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Pharmacology Test #1 Outline Lec. 1: Intro to Principles of Therapeutics Pharmacology: John Jacob Abel- “Father of American Pharmacology”- 1st pharm dept University Pharmacotherapies: use of drugs in the treatment of patients with the disease Pharmacognosy- study of drugs isolated from natural sources (plants, microbes, animal tissues, minerals) Pharmaceutics: formulation & chemical properties of pharmaceutical products (tablets, fluids, aerosols) Pharmacogenetics: unusual responses to drugs b/c of genetic differences Toxicity: study of poisons and organ toxicity, harmful effects of drugs, adverse effects at therapeutic doses 2 branches o pharmacokinetics o pharmacodynamics Drug Names o Chemical o Nonproprietary (Generic)- helps identify class of drug, most often used, USAN o Proprietary (trade/brand)- registered trademark, belongs to drug manufacturer Potency- amount of drug necessary to elicit a response (1mg of drug induces response, it is more potent than drug that requires 10mg for same effect) Efficacy: ability to produce the max desired response Therapeutic index: margin of safety of a drug o Ratio of dose producing undesirable effects to the dose producing the desired therapeutic response o Large TI: large margin of safety o Low TI: small margin of safety (narrow therapeutic window) Drug Preparations o Tablets and capsules- oral administration enteric coating (dissolves in intestines) sustained/extended release products undergo 1st pass metabolism o Solutions and suspensions- oral, parenteral (IV, IM), other (ophthalmic, otic) o Skin Patches- transdermal use, rate controlling membrane, potent drugs with lipid solubility penetrate skin Most common side effect- skin irritation from patch adhesive!! o Ointments, crèmes, lotions- topical application to skin or mucous membranes active drug incorporated into vehicle (polyethylene glycol) for tissue adherence for rectal, vaginal, urethral administration local or systemic effects o Aerosols Inhalation though the nose or mouth Respiratory disorders Routes of Administration o Enteral- drug absorbed from GI Tract Sublingual, buccal, rectal- readily absorbed, no 1st pass Oral- by mouth, per os – 1st pass metabolism o Parental- bypasses intestines (anything using needle or syringe) IV: NO absorption, F=1 IM: treatment w/ drug solution, particle suspensions (rapid absorption from solutions, slow and sustained from suspensions) SC: treatment w/ suspensions and pellets, slower absorption than IV and IM Intrathecal: subarachnoid space of SC Epidural: space above dura membranes of SC Intra-articular: joint space o Transdermal: patch or ointment, bypasses 1st pass, release meds for days o Inhalation: local or systemic effects o Topical: body surfaces (everywhere)- localized effect Treating Patients: o Need to individualize patient drug therapy (increase efficacy and decrease toxicity= therapeutic range) o Disease Oriented Evidence: numbers, markers that the physician uses to treat patient o Patient Oriented evidence: 2 goals of Longer (mortality) and better (morbidity) outcome the patient understands o Absolute Risk Reduction: decrease in risk of a treatment (how risky is the treatment compared to control treatment?) o Relative Risk Reduction: extent to which a treatment reduces a risk (How is this treatment going to lower my risk of high blood pressure compared to those not taking the treatment?) o Numbers Needed to Treat: prevent one adverse outcome o Numbers needed to harm: incur one adverse outcome Pharmacokinetics (Lectures 2,3,4,5) pharmacokinetics: what the body is doing the drug o focuses on changes in drug plasma concentration o ADME o Influenced by blood flow, passage out of vasculature, rate of entry into the cell Absorption: movement of drug into the bloodstream Movement across a biological membrane (active transport or passive diffusion) o Carrier Mediated Transport: transports large, hydrophilic, ionized species (saturation limit, competitive inhibition) facilitated diffusion: requires carrier molecule, NO E used Active Transport: requires E to pump drug against concentration gradient (kidney, biliary excretion, CNS, choroid plexus, ciliary body) o Passive Transport Endocytosis Passive Diffusion Fick’s Law flux= (C1-C2) (Area x Permeability)/ Thickness of the membrane physiochemical properties determine permeability o ionized acids/bases will NOT cross membrane o weak acid: when protinated, not ionized (HA) o weak base: when protinated, ionized (BH+) o used dissociation constant (Ka) to determine distribution of drugs to cross