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Pharmacology Chapter 4
Terms in this set (128)
the study of drug movement throughout the body
includes metabolism and drug excretion
What are the 4 processes of pharmacokinetics?
1.absorption 2. distribution 3. metabolism 4. excretion
the movement of drug from its site of administration into the blood
drug movement from the blood to the interstitial space of tissues and from there into cells
an enzymatically mediated alteration of drug structure
the movement of drugs and their metabolites out of the body
the combination of metabolism plus excretion
What does the 4 pharmacokinetic processes determine?
the concentration of a drug at its sites of action
What is the major barrier to passage through a cell?
the cytoplasmic membrane (the membrane that surrounds the cell)
What is the basic membrane structure consist of?
a double layer of molecules known as phospholipids
are simply lipids (fats) that contain an atom of phosphate
the molecule has a round head (the phosphate-containing component) and two tails (long-chain hydrocarbons)
the large objects embedded in the membrane represent protein molecules which serve a variety of functions
What are the 3 important ways by which drugs cross cell membranes?
1. passage through channels or pores 2. passage with the aid of transport system 3. direct penetration of the membrane itself
Which passage way is the most common?
direct penetration of the membrane
Channels and Pores
very few use this way
channels are extremely small and specific for certain molecules
What are some examples of compounds that cross membranes via channels?
ions such as potassium and sodium
carriers that can move drugs from one side of the cell membrane to the other
some require the expenditure of energy others don't
they are all selective (depending on the drug structure)
AKA multidrug transporter protein
a transmembrane protein that transports a wide variety of drugs out of cells
What sites is P-Glycoprotein located in?
kidney, placenta, intestine, and capillaries of the brain
Examples of P-Glycoprotein transportation?
in the liver p-glycoprotein transports drugs into the bile for elimination
in the kidneys it pumps drugs into the urine for excretion
in the placenta it transports drugs back into maternal blood (reducing fetal drug exposure)
in the intestine it transports drugs into the intestinal lumen to reduce drug absorption into the blood limiting access to the brain
Direct Penetration of the membrane
most drugs are too large to pass through channels or pores
most drugs lack transport systems to help them across all the membranes that separate them from their sites action, metabolism and excretion
What does a drug need to directly penetrate a membrane?
it needs to be lipid soluble (lipophylic)
Polar Molecules and Ions
are not lipid soluble and therefore cannot penetrate membranes
molecules with uneven distribution of electrical charge
positive and negative charges within the molecule tend to congregate separately from one another
no net charge (equal number of protons and equal number of electrons)
What is an example of a polar molecule?
-the electrons (negatively charged) in water molecules tend to spend more time in the vicinity of the oxygen atom than in the vicinity of 2 hydrogen atoms
as a result the area around the oxygen atom tends to be negatively charged whereas the area around the hydrogen atom tends to be positively charged
molecules that do bear a net electrical charge (either positive or negative)
unable to cross membranes
How do polar molecules dissolve?
polar molecules dissolve in polar solvents (such as water) but not in nonpolar solvents (such as oil)
What is an example of a polar molecule dissolving?
table sugar (a polar compound) readily dissolves in water but not in salad oil, butter and other lipids which are nonpolar compounds
Polar drugs are unable to dissolve where?
in the lipid bilayer of the cell membrane
pH dependent ionization rules for acids and bases
acids tend to ionize in basic (alkaline) media
bases tend to ionize in acidic media
Ion trapping rules for acids and bases
acidic drugs will accumulate on the alkaline side
basic drugs will accumulate on the acidic side
What does the rate of absorption determine?
how soon effects will begin
What does the amount of absorption determine?
how intense effects will be
What is the rate at which a drug undergoes absorption influenced by?
