Pharmacology Lecture Notes PDF

ORAL HEALTH SCIENCES 5 FACILITATOR: DR KEREANN NELSON OHS 3011 PHARMACOLOGY Reference: Kaplan Review Notes ASSESSMENTS Class test 1 -20% Class test 2 - 20% Class test 3 - 20% Final Examination - 40%  Pharmacology T...

ORAL HEALTH SCIENCES 5 FACILITATOR: DR KEREANN NELSON OHS 3011 PHARMACOLOGY Reference: Kaplan Review Notes ASSESSMENTS Class test 1 -20% Class test 2 - 20% Class test 3 - 20% Final Examination - 40%  Pharmacology The science of drugs including their origin, composition, pharmakinetics, therapeutic use, and toxicology  GENERAL PRINCIPLES: Pharmacodynamics characterize the action of drugs on the biochemical & physiologic systems of the body, and identifies the sites & modes of action PHARMACODYNAMICS & PHARMACOKINETICS Pharmacokinetics characterize quantitative aspects of drug absorption, distribution, metabolism & excretion, and describe the time course of drug & metabolite concentration at their site of action  DRUGS THAT ACT INDEPENDENTLY OF RECEPTORS Antacids: neutralize stomach acids Chelating Drugs: bind metallic ions PHARMACODYNAMICS Osmotically Drugs: Diuretics (mannitol) Cathartics (methylcellulose) Volatile General Anesthetics: Cause reversible change in synaptic junction Potency depend on lipid solubility  DRUG RECEPTOR INTERACTIONS Receptor: Drug combine with specific target molecule on cell to initiate a biochemical “cascade” to PHARMACODYNAMICS produce an effect May be protein, carbohydrate nucleic acid or lipid Binding may involve ionic, covalent, hydrogen or van der Waals bonds  Drug Receptor Interactions (cont) Agonists bind to receptor & stimulate them Antagonist bind to receptor & decrease or PHARMACODYNAMICS block the effect of an agonist Competitive antagonist Bind to receptor & prevent binding of agonist Can be overcome by high [agonist] Produce parallel right shift on dose- response curve  Drug Receptor Interactions (cont) Antagonist (cont) Non-competitive antagonist PHARMACODYNAMICS Bind to receptor in irreversible way Prevent any agonist action Can not be reverse by high [agonist] Decrease height of dose-response curve PHARMACODYNAMICS E F Agonist F alone Agonist with E Agonist with C noncompetitive competitive T antagonist antagonist Log (dose) Graded dose-respone Curve  SUMMARY Competitive Antagonist: Bind reversibly to agonist Can be overcome by large amount of PHARMACODYNAMICS agonist Non-competitive Antagonist: Bind irreversibly Cannot be overcome by agonist  GRADED DOSE-RESPONSE CURVES Response of a system to increasing dose of drug (agonist) Agonist = drug that binds to receptor  PHARMACODYNAMICS stimulation Effect analyzed by plotting response versus log of drug concentration (dose) Efficacy = maximum response by agonist Increase as effect increases (y - axis)  GRADED DOSE-RESPONSE CURVES (cont) Potency: Measure of how much drug is needed to produce a given effect PHARMACODYNAMICS Expressed as concentration that can give a 50% response (EC50) Less drug needed to produce effect, more potent drug is. Potency increases as curve shifts left on x-axis  QUANTAL DOSE-RESPONSE CURVES Show minimum drug dose needed to produce a pre- determined response in a population. Percent of population plotted against the log (dose) ED50 (median effective dose) = dose that will PHARMACODYNAMICS produce effect in 50%of the population TD50 = minimum dose that produce a specific toxic effect in 50% of the population LD50 = minimum dose that will kill 50% of the population PHARMACODYNAMICS QUANTAL DOSE-RESPONSE CURVES (cont TI (therapeutic index) = ratio of dose required to produce toxic or lethal effect to the dose needed for a therapeutic effect TI = or = or > 4 == good TD50 LD50 ED50 ED50 PHARMACODYNAMICS Therapeutic Death 100 effect 50 % of population responding 0 Log [drug] LD50 ED50 Quantal Dose-Response Curves  SUMMARY Drug with high efficacy but low potency reaches a high level of response with a greater dose PHARMACODYNAMICS Low TI (Therapeutic index) indicates a high incidence of side effect at usual doses (narrow range of therapeutic & toxic doses)  SUMMARY High TI indicates low incidence of side effects at usual doses High TI = safer drug PHARMACODYNAMICS Drug companies strive for ratio of at least 4 Anything less than 2 requires close patient monitoring e.g. lithium (Rx manic disorder) PHARMOCOKINETICS Factors That Effect [Drug] At Site Of Action Dose & Route of Administration (Absorption) Circulatory System (Distribution) Other Metabolism Excretion Compartments Site of Action or “biophase Effect  DRUG ABSORPTION Factors Affecting Absorption: Permeability Lipid solubility PHARMOCOKINETICS Correlates to ability to cross cell wall Weak acids & bases more lipid soluble Aqueous solubility