membrane o pKa: pH when half of the drug is ionized o pka-pH= log [protinated]/[unprotinated] Bioavailability (F): amount of extravascular administered drug that reaches systemic circulation (due to incomplete absorption and 1st pass effect/metabolism in liver ) Rate of absorption: fastest (IVIMSC) slowest Distribution Drug can stay in blood and begin elimination or Distribute to other organ/tissue Barriers to distribution: BBB b/c of tight jxns, only small hydrophobic drugs (gases) can cross, requires active transport o Quaternary ammonium (always charged, never going to get into the brain) Distribution and Elimination phases o After drug is distributed though body, will reach equilibrium and will enter plasma again or get eliminated from body (1st order kinetics) Volume of distribution (Vd): amount of drug in body compared to amount in plasma o Vd= D/C o Use to determine amount of drug that will go into tissue vs plasma o Vd= distribution in tissues/fluids o Vd= limited drug distribution (blood) o used to calculate loading dose (LD) to achieve steady state conc. (Css) LD= Css x Vd If LD is not IV, divide by bioavailability LD used to get therapeutic effect quick (emergency) LD does not change based on liver or renal disease Plasma Protein Drug Interactions o Albumin most common, binds drugs, makes them unable to reach target site o Drugs that bind plasma proteins have Vd (remain in plasma) One-compartment model: o used w/ drugs that distribute to tissue instantaneously following IV injection or stay in plasma and elimination begins instantly (ke- elimination rate constant), o follows first order kinetics o One compartment: all body tissues and fluids (has own Vd) o Used most commonly for clinical dose adjustments Two-compartment model: o Central compartment (initial distribution volume) o Final compartment (distribution volume following EQ) o Used w/ drugs that distribute to tissue more slowly (extrapolate backwards to get Co) o 2 compartments, drug moves between compartments, then reaches EQ Multi-compartment model: drugs that distribute into multiple tissues at different rates o fast (vessel richmuscleadipose) slow Metabolism 3 Types o Phase 1: oxidation/reduction Adds or exposes polar fxnal groups (OH, NH2) Oxidases Heme Protein Oxidases- Cytochrome P450 o Microsomal mixed function oxidases o 75% of all drugs o 95% of all oxidation biotransformations o 36% in CYP3A 4/5 Isoforms o requires O2, NADPH, H+ o hydroxylates drug o CYP450 Induction: increases transcription own metabolism, increase active metabolite o PYP450 Inhibition: inhibiting metabolism Can lead to active drug levels of substrate (competitive, can be irreversible) Non-CyP450 oxidation (ADH) Monoamine oxidase (catecholamines/tyramine) o Phase II: Conjugation/Hydrolysis Conjugation Products more polar, water soluble, and inactive (can be more readily excreted via kidneys/bile) Glucuronidation most common conjugation rxn Acetylation (N-acetyltransferase- NAT) Glutathione (UDP-glucouronosyltransferase)- UGT- not active in newbies (jaundice) o Phase III: transport Multidrug resistance protein 1 (MDR 1) or P-glycoprotein 1, or ABCB1) Transports drugs back into GI tract, or brain, or into proximal tube for excretion Substrates: Antiretrovirals, antifungals, macrolides, chemotherapeutic agents Bind P-glycoprotein 1 and remove from target tissues, bad in treating bacterial infections, cancer Excretion Drug compounds now more hydrophilic and can be excreted Renal Excretion: 25% of blood flow Typically only free, unbound, drug is filtered though glomerulous (passive diffusion) o excretion rate by filtration, renal blood flow, GFR, plasma protein binding o proximal tubule uses active transport to remove drug and concentrate them into proximal tubule, can remove protein bound drugs Biliary Excretion o Metabolites from liver via common bile duct enter small intestine (if lipophilic enough, drug will get reabsorbed into liver w/ bile salts) o Other bile salts excreted in bile Rate of Elimination (v) o V=max rate of drug elimination x Conc. of drug in plasma/ Km + C o MM graph, 1st order o V=CssCL (steady state conc x clearance) o Faster rate of infusion does NOT change time needed to achieve steady state (only conc. changes) 1st order kinetics o most drugs o clearance process NOT saturable o rate of drug elimination proportional to plasma drug concentration o half life and clearance of drug remain constant o Km>>C o Linear kinetics o Zero order kinetics: o Carrier mediated elimination (enzyme saturation) o Rate is independent of drug concentration (elimination is constant) o