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Pharm Basics High Yield Greg Gayer (C) Greg Gayer Do Not Distribute without permission 1 Pharmacokinetic Key Concepts (C) Greg Gayer Do Not Distribute without permission 2 Pharmacokinetics: Key concepts Bioavailability (F) Drug absorbed distribute to (carrier protein for lipophilic drugs) Barrier Target Oral (F=depends on absorption and 1st pass) Free Drug--Permeate across barriers transporters (facilitated/active) passive diffusion acid:base distributed IV (F=1) Liver metabolism (1st pass) Absorbed (lipid solubility, charge, size, structure) (C) Greg Gayer Do Not Distribute without permission 3 Pharmacokinetics: Permeation (high yield) • Most drugs are weak acid and bases Log P/unP = Pka-pH Weak acid H+ + A- = HA •Unprotonated •charged •Hydrophilic •excreted O - H3C + H+ O Weak base Note: opposite •Protonated •uncharged (neutral) •Lipophilic (crosses membranes absorbed or reabsorbed) OH = H3C B + H+ = BH+ •Unprotonated •Uncharged •lipophilic (crosses membranes absorbed or reabsorbed) NH2 O N CH3 CH3 Ibuprofen (Advil, etc.) CH3 (C)CH Greg Gayer Do Not Distribute without 3 permission + H+ = •Protonated •charged •Hydrophilic •excreted + NH3 N Tacrine (Cognex) 4 Renal Drug Excretion High pH (making urine more basic accelerates excretion of weak acid) Low pH (acidifying urine accelerates excretion of a weak base) Urine pH X Urine pH X H+ + A- H+ + A- = HA = HA ↓[H+] ↑[H+] B + H+ = BH+ B + H+ = BH+ Excretion accelerated Weak acid: protonated, uncharged, lipid soluble, reabsorbed Weak base: protonated, charged, lipid insoluble, excreted (C) Greg Gayer Do Not Distribute without 5 permission Excretion accelerated 5 Volume of distribution (Vd) Cp X Vd Loading dose F Cp X Vd t1 / 2 F Used to calculate Loading dose and t1/2 Amount of drug in body Vd Cplasma (Units=volume) Water soluble drugs A A A A A A A A A Vd = 10/10 =1L A Small Vd B B B B B B B B B B Fat soluble drugs Vd = 10/1 =10L Large Vd apparent volume: “the volume needed to contain the amount of drug at the concentration found in the blood” (C) Greg Gayer Do Not Distribute without permission 6 Clearance (CL) Rate of eliminatio n CL C in (Units = volume per unit time) (L/h/70kg) out Dosing rate = Cl (Css) •Used to calculate maintenance dose (steady state level) •Used to calculate drug half life •Varies with age (C) Greg Gayer Do Not Distribute without permission 7 Two types of drug elimination 1) “Zero-order” : saturable • Ethanol, high dose (aspirin, phenytoin) 2) “First-order” : non-saturable (C) Greg Gayer Do Not Distribute without permission 8 Zero-Order Elimination Rate •Other names: capacity-limited, saturable, dose- or concentrationdependent, Michaelis-Menten elimination etc. •Rate of elimination = Vmax x C Km + C •At high concentration (relative to KM) elimination becomes independent of C •Drugs: Ethanol, Phenytoin, and Aspirin Zero order = Vmax x Km + C C = Vmax (C) Greg Gayer Do Not Distribute without permission 9 Zero-Order Elimination Rate 1000 Molecules 100 Molecules 500 • A constant amount of drug is eliminated per unit time. • Drugs with zero-order elimination have no fixed half-life (t1/2 is a variable). Unit of Drug – E.g. 1000 v 500 units ingested • Metabolize 100 units per hour 100 250 – It would take 5 hours and 2.5 to reduce 1000 units and 500 in half, respectively 100 TIME (C) Greg Gayer Do Not Distribute without permission 10 First-Order Elimination Rate • Most drugs • A constant fraction of the drug is eliminated per unit time. Fraction • Non-saturable metabolized – Note: blood flow can be limiting factor • t1/2 is a constant dependent on Vmax and Km of metabolic enzymes (C) Greg Gayer Do Not Distribute without permission 3 different drug concentrations First order A vast excess of enzymes per drug ratio = first order kinetics. Metabolic capacity cannot be saturated at therapeutic