Charged (ions), water soluble molecules excluded from crossing epithelial lining of skin & GIT (unless very small)  Factors Affecting Absorption: (cont) Permeability Bioavailability Fraction of drug that reaches systemic PHARMOCOKINETICS circulation = 1 (100%) when given IV = less than 1, Permeability given by other routes (e.g. orally) due to incomplete absorption or first-pass metabolism (Drug  GIT  Liver  decreased bioavailability)  ROUTES OF ADMINISTRATION Oral: Most common, safe, economical, convenient PHARMOCOKINETICS Drug must be lipid soluble, resistant to GI acid, GI digestive enzymes & GI bacterial flora Rate & degree of absorption can vary  ROUTES OF ADMINISTRATION (cont) Sublingual (buccal) Venous drainage enter systemic circulation PHARMOCOKINETICS (superior vena cava), bypassing Liver Good for self-administration, rapid onset (e.g. nitroglycerin for angina pectoris) Good for drugs highly metabolized by Liver  ROUTES OF ADMINISTRATION (cont) Rectal Less of a first pass effect than oral route Useful in vomiting & unconscious cases Absorption irregular PHARMOCOKINETICS Intravenous (IV) Rapid & complete delivery to target tissues Useful in emergencies, & drugs highly metabolized by Liver, or poorly absorbed from GIT Dose levels titrated very accurately  ROUTES OF ADMINISTRATION (cont) Intramuscular (IM) Contraindicated for patients on anticoagulants Aqueous solutions absorbed rapidly PHARMOCOKINETICS Oil solution absorbed slowly Subcutaneous (SC) Small volumes only Drugs slowly absorbed  ROUTES OF ADMINISTRATION (cont) Topical: Skin, vagina, eyes, ear, nose & throat Transdermal for systemic administration of drugs to skin PHARMOCOKINETICS Absorption slow (nicotine or nitroglycerin patch) Absorption higher for mucous membrane (topical lidocaine)  ROUTES OF ADMINISTRATION (cont) Intrathecal (IT) Injection into subarachnoid space (lumbar puncture) or ventricular system (Ommaya reservoir) PHARMOCOKINETICS Bypass blood-brain barrier & blood–CSF barrier Useful for drugs with poor or slow CNS penetration or when rapid high CSF concentrations is needed (e.g. severe meningitis, spinal anesthesia) PHARMOCOKINETICS ROUTES OF ADMINISTRATION (cont) Intra-arterial (IA) Delivery of high concentration to selective sites Used for x-ray contrast studies (e.g. angiogram) Inhalation For gaseous & volatile drugs (e.g. anesthetics bronchodilator (asthma)  DRUG DISTRIBUTION Plasma Protein Binding Determined by: Amount of tissue protein PHARMOCOKINETICS (albumin) Binding constant for the drug Binding is non-specific, several drugs may compete for same binding site PHARMOCOKINETICS DRUG DISTRIBUTION (cont) Volume of Distribution (Vd) = Total drug in body(g) Plasma [drug] Lipid-soluble drugs have Vd > total body water Drugs that bind strongly to proteins have Vd approaching plasma volume Greater the Vd the slower the excretion rate  DRUG DISTRIBUTION (cont) Unequal Distribution Tissue affinity: binding to mucopolysaccharide, nucleoprotein & phospholipid reduces availability of drug PHARMOCOKINETICS Body fat act as a reservoir for lipid-soluble drugs Blood-Brain Barrier highly selective for lipid-soluble, non-ionized drugs Blood flow if high allow drugs to reach equilibrium fast (e.g. brain)  DRUG DISTRIBUTION (cont) CLINICAL CORRELATION Competition for plasma protein binding explain drug-drug interaction PHARMOCOKINETICS Both fonamide & coumarin bind to proteins Administration of fonamide to patient on chronic warfarin can displace it causing dangerously high levels of free warfarin in the blood  severe bleeding  DRUG ELIMINATION Pharmacologic effects terminated by: transformation of drug to an inactive metabolite prior to excretion PHARMOCOKINETICS excretion of unchanged drug active metabolite  DRUG ELIMINATION Metabolism & Transformation: Liver most important site Metabolic enzymes & hepatic microsomal enzymes found in smooth endoplasmic PHARMOCOKINETICS reticulum (e.g. cytochrome P-450 system) Other enzymes located in: Mitochondria (e.g. monoamine oxidase) In cytosol (e.g. alcohol dehydrogenase) Lysosomes  DRUG ELIMINATION Metabolism & Transformation: (cont) Phase 1 Mostly oxidations, reductions, or hydrolysis Phase 11 PHARMOCOKINETICS Conjugation of drug or metabolite Involve addition of endogenous substance (e.g. carbohydrate or sulfate) Inactivate drug or metabolite (hydrophilic form)  facilitate excretion  Phase 11 (cont) Conjugation occur with: glucuronic acid mostly sulfate, amino acid or actylation PHARMOCOKINETICS Enterohepatic Circulation Conjugated drug actively secreted in bile Drugs hydrolyzed in small intestine Most bile salts reabsorbed in terminal ileum Drug may be excrete in feces, urine, saliva or reabsorbed  DRUG ELIMINATION (cont) Factor