Pharmacotherapeutics Lecture Notes PDF

Pharmacotherapeutics lecture 3&4 Adams: review chpt 1-10 Readings: see Course Outline on eclass Assoicate Teaching Professor Helena Schaefer, MN H. Schaefer MN ADME general rule: lipophilic, non-ionized, small = easy Absorption & Distribution hydrophilic...

Pharmacotherapeutics lecture 3&4 Adams: review chpt 1-10 Readings: see Course Outline on eclass Assoicate Teaching Professor Helena Schaefer, MN H. Schaefer MN ADME general rule: lipophilic, non-ionized, small = easy Absorption & Distribution hydrophilic, ionized = easy Excretion H. Schaefer MN 2 ADME general rule: lipophilic, non-ionized, small = easy Absorption & Distribution hydrophilic, ionized = easy Excretion H. Schaefer MN 3  Distribution transport through the body to target tissues -can be calculated for relative comparison of distribution to tissues = Vd Factors effecting it: 1. blood flow to the tissue (=> CO, BBB, injury,..) 2. size of the tissue 3. molecular characteristics (lipophillicity, size, ….) 4. PPB H. Schaefer MN 4 Blood brain barrier review Capillaries within the CNS (brain & spinal cord) are lined by specialized endothelial cells that allow only for selective transport of substances P-glycoprotein pump except in the hypothalamus H. Schaefer MN 5  PPB: cohesion (‘binding’) with plasma protein molecules drugs have varying ‘affinity’ for plasma carrier proteins e.g. plasma proteins Albumin = acidic drugs Alpha-1-acid glycoprotein = basic drugs binding decreases distribution rates Competitive, Reversible, Saturable Unbound drugs - effective Bound drugs – NOT effective H. Schaefer MN 6 Drugs EXTENSIVELY bound (>90%) Oral anticoagulants: warfarin Oral antidiab.: glimepiride, glipizide, glyburide Lipid lower. drugs: gemfibrozil, statins NSAID: ibuprofen, naproxen, indomethacine, diclophenac Loop diuretics: furosemide Cardiac: diazoxide, losartan, amiodarone, prazosin, felodipine, nicardipine, digitoxin, ticlopidine Antiinfectives: ceftriaxone, nalidixic acid, ketoconazole, itraconazole, suramin, nelfinavir Benzodiazepines: diazepam, midazolam Others: montelukast, zafirlukast, entacapone leflunomide H. Schaefer MN 7 Brainstorm: What would happen, if a patient on Warfarin (Coumadin) which is 99% plasma protein bound, took another highly PP bound drug? H. Schaefer MN 8  ‘Volume of Distribution’ (Vd) estimates how extensively a drug is distributed into tissues relative comparison between drugs (assumes all drugs distribute equally) Vd is used in formulas e.g. calculating a Loading Dose Vd calculation: drug dose / measured drug plasma concentration e.g: drug dose = 100 mg plasma (serum) concentration = 30 mg/L Vd = 100mg / 30mg/L = 3.3 L FYI: relative comparison Furosemide = 8 L Morphine = 230 L Amiodarone = 5000 L H. Schaefer MN 9 H. Schaefer MN 10 Metabolism (aka biotransformation) an enzymatic chemical conversion to prepare the drug/substance for excretion -goal of drug metabolism is to prepare the drug for excretion = termination of drug action LIVER – primary metabolizing organ others: lungs, kidneys, intestines, … ‘hepatic microsomal enzymes’ Drug metabolism: active drug to inactive metabolite active drug to active metabolite (benign or toxic) inactive drug to active metabolite: prodrug note: PO drugs -‘First pass’ metabolism (is already metabolism) Some drugs are not metabolized = ‘travel unchanged’ H. Schaefer MN 11 BRAINSTORM: Turn to your neighbour: do you like drinking coffee or tea? What’s your favourite one? Have you thought about how it moves through the body, when you drink it (kinetics) ? Have you thought about how it works (dynamics) ? FYI: caffeine metabolism 2 Main Phases of metabolism Phase I: HYDROLYSIS, REDUCTION, OXIDATION Main enzymes: Cytochrome P450 enzyme group => ionized => polar metabolite => excreted ? H. Schaefer MN 14 Main CYP 450 enzyme groups: (note: CYP 3A4 + CYP 3A5 = 50% of drugs utilize these enzymes) FYI: breakdown below; know the names of enzymes e.g. CYP1A2 Saturable Dynamic drugs can induce or inhibit certain enzyme function => the enzyme will become more active = metabolizes faster less active = metabolizes slower Drug interactions ! E.g. Tylenol (Acetaminophen) metabolized via 3A4 & 1A2 Inducers – e.g. tobacco Inhibitors – e.g. some antibiotics Reversible H. Schaefer MN 15 Brainstorm: Grapefruit Juice Mr. Smith is taking Lovastatin PO (a drug used to lower cholesterol) a substrate of the CYP3A4 P450 hepatic enzyme system. Grapefruit juice’s furanocoumarins are a known inhibitor of the CYP3A4. Mr. Smith takes the drug and drinks the above juice for breakfast. 1. What effect will this have on the plasma drug levels? 