Km<<C (seen with large drug dosages) o Aka: non-linear kinetics (MM kinetics) o V=Vmax (rate stays the same when you concentration) o Serum conc. change more or less than expected w/ change in dose o Clearance o Rate of elimination relative to conc. of drug in plasma o CL= v/Css o CL total: total clearance from body of all organs o Determines Css for a given dosage rate o 2 major sites of elimination: kidneys and liver o can change based on disease states or enzyme inducing/inhibiting drugs o Maintenance dosing: used to maintain Css Rate of drug going in=rate of drug going out MD= CL x Css / F Organ clearance (extraction) o Ca: drug entering organ Ca= dose x absorption o Cv: drug leaving organ Cv= dose x bioavaiibility o Extraction ratio (E)= (Ca-Cv)/ Ca o Cl (organ)= blood flow though organ (Q) x E (extraction ratio) Elimination Rate Constant (ke)- single compartment model, follows 1st order kinetics Half-Life o Time taken for a drug to be reduced to half it’s value o T1/2 = 0.693 / ke or ln2/ke o 1st order half life: independent of drugs concentration (1st order kinetics) half life does not change w/ increase of plasma concentration time to eliminate all of drug does increase ke is slope of line o Zero order half life: does when plasma conc. Time to eliminate all of drug also increases w/conc. o Half time determines time to reach Css and dosing interval Css usually achieved after 4-5 half lives T1/2= 0.693 X Vd / CL AUC= area under the curve (once Clearance is constant, AUC directly proportional to dose administered) LDs and MD’s based on a desired Css w/in therapeutic range (4-5 half lives) Can calculate new dose (desired Css) Xnew=Xold (Css, new/ Css, old) o Factors Affecting Half Life Age (half life) Obesity (half life) Pathologic fluid (half life) CYP450 induction (half life) CYP450 inhibition (half life) Cardiac, hepatic, renal failure ( half life) Individualizing Drug therapy PK parameters can be altered by o Age Neonates: biotransformation/elimination oxidative and glucoronate conjugation renal excretion mg/kg dosing Elderly: Vd for fat-soluble drugs (less learn muscle) Lower rate of oxidative metabolism Conjugation is okay Renal excretion o Gender: women more vulnerable than men to alcohol-induced liver, heart damage o Weight: Fat-soluble drugs Vd w/ obesity Vd w/ cachexia Multiply TBW by 0.4 to get adjusted body weight o o o o Disease States Renal Disease Cockroft-Gault eqn used to estimate creatinine clearance (Clcr) Clcr= (140-age) IBW/SCr x 72 Females: multiply 0.85 (140-age) For drugs mainly eliminated via kidney: o If Clcr is 30-60 minor dose adjustment o If Clcr is 15-30 moderate dose adjustment o If Clcr is <15 major dose adjustment (Drug not being cleared well by kidneys) Hepatic Disease No test to estimate liver drug metabolism Indicators of poor metabolism in liver: serum bilirubin, serum albumin, prolonged prothrombin, cirrhosis Heart Failure CO which liver blood flow Decrease initial doses by 25-50% in moderate to severe HF Genetics Polymorphism-individual variation in the genes coding for drugmetabolizing enzymes N-acetyltransferase- slow acetylators- higher levels of certain drugstoxicity Transport Proteins Interactions w/ other drugs/foods Specific Drugs to use PK on Aminoglycosides: nephro, ototoxicity at toxic levels o Gentamicin, tobramycin, amikacin (antibiotics) o Cleared renally o Hartford nomogram (ODA)- concentration dependent killing and postAntibiotic effect of the drugs Can change the interval, NOT the dose Vancomyocin: very toxic o Time dependent bacterial killing, min conc. is important!! o Use Matzki nomogram Digoxin: long half life (40 hrs) o Used for afib and HF o Cleared renally o Narrow therapeutic index o Calculate Clcr, calculate Vd, calculate LD Phenytoin: large amount of patient variability (unpredictable) o Anticonvulsant o Non-linear kinetics (half time as MD ) o Approximate new concentrations after dose adjustment by assuming linear kinetics and adding/subtracting 15-33% Drug Interactions Lec. 6-7 Mechanisms of Drug Interactions Pharmaceutical interactions (Drug incompatibilities) o A chemical rxn between drugs PRIOR to administration (combo of drug solutions- IV, are incompatible, pharmacist concern Pharmacodynamic interactions o Effects on tissues, organ system, microbes, tumor cells o Additive: add up to the sum to individual drug effects o Synergistic: > sum of individual drug effects Sildenafil (Viagra) and Nitroglycerin: hypotension risk o Antagonistic: affecting same fxn w/ opposing effects Pharmacokinetic interactions o Altered Drug absorption Altered gut motility or secretion