretion of drugs is by glomerular filtration. The rate of excretion of drugs by this route is proportional to the amount of renal blood flow. The increased blood volume associated with pregnancy and the resulting increased cardiac output will produce an increased GFR and increased excretion of drugs normally excreted by the mechanism.The Pregnant Patient- PLACENTAL TRANSFER OF DRUGS- All drugs (with very few exceptions) and their metabolites, given enough time, will get across the placental membrane and enter fetal circulation. - Drugs cross the placental membrane by the process of passive diffusion, (i.e., by moving from an area in which they are in high concentration [mother's blood] to an area in which they are in low concentration [fetal blood]). As long as there is a concentration difference (i.e., a gradient), drug molecules will continue to move across. Therefore, the longer the mother takes the drug, the longer the fetus will be exposed to the drug and the more drugs molecules will enter the fetal body. - The rate at which drugs cross by passive diffusion, is directly proportional to the magnitude of the mother's serum drug concentration. In other words, the speed of placental drug transfer across the placenta is directly proportional to the size of the concentration gradient. The higher the drug concentration in the mother's blood, the faster will be the rate of placental crossing and the greater will be the drug's eventual concentration in fetal blood. - Because fetal blood pH is slightly more acidic than mother's blood, drugs that are weak bases will cross the placenta faster and in greater magnitude than will weak acids. A weak base, when it enters fetal blood, becomes more ionized (i.e., more water soluble) and cannot easily move back across the placenta into mother's blood.The Pregnant Patient-DRUG ACTION IN THE FETUSPharmaceutical companies do not do pre-marketing studies of their drugs on pregnant women to see what effects a new drug will have on a fetus. The only ways that drug effects on a fetus are detected are 1) by performing studies on pregnant animals, 2) by releasing the drug in foreign countries and awaiting data from unrestricted use on pregnant women in those countries, and 3) by gathering post-marketing anecdotal data about the drug from its being used on pregnant women in this country. - It is known that serum drug levels of most drugs in a fetus can reach at least 50% (and sometimes 100%) of the levels in the mother. - The total effect that a given drug will have in a fetus will be dependent on several factors. These are 1) the drug itself, 2) the dose (taken by the mother), 3) the concentration of the drug in the fetal blood, 4) the duration of fetal drug exposure, and 5) the gestational age of the fetus. - Drug Effects in the First Trimester - Teratogenic Effects 1. Teratogenic effects can only occur during the period of fetal organogenesis. For the great majority of organ systems this is day 18 (week 3) to day 55 (week 8) of gestation. [Note: Injury to palate, limbs, and GU tract may occur as late as week 12-15.] 2. Teratogenic injury typically requires more than just one exposure to the drug; it usually requires weeks or months of continuous exposure during the organogenesis period. There are, however, some highly teratogenic drugs that seem to be able to produce fetal malformations in just a few doses. 3. It is difficult to prove (in every case) that a particular congenital malformation is caused by a drug exposure because there is already a 2% incidence of congenital malformations in fetuses that have never been exposed to any drug. 4. A direct cause-and-effect relationship between a given drug and a specific congenital malformation is also difficult to prove because it is not possible to measure fetal tissue drug levels of the suspect drug to establish that the drug was actually present in the deformed tissue. 5. Although there may be significant animal data linking a given drug to congenital malformations in animal fetuses, animal data is not always applicable to human fetuses.Drug Effects After the First Trimester - Toxic Effects1. METABOLISM - Because of the immaturity of the fetal liver, any drugs that enter fetal circulation cannot be effectively metabolized. 2. EXCRETION - Because of the immaturity of the fetal kidney, any drugs that enter the fetal circulation cannot be effectively excreted by the fetal renal system. They must re-enter the mother's blood for excretion. 3. DISTRIBUTION - Because of a poorly formed, immature, and defective blood brain barrier, any drugs that enter the fetal circulation will be able to enter fetal brain (i.e., have a wider and possibly harmful distribution). 4. DISTRIBUTION - Because of the naturally lower serum albumin levels in fetuses, any drug that is protein bound will have fewer available protein binding sites and will exist in the fetal blood as free drug (i.e., pharmacologically active drug).PREGNANCY RISK CATEGORIES- In an attempt to minimize the risk of drug-induced injury in the fetus, the FDA has established Pregnancy Risk Categories for most drugs. These categories deal not only with teratogenic injury but also with any drug effects in the mother that may prove harmful or fatal to the fetus, such as stimulating premature labor. The categories established by the FDA are ranked as to the level of risk to the fetus and are defined as follows: (Notice there are two Category B and two Category C definitions.) 1. Category A - Adequate studies have been performed on pregnant animals and adequate studies have been done (i.e., information has been gathered) on pregnant women. There is no evidence that the drug causes fetal defects (or injury) in animals or in humans. 2. Category B - Adequate studies have been done on pregnant animals but there are no studies done on pregnant women; there is no evidence that the drug causes fetal defects (or injury) in animals but its effects in humans is unknown. 3. Category B - Adequate studies have been done on pregnant animals and in human pregnancy; the drug does cause fetal animal defects (or injury) but does not harm developing human fetuses. 4. Category C - Adequate studies have been done on pregnant animals but the drug has never been used in human pregnancy; there is evidence that the drug causes fetal animal defects (or injury) but the effects in human pregnancy is unknown. 5. Category C - There are no adequate studies of the drug in either pregnant animals or in human pregnancy; the effects in human pregnancy is unknown. [Note: The drug can be used in human pregnancy if the benefits to the mother outweigh the potential risks to the fetus.] 6. Category D - The drug has been used in human pregnancy and there is evidence that it causes human fetal defects (or injury). [Note: The drug can be used in human pregnancy if the benefits to the mother outweigh any potential risks to the fetus.] 7. Category X - Adequate studies in both animal and in human pregnancy reveal evidence that the drug causes fetal defects (or injury) to both animal and human fetuses. [Note: These are drugs that are never needed in pregnancy and they are contraindicated in pregnancy. The benefits to the mother never outweigh the risks to the fetus.]The Lactating Patient - Variations in PharmacokineticsDRUG ENTRY INTO BREAST MILK - Most drugs and their metabolites can enter breast milk. Drugs (and metabolites) that are excreted by the mother in her breast milk can be absorbed by the nursing infant through its GI tract. - Most drugs that enter breast milk have already undergone some degree of maternal drug biotransformation. - Because milk is a mixture of both fat globules and a protein-based liquid, both fat-soluble and water-soluble drugs can enter breast milk. - Because breast milk is more acidic than maternal plasma, drug molecules that are weak bases can enter (and remain in) breast milk more readily than drug molecules that are weak acids. - The risk of drug-induced injury to the infant is directly proportional to the amount of milk consumed. - Drug levels in breast milk will vary but are usually low. Therefore the risk of injury to the nursing infant from ingested drugs is real but low.The Pediatric Patient - Variations in PharmacokineticsFew pre-marketing studies are done of the effects of drugs on pediatric patients. Only one-fourth of the drugs approved by the Food and Drug Administration have indications specific for use in the pediatric population. Although pediatrics is often defined as those younger than 18 years, in this course the term pediatric dosing will be applied to children under 12 years of age. Dosing for this population is based on body weight or, less commonly, body surface area. Doses are expressed as milligrams per kilogram of body weight per day, to be administered in one or more portions daily. Doses calculated on body surface area are expressed as milligrams per square meter to be given as one or more doses daily. Careful attention must be given to whether the calculated dose is a single dose or divided into multiple doses to avoid medication error. Another challenge in this population is the increasing incidence of obesity, which can create situations where dosages for children approach those given to adults. In general, the highest dose recommended for a child is the maximum dose approved for adults.The Pediatric Patient-ABSORPTION- Very young pediatric patients cannot take solid oral medications. Liquid oral medications are frequently "spit back" making it difficult for the clinician to know how much of the drug will actually reach its site of absorption and be absorbed. - Very young pediatric patients (neonates, infants, and young children) have higher gastric pH (i.e., they produce less acid) compared to their adult counterparts. This will affect the ionization of orally ingested medications that will, in turn, affect drug absorption. - Neonates and infants have delayed gastric emptying. This will delay the delivery of orally ingested drugs to the small intestine and will, therefore, delay the absorption and the onset of action of these drugs. - Drugs administered I.M. into the muscle tissues of neonates and infants will have a slower rate of absorption because of the relatively small muscle mass in these patients (compared to adults) that has a correspondingly diminished blood supply. The less vascular the site of drug absorption, the slower will be the process of absorption. - Drugs administered topically to the skin in neonates and infants and small children will be absorbed faster than the same drug applied to the skin of an adult. This is because of the relative thickness of the skin in these two groups; small pediatric patients have very thin skin that allows drug absorption to occur much faster compared to adults.The Pediatric Patient- DISTRIBUTION- Neonates have a larger percentage of their body weight as water compared to adults. This allows a wider distribution of water-soluble drugs in small pediatric patients. - Conversely, neonates have a smaller percentage of their body weight as fat, restricting the distribution of fat-soluble drugs. - Neonates and infants have a comparatively low serum albumin; this results in a relative decrease in the level of protein bound drugs and a correspondingly higher serum concentration of free drug. - The fewer available protein-binding sites are further reduced by increased competition from the normally increased pediatric serum levels of free fatty acids, maternal estrogen, and bilirubin, all of which also bind to these same albumin sites. - Neonate and young infants have an incompletely developed blood brain barrier and will have a wider distribution of drugs into pediatric brain.The Pediatric Patient-METABOLISM- Neonates and infants have immaturity in development of the drug metabolizing functions of the liver. As a result, drug metabolism will be impaired. This will continue for the first year of life; longer for premature infants. [Note: The liver matures as a drug-metabolizing organ at about one year of age.] - Neonates and infants have generally higher and more erratic basal body temperatures compared to adults. Because drug metabolic rates are proportional to basal body temperatures, drug metabolic rates will be generally higher and more erratic in these very young patients than they are in adults.The Pediatric Patient-EXCRETIONBecause of immaturity of the neonatal and infant kidney, drug excretion by this route will be decreased compared to adults; the pediatric GFR is about 30% of a normal healthy adult GFR. This affects drug excretion by both glomerular filtration and by renal tubular excretion. [Note: Pediatric renal function also matures at about one year of age.]The Older Adult Patient - GENERAL CONSIDERATIONS- Older adults typically have organ system degeneration both because of aging of the systems and because of concurrent diseases affecting them. The organ systems of greatest concern are the hepatic, renal, and cardiovascular systems. - There is also an increased incidence of organ system diseases that are not directly responsible for pharmacokinetics but will indirectly affect the way in which these patients handle their drugs. (For example: brain dysfunction, pulmonary diseases, etc.) - There is a significant incidence of polypharmacy in these patients, in part, due to the high frequency on concurrent disease states. This will result in numerous drug-drug pharmacokinetic interactions. Older adult patients also consumed the greatest proportion of prescription and over-the-counter drugs. - There is a high rate of poor compliance to drug pharmacotherapeutic plans in these patients for a variety of reasons. This can result in variations in pharmacokinetics. - There is a marked degree of variability in the older adult; generalizations about the pharmacokinetics in this age group are inaccurate at best.The Older Adult Patient - ABSORPTION- Decreased Gastric acid production - Older adults have decreased capacity for the production (secretion) of HCl acid. They, therefore, have a higher gastric pH when compared to otherwise healthy younger adults. This will affect the degree of ionization of orally ingested drug molecules which will, in turn, affect their water/fat solubility and their absorption rates. - Altered gastric emptying - The variability in gastric pH and the variability in patterns of peristalsis often seen in older adults will affect the delivery of drugs into the small intestine. A delayed movement into the small intestine will delay the absorption of drugs normally absorbed there and this will affect the onset of action of those drugs. - Decreased intestinal blood flow - Older adults frequently have a variety of vascular diseases, most often impaired blood flow, to various body tissues. They commonly have decreased blood flow to the small intestine where many drugs are absorbed into the bloodstream.The Older Adult Patient - DISTRIBUTION- Decrease in lean body mass- Older adults have decreased lean body mass which decreases the volume of distribution for water-soluble drugs and can lead to higher plasma concentrations following administration of a standard drug dose. - Increase in body fat- Older adults have increase body fat which increases the volume of distribution for fat-soluble drugs and can lead to lower plasma concentrations after a standard dose is administered.The Older Adult Patient- METABOLISM- Changes in liver function- The phase I pathway of metabolism is often reduced in the elderly, which may have the effect of decreasing clearance of certain drugs (certain benzodiazepines) and prolonging the half-life of elimination. Although data are limited, drugs with high rates of first-pass metabolism (calcium channel blockers, tricyclic antidepressants and major tranquilizers) should be administered cautiously as lower doses may be sufficient to see therapeutic effects.The Older Adult Patient- EXCRETION- Reduction in glomerular filtration rate and renal tubular function- Between the ages of 20 and 90 renal function declines on average of 35%. Drugs that are largely excreted by the kidney will have decreased clearance of plasma in proportion to the decrease in the individual patient's kidney function. For this reason measuring plasma drug levels can be helpful for certain drugs (such as digoxin).1. Which statement(s) is/are true regarding the disadvantages of orally ingesting medications? a. Food in the intestinal tract delays the absorption of many medications b. Vomiting of drug causes uncertainty about how much drug was absorbed c. Intestinal edema can impair drug absorption d. Absorption may be delayed in elderly patients1. Four correct answers: a, b, c and d2. Regarding the mechanisms of pharmacodynamics, which of the following is/are (an) example(s) of non-specific, physio-chemical interaction? a. Interaction between a drug molecule and its intracellular target enzyme b. Affinity between a drug molecule and its receptor c. Binding of a drug molecule to its extracellular receptor d. Alteration of cellular environments by imposition of a physical barrier2. One correct answer: d3. Log-dose response curves can be used in which of the following ways? a. Determine the most effective dosing interval for a given drug b. Compare the relative potencies of two drugs c. Find the effective dose-50% (ED50) of a given drug d. Determine the therapeutic index of a given drug3. Three correct answers: b, c and d4. Toxic effects of drugs on a fetus occur due to: a. recirculation of the drug to the fetus multiple times by the placenta b. hypersensitivity reactions generated by the mother's immune system c. immaturity of the fetal liver and kidney d. failure of the immature blood-brain barrier to trap the drugs before they enter the fetal brain4. Two correct answers: c and d.SIDE EFFECTA nearly unavoidable secondary effect of a drug produced at therapeutic doses which is generally predictable and with an intensity that is dose-dependent. - This is a standard textbook definition of "side effect". The problems with this definition are: 1. The lack of precision in terms such as "nearly unavoidable" and "generally predictable". 2. The variability in "therapeutic dose"; this dose will vary depending on the patient, the clinical circumstances, etc. 3. The lack of a clearly defined point where "side effect" ends and "adverse effect or toxicity" begins.ADVERSE EFFECTA drug-induced, secondary effect of a drug that produces a change in a patient's condition which is noxious, harmful or unpleasant, which requires treatment or reduction or discontinuation of the drug, and which occurs at usual therapeutic doses. - The FDA requires that the definition of adverse effect include intentional or unintentional overdoses, actual or potential drug abuse, symptoms associated with the withdrawal of the drug, and medical complications due to the failure of the drug to produce its desired, intended therapeutic response.Difference between SIDE EFFECT and ADVERSE EFFECTBecause of the difficulties with the two definitions, the best way to resolve this confusion is to refer to all unintended drug reactions as adverse drug reactions and realize that there are degrees of seriousness associated with ADR's; that some are mild, easily tolerated, and acceptable and others are very harmful and possibly fatal. In addition, what is regarded as an unintended drug reaction in one clinical circumstance may be a welcome and desired reaction to the drug in another. For example, taking an antihistamine for the symptoms of a "head cold" may produce drowsiness which may be very desirable for rest and recovery from the cold. However, taking the antihistamine and becoming drowsy when the patient must remain alert (e.g., to drive an automobile) will be regarded as a serious ADR of the antihistamine.How can a clinician recognize that a given sign or symptom is actually causally related to a drug that the patient may be taking?Too often, symptoms that arise during therapy with drugs are not considered to be caused by the drug itself. New symptoms are often automatically regarded as a new pathophysiology which is commonly "treated" with yet another drug. While this may be the correct approach in some cases, greater attention should be paid to the fact that symptoms that arise during therapy with pharmaceutical agents may actually be the ADR's of one of the drugs being given. The correct approach in this case would be to revise the pharmacotherapeutic plan and even discontinue the offending medication if possible. It is a relatively simple matter to learn what the ADR's are for any given drug. Standard drug references list most or all of the known ADR's for each drug and even specify which ones are common or life-threatening. Clinical recognition of a suspected ADR is another matter. There are some basic guideline questions that have been suggested as aids in establishing a cause-and-effect relationship between a given drug and a given sign or symptom a patient may be having. While these questions seem very straight forward, there are problems associated with their implementation.1. Does the suspected ADR occur only after the drug is administered?Problem: It stands to reason that a drug cannot cause an ADR in a patient until after the patient has received the drug. An ADR however may occur immediately after the patient takes the drug or it may occur days, weeks, months or even years after the patient is exposed to the drug. Establishing the correct timing relationship