2. What if this juice was an INDUCER? H. Schaefer MN 16  Phase II metabolism only some drugs require this phase CONJUGATION (ionization of the substance) 5 main enzymes used N-acetyl-p- Acetaminophen Phase I benzoquinoneimine (Hepatotoxic) Phase II Glutathione enzyme conjugation => inactive metabolite e.g. Acetaminophen overdose depletes stores of glutathione, resulting in build-up of toxic intermediate metabolite; saturable! H. Schaefer MN 17 H. Schaefer MN 18 H. Schaefer MN 19 Excretion elimination of drugs metabolites are eliminated molecular characteristics: e.g. hydrophilic KIDNEYS - primary organ of excretion Other excretory pathways: saliva, bile, lungs,… H. Schaefer MN 20  Cont. - filtrate, from blood: glomerulus e.g. not filtered: large drug-protein complexes, non-polar drugs H. Schaefer MN 21  Factors Affecting Renal Excretion Molecular characteristics: ionization, hydrophilicity, small size PPB ? Metabolized ? Urinary pH ? Medically altered to excrete specific drugs e.g. ASA excretion in OD Cardiac Output renal blood flow Renal fx: 1%/year decline in the elderly neonates & young infants integrity of the glomerulus – renal disease H. Schaefer MN 22 Renal function in clinical practice: GFR calculation (normal = 125 ml/min) Creatinine – bloodwork lab results Clearance – requires calculation  Clearance (Cl) ‘RATE OF ELIMINATION of drug in an hour’ 1st order elimination kinetics elimination proportionate to the drug serum concentration Drug plasma concentration mg/dL or L Calculated: Cl = elimination/peak plasma concentration (total amount of urine voided in an hour:peak plasma concentration of drug) => mg/dL/hr or mg/L/hr Zero order elimination kinetics rate of elimination or ‘clearance’ is constant E.g.: ethanol (ETOH), aspirin (ASA), phenytoin (dilantin) H. Schaefer MN 24 Brainstorm ETOH: why 10 shooters of hard alcohol within an hour can cause alcohol poisoning? 1-2 drinks = 20-30 mg/dL Clearance rate = 20 mg/dL/hr ETOH poisoning ER admissions average = >295 mg/dL  Half-life (t ½) time required for Cmax drug plasma concentration to decrease by one half (by 50%) circulating drug is continuously biotransformed for excretion if ‘unchanged’ => biotransformation not required circulating drug is continuously excreted t1/2 is: calculated & known per each drug broad guideline to estimate frequency of administration 4x t1/2 = 90% of drug cleared H. Schaefer MN 26 Inverse agonists e.g. Caffeine Binds to receptor Induces the OPPOSITE effect of the naturally binding substance Pharmacodynamics Once a drug is distributed – where does it cause the therapeutic effect? Some drugs (e.g. antiinfectives) bind directly to/in bacteria/viruses Most drugs bind protein structures: receptors 6 major types Drug-receptor binding is: saturable dynamic: increases OR suppresses existing processes only blocks the receptor reversible Helena Schaefer MN 27  Terminology Receptor Affinity ‘strength’ of binding or ’length’ of binding is: specific, saturable, reversible Drug Efficacy effectiveness Degree to which a drug induces maximum therapeutic effect E.g. Motion sickness nausea – Gravol; chemo tx nausea – Ondansetron Note: antagonists have no efficacy (only block receptor) Potency = strength How much of the drug is required! Amount! Eg. Drug A 20 mg & Drug B 10 mg = Drug B potency is higher! Helena Schaefer MN 28  Drug-receptor interactions: Agonists Agonist Drug mimics the endogenous substance Binds to receptor readily & produces very good effects Eg. Morphine Primary (aka Full) agonist Extensively & successfully binds to existing receptor Partial Agonist the maximum response is smaller even if all receptors occupied lower efficacy E.g. Buprenorphine in the presence of a full agonist, a partial agonist acts like an antagonist Helena Schaefer MN 29 Inverse agonists e.g. Caffeine Binds to receptor Induces the OPPOSITE effect of the naturally binding substance Antagonists Antagonist Drug ‘blocks’ the receptor site to prevent endogenous or endogenous-like substance from binding No effect other than to block other substances from binding E.g. Naloxone (Narcan) no efficacy at cellular level (only blocks the receptors) Helena Schaefer MN 31  6 major receptor types: summary 1. G-protein (GPCR) 2. Ion channels 3. Nuclear receptors 4 & 5. Enzyme types 6. Non-enzyme ‘JAK-STAT’ Helena Schaefer MN 32 1. G-protein Helena Schaefer MN 33 G-protein (eg.:Epinephrine)stimulates G-protein & second messenger systems = sympathomimetic stimulation Helena Schaefer MN 34 2. Ion channels https://www.youtube.com/watch?v=Mc0rRLlVi6w (eg. Lidocaine) most bind to voltage-gated channels E.g. Lidocaine Closes ion channels=> no action potential => no cellular depolarization => no pain transduction (no pain sensation) Helena Schaefer MN 35 3. Nuclear receptors Nuclear receptors (eg. hormones) aka ‘steroid’ receptors most bind in cytoplasm = change cell fx via DNA Helena Schaefer MN 36  4&5. Enzyme binding 2 types: Intracellular enzymes Transmembrane enzymes Eg. Insulin => cell membrane receptors = stimulate ‘transmembrane enzyme’: Tyrosine kinase => activate cellular glucose uptake Helena Schaefer MN 37 6. Non-enzyme Transmembrane http://www.dnatube.com/video/4103/Cytokine-Binding-or-JAKSTAT-Signaling-Pathway Eg. JAK-STAT receptors (e.g. used by interferons) Helena Schaefer MN 38  tolerance & resistance Drug tolerance (aka Down-regulation) most common receptor de-sensitization OR decreased number of viable receptors to a substance => more drug required for same response Eg. Addictive substances (opiates, benzodiazepines, alcohol…) Drug resistance Many variations of kinetic alterations E.g. increased drug metabolism => drug metabolized at a faster rate, therefore less bioavailable therefore less effective Note: this is NOT the same as resistance discussed in antibiotic resistance Helena Schaefer MN 39 H. Schaefer MN