Lecture 2: Pharmacotherapeutics

Lecture 2: Pharmacotherapeutics Distribution · Distribution: how drugs are transported through the body to target tissues · Factors affecting distribution: ① blood flow to the tissue (CO, BBB, injury) ② Size of the tissue (the bigger the easier to get there) ③ molecular characteristics (lipophilicity, size...) ④ plasma protein binding (PPB) Plasma Protein Binding (PPB) · cohesion (binding) with plasma protein molecules ↳ drugs have an affinity for plasma carrier proteins eg. plasma proteins: albumin (acidic drugs) Drugs on plasma proteins can be displaced Alpha-1-acid glycoprotein (basic drugs) by those with higher affinity · binding decreases distribution rates · competitive, reversible, saturable (WIND-F) Drugs EXTENSIVELY Bound (90% ) · interactions may occur when one agent displaces · oral anticoagulants: Warfarin another from plasma proteins, leading to · oral antidiab: glimepiride, glipizide, glyburide extremely high levels of a drug in the blood and · lipid lower. drugs: gemfibrozil, statins adverse effects · NSAID: indomethacine, phenylbutazone, ibuprofen, naproxen, ↳ counterindicated diflunisal, diclophenac, loop diuretics, eg. Furosemide · antihypertensives: diazoxide, losartan · cardiovasc.: amiodarone, prazosin, felodipine, nicardipine, digitoxin, ticlopidine · antiinfectives: ceftriaxone, nalidixic acid, ketoconazole, itraconazole, suramine, nelfinavir · benzodiazepines: diazepam, midazolam · others: montelukast, zafirlukast, entacapone, leflunomide Volume of Distribution (vd) · estimates how extensively a drug is distributed into tissues · assumes total drug equally reaches tissues · relative comparison only · calculation: drug dose/measured drug plasma concentration · low vd indicates that the drug may not be reaching all the tissues all the time ↳ less distributed, binding to less unwanted receptors and less side effects Most common Biotransformation: Metabolism (aka Biotransformation) 1. active drug to inactive metabolite · metabolism/biotransformation: the process of chemically converting a 2. active drug to active metabolite (toxic?) drug to a form that is usually removed from the body more easily 3. inactive drug to active metabolite ↳ termination of drug action, and preparation for excretion ("prodrugs") · Liver: primary metabolizing organ (hepatic microsomal enzymes) - - 2 Phases of Metabolism ① Phase I · hydrolysis, reduction, oxidation ↳ removal of hydrogen proton, addition of oxygen · cytochrome P450 enzyme group ② Phase II · conjugation and polarization (not all drugs require this phase) · 5 main enzymes used “Golden rule” Main CYP 450 Enzyme Groups · note: CYP3A4 + CYP3A5 = 50% of drugs use these enzymes · saturable · dynamic ↳ drugs can increase or inhibit certain enzyme function - more active: metabolizes faster - less active: metabolizes slower ↳ inducers vs. inhibitors Excretion · excretion: the elimination of drugs from the body after they have been metabolized ↳ inactive substances and inactive metabolites are eliminated · Kidneys: primary organ of excretion · Factors effecting renal excretion: ① molecular characteristics ↳ PPB ↳ ionization, hydrophilicity, size ↳ urinary PH? ↳ metabolized? Large drug-protein complexes aren’t filtered in glomerulus ② Cardiac output ↳ renal blood flow ③ Renal Function ↳ low function in elderly and children ↳ renal disease - Renal Function and Clearance · GFR calculation → creatinine clearance test ↳ reduced creatinine clearance indicates reduced kidney function · Clearance (Cl): the rate of drug elimination in an hour · 1st order elimination kinetics: ↳ elimination is proportional to the drug serum concentration (mg/dl or L) ↳ calculation: Cl = elimination/peak plasma concentration (mg/dL/hr or L) ↳ total amount voided in an hour: peak plasma concentration ↳ calculation only needed if you want to keep therapeutic amount constant → match clearance to infusion rate · zero order elimination kinetics: ↳ rate of elimination or "clearance" is constant (no matter how much drug is given, clearance rate stays the same) - - Pharmacodynamics · pharmacodynamics: how the drug changes the body, concerned with the mechanism of drug action and the relationships between concentration and responses on the body · side effects: when drugs bind to receptors they weren't intended to bind to · some drugs bind directly to/in bacteria and viruses, while others bind to receptors · drug receptor binding: ↳ is saturable ↳ increases or suppresses existing processes ↳ can block receptors to prevent binding Affinity, Efficacy, and Potency · affinity: the “strength" with which a drug binds to a receptor or the "length" of binding (duration of action) ↳ is specific, saturable, and reversible · efficacy: the degree to which a drug induces maximum therapeutic effect or the "effectiveness" of that drug ↳ note: antagonists have no efficacy, they only block the receptor · potency: the strength of a drug in terms of how much is needed to elicit an effect ↳ a drug that is more potent will produce a therapeutic effect at a lower dose as compared with another drug in the same class · example: ibuprofen relieves pain at a lower dose indicates that this agent is more potent than acetylsalicic acid, but at recommended dosages they are equally as effective at relieving headaches so they have the same efficacy · efficacy is almost always more important than potency - - Drug-Receptor Interactions · Agonist: a drug that produces the same type of response as the endogenous substance "mimics" ↳ full agonists extensively binds to receptors and may produce greater maximum effects than the endogenous substance eg. Morphine mimics endorphins · Partial Agonist: a medication that produces a smaller maximum response, even if all receptors are occupied → lower efficacy ↳ in the presence of a full agonist, a partial agonist acts as an antagonist · Inverse Agonist: a drug that induces the opposite effect of the naturally binding substance eg. Caffeine binds to adenosine receptors and increases sympathetic NS activity (adenosine usually increases parasympathetic NS) · Antagonist: a drug that binds to a receptor to block the endogenous substance from binding ↳ no effect other than to block other substances from binding eg. Naloxone (Narcan) can reverse opioid overdoses because it has a higher affinity to receptor than opioid (displaces opioid) eg. Antihistamines - ① G-protein · binding to channels outside of the cell to exert effects or use secondary messengers · review A & P eg. Epinephrine → Stimulates G-protein & second messenger systems = Sympathomimetic stimulation 6 Major Receptor Types: ① G-protein (GPCR) ② Ion channels ③ Nuclear receptors ④ Intracellular enzymes ⑤ Transmembrahe enzymes ⑥ Non-enzyme JAK-STAT ② Ion Channels · most bind to voltage-gated channels eg. Lidocaine closes ion channels so cells cannot communicate with environment or fire action potentials (no pain sensation) Lidocaine ③ Nuclear Receptors · in nucleus like hormones → must be lipophilic and are often large and require special channels ↳ aka "steroid" receptors ↳ most bind to cytoplasm and change cell effects via DNA ④&⑤ Enzyme Binding · 2 types: intracellular and transmembrane eg. insulin → cell membrane receptors = stimulate transmembrane enzyme: tyrozine Kinase → activates cellular glucose uptake ⑥ Non-Enzyme Transmembrane · JAK-STAT receptors (used by interferons) Tolerance and Resistance · Drug Tolerance (down-regulation) ↳ most common ↳ receptor de-sensitization OR decreased number of viable receptors ↳ more drug required for same response · Drug Resistance ↳ many variations of Kinetic alterations ↳ eg. increased drug metabolism (drug metabolized at a faster rate, therefore less bioavailable and less effective) ↳ note: this is NOT the same as antibiotic resistance - -