is relatively easy when the ADR occurs immediately or shortly after the patient has taken a drug; it becomes more difficult the longer the interval between the taking of a drug and the suspected ADR.2. Is the suspect ADR a known and previously reported event associated with the particular suspect drug?Problem: For many drugs that have been on the market for a number of years, clinicians are well aware of the most common or most dangerous ADR's associated with them. The reference books can be used for those suspected ADR's that are not commonly known but which have been clearly shown to be associated with a given drug. The problem arises with "newly released drugs" that have had relatively little exposure in the general public. Drugs that have been on the market for up to two years are considered "newly released" and all of the potential ADR's for that drug have not yet been noted. Any clinician using such a drug may be the first practitioner to note a specific ADR for that drug. Just because a specific sign or symptom has not been reported and published in the general drug literature in connection with a specific drug does not mean that it cannot be an ADR for that drug.3. Is the noted event due to the drug or is it explained by the pathophysiologic process that is being treated?Problem: Many of the ADR's that have been noted with specific drugs are very similar or identical to the signs and symptoms that are associated and caused by the very condition for which the drug is being given. In that case, how can the distinction be made between a drug-induced symptom (i.e., an ADR) and a symptom caused by the patient's pathophysiology? This is not always possible. For example, inhalant bronchodilators are administered for the relief of asthma-associated bronchospasm. Inhalant bronchodilators, however, may provoke paradoxical bronchospasm when being administered. In this case, is the bronchospasm asthma-related or drug-related? The answer may not be clear.4. Does the suspect ADR improve or disappear when the drug is reduced or discontinued?Problem: If a given sign or symptom is suspected to be the result of a given drug, common sense dictates that if the drug is discontinued and if the suspect ADR also disappears, then a cause-and-effect relationship between the two may be established. As simple as this logic is, what does a clinician do when the patient is on multiple drugs, any one of which may be the culprit? Does the clinician stop all of them? Also what does the clinician do when the drug or drugs cannot be discontinued because it is a necessary drug for the patient's condition? It is not always possible to discontinue a suspect drug to prove its relationship to a given suspected ADR.5. Does the suspect ADR recur when the drug is resumed?Problem: Continuing the logic of the above question, the final piece of evidence that a suspected symptom is truly associated with a given drug would be the return of a symptom upon the resumption of the drug. If a particular symptom was particularly dangerous or very unpleasant (like an arrhythmia or severe nausea) it may not be possible or safe to resume the suspect drug. In this case, the final proof would be impossible to obtain. Although this question-and-answer format is frequently helpful in connecting a given drug with a given symptom, establishing a clear-cut cause-and-effect relationship between the two is not always possible. Very often, the best that can be said is that there is a presumed relationship between a drug and an ADR. Adverse drug reactions are a major and very common occurrence in many pharmacotherapeutic plans and must be continually evaluated and re-evaluated during the course of therapy to ensure safe and effective (i.e., rational) drug therapy.There are two final points to be made in the question of clinical recognition of adverse drug reactions.(1) Be careful not to accuse an innocent drug. Although it is important to continuously be on the lookout for ADR's to the drugs being used in any pharmacotherapeutic plan, it is equally important not to erroneously blame a drug for causing a symptom that it did not cause. In doing so this drug may be withheld from a patient for whom it is vitally needed. Too often, clinicians erroneously tell a patient that, because of a symptom that arose during therapy with a given drug, that the patient "is allergic" to the drug. This has resulted in that drug never being given again to that patient. This is unfortunate when the patient is not allergic to the drug but, because of this erroneous claim, the drug cannot ever be used again in the future for that patient. (2) ADR's to a given drug may be caused by additives in the drug preparation and not to the drug itself. Such additives as the vehicle or the dye used to color the preparation can be the cause of the reaction, especially allergic reactions, and not the active ingredient at all. This is difficult to prove but if other preparations of the drug are available that contain different additives, it may be worthwhile trying them before condemning the drug as the causative agent.Clinical Situations of Increased Risk for Adverse Drug Reactions Adverse drug reactions are common and should be continuously looked for during any pharmacotherapeutic plan. There are, however, certain categories of drugs and certain categories of patients which are particularly well known to be related to an increased risk for ADR's. These categories are:1. CERTAIN DRUG CATEGORIES 2. DRUG THERAPY AT THE EXTREMES OF AGE 3. FEMALES 4. POLYPHARMACY 5. THERAPY WITH A NEWLY RELEASED DRUG 6. THERAPY WITH UNUSUALLY HIGH DOSES OF A DRUG 7. THERAPY IN PATIENTS WHO ARE EXTREMELY UNDERWEIGHT OR EXTREMELY OVERWEIGHT 8. THERAPY IN PATIENTS WITH RENAL OR HEPATIC DISEASE - 9. THERAPY IN PATIENTS WITH ALTERED BLOOD FLOW STATES 10. THERAPY IN PATIENTS WITH A PAST HISTORY OF ADR'S (ESP. ALLERGY) 11. THERAPY IN DEPRESSED OR ANXIOUS PATIENTS 12. THERAPY IN PATIENTS WHO ABUSE (OR MISUSE) NICOTINE, ALCOHOL, OR ILLICIT STREET DRUGS 13. THERAPY IN PATIENTS WHO SELF-DIAGNOSE AND SELF-TREAT WITH OVER-THE-COUNTER DRUGS, SUPPLEMENTS OR HERBS1. CERTAIN DRUG CATEGORIESanalgesics, anti-infectives, anticoagulants, anticonvulsants, hypoglycemics, psychotropics, anti-neoplastics, cardiovascular drugs, anti-inflammatory drugs, etc.2. DRUG THERAPY AT THE EXTREMES OF AGEPatients who are among the very young and those considered older adults are more likely to suffer ADR's than those in between these ages. The reasons for this are multiple but many ADR's are the result of the altered pharmacokinetics in these age groups.3. FEMALESWomen are at greater risk for ADR's than men. This may be related to the greater number of clinician visits by women compared to men and/or it may be related to the altered pharmacokinetics seen in women in association with pregnancy, lactation, and menopause. It may also be related to the fact that women, in general, take more medications than men.4. POLYPHARMACYThe incidence of adverse drug reactions goes up in proportion to the number of drugs taken.5. THERAPY WITH A NEWLY RELEASED DRUGWhen a drug is first released by a pharmaceutical company for general use, it has had a relatively limited exposure in the public. The true picture of its ADR's is not completely realized until millions of patients have taken the drug and this may take several years depending on how widespread the use of the drug. A drug is considered to be "newly released" for at least the first two years that it is on the open market and is freely prescribed.6. THERAPY WITH UNUSUALLY HIGH DOSES OF A DRUGAlthough not always the case, the incidence of most ADR's is directly proportional to the dose of the drug. Any excessively high doses of a drug, even though they may be indicated, are considered to be associated with an increase risk of ADR's to the drug.7. THERAPY IN PATIENTS WHO ARE EXTREMELY UNDERWEIGHT OR EXTREMELY OVERWEIGHTBecause of the altered pharmacokinetics in patients who fall well outside of the normal parameters of body weight, drug therapy in these groups is frequently associated with an increased risk of ADR's. This is especially true for weight based medications.8. THERAPY IN PATIENTS WITH RENAL OR HEPATIC DISEASEBecause of the importance that these organ systems play in drug pharmacokinetics, patients who have difficulty metabolizing and/or excreting drugs are at increased risk for ADR's. It is often very difficult to correctly calculate the dosages and the dosing intervals for drugs in patients with imprecise pharmacokinetic mechanisms.9. THERAPY IN PATIENTS WITH ALTERED BLOOD FLOW STATESThe importance of drug distribution in any pharmacotherapeutic plan cannot be over-emphasized. Drugs cannot be expected to interact properly with their target cells if they cannot reach them. Patients with impediments to drug distribution are at increased risk for problems with drug dosages and dosing frequencies.10. THERAPY IN PATIENTS WITH A PAST HISTORY OF ADR'S (ESP. ALLERGY)There are certain patients who, for many reasons, are particularly susceptible to ADR's. These patients will continue to be at increased risk for ADR's to any new drug as well as new ADR's to drugs to which they have been previously exposed. This is especially true for drug allergies. Patients with a sensitive immune system who have developed hypersensitivity reactions to other drugs, are at increased risk for allergic reactions to many new drugs as well. *A history of hypersensitivity to a drug is a CONTRAINDICATION for prescribing that particular drug to the patient again.*11. THERAPY IN DEPRESSED OR ANXIOUS PATIENTSThe types of medications these patients require, are in themselves, associated with an increased risk of ADR's. In addition, these patients, as a group, may have difficulties with compliance with planned drug regimens. For these reasons, increased risks for ADR's can be expected.12. THERAPY IN PATIENTS WHO ABUSE (OR MISUSE) NICOTINE, ALCOHOL, OR ILLICIT STREET DRUGSSuch pharmacologically active substances as caffeine, nicotine, alcohol, etc. can produce pharmacologic effects of their own. When prescribed drugs are added to these commonly used substances, the potential for ADR's to the prescribed drugs increases. Although the pharmacologic effects of caffeine, nicotine and alcohol are fairly well known and somewhat predictable, the wide array of street drugs and potential drug combinations possible today are completely unpredictable in their potential to cause ADR's and drug interactions with prescribed drugs. The risks associated with these combinations, however, is great.13. THERAPY IN PATIENTS WHO SELF-DIAGNOSE AND SELF-TREAT WITH OVER-THE-COUNTER DRUGS, SUPPLEMENTS OR HERBS-There is an erroneous assumption by the general public that if a medication, supplement or herb is sold OTC, or if it is "natural" that it is somehow completely safe. It is common for patients today to self-diagnose and self-prescribe based on the promises made by the manufacturer, internet websites, or flashy advertising. The addition of prescribed medications to the unknown quantities of OTC drugs/herbs that the patient may have been taking sets the stage for increased risks for ADR's. This is a variant of polypharmacy and it is also a clue to the possibility of non-compliance by this patient group.Classification of Adverse Drug Reactions According to Pharmacodynamic Action There are two classifications of ADR's based on pharmacodynamic actions:TYPE A: INTRINSIC ADVERSE DRUG REACTION TYPE B: IDIOSYNCRATIC ADVERSE DRUG REACTIONTYPE A: INTRINSIC ADVERSE DRUG REACTIONA direct (excessive) extension of the known pharmacodynamic actions of the drug (or its metabolites). Intrinsic ADR's are the most common type of ADR (accounting for 60-70% of all known ADR's), are predictable, and are dose-dependent (i.e., the intensity of the ADR is directly proportional to the size of the dose administered). - Example: An antihypertensive drug causes hypotension. This is an intrinsic ADR because, as an antihypertensive drug, it can be expected to cause of lowering of blood pressure by its expected pharmacodynamics. Inappropriate use of this medication can be expected to cause an excessive lowering of blood pressure. It is common and predictable.TYPE B: IDIOSYNCRATIC ADVERSE DRUG REACTION -An uncommon, unpredictable ADR that is not explained by the known pharmacodynamics of the drug or its metabolites. They account for 20-30% of all ADR's, and they are independent of the size of the dose of drug administered. These types of reactions are poorly understood but might be explained on the basis of some genetic abnormality in the patient's metabolism of the drug or on some immunologic basis. - Example: An antibiotic (gentamicin) causes psychologic depression and twitching. This is not an expected pharmacodynamic action of an antibiotic which is formulated to kill (or damage) bacterial cells. This type of reaction is uncommon and unpredictable and completely unexplainable.CAUSES OF TYPE A REACTIONS:1. TOXIC REACTION 2. CHAIN REACTION 3. CUMULATIVE REACTION 4. TOLERANCE 5. DEPENDENCE1. TOXIC REACTIONA severe drug reaction (often considered a drug poisoning) that is caused by either a quantitative or a qualitative overdose of the drug. A quantitative overdose is an excessive serum level of the drug whereas a qualitative overdose occurs in those patients who, for whatever reason, are excessively sensitive to even normal serum levels of the drug. Toxic drug reactions can be local (at the site of drug administration) or systemic, producing dangerous or even fatal generalized reactions involving several body systems. Toxic drug reactions can occur immediately after the drug is administered or they can be delayed days, weeks or even months after a drug is given. They can be reversible in many cases but can also be irreversible, producing permanent injury, even death, to patients or their organ systems. Toxic drug reactions are more likely to occur with drugs that have a low margin of safety (i.e., that have a low therapeutic index). EXAMPLES: o An excessive dose of meperidine (Demerol) causing respiratory suppression o An excessive dosing of gentamicin (Garamycin) causing nephrotoxicity and eventual renal failure EXAMPLE: o Administration of the sedative-hypnotic triazolam (Halcion) causing CNS excitation; this would also qualify as a paradoxic response.2. CHAIN REACTIONAn adverse reaction in which the adverse reactions of one drug require "treatment" with another drug which can itself cause adverse reactions which can, in turn, require yet another drug for correction and so on. EXAMPLE: o Administration of an ACE inhibitor for control of hypertension which results in a nocturnal cough which is then treated with a cough suppressant which then causes excessive sedation which requires the administration of a CNS stimulant to awaken the patient enough to drive a car to work, etc., etc...3. CUMULATIVE REACTIONAn adverse reaction in which there is a progressively increasing response to a drug dosage, given repeatedly, which is associated with progressively increasing serum levels of the drug. This occurs when the rate of absorption of the drug exceeds its rate of elimination and is commonly seen in patients with renal insufficiency in whom there is a decreased rate of excretion of the drug in the face of its continued administration. EXAMPLE: o Administration of digoxin (Lanoxin) daily for weeks to a patient with compromised renal excretion, allowing the serum levels of digoxin to eventually rise to toxic levels and causing digitalis toxicity.4. TOLERANCEA phenomenon in which the response to a particular drug dosage, given repeatedly, becomes less intense over time. There are two types of tolerance: (1) pharmacodynamic tolerance in which continuous administration of an agonist drug eventually results in down-regulation of its receptors until the target cell becomes desensitized to the drug and cannot respond as well and (2) pharmacokinetic tolerance in which the metabolism of a drug becomes enhanced (presumably by increased synthesis of hepatic drug-metabolizing enzymes) so that it is cleared more rapidly from the serum as therapy with the same dose is continued. EXAMPLE: o After several weeks of adequate arthritic pain relief with two aspirin tablets q6h, it now takes three aspirin tablets q4h to achieve the same degree of pain relief. Tachyphylaxis is a special type of tolerance in which the phenomenon occurs very rapidly in just a few doses of the drug. EXAMPLE: o Whereas it took only one spray of a nasal decongestant to open a clogged nose the first time, a few hours later it takes two or three sprays to do the job and by the next day, the nasal spray doesn't work at all. To overcome tolerance, the dosage of a given drug must be repeatedly increased in order to achieve the same clinical response.5. DEPENDENCEA drug reaction in which the continuous use of a drug results in the drug molecule becoming an integral part of the "daily" functioning biochemistry of the target cell and, in the absence of the drug, that biochemistry is significantly disrupted. There are two basic types of dependence: Physical Dependence - An adverse drug reaction which is characterized by physiological and/or behavioral changes after the drug is abruptly discontinued or after an antagonist to the drug is administered. The physiological/behavioral changes are referred to as a withdrawal phenomenon (syndrome) and are manifested by symptoms usually directly opposite to the expected pharmacologic effects of the drug. EXAMPLE: o Strong opiate analgesics like morphine and heroin can produce physical dependence if used on a continual basis. Any attempt to suddenly stop them results in the extreme agitation of the CNS. Psychological Dependence - An adverse drug reaction characterized by an intense craving for the drug to the point that the patients truly believe that they cannot function without the drug and engage in compulsive, often risky, drug-seeking behavior to obtain the drug. Psychological dependence is not usually characterized by a withdrawal syndrome. It is commonly the aftermath of physical dependence. EXAMPLE: o Many of the street drugs (i.e., hallucinogens) produce the memory of the extreme pleasure that the drug invoked when it was being used. This results in a strong craving to once again resume the use of the drug to recapture that pleasurable sensation. o Cigarettes (actually the drug nicotine) produces a strong craving in those who have stopped smoking.CAUSES OF TYPE B REACTIONS:1. ALLERGIC REACTION 2. IDIOSYNCRATIC OR PARADOXICAL RESPONSE1. ALLERGIC REACTIONA drug reaction in which a drug activates an immune response in a patient because of prior recognition by the patient's immune system of the drug as a foreign substance. Allergic reactions typically occur only after a patient has been exposed to the drug at least once and the immune system has had time (usually 8-9 days) in which to develop antibodies to the drug (now the antigen). Occasionally patients (and clinicians) are unaware of a patient's prior exposure to the drug. Although theoretically not possible with the first exposure to a drug, an allergic reaction can occur on any subsequent exposure to the drug even after years of taking it without a reaction. Allergic reactions can be manifested on the skin only (hives, rashes, whelps, etc.) or they can cause a severe systemic reactions (anaphylaxis, bronchospasm, hypotension, gastrointestinal disturbances, etc.). Allergic reactions are considered to be permanent and are independent of the dose of the drug given. They are more common in patients who have multiple other drug or environmental allergies. Allergic reactions are typically idiosyncratic ADR's. [Note: Not all idiosyncratic ADR's are allergic.] EXAMPLES: o A dose of penicillin in a penicillin-allergic patient causing a rash, hives, and bronchospasm o Allergic myocarditis following administration of a sulfonamide antibiotic2. IDIOSYNCRATIC OR PARADOXICAL RESPONSEAn adverse drug reaction in which the response to a drug is unusual, unpredictable and at variance to the expected response of the drug. When the response is directly opposite to what is expected from the drug the reaction is called a paradoxical response. Idiosyncratic responses are probably caused by a genetically-determined alteration in the pharmacokinetics of the drug, especially metabolism, and may be related to the production of an unusual metabolite not normally produced in the majority of the population. Many idiosyncratic responses are predominant within families or racial groups. EXAMPLE: o Administration of the sedative-hypnotic triazolam (Halcion) causing CNS excitation; this would also qualify as a paradoxic response.DELAYED ADVERSE DRUG REACTIONS:1. CARCINOGENIC REACTION 2. MUTAGENIC REACTION 3. TERATOGENIC REACTION1. ALLERGIC REACTIONA drug reaction in which a drug activates an immune response in a patient because of prior recognition by the patient's immune system of the drug as a foreign substance. Allergic reactions typically occur only after a patient has been exposed to the drug at least once and the immune system has had time (usually 8-9 days) in which to develop antibodies to the drug (now the antigen). Occasionally patients (and clinicians) are unaware of a patient's prior exposure to the drug. Although theoretically not possible with the first exposure to a drug, an allergic reaction can occur on any subsequent exposure to the drug even after years