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Pharm Basics High Yield

Pharm Basics High Yield. Greg Gayer. Pharmacokinetic. Key Concepts. Pharmacokinetics: Key concepts. Bioavailability (F). Drug  absorbed  distribute to (carrier protein for lipophilic drugs) Barrier Target. Oral (F=depends on absorption and 1 st pass). IV (F=1).

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Pharm Basics High Yield

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  1. Pharm Basics High Yield Greg Gayer (C) Greg Gayer Do Not Distribute without permission

  2. Pharmacokinetic Key Concepts (C) Greg Gayer Do Not Distribute without permission

  3. Pharmacokinetics:Key concepts Bioavailability (F) Drug  absorbed  distribute to (carrier protein for lipophilic drugs) Barrier Target Oral (F=depends on absorption and 1st pass) IV (F=1) Liver metabolism (1st pass) Free Drug--Permeate across barriers transporters (facilitated/active) passive diffusion acid:base distributed Absorbed (lipid solubility, charge, size, structure) (C) Greg Gayer Do Not Distribute without permission

  4. - O + O H N H N H 3 2 O H C O 3 H C 3 N N C H 3 C H 3 C H 3 C H 3 Pharmacokinetics:Permeation(high yield) Log P/unP = Pka-pH • Most drugs are weak acid and bases Weak acid Weak base Note: opposite H+ + A-= HA B + H+= BH+ • Unprotonated • charged • Hydrophilic • excreted • Protonated • uncharged (neutral) • Lipophilic (crosses membranes absorbed or reabsorbed) • Unprotonated • Uncharged • lipophilic (crosses membranes absorbed or reabsorbed) • Protonated • charged • Hydrophilic • excreted + H+ + H+ = = Tacrine (Cognex) (C) Greg Gayer Do Not Distribute without permission Ibuprofen (Advil, etc.)

  5. 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-= HA H+ + A-= HA ↓[H+] ↑[H+] B + H+= BH+ B + H+= BH+ Weak acid: protonated, uncharged, lipid soluble, reabsorbed Weak base: protonated, charged, lipid insoluble, excreted Excretion accelerated Excretion accelerated 5 (C) Greg Gayer Do Not Distribute without permission

  6. (Units=volume) Volume of distribution (Vd) Used to calculate Loading dose and t1/2 Water soluble drugs A A A A Vd = 10/10 =1L A A A A A A Small Vd B B B B Vd = 10/1 =10L B B Large Vd B B B B • apparent volume: “the volume needed to contain the amount of drug at the concentration found in the blood” Fat soluble drugs (C) Greg Gayer Do Not Distribute without permission

  7. Clearance (CL) (Units = volume per unit time) (L/h/70kg) in 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

  8. Two types of drug elimination • “Zero-order” : saturable • Ethanol, high dose (aspirin, phenytoin) • “First-order” : non-saturable (C) Greg Gayer Do Not Distribute without permission

  9. Zero-Order Elimination Rate Vmax x C = Km + C Vmax = • Other names: capacity-limited, saturable, dose- or concentration-dependent, Michaelis-Menten elimination etc. • Rate of elimination = Vmax x C • At high concentration (relative to KM) elimination becomes independent of C • Drugs: Ethanol, Phenytoin, and Aspirin Zero order Km + C (C) Greg Gayer Do Not Distribute without permission

  10. 1000 Molecules 100 Molecules 500 100 250 100 Zero-Order Elimination Rate • 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). • E.g. 1000 v 500 units ingested • Metabolize 100 units per hour • It would take 5 hours and 2.5 to reduce 1000 units and 500 in half, respectively Unit of Drug TIME (C) Greg Gayer Do Not Distribute without permission

  11. First-Order Elimination Rate • Most drugs • A constant fraction of the drug is eliminated per unit time. • Non-saturable • Note: blood flow can be limiting factor • t1/2 is a constant 3 different drug concentrations First order Fraction metabolized dependent on Vmax and Km of metabolic enzymes A vast excess of enzymes per drug ratio = first order kinetics. Metabolic capacity cannot be saturated at therapeutic concentrations (C) Greg Gayer Do Not Distribute without permission

  12. e.g 90% eliminated 1000 molecules 900 molecules 100 90 10 9 First-Order Elimination Rate Constant fraction cleared more drug = more elimination Clearance CL = Rate of elimination Plasma Concentration (Cp) Unit of Drug Rate of elimination = Cl X Cp Cl = k X Vd TIME (C) Greg Gayer Do Not Distribute without permission

  13. Half-Life (1st order elimination) • After 4 half lives 93.75% of the drug is removed from the body 100 Amount in body 50 25 1 t1/2 12.5 2 3 6.25 4 0 time (C) Greg Gayer Do Not Distribute without permission

  14. AUCIV Bioavailability (F) Fraction of a dose that reaches the systemic circulation F = AUCPO AUCIV Metabolism by liver (1st pass) Plasma [drug] AUCPO Absorption through gut Time By definition IV admin F=1 (C) Greg Gayer Do Not Distribute without permission

  15. Bioequivalence Preparations of drug have the same bioavailability FDA: Trade v Generic should be 80-120% similar AUC AUCPO AUCPO absorption absorption Minimum effective concentration Minimum effective concentration Plasma [drug] Yes No Duration of action Duration of action Time Time (C) Greg Gayer Do Not Distribute without permission

  16. 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 toxicity 8 Dose X dosing rate Steady state 4 Plasma levels (ug/ml) (In = out) 2 Minimum effectiveness clearance 1 1 2 3 4 5 6 (C) Greg Gayer Do Not Distribute without permission