physical and chemical properties of the drug itself and by physiologic and anatomic factors at the absorption site
Rate of Dissolution
has to happen before a drug is absorbed
the rate of dissolution will help determine the rate of absorption
drugs with a faster rate of dissolution will have a faster onset
major determinant of the rate of absorption
the larger the surface area the faster the absorption will be
-that's why drugs administered orally are absorbed in the small intestine instead of the stomach
drugs are absorbed more rapidly from sites where blood flow is high
-because blood containing newly absorbed drug will be replaced rapidly by drug free blood to maintain a large gradient between the concentration outside the blood and the concentration of drug in the blood
the greater the concentration gradient the more rapid absorption will be
high-lipid soluble drugs will be absorbed more rapidly because lipid-soluble drugs can readily cross the membranes that separate them from the blood whereas drugs of low-lipid solubility cannot
influences drug absorption
absorption will be enhanced when the difference between the pH of plasma and the pH at the site of administration is such that drug molecules will have a greater tendency to be ionized in the plasma
What are the 2 categories in which routes of administration used more commonly fall under?
1. enteral 2. parenteral
Enteral Vs. Parenteral
enteral is via the GI tract
parenteral is outside the GI tract (mostly by injection)
-intravenous, subcutaneous, and intramuscular
What will the route of administration affect?
the onset and intensity of the effects
-because the barriers to absorption associated with each route is different
Intravenous Route of Administration Barriers to Absorption
there are no barriers
with IV absorption is bypassed
IV puts the drug directly into the blood because absorption is the movement of the drug from its site of administration to the blood
Intravenous Route of Administration Absorption Pattern
instantaneous because drug enters the blood directly and complete because all of the administered drug reaches the blood
Intravenous Route of Administration Advantages
*Rapid Onset- beneficial in cases of emergencies
*Control- we have precise control over levels of drug in the blood
*Permits Use of Large Fluid Volume- only route that permits this
*Permits Use of Irritant Drugs- anticancer drugs- these drugs are rapidly dilute in the blood and cause no harm
Intravenous Route of Administration Disadvantages
*High Cost, Difficulty, & Inconvenience- takes time and training (cannot be self-administered), mobility is limited because of all the bottles and lines they are attached to
*Irreversibility- once it is injected there is no turning back because it is directly in the blood
*Fluid Overload- can be significant to patient's with HTN, kidney disease, and heart failure
*Infection- injecting a contaminated drug
*Embolism- blood vessel blockage at a site distant from the point of administration
*The Importance of Reading labels- to know if it is appropriate for the given route (concentrated with SubQ and diluted with IV)
What can be done to decrease the harm of IV administration?
inject the drug slowly (within 1 minute)
What is the advantage of injecting IV drugs in slowly?
this will allow the drug to be diluted in the largest amount of blood possible
it will also reduce the risk of toxicity to the CNS
-if injected in the anticubital area it will reach the brain within 15 seconds
-if done slowly, it can be discontinued immediately to reduce harm
How is Embolism caused when injecting IV drugs?
*insertion of IV needle can injure the venous wall and cause a formation of a thrombus (clot)
-if clot breaks lose and becomes lodged in other vessels
*insertion of hypotonic or hypertonic fluids can destroy red blood cells; the debris from these cells can produce embolism
*by particles of undissolved drugs
- particles become embedded in blood vessels and cause blockage
What must you do to avoid embolism?
check the IV solutions to ensure the drugs are in a solutions
-if the fluid is cloudy or contains particles the drug is not dissolved and must not be administered
Intramuscular Route of Administration Barriers to Absorption
-capillary beds that are in muscles and other tissues there are large spaces between cells that compose the capillary wall
-passing is easy
Intramuscular Route of Administration Absorption Pattern
either rapid or slow
determined by 2 factors: 1. water solubility of the drug (faster) and 2. blood flow to the site of injection
Intramuscular Route of Administration Advantages
*Permits use of Poor Soluble Drugs- can not be done with IV drugs
-also acceptable for drugs whose water solubility is poor
*Depot Preparations- they reduce the number of injections required during long-term therapy
preparations from which the drug is absorbed slowly over an extended time
a single injection can last for days, weeks, or even months
Intramuscular Route of Administration Disadvantages
*Discomfort & Inconvenience- they can be painful
*Can cause local injury and nerve damage (if you dont aspirate to make sure you are not in the vein)
*Cannot be done for patients receiving Anticoagulant Therapy
Subcutaneous Route of Administration
*nearly identical to IM injection's pharmacokinetics
-no barriers to absorption (capillary wall
-suitability of poorly soluble drugs and depot preparations
-discomfort, inconvenience, potential for injury
What are the major determinants of how fast drug absorption is with Subcutaneous Injections?
