A4. Drug biotransformation, linear and non-linear kinetics. Enzyme inhibition and induction. Clearance, half-life, loading and maintenance dose. Elimination. Pharmacokinetic drug interactions Flashcards
Biotransformation:
inactivation of molecules + making them more water-soluble so they can be excreted in the urine. (If molecules are too lipid-soluble, they will be reabsorbed in the kidneys) • Takes place in hepatocytes. Divided into Phase I and Phase II reactions. • Phase I reactions: Yields slightly polar, water-soluble metabolites that are often still active. o Main chemical reactions: oxidation, reduction, or hydroxylation. o Usually performed by CYP450. Most important ones are CYP3A4/A5 and CYP2C9. o If not CYP450, then can be flavin monooxygenase, amine oxidases, or dehydrogenases • Phase II reactions: also called conjugation. Usually yields very polar, inactive metabolite to be excreted by kidney o Main chemical reactions: Methylation, glucuronidation, acetylation, sulfation. o Not always inactivated: e.g. Morphine-6-OH glucuronide can still have an effect o Some genetic variability, e.g. slow acetylators have ↑ duration of effects due to lower rate of metabolism • CYP450 induction: increased transcription and inhibited degradation. Means that drugs are metabolized/inactivated more quickly. o Examples: barbiturates, rifampin, griseofulvin, nevirapine, phenytoin, carbamazepine, St. John’s Wort • CYP450 inhibitors: usually to CYP3A4. Means that drug effects may last longer. o Examples: -azole antifungal drugs, ritonavir, macrolides (especially clarithromycin and erythromycin, not azithromycin), isoniazid, sulfa antibiotics, chloramphenicol, streptogramins, cimetidine, ethinylestradiol, grapefruit juice
Linear and Non-linear Kinetics:
• First Order (Non-Linear) Kinetics: applies to the vast majority of drugs. o Rate of drug metabolism is directly proportional to concentration of the free drug. A constant fraction of the drug is eliminated per unit time o V = Vmax * [C] / Km o (V = rate of metabolism / Vmax = rate when system is saturated / [C] = drug conc. / Km = conc. when rate is 1/2 Vmax) • Zero Order (Linear) Kinetics: o Rate of elimination is independent of concentration. Occurs when elimination process is saturated. Elimination is slower than first-order, and half-life cannot be determined – fraction of drug eliminated per unit time is not constant o Main examples are phenytoin and alcohol
Clearance:
aka CL. The volume of blood cleared of a drug by metabolism and excretion per unit time • Katzung: Clearance = Rate of elimination of drug / plasma drug concentration • Lecture: Clearance = M * AUC. (M = dose, AUC = area under the curve). AUC represents total drug exposure over time, and it is proportional to the total amount of drug absorbed by the body. • (Units = volume per unit time) • First-order kinetics: clearance is constant. • Zero-order kinetics: elimination rate is constant, but clearance is not constant. • Clearance depends on drug, blood flow, and condition of organs for eliminating (e.g. renal failure → ↓ clearance) • Total body clearance = metabolic clearance + renal clearance + other clearances (e.g. total clearance = hepatic clearance + renal clearance + pulmonary clearance + other clearance)
Half-life: aka T1/2
• The time interval during which the concentration of a drug in the body changes by 50%. Note that this can refer to an increase or decrease in concentration, depending on whether absorption/distribution or elimination is being observed. • Must know volume of distribution and clearance to determine half-life. It is directly proportional with volume of distribution, and inversely proportional to clearance. • T1/2 = (0.693 x Vd) / CL. Can also be written T1/2 = Vd / CL * ln 2. [Note: ln 2 = natural log of 2]
Steady State Concentration; Loading and Maintenance Doses:used to determine the proper dose regimen
• Steady State Concentration (CSS) is the concentration of the drug in the plasma when the rate of infusion equals the rate of elimination. o CSS = R0 / CL. o (CSS is positively correlated with infusion rate (R0), while inversely proportional to clearance) o At one half-life, the drug is at 50% of CSS. At 2 half-lives, the drug is at 75% of the CSS. It takes 3 half- lives to reach about 90% of the full CSS. o Increasing the dose → CSS ↑ because it essentially increases the infusion rate. Increasing the dose interval also increases the CSS
• Loading dose
: if it is necessary to reach the target plasma level rapidly, a (typically larger) initial dose can be used to “load” the Vd with the drug o Loading dose = (Vd x CSS) / bioavailability o Note that clearance is not part of this equation. o If loading dose is large, the dosage should be given slowly to prevent toxicity due to higher plasma levels in the beginning (distribution) phase.
