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Pharmacology 2060A/B Midterm: Midterm Exam Summary.docx

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Western University
Pharmacology 2060A/B
David Lamari

Midterm Modules Summary Module 1 - Introduction  Drug Legislation o Therapeutic Products Directorate - traditional drugs o Biologics and Genetic Therapies Directorate - hormones and antibodies o Natural Health Products Directorate - herbals, vitamins, minerals  Approval of Marketed Drugs 1. Preclinical testing - animals; pharmacokinetics and toxicity 2. Clinical Trial Application 3. Phase I Clinical Trial - healthy volunteers; pharmacokinetics and pharmacodynamics 4. Phase II Clinical Trial - patients; effectiveness, side effects 5. Phase III Clinical Trial - more patients; LT side effects 6. NDS submitted to Health Canada - issued NOC and DIN 7. Phase IV Clinical Trial - post-marketing; efficacy and safety  Pharmacokinetics o What body does to drug - ADME o Absorbed by: stomach, small intestine then sent to portal vein o Metabolized by: liver (primary site) o Distributed by: systemic circulation o Excreted by: kidney (urine; low molecular weight), biliary route (feces; large molecular weight and undergo metabolism)  Physiological barriers to drug transport - intestinal villi, tight junctions  Crossing the Cell Membrane 1. Direct penetration - must be lipid soluble 2. Through ion channels and pores - must be small; eg. Sodium, potassium, lithium 3. Drug transporters  Uptake - move drugs from outside to inside cell  Efflux - move drugs from inside to outside cell; present in intestine, placenta, kidney, and BBB  Types of Drug Molecules o Polar molecules - water soluble; uneven distribution of charge; no net charge o Ions - net charge; pass through ion channels or pores o Quaternary ammonium compounds - at least on N atom; positive charge; unable to cross membrane o Ionizable molecules - can be charged or uncharged; weak acids or bases Acidic Medium Alkaline Medium (stomach) (small intestine) Weak Acid Non-ionized Ionized Weak Base Ionized Non-ionized  Cell membrane repels charged (ionized) molecules  Ion Trapping - drugs accumulate on side of membrane where they're ionized because ionized drugs can't cross cell membrane  Capillaries supply tissue with oxygenated blood and allow drugs to move from blood to tissue o Out of capillaries - hydrophilic drugs pass through fenestrations; lipophilic can directly pass through plasma membrane o Out of brain capillaries - drugs must be lipophilic or have specific transport protein because BBB has tight junctions Module 2 - Pharmacokinetics (Absorption)  Absorption is movement of drug from site of administration into blood  RATE of absorption determines how quickly effect will occur  AMOUNT of drug absorption determines how intense effect will be  Factors Affecting Absorption o Rate of dissolution - faster rate = faster onset of action o Surface area - larger surface area = faster absorption  Villi in intestine make surface area very large; always has fastest absorption o Blood flow - Higher blood flow = concentration gradient = faster absorption o Lipid solubility - high lipid solubility = faster absorption than water soluble o pH partitioning - higher difference in pH bw site of admin and blood = greater absorption (ion trapping) o Activity of drug transport proteins - uptake transporter increase absorption; efflux transporters decrease absorption  Routes of administration 1. Enteral (involves GI tract) - oral, rectal 2. Parenteral (doesn't involve GI tract) - IV, IM, subcutaneous 3. Other - sublingual, transdermal, pulmonary 1. Oral o Pharmaceutical phase  Occurs after patient swallows tablet  Involves: 1) Disintegration and 2) Dissolution o Gastric emptying  Movement of stomach contents into intestine  Increase gastric emptying = increase rate of absorption o Enteric coating  Special coating that prevents dissolution in acidic environment of stomach  Intention is to allow drug to bypass stomach without undergoing pharmaceutical phase o Bioavailability  Fraction of dose of drug that reaches systemic circulation unchanged  Influenced by: drug formulation, route of administration, degree of metabolism 2. Sublingual o Drug dissolves and is absorbed across oral mucosa o Avoids first pass metabolism through liver o Must be lipophilic and uncharged 3. Transdermal o Must be lipophilic enough to penetrate skin (lipid barrier) o Must be relatively hydrophilic to dissolve in extracellular fluid o Usually small molecules o Provides constant plasma levels with minimal peaks and troughs; tolerance may develop o Factors affecting transdermal absorption:  Thickness of skin - thicker skin = decreased absorption  Hydration - increased hydration = increased absorption  Hair follicles - more hair = increased absorption  Application area - larger area = increased absorption  Integrity of barrier - weakened barrier = increased absorption 4. Rectal o Crosses rectal mucosa into blood o 1/2 of these drugs bypass liver 5. Intravenous o Drug injected into peripheral vein o Bolus - single dose administered over short time o IV drip - administered under continuous infusion for prolonged period; typically diluted in saline o 100% bioavailability 6. Subcutaneous o Only barrier is capillary wall o Primary determinants of rate of absorption are blood flow and water solubility 7. Intramuscular o Absorption determined by ability of drug to pass through fenestrations in capillary wall o Primary