blood flow and drug solubility
Oral Route of Administration
*preferable route of administration
Oral Route of Administration Barriers to Absorption
*may be absorbed from the stomach, intestine, or both
*2 main layers to cross- 1. the layer of epithelial cells that lines the GI tract 2. the capillary wall
What is the major barrier to absorption for the Oral Route?
the GI epithelium
-the drug must pass through cells rather than between them
Intestinal absorption may be reduced by what system?
-transports drugs out of epithelial cells back into the intestinal lumen
Oral Route of Administration Absorption Pattern & Factors Affecting it
can be highly variable
*Factors that can Affect it:
-solubility and stability of the drug
-gastric and intestinal pH
-gastric emptying time
-food in the gut
-coadministration of other drugs
-special coatings on drug preparation
Drug Movement following Absorption of Oral Administration (GI tract)
except the oral mucosa and distal segment of the rectum
must pass through the liver via the portal blood vein before it can reach general circulation
-some drugs go through the liver, enter the inferior vena cava and eventually reach the general circulation
-other drugs may undergo enterohepatic recirculation
a repeating cycle in which a drug moves from the liver into the duodenum (via the bile duct) and then back to the liver (via the portal blood)
-specific for drugs that have undergone glucuronidation, then those drugs can enter the bile and pass to the duodenum
-once there they can be hydrolyzed by intestinal beta-glucuronidase
-the free drug is lipid soluble therefore can undergo reabsorption across the intestinal wall followed by transportation back to the liver where the cycle can start again
Oral Administration Advantages
*Easy, Convenient, and Inexpensive
-there is no cost for the administration process
*No risk of fluid overload, infection, or embolism
*Ideal for Self-Administration
-there are steps we can take to prevent absorption following inappropriate oral administration
-giving active charcoal
a compound that absorbs (soaks up) drugs while they are still in the GI tract
once they are absorbed onto the charcoal they cannot be absorbed into the bloodstream
Oral Administration Disadvantages
-rapidly or slowly and incompletely
-makes it difficult to control concentration, onset, intensity, and duration of responses
-some drugs can be destroyed by stomach acid, digestive enzymes or inactivation as they pass through the liver
-penicillin and insulin
-pt must be conscious and cooperative
-to the GI tract that can result in discomfort, nausea, and vomiting
First Pass Effect
drugs undergo extensive inactivation as they pass through the liver
Comparing Oral Administration with Parenteral Administration
Oral Administration is generally preferred
In what situations is parenteral administration preferred?
*Emergencies that requires rapid onset of drug reaction
*Situations in which plasma drug levels must be tightly controlled
*Treatment with drugs that would be destroyed by gastric acidity, digestive enzymes, or hepatic enzymes if given orally
*Treatment with drugs that would cause severe local injury if administered by mouth
*Treating a systemic disorder with drugs that cannot cross membranes
*Treating patients who cannot or will not take drugs orally
What are the different formulations into which a drug can be put for oral medication?
1. tablets 2. enteric-coated preparations 3. sustained-release preparations
if they contain the same amount of the identical chemical compound (drug)
if the drug they contain is absorbed at the same rate and to the same extent
-2 drugs can be chemically equivalent while differing in bioavailability
a mixture of a drug plus binders and fillers all of which have been compressed together
tablets made from different manufacturers can vary in disintegration and dissolution causing differences in bioavailability
*two tablets can contain the same drug and differ with respect to onset and intensity effects
consist of drugs that have been covered with a material designed to dissolve in the intestine but not the stomach
-include fatty acids, waxes, and shellac
What are the reasons for an enteric-coated preparations?
1. to protect drugs from acid and pepsin in the stomach
2. to protect the stomach from drugs that can cause gastric discomfort
What is the primary disadvantage of Enteric-Coated Preparations?