• Maintenance dose:
continuous administration to keep the plasma drug level at around a certain level o Maintenance dose = (clearance x CSS) / bioavailability o Note this means that maintenance rate should be equal to the rate of elimination at steady state
Elimination:
• Modes of Elimination: o Renal: Glomerular filtration, active tubular secretion, passive diffusion o Biliary excretion: e.g. digitoxin, morphine, chloramphenicol, nafcillin, warfarin o Lungs: mostly for inhaled gases o Breast milk o Assorted: Sweat, saliva, tears, hair, skin • Renal or cardiac disease often reduce the rate of renal elimination. Liver disease may sometimes also impair elimination. Must correct adapt the doses to these parameters, especially by using the creatinine clearance/GFR. • Weak acids (e.g. phenobarbital, methotrexate, aspirin) won’t be reabsorbed from the urine if it’s basic. Alkalinize the urine to increase elimination. • Weak bases (e.g. TCAs, amphetamines) won’t be reabsorbed from the urine if it’s acidic. Acidify the urine to increase their elimination.
Pharmacokinetic drug interactions: examples
• Synergistic good: synergistic combinations that can be used to help patients o Ritonavir inhibits CYP metabolism of many drugs: AIDS treated with protease inhibitors, including ritonavir. Combining ritonavir with other protease inhibitors like darunavir means that a lower dose can be taken as the drug will stay active in the body longer. o Imipenem + cilastatin: imipenem metabolized by kidney, cilastatin can inhibit. o Amoxicillin + beta lactamase inhibitors – inhibit bacterial beta lactamases so that beta lactams can continue to be effective o (Second semester) - Glycoprotein P pumps out drugs from the CNS. If you block glycoprotein P, then you allow it to work in CNS better. Loperamide opioid gets pumped out of CNS this way despite mu activity, theoretically could inhibit glycoprotein P and make it have CNS effects like morphine. • Synergistic bad: synergistic combinations that can harm patients o Warfarin + Clarithromycin: clarithromycin inhibits CYP3A4 → warfarin level increases → bleeding o Ethynyl estradiol + clarithromycin: ethynyl estradiol is in contraceptive pills, also metabolized by CYP3A4. In this case, an interaction can occur when you stop clarithromycin: the CYP enzymes are over-active and ethynyl estradiol is metabolized too much, and then get no more contraceptive benefit • Antagonistic good: drug effects oppose each other in a beneficial way o Toxin + activated charcoal: activated charcoal helps prevent absorption of the drug o Unconjugated bilirubin + phenobarbital: phenobarbital is an enzyme inducer, can be used to induce UGT and conjugate bilirubin faster o Phenobarbital + acetazolamide + NaHCO3: phenobarbital is acidic so in case of overdose, you can alkalinize the urine with acetazolamide and bicarbonate to prevent reabsorption of phenobarbital • Antagonistic bad: drug effects oppose each other in a harmful way o Cholestyramine + thiazide diuretics: cholestyramine binds to many drugs, in this case would prevent thiazides from being absorbed o Tetracycline + Calcium-Magnesium-Iron containing medicines or food: bivalent cations precipitate with tetracycline in the gut, prevent absorption o Nifedipine + rifampin: rifampin speeds up enzymes, negates the effect of nifedipine.