Binding or chelation of drugs Divalent cations (Ca+2, Al+2 in antacids bind drugs(fluoroquinolones, tetracyclines) Competition for active transport (p-glycoprotein) OATP Fruit Juice Interaction Organic anion transporting peptide, transports drugs into cells, absorption Fruit juices inhibit OATP, absorption o Altered Drug distribution Can displace drugs from plasma proteins, resulting in greater “free” drug, increasing the effects (as conc. increases, so does clearance) Liver disease: albumin (unbound drug concentrations) o Altered Biotransformation CYP450 Enzymes CYP3A4- responsible for over 50% of drugs, most important for drug interactions!! CYP 450 Enzyme induction metabolism, clearance, half life, pharmacologic action Barbituates, Carbamazepine, Rifampin, tobacco smoke CYP 450 Enzyme inhibition: metabolism, clearance, half life, pharmacologic action “azole” antifungals- notorious CYP450 inhibitors o itraconazole inhibits CYP3A4, conc. of HMG-CoA reductase inhibitors (simvastatin) “ ketoconazole o Altered Drug Excretion Change in renal pH Competition for active transport in renal tubules Probenecid conc. of certain antibiotics biliary clearance Nephrotoxicity Change in renal blood flow (NSAIDS, ACE inhibitorsPG inhibitors, renal blood flow) o Drug-Food interactions Absorption (dairy products Ca+2 bind drugs, absorption (tetracyclines, fluoroquinolones) Metabolism- Flavonoids in Grapefruit juice (CYP3A4 inhibitor, conc. and effects of simvastatin/statins) o P-glycoprotein: drugs can induce or inhibit P-gp St. John’s Wort: bioavailability of many drugs, induces P-gp Can use drug interactions to our advantage (additive effect) Clinically Significant Drug Interactions o Drugs w/ low therapeutic indices (potential for significant medical interactions!!) Digoxin Lithium Warfarin o Multiple meds-polypharmacy o Drugs w/ bioavailability (F<10%) o Concomitant illness o Genetic Polymorphisms “Red” Flag Drugs Azole Antifungals H2 blockers (cimetidine) Griseofulvin Macrolide antibiotics (erythro, clarithryomyocin) Omeprazole Paroxetine & fluoxetine Phenytoin Probenecid Ritonavir Theophylline Warfarin Smoking Antacids (Omeprazole) Carbamazepine Diltiazem- HR: inhibits metabolism of simvastatin (simvastatin conc) Grapefruit Juice MAOIs Phenobarbitol Quinidine Rifampin/rifabutin St. Johns Wort Valproic acid Verapamil Clinical Cases: Clopidogrel: omeprazole (antacid) reduces clipidogrel’s antiplatelet effect, but research is debatable. Treatment: weaker Cyp2C19 inhibitors (Pantoprazole) Itraconazole (azole antifungals) are CYP3A4 inhibitors, can decrease the metabolism of drugs (warfarin) Ibuprofen (PG inhibitor, renal blood flow) can decrease the elimination of lithium (eliminated by kidneys) Antacids fluoroquinolone antibiotic absorption by binding the drug o “Take your quin “alone” – don’t take you quinolone antibiotics w/ anything Diltiazem inhibits metabolism of simvastatin, conc. muscle pain, myopathy Pharmacodynamics (Lec 8,9,10) What the drug does to the body (Mechanism of Action) Sites of Drug Action o Drug Action NOT involving specific protein/receptor Physical Actions (lipid soluble anesthetic agents, osmotic diuretics (mannitol), osmotic cathartics Chemical Actions (Antacids, chelating agents (removes Lead, copper) o Drug action involving specific protein/receptor Enzymes: Act directly (mimic substrate, and inhibit enzyme’s activity) Competitive and Noncompetitive Selective Toxicity though inhibition of a unique metabolic pathway Selective toxicity though species different in enzyme selectivity Incorporation of a drug into a macromolecule (produces desired response) Inhibitors of enzyme activity in specialized cells o Inhibitors of the synthesis/degradation of NT Stoichiometric and irreversible inhibition o Cyclooxygenase inhibitors (aspirin) permanently binds enzyme, have to make more enzyme to make more platelets Carrier molecules Carry polar and non-lipid soluble molecules across cell membranes Ex: SSRI (serotonin uptake) Specific physiological tissue/cellular receptor Receptor is physiological target for drugs, transduction Specificity: selective attachment or influence of one substance on another (interaction w/ drug on receptor) o Determined by drug/receptor structure, chemical forces of interaction, drug solubility, cellular fxn of receptor Selectivity: ability to achieve the desired therapeutic effect while minimizing unwanted effects o Determined by cell type specificity of receptor and specificity of the binding out receptor-effector Response by a Drug o Initial stimulus (drug + receptor) Binding forces Attractive Forces o