*that absorption can be even more variable than with standard tablets
-gastric emptying time can vary from minutes up to 12 hrs
- enteric-coated preparations cannot be absorbed until they leave the stomach
*sometimes fail to dissolve
Sustained- Release Preparations
capsules filled with tiny spheres that contain the actual drug; the individual spheres have coatings that dissolve at variable rates
drug is released steadily throughout the day
What is the primary advantage of sustained- release preparations?
they permit a reduction in the number of doses
they produce steady drug levels over an extended time
What are the major disadvantages of sustained- release preparations?
high cost and the potential for variable absorption
What other routes of administration can be used?
*topically for local therapy of the skin, eyes, nose, mouth, and vagina
*transdermal absorption into the systemic circulation
*inhaled to elicit local effects in the lungs (asthma)
*rectal suppositories for local effects
*direct injection into a specific site
What is distribution determined by?
1. blood flow to tissues 2. the ability of a drug to exit the vascular system 3. the ability of a drug to enter cells
Blood Flow to Tissues is obstructed by two types of conditions, which ones?
abscesses and tumors
-antibiotics cannot reach the bacteria within
refers to the unique anatomy of the capillaries in the CNS
tight junctions between the cells that compose the walls of most capillaries in the CNS
-these junctions prevent drug passage
only drugs that are lipid-soluble or have a transport system can cross the BBB
*it contains P-glycoprotein
-pumps drugs back into the blood and limits access to the brain
What is the advantage and disadvantage of BBB?
advantage-it protects the brain from injury by toxic substances
disadvantage- can be obstacle to therapy of the CNS disorders
Placental Drug Transfer
does not constitute an absolute barrier to the passage of drugs
lipid-soluble and nonionized compounds readily pass from the maternal
highly-polar or protein bound are excluded
substrates for p-glycoprotein are excluded
the most important and abundant protein in plasma
it always remains in the blood
Binding between albumin and drugs
Protein Binding's percentage is determined by what?
the strength of the attraction between the albumin and the drug
Hepatic Microsomal Enzyme System
AKA P450 system
-cytochrome a key component of this enzyme system
-not a single molecule entity but a group of 12 closely related enzyme families
-3 of the cytochrome P450 (CYP) families metabolize drugs
What are the possible consequences of metabolism?
-accelerated renal excretion of drugs
-increased therapeutic action
-activation of prodrugs
What is the main organ for excretion?
Which drugs are the kidneys unable to excrete?
highly lipid soluble
-drugs have to be more hydrophilic and this will accelerate the renal excretion
What kinds of metabolic transformations enhance excretion?
Panels 1A and 1B
a simple structural change (addition of a hydroxyl group) converts pentobarbital into a more polar (less lipid-soluble) form
a highly lipophilic drug is converted into a highly hydrophilic form by undergoing glucoronidation
a process in which a hydrophilic glucose derivative (glucoronic acid) is attached to phenytonin
-as a result phenytonin is rendered much more water soluble and can be rapidly excreted by the kidneys
How are glucuronides excreted?
by the kidneys or into the bile and then transported to the duodenum then excreted into the feces
a compound that is pharmacologically inactive as administered and then undergoes conversion to its active form within the body
process of stimulating enzyme synthesis
-Example: phenobarbital increasing metabolism by causing the liver to synthesize drug-metabolizing enzymes
What are the consequences of induction?
1. stimulating the liver to produce more drug-metabolizing enzymes
-increase in dosage to maintain therapeutic effects
2. can accelerate the metabolism of other drugs used concurrently necessitating an increase in their dosages
*the rapid hepatic inactivation of certain oral drugs
*if the capacity of the liver to metabolize a drug is extremely high that drug can be completely inactivated on its first pass through the liver
-to circumvent it, a drug is often administered parenterally
What processes result in urinary excretion?