of taking it without a reaction. Allergic reactions can be manifested on the skin only (hives, rashes, whelps, etc.) or they can cause a severe systemic reactions (anaphylaxis, bronchospasm, hypotension, gastrointestinal disturbances, etc.). Allergic reactions are considered to be permanent and are independent of the dose of the drug given. They are more common in patients who have multiple other drug or environmental allergies. Allergic reactions are typically idiosyncratic ADR's. [Note: Not all idiosyncratic ADR's are allergic.] EXAMPLES: o A dose of penicillin in a penicillin-allergic patient causing a rash, hives, and bronchospasm o Allergic myocarditis following administration of a sulfonamide antibiotic2. IDIOSYNCRATIC OR PARADOXICAL RESPONSEAn adverse drug reaction in which the response to a drug is unusual, unpredictable and at variance to the expected response of the drug. When the response is directly opposite to what is expected from the drug the reaction is called a paradoxical response. Idiosyncratic responses are probably caused by a genetically-determined alteration in the pharmacokinetics of the drug, especially metabolism, and may be related to the production of an unusual metabolite not normally produced in the majority of the population. Many idiosyncratic responses are predominant within families or racial groups. EXAMPLE: o Administration of the sedative-hypnotic triazolam (Halcion) causing CNS excitation; this would also qualify as a paradoxic response.DELAYED ADVERSE DRUG REACTIONS:1. CARCINOGENIC REACTION 2. MUTAGENIC REACTION 3. TERATOGENIC REACTION1. CARCINOGENIC REACTIONA drug reaction in which a drug induces transformation of benign cells into malignant cells. These are the most difficult ADR's for a pharmaceutical company to investigate prior to a drug's release because of the very long latency period between exposure to the drug and the development of a clinical cancer. These effects may take many years (sometimes 20-30) to become manifest. EXAMPLE: o The drug diethylstilbesterol (DES) is an estrogen which, when given to pregnant women carrying a female fetus, caused an increased incidence of breast and vaginal cancer in these fetuses when they became 20-30 years of age. o Estrogens are known to increase the incidence of endometrial and breast cancer.2. MUTAGENIC REACTIONAn adverse reaction in which a drug induces alteration in the chromosomes (i.e., DNA) of sperm or egg cells. These alterations occur in the sperm and egg cells of an adult who can then become a parent and pass these defects along to his or her offspring. EXAMPLE: o Many antineoplastic drugs are known to damage cellular DNA o Marijuana (active ingredient is tetrahydrocanabinol [THC]) has been studied as a mutagenic drug.3. TERATOGENIC REACTIONAn adverse reaction in which a drug causes malformations in the developing organ systems of a fetus. These are the reactions that can occur when a potentially teratogenic drug is given to a pregnant women during the first trimester of pregnancy. EXAMPLE: o The acne drug isotretinoin (Accutane) is teratogenic in pregnancyClassified According to Effects on Selected Organ Systems The adverse effects of drugs can be classified according to the anatomical areas where they manifest themselves. Any given drug may produce manifestations in more than one anatomical area. When classifying drugs in this way, they are referred to as toxicities and are grouped as follows:1. DERMATOLOGIC TOXICITY 2. OTOTOXICITY 3. OCULAR TOXICITY 4. HEMATOPOIETIC TOXICITY 5. CARDIOTOXICITY 6. NEPHROTOXICITY 7. HEPATOTOXICITY 8. PULMONARY TOXICITY 9. NEUROLOGIC TOXICITY1. DERMATOLOGIC TOXICITYo Urticaria o Pruritis o Generalized erythroderma o Vasculitis (purpura, erythema multiforme, erythema nodosum) o Photosensitivity o Steven's Johnson Syndrome o Toxic epidermal necrolysis o Generalized exfoliative dermatitis o Alopecia o Pustular acneiform eruptions o Fixed drug eruptions2. OTOTOXICITYImpaired hearing (deafness) o Dizziness - Vertigo o Tinnitus3. OCULAR TOXICITYo Photophobia o Blurred vision o Altered color vision o Optic neuritis - blindness o Scotomata o Cataracts o Ocular muscle palsy4. HEMATOPOIETIC TOXICITYo Aplastic anemia o Platelet dysfunction - bleeding o Thrombocytopenia - bleeding o Agranulocytosis5. CARDIOTOXICITYo EKG changes o Arrhythmias o Myocarditis o Congestive heart failure o Myocardial ischemia6. NEPHROTOXICITYo Azotemia o Acute tubular necrosis o Nephrolithiasis o Interstitial nephritis7. HEPATOTOXICITYo Jaundice (cholestasis) o Hepatitis o Cirrhosis o Benign and Malignant tumors o Steatosis o Vascular injury (hepatic vein occlusion)8. PULMONARY TOXICITYo Pneumonitis o Pulmonary fibrosis o Bronchiolitis o Bronchospasm o Pulmonary edema9. NEUROLOGIC TOXICITYo CNS excitation o Insomnia o CNS depression, drowsiness, sedation o Ataxia o Seizures o Headache o Dizziness o Diplopia o Confusion, hallucination o Psychotic behavior o Memory loss o Paralysis, muscle weakness o ParesthesiasBefore choosing a drug or drugs for a given patient, the prescriber must:1. ALWAYS BEGIN WITH A DIAGNOSIS 2. UNDERSTAND THE PATHOPHYSIOLOGY OF THE MEDICAL DIAGNOSIS 3. REVIEW THE MENU OF PHARMACOTHERAPEUTIC OPTIONS 4. SELECT PATIENT-SPECIFIC DRUG AND DOSE 5. ESTABLISH THERAPEUTIC GUIDELINES AND END-POINTS FOR DRUG THERAPY 6. PREDICT, WITH REASONABLE CERTAINTY, THE EXPECTED COMPLIANCE BY THE PATIENT TO A CHOSEN PLAN OF THERAPY1. ALWAYS BEGIN WITH A DIAGNOSIS(or at least a reasonable working diagnosis) - Efforts to establish a medical diagnosis of the patient's condition or complaint is an essential first step in rational drug selection. Usually accomplished by careful history and physical examination, it may also include additional laboratory and radiologic tests. These discoveries simply point the prescriber in the general direction of choosing the best drug for a given patient. Although it is simple and tempting to make a diagnosis and then select a drug from pre-established protocols, arriving at the medical diagnosis should not be the concluding step in the thought process; it is only the beginning. On occasion, despite the best efforts, the medical diagnosis remains elusive. The practitioner is then forced to select therapy tailored to symptom relief (e.g., treating nausea with an antiemetic drug without knowing the cause of the nausea; treating pain with an analgesic without knowing the cause of the pain). While this is acceptable (up to a point), it is certainly not the optimal method of drug application and is often associated with inappropriate drug administration. If symptomatic treatment is required initially, efforts should continue to determine the medical cause of the symptom which might signal a change in the medication.2. UNDERSTAND THE PATHOPHYSIOLOGY OF THE MEDICAL DIAGNOSISDrug therapy is not optimally targeted to a named medical diagnosis; rather it should be targeted to specific components of the altered physiologic mechanisms (i.e. the pathophysiologic processes) that characterize the condition. For example, drugs should not be selected to treat "chronic heart failure"; rather rational drug selection is targeted to such things as decreased cardiac output, increased ventricular afterload, increased left ventricular preload, increased myocardial oxygen consumption, increased left ventricular filling pressure, etc. Drugs work by correcting pathophysiologic mechanisms and not by treating the words of a medical diagnosis. The practitioner must have specific pathophysiologic mechanisms in mind and how each selected drug will positively or negatively affect that mechanism. The practitioner must also realize that not every altered physiologic mechanism can be treated with drugs and that the choice of certain drugs will actually worsen a pathophysiologic mechanism.3. REVIEW THE MENU OF PHARMACOTHERAPEUTIC OPTIONSThis includes making a decision whether to treat with drugs or not. With the enormous number of drugs available today, it is tempting to think that there is at least some drug available for every condition. Certainly this is the belief held by many patients. One very important job for a practitioner is to correct this erroneous impression. Along with understanding the pathophysiology of a condition, it is important to realize that if there is not a specific target for a drug, that drug therapy should not be used, even if the patient demands it. Only those conditions which have "drug-correctable" pathophysiologic mechanisms should be treated with specifically selected drugs for those targets. One of the most difficult decisions for a practitioner is to choose NOT to treat a patient with drugs. Unless specific targets are chosen for drug therapy, the risks of using drugs may outweigh their benefits. 1) UNDERSTAND (I.E., HAVE KNOWLEDGE OF) "ALL THE POSSIBLE DRUGS" THAT COULD BE USED TO TREAT A SPECIFIC CONDITION AND ESTABLISH A PRIORITY RANKING FOR THEM 2)UNDERSTAND THE PHARMACODYNAMICS OF THE CHOSEN DRUG(S) 3)UNDERSTAND THE PHARMACOKINETICS OF THE CHOSEN DRUG(S) 4)UNDERSTAND POTENTIAL ADVERSE DRUG REACTIONS AND DRUG INTERACTIONS AND CONTRAINDICATIONS 5)BE ABLE TO ACQUIRE "ACCURATE" DRUG INFORMATIONUNDERSTAND (I.E., HAVE KNOWLEDGE OF) "ALL THE POSSIBLE DRUGS" THAT COULD BE USED TO TREAT A SPECIFIC CONDITION AND ESTABLISH A PRIORITY RANKING FOR THEMThe large number of drugs available today has created quite a dilemma for the practitioner. On one hand, having a wide variety of drugs from which to choose allows very tailored and specific therapy for individual patients. On the other hand, there are too many drugs for any practitioner to be totally familiar with all of them. Individual practitioners can handle this dilemma in two ways. First, they can attempt to know the details of as many drugs as possible so that they have great latitude in choosing the best drug for an individual patient. Attempting to know a great many drugs well, however, is usually impossible and the practitioner finds that there are just too many drugs to use safely. The second approach is to learn just a few drugs but to know them very well. The practitioner feels confident that these drugs are used safely and effectively. The patient, however, may be denied the best drug for his individual condition because it is not on the practitioner's list of known drugs. Each practitioner must choose a comfortable medium between these two extremes. Practitioners must know well as many drugs as can be competently mastered so that individual patients have the best chance of being offered the best drug for their unique condition. Once a list of all of the possible drugs that can be used for a given condition is established, they must then be prioritized into a ranking for selection. Although, pharmacologically speaking, it seems like there is only one best drug for a given condition, in reality this priority ranking will vary among individual patients depending on their unique circumstances. A drug considered to be the best for a healthy adult with good liver and renal function may be the absolutely wrong drug for a patient with liver or renal insufficiency. All of a patient's individual special circumstances must be considered when selecting and prioritizing drugs for inclusion in a therapeutic plan.UNDERSTAND THE PHARMACODYNAMICS OF THE CHOSEN DRUG(SIt is not sufficient for a practitioner to simply know the name, dose, and therapeutic category of a drug for it to be included into a rational plan of pharmacotherapy. It is also necessary that a drug be understood (as far as possible) as to the exact mechanism by which it will achieve correction of the targeted pathophysiologic mechanism. A drug cannot be rationally selected for treatment of a condition unless the way it will alter that condition is understood. How else will the practitioner know what the drug is doing so that therapeutic guidelines can be followed and the end-point is recognized? One way of mastering this is to know the pharmacodynamics of the pharmacologic class to which a drug belongs. For example, by knowing the pharmacodynamics of the non-selective Beta Blockers or of the opiate analgesics, one will also then know the general pharmacodynamics of each of the drugs within these classes. The only feasible way to learn pharmacodymanics is to, first, learn drugs as groups and not as individuals. Once this is mastered, then the individual pharmacodynamic variances of each drug within its class can then be learned.UNDERSTAND THE PHARMACOKINETICS OF THE CHOSEN DRUG(S)An effective therapeutic plan must take into consideration how the patient's body will "handle" the drug once it is administered. Understanding the components of pharmacokinetics will enable the practitioner to select the best route for the drug's administration, the best dosage, and the best way to monitor the drug's presence and actions in the patient's body. An extremely important component of the decision-making in drug selection is how will the drug be eliminated from the patient's body. Drug elimination is often a function of both the metabolism (or biotransformation) that the drug will undergo while in the patient and the method that the patient's body will use to remove the drug and/or its by-products from the body. Before a drug is introduced into the body, the practitioner must know how the patient's body is equipped to handle and process the drug while it is inside the patient.UNDERSTAND POTENTIAL ADVERSE DRUG REACTIONS AND DRUG INTERACTIONS AND CONTRAINDICATIONS -Virtually every drug has potential adverse drug reactions and possible drug interactions when administered together with other drugs. Knowing in advance the possible ADR's that a given drug can produce will allow more precision in the selection of drugs for patient conditions that could not tolerate those ADR's. This will also improve compliance and avoid drug-related complications of the pharmacotherapeutic plan. In view of the fact that most patients take more than one drug at a time it is easy to see why drug interactions are extremely common. Many are simply inconvenient nuisances but some are lethal disasters. Again having advanced knowledge of the common drug interactions possible with each specific drug will allow better, safer drug selection and will afford the practitioner with an opportunity to do some patient teaching about potentially harmful interactions among that patient's various other medications. What they say about "an ounce of prevention being worth a pound of cure" is especially true in pharmacotherapy. Contraindications are conditions that would preclude the administration of a drug to an individual due to a high potential that harm will result. For example, it is contraindicated to give a pregnant woman a drug classified as Category X. Hypersensitivity, an exaggerated immune response triggered by a drug (such as anaphylaxis after penicillin), is also considered a contraindication.BE ABLE TO ACQUIRE "ACCURATE" DRUG INFORMATIONWith the rapidly expanding formulary available to the American practitioner, it is a daunting task to remain up-to-date on all the new drugs that ought to be considered in pharmacotherapeutic planning. In addition, knowledge about all the "old drugs" is continuously evolving and it is the responsibility of the practitioner to remain aware of new knowledge about these "old drugs". Sources of drug information are everywhere and readily available to practitioners, patients and lawyers. The question remains, however: Is the information in a given source reliable and accurate? Practitioners should know that every source of drug information is inherently biased in some way; by the author, the drug company, or even the government. Not even the FDA can be completely trusted. Practitioners must take in as much of this information as possible and judge for themselves its accuracy. They must be able to "read between the lines" and recognize the bias. Since there is no single "best" source for drug information, practitioners will find themselves using a variety of sources to get the best and most complete story on the drugs in question. This is not an easy task but it is one that is required for a rational pharmacotherapeutic plan.4. SELECT PATIENT-SPECIFIC DRUG AND DOSEThe prescriber must understand the special circumstances and needs of specialized patient populations. Most drug references describe drug action in otherwise healthy young adults. They also describe drug action in those being treated for various disease states, such as renal and hepatic disease. There are, however, several groups of healthy patients who fall outside these two categories and for whom drug therapy is frequently required as well. These are the specialized patient populations and include 1) the fetus, 2) the pregnant female, 3) the lactating patient, 4) the pediatric patient, and 5) the older adult. Each of the special groups have unique physiologic differences that alter the actions of drugs on their pharmacologic targets and in the way drugs are "handled" in their bodies. It is essential that these differences are taken into consideration when selecting drug therapy for these groups and that the necessary changes are made from the patterns usually used in healthy or ill patients.5. ESTABLISH THERAPEUTIC GUIDELINES AND END-POINTS FOR DRUG THERAPYBefore any drug therapy is initiated, the practitioner must have a good idea of what the drugs are expected to do. The practitioner must know what objectives are to be met and how to recognize when those objectives are met. In other words, what therapeutic guidelines will be used to gauge the effectiveness or lack of effectiveness of any drug's therapeutic plan? Also, how will the practitioner determine (i.e., measure) when the planned objectives have been met so that therapy can be discontinued? In some cases, this seems to be obvious. Pain medication is given to achieve pain relief and is discontinued when pain has been relieved. But what about persistent or chronic pain conditions? The therapeutic plan must consider some guideline for changing from an ineffective pain medication to a possibly more effective drug. How long will the practitioner attempt to control hypertension with one drug before deciding to change drugs or add a second drug to the patient's regimen? For effective medication management, types and durations of drug therapy will depend on a sound rational plan that has guidelines and end-points that are set before therapy begins and may require interval adjustments as therapy progresses.6. PREDICT, WITH REASONABLE CERTAINTY, THE EXPECTED COMPLIANCE BY THE PATIENT TO A CHOSEN PLAN OF THERAPYThere is no value in a practitioner's selection of the best drug for a given patient's condition if the patient cannot or will not take the medication once it is prescribed. There are many reasons for a lack of compliance on the part of the patient, some rational and completely understandable and some totally irrational. Each practitioner must investigate all of the potential reasons for non-compliance and address them before a drug is selected and prescribed. Although it is not possible to accurately predict, in every instance, all of the circumstances that will trigger non-compliance, assessing every patient in this way will do much to ensure the best compliance. In addition, explaining to a patient the reasons why one drug is selected over another will demonstrate to the patient that the practitioner has put some educated thought into the process of drug selection. This will go a long way toward establishing confidence in the practitioner and will help to promote compliance with the practitioner's pharmacotherapeutic planDeterminants of Drug-Response RelationshipsBefore prescribing a medication (or approving an over-the-counter medication), the clinician must consider all the things that will ultimately determine the effects (both good and bad) that a given drug will have in a given patient. There is clearly a relationship between the dose of a drug prescribed and the response that that dose will have in the patient. This relationship can be regarded as a seven step process with several determinants to each step:Determinants of Drug-Response Relationships 7 steps- STEP 1 - ESTABLISHING A DIAGNOSIS - STEP 2 - CHOOSING A SPECIFIC DRUG - STEP 3 - DECIDING ON A DOSE AND FORM TO BE PRESCRIBED - STEP 4 - DETERMINING WHETHER THE DOSE WILL ACTUALLY BE TAKEN - STEP 5 - WHAT WILL BE THE DRUG CONCENTRATION IN PLASMA (OR TISSUE) - STEP 6 - WHAT WILL BE THE PHARMACOLOGIC RESPONSE - STEP 7 - WHAT WILL BE THE ULTIMATE DRUG RESPONSESTEP 1 - ESTABLISHING A DIAGNOSIS DETERMINANTS:* Reported symptoms - Clinical impressions begin with the voluntary reporting of symptoms by the patient. Symptoms, by themselves, are not diagnoses. Clinicians must be skillful in history-taking to draw out the subtle details of these symptoms and develop them into a presumptive diagnosis. * Clinical assessment - All diagnoses are strengthened by supportive physical findings that correspond to the reported symptoms. * Laboratory and X-ray - Additional laboratory and /or x-ray evaluations are occasionally needed to establish a presumptive diagnosis. While these can occasionally be obtained urgently, often, the drug selection process will have to be delayed until these results are available. If drug therapy is required before such results are available, the clinician must "predict" the most likely results of these tests and prescribe accordingly. The drug therapy selected in this way may have to be changed when results are different than was predicted.