concentrations 11 First-Order Elimination Rate e.g 90% eliminated 1000 molecules Constant fraction cleared more drug = more elimination Unit of Drug 900 molecules Clearance CL = Rate of elimination Plasma Concentration (Cp) 100 Rate of elimination = Cl X Cp 90 Cl = k X Vd 10 9 TIME (C) Greg Gayer Do Not Distribute without permission 12 Half-Life (1st order elimination) • After 4 half lives 93.75% of the drug is removed from the body 4 12.5 6.25 0 3 25 2 50 1 t1/2 Amount in body 100 time (C) Greg Gayer Do Not Distribute without permission 13 Bioavailability (F) F = AUCPO AUCIV By definition IV admin F=1 Metabolism by liver (1st pass) Plasma [drug] Fraction of a dose that reaches the systemic circulation AUCIV Absorption through gut (C) Greg Gayer Do Not Distribute without permission AUCPO Time 14 Bioequivalence Preparations of drug have the same bioavailability FDA: Trade v Generic should be 80-120% similar AUC Plasma [drug] AUCPO AUCPO Minimum effective concentration Minimum effective concentration Yes No Duration of action Duration of action Time (C) Greg Gayer Do Not Distribute without permission Time 15 Steady State Plasma levels • Target concentration (TC): serum level that produces desired effect. When the curve is no longer rising steady state is reached. At this point the amount given matches the amount cleared (in = out) and is defined as steady state Cl X Cp Maintence Dose F toxicity Plasma levels (ug/ml) 8 Dose X dosing rate Steady state 4 (In = out) 2 Minimum effectiveness clearance 1 1 2 3 4 (C) Greg Gayer Do Not Distribute without permission 5 6 16 Time to steady state and Maintenance dose • Time to steady state is dependent on drug ½ life only. Or, the shape of the curve reflects half life of the drug Dose 1 2 3 4 5 In this diagram several doses of the same drug are administered 50 25 3 2 1 t1/2 0 4 Plasma levels (ug/ml) 100 1 2 3 time (C) Greg Gayer Do Not Distribute without permission 4 5 6 17 TIME to steady state Plasma levels (ug/ml) Run this slide in PPT mode: Note: 1) How stacking the new dose on top of the amount remaining from the previous dose increases the plasma level. 2) When the amount of the first dose becomes negligible it no longer contributes to the overall plasma level. In general 4 half lives. 3) How the overall plasma level curve at the top mirrors the elimination curve. This the underlying basis for why t1/2 dictates time to steady state. (C) Greg Gayer Do Not Distribute without permission Css time 18 Shape of curve reflects Drug t1/2 and Time to Steady state Steady State Levels Unit of Drug 100 Multiple doses are not shown 50 Drug B Elimination rate Drug A TIME (C) Greg Gayer Do Not Distribute without permission 19 STEADY STATE RULE Plasma levels (ug/ml) If all of this PPT fails to help MEMORIZE the Rule below 16 14 12 8 93.75% 87.5% Css 75% • Quick rule of thumb – – – – 50% t 1/2 t 1/2 t 1/2 1 (C) Greg Gayer Do Not Distribute without permission 2 50% of steady state = 1 ½ life 75% = 2 87.5% = 3 93.75 = 4 or 90% =3.3 t 1/2 3 time 4 5 e.g. Drug A half life of 1 20 hour Why is biotransformation necessary? • Lipophilic molecules (xenobiotics, foreign molecules) must be charged to be excreted without reabsorption. reabsorption Lipophilic molecule Biotransformation+ Excretion = termination of drug effect -(C) Greg Gayer Do Not Distribute without permission 21 Phase I & II biotransformation • Phase I • Phase II – add or expose functional groups on parent molecules (OH, -NH2, -SH) – Elderly lose phase 1 – loss of pharmacologic activity • sometimes increase activity, eg. prodrugs – Located on smooth ER • Cytochrome P450 family (CYP) – Drug interactions » Inhibited » Induction (gene expression) – Biosynthetic reactions – covalent linkage (conjugations) with various molecules • glucuronic acid, sulfate, glutathione, amino acids, acetate – Mostly cytosolic localization – May precede