1. glomerular filtration 2. passive tubular reabsorption 3. active tubular secretion
where renal excretion begins
consists of the capillary network surrounded by bowman's capsule
as blood flows through the glomerular capillaries, fluids and small molecules (drugs) are forced through the pores of the capillary wall
*moving drugs from the blood to urine
*blood cells and large molecules (proteins) do not undergo filtration
Passive Tubular Reabsorption
drug concentrations in the blood are lower than drug concentrations in the tubule
this concentration gradient acts as a driving force to move drugs from the lumen of the tubule back into the blood
-drugs that are lipid-soluble undergo this process but if not they remain in the urine for excretion
Active Tubular Secretion
pumps drugs from the blood to the tubular urine
*2 pumps: 1.one for organic acids and 2. one for organic bases
contain p-glycoprotein (into the urine)
pH dependent ionization
accelerated renal excretion of drugs
-because passive tubular reabsorption is limited to lipid-soluble drugs, ions are not lipid-soluble, drugs that are ionized will remain in the tubule to be excreted.
-by manipulating the pH in such a way as to promote the ionization of a drug, we can decrease passive reabsorption back into the blood and hasten the drug's elimination
What is an example in which pH dependent ionization is being manipulated?
aspirin poisoning (acidic drug)
-manipulating the urine's pH to become more basic (giving an agent that elevates urine pH)
-since aspirin is acidic and acid drugs tend to be ionized in basic environment, elevation of the pH will cause aspirin molecules to be ionized
Competition for Active Tubular Transport
-too many drugs will be waiting
-it can only carry a certain amount of drugs at once
-when administering 2 drugs at once that use the same transport system, excretion of each will be delayed by the other
When is competition of transport wanted?
when administering penicillin
-it excretes way too fast so they give it with another medicine so it stays in the body longer
Breast Milk Excretion
the factors that influence the appearance of drugs in breast milk are the same factors that determine the passage of drugs across membranes
-lipid-soluble drugs have ready access to breast milk
-polar, ionized, or protein bound cannot enter
*mothers should avoid all drugs because infants can be affected
What is the major route by which volatile anesthetics are excreted?
What is the significance of plasma levels?
the levels of plasma levels will indicate drug levels as well
-the therapeutic responses and the amount of drug present in plasma is directly correlated
What are the most important plasma drug levels?
1. the minimum effective concentration 2. the toxic concentration
Minimum Effective Concentration
-MEC is the plasma drug level below which therapeutic effects will not occur
-for a drug to be of benefit, it must present concentrations at or above MEC
occurs when plasma drug levels climb too high
doses must be kept small enough so that the toxic concentration is not reached
falling between the MEC and the Toxic Concentration
-there's enough drug present to produce therapeutic responses but not so much to cause toxic results
-drugs with a narrow therapeutic range are difficult to administered, but those with a wide therapeutic range can be administered safely with ease
Single-Dose Time Course
drug levels rise as the medicine undergoes absorption
drug levels then decline as metabolism and excretion eliminate the drug from the body
*latent period- between drug administration and onset of effects where the drug has not reached MEC yet
-this is determined by the rate of absorption
The duration of effects of a single dose is determined by what? -they are the primary determinants of how long drug effects will persist
combination of metabolism and excretion
-as long as drug levels remain above the MEC therapeutic responses will be maintained
-when drug levels fall below MEC, responses will cease
the time required for the amount of drug in the body to decrease by 50%
-some are short some are long
Example: Morphine 50 mg (half-life is 3 hrs)
-25 mg will be lost in 3 hrs
how much time separates each dose
- for drugs with a short half-life, the dosing interval must be short and vise versa
-that means that drugs with long intervals can separate doses without loss of benefits
when the amount of drug eliminated between doses equals the dose administered and average drug levels remain constant
-if administering a second dose before the 1st dose is completely eliminated, will tell us that the total dose will be higher than the initial dose
What is the plateau time?
approximately 4 half-lives
the highest level when drug is administered
-must be kept above MEC and below toxic concentration
the lowest level when drug is administered
-must be kept above MEC and below toxic concentration
What technique can be used to reduce fluctuations?
to administer drugs by continuous infusion
-this way plasma levels will be kept constant
to administer a depot preparation
-releases the drug slowly and steadily
to reduce both the size of each dose and the dosing interval
(giving a drug instead of 2 mg every 24 hours, 1 mg every 12 hours)
given when drug's half-lives are long and plateau must be achieved quickly
when drug levels have been established with a loading dose, plateau can be maintained by giving smaller doses
What is the usual half-life for drugs?
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