- STEP 2 - CHOOSING A SPECIFIC DRUG * DETERMINANTS:Multiple drug choices - For any given diagnosis there may be and usually are multiple appropriate drugs from which to choose. Selection will be based on a priority ranking of the drugs by the clinician. This ranking will be based on recent reports in the clinical literature, clinician's knowledge of the drug, prior clinician experience with the drug, prior patient experience with the drug, predictable patient compliance with a specific drug, and many others. * Possible drug interactions - The choice of a new drug to add to the patient's therapeutic plan must take into consideration the other pharmacologically active substances (including alcohol, nicotine, and caffeine, etc.) that the patient is taking, has recently taken, or is likely to take in the near future. A thorough drug history must be taken so as to avoid the possibility of harmful interactions between all pharmacologically active substances concerned. * Patient compliance factors - Before choosing a specific drug, the clinician must investigate the possibility that the patient may not be able to take the drug as prescribed. There are many reasons why a patient may not be able to take one or more of the potential drug selections from the list of multiple drug choices. This requires an understanding of the patient's psychology about drugs, their financial and family circumstances, and many others characteristics unique to the individual patient. Knowing about these things may require the practitioner to re-prioritize the ranking of the possible drug choices. * Contraindications - It is essential that clinicians know the numerous possible patient or drug contraindications that may exist in any given clinical situation. Prescribing a contraindicated drug is negligence at best and may be fatal at worst. It is a critical determinant. * Accurate drug information - Before selecting a drug from the potential multiple possible drugs on the list, the clinician must be assured that he or she has all of the currently available and accurate drug information about each of the possible selections. What was accurate 6 months ago may be totally inaccurate today. The clinician must remain up-to-date.- STEP 3 - DECIDING ON A DOSE AND FORM TO BE PRESCRIBED * DETERMINANTS:* Available formulations - After deciding on a specific drug to be prescribed, the clinician must decide which form of the medication to prescribe. Many medications only come in one from and the decision is easy. Some medications, however, are available in multiple formulations (i.e., capsule, tablet, elixir, etc.). Practitioners must understand the unique differences among these various formulations and what makes each more or less suitable for an individual patient. Different formulations of a given drug can account for the speed of its onset of action, its availability to various tissue sites, the dosages to be used safely, etc. * Available routes of administrations - Some medications are available in multiple formulations that can be administered by different routes (i.e., orally, parenterally, by suppository). The clinician must be aware of all of the possible routes by which the selected medication can be given and choose the formulation that will best fill the therapeutic goals required by the patient. * Chosen amount - Once a specific drug is chosen, the clinician must decide on how much of the drug to administer with each dose. Guidelines are available from the literature and from the pharmaceutical companies but dosing for every drug must be tailored to specific patients and their individual needs and tolerances. The doses recommended in the literature are simply an average dose for the average patient. Any patient may require some dosage adjustment depending on their specific set of circumstances. * Patient compliance factors - As in the other steps, patient compliance factors also play a role in dose and formulation selection. Can or will the patient take a tablet or capsule- Can the patient afford one formulation of a medication if it is more expensive than another- Does the patient believe that one dose or route of administration is as effective as another- Clinicians must predict patient attitudes about dosage size and form and prescribe accordingly. If the clinician has strong feelings about a particular form or route of a medication, it may require considerable education of the patient to change attitudes.- STEP 4 - DETERMINING WHETHER THE DOSE WILL ACTUALLY BE TAKEN * DETERMINANTS:* Patient compliance factors - All of the effort put forward by the clinician when the patient is present may amount to little after the patient goes home. If the clinician is remiss in educating the patient or in engendering the patient's trust, there is still the possibility that the drug will not be taken in the dose prescribed. If the drug is not taken as prescribed or in the dosage prescribed, it is impossible to correlate the drug prescribed with the pharmacologic response noted.- STEP 5 - WHAT WILL BE THE DRUG CONCENTRATION IN PLASMA (OR TISSUE) * DETERMINANTS:* Drug absorption - All of the best intentions and prescribing efforts of the clinician and the most complete compliance by the patient will be for nothing if the drug cannot enter the patient's body and reach the site at which it is expected to work. Drug absorption is one of the determinants of how much drug gets into the patient's blood. Clinicians must predict how effectively the drug will be absorbed. * Drug distribution - Drugs may be absorbed as completely as they are supposed to but if they cannot be transported in the blood stream to the sites where they are needed, they cannot be expected to have a beneficial pharmacologic response for the patient. Clinicians must be able to predict how completely the drug will be distributed in the patient's body and how efficiently it will reach the tissues where it is needed. These issues are embodied in the pharmacologic principle of drug bioavailability. * Drug metabolism - Once drugs enter the blood and tissues of a patient, most of them will undergo degradation by the body (metabolism). As they are metabolized, their serum concentrations decrease which, in effect, will remove the drugs from their sites of action. Clinicians must be able to predict how quickly and how completely the drug will be degraded in order to know how long it will be present in the patient's body in its active form. * Drug excretion - No drug remains in the patient's body forever. It will be eliminated by a variety of mechanisms. As it is eliminated, its serum concentration will decrease and its ability to produce a beneficial pharmacologic response will correspondingly decrease. Clinicians must be able to predict how quickly the drug will be eliminated from the patient's body and when its pharmacologic actions will cease. This is especially important for drugs that are administered in multiple dosing regimens.- STEP 6 - WHAT WILL BE THE PHARMACOLOGIC RESPONSE * DETERMINANTS:* Drug pharmacodynamics - Before prescribing a specific dose and formulation of a drug, a clinician must know or be able to predict how the drug will act in the patient in order to produce the desired therapeutic response. Prescribing drugs just to see what will happen is inappropriate. A clinician must have reason to believe that a given drug will have a clearly beneficial result. This is based on knowing the selected drug's pharmacodynamics. * Time course of the drug's action - The pharmacologic response of a selected drug is predicated on its time course of action. That is, a drug, once given, will have a predictable onset of its action, a time until it has its maximal action, and then a gradually weaning effect until that one dose is eliminated. Unless a second dose of the drug is taken, all pharmacologic effect will end. This timing of the magnitude of the drug's pharmacologic effects must be known in order for the clinician to prescribe any and all subsequent doses.- STEP 7 - WHAT WILL BE THE ULTIMATE DRUG RESPONSE * DETERMINANTS:* Therapeutic response of the drug - Medications, in order to be legally and ethically prescribed, must be expected to have a greater chance of producing a beneficial response in the patient than a harmful response. Clinicians prescribe medications in good faith that this will be the result. Beneficial and therapeutic responses, however, are not the only responses that can result. * Unintended response of the drug - All drugs have the potential to produce harmful responses in the patient. While efforts should be made to eliminate or, at least, minimize these, they cannot always be totally prevented. The ultimate response of any drug, therefore, will be a combination of the both therapeutic and the unintended responses of a drug.Time Course of Drug ActionDEFINITION - The time course of a drug's action is defined as the relationship between the efficacy of an individual drug dose(s) and the time that elapses following its administration. The time course of drug action is actually a composite of pharmacodynamic and pharmacokinetic principles and reveals the relationship between the absorption and distribution of a drug, its ability to interact with its targets (receptors or extracellular components) governed by the modified theory of drug-receptor interaction, and then to finally undergo either metabolism or excretion or both until the drug molecules are completely cleared from the body. Each of these stages in the natural life of a drug are timed events that relate to the time of the drug's administration and that must be considered in the selection of a rational pharmacotherapeutic plan.The various stages of the time course of drug action are defined as follows:1. ONSET OF DRUG ACTION - The time it takes, after a drug is administered, to reach an effective serum (or tissue) concentration that is capable of producing a minimal clinical response. 2. TIME TO PEAK EFFECT - The time it takes, after a drug is administered, to reach a serum (or tissue) concentration capable of producing its maximal clinical response. 3. DURATION OF ACTION - The total time that a drug is present in the serum (or tissues) for it to produce any clinical effects (minimal or maximal). 4. DRUG HALF-LIFE - The time it takes following a drug's administration for it to reach a serum concentration equal to one half of what it was at its peak.Definition of Drug-Drug InteractionA measurable modification of the magnitude or the duration of action of one drug (the index drug) caused by the prior administration, concurrent administration, or the withdrawal of another drug. In terms of overall effects, drug-drug interactions can be classified in two ways: potentiative vs. inhibitory and pharmacodynamic vs. pharmacokinetic. Both types can be further classified as either beneficial or harmful.POTENTIATIVE (Drug-Drug Interaction)If the drug-drug interaction results in an increase in the response (or clinical effects) of one or both drugs, it is referred to as a potentiative or synergistic response or a summation effect. This type of interaction may be beneficial or it may be harmful. If beneficial, it may be intentionally utilized in a pharmacotherapeutic plan. BENEFICIAL POTENTIATIVE DRUG-DRUG INTERACTION: * EXAMPLE 1: Both aspirin and codeine are analgesic drugs. When they are administered concurrently, the combination of the two provides better pain relief than either one alone. * EXAMPLE 2: The use of a beta blocker drug and a diuretic together for hypertension will potentiate each others effects and provide better control of hypertension HARMFUL POTENTIATIVE DRUG-DRUG INTERACTION: * EXAMPLE 1: The use of diazepam (Valium) together with morphine (both CNS depressant drugs) will have additive CNS depression and could lead to respiratory arrest * EXAMPLE 2: The concurrent use of aspirin together with coumadin (both anticoagulant drugs) will significantly increase each others inhibitory effects on blood coagulation, resulting in an increased risk for bleedingINHIBITORY (Drug-Drug Interaction)If the drug-drug interaction results in a decrease in the response (or clinical effects) of one or both drugs, it is referred to as an inhibitory or antagonistic interaction. This definition includes an interaction between two or more drugs that occurs outside the patient (usually in I.V. bottles) in which a chemical reaction takes place inactivating one or all of the involved drugs, frequently producing a precipitate within the I.V. bottle. These types of drug-drug interaction also may be beneficial or harmful to the patient. If beneficial, it may be deliberately utilized in a pharmacotherapeutic plan. BENEFICIAL INHIBITORY DRUG-DRUG INTERACTION: * EXAMPLE 1: An overdose of meperidine (Demerol) may cause severe respiratory depression. The concurrent use of the antagonist drug naloxone (Narcan) can beneficially inhibit or reverse Demerol's effect on the respiratory system. * EXAMPLE 2: The excessive bleeding associated with an overdose of heparin can be stopped by concurrently giving the antagonist drug protamine. HARMFUL INHIBITORY DRUG-DRUG INTERACTION: * EXAMPLE 1: Administering naloxone (Narcan) to a patient who is physically dependent to morphine will reverse morphine's effect, provoking an acute withdrawal syndrome. * EXAMPLE 2: Administering loperamide (Imodium), an antidiarrheal drug concurrently with Milk of Magnesia, a drug used for treatment of constipation, will result in a "cancellation" of each others action, producing no appreciable benefit for the patient either way. * EXAMPLE 3: Injecting NPH insulin into a bottle of regular insulin; a precipitate (i.e., cloudy suspension) results and the regular insulin may be inactivated.PHARMACODYNAMIC Drug-Drug InteractionDefinition - A drug-drug interaction that occurs when the pharmacodynamics of one drug (the index drug) influences the action of a second concurrently administered drug. In this type of interaction, the drugs influence each other by either enhancing or interfering with the mechanisms by which they produce their pharmacologic effects. As with any drug-drug interaction, these types of interactions can be either beneficial or harmful. If beneficial, they can be intentionally included in a rational pharmacotherapeutic plan. The interactions produced by pharmacodynamic interaction can also be either potentiative or inhibitory.POTENTIATIVE PHARMACODYNAMIC DRUG-DRUG INTERACTIONS1. The concurrent administration of two similar agonist drugs (i.e., two drugs that interact with the same receptor) BENEFICIAL * EXAMPLE: Concurrent administration of a long-acting Beta 2 agonist bronchodilator for asthma as prophylaxis together with an additional short-acting Beta 2 agonist used for acute intervening bronchospasm. This combination provides better long-term control of bronchospasm in asthmatics. [Note: Both of these drugs interact with the same receptor.] HARMFUL * EXAMPLE: Administration of the Beta blocker atenolol (Tenormin) for control of hypertension concurrently with the beta blocker propranolol (Inderal) for treatment of migraine headache. This combination can produce excessive blockade of Beta 1 receptors causing excessive slowing of heart rate and/or hypotension. [Note: Both of these drugs have the same pharmacodynamics; they both act by blocking the same receptor.] 2. Simultaneous administration of two (or more) drugs that interact with separate receptors but which have the same general physiologic effect. BENEFICIAL * EXAMPLE: Administration of Beta 2 agonist bronchodilators concurrently with inhalational steroids for better control of asthma. [Note: Both of these drugs produce improvement in pulmonary function by decreasing the resistance to air flow in the lung but by two totally different pharmacodynamic mechanisms.] HARMFUL * EXAMPLE: Administration of digoxin concurrently with propranolol (Inderal); both can decrease heart rate and the combination can produce severe bradycardia. [Note: Both of these drugs decrease heart rate but by two totally different pharmacodynamic mechanisms.]INHIBITORY PHARMACODYNAMIC DRUG-DRUG INTERACTIONS1. The concurrent administration of an agonist drug together with an antagonist drug which interacts with the same receptor BENEFICIAL * EXAMPLE: Administering naloxone (Narcan), an opiate receptor antagonist to treat respiratory suppression caused by an overdose of meperidine (Demerol), an opiate receptor agonist. [Note: Both of these drugs compete with each other for occupancy of the same opiate receptor. The antagonist Narcan can actually "push" the agonist Demerol off of the receptor.] HARMFUL * EXAMPLE: Having an asthma patient's bronchospasm well-controlled with a Beta 2 agonist (i.e., albuterol [Ventolin]) and then administering propranolol (Inderal), a beta 2 antagonist, for a migraine headache. [Note: The propranolol would compete with the albuterol for occupancy of the Beta 2 receptor and reduce albuterol's therapeutic efficacy.] 2. The concurrent administration of two drugs that interact with different receptors but have opposite pharmacologic responses on a tissue or organ BENEFICIAL * EXAMPLE: Administration of diphenoxylate (Lomotil), an opiate antidiarrheal drug to treat diarrhea caused by the administration of ampicillin. [Note: Each of these drugs produces its effects (both therapeutic and adverse) at different anatomic sites in the body; their opposite clinical effects on the bowel can return bowel function to normal in patient's requiring ampicillin therapy.] HARMFUL * EXAMPLE: Concurrent administration of flurazepam (Dalmane), a CNS depressant, for sleep together with theophylline, a CNS stimulant and bronchodilator, for a respiratory condition. [Note: Although these drugs act at two different receptors and have two different pharmacodynamic mechanisms, they have opposite clinical effects on the patient and may cancel each other's effects.]-PHARMACOKINETIC Drug-Drug InteractionsDefinition - A type of drug-drug interaction that occurs when the pharmacokinetics (i.e., absorption, distribution, metabolism, or excretion) of one drug (the index drug ) alters the clinical effects (responses) of another drug or drugs by altering its pharmacokinetics. In contrast to pharmacodynamic drug-drug interactions, pharmacokinetic drug-drug interactions occur between drugs as they are being processed by the body. Each of the components of pharmacokinetics can be examined separately to understand these principles. Just as with pharmacodynamic drug-drug interactions, these interactions can be potentiative or inhibitory and beneficial or harmful.ABSORPTION1. Alteration of Gastric pH - Drugs which alter gastric pH will change the rate of dissolution of other orally administered solid medications, change the degree of ionization of weakly acidic or weakly basic drug molecules, change the water/fat solubility of drug molecules, and either enhance or inhibit absorption across intestinal absorptive surfaces. (Example: antacids, H2 receptor blockers) 2. Alteration of Gastric Emptying Time - Drugs which alter the rate of gastric emptying time (either speed it or slow it down) will alter the rate of absorption of other drugs depending on whether they are absorbed in the stomach or in the small intestine.(Example: metoclopramide [Reglan]) 3. Alteration of Gastrointestinal Motility - Drugs which alter the speed of GI peristalsis (either speed it or slow it down) will change the absorptive patterns of other orally administered drugs. By speeding the rate of transit through the GI tract, the time that other drugs are in contact with the intestinal absorptive surface will be decreased and there may be a decrease in the amount of absorption of the other drugs.(Example: metoclopramide [Reglan], cholinergic agents) 4. Production of Emesis - Drugs which provoke nausea and vomiting can decrease the time that other drugs, taken concurrently, stay in contact with absorptive surfaces and, consequently, decrease their absorption. (Example: Syrup of Ipecac, many drugs) 5. Presence of "Interfering" Substances in the Gastrointestinal Tract - Drugs which are classified as resins or as absorbant drugs have the ability to physically bind to other drugs in the lumen of the GI tract and prevent the absorption of the bound drug.(Example: cholestyramine [Questran], antacids)DISTRIBUTION1. Competition for Protein Binding Sites - Drugs (i.e. highly protein-bound drugs) which compete with each other for the limited number of albumin binding sites have the ability to "knock" each other off of albumin, thereby increasing the free drug serum levels of each other. This will have the effect of increasing the pharmacologic activity of all drugs involved whose free drug serum levels have increased. (Example: benzodiazepines, oral hypoglycemics, Beta blockers, NSAIDs, coumadin, and many others) 2. Alteration of Extracellular pH - Drugs which have the ability to alter the pH of extracellular fluids will alter the degree of ionization (and the water/fat solubility) of other drugs and affect their movements across cell membranes and between body compartments. In other words, affect their distribution around the body. (Example: sodium bicarbonate)METABOLISM1. Hepatic Enzyme Induction - Drugs which can increase the rate of synthesis of hepatic drug-metabolizing enzymes will have the effect of enhancing their own metabolism as well as any other drugs that are metabolized by the same enzyme system. This will have the effect of provoking faster clearance of all affected drugs from the body, reducing their clinical effects. (Examples: cigarettes, barbiturates, phenytoin, rifampin, chronic ethanol ingestion). Hepatic enzyme inducers take about three weeks before their effect is noted (it takes that long to synthesize new enzymes). 