phase1 reactions with some drugs (C) Greg Gayer Do Not Distribute without permission 22 Phase I & II biotransformation acetaminophen isoniazid 2E1 (induced by ethanol) INH (isoniazid) (TB med) Treats neurons and hepatocytes poorly Antidote: N-acetylcysteine regenerate glutathione (C) Greg Gayer Do Not Distribute without Figure 4.4, Katzung permission 23 Human liver P450 family CYP isotype Substrate Example Inducers (gene expression ↑ Inhibitors (inhibit activity of # enzymes = less drug effect) existing enzymes = more drug toxicity) 1A2 12% drugs Theophylline Acetaminophen Aromatic Hydrocarbons (smoke) Cruciferous vegetables, omeprazole Cimetidine, quinolones, grapefruit juce, macrolides, isoniazid, zileuton 2C9 4% of drugs Phenytoin Warfarin General inducers (see next slide) Amiodarone, cimetidine, isoniazid, metronidazole, SSRIs, zafirlucast 2D6 28% of drugs Many CV & CNS drugs St. John’s wort rifampin Amiodarone, paroxetine Quinidine 2E1 Acetaminophen, gas anesthetics, Ethanol, isoniazid disulfiram 3A4 50% of drugs General inducers (see next slide) General Inhibitors (see following 24 slide) Grapefruit juice in PDR (C) Greg Gayer Do Not Distribute without permission Board Mnemonics General inducers: Drug-drug interaction: More enzymes = metabolism = effect • Barbiturates, Phenytoin, Rifampin, Griseofulvin, Carbamazepine (Barb takes Phen-phen & Refuses • Rifampin’s 4 R’s: Greasy Carbs) •RNA polymerase inhibitor •Revs up microsomal P-450s •Red/orange body fluids •Rapid resistance General Inhibitors: Drug-drug interaction: inactive enzymes = metabolism = effect or toxicity • Isoniazid, Sulfonamides, Cimetidine, Ketoconazole, Erthromycin, Grapefruit juice. Inhibitors Stop CyberKids from Eating Grapefruit. 25 (C) Greg Gayer Do Not Distribute without permission Development & Regulation of Drugs In vitro studies Animal Testing Human Clinical Trials Screening Testing Lead drug: Mechanism Efficacy Selectivity Toxicity (minimum and median lethal dose, terato-, carcino-, mutagenicity Pharmacokinetics 0 Phase 1 Non-blind small # (25-50) study in healthy volunteers comparing animals to humans: testing safe dose, pharmacokinetics, 4 8-9 IND NDA (C) Greg Gayer Do Not Distribute without permission 26 Development & Regulation of Drugs In vitro studies Animal Testing Human Clinical Trials Screening Testing Lead drug: Mechanism Efficacy Selectivity Toxicity (minimum and median lethal dose, terato-, carcino-, mutagenicity Pharmacokinetics 0 Phase 1 Phase 2 single-blind small # (100-200) study in patients with target disease. Efficacy in patients 4 8-9 IND NDA (C) Greg Gayer Do Not Distribute without permission 27 Development & Regulation of Drugs In vitro studies Animal Testing Human Clinical Trials Screening Testing Lead drug: Mechanism Efficacy Selectivity Toxicity (minimum and median lethal dose, terato-, carcino-, mutagenicity Pharmacokinetics 0 double-blind large multi-center study in Phase 1with target disease. Efficacy in patients patients without placebo effect Phase 2 Phase 3 4 8-9 IND NDA (C) Greg Gayer Do Not Distribute without permission 28 Development & Regulation of Drugs In vitro studies Animal Testing Human Clinical Trials Screening Testing Lead drug: Mechanism Efficacy Selectivity Toxicity (minimum and median lethal dose, terato-, carcino-, mutagenicity Pharmacokinetics 0 Phase 1 Post marketing surveillance Phase 2 Phase 3 Phase 4 4 8-9 IND NDA (C) Greg Gayer Do Not Distribute without permission 20 Patent expired29 Pharmacodynamic Key Concepts (C) Greg Gayer Do Not Distribute without permission 30 Quantitation of Drug-Receptor Interactions and Elicited Response Drug (C) + receptor (R) k1 k2 CR effect Reflects Efficacy Emax Maximal intracellular response produce when all receptors are occupied R Reflects Affinity or potency KD = [free drug] at which half-maximal binding R is observed or the [drug] in which half