Principles of Pharmacokinetics Flashcards
Describe the overall general principles involved in absorption
-goal is to attain a therapeutic drug concentration in the plasma from which drug enters tissues so that a therapeutic window between toxic drug concentration and minimal effective concentration of the drug is reached
Describe the overall general principles involved in distribution
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Describe the overall general principles involved in metabolism
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Describe the overall general principles involved in elimination/excretion
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Describe the principles controlling the rate and extent of drug absorption with different routes of drug administration (i.e., oral vs. sublingual vs. IV vs. IM administration)
drug related properties -lipid-water solubility --> how much drug is dissolved in liquid vs water (polar coefficient) -molecular size -particle size -degree of ionization --> + or - charged; concerns pH --> unionized drugs cross membrane easily -physical forms -chemical nature -doasage forms -formulation -concentration Body related properties -want large area of absorptive surface -want high vascularity -pH (affected by ionization of drug) -presence of other substances --> creates competition -GI motility -functional integrity and absoprtive srface -diseases
Describe the principles determining the distribution of drugs throughout major body compartments
- endothelium: uncharged molecules best, p-glycoprotein transporters transport quaternary amines back into intestines
- BBB: poor transport due to tight junctions, antibiotics are too large
- Epithelium: acts as a barrier to poorly lipid soluble drugs, injury inflammation increases absorption
- site dependent high absorption areas: scrotum, forehead, abdomen
- Compartmentalization: absess formation, poor blood flow (ischemia)
- 2 Compartment Model:
- alpha phase: rapid redistribution (sent to tissue storage)
- beta phase: slow metabolism or excretion (slowly moves back into plasma
- drug is trapped by pH, chemcial composition, lipid solubility gradients
Describe the role of plasma protein binding in determining drug distribution, metabolism, & excretion
- only free drugs can be metabolized or excreted
- binding proteins for excess capacity: albumin, a1-glycoprotein, lipoproteins
- competitive binding between drugs – displaced drug must be highly bound; displacement drug must be highly bound and less potent/toxic; displaced dru must be highly potent
Describe the physiologic processes determining the rate of drug excretion by the kidney
- reversible to redistribution in fat (thiopental, general anesthetics)
- metabolism causes a more active drug
- metabolizes to pharmacologically inactive form of drug OR to water-soluble version –> excreted
Describe the calculation do renal clearance
liver blood flow * extraction ratio
(the volume of blood perfusing the liver that is cleared of the drug per unit time)
-genetics and cytochrome C affect extraction ratio
-large steroid-like drugs transported into bile and excreted
-lipid soluble have higher extraction ratio
Describe the process of phase I drug metabolism, providing three different examples
(mixed function oxidases) -located in SER Oxidative Reactions -hydroxylation, epoxide formation, desulfuration, desulfuration, dehalogenation, dealkinations Reduction Reactions -aldehydes and ketones Hydrolytic Reactions
Describe the process of phase II drug metabolism, providing three different examples
-glucuronic acid conjugation
-sulfate conjugation
-AA conjugation
-acetylation (N-acetylation is most common)
methylation
Describe the various reactions mediated by P-450 mixed function oxidases in phase I metabolism
- Reduced flavoprotein oxidized flavoprotein
- various isoforms used to metabolize endogenous steroids; make drugs more polar and water soluble; can be induced or inhibited
Describe the importance of cytochrome P450 polymorphisms in the actions of prodrugs and drugs dependent upon P450 inactivation
-turns morphine on and off by demethylating 2 different side groups
Calculate renal (and hepatic) clearances from physiologic data
(urine conc. * urine volume)/plasma conc.
Define “apparent volume of distribution”
Vd(L) = (absorbed dose (mg))/(Cp(time 0)(mg/L))
- caffeine and theophylline distribute evenly in total body water
- lidocaineextensive binding to plasma proteins
- Digoxin extensively binds to skeletal muscle
- Chloroquine and nortriptyline accumulate in body fat