determinants are blood flow and water solubility o Factors affecting absorption:  Blood flow is deltoid > vastus lateralis > gluteal  Exercise increases blood flow  Heart failure, hypotension, hypothermia decrease blood flow 8. Pulmonary o Gaseous and volatile drugs can be inhaled and absorbed into blood through pulmonary epithelium o Very rapid absorption due to large SA Module 3 - Pharmacokinetics (Distribution)  Free drug - site of action, stored, metabolized, or excreted  Protein-bound drug - stuck in plasma  Drug Distribution o Determined by: blood flow to tissues, ability of drug to move out of capillaries, ability of drug to move into cells o Blood flow to tissues  Key determinant of distribution  High blood flow in liver, kidney, brain; distribution is rapid  Low blood flow in skin, fat, bone; distribution is slower o Ability of drug to move out of capillaries  Drug movement out of capillaries into interstitial space occurs rapidly due to permeability, with exception of brain o Ability of drug to move into cells  Drugs must be lipophilic to cross cell membrane or be carried by uptake transporter  Some drugs removed from cells by efflux transporters (limits penetration into cell)  P-Glycoprotein (P-GP) o Efflux transporter; important in drug distribution o Liver - pumps drugs from hepatocytes into bile; facilitates excretion o Intestine - pumps drugs into lumen; prevents absorption o Kidney - pumps drugs into lumen; facilitates excretion o Brain - pumps drugs into blood; limits brain exposure  Plasma Protein Binding o Only free drug is able to elicit pharmacological response; proteins unable to pass through capillary fenestrations o Albumin - affinity for lipophilic and anionic (weakly acidic) drugs  Malnutrition, trauma, aging, liver and kidney disease increases free drug concentration, which may result in toxicity o Alpha 1 acid glycoprotein - affinity for hydrophilic and cationic (weakly basic) drugs  Aging, trauma, and hepatic inflammation decreases free drug concentration, which may lead to ineffective therapy  Volume of Distribution (Vd) o The apparent volume that a drug distributes into o More drug in body=less blood concentrations=higher Vd o TBW (42L) = plasma(4L) + interstitial fluid(10L) +intracellular fluid(28L)  Vd = (total amount of drug in body)/(plasma concentrations of drug) o Small Vd (<4L) Highly protein bound drugs   Large molecular weight  Drug unable to leave vascular space (blood plasma) o Intermediate Vd (<14L)  Intermediate protein binding  Low molecular weight and very hydrophilic (can't cross membrane)  Drug able to leave plasma and enter interstitial space, but unable to enter cells o Large Vd (>14L)  Minimal protein binding  Low molecular weight and lipophilic (can cross membrane)  Drug able to leave plasma and interstitial space, and distribute into body compartments o Drug displacement from protein  Fate of displaced drug depends on Vd  Small Vd - displaced drug stays in plasma and does NOT distribute into tissues  Free drug concentration increases  Large Vd - displaced drug leaves plasma and distributes into tissues  Total plasma concentration decreases, and Vd increases even further  Body Composition o As we age, TBW decreases o Newborns and most obese patients have less muscle mass o Less drugs distribute in newborns' fat, whereas obese patients can hold a larger amount of lipophilic drug in fat tissue Module 4 - Pharmacokinetics (Metabolism)  Enzyme mediated alteration of a drug's structure  Sites of drug metabolism: o Liver - primary site of metabolism o Intestine - enterocytes lining gut metabolize o Stomach - site for alcohol metabolism o Kidney o Intestinal bacteria - normal bacterial flora play important role  Therapeutic consequences of metabolism: o Increase water solubility of drugs to promote excretion (*most important) o Inactivate drugs o Increase drug effectiveness o Activate prodrugs (inactive drugs until metabolized) o Increase drug toxicity (least favourable)  Kinetics o First Order - drug concentration is much lower than metabolic capacity of body  Rate of metabolism is directly proportional to concentration of free drug  Constant fraction metabolized per unit time  High drug concentration early=higher rate of metabolism o Zero Order - drug concentration is much higher than metabolic capacity of body  Rate of metabolism is constant over time  Constant amount metabolized per unit time  High concentration=low concentration=rate of metabolism  First Pass Metabolism o Oral drugs undergo significant metabolism before entering systemic circulation, resulting in a decreased amount of parent drug entering circulation o Occurs via:  Hepatocytes in liver (CYP enzyme)  Intestinal enterocytes (CYP enzyme)  Stomach (alcohol dehydrogenase) Intestinal bacteria (bacterial enzymes)  o Extraction Ratio (ER)  Amount of first pass metabolism can greatly determine a drug's bioavailability  High ER - high first pass metabolism; low oral bioavailability  Low ER - low first pass metabolism; high oral bioavailability  Types of Metabolism o Phase I metabolism  Involves oxidation, reduction, and hydrolysis reactions  Metabolites formed can be more, less, or equally active than parent drug  Occurs in smooth endoplasmic reticulum  Metabolized by CYPs (oxidize drugs)  50% of drugs are metabolized by CYP3A4 o Phase II metabolism  *Some drugs directly enter phase II metabolism  Conjugation reactions  Metabolites are less active than parent drug  Occurs in cytosol  Metabolized by:  UGTs - transfers