  17. 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 5 100 In this diagram several doses of the same drug are administered 50 6 1 t1/2 Plasma levels (ug/ml) 25 3 1.5 2 0 .75 3 4 1 2 3 4 5 6 time (C) Greg Gayer Do Not Distribute without permission

  18. TIME to steady state 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. 6 Plasma levels (ug/ml) 3 Css 1.5 .75 time (C) Greg Gayer Do Not Distribute without permission

  19. Shape of curve reflects Drug t1/2 and Time to Steady state Steady State Levels 100 Unit of Drug Multiple doses are not shown 50 Drug B Elimination rate Drug A TIME (C) Greg Gayer Do Not Distribute without permission

  20. STEADY STATE RULE t 1/2 t 1/2 t 1/2 t 1/2 If all of this PPT fails to help MEMORIZE the Rule below 16 93.75% Css 87.5% 14 75% • Quick rule of thumb • 50% of steady state = 1 ½ life • 75% = 2 • 87.5% = 3 • 93.75 = 4 or 90% =3.3 12 Plasma levels (ug/ml) 50% 8 1 2 3 4 5 time e.g. Drug A half life of 1 hour (C) Greg Gayer Do Not Distribute without permission

  21. + - - Why is biotransformation necessary? • Lipophilic molecules (xenobiotics, foreign molecules) must be charged to be excreted without reabsorption. reabsorption Lipophilic molecule Renal Tubule Biotransformation Excretion = termination of drug effect - Renal Tubule (C) Greg Gayer Do Not Distribute without permission

  22. Phase I & II biotransformation • Phase I • 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) • Phase II • 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

  23. isoniazid Phase I & II biotransformation acetaminophen 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 permission Figure 4.4, Katzung

  24. Human liver P450 family (C) Greg Gayer Do Not Distribute without permission

  25. General inducers: Drug-drug interaction: More enzymes =  metabolism = effect • Barbiturates, Phenytoin, Rifampin, Griseofulvin, Carbamazepine (Barb takes Phen-phen & Refuses Greasy Carbs) Board Mnemonics • Rifampin’s 4 R’s: • 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 Cyber-Kidsfrom Eating Grapefruit. (C) Greg Gayer Do Not Distribute without permission

  26. Phase 1 Non-blind small # (25-50) study in healthy volunteers comparing animals to humans: testing safe dose, pharmacokinetics, 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-, muta-genicity Pharmacokinetics 4 0 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-, muta-genicity Pharmacokinetics Phase 1 Phase 2 single-blind small # (100-200) study in patients with target disease. Efficacy in patients 4 0 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 double-blind large multi-center study in patients with target disease. Efficacy in patients without placebo effect Screening Testing Lead drug: Mechanism Efficacy Selectivity Toxicity (minimum and median lethal dose, terato-, carcino-, muta-genicity Pharmacokinetics Phase 1 Phase 2 Phase 3 4 0 8-9 IND NDA (C) Greg Gayer Do Not Distribute without permission

  29. 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-, muta-genicity Pharmacokinetics Phase 1 Phase 2 Post marketing surveillance Phase 3 Phase 4 4 0 20 8-9 IND NDA Patent expired (C) Greg Gayer Do Not Distribute without permission

  30. Pharmacodynamic Key Concepts (C) Greg Gayer Do Not Distribute without permission

  31. Quantitation of Drug-Receptor Interactions and Elicited Response k1 Drug (C) + receptor (R) CR effect k2 Reflects Efficacy Maximal intracellular response produce when all receptors are occupied Emax R % Maximal Effect Reflects Affinity or potency KD= [free drug] at which half-maximal binding is observed or the [drug] in which half the receptors are filled . KD = EC50 (no spare receptors). KD >EC50 (+ spare receptors). R EC50 R log[Agonist]

  32. 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 Drug C Drug A 100 Drug B % Maximal Effect Efficacy 50 EC50 EC50 log[Agonist]

  33. Full Partial Partial Agonist • Partial agonist: produce a lower response than full agonist when all receptors are bound • This effect has nothing to do with affinity of the drug for the receptor Full Agonist 100 Full Agonist % Maximal Effect 50 Partial Agonist Partial Agonist log[Full Agonist or Partial Agonist] log[Agonist]

  34. Partial agonist contribution Partial agonist can act as antagonist Net response E.g pindolol use in hypertension Pharmacologic Response Full agonist contribution Log (partial agonist) See Fig. 2-6C Katzung

  35. No conformational change in receptor Intracellular cascade (biologic response) agonist Antagonist have no intracellular effects when given alone antagonist Competitive & Irreversible Antagonist inside inside outside outside Antagonist work by blocking function of agonist Full agonist or partial agonist will produce a biologic response (intracellular cascade)

  36. Competitive Antagonist Low [ ] compared to [ ] Agonist High [ ] compared to [ ] Agonist = Antagonist = Antagonist 100 Bind to receptor without activating them. Binding can be competed for by increasing agonist amount % Maximal Effect 50 EC50 (+competitive antagonist) EC50 (agonist alone) log[Agonist]

  37. Irreversible Antagonist Covalent linkage Agonist alone 100 % Maximal Effect 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)

  38. Signal Transduction • 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 hormone receptors (C) Greg Gayer Do Not Distribute without permission

  39. Quantal Dose Response Curves Potential Variability Between Individuals 100 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 Number of persons responding 40 20 o Drug Concentration

  40. 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 Therapeutic index = LD50/ED50: A rough measure of drug safety margin.

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