Pharmacology 2060A/B Midterm: 2060 Pharmacology Midterm Notes

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Pharmacology 2060A/B
Andrea Di Sebastiano

2060 Pharmacology Midterm Notes Module 1: • What is Pharmacology? o Study of drugs o Includes how drug is delivered, how it works, therapeutic effects, adverse effects • Classification o Drugs: this classification describes traditional drugs including chemical agents o Biologics: this classification includes things that naturally occur in the body such as antibodies or hormones o Natural Health Products: this includes herbal supplements, vitamins, and minerals • Canadian Legislation o Before a drug is released there is a lot of research that goes into it o It must pass the Food and Drugs Act & Regulations o Then it must be approved by Health Canada and their Products and Food Branch o Then it is categorized into each of the classifications and reviewed by that classifications specific board • What is a Drug? o Typically a drug or capsule o Drugs are chemicals and within each pill there are many molecules of a chemical that produces a pharmacological effect • Naming o Chemical Name: describes the chemical structure of the molecule and is used almost exclusively by chemists. Ex. 7-chloro-1,3-dihydro-1-methyl-5-pheyl-1,4-benxodiazepin- 2(2H)-one o Generic Name: Unique name that identifies the drug. The generic name is most often used in pharmacology and with healthcare professionals Ex. Diazepam. o Trade Name: name assigned by the drug company that is easy to remember and marketable. Many companies make the same drug and have many trade names Ex. Valium. • Approval Timeline o Preclinical testing: evaluate biological effects and toxicity in cells or animals o Clinical Trial Application: submitted to health Canada before human trials o Phase I Clinical Trial: 20-100 healthy volunteers to evaluate pharmacokinetics and pharmacodynamics o Phase II Clinical Trial: 300-500 patients with target disorder to test side effects and gather dosing information o Phase III Clinical Trial: 500-5000 patients with target disorder to monitor therapeutic effectiveness over the long term o New Drug Submission: report of therapeutic effectiveness and safety o Phase IV Clinical Trials: Post marketing surveillance of side effects • Pharmacokinetics o What the body does to the drug o Encompasses drug ADME (absorption, distribution, metabolism, and excretion) • Physiological Barriers to Transport o Barriers to protect us from foreign invaders but also drugs o Intestinal villi barrier against ingested drugs, toxins, nutrients o Some cells have tight junctions to prevent molecules passing between o Drug must surpass these barriers to exert its effect • Components of Cell o Nucleus – store of genetic information o Smooth ER – metabolizes drugs, carbohydrates, and steroids o Rough ER – synthesizes proteins o Golgi – Process packaged proteins and lipids o Mitochondria – Is the power house of the cell (produces ATP) • Cell Membrane o Composed of phospholipids creating a lipid bilayer o Fluid and there are embedded proteins o Drugs can cross membrane by: ▪ Direct penetration • If the drug is lipid soluble it can cross the membrane unaided ▪ Through Ion Channels and pores • Pores are very small and only very small compounds can pass through (molecular weight <200) • Ion channels are selective based on charge ▪ Specific transport of proteins • These are carriers of proteins that move drugs from one side to the other • They are important for mediating intestinal absorption, renal excretion, and reaching target effectors inside cells • Uptake take drugs in while efflux move drugs out • Types of Drug Molecules o Ions ▪ Atoms or molecules where the total number of electrons is not equal to protons ▪ Net charge negative or positive ▪ Cannot pass through the membrane without ion channel or being very small in size o Quaternary Ammonium Compounds ▪ Have at least one nitrogen compound and carry a positive charge at all times ▪ Unable to cross the membrane because of charge o Ionizable Molecules ▪ Exist in charged or uncharged form ▪ They are weak acids or weak bases ▪ The pH of the solution changes the charge ▪ Weak acids are ionized in bases and vice versa o Lipophilic Molecules ▪ Lipid Soluble and can pass through the membrane without aid o Polar Molecules ▪ Water soluble and have an uneven distribution of charge • Impact of PH on Drug Movement o Only non-ionized drugs can directly penetrate the cell membrane o Most drugs are weak bases and therefore cross in alkaline solutions • Ion Trapping o This occurs when there is a difference in pH on either side of the cell membrane o Drugs accumulate on the side of the membrane where they are ionized o Occurs clinically occasionally in overdose • Capillaries and Drug Movement o Are the smallest blood vessels in the body o Capillary beds supply tissue with oxygenated blood and allow drugs and other molecules to move from blood to tissue o Many Capillaries have large gaps called Fenestrations that allow hydrophilic drugs to pass through and leave he blood o Lipophilic drugs can either pass between the fenestrations or directly through the plasma membrane of the capillary endothelial cells o Capillaries in the blood brain barrier have tight junctions and do not have fenestrations and therefore for drugs to pass into the brain they would need to be lipophilic or have a specific transport protein Module 2: Pharmacokinetics Absorption • Pharmacokinetics – what the body does to the drug • Absorption is the movement of the drug from the site of administration into the blood • This will effect the onset of the drug effect and how intense the effect will be • Factors affecting absorption: o Rate of Dissolution o Surface Area o Blood Flow o Lipid Solubility o pH Partitioning o Activity of drug transport proteins • Rate of Dissolution o Dissolving in solution is dissolution o Drugs must be dissolved before they can be absorbed o Drugs with a fast rate of dissolution will have a faster onset • Surface Area o Major determinant of absorption o Larger the surface area of