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Edit Comment Close Premium member Presentation Transcript Pharmacology : Pharmacology Pharmacokinetics Pharmacodynamics Pharmacokinetics : Pharmacokinetics Time course of drug absorption, distribution, metabolism, excretion How the drug comes and goes. Pharmacokinetic Processes : “LADME” is key Pharmacokinetic Processes Liberation Absorption Distribution Metabolism Excretion Liberation : Liberation Applies to drugs given orally Components Release of drug from pill, tablet, capsule Dissolving of active drug in GI fluids Ex: Enteric coated aspirin slows absorption in stomach vs non-coated Absorption : Absorption Movement from administration site into circulation Factors Affecting Liberation/Absorption : Factors Affecting Liberation/Absorption Formulation factors Tablet disintegration Inert ingredient / solvent effects Solubility Drug pH Concentration Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food, other drugs Membranes and Absorption : Lipid Bilayer Small, uncharged Large, uncharged Small charged ions H2O, urea, CO2, O2, N2 Glucose Sucrose H+, Na+, K+, Ca2+, Cl-, HCO3- DENIED! DENIED! Swoosh! Membranes and Absorption LaChatlier’s Principle : 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 Slide 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 Ionization : Ionization Acids Release/Donate H+ HA H+ + A- Bases Bind/Accept H+ H+ + B- HB 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? Environmental pH and Ionization HA HA Non-ionized form predominates! 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 A real live, actual clinical question... Why? How will this affect aspirin absorption? : Lipid Bilayer How will this affect aspirin absorption? Ionized form (charged) A- Ionized form (uncharged) HA HA Moral of the story... : Moral of the story... Acidic drugs are best absorbed from acidic environments Basic drugs are best absorbed from basic environments So... : So... To absorption of an acidic drug… acidify the environment To absorption of an acidic drug… alkalanize the environment... Distribution : Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes Blood-brain barrier Placental barrier 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. Plasma Protein Binding 1) Why? 2) Why do we care? 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 Blood-Brain Barrier Why? Metabolism (Biotransformation) : Metabolism (Biotransformation) Two effects Transformation to less active metabolite Enhancement of solubility Liver = primary site Liver disease Slows metabolism Prolongs effects Hepatic ‘First-Pass’ Metabolism : Hepatic ‘First-Pass’ Metabolism Affects orally administered drugs Metabolism of drug by liver before drug reaches systemic circulation Drug absorbed into portal circulation, must pass through liver to reach systemic circulation May reduce availability of drug Elimination : Elimination Kidneys = primary site Mechanisms dependent upon: Passive glomerular filtration Active tubular transport Partial reabsorption Hemodialysis Renal disease Slows excretion Prolongs effects Active Tubular Transport : 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. 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... Urine pH and Elimination How will this affect phenobarbital reabsorption by the kidney? : Non-ionized HA H+ + A- How will this affect phenobarbital reabsorption by the kidney? Decreased reabsorption Increased elimination Ionized Elimination : Elimination Other sources Feces Exhaled air Breast milk Sweat Biological Half-life (t 1/2) : Biological Half-life (t 1/2) Amount of time to eliminate 1/2 of total drug amount Shorter t 1/2 may need more frequent doses Hepatic disease may increase t1/2 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? : 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 Administration Routes : Administration Routes Intravenous Fastest, Most dangerous Endotracheal Lidocaine, atropine, narcan, epinephrine Inhalation Bronchodilators via nebulizers Transmucosal Rectal or sublingual Administration Routes : Administration Routes Intramuscular Depends on perfusion quality Subcutaneous Depends on perfusion quality Oral Slow, unpredictable Little prehospital use Pharmacodynamics : Pharmacodynamics The biochemical and physiologic mechanisms of drug action What the drug does when it gets there. Drug Mechanisms : Drug Mechanisms Receptor interactions Non-receptor mechanisms Receptor Interactions : Receptor Interactions Agonist Receptor Agonist-Receptor