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Lecture 3
Pharmacokinetics II
| Question | Answer |
|---|---|
| Metabolism | process of eliminating from the body; liver = main organ of metabolism; first pass = oral & rectal; kidneys don't excrete lipophilic drugs well --> high absorption; hydrophilic --> high elimination |
| Metabolism | Start= inactive (prodrug) Result = active drug Examples = codeine --> morphine |
| Inducers: SCRAP GP | Sulfonylureas, smoking carbamazepine, corticosteroids Rifampin Alcohol (chronic) Phenytoin Griseofulvin Phenobarbital |
| Inhibitors: VIDEOCASE | valproate isoniazid disulfiram erythromycin, clarithromycin (not azithromycin) omezaprole clmetidine allopurinol sulfonamides ethanol (acute) |
| Clearance ** | volume of blood from which drug is cleared per unit of time (volume/time = mL/min) |
| Clearance ** | volume needed to clear drug NOT amount of drug cleared |
| Clearance | kidneys most important route of elimination; renal function important |
| Clearance | clearance of unchanged drug in urine is due to renal clearance; liver = biotransformation of parent drug to metabolites and/or excretion of unchanged drug into bile |
| Renal elimination | drug passes through several processes in kidney prior to elimination: glomerular filtration, active tubular secretion, passive tubular reabsorption |
| Reabsorption** | back into blood |
| Secretion** | drug excreted into urine |
| Glomerular Filtration | drugs enter through renal arteries; free drug flows into Bowman space as part of glomerular filtrate; lipid solubility and pH not a factor; GFR and protein binding are factors |
| Glomerular Filtration Rate (GFR) ** | normally about 120mL/min/1.73m^2 |
| Proximal tubular secretion | secretion primarily occurs in proximal tubules through energy-requiring active transport systems |
| Ion trapping ** | changing pH of urine can increase amount of charged drug --> decreases reabsorption of drug; weak acids eliminated by alkalization of urine; weak bases eliminated by acidification of urine |
| Clearance types of elimination ** | capacity-limited: Michaelis Menten Kinetics; clearance has no real meaning (varies with drug concentration); flow-dependent |
| Flow dependent elimination ** | main determinant of drug delivery = blood flow to organ |
| Lipid soluble drugs metabolized into more polar substances through 2 sets of reactions: Phase 1 | introduces or unmasks a polar functional group, usually involves reduction, oxidation, or hydrolysis, involves the cytochrome p450 system (heme containing enzymes), |
| Lipid soluble drugs metabolized into more polar substances through 2 sets of reactions: Phase 1 | convert parent drug to more polar metabolite by introducing or exposing a functional group, if sufficiently polar, drug eliminated |
| Lipid soluble drugs metabolized into more polar substances through 2 sets of reactions: Phase 2 | conjugation rxns, glucuronidation, parent drugs or phase I metabolites undergo coupling or conjugation rxns, uses enzymes (transferases) to attach small endogenous polar molecules to drug |
| Lipid soluble drugs metabolized into more polar substances through 2 sets of reactions: Phase 2 | faster than P450 reactions --> accelerated drug biotransformation, involves high energy intermediates and transferases, transferases located in microsomes or cytosol, UGT's most dominant enzymes |
| cytochrome p450 system | drug metabolizing enzymes located in ER membranes of liver |
| cytochrome p450 system | CYP3A4 most common; metabolizes 50% of drugs 3: family A: subfamily 4: isozyme |
| cytochrome p450 system | CYP2D6 famous for polymorphisms (codeine --> morphine) |
| cytochrome p450 system induction | induction: enhances its rate of synthesis or reduces rate of degradation --> increases availability of enzyme; environmental chemicals and pollutants able to induce P450 (tobacco smoke, charcoal-broiled meat) |
| cytochrome p450 system induction | P450 synthesis increased by enhancing transcription, translation, heme synthesis; induced by substrate stabilization |
| cytochrome p450 system ** induction | induce --> "activate" or "increases its activity" --> increases metabolism by CYP enzyme --> decreases plasma concentrations of substrates |
| cytochrome p450 system induction | isozyme: CYP2C9/10 warfarin = substrate metabolized by that substrate |
| inhibition | certain drugs able to inhibit CYP450 activity |
| inhibition | may lead to increases in plasma drug concentration |
| inhibition | most common form of inhibition = competition for same isozyme |
| inhibition ** | if cyp enzymes inhibited --> metabolism of meds metabolized by specific CYP enzyme is inhibited --> increases plasma drug concentration & increases potential for adverse effects/drug toxicity |
| Kinetics of metabolism: first order | rate of drug metabolism and elimination directly proportional to concentration of free drug; concentration dependent; constant fraction of drug metabolized per unit of time; also known as linear kinetics |
| Kinetics of metabolism: first order | increasing plasma drug concentration --> increases rate of metabolism; rate of metabolism proportional to drug concentration --> constant proportion/time = 20%/hour; constant half-life; clearance is constant; most drugs |
| Kinetics of metabolism: zero order | rate of metabolism remains constant over time; not dependent on drug concentration; constant amount of drug metabolized per unit of time; nonlinear kinetics |
| Kinetics of metabolism: zero order | at max capacity, all enzymes working --> rate of metabolism independent of drug concentration; rate of metabolism is constant; ASA, phenytoin, ethanol |
| Half life ** | time required to change amount of drug in body by one half during elimination |
| half life ** | 95% of drug eliminated after approximately 4.5 half lives |
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bluedolphin7
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