Covalent bonds (irreversible w/o catalyst) o Ionic Bonds H bonds Van der Waals: significant role in determining relative affinity o Hydrophobic Effect: attraction between two apolar groups in an aqueous environment Repulsive forces o Ionic and dipole repulsions o Steric hinderance Transduction, modulation, or amplification Agonist: binding causes change in the activity of the target Full: max activation (Agonist and allosteric activator) Partial: agonist alone Inverse: agonist and allosteric inhibitor Antagonist: inhibit the ability of their targets to be activated/inactivated by agonist Competitive or Noncompetitive Drug Receptor Types Ion Channels o Ligand gated: binds ligand,voltage sensitive (nicotinic receptors) Excitatory amino acid receptors Inhibitor amino acid receptors o Voltage gated (can fxn w/o endogenous ligand) Activated w/ change in transmembrane potential, ion can flow though (Na, Ca, K) Drug can directly block channel (anesthetic) Drug can bind integral part of channel, modulate receptor (Ca+2 channel blockers) o Second messenger regulated Ion channels can be modulated by G protein receptor activation G protein coupled Receptors o G isoforms Gs (activates Ca+ channels, activates AC) Gi (activates K channels, inhibits AC) Gq (activates PLC) G12/13 (activates Rho) o subunits o GDPGTP (subunits interact w/ effectors) Adenylate Cylase (AC): cAMP Phospholipase C (PLC): cleaves PIP2DAG and IP3 o Effectors interact w/ second messenger (cAMP) Amplification of response by cAMP IP3 increases intracellular Ca+2 DAG activates PKC (binds Ca+2) o GTPGDP (subunit deactiation, subunits return cAMP inactivated 5’AMP (via phosphodiesterases- PDE) o o o Transmembrane enzymatic Receptors o Cysolic domainsdimers, multisubunit complexes o Fxns: kinase (major player), phosphatase o 5 major classes Tyrosine kinase- major player (insulin) Tyrosine phosphatases Tyrosine kinase-assicated (JAK) Serine/threonine kinases Guanylyl cyclases ANP-Atrial Natiuretic factor, enterotoxion bind membrane NO binds intracellular enzyme cGMP- 2nd messenger o Receptors linked to Guanylyl cyclase Intracellular Receptors o Intracellular enzymes o Transcription factors: steroid hormones o Structural proteins (antibiotics target ribosomes) o Nuclear Receptors o Generation of an effect Regulation of Drug-Receptor Interactions o Tachyphylaxis: repeated administration of the same dose of a drug results in a reduced effect of the drug over time (rapid tolerance buildup) o Desensitization: decreased ability of a receptor to respond to stimulation by a drug or ligand Homologous (same receptor) Heterolgous (2> receptor types) Occupancy Theory Ligand-receptor binding: once a sufficient number of receptors are bound on/in a cell, a response occurs (L+RLR response) o Dissociation constant Kd=koff/kon Dose-Receptor Relationship o If receptors remain constant (Ro) o Percent bound/binding affinity = LR/Ro o Kd=50 when 50% of receptors bound o Drug with lowest Kd has highest affinity (binds to receptor) o Dose Receptor binding curve: Dose Response Relationship o Relationship between the dose and the response of the organism (measures drug effectiveness), usually mirrors drug-receptor binding o DR/Ro= dose response/max response o EC50- where you have half of your max efficiency o Dose Response Curve- goes from no response, to minimal effective dose to graded response (dose dependent) to max effect o Quantal: relationship between dose of the drug and % of pop who have defined response (all or nothing) ED50: median effective dose TD50: median toxic dose LD50: medial lethal dose Therapeutic window: range between the ED50 and beginning of TD50 curve Therapeutic index: TD50/ED50 o Graded (effect on individual, therapeutic window-looking at potency and efficacy) EC50-potency, left shift Emax (efficacy)- higher curve Agonist: 2 state model (active/inactive) o 4 possible states in EQ (D+R, D+R*, DR, DR*) o Partial Agonist o Inverse Agonist: effect on constitutively active receptors o Spare Receptors Antagonist o Inhibits the action of the agonist o No effect on its own, requires agonist o Competitive: binds to active site on receptor, reversible, stabilizes receptor in an inactive state (shifts dose response curve to the right)kd of agonst, potency o Noncompetitive: antagonist binds irreversible to active site of receptor Binds allosteric site, or active site (irreversible) Shift the dose-response curve downward (efficacy of the agonist) o Nonreceptor: chemical antagonist: binds agonist before it can work (neutralizes) physiologic antagonist: opposite effect but at different receptor