2. Hepatic Enzyme Reduction - Drugs which inhibit existing drug-metabolizing enzymes or inhibit the synthesis of these enzymes will have the effect of decreasing the rate at which they and any other drugs that utilize the same enzymes are metabolized, resulting in an increase in their clinical effects. (Examples: cimetidine [Tagamet], oral contraceptives, sulfonamides, phenothiazines, erythromycin, some antifungals, acute ethanol ingestion). Hepatic enzyme inhibitors generally have an immediate effect as opposed to hepatic enzyme inducers (see above). 3. Herbs may also induce or inhibit hepatic enzymes that metabolize drugs. For example, Hypericum perforatum (St. John's wort) is a strong inducer of CYP450 enzymes and when taken with warfarin, digoxin or amitriptyline may decrease therapeutic drug levels of these medications.EXCRETION1. Increased Renal Blood Flow - Drugs which can increase renal blood flow will enhance the glomerular filtration rate and increase the excretion of themselves and any drugs excreted by this pathway. This will result in a decrease in this drug's clinical effects. (Example: digoxin, vasodilators) 2. Competition For Renal Tubule Excretion Ports - Drugs excreted by renal tubular excretion utilize excretion transporter channels for their entry into the lumen of the nephron. Because there are a limited number of these transporter channels, drugs using them must compete with each other for access to them. Access is directly proportional to the concentration of the drug in the serum. Drugs which are present in higher concentration may inhibit excretion of drugs present in lower concentration, resulting in an increase in their clinical effects. (Example: many drugs) 3. Alteration of the pH of the Urine - As with the gastric pH, drugs which alter the pH of the urine will affect the degree of ionization (and the water/fat solubility) of other drugs present in the urine. Drugs which are highly ionized (and water soluble) at a given urinary pH will remain in the water of the urine and will be more readily excreted, increasing their excretion and decreasing their clinical effects. Drugs which are less ionized (and more fat soluble) at a given urinary pH will be more likely to be reabsorbed from the urine back into the blood in the distal renal tubule, decreasing their excretion and increasing their clinical effects. * (Example: URINE ALKALINIZERS - sodium bicarbonate, antacids, certain diuretics) * (Example: URINE ACIDIFIERS - ammonium chloride, any drug causing metabolic acidosis) 4. Alteration of the Formation (and the Flow) of the Urine - Drugs which increase the production, the volume, and the flow rate of urine through the nephron will affect the ability of the distal renal tubule to reabsorb any drugs back into the blood. High urinary flow rates will increase the excretion of drugs by the kidney, decreasing their clinical effects. (Example: diuretics)Interactions Between Drugs and FoodThere are many ways in which the interaction between the consumption of food and certain medications are manifested. These manifestations go both ways; food can affect the pharmacology of drugs and drugs can affect the consumption of food. These mechanisms are as follows: - Drug Alteration of Food Palatability and Appetite - Many drugs have the effect of altering the taste of food. Others have the ability to directly inhibit the appetite centers in the brain and are used for weight control. Some drugs have the ability to stimulate the appetite centers and are used as appetite enhancers. - Drug-Induced Nausea and Vomiting - Many drugs indirectly affect appetite and food consumption by inducing nausea. This generally has an inhibitory effect on food intake. - Food Inhibition of Drug Absorption - Many drugs, if taken with meals, are inhibited from being absorbed at the same rate as they would be if taken on an empty stomach. Drugs are absorbed by the same intestinal absorptive surface that absorbs foodstuffs and the competition between the two can significantly alter the desired absorption of some drugs. In addition, some drugs are rendered non-absorpable by certain foods because they form and insoluble compound with certain items in the diet. Specifically, the binding of tetracycline by the polyvalent cations (Ca++, Mg++, Fe++, Al++) found in dairy products and other items significantly impairs the absorption of tetracycline antibiotics. - Food Inhibition of Drug Metabolism - (The Grapefruit Juice Effect) - Recently, grapefruit juice has been noted to have an impact on the pharmacologic actions of many drugs. Investigations have revealed that a substance found in grapefruit juice (i.e., naringenin) is a potent inhibitor of hepatic P-450 drug-metabolizing enzymes. Patients who consume large quantities of grapefruit juice will seriously affect the clearance of many drugs that are metabolized by these affected enzymes. The result will be that the affected drugs will be metabolized at a slower than normal rate, resulting in higher than expected serum drug levels and greater activity pharmacologically.Methamphetamine binds to and activates norepinephrine receptors. How is this pharmacodynamic action classified? Select one: a. partial agonist b. agonist c. antagonist d. none of the aboveb. agonistMethamphetamine is a weak base. If the patient is administered an acid, such as ammonium chloride, what effect will this have on the elimination of methamphetamine? Select one or more: a. the weak base will be excreted slower in acidic urine b. less of the drug will be reabsorbed from the renal tubule c. the basic drug will become more ionized in the acidic urine d. it will enhance drug metabolism by the liverb. less of the drug will be reabsorbed from the renal tubule c. the basic drug will become more ionized in the acidic urineHow would the pharmacokinetic interaction of methamphetamine and ammonium chloride be classified in this example of treating a drug overdose? Select one: a. harmful inhibitory b. harmful potentiative c. beneficial potentiative d. beneficial inhibitoryd. beneficial inhibitory the patient benefits from the trapping of methamphetamine in the acidified urine, speeding up the excretion of the drugBLOOD PRESSUREThe basic formula for the determination of blood pressure is: Blood Pressure = Cardiac Output x Total Peripheral Resistance o Since Blood pressure is determined by the product of cardiac output (C.O.) and total peripheral resistance (T.P.R.), it stands to reason that alterations in either or both of these will affect blood pressure. In other words, an increase in either one or both of these will increase blood pressure and, conversely, a decrease in either will produce a decrease in blood pressure. o Of the two factors, T.P.R. is far more responsible for blood pressure than is cardiac output. In other words, alterations in T.P.R. produce much more dramatic changes in blood pressure than will alterations in cardiac output.CARDIAC OUTPUTThe basic formula for the determination of cardiac output is: Cardiac Output = Heart Rate x (Ventricular)Stroke Volume o Since cardiac output (C.O.) is determined by the product of heart rate (H.R.) and Stroke Volume (S.V.), it stands to reason that any alteration of one or both of these factors will affect cardiac output and, consequently, blood pressure. In other words, an increase in heart rate (up to a point) and/or an increase in ventricular stroke volume will result in an increase of cardiac output and blood pressure. [Note: Excessively fast heart rate will actually result in a decrease in cardiac output because the heart rate is too fast to allow the ventricle to fill with blood.] [Note: Stroke Volume refers to the number of cc's of blood ejected by the ventricle with each systole.] By combining these two definitions, a new formula for blood pressure is recognized. It is: Blood Pressure = Heart Rate x Stroke Volume x Total Peripheral Resistance Or B.P. = H.R. x S.V. x T.P.R.physiologic determinants of HEART RATECirculating Catecholamines (especially norepinephrine, epinephrine, and dopamine) o Serum Calcium Ion Concentration o The Neurotransmitters of the Autonomic Nervous System (especially norepinephrine and epinephrine)physiologic determinants of STROKE VOLUMEMyocardial Contractility (the muscular force with which the ventricle contracts) o Ventricular Preload (the force exerted on the ventricular wall by the contained volume of blood inside)[Note: Ventricular preload is proportional to end-diastolic ventricular volume or the amount of blood contained inside the ventricle at the end of ventricular diastole.] o Ventricular Afterload (the force that the ventricle must contract against) [Note: In the case of the left ventricle, left ventricular afterload is proportional to systemic arterial blood pressure.] o Blood Volume (this refers to the total circulating blood volume) o Venous Tone (this refers to degree of contraction of the venous smooth muscles and the diameter of the venous vasculature which is proportional to the amount of blood volume "temporarily held" in the venous side of the circulation). o Serum Calcium Ions (this relates directly to the force of muscular contraction in both cardiac muscle and vascular smooth muscle). o Serum Catecholamines o Neurotransmitters o Renal Function (as it relates to total circulating blood volume).physiologic determinants of TOTAL PERIPHERAL RESISTANCEArteriolar Smooth Muscle Tone (this relates to the degree of contraction of smooth muscles in the wall of arterioles and the diameter of these vessels which is proportional to the amount of resistance created by the peripheral arteries to the flow of blood out of the left ventricle). o Blood Viscosity (this relates to the thickness of blood which, in turn, is proportional to hematocrit and to some extent to the amount of solutes (fat and protein) contained in the blood). o Arterial Elasticity (the amount of stretch allowed within the walls of the major arteries and aorta to the sudden ejection of blood by the left ventricle). o NeurotransmittersAUTONOMIC RECEPTORSThe autonomic receptors can be divided into sympathetic (or adrenergic) receptors and parasympathetic (or cholinergic) receptors. While the cholinergic receptors play a role in heart rate (muscarinic type of cholinergic receptors activated by the vagus nerve), the main autonomic receptors affecting the cardiovascular system are the adrenergic receptors that extensively affect the heart and the arterial and venous vasculature. The adrenergic receptors are further divided into alpha 1, alpha 2, beta 1 and beta 2 receptors. There are three main concepts relating to these receptors that will assist in understanding the pharmacodynamics of the cardiovascular drugs. These are (1) their activation, (2) their function, and (3) their location. * Activation - These receptors are activated by both the naturally occurring catecholamines and neurotransmitters and the agonist drugs of these naturally occurring substances. Adrenergic agonist drugs can activate them and adrenergic antagonist drugs can block them. * Function - As a general rule, if the receptor has a subscript of 1, when it is activated, the target cell upon which it is located will be stimulated (e.g., if a muscle cell, the muscle cell will contract; if a nerve cell, its firing will increase). If, on the other hand, the receptor has a subscript of 2, when activated, the target cell where it is located will experience a decrease in its function (e.g., if it is a muscle cell, it will relax; if a nerve cell, its firing will become less frequent). * Location - 1. Alpha 1 - located (1) on the vascular smooth muscle cells of the walls of arteries that supply blood to the skin, mucous membranes, kidney and intestinal tract, (2) on the smooth muscle cells of the walls of veins, and (3) on the radial muscles of the iris of the eye (i.e., the muscles that are responsible for pupillary dilation). 2. Alpha 2 - located on the nerve cells of the cardiovascular control center in the brain stem. 3. Beta 1 - located (1) on the myocardial muscle cells and the cardiac conduction system cells in the heart, (2) on neurons in the brain, and (3) on the intraocular fluid producing cells inside the eye. 4. Beta 2 - located (1) on the bronchial smooth muscle cells that line the bronchus and bronchioles, (2) on the smooth muscle cells in the walls of the arteries that supply blood to the skeletal muscles, and (3) on liver cells associated with the enzyme systems responsible for glycogen systhesis. [Note: Activation of these receptors results in decreased entry of glucose into the liver and more glucose in the blood.]CLINICAL CONSEQUENCES OF ADRENERGIC RECEPTOR ACTIVATIONALPHA RECEPTORS Interaction and activation of alpha 1 receptors either by endogenous hormones or adrenergic drugs results in contraction of vascular smooth muscles primarily in arterial beds but also, to some extent, in venous beds. This, in turn, results in vasoconstriction, increased peripheral resistance, increased blood pressure, and if high enough, decreased cardiac output. If venous smooth muscles are sufficiently activated to contract, venous vasoconstriction occurs which increases venous return to the heart, increased ventricular preload and ventricular filling pressures, increased ventricular volume, increased stroke volume, and possibly increased cardiac output. If ventricular preload increases too much, however, excess strain is placed on the wall of the left ventricle and heart failure ensues with decreased stroke volume and decreased cardiac output. An additional consequence of alpha 1 activation is contraction of the radial muscles of the iris resulting in pupillary dilatation. Blocking alpha 1 receptors with adrenergic antagonist drugs prevents the body's endogenous hormones from maintaining normal tone in these vascular beds and the clinical consequences associated with alpha 1 activation are reversed. Interaction and activation of alpha 2 receptors by hormones or endogenous drugs results in a sharp reduction in sympathetic nervous system output to the heart and the vascular beds (arterial and venous). Reduction in sympathetic stimulation of these organs results in decreased activation of alpha 1, beta 1, and beta 2 receptors. BETA RECEPTORS Interaction and activation of beta 1 receptors results in clinical consequences primarily in the heart. Activation of the beta 1 receptors on the electrical conductive system of the heart (SA node, AV node, His-Purkinge system) results in increased firing of the heart's electrical system manifested as increased heart rate and increased impulse propagation through the system. Activation of the beta 1 receptors on the myocardial cells results in an increased force of myocardial contraction and increased stroke volume. Increases in both heart rate and stroke volume result in an increase in cardiac output. Increasing the speed of impulse propagation in the heart's electrical can result in dysrhythmias. Since beta 1 receptors are also located in the brain, activation here results in increased firing of CNS neurons and an increased level of CNS activity. Blockade of beta 1 receptors with adrenergic antagonist drugs prevents the body's endogenous hormones from maintaining tone in the heart and brain and opposite clinical consequences ensue. Interaction and activation of beta 2 receptors by endogenous hormones or adrenergic agonist drugs results in consequences in the bronchus, skeletal muscle arteries and the liver. By activating beta 2 receptors on the smooth muscle cells of the skeletal muscle arteries, vasodilatation occurs, theoretically improving blood flow to the muscles. By activation of beta 2 receptors in the bronchi, bronchial smooth muscle cells relax, resulting in bronchodilatation. By interacting and activating beta 2 receptors in the liver, the enzymes responsible for mobilization of glucose from the blood into the liver and stored as glycogen are blocked and hyperglycemia can occur. Blockade of these beta 2 receptors by adrenergic antagonist drugs will result in opposite consequences. In addition, blockade of the beta 1 receptors in the eye will result in a decrease in the production of intraocular fluid and will benefit patients with glaucoma.TREATMENT OF HYPERTENSIONThe treatment of essential hypertension is usually an endeavor that will continue for the remainder of the patient's life. Selection of initial therapy should be geared at controlling blood pressure with minimal side effects in order to enhance patient compliance. First-line treatment of hypertension includes 4 classes of medications: thiazide-type diuretics, calcium channel blockers (CCBs), ACEIs, and ARBs, used alone or in combination (second-line treatment). Other medications discussed in this section have indications for individuals with comorbid conditions (such as pregnancy, benign prostatic hyperplasia or myocardial infarction).List of Available Thiazide Diuretics in the Treatment of Hypertension- hydrochlorothiazide (HCTZ) (HydroDiuril) - chlorothiazide (Diuril) - chlorthalidone (Hygroton) - indapamide (Lozol) - metolazone (Zaroxolyn)Pharmacodynamics of the Thiazide DiureticsSomewhat unclear as to the precise mechanism of action, the thiazide diuretics act in the distal renal tubules to block the reabsorption of the filtered load of NaCl from the nephron back into the blood. In this way, the thiazides are said to have a natriuretic effect; they promote the renal excretion of sodium (and consequently water) from the body. [Note: Where sodium goes - so goes the water.] By reducing the amount of water in the body, the amount of water in the blood (i.e., blood volume) is also reduced. This results in decreased stroke volume and decreased cardiac output. The overall result of a reduction in blood volume, stroke volume, and cardiac output is that blood pressure is reduced.Pharmacokinetics of the Thiazide DiureticsThe thiazides are administered orally and are well absorbed by this route. Many of the thiazides are not metabolized and are excreted primarily by the kidney by way of the organic acid secretory ports of the renal tubule, competing with the body's normal organic acid waste products. They are water-soluble drugs. Some of the thiazides are metabolized by the liver and their metabolites are also excreted in the urine.Advantages of Using Thiazide Diuretics in the Treatment of Hypertension- Administered orally; this is an advantage in any pharmacotherapeutic plan that will be long-term, as is the case with hypertension. - Once daily or BID dosing regimen; this is very important in the long-term management of any condition. The fewer times a day a patient is required to take medication, the more likely he is to be compliant. - Inexpensive; again, very important in any long-term therapy plan, especially one that is likely to be for a lifetime. - Significant reduction in blood volume; reduction of blood volume is the main mechanism by which thiazides reduce blood pressure. Although the reduction in pressure is limited to a certain extent, they will still deplete the blood volume considerably. - Very effective in African-Americans; although anyone can be treated with diuretics, African-Americans commonly have a "salt-sensitive" type of hypertension which responds particularly well to a diuretic-induced reduction in sodium, water, and blood volume. - Can be used together with other antihypertensive drugs in a pharmacodynamic, potentiative drug-drug interaction for enhanced blood pressure control.Disadvantages of Using Thiazide Diuretics in the Treatment of HypertensionCommonly causes electrolyte depletion, especially hypokalemia, hyponatremia, and hypochloremia. [Note: Any natriuretic drug produces a large sodium ion load delivered to the distal collecting tubule; here the renal cells attempt to reabsorb the large number of sodium ions by exchanging them for potassium which decreases the potassium levels in the body.] - May cause hypotension (and/or orthostatic hypotension) and hypovolemia; this is seen predominantly in patients who are already dehydrated for other reasons and especially in older adults who normally already have a contracted blood volume. - Have a limited efficacy in lowering blood pressure because as blood volume is decreased, the kidney activates its compensatory mechanism of blood pressure / volume protection and triggers the renin-angiotensin-aldosterone mechanism which then begins to ameliorate the loss of volume and pressure. - May produce increases in serum cholesterol, LDL cholesterol, and triglycerides; the mechanism for this is unknown and may worsen serum levels of these compounds in patients who are already hyperlipidemic - May increase serum glucose and cause hyperglycemia; thiazides impair the release of insulin by the pancreas and inhibit tissue utilization of insulin. Usually not a problem in most patients, thiazides may, however, cause serious problems with glucose regulation in diabetics. - May cause an increase in serum uric acid: uric acid (an organic acid) and thiazides compete for the same excretion port in the renal tubule and the excretion of uric acid is slowed. This may not be a problem for most patients but may