7. Membranes and Absorption Lipid Bilayer Small, uncharged Large, uncharged Small charged ions H 2 O, urea, CO 2 , O 2 , N 2 Glucose Sucrose H + , Na + , K + , Ca 2+ , Cl - , HCO 3 - DENIED! DENIED! Swoosh! Hydrophobic Tails Hydrophilic Heads
8. LaChatlier’s Principle a.k.a . Mass Action A reaction at equilibrium responds to stress in a way to best return to equilibrium 4 Na + 4 Cl _ 4 NaCl + System at Equilibrium
9. 4 4 Cl - 4 NaCl + 12 NaCl 1. System at equilibrium by 8 2. Stress applied to system 3. System responds to stress System not at equilibrium! 4 Na + 4. System returns to equilibrium! 4 NaCl dissociate An example of LaChatlier’s Principle by 4 by 4 8 Na + 8 Cl - 8 NaCl
11. Environmental pH and Ionization If we put an acidic drug in an environment with a lot of H + (low pH) what will this equilibrium do? H A H A Non-ionized form predominates! H A H + + A - System at Equilibrium H + from acid environment
12. A real live, actual clinical question... Aspirin is an acidic drug. In the stomach will it exist mostly in ionized or non-ionized form? NON-IONIZED Why?
13. How will this affect aspirin absorption? Lipid Bilayer Ionized form (charged) A - Ionized form (uncharged) H A H A
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15. So... To absorption of an acidic drug… acidify the environment To absorption of an acidic drug… alkalanize the environment...
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17. Plasma Protein Binding warfarin (Coumadin) is highly protein bound (99%). Aspirin binds to the same site on serum proteins as does Coumadin. If a patient on Coumadin also takes aspirin, what will happen? The available Coumadin will increase. 1) Why? 2) Why do we care?
18. Blood-Brain Barrier The blood brain barrier consists of cell tightly packed around the capillaries of the CNS. What characteristics must a drug possess to easily cross this barrier? Non-protein bound, non-ionized, and highly lipid soluble
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22. Active Tubular Transport Probenecid is moved into the urine by the same transport pump that moves many antibiotics. Why is probenecid sometimes given as an adjunct to antibiotic therapy? It competes with the antibiotic at the pump and slows its excretion.
23. Urine pH and Elimination A patient has overdosed on phenobartital. Phenobarbital is an acid. If we ‘alkalinalize’ the urine by giving bicarbonate what will happen to the phenobarbital molecules as they are filtered through the renal tubules? They will ionize...
24. How will this affect phenobarbital reabsorption by the kidney? Non-ionized H A H + + A - Decreased reabsorption Increased elimination Ionized
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27. A drug has a half life of 10 seconds. You give a patient a dose of 6mg. After 30 seconds how much of the drug remains? Time Amount 0 sec 6 mg 10 sec 3 mg 20 sec 1.5 mg 30 sec 0.75 mg
59. DISPOSITION OF DRUGS The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology , 5th ed., New York: McGraw-Hill, 1996). www.freelivedoctor.com
60. Bound Free Free Bound LOCUS OF ACTION “ RECEPTORS ” TISSUE RESERVOIRS SYSTEMIC CIRCULATION Free Drug Bound Drug ABSORPTION EXCRETION BIOTRANSFORMATION www.freelivedoctor.com
61. Plasma concentration vs. time profile of a single dose of a drug ingested orally Plasma Concentration www.freelivedoctor.com
63. Bound Free Free Bound LOCUS OF ACTION “ RECEPTORS ” TISSUE RESERVOIRS SYSTEMIC CIRCULATION Free Drug Bound Drug ABSORPTION EXCRETION BIOTRANSFORMATION www.freelivedoctor.com
64. Bioavailability Definition: the fraction of the administered dose reaching the systemic circulation for i.v.: 100% for non i.v.: ranges from 0 to 100% e.g. lidocaine bioavailability 35% due to destruction in gastric acid and liver metabolism First Pass Effect www.freelivedoctor.com
65. Bioavailability Dose Destroyed in gut Not absorbed Destroyed by gut wall Destroyed by liver to systemic circulation www.freelivedoctor.com
66. PRINCIPLE For drugs taken by routes other than the i.v. route, the extent of absorption and the bioavailability must be understood in order to determine what dose will induce the desired therapeutic effect. It will also explain why the same dose may cause a therapeutic effect by one route but a toxic or no effect by another . www.freelivedoctor.com
67. Drugs appear to distribute in the body as if it were a single compartment. The magnitude of the drug’s distribution is given by the apparent volume of distribution (V d ). Vd = Amount of drug in body ÷ Concentration in Plasma PRINCIPLE (Apparent) Volume of Distribution: Volume into which a drug appears to distribute with a concentration equal to its plasma concentration www.freelivedoctor.com
73. The enterohepatic shunt Portal circulation Liver gall bladder Gut Bile duct Drug Biotransformation; glucuronide produced Bile formation Hydrolysis by beta glucuronidase www.freelivedoctor.com
75. Plasma concentration Influence of Variations in Relative Rates of Absorption and Elimination on Plasma Concentration of an Orally Administered Drug Ka/Ke=10 Ka/Ke=0.1 Ka/Ke=0.01 Ka/Ke=1 www.freelivedoctor.com
