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Because 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.]
Advantages:
- 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.
Drugs 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.
After 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.
Much 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.
- 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.
- 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 medication
Pharmaceutical 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.
- 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.]
A 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.
The 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.
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.
* 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.
* 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.
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.
1. 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.]
1. 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.]
1. 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)
1. 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)
There 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.
The 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.]
ALPHA 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.
Commonly 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 drug
Commonly 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 activation
The 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).
- 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.
- 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.
Note: 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.
In 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.