that affect Hepatic Metabolism Age: very young or old  impaired metabolism or conjugation PHARMOCOKINETICS Genetics: Regulates activity of N-acetyltransferase Influence metabolism of: procainamide (Rx arrhythmia) dapsone (Rx auto-immune disease) isoniazid (Rx TB)  Factor that affect Hepatic Metabolism (cont) Hepatic insufficiency impair metabolism (e.g. cimetidine – Rx peptic ulcer) Drug interactions Drugs may competitively inhibit the metabolism of other drugs by microsomal PHARMOCOKINETICS enzymes  increasing metabolism of other drugs Reduced Hepatic Blood Flow caused by Congested Heart Failure (CHF) & drugs that reduce cardiac output ( e.g. propanolol)  SUMMARY An important source of drug interaction is induction & inhibition of metabolism by the liver INDUCERS INHIBITORS Barbiturates Cimetidine Phenyton (Rx epilepsy) Ketoconazole PHARMOCOKINETICS Rifampin (Rx TB) Isoniazid Carbamazepine (Rx epilepsy, Trigeminal neuralgia)  DRUG EXCRETION Kidney: Primary site of excretion Glomerular Filtration Passive & non-saturable process Drug bound to protein not readily filtered Tubular Secretion PHARMOCOKINETICS Active & saturable process Mostly in proximal convoluted tubules Passive: neutral molecules  enhance secretion of toxic charged particles  DRUG EXCRETION (cont) Lung: Excretion of: Gaseous anesthetics Paraldehyde (sedative & hypnotic) PHARMOCOKINETICS ETOH Garlic GIT: Drug secreted into liver biliary tract & eliminated in feces  DRUG EXCRETION (cont) Sweat, Saliva, Tears, & **Breast Milk Minimally involved Lactating mothers should be PHARMOCOKINETICS under close medical supervision because many drugs are excreted in breast milk  neonatal toxicity PHARMOCOKINETICS DRUG DECAY CURVES Based on kinetic model i.e. the body is a single compartment Describe the time course of drug in the body Zero-order kinetics Occur when elimination process is saturated Constant amount (not a fraction) of drug eliminated over a given time (e.g. ETOH)  PHARMOCOKINETICS Elimination is Processes necessary DRUG DECAY CURVES First-order kinetics concentration for absorption or not (cont) (MOST DRUGS) dependent saturable Rate of drug removal Concentration of Constant fraction is proportional to drug diminishes eliminated per unit plasma logarithmically with time concentration time  DRUG DECAY CURVES (cont) First-order kinetics (MOST DRUGS) [cont] Rate of elimination described in 2 ways: PHARMOCOKINETICS Physiologic half-life (t ½ ) = time required for 50% of drug to be eliminated Rate constant of elimination (ke) = percent change per unit time PHARMOCOKINETICS DRUG DECAY CURVES Plasma Plasma [drug] [drug] Time Time Zero-order kinetics First-order kinetics  DRUG DECAY CURVES SUMMARY Zero-order kinetics: drug decrease at a PHARMOCOKINETICS constant rate regardless of plasma drug concentration First-order kinetics: drug elimination rate is proportional to plasma drug concentration  Drug Clearance mathematically equivalent to volume of blood that can be completely cleared of a drug per unit time DRUG ACCUMULATION PHARMOCOKINETICS Repeated doses may cause accumulation Assuming First-order kinetics: If the rate of administration exceeds rate of elimination  accumulation Accumulation stops when rate of elimination = rate of administration (steady state)  CLINICAL IMPLICATIONS HALF-LIFE: Determine dose interval necessary to obtain desired level of drug PHARMOCOKINETICS Drug with short half-life: Giving twice the dose does not double the duration of action Drug with long half-life: Larger loading dose, followed by smaller maintenance doses (e.g. penicillin)  CLINICAL IMPLICATIONS HALF-LIFE: (cont) Drug accumulation PHARMOCOKINETICS Since approx 4 half-lives are required for almost complete elimination of a drug, any dosage interval shorter than this  accumulation  CLINICAL IMPLICATIONS (cont) PROLONGATION OF DRUG ACTION Frequent doses necessary (tetracyline q 6 hrs) Coating tablet (time release) “depot” form allow slow absorption (crystalline PHARMOCOKINETICS insulin) Slow excretion of drug (blocking secretion of penicillin G with probenecid) Inhibiting the metabolism of the drug [blocking metabolism of 6-mercaptopurine with allopurinol (Rx gout)]  CLINICAL IMPLICATIONS (cont) LOADING DOSE To produce therapeutic levels without delay PHARMOCOKINETICS of 4-5 half-lives (amoxicillin 500 mg, starting with 1000 mg STAT in cases of significant infection)  DISEASE STATES REQUIRING ADJUSTMENT OF DOSE & DOSING LEVELS Renal Insufficiency Creatinine clearance correlates well with PHARMOCOKINETICS elimination of drug by kidney Initial loading dose usually the same; maintenance dose decreased or intervals between doses increased. Hepatic Insufficiency: monitor serum levels & clinical sign of toxicity