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78. First Order Elimination Plasma concentration C t = C 0 . e – K el • t lnC t = lnC 0 – K el • t logC t = logC 0 – K el • t 2.3 DC/dt = – k • C y = b – a.x dA/dt ∝A DA/dt = – k • A www.freelivedoctor.com
79. Time Plasma Concentration 0 1 2 3 4 5 6 1 10 100 1000 10000 First Order Elimination logC t = logC 0 - K el . t 2.303 www.freelivedoctor.com
81. lnC t = lnC o – K el .t When t = 0, C = C 0 , i.e., the concentration at time zero when distribution is complete and elimination has not started yet. Use this value and the dose to calculate V d . V d = Dose/C 0 www.freelivedoctor.com
82. lnC t = lnC 0 – K el .t When C t = ½ C 0 , then K el .t = 0.693. This is the time for the plasma concentration to reach half the original, i.e., the half-life of elimination. t1/2 = 0.693/K el www.freelivedoctor.com
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85. Rate of elimination = K el x Amount in body Rate of elimination = CL x Plasma Concentration Therefore, K el x Amount = CL x Concentration K el = CL/V d 0.693/t1/2 = CL/V d t1/2 = 0.693 x V d /CL www.freelivedoctor.com
89. Time Plasma Concentration Repeated doses –Maintenance dose Therapeutic level Single dose – Loading dose www.freelivedoctor.com
90. Concentration due to a single dose Concentration due to repeated doses The time to reach steady state is ~4 t1/2’s www.freelivedoctor.com
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92. But C x dt = small area under the curve. For total amount eliminated (which is the total given, or the dose, if i.v.), add all the small areas = AUC. Dose = CL x AUC and Dose x F = CL x AUC dC/dt = CL x C dC = CL x C x dt www.freelivedoctor.com
93. Plasma concentration Time (hours) Bioavailability (AUC) o (AUC) iv = i.v. route oral route www.freelivedoctor.com
97. Bound Free Free Bound LOCUS OF ACTION “ RECEPTORS ” TISSUE RESERVOIRS SYSTEMIC CIRCULATION Free Drug Bound Drug ABSORPTION EXCRETION BIOTRANSFORMATION www.freelivedoctor.com
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100. WHY BE CONCERNED ABOUT HOW DRUGS WORK? The patient has more respect for and trust in a therapist who can convey to the patient how the drug is affecting the patient’s body. AIDS PATIENT-DOCTOR RELATIONSHIP: A patient who understands his/her therapy is more inclined to become an active participant in the management of the patient’s disease. www.freelivedoctor.com
101. WHY BE CONCERNED ABOUT HOW DRUGS WORK? Knowledge of how a drug works increases the therapist’s confidence that the drug is being used appropriately. PEACE OF MIND! www.freelivedoctor.com
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104. A macromolecular component of the organism that binds the drug and initiates its effect. Definition of RECEPTOR : Most receptors are proteins that have undergone various post-translational modifications such as covalent attachments of carbohydrate, lipid and phosphate. www.freelivedoctor.com
105. A receptor that is embedded in the cell membrane and functions to receive chemical information from the extracellular compartment and to transmit that information to the intracellular compartment. Definition of CELL SURFACE RECEPTOR : www.freelivedoctor.com
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107. Footnote: Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent endogenous agonist from binding. If binding is reversible - Competitive antagonists If binding is irreversible - Noncompetitive antagonists However, antagonists may bind to remote site on receptor and cause allosteric effects that displace endogenous agonist or prevent endogenous agonist from activating receptor. (Noncompetitive antagonists) HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? www.freelivedoctor.com
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111. HOW DO DRUGS WORK BY INHIBITING ENZYMES? Active Enzyme Substrate Product Cellular Function Inactive Enzyme Substrate Bound Enzyme Inhibitor (Drug) www.freelivedoctor.com
126. k1 D + R <=> DR k2 By Law of Mass Action: [D] • [R] • K 1 = [DR] • K 2 Therefore K 2 /K 1 = K d = [D] • [R]/[DR] If R T = total # of receptors, then R T = [R] + [DR] Replace [R] by (R T -[DR]) and rearrange: [DR] [D] RT Kd + [D] = OCCUPATION THEORY OF DRUG-RECEPTOR INTERACTIONS EFFECT effect Max. effect = www.freelivedoctor.com
128. Receptor Binding % Bound Concentration of Ligand K d www.freelivedoctor.com
129. [D] (concentration units) [DR]/R T 0.01 0.10 1.00 10.00 100.00 0.00 0.25 0.50 0.75 1.00 Kd=1 kd=5 Kd=0.5 Compounds Have Different Affinities for the Same Receptor www.freelivedoctor.com
132. [D] (concentration units) % Maximal Effect 0.01 0.10 1.00 10.00 100.00 1000.00 0.0 0.2 0.4 0.6 0.8 1.0 Partial agonist Full Agonist Partial agonist PARTIAL AGONISTS - EFFICACY Even though drugs may occupy the same # of receptors, the magnitude of their effects may differ. www.freelivedoctor.com
134. Drug (D) Ri DRi DRa Ra CONFORMATIONAL SELECTION HOW TO EXPLAIN EFFICACY? The relative affinity Of the drug to either conformation will determine the effect of the drug www.freelivedoctor.com
135. R R 1 * R 2 * R 3 * R R R 1 * R 1 * R 2 * R 2 * R 3 * R 3 * www.freelivedoctor.com
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