glucuronic acid; more polar  SULTs - transfers sulfate group; more polar  GSTs - transfers glutathione; less toxic  NATs - transfers acetyl group; more soluble  TPMT - transfers methyl group; subject to genetic polymorphisms  Factors Affecting Metabolism o Age  Newborns have almost no hepatic metabolic activity  Metabolism slowly increases as we age, and begins to decrease when elderly o Drug interactions  Enzyme induction - cell synthesizes an enzyme in response to a drug or other chemical  Results in increased drug metabolism which can decrease plasma drug concentrations, decrease drug activity (if metabolite is inactive), or increase drug activity (if metabolite is active)  Enzyme inhibition - drugs inhibit CYPs  Results in decreased drug metabolism which can increase plasma drug concentrations, increase therapeutic effect of drugs, or increase drug toxicity o Disease state  Diseases that decrease CYP activity include liver disease, kidney disease, inflammatory diseases, infection o Genetic polymorphisms  Genes for some enzymes have genetic polymorphisms, or single nucleotide polymorphisms (SNPs)  SNP is a change in a single nucleotide (A,T,G,C)  Often affects protein that is produced Module 5 - Pharmacokinetics (Excretion)  Removal of parent drug and drug metabolites from body  Sites of drug excretion: o Kidney - urine; most common site  Kidneys limit duration and intensity of drug effects  Nephron is functional unit; regulates water, electrolyte and drug excretion  Controls blood volume, blood pressure blood pH, and solute (drug) excretion o Bile - feces; most common site o Lung o Breast milk Renal Excretion  o ***Review kidney anatomy** o Factors affecting renal excretion 1. Glomerular filtration  Only non-protein bound (free) drugs are filtered here  Ions filtered here; lipid solubility and pH have no effect on glomerular filtration 2. Tubular secretion  Drugs can be secreted from blood into lumen of proximal tubule  Occurs via two transport systems - one for weak acids and one for weak bases 3. Tubular reabsorption  In distal tubule, drug concentrations often exceed blood concentrations  If drug is uncharged or lipid soluble, able to leave tubule and get reabsorbed back into blood o Effect of age  Kidney function is low in newborn infants  Reaches adult levels, and function decreases as we age, thereby decreasing renal drug excretion  Biliary Excretion o Eliminated into bile and excreted in feces o Characteristics of drugs eliminated in bile:  Large molecular weight  Have both polar AND lipophilic groups  Are glucuronidated  P-GP and MRP2 transport metabolites into bile o Enterohepatic Recycling  Drugs excreted in bile enter intestinal lumen  Intestinal bacteria cleave conjugate metabolites, leaving original drug Original drug may be reabsorbed in intestine to re-enter body   Drugs that undergo this process persist in body for much longer  Pulmonary Excretion o Drugs usually gaseous or highly volatile o Not heavily reliant on drug metabolism o Factors affecting pulmonary excretion:  Rate of respiration  Cardiac output  Solubility of drug in blood  High drug solubility = low pulmonary excretion  Excretion in Breast Milk o Drugs excreted in breast milk:  Low protein binding (more free drug)  Low molecular weight  High lipophilicity o Drug transporter BCRP transports drugs into breast milk  Other Routes of Excretion o Hair o Saliva o Sweat Module 6 - Clinical Pharmacokinetics (Time Course of Drug Action)  In clinical pharmacokinetics, try to provide: o Quantitative relationship between dose and effect o Framework to interpret measurements of drug concentrations in fluids to benefit patient  Parameters determining drug disposition: o Clearance - body's efficiency in drug elimination o Volume of distribution - apparent space in body available to contain drug o Elimination half-life (T ) - measure of rate of removal of drug from body 1/2 o Bioavailability - fraction of drug that reaches systemic circulation unchanged  Plasma Drug Concentrations o Drug concentrations usually measured in plasma because: o Only free drugs elicit response but just measuring this is too difficult; measuring total plasma concentration provides enough info to guide drug dosing  Drug Concentration Time Curves o Oral administration - at beginning, absorption rate > elimination rate; plasma concentrations increase  Later, absorption rate = elimination rate; peak of time curve (max  After C , elimination rate > absorption rate; plasma concentrations decrease max o Characteristics of plasma concentration time curves  Minimum effective concentration (MEC) - minimum concentration required to have therapeutic effect  Duration - length of time drug concentration is above MEC  Toxic concentration - if plasma concentrations are too high, toxic side effects will occur  Therapeutic range - drug concentrations above MEC but below toxic concentrations  Width is an index of how safely drug can be used  Drugs with narrow therapeutic range often undergo therapeutic monitoring o Onset of action  Oral drugs are subject to a lag time before reaching MEC  Rate and extent of absorption affects onset of action o Continuous IV infusion  Rate of drug entry into body is constant  NO drug absorption; directly enters systemic circulation After initiation of infusion, plasma concentrations rise until elimination rate = infusion rate   Known as steady state; plasma drug levels don't change over time o IV bolus 
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