ADME-Sept 11.key - Pharmacokinetics A-D-M-E Fri Sept 11...

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Unformatted text preview: Pharmacokinetics A-D-M-E Fri. Sept. 11, 2015 Golan Chap. 3 Katzung Chap. 3 Understanding the concepts critical to effective drug delivery. 1 Learning Objectives ๏ ! Describe the importance of pharmacokinetics in therapeutics. ๏ ! Differentiate among the four basic processes of pharmacokinetics. ๏ Know the main advantages and disadvantages of the major routes of drug administration. ๏ ! Understand the parameters that regulate movement of drugs across cells and membranes. ๏ Know the factors that impact drug distribution. ๏ ! Explain the processes of drug metabolism and elimination. 2 3 Essential Questions 1. How much of the drug that is given to the patient actually reaches the target organ? 2. Where in the body does the drug go? 3. How long does the drug stay in the body? 3 A-D-M-E Drug administration 4 Common Routes of Administration **Enteral Parenteral Topical 5 Comparison of Common Routes Route Enteral (Oral) (e.g. aspirin) Golan Table 3-1 Advantages Disadvantages Simple, least expensive, convenient, painless, no infection, safe Drug exposed to harsh GI environments and first-pass metabolism, requires GI absorption, slow delivery to site of pharmacologic action Parenteral (Injection, Rapid delivery to site of pharmacologic Irreversible, infection, cost, action (IV), highest bioavailability, IM, SC, IV) (e.g. morphine) Mucous membrane (Inhalation) (e.g. asthma inhalers) Transdermal (e.g. nicotine patch) bypasses first-pass metabolism & the GI tract, depot dosing possible (IM) Rapid delivery to site of pharmacologic action, not subject to first-pass metabolism or harsh GI environments, often painless, simple, convenient, low infection, direct delivery to affected tissues (e.g. lung) possible painful, fear, skilled personnel required Few drugs available to administer via this route, and cost Simple, convenient, painless, excellent Requires highly lipophilic for continuous or prolonged drug, slow initial delivery to administration, bypasses first-pass site of pharmacologic metabolism & the GI tract action, may be irritating 6 Absorption • The movement of a drug from its site of administration into the blood ‣ Rate of absorption determines how soon effects will begin. ‣ Amount of absorption helps determine how intense the effects will be. ‣ Passage of drugs across biological membranes is key. 7 Three Main Ways Drugs Cross Cell Membranes 8 Factors Affecting Drug Absorption Rate of dissolution Surface area Blood flow Lipid solubility pH partitioning *Bioavailability* ….. 9 Drugs are Chemicals Properties of drugs that predict lipid solubility and pH-partitioning. Polarity of drug Ionic nature of drug Weak acid or weak base and pH-dependence 10 For weak bases, the protonated form is ionized. I Principles of Pharmacology HB+ 12 SECTION I nized form of a drug can readily penetrate cell membranes. BOX 2–1 EFFECT OF pH ON THE ABSORPTION O AND A WEAK BASE HA Weak acidsEffect of pH (H+) to form anions (A−), whereas weak bases (B (HA) donate a proton on Ionization State H+ + A– B + H+ For weak acids, the protonated form is nonionized. HB+ HA B For weak bases, the protonated form is ionized. ane Only the non-ionized form of a drug can readily penetrate cell membranes. weak acid or weak base is the pH at which there are Equation Henderson-Hasselbalch equal amounts of the protonate m. The Henderson-Hasselbalch equation can be used to determine the ratio of the two fo HA A– log HA [protonated form] Nonprotonated [Nonrotonated form] = pK a -pH id, which is a weak acid with a pKa of 3, log [HA]/[A−] is 3 minus the pH. At a − 2 = 1.B Therefore, The pKa is ] = pHB [HA]/[A− the 10/1. where [protonated] = [nonprotonated] HB+ 11 COO– Cell membrane + H+ OH The pKa of a Nonprotonated weak base is the pH at which there are equal am weak acid or nonprotonated form. The Henderson-Hasselbalch equation can be used to determi ne, which is a weak base with a pKa of 10, log [HB+]/[B] is 10 minus the pH. At a − 8 = 2. Therefore, [HB+]/[B] = 100/1. Weak acids (HA) donate a proton (H+) to form anions (A−), whereas weak bases (B) accept a proton to form cations (HB+). BOX 2–1 E F F E C T O F p H O N T H E A Bthe O R P T I O N O F A W E A K A C I D S protonated For weak acids, – H+ A N HA A W E A K B A S+EA D form is nonionized. Weak acids (HA) donate a proton (H+) to formFor weak(A−), whereas weak bases (B) accept a proton to form cations (HB+). anions bases, the protonated + + B + H HB form is ionized. + – For weak acids, the protonated HA H + A Only the non-ionized form of a drug can readilyis nonionized. membranes. form penetrate cell B + H+ For weak bases, the protonated form is ionized. HB+ HA HA Only the non-ionized form of a drug can readily penetrate cell membranes. A– pH – B HA Dependent Ionization Cell membrane B HA HB+ A– B HB+ B The pKa of a weak acid or weak base is the pH at which there are equal amounts of the protonated form and the nonprotonated form. The Henderson-Hasselbalch equation can be used to determine the ratio of the two forms: Cell membrane [ [ protonated form log = pK a -pH Nonrotonated form are equal amounts of the protonated form and the The pKa of a weak acid or weak base is the pH at which there nonprotonated form. The Henderson-Hasselbalch equation can be used to determine the ratio of the two forms: For salicylic acid, which is a weak acid with a pKa of 3, log [HA]/[A−] is 3 minus the pH. At a pH of 2, then, log [HA]/[A−] = 3 − 2 = 1. Therefore, [HA]/[A−] = 10/1. protonated form log = pK a -pH Nonrotonated form [ [ COOH COO– + + For salicylic acid, which is a weak acid with a pKa ofH3, log [HA]/[A−] is 3 minus the pH. At a pH of 2, then, OH OH log [HA]/[A−] = 3 − 2 = 1. Therefore, [HA]/[A−] = 10/1. Protonated COOH Nonprotonated COO– + H+ For amphetamine, which is a weak base with aOH a of 10, log [HB+]/[B] is 10 minus the pH. At a pH of 8, then, pK OH +]/[B] = 10 − 8 = 2. Therefore, [HB+]/[B] = 100/1. log [HB Protonated Nonprotonated CH2 CH NH3+ 12 + H+ For amphetamine, which is a weak base with a pKa of 10, log [HB+]/[B] is 10 minus the pH. At a pH of 8, then, CH3 CH3 + + CH2 CH NH2 log [HB ]/[B] = 10 − 8 = 2. Therefore, [HB ]/[B] = 100/1. Nonprotonated CH2 CH CH3 Nonprotonated NH2 + H+ Protonated CH2 CH CH3 NH3+ (Continued) Protonated (Continued) Effect of a pH Gradient 13 Ionization in Body Compartments 14 Examples of Drug pKa’s Bases Acids Strong Chloroquine pKa 12 Desmethylimipramine Amphetamine Atropine Histamine Ascorbic acid 11 Propranolol Chlorpromazine Weak 9 10 Mepyramine Dopamine 8 7 Noradrenaline (norepinephrine) Morphine Phenytoin Thiopental Phenobarbital Chlorothiazide 6 Ergometrine Trimethoprim Chlordiazepoxide Diazepam Sulphamethoxazole Warfarin 5 Methotrexate 4 Aspirin Probenecid 3 Penicillins 2 Weak 1 Levodopa Strong 15 Bioavailability 16 Rate of Absorption 17 Distribution Movement of drugs from the blood into body compartments Tissue blood flow Plasma protein binding Blood-Brain Barrier Volume of distribution (Vd) 18 Exiting the Vascular System Typical capillaries are porous Specialized capillaries are NOT porous Drug movement across the blood-brain barrier or between fetus and placenta. 19 Tissue Distribution 20 Plasma Protein Binding 21 Tissue Distribution Compartment and Volume V (70 kg) Water Total body water (0.6 L/kg) 42 L Extracellular water (0.2 L/kg) 14 L Blood (0.08 L/kg) Plasma (0.04 L/kg) Fat Bone 5.6 L 2.8 L (0.2-0.35 L/kg) 14 - 24.5 L (0.07 L/kg) 4.0 L Examples of drugs Small water-soluble molecules; e.g., ethanol Larger water-soluble molecules; e.g., gentamicin Strongly plasma protein-bound molecules and very large molecules; e.g., heparin Highly lipid-soluble molecules; e.g., DDT Certain ions; e.g., lead, fluoride 22 What is Volume of Distribution? ! ! ! Not a physical volume Extrapolated based on drug concentration in the plasma Relates concentration of drug in the plasma to the total amount of drug in the body Dose of the drug VD = [Drug] plasma 23 Drug Metabolism aka - Biotransformation Hepatic drug-metabolizing enzymes Therapeutic consequences of drug metabolism Special considerations in drug metabolism 24 Hepatic Drug-Metabolizing Enzymes Most drug metabolism that takes place in the liver is performed mainly by the hepatic microsomal enzyme system, also known as the cytochrome P450 system. 25 1st Pass Effect 26 Renal Excretion Poorer in neonates, the aged and in those with renal failure Subject to pH-dependent ionization, the pH can vary from 4.6 – 8 Secretion: Esp. for organic acids and bases. 27 Elimination Rate Renal Clearance: Excretion rate/[plasma] The volume of plasma cleared of drug/min (e.g. ml plasma/min) Excretion Rate = [urine] X urine vol/time OR Drug filtration rate + secretion – reabsorption (e.g. mg drug/min) 28 What is clearance? ! Clearance is defined as the efficiency of irreversible elimination of a drug from the systemic circulation. ! ! ! Rate of irreversible elimination of the drug from the body relative to the concentration of drug in plasma. It is the PK parameter that “most significantly limits the time course of action of the drug” at its sites of action. It is the volume of blood cleared of drug per unit time. ! Units = volume per time = Clearance Clearancetotal = Clearancerenal + Clearancehepatic + Clearanceother 29 ...
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