Interaction Lock and key mechanism Receptor Interactions : Receptor Interactions Receptor Perfect Fit! Induced Fit Receptor Interactions : Receptor Interactions Antagonist Receptor Antagonist-Receptor Complex DENIED! Competitive Inhibition Receptor Interactions : Agonist Receptor Antagonist ‘Inhibited’-Receptor DENIED! Receptor Interactions Non-competitive Inhibition Non-receptor Mechanisms : Non-receptor Mechanisms Actions on Enzymes Enzymes = Biological catalysts Speed chemical reactions Are not changed themselves Drugs altering enzyme activity alter processes catalyzed by the enzymes Examples Cholinesterase inhibitors Monoamine oxidase inhibitors Non-receptor Mechanisms : Non-receptor Mechanisms Changing Physical Properties Mannitol Changes osmotic balance across membranes Causes urine production (osmotic diuresis) Non-receptor Mechanisms : Non-receptor Mechanisms Changing Cell Membrane Permeability Lidocaine Blocks sodium channels Verapamil, nefedipine Block calcium channels Bretylium Blocks potassium channels Adenosine Opens potassium channels Non-receptor Mechanisms : Non-receptor Mechanisms Combining With Other Chemicals Antacids Antiseptic effects of alcohol, phenol Chelation of heavy metals Non-receptor Mechanisms : Non-receptor Mechanisms Anti-metabolites Enter biochemical reactions in place of normal substrate “competitors” Result in biologically inactive product Examples Some anti-neoplastics Some anti-infectives Drug Response Relationships : Drug Response Relationships Time Response Dose Response Time Response Relationships : Effect/ Response Time Time Response Relationships Time Response Relationships : Effect/ Response Time IV SC IM Time Response Relationships Dose Response Relationships : Dose Response Relationships Potency Absolute amount of drug required to produce an effect More potent drug is the one that requires lower dose to cause same effect Potency : Potency Which drug is more potent? A! Why? Therapeutic Effect Dose Response Relationships : Dose Response Relationships Threshold (minimal) dose Least amount needed to produce desired effects Maximum effect Greatest response produced regardless of dose used Dose Response Relationships : Dose Response Relationships Which drug has the lower threshold dose? A B Which has the greater maximum effect? A B Therapeutic Effect Dose Response Relationships : Dose Response Relationships Loading dose Bolus of drug given initially to rapidly reach therapeutic levels Maintenance dose Lower dose of drug given continuously or at regular intervals to maintain therapeutic levels Therapeutic Index : Therapeutic Index Drug’s safety margin Must be >1 for drug to be usable Digitalis has a TI of 2 Penicillin has TI of >100 Therapeutic Index : Therapeutic Index Why don’t we use a drug with a TI <1? ED50 < LD50 = Very Bad! Factors Altering Drug Responses : Factors Altering Drug Responses Age Pediatric or geriatric Immature or decreased hepatic, renal function Weight Big patients “spread” drug over larger volume Gender Difference in sizes Difference in fat/water distribution Factors Altering Drug Responses : Factors Altering Drug Responses Environment Heat or cold Presence or real or perceived threats Fever Shock Factors Altering Drug Responses : Factors Altering Drug Responses Pathology Drug may aggravate underlying pathology Hepatic disease may slow drug metabolism Renal disease may slow drug elimination Acid/base abnormalities may change drug absorption or elimination Influencing factors : Influencing factors Genetic effects Lack of specific enzymes Lower metabolic rate Psychological factors Placebo effect Pediatric Patients : Pediatric Patients Higher proportion of water Lower plasma protein levels More available drug Immature liver/kidneys Liver often metabolizes more slowly Kidneys may excrete more slowly Geriatric Patients : Geriatric Patients Chronic disease states Decreased plasma protein binding Slower metabolism Slower excretion Dietary deficiencies Use of multiple medications Lack of compliance Web Resources : Web Resources Basic Pharmacokinetics on the Web http://pharmacy.creighton.edu/pha443/pdf/Default.asp Merk Manual: Overview of Drugs http://www.merck.com/pubs/mmanual_home/sec2/5.htm Web Resources : Web Resources Merk Manual: Factors Affecting Drug Response http://www.merck.com/pubs/mmanual_home/sec2/8.htm Merk Manual: Pharmacodynamics http://www.merck.com/pubs/mmanual_home/sec2/7.htm You do not have the permission to view this presentation. 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