precipitate an attack of gout in patients prone to this condition. - May cause a cross-sensitivity reaction (rash and photosensitivity) with the sulfonamide antibiotics; the thiazides have a sulfur atom just like the sulfonamide antibiotics and the immune system frequently confuses them. - Some patients experience bone marrow suppression - May cause rare instances of anorexia, nausea, and vomiting - Impotence may be a problem by virtue of a general lowering of blood pressure and not because of a direct effect of the thiazide drugList of Available Loop Diuretics in the Treatment of Hypertension- furosemide (Lasix) - bumetanide (Bumex) - ethacrynic acid (Edecrin) - torsemide (Demedex)Pharmacodynamics of the Loop DiureticsThe loop diuretics exert their effects in the loop of Henle of the renal nephron. There they block the reabsorption of NaCl back into the blood. Because this is the site in the nephron where most of the NaCl is reabsorbed, loop diuretics produce a significant natriuretic (salt-losing) and diuretic (water-losing) effect. This results in marked reduction in blood volume and contributes to a reduction in blood pressure. In addition, loop diuretics increase renal blood flow (and therefore GFR) by reducing renal vascular resistance. Therefore, they have a dual mechanism of action.Pharmacokinetics of the Loop DiureticsLoop diuretics for use in the management of hypertension are usually administered orally but can also be administered I.V. when needed for acute reduction of blood pressure. They are water soluble and highly protein-bound. They undergo some hepatic metabolism and are excreted in the urine both as parent drug and as metabolite.Advantages of Using the Loop Diuretics for Hypertension- Administered orally and (if necessary) I.V.; the oral route is a distinct advantage in the therapy of long-term conditions like hypertension. - Inexpensive; this is important for compliance in therapeutic plans that require long-term therapy on a daily basis. - Administered in a once daily or BID dosing regimen; ensures better compliance when long-term therapy is required. - More potent diuretic effect than the thiazides; this may be important in the therapy of hypertensive patients with some degree of renal insufficiency and when there is some urgency in reducing blood pressure. - Have a very rapid onset of action; this is not as important in the therapy of hypertension as it may be in patients with a combination of hypertension and pulmonary edema, acute congestive heart failure, etc. whose therapy may require some urgency.Disadvantages of Using the Loop Diuretics for HypertensionMore potent than the thiazides; although this is usually considered an advantage, it also has to be considered a disadvantage because the increased potency may mean that the adverse effects are more likely and may be more severe. - Electrolyte depletion; hypokalemia and hypomagnesemia are the most likely electrolyte abnormalities and are dose related. Loop diuretics cause a greater loss of calcium compared to the thiazides. - Dehydration and hypotension; results from excessive use of loop diuretics and is more likely in patients who already have a contracted blood volume for other reasons (like older adults). - Have limited antihypertensive effects; as with the thiazides, blood volume reduction will activate the renin-angiotensin-aldosterone system, which will ameliorate volume depletion and lessen the effect of volume reduction on blood pressure. - Ototoxicity; this may not be a problem for the average patient but may worsen the hearing of a patient who already has limited hearing or in patients who are on other ototoxic drugs. - Bone marrow suppression; may require frequent checks of the blood count which adds to the cost of therapy. - Cross-sensitivity (rash and photosensitivity) with the other sulfur-containing drugs like the sulfonamide antibiotics because of misdirection in a patient's immune system. - Have a limited duration of action (about 6 hours) requiring frequent dosing and rendering them relatively unsuitable for chronic management of hypertension.List of Available Potassium-Sparing Diureticsspironolactone (Aldactone) eplerenone (Inspra) amiloride (Midamor) triamterene (Dyrenium)Common combinations with the thiazides:spironolactone + HCTZ (Aldactazide) amiloride + HCTZ triamterene + HCTZ (Maxzide) (Dyazide)Pharmacodynamics of the Potassium-Sparing DiureticsSpironolactone and eplerenone are specific aldosterone receptor antagonists; they block the interaction of aldosterone with its receptor in the distal renal tubule and prevent the excretion of potassium in exchange for sodium. The end result is a natriuretic effect in which sodium ions remain in the urine and are excreted together with a large amount of water. In addition, potassium ions that should have been excreted remain in the blood leading to possible hyperkalemia. Amiloride and triamterene are not specific antagonists of the aldosterone receptors. Instead, they block sodium reabsorption channels that are linked with potassium excretion channels. The end result is, however, the same; sodium and water are excreted and potassium is retained.Pharmacokinetics of the Potassium-Sparing DiureticsThe potassium-sparing diuretics are all administered orally. Spironolactone is a prodrug, requiring hepatic metabolism. Eplerenone has a shorter half-life than its predecessor spironolactone. Triamterene is partially metabolized in the liver but amiloride is not metabolized at all. All are excreted in the urine.Advantages of Using the Potassium-Sparing Diuretics for Hypertension- Administered orally; an advantage in the chronic therapy required for treatment of hypertension. - Once a day or BID dosing; an advantage for better compliance for daily, long term hypertensive therapy. - Offsets the potential for hypokalemia seen with the thiazides and the loops; the most common use of the potassium-sparing diuretics is in combination with the thiazides for the intentional inhibitory, pharmacodynamic drug-drug interaction they produce with each other with regard to the serum potassium levels. - Reduction of blood volume,; a successful mechanism for the reduction of blood pressure. - Less potent than other diuretics; may be a disadvantage but limited potency will also limit the severity and the frequency of adverse effects.Disadvantages of Using the Potassium-Sparing Diuretics for HypertensionLimited antihypertensive efficacy; as with other diuretics, blood volume reduction (and blood pressure reduction) will be ameliorated by the activation of the renin-angiotensin-aldosterone mechanism. - Potential for hyperkalemia; the retention of potassium caused by these drugs will cause dangerous hyperkalemia in some patients. These drugs will require extreme precaution in patients with renal insufficiency because they cannot excrete potassium as efficiently as patients with normal renal function. - Spironolactone has anti-androgenic effects and may cause gynecomastia. Eplerenone is less likely to do so. - More expensive than the thiazides and the loop diuretics; can lead to noncompliance in patients with limited financial resources. - May cause bone marrow suppression (thrombocytopenia, agranulocytosis); may require frequents checks of the blood count, increasing the cost of therapy. - Add disadvantages of the thiazides when the two are used as combination products.List of Available Centrally-Acting Alpha 2 Adrenergic Agonistsalpha - methyldopa clonidine (Catapres) guanfacine (Tenex)Pharmacodynamics of Centrally-Acting Alpha 2 Adrenergic AgonistsCentrally-acting alpha 2 adrenergic agonists interact with alpha 2 receptors in the cardiovascular control center in the brain stem. In doing so they inhibit the discharge of the sympathetic nervous system and reduce sympathetic activation of the heart and the peripheral vascular system (both arteries and veins). The end results on the heart are decrease of myocardial contractility and heart rate and reduction in cardiac output and blood pressure. The end results on the peripheral vascular system are vasodilatation of peripheral arteries and veins. Arterial vasodilatation results in decrease in peripheral arterial resistance and blood pressure. Peripheral venous vasodilatation results in peripheral venous blood pooling and reduction in venous return. This, in turn, results in decreased cardiac output and decreased blood pressure.Pharmacokinetics of Centrally-Acting Alpha 2 Adrenergic AgonistsAlpha-methyldopa is usually administered orally but can be given I.V. It is a prodrug and requires hepatic metabolism for activation to its pharmacologically active form. It is excreted in the urine. Clonidine and the others are not prodrugs, are administered orally, and are metabolized in the liver and excreted in the urine. Clonidine is also available in a transdermal formulation.Advantages of Centrally-Acting Alpha 2 Adrenergic Agonists for HypertensionAdministered orally; an advantage in the long-term therapy required for hypertension. Clonidine can be administered transdermally; an additional advantage and a promoter of better compliance. - Administered once daily or BID; This frequency of dosing is a strong promoter of better compliance. - Clonidine, especially in its transdermal formulation, is also used for the vasomotor symptoms of the post-menopausal syndrome; it is always an advantage to be able to use one drug to treat more than one condition at a time. - Clonidine reduces the tendency for reflex tachycardia that is caused by other agents used for hypertension management. - Alpha-methyldopa can be safely used in pregnant women to control hypertension.Disadvantages of Centrally-Acting Alpha 2 Adrenergic Agonists for HypertensionCommonly causes CNS sedation and dizziness upon initiation of therapy; they inhibit some of the functions of other neurologic pathways leading to generalized reduction of CNS activity. This would not be a good choice for therapy in patients who must remain awake and alert during the day. Taking the medication at night however may be an option. Tolerance to the sedation develops in many patients with continued use. - May cause orthostatic hypotension; by blocking the normal vasoconstriction mediated by the sympathetic nervous system on peripheral veins, sudden change of body position to a standing posture results in a lack of the reflex sympathetic venous vasoconstriction that normally protects the blood pressure. This may be an additive disadvantage if the drug is used concurrently with other drugs that also have this problem (i.e, diuretics) or in patients who are prone to this condition (i.e, older adults). - Commonly causes impotence and decreased libido beyond what is caused simply by a reduction in blood pressure. These drugs directly interfere with the blood supply to the penis. This would not be a good drug to begin therapy within a sexually active male. - Associated with a rebound hypertension upon too rapid reduction in dose or discontinuation of the drug. Patients on long-term therapy with this drug require gradual reduction in dose (usually over 2-3 weeks) if the drug must be discontinued. - Can cause bradycardia, especially in older adults. Bradycardia in these patients can provoke severe decreases in cardiac output. - Some patients on clonidine experience dry mouth. - Special disadvantages of alpha-methyldopa (Aldomet): 1. Drug-associated hepatitis (requiring discontinuation of the drug) 2. Bone marrow suppression 3. Delayed onset of action because of its required hepatic activationList of Available Selective Alpha 1 Blockersprazosin (Minipress) doxazosin (Cardura) terazosinPharmacodynamics of the Selective Alpha 1 Adrenergic BlockersSelective alpha 1 blockers are direct antagonists on alpha 1 receptors located on the smooth muscle cells making up the walls of the peripheral arterioles and peripheral veins. In doing so, the normal vasoconstrictive effects of the sympathetic nervous system are blocked and peripheral arterioles and veins become vasodilated. This results in decreased peripheral resistance of the arterial system and decreased venous return from the venous system. Decreasing arterial resistance is the most effective mechanism of reducing blood pressure and the decreased cardiac output resulting from reduction in venous return is an additive effect. There are also alpha 1 receptors located on the smooth muscle cells of the drainage ducts of the prostate gland and in the neck of the urinary bladder. These receptors are also blocked by these drugs.Pharmacokinetics of the Selective Alpha 1 Adrenergic BlockersThese drugs are administered orally. They are metabolized in the liver and are excreted in the urine.Advantages of the Selective Alpha 1 Adrenergic Blockers for HypertensionAdministered orally; an advantage in therapy for long-term conditions like hypertension. - Administered once daily or BID; improves compliance in chronic conditions. - Has dual action for decreasing blood pressure; (decreases peripheral resistance and decreases cardiac output). Having more than one mechanism to achieve correction of the same pathophysiologic mechanism makes any drug more effective. - Can significantly reduce left ventricular afterload as a peripheral vasodilator and can be effective in the management of congestive heart failure. - Can produce a small decrease in serum total and LDL cholesterol; the mechanism for this is unknown and its significance is doubtful. - May increase the sensitivity of insulin receptors; this improves the efficacy of insulin, especially in diabetics and would be a good choice for antihypertensive therapy in diabetics. - Relaxes bladder neck spasm; this improves urinary output and drainage from the prostate in patients with benign prostatic hypertrophy (BPH). [Note: There are also alpha 1 receptors on the smooth muscle cells of the bladder neck. Blocking them results in widening of the diameter of the bladder neck at the level of the prostate.] In male hypertensive patients who also have BPH, it is a significant advantage to be able to treat two different problems with one drug.Disadvantages of the Selective Alpha 1 Adrenergic Blockers for Hypertension- Commonly causes orthostatic hypotension; this is caused by the blockade of the normal sympathetically-induced vasoconstriction that normally occurs with assuming the upright posture. Orthostatic hypotensive symptoms are particularly dangerous in older adults and are more likely to occur with the initial dose of drug; they may dissipate with continued use. - May produce reflex tachycardia; this is a direct result of orthostatic hypotensive effects which activate a "protective" increase in heart rate to maintain cardiac output. - Commonly produces impotence in male hypertensive patients; drugs which disturb the balance of sympathetic receptors frequently produce impotence by disturbing the delicate balance of blood flow to the penis. These drugs may not be good choices for antihypertensive therapy in sexually active males. - May cause weakness, dizziness and nausea; probably related to disturbances of blood flow to critical areas of the brain. These symptoms are possibly related to orthostatic hypotension. - May cause headache; also related to disturbances to blood flow to the brain. - Commonly produces nasal stuffiness; by blocking alpha 1 receptors in the vascular smooth muscles of the arterioles of the nasal mucosa, there is a vasodilatation of nasal arterioles and capillaries, promoting leakage of fluid into the interstitial spaces of the nasal mucosa which swells and blocks nasal passages.List of Available Adrenergic Neuron BlockersreserpinePharmacodynamics of Adrenergic Neuron BlockersThese drugs lower blood pressure by either directly preventing the release of norepinephrine from sympathetic nerve endings or by depleting the nerve endings of stored norepinephrine and therefore, indirectly preventing its release. Reserpine depletes norepinephrine stores from adrenergic nerve endings. By interfering with the actions of norepinephrine, the normal blood pressure elevating mechanisms that are mediated by norepinephrine and the sympathetic nervous system are prevented.Pharmacokinetics of Adrenergic Neuron BlockersAdrenergic neuron blockers are administered orally; they are metabolized in the liver and are excreted in the urine.Advantages of Adrenergic Neuron Blockers for Hypertension- Administered orally; an advantage when treating long-term conditions like hypertension. - Administered once a day or BID; improves compliance especially in conditions that require long-term therapeutic plans. - Inexpensive; these drugs have been around for decades and their cost is comparatively less than some of the newer agents.Disadvantages of Adrenergic Neuron Blockers for Hypertension- Have a slow onset of action; their antihypertensive effects take about 1-2 weeks to reach peak effect. - Commonly cause dizziness and sedation; depletion of norepinephrine stores from the brain interferes with other forms or neural transmission and may block other central neurological functions. - May cause fatigue and lethargy; same mechanism as above. - May cause psychological depression and suicide; same mechanism as above. Reserpine is contraindicated in patients with pre-existing psychological depression and has been linked to suicide in some of these patients. - Possible bradycardia and congestive heart failure; inhibition of the sympathetic neurotramsmitter (i.e., norepinephrine) results in decreased sympathetic stimulation of the heart and reduction in heart rate and in myocardial contractility. - Nasal stuffiness is common; blockade of the sympathetic tone in nasal mucosal blood vessels results in vasodilatation of these vessels and leakage of fluid into the interstitial spaces of the mucosa. Swelling occurs, producing nasal obstruction. - Produces some cholinergic effects (increase secretion of HCl acid, diarrhea, abdominal cramps); these drugs should be used with precaution, if at all, in patients with a history of peptic ulcer or diarrheal diseases.Beta Adrenergic Antagonists (Beta-blockers)In this category, there are 3 subcategories of medications: - Non-Selective Beta-blockers - Combination non-selective Beta-blocker and selective Alpha 1 Blockers - Selective Beta 1 BlockersList of Available Non-Selective Beta-blockers Drugs with Non-selective Beta-blocker action only:propranolol (Inderal) nadolol (Corgard) pindolol penbutalol (Levatol) timolol sotalol (Betapace)Combination Non-selective Beta-blockers and Selective Alpha 1 Blockers:labetalol (Trandate) carvedilol (Coreg)Pharmacodynamics of Non-Selective Beta-blockersThe non-selective Beta-blockers are antagonists to the adrenergic neurotransmitters (i.e., norepinephrine and epinephrine) on both the Beta 1 and Beta 2 adrenergic receptors. The Beta 1 receptors are located on: 1) the cardiac electrical system and on the myocardial muscle cells, 2) certain brain cells, 3) the ciliary body of the eye, and 4) renin-producing cells in the kidney. The Beta 2 receptors are located on 1) the vascular smooth muscle cells of the skeletal muscle arteries, 2) on the smooth muscle cells that line the bronchioles, and 3) liver cells. By blocking the Beta 1 receptors in the heart, heart rate slows and myocardial contractility decreases. Both of these actions decrease cardiac output and blood pressure. These are the main therapeutic actions of the nonselective Beta-blockers when used in the therapy of hypertension. Blockade of the other Beta 1 receptors is responsible for other pharmacologic or clinical indications, specifically glaucoma and psychological anxiety states. When used in the therapy of glaucoma, the main action of beta 1 blockade is to reduce the production of intraocular fluid from the ciliary body of the eye that decreases intraocular pressure. This is therapeutic in patients with either open-angle or closed-angle glaucoma. By blocking Beta 1 receptors in the brain, there results a generalized reduction in the activation of Beta 1-mediated CNS stimulation which is useful in the treatment of mild anxiety states such as stage fright. Blockade of Beta 2 receptors in the lungs and in the peripheral muscular arteries is not a therapeutic action of these drugs but is responsible for many of the adverse effects of these drugs (see below).Pharmacokinetics of Non-Selective Beta-blockersAll of the non-selective Beta-blockers are administered orally; some can also be administered I.V. Some are extensively metabolized in the liver; others are only minimally metabolized by hepatic enzymes. All are excreted in the urine.Advantages of Non-Selective Beta-blockers for Hypertension- Administered orally; an advantage in conditions like hypertension requiring daily long-term therapy. - Administered once-a-day or BID; minimal dosing frequency improves compliance in long-term therapy. - Some are inexpensive; especially those that have been around for a long time. If possible, use of the inexpensive agents is advantageous considering that therapy will be required on a daily basis and probably for many years. Some patients, however, do not respond as well to these inexpensive drugs and may require the more expensive products. - They prevent reflex tachycardia associated with lowering of blood pressure; by blocking Beta 1 receptors, any reflexive sympathetic stimulation of the heart to increase cardiac output triggered by a sudden lowering of blood pressure is prevented. These drugs are useful in combination with other