the receptors are filled . KD = EC50 (no spare receptors). KD >EC50 (+ spare receptors). EC50 log[Agonist] R 31 Clinical Relevance • Potency: drug concentration (EC50) or dose (ED50) required to produce 50% of drugs maximal effect. – Depends on affinity (KD) of drug-receptor binding – determines the dose necessary to administer to patient • Efficacy: magnitude of response produced by drug – clinically more important than potency when selecting a drug Potency 100 Drug C Drug A Drug B 50 EC50 log[Agonist] EC50 32 Partial Agonist •Partial agonist: produce a lower response than full agonist when all receptors are bound 100 •This effect has nothing to do with affinity of the drug for the receptor Full Agonist Full Agonist 50 Partial Agonist log[Full Agonist or Partial Agonist] Partial Agonist log[Agonist] 33 Partial agonist can act as antagonist Pharmacologic Response Net response E.g pindolol use in hypertension Partial agonist contribution Full agonist contribution Log (partial agonist) See Fig. 2-6C Katzung 34 Competitive & Irreversible Antagonist Intracellular cascade (biologic response) agonist outside No conformational change in receptor antagonist inside outside inside Antagonist have no intracellular effects when given alone Antagonist work by blocking function of agonist Full agonist or partial agonist will produce a biologic response (intracellular cascade) 35 Competitive Antagonist Low [ ] compared to [ ] Agonist High [ ] compared to [ ] Antagonist Agonist = Antagonist = 100 Bind to receptor without activating them. Binding can be competed for by increasing agonist amount 50 EC50 (agonist alone) log[Agonist] EC50 (+competitive antagonist) 36 Irreversible Antagonist Covalent linkage 100 Agonist alone 50 + antagonist log[Agonist] Also know as noncompetitive antagonist: Antagonist bind with such tight affinity that they never come off no matter how much agonist is present. Usually covalent bonds (phenoxybenzamine is an example) 37 Signal Transduction Autonomic Receptor Mnemonic HAVe 1 M&M H1, 1, V1, M1, M3 R Gq PIP2 DAG • “Qiss (kiss) and qiq (kick) till you’re siq receptor G-protein class (sick) of sqs (sex)” [Ca]in IP3 PLC Autonomic Receptor mnemonic Or X1 = Gq but betas (all Gs coupled) and the dumb Ds PKC 1, 2, D1, H2, V2 R Gs AC cAMP MAD 2s M2, 2, D2 R Gi AC (C) Greg Gayer 1/2008 • • • • PKA cAMP PKA 1st Aide USMLE 17 X2 = Gi coupled but betas and V2 MI M2 M3 D1 D2 H1 H2 V1 V2 q i s s q i q s i q s q s Kiss kick sick sex 1st Aide USMLE Ligand-gated ion channels: N-Ach (Na+/Ca++), GABAa (Cl-), NMDA (Na+/Ca++), Intracellular receptors: steroids, thyroxine, Tyrosine Kinase (transmembrane with TK intracellular domain): Insulin and some growth factor receptors (PDGF, EFF) Transmembrane receptors that activate intracellular cytoplasmic tyrosine kinases then Jac/STAT transcription factors: cytokines, erythropoietin, and growth (C) Greg Gayer Do Not Distribute without hormone receptors 38 permission Quantal Dose Response Curves Potential Variability Between Individuals 100 Number of persons responding 80 Quantal dose response curves represent large number of individual patients or experimental animals response to various drug concentrations while observing a single set data point--e.g. lower bp 10 mmHg, speed HR by 10 bpm, etc. It is useful in determining a drug concentration that 50% of the population will respond to in the expected therapeutic end point. 60 40 20 o Drug Concentration 39 Quantal Dose Response Curves Measure of the safety or therapeutic window of a drug. Goodman & Gilman’s The pharmacological basis of therapeutics, 9th edition, Fig 3-3 ED50: median effective dose (dose at which 50% of individuals exhibit specific effect). TD50: dose required to produce a particular toxic effect in 50% of animals tested. LD50: 50% death 40 Therapeutic index = LD50/ED50: A rough measure of drug safety margin.