antihypertensive drugs that have the tendency to cause reflex tachycardia. [Note: Blockade of reflex tachycardia is dangerous in diabetics because this normal reflexive reaction (along with anxiety) is the diabetic's earliest warning signal to alert him/her to hypoglycemia.] - Prevents release of renin; any renally-regulated elevation of blood pressure is mediated by the renin-angiotensin-aldosterone system. Renin release is a Beta 1 function in the kidney; blockade of this Beta 1 receptor blocks any component of hypertension caused by elevated serum levels of renin and, therefore, angiotensin II. - Reduces potential for arrhythmias; blockade of Beta 1 receptors in the heart decreases the electrical system and reduces electrical excitability and the potential for both tachycardia and tachyarrhythmias. - Non-selective Beta-blockers can also be used for angina, arrhythmia therapy, migraine headaches, and hyperthyroidism; the use of one drug for multiple simultaneous therapeutic indications is a distinct advantage in favor of better compliance. - Decreases anxiety; therapy of cardiovascular conditions is often associated with, and possibly worsened by, anxiety. Non-selective Beta-blockers ameliorate anxiety while reducing blood pressure. - Some non-selective Beta-blockers are available with intrinsic sympathomimetic activity (ISA); these drugs (pindolol, penbutolol) have the ability to both block Beta 1 receptors and, at a certain level of blockade of intrinsic activity, simultaneously stimulate them. This modifies the beta blocking effects of the drugs and lessens some of the adverse effects. Betablockers with ISA are generally safer to use in diabetics (they do not produce as much hypoglycemia), in patients with peripheral vascular disease (they do not cause as much peripheral vasoconstriction), and in patients with hyperlipidemias (they do not increase cholesterol and triglycerides as much). The ISA Beta-blockers do not cause as much bradycardia and have less of an inhibitory effect on cardiac output.Disadvantages of Non-Selective Beta-blockers for Hypertension- Potential for bradycardia and congestive heart failure; excessive blockade of Beta 1 receptors will slow heart rate too much and decrease the force of myocardial contractility to the point of markedly reduced cardiac output. This is more likely to occur with moderate to high doses of the drugs. This is less of a problem with the ISA non-selective Beta-blockers. - Potential for bronchospasm; Blockade of Beta 2 receptors in the lungs will prevent the normal bronchodilatory actions of the sympathetic nervous system which are mediated by the Beta 2 receptors. This will produce problems in patients with bronchospastic conditions and may provoke an episode of acute bronchospasm in asthmatics or inhibit the efficacy of their bronchodilatory medications. - Potential for peripheral vasoconstriction; in patients with peripheral vascular diseases, Beta 2 receptors help to maintain some degree of vasodilatation in skeletal muscle arteries. Blockade of these receptors in patients who have compromised vascular flow can prevent the vasodilatory contribution of the beta 2 receptors and provoke claudication and even ischemia and gangrene in severe cases. - Possible hypoglycemia; Also mediated by blockade of Beta 2 receptors in the liver, blood glucose levels can become reduced because Beta 2 receptors are responsible for glycogenolysis which maintains a normal serum concentration of glucose under certain conditions. This is not a problem in normal individuals but may produce serious problems in patients with diabetes. - Increases triglycerides and lowers high density lipoproteins (HDL's) - Commonly results in Beta receptor up-regulation and target cell hypersensitivity; this effect requires that Beta-blocker drugs that have been used for any length of time be withdrawn slowly (over three weeks) to prevent rebound tachycardia, angina, hypertension, etc. - The antihypertensive effects of Beta-blockers are blunted by the concurrent administration of NSAIDS.List of Available Selective Beta 1 Blockersmetoprolol (Lopressor) atenolol (Tenormin) betaxolol (Kerlone) acebutolol (Sectral) bisoprolol (Zebeta) esmolol (Brevibloc)Pharmacodynamics of Selective Beta 1 BlockersSelective Beta-blockers (commonly referred to as "cardio-selective" Betablockers), block only Beta 1 receptors when administered at normal dosages (See Non-Selective Beta-blockers above). There are usually no antagonistic effects on Beta 2 receptors. In this way the beneficial effects of Beta 1 blockade can be accomplished without the adverse effects provoked by blockade of Beta 2 receptors (described above).Pharmacokinetics of Selective Beta 1 BlockersThe selective Beta-blockers are administered orally and most are metabolized to some degree in the liver. They are excreted in the urine. [Note: The only exception is atenolol, which is not metabolized at all.]Advantages of Selective Beta 1 Blockers for HypertensionBy only blocking Beta 1 receptors (at usual dosages), the advantages mentioned for the non-selective Beta-blockers above apply here also and for the same reasons. These are: - Administered orally - Once-a-day or BID dosing - Blocks reflex tachycardia - Prevents renin release - Decreases risk for arrhythmias - Reduction of anxiety - Useful in combination with other drugs that may provoke reflex tachycardia - Multiple simultaneous therapeutic indications. Low doses of these agents are useful in the management of congestive heart failure. - Some have intrinsic sympathetic activity (i.e., acebutolol) [See Advantages of the Non-selective Beta-blockers.] - Some are inexpensive (metoprolol is least expensive of the selective betablockers) - By NOT blocking Beta 2 receptors, many of the disadvantages of the nonselective Beta-blockers are eliminated or reduced: - Relatively safe to use in asthmatics - Relatively safe to use in diabetics - Relatively safe to use in patients with peripheral vascular diseasesDisadvantages of Selective Beta 1 Blockers for Hypertension- Generally more expensive than the non-selective beta-blockers; this may create problems with patient compliance. - Possible bradycardia and congestive heart failure; (see non-selective Betablockers) - Increases triglycerides and decreases HDL's; (see non-selective Betablockers) - May provoke bronchospasm in asthmatics at high doses; Although considered to block only Beta 1 receptors, this receptor selectivity is lost when the drug is administered at higher than the usual doses. - May mask hypoglycemia in diabetics at high doses; although this is not a problem for most individuals, high doses of these drugs will also block Beta 2 receptors to some extent and will enhance hypoglycemia - a problem for the patient with diabetes.List of Available ACE Inhibitorscaptopril enalopril (Vasotec) benazepril (Lotensin) lisinopril (Prinivil) (Zestril) fosinopril (Monopril) moexipril (Univasc) perindopril (Aceon) quinapril (Accupril) ramipril (Altace) trandolapril (Mavik)Pharmacodynamics of ACE InhibitorsThe ACE inhibitor drugs block angiotensin-converting enzyme (ACE) which converts the inactive protein, angiotensin I into the very active protein, angiotensin II. In this way, the normal actions of angiotensin II (peripheral arterial vasoconstriction and stimulation of aldosterone secretion by the adrenal gland) are blocked. ACE also inactivates bradykinin, which has vasodilating effects (Figure 16-1, page 304 in text). ACE inhibitors, therefore, have multiple mechanisms by which they lower blood pressure; they reduce peripheral arterial resistance, decrease aldosterone-stimulated increase in blood volume, and increase vasodilation.Pharmacokinetics of ACE InhibitorsAll ACE inhibitors are administered orally. Although some ACE inhibitors are not metabolized (i.e., lisinopril), most are metabolized to varying degrees by the liver. They are excreted in the urine.Advantages of ACE Inhibitors for Hypertension- Administered orally; this is desirable for a drug that must be administered daily and for long periods (i.e., lifetime). - Administered once daily - (only captopril is administered BID); once daily therapy is advantageous from a compliance point of view. - Multiple mechanisms of action; with the complex nature of the pathophysiology of hypertension, it is an advantage to use a drug that can work in several ways to achieve the desired therapeutic endpoint. - Does not produce reflex tachycardia; the mechanism for this is unclear but this is an advantage in patients who would do not tolerate tachycardia (such as patients with ischemic heart disease). - Tends to increase serum potassium; due to blockade of aldosterone - this is more likely to occur in patients with renal insufficiency. When ACE inhibitors are used together with the thiazide diuretics, the hyperkalemia of the ACE inhibitors may offset the hypokalemia of the thiazides. - Glucose neutral; ACE inhibitors do not affect serum glucose levels and can be used relatively safely in diabetics. - Multiple therapeutic uses; ACE inhibitors are very effective in the management of congestive heart failure which is a frequent co-morbid condition together with hypertension. Use in diabetics may significantly delay development of diabetic nephropathy. May reduce complications in patients with chronic stable angina.Disadvantages of ACE Inhibitors for Hypertension- Very potent; may lower blood pressure too much, especially when used in combination with diuretics and other antihypertensive drugs. Diuretics should be stopped for 2 or 3 days before starting an ACE inhibitor. - May produce severe hyperkalemia; this is more likely to occur in patients with renal insufficiency and use of ACE inhibitors may have to be restricted in these patients. - May cause angioedema; patients should be cautioned that voice changes and swelling of the tongue are symptoms of this complication; may occur with the first dose or within the first month of use. Drug must be discontinued and avoid the entire class of drugs. - May cause an increase in renal insufficiency by markedly decreasing renal perfusion pressure. This requires a close watch of a patient's renal function studies and consequently increases the cost of therapy. Contraindicated in patients known to have bilateral renal artery stenosis. - May provoke a persistent nocturnal cough; the mechanism for this is unclear but may occur in as many as 20% of users. - Is teratogenic and toxic in pregnancy; ACE inhibitors are contraindicated in pregnancy. - More expensive; compared to some of the other antihypertensive drugs, ACE inhibitors are more costly for the patient.List of Available Calcium Channel Blockersverapamil (Calan) nifedipine (Procardia) diltiazem (Cardizem) amlodipine (Norvasc) felodipine isradipine nicardipine (Cardene) nisoldipine (Sular)Pharmacodynamics of Calcium Channel BlockersThe calcium channel blockers (CCBs) work by binding to various sites on the calcium transport channels, inhibiting the entry of calcium ions into muscle cells (especially arteriolar and venous smooth muscle and cardiac muscle). In this way, these drugs decrease the force of contraction of these muscle cells. The result is a decrease in myocardial contraction, a decrease in cardiac output, a decrease in peripheral vascular tone and peripheral resistance, and a decrease in blood pressure. [Note: There are three different classes of calcium channel blockers and several different types of calcium channels on the different tissue types. This accounts for the variety in actions, therapeutic indications, and adverse effects of the different drugs. The three types of receptors that are blocked are the diphenylalkylamine-based and benzothiazepine-based (type 1) and dihydropyridine-based (type 2) receptors. ]Pharmacokinetics of Calcium Channel BlockersAll CCBs are administered orally and all are extensively metabolized in the liver. Some are available in I.V. formulations for emergency use. They are highly protein-bound. Excretion is mainly by the kidney but some are also excreted in the feces. They have a short serum half-life (regular forms) but extended-release forms are available.Advantages of Calcium Channel Blockers for Hypertension- Administered orally; an advantage in long-term therapy but oral bioavailability is limited due to extensive first-pass hepatic metabolism. - Can be effective as monotherapy in older adults and African Americans because hypertension in these groups is not related to increased renin levels. - Some (especially verapamil and diltiazem) ease the strain on the heart by decreasing myocardial oxygen consumption; this is an advantage for patients with ischemic heart disease also. - Multiple therapeutic uses - In addition to hypertension, calcium channel blockers are also used for angina, arrhythmias, M.I., migraine headache, etc.; this is an advantage because many of these are typical co-morbid conditions with hypertension and allows one drug to treat more than one condition. - Some available in I.V. formulations; can be used for emergency control of severe hypertension or when oral therapy is not feasible.Disadvantages of Calcium Channel Blockers for HypertensionNote: The disadvantages will vary depending on which drug is used (i.e., on which type of calcium channel is blocked).] - Possible bradycardia and congestive heart failure; this is a problem in patients who have pre-existing bradycardia, especially if they also have ischemic heart disease. Verapamil (Calan) is most likely to cause this effect. - Orthostatic hypotension results from blockade of the calcium channels in peripheral venous smooth muscle and the postural vasodilatation that occurs with assuming the upright position. - Short duration of action (regular forms); amlodipine is the exception (with a half-life of 30 to 50 hours). For this reason sustained-release formulas may need to be used to improve compliance in some patients. - Arrhythmias; calcium channel blockade also occurs in the electrical system of the heart and can provoke a variety of rhythm disturbances. This is especially likely with verapamil and nifedipine; a bradyarrhythmia is most common. - Constipation; not only are calcium channels blocked in vascular smooth muscle, they are also blocked in GI tract smooth muscle. This inhibits peristalsis and leads to constipation, especially in older adults. - May worsen symptoms of gastroesophageal reflux disease (GERD) by relaxing esophageal smooth muscle. - More expensive; as a class, calcium channel blockers are more costly to the patient than some of the other antihypertensive drugs. - Limited studies of nifedipine in pregnancy; as a class, CCBs not considered safe for use in pregnancy. This should be taken into consideration in planning long-term antihypertensive therapy in a woman trying to get pregnant. - Concomitant use of drugs that inhibit the CYP-450 system, including grapefruit juice, may increase free drug levels of CCBs.List of Available Direct-Acting VasodilatorsORAL AGENTS: - hydralazine - minoxidil PARENTERAL AGENTS: - nitroprusside (Nitropress)Pharmacodynamics of Direct-Acting VasodilatorsThe mechanism by which the direct-acting vasodilators work is incompletely understood. They interact directly with vascular smooth muscle possibly increasing the nitric oxide content of the muscle cells, and produce peripheral arteriolar vasodilatation (nitroprusside also produces venous vasodilatation). In producing vasodilatation, they have a profound effect on blood pressure by decreasing peripheral vascular resistance. [Note: The direct-acting vasodilators do not inhibit the sympathetic compensatory mechanisms that are activated by a lowering of blood pressure. As a result, the pharmacologic effects of the direct-acting vasodilators are accompanied by reflex tachycardia, renin release, aldosterone activation (reninangiotensin- aldosterone system), sodium and water retention, and absence of orthostatic hypotension.]Pharmacokinetics of Direct-Acting VasodilatorsMinoxidil and hydralazine can be administered orally; hydralazine is also given parenterally. Minoxidil is also available as a topical agent (Rogaine). Diazoxide and nitroprusside are only administered parenterally. All are metabolized in the liver. Nitroprusside has a unique metabolite (thiocyanate) that can accumulate and cause thiocyanate (cyanide) poisoning which is characterized by tinnitus, confusion, hyper-reflexia, metabolic acidosis, arrhythmias, hypotension, and death. All direct-acting vasodilators are excreted in the urine.Advantages of Direct-Acting Vasodilators for Hypertension- Some administered orally for long-term therapy; an advantage when therapy is required on a daily basis for long periods of time. - Some available I.V.; useful for the emergency control of hypertensive crisis. - Useful for control of pregnancy-associated hypertension (PAH); no evidence of teratogenic injury or toxicity to mother or fetus. - Hydralazine is inexpensive; this drug has been around for decades and its cost is minimal. - Rapid onset of action; especially true for the parenteral formulations. - Absence of orthostatic hypotension; this is a common ADR with other drugs that markedly decrease peripheral resistance.Disadvantages of Direct-Acting Vasodilators for Hypertension- Reflex tachycardia; because the sympathetic system remains intact, compensatory reflex tachycardia can occur with lowering of blood pressure. This can be a problem for patients with ischemic heart disease because it increases myocardial oxygen consumption. - Sodium and water retention and edema; because renin is released in response to lowering of blood pressure, aldosterone is activated and its sodium retention effects produce edema. - Frequently requires the concomitant use of Beta-blockers and diuretics; because of the reflex tachycardia and aldosterone effects, these drugs are often necessary to prevent the adverse effects of edema and tachycardia seen with the direct-acting vasodilators. This adds to the cost of therapy. - Minoxidil produces hypertrichosis; (this is the basis for the release of topical minoxidil (Rogaine) as a hair restorer). Hypertrichosis is common on the face and arms and can occur with just one month of use. - Apresoline produces a lupus-like syndrome; long-term therapy with oral Apresoline can cause myalgia, arthralgia, fever, and rashes - a syndrome resembling systemic lupus erythematosis. - Usually not first-line drugs; these drugs are usually reserved for cases of hypertension that require emergency treatment or those that do not respond to other, safer drugs. - Not useful as monotherapy; the sodium and water retention must be treated with concurrent diuretics.List of Available Angiotensin II Receptor Antagonists (also called ARBs)losartan (Cozaar) valsartan (Diovan) irbesartan (Avapro) candesartan (Atacand) eprosartan (Teveten) azilsartan (Edarbi) olmesartan (Benicar) telmisartan (Micardis) Common combinations with the thiazides: losartan + HCTZ (Hyzaar) eprosartan + HCTZ (Teveten HCT) olmesartan + HCTZ (Tribenzor) telmisartan + HCTZ (Micardis HCT) azilsartan + chlorthalidone (Edarbyclor)Pharmacodynamics of Angiotensin II Receptor Antagonists (ARBs)These drugs are competitive antagonists of angiotensin II on its receptors. They block angiotensin II-stimulated vasoconstriction and angiotensin II-stimulated aldosterone secretion. By these two mechanisms, the angiotensin II receptor blockers decrease peripheral resistance and blood volume (i.e., sodium and water retention) and lower blood pressure.Pharmacokinetics of Angiotensin II Receptor Antagonists (ARBs)Angiotensin II receptor blockers are administered orally and are metabolized in the liver. They are highly protein-bound. They are excreted both in the urine and in the bile.Advantages of Angiotensin II Receptor Antagonists for Hypertension- Administered orally; an advantage when treating a long-term problem like hypertension. - Once-a-day or BID dosing; infrequent dosing improves compliance in therapeutic plans that require daily doses for extended periods of time. - Dual mechanisms of action; improves control of hypertension by affecting more than one of its pathophysiologic mechanisms. - Dual routes of excretion; drugs that have two routes of excretion do not generally require dosage adjustments (i.e., reductions) in patients with renal insufficiency. - Glucose neutral; good drugs to use in diabetics. - Lipid neutral; good drugs to use in patients with hyperlipidemias. - Minimal adverse effects; well tolerated by most individuals.Disadvantages of Angiotensin II Receptor Antagonists for Hypertension- May produce hypotension; this is especially a problem in volume-depleted patients. - Contraindicated in pregnancy; has caused an increased incidence of fetal death especially in the second and third trimesters. - Very expensive; this is the newest class of antihypertensive drugs. As such, they will be quite expensive for a while and may lead to poor compliance by the patient. - May cause some skeletal muscle cramping. - Some references report a persistent nocturnal cough in some patients; the mechanism form this is unclear. - Headache and diarrhea are occasionally reported.Selection of a Therapeutic Plan for Hypertension Tailored to Specific Patients NeedsIn hypertensive patients aged 60 years of age or older who do not have diabetes or chronic kidney disease, treat to a blood pressure goal of less than 150/90 mmHg. In all other hypertensive patients, including patients aged 18 to 59 years of age, patients with diabetes, or patients with chronic kidney disease (CKD), treat to a blood pressure goal of less than 140/90 mmHg. In most patients with uncomplicated hypertension, initiate therapy with a thiazide diuretic, an ACE inhibitor, an ARB, or a calcium channel blocker, either alone or in combination. Initial therapy in the black hypertensive population, including those with diabetes, should include a thiazide diuretic or a calcium channel blocker, alone or in combination. It is also recommended to initiate therapy with an ACE inhibitor or ARB, alone or in combination with another drug class, in persons with CKD to improve kidney outcomes. The new guidelines also introduce new recommendations designed to promote safer use of ACE inhibitors and ARBs; it is recommended to avoid concomitant uses of these drug classes. The main objective of hypertension treatment is to attain and maintain goal blood pressure. The clinician should continue to assess and adjust the treatment regimen until goal blood pressure is reached; many patients will require treatment with more than one agent. If goal blood pressure cannot be reached using the recommended drug classes because of a contraindication or the need to use more than 3 medications, medications from other drug classes can be used. Referral to a hypertension specialist may be indicated for patients in whom goal blood pressure cannot be attained or for the management of complicated patients for whom additional clinical consultation is needed. Although this guideline provides evidence-based recommendations for the management of hypertension and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment. Decisions about care must be carefully considered and incorporated in the clinical characteristics and circumstances of each individual patient.POTENTIAL FOR ADVERSE DRUG REACTIONS1. Avoid drugs that alter blood glucose in the therapy of hypertensive patients with diabetes. 2. Avoid drugs that increase serum lipids in the therapy of hypertensive patients with hyperlipidemia. 3. Avoid non-selective Beta-blockers in patients with peripheral vascular disease. 4. Avoid drugs that induce sedation in the therapy of patients who must remain alert during the day. 5. Avoid drugs that induce impotence in the therapy of male hypertensive patients. 6. Avoid drugs that cause hyperkalemia in patients with renal insufficiency.CO-MORBID CONDITIONS - The following are common co-morbid conditions seen in hypertension that will influence drug selection:1. Pregnancy 2. Diabetes 3. Hyperlipidemia 4. Gout (hyperuricemia) 5. Migraine 6. Asthma (bronchospastic conditions) 7. Peripheral vascular disease 8. Coronary Artery Disease (angina)RACIAL DIFFERENCES- Some drugs have greater efficacy in white patients while others are more effective in African-Americans. In African-Americans, calcium channel blockers and thiazide diuretics are particularly effective, alone or used in combination.AGE-RELATED CONCERNS- Older adults are more susceptible to orthostatic hypotension than other patients; avoid selective alpha 1 receptor blockers and calcium channel blockers in this population if possible. - Older adults are more susceptible to constipation than other patients; calcium channel blockers may aggravate constipation if already present. - Older adults are more likely to have CHF than other patients; exercise caution in using beta-blockers and calcium channel blockers in them. - Older adults already have a contracted blood volume; use precaution when using diuretics in them (i.e., may have to use a lower than normal dose to begin therapy).DOSING FREQUENCYChoose drugs that can be given on a once-a-day or at most BID dosing schedule; this will improve compliance and will help to reduce costs.DRUG-DRUG INTERACTIONSThere are many potential drug-drug interactions that can occur with the antihypertensive drugs. Consider these as the possible reason for ineffectiveness of a therapeutic plan instead of blaming an individual drug as being ineffective.DRUG COSTSKeep drug cost in mind when selecting a pharmacotherapeutic plan. With hypertension, it is a daily drug administration that will be taken for years. The costs can mount up considerably. While the newer drugs may offer fewer side effects and be better tolerated, they will not be effective if the patient can't afford to buy them. If cost will be a major issue for the patient, consider choosing an older drug and explain to the patient that they may have to accept some side effects in exchange for affordability. The general relative costs for the various drug categories are as follows: Most Expensive→ → →Least Expensive 1. Calcium channel blockers 2. Angiotensin II antagonists (ARBs) 3. ACE inhibitors 4. Selective alpha 1 receptor antagonists 5. Beta-blockers (non-generic) 6. Reserpine 7. Beta-blockers (generic) 8. DiureticsFACTORS COMPOUNDING THE COSTSPharmacy fees for filling the prescription - Ancillary blood tests to check on renal function, serum potassium, serum uric acid, serum lipids, etc. - Costs of return office visits to check for adverse effects, etc. - Costs of treatment failure (i.e., renal failure, blindness, ischemic extremities, angina, etc.)Treatment of Hyperlipidemias (also called dyslipidemias)Initial therapy for all patients with hyperlipidemia should be dietary modification. However, most patients will require the addition of medication to reduce cholesterol and achieve desirable levels of LDL cholesterol (the actual numerical goal is defined by the patient's number of risk factors for, or presence of, coronary artery disease). The five major categories of medications used to treat lipid disorders are Bile Acid Sequestrants, Nicotinic Acid Derivatives, Fibric Acids, HMG Co-A Reductase Inhibitors (also called Statins) and Cholesterol Absorption Inhibitors. These drugs vary in their effects on lipids so selection is guided by the goal of therapy: to reduce LDL, reduce triglycerides or raise HDL.List of Available Bile-Acid Sequestrantscholestyramine (Questran) (Cholebar) colestipol (Colestid) colesevelam hydrochloride (WelChol)Pharmacodynamics of the Bile-Acid SequestrantsBile-acid sequestrants are resins that irreversibly bind to the naturally occurring bile salts in the G.I. tract, preventing their action in dietary fat absorption. By preventing the absorption of dietary fat and cholesterol (and the reabsorption of the bile salts themselves), the pool of bile salts in the body is decreased. In order to replace the diminishing pool of bile salts, the body mobilizes cholesterol from storage sites in the adipose tissue in order to convert it into more bile salts. By these mechanisms, the bile-acid sequestrants decrease entry of cholesterol into the body and reduce the amount of stored cholesterol by converting it to bile salts.Pharmacokinetics of the Bile-Acid SequestrantsThe bile-acid sequestrants are administered orally. They (and anything bound to them) are not appreciably absorbed. They are excreted in the stool.Advantages of Using the Bile Acid Sequestrants in the Treatment of Familial HyperlipidemiaAdministered orally (with large amounts of water) - Administered once-a-day (cholestyramine) or BID (colestipol); colesevelam can be given once-a-day or divided BID - Drug is not absorbed; eliminates the risk of systemic adverse effects from the drug itself - Dual mechanisms of action; inhibits absorption of dietary fat and cholesterol and lowers total body cholesterol stores - Useful in any of the familial hypercholesterolemias; can be effective in a number of genetic types of hyperlipidemia - Lowers both total cholesterol and LDL cholesterol - Minimal adverse effects; considered very safe among the antilipidemic drugs - Can be used synergistically with the other lipid-lowering drugs to produce a potentiative, pharmacodynamic drug-drug interaction on serum lipids - Can be used safely in children and in pregnancy - Can be used as a first-line drug in familial hyperlipidemias - Clinical studies in patients with both hyperlipidemia and diabetes show that cholestyramine and colesevelam can also reduce blood glucose levels in patients with type 2 diabetes - Other uses include treatment of pruritis associated with hyperbilirubinemia and in post-cholecystectomy diarrheaDisadvantages of Using the Bile Acid Sequestrants in the Treatment of Familial Hyperlipidemia- Usually life-time therapy is required for familial hyperlipidemias - Expensive drugs; this can lead to poor compliance considering that the expense can accrue over a lifetime - Prevents absorption of other concurrently administered oral medications; since the bile acid sequestrant itself is not absorbed, anything bound to it will also not be absorbed. This requires that other orally administered medications be given at separate times and this can present a timing problem when a patient is on several different daily medications - Requires daily drug administration; since this is a lifetime disease, daily administration of a costly medication can lead to poor compliance - Commonly causes G.I. symptoms; constipation, bloating, indigestion, nausea - May cause poor absorption of the fat soluble vitamins (A,D,E, and K). These may have to be given as supplements, which can increase the cost of therapy - Poor palatability; this also could lead to poor complianceList of Available Fibric Acid Derivatives (also called Fibrates)fenofibrate (Tricor) gemfibrozil (Lopid)Pharmacodynamics of the Fibric Acid DerivativesThe fibric acid derivatives activate PPAR-alpha, which leads to an increase in the enzyme lipoprotein lipase. In doing so, the drugs increase lipolysis of lipoprotein triglycerides (VLDL) while reducing lipolysis in adipose tissue. These drugs also increase HDL but they have a variable action on LDL. If a patient has familial hypercholesterolemia, LDL will be reduced but if they have familial hypertriglyceridemia, LDL will be elevated.Pharmacokinetics of the Fibric Acid DerivativesFibric acids are administered orally. They are metabolized in the liver. Both are highly protein-bound. They are excreted in the urine.Advantages of Using the Fibric Acid Derivatives in the Treatment of Familial Hyperlipidemia- Administered orally - Useful in lowering triglycerides; less useful in lowering LDL - Increases HDL - BID dosingDisadvantages of Using the Fibric Acid Derivatives in the Treatment of Familial Hyperlipidemia- Increases liver enzymes; requires frequent checks of liver function studies and may be precluded in patients with liver disease - May cause abdominal pain, diarrhea, nausea, vomiting - Increases cholesterol in bile; may lead to increased incidence of cholesterol gall stones (i.e., lithogenic bile) - May cause hypercoagulability; use may be precluded in patients who are already hypercoagulable - May cause myopathy; requires close observation of patients for muscle complaints that may require discontinuation of the drug - Concurrent use of fibric acid derivatives and HMG-CoA reductase inhibitors (statins) should generally be avoided unless the benefit of further alterations in lipid levels is anticipated to outweigh the potential risks. Severe myopathy and rhabdomyolysis have been reported during concomitant use of statins and fibric acid derivatives, especially gemfibrozil. If the combination is prescribed, caution is advised to start with fenofibrate and a low dose of statin, and monitor muscle enzyme (creatinine kinase) levels. This combination should be avoided in patients with preexisting muscle abnormalities, such as inflammatory myopathyList of Available HMG-CoA Reductase Inhibitors (also called Statin drugs)atorvastatin (Lipitor) fluvastatin (Lescol) lovastatin (Mevacor) pravastatin (Pravachol) rosuvastatin (Crestor) simvastatin (Zocor)Pharmacodynamics of the StatinsThese drugs inhibit the enzyme (HMG Co-A Reductase) that is responsible for the de novo hepatic synthesis of cholesterol from acetate. When the intracellular concentration of cholesterol decreases, the liver cells are stimulated to increase the number of surface LDL receptors that are designed to remove LDL from the blood. This increases the clearance of LDL from the serum.Pharmacokinetics of the StatinsAll are administered orally (preferably with the evening meals). All are metabolized in the liver and excreted both in the urine and in the bile. Lovastatin and simvastatin are highly protein bound and are pro-drugs.Advantages of the Statins in the Treatment of Familial Hyperlipidemia- Administered orally - Administered once daily (preferably in the evening since this is when the HMG Co-A reductase enzyme is most active) - Can be administered with meals or on an empty stomach - Can be used in all types of familial hyperlipidemias - Most efficacious class of drugs for treating hyperlipidemia - Multiple beneficial effects on serum lipids; lowers total cholesterol and LDL - May cause a slight increase in serum HDL - Can be prescribed in conjunction with the bile acid sequestrants or niacinDisadvantages of the Statins in the Treatment of Familial Hyperlipidemia- Commonly produces elevation of hepatic enzymes; requires close observation of patient's liver functions with laboratory monitoring - Can cause myopathy; requires close observation for muscle complaints (pain, weakness) by the patient. Patients with the greatest risk of myopathy are women, age >65 yrs., having impaired renal function, hepatic disease, or hypothyroidism - Concurrent use of fibric acid derivatives and HMG-CoA reductase inhibitors (statins) should generally be avoided unless the benefit of further alterations in lipid levels is anticipated to outweigh the potential risks. Severe myopathy and rhabdomyolysis have been reported during concomitant use of statins and fibric acid derivatives, especially gemfibrozil. If the combination is prescribed, caution is advised to start with fenofibrate and a low dose of statin, and monitor muscle enzyme (creatinine kinase) levels. This combination should be avoided in patients with preexisting muscle abnormalities, such as inflammatory myopathy - Herbal alert: concomitant use of statins and St. John's wort (Hypericum perforatum) may decrease serum plasma levels of statins - Contraindicated in pregnancy; may damage normal development in the fetus - Most are very expensive drugs; cost may decrease compliance - Requires precaution in children (i.e., less than 20 years of age); use of these drugs in children is not studied and not recommended - Can cause headache and dizziness - Can cause G.I. symptoms; flatulence and diarrheaList of Available Nicotinic Acid Derivativesniacin (Niacor) (Nicobid tempules) (Slo-niacin) (Niaspan)Pharmacodynamics of the Nicotinic Acid DerivativesThe exact pharmacodynamics are complex and no one mechanism explains all of the effects of niacin, also known as vitamin B3. By blocking some enzymes and enhancing others, niacin causes a decrease in the synthesis of VLDL (the precursor of LDL), a decrease of fatty acid delivery to the liver for production of LDL, and increased synthesis of HDL.Pharmacokinetics of the Nicotinic Acid DerivativesNiacin is administered orally and is well absorbed. Depending on the product, niacin exists as an immediate-release, a sustained-release, and an extended-release formulation. Also, depending on how rapidly the niacin is absorbed, the hepatic metabolic pathways differ with different metabolic end-products. The immediate-release niacin is primarily converted to nicotinuric acid whereas the sustained-release formulation is primarily converted to nicotinamide and niacinamide. (The extended-release product is equally metabolized to all of these metabolites.) The importance of knowing these metabolic end-products lies in the fact that the adverse effects of these different formulations is linked to the type of metabolite they form. All of the drug formulations are excreted in the urine.Advantages of the Nicotinic Acid Derivatives in the Treatment of Familial HyperlipidemiaAdministered orally; ease of administration is an inducement to better compliance - Multiple formulations available; therapy can be tailored to patient need - Has wide variety of effects on lowering serum lipids; reduces total cholesterol, LDL and triglycerides - Can be used as a first-line drug in familial hyperlipidemias - Has synergistic effects with the other lipid-lowering drugs - Has dual beneficial effect; lowers harmful lipids and also increases HDL - Inexpensive; important considering that therapy for hyperlipidemias can be for a lifetimeDisadvantages of the Nicotinic Acid Derivatives in the Treatment of Familial Hyperlipidemia- Causes an intense flushing or pruritic rash (initial doses) on the face, neck, and upper chest; this is probably caused by a release of prostaglandins and can be prevented by pre-treating with aspirin. This is less likely to happen with the extended-release formulation - Causes hepatic dysfunction; requires that liver function tests be done periodically which increases the cost of therapy. This is more likely to occur with the sustained-release formulations. The extended-release formulation is the least hepatotoxic - May cause abdominal pain, nausea, vomiting, and diarrhea - Causes an increase in HCl acid production by the stomach; may preclude its use in patients with acid-peptic diseases - May cause hyperglycemia; requires caution (and may preclude the use) in diabetics - May cause hyperuricemia; requires caution (and may preclude the use) in patients with goutList of Available Cholesterol Absorption Inhibitors- ezetimibe (Zetia)Pharmacodynamics of Cholesterol Absorption InhibitorsEzetimibe works by preventing the absorption of cholesterol in the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol.Pharmacokinetics of Cholesterol Absorption InhibitorsEzetimibe is given orally and is metabolized in the liver. There is enterohepatic circulation of the drug and its metabolite. It should not be given to patients with moderate to severe liver impairment.Advantages of Cholesterol Absorption Inhibitors in the Treatment of Familial Hyperlipidemia- Administered orally - Once-daily dosing, may be taken without regard to meals - Does not affect bile acid or absorption of fat-soluble vitamins - Minimal systemic absorption; few drug interactions - Side effects comparable to placebo - No laboratory monitoring required when used as monotherapyDisadvantages of Cholesterol Absorption Inhibitors in the Treatment of Familial Hyperlipidemia- May cause elevation of liver enzymes; not recommended in hepatic failure - Not recommended in pediatric population; not studied in pregnancyOther drugs used to treat hyperlipidemiaOmega-3 Fatty Acids (Lovaza) Combination drugs - Vytorin (simvastatin plus ezetimibe) - Caduet (atorvastatin plus amlodipine [antihypertensive])Pharmacodynamics of LovazaThis is the only prescription form of omega-3 fatty acid as a single agent (also available as food supplements- these are not regulated by the FDA). The mechanism of action is not completely understood. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the effective natural ingredients in the drug. The drug may decrease synthesis of triglycerides in the liver because EPA and DHA interfere with the enzymes responsible for triglyceride synthesis. Lovaza is indicated in patients with triglyceride > 500.Pharmacokinetics of LovazaWhen Lovaza is given orally serum levels of EPA increase in a dose-dependent fashion. Levels of DHA are less than EPA.Advantages of Lovaza in the Treatment of Hypertriglyceridemia- Administered orally - Useful in lowering triglyceride; offers an alternative to patients who cannot tolerate the FibratesDisadvantages of Lovaza in the Treatment of Hypertriglyceridemia- Should be taken with meals, two or three times daily; this may reduce compliance - May cause eructations, dyspepsia and unpleasant aftertaste - May cause increase in liver function tests - May cause an increase in LDL levels - Should not be taken by patients on anticoagulants or with abnormal bleeding times - Not recommended in pediatric age group, pregnancy or nursing mothersPharmacodynamics of VytorinThis drug is a combination of ezetimibe, 10 mg., and varying dosages of simvastatin (10 to 80 mg.). Ezetimibe blocks absorption of cholesterol from the small intestine, and simvastatin reduces cholesterol by inhibiting the conversion of HMG-CoA to mevalonate, an early step in the biosynthetic pathway for cholesterol.Pharmacokinetics of VytorinIdentical to coadministered ezetimibe and simvastatin.Advantages of Vytorin in the Treatment of Familial Hyperlipidemia- Combines efficacy of a statin with inhibition of cholesterol absorption (two different action pathways) - May afford results with a lower dose of statin for patients who have experienced side effects from previous use of a statinDisadvantages of Vytorin in the Treatment of Familial Hyperlipidemia- Same as for statins and ezetimibePharmacodynamics of CaduetIdentical to coadministered atorvastatin and amlodipineAdvantages of Caduet in the Treatment of Familial Hyperlipidemia- Single pill may improve compliance for patients who have both hyperlipidemia and hypertension - May be taken at any time of day without regard to mealsDisadvantages of Caduet in the Treatment of Familial Hyperlipidemia- Same as for statins and amlodipine (calcium channel blocker)Other ways to combine lipid lowering drugs (prescribed separately)- bile acid sequestrant plus statin - niacin plus statin - Lovaza plus statin

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