the drug is the faster the absorption is • Blood Flow o Absorption is fastest in areas with high blood flow o Areas with high blood flow contain a concentration gradient which drives absorption o Areas with low blood flow do not maintain this gradient and therefore make it difficult to absorb the drug o Blood flow decreases in heart failure, hypotension, hypothermia, and shock • Lipid Solubility o Drugs that are lipid soluble are absorbed more rapidly than water soluble because they are able to cross the membrane • pH Partitioning o Drug absorbed is greater when there is a difference in pH at site of administration and blood so that the blood ionizes the drug o Depends on the pH dependant ionization and ion trapping • Activity of drug transport proteins o Rate and extent of absorption can be significantly impacted by transporters o Uptake transporters increase absorption of the drugs o Efflux drug transporters decrease the absorption of drugs • Routes of Administration o Referred to as enteral or parenteral o Enteral are routes that involve the gastrointestinal tract o Parenteral routes of administration that do not involve the GI tract • 1) Oral (PO = per os which is Latin for by mouth) o Enteral absorption o Despite the concept that weak acids are better absorbed in an acidic environment, all drugs are significantly better absorbed by the small intestine o Pharmaceutical Phase ▪ Occurs after patient swallows the tablet ▪ This involves the disintegration and dissolution of the drug ▪ If the drug does not completely disintegrate absorption is reduced o Gastric Emptying ▪ The movement of the stomach contents ▪ Since the rate of drug absorption is greater in the intestine, things that increase gastric emptying increase rate of absorption ▪ Increases: medications on empty stomach, cold water, lying on the right side, feeding tube with high osmolarity, taking a drug that increase GI movement ▪ Decreases: high fat meal, heavy exercise, lying down on left, taking drugs that inhibit the valgus nerve (anticholinergic drugs) o Bioavailability ▪ Enteric coating is a special coating to prevent the dissolution of drugs in acidic environment and delay until it reaches the small intestine ▪ This is important for drugs that would damage the layer of the stomach or would be inactivated by acid ▪ Bioavailability is the fraction of the dose that reaches systemic circulation unchanged ▪ Can be influenced by drug formulation, rate of administration, and degree of metabolism ▪ With oral from most to least bioavailable is aqueous solution, syrup, suspension, chewable tablet, granules, capsules, compressed capsule, enteric coated tablet, time release tablet • 2) Sublingual o Placing the drug under the tongue and absorbed across the oral mucosa o Venous drainage from oral mucosa to vena cava takes blood directly to heart o Drugs from sublingual avoid first pass metabolism through the liver o In order to be absorbed drugs must be lipophilic o Often used for heart drugs • 3) Transdermal o Absorption through the skin o Must be lipophilic and also hydrophilic enough to dissolve once absorbed in the extracellular fluid o Usually a combination of both and very small <600 Da o Patches, ointment, spray, lotion o Provide a constant plasma level of drugs with minimal peaks and troughs o Tolerance may be developed if left on so patches are removed 6-10 hours daily o Affected by: ▪ Thickness of the skin – inversely proportional ▪ Hydration – increased when well hydrated ▪ Application area – proportional ▪ Hair follicles – proportional ▪ Integrity of barrier - psoriasis, burned, or abraded skin causes increase in absorption • 4) Rectal o Useful when the patient is unconscious or vomiting o 50% of the drug bypasses the liver and isn’t metabolized o Suppository dissolves and crosses rectal mucosa o Can be incomplete absorption or irritate rectal mucosa • 5) Intravenous (IV) o Drug is injected directly into a peripheral vein o Commonly used median cubital or hand o Can be given by bolus or IV drip o There are no barriers of absorption and bioavailability is 100%, allows for administration of poorly soluble drugs and allows for injection of irritants o Expensive and inconvenient, cannot be removed once injection, risk of infection or fluid overload, risk of injecting wrong formulation • 6) Subcutaneous (SubQ or SC) o Just beneath the skin o Only barrier is the capillary wall o Irritants cannot be injected this way o Determinants of rate of absorption are blood flow and water solubility • 7) Intramuscular (IM) o Into muscle tissue o Absorption is determined by ability of drug to pass through fenestrations in the capillary wall o Blood flow and solubility are determinants o Can be used for poorly soluble drugs or administer depot preparations in which drug is slowly absorbed over time o Can be painful or uncomfortable, can cause nerve damage if done improperly o Increased blood flow increases absorption o Increased exercise increases absorption • 8) Pulmonary o Gaseous and volatile drugs can be inhaled and absorbed through pulmonary epithelium o Absorption is very rapid due to large surface area o In case of pulmonary disease, the drug is delivered right to site of action o General anesthetic used in surgery are often administered this way Module 3 – Pharmacokinetics Distribution • Drugs distribute into compartments in the body where they may be stored, metabolized, excreted or exert their pharmacological effects • All drugs consumed or administered end up in the blood plasma, from there only drugs that are free and not bound to plasma proteins may proceed to site of action. • Body compartments include: o Interstitial space – the extracellular fluid that surrounds cells. Drugs that are of low molecular weight and water soluble distribute in the interstitial space o Total body water – includes the fluid in interstitial space, intercellular fluid, and blood plasma o Plasma – the non-cell containing component of the blood. Drugs strongly bound to plasma protein and high molecular weight drugs often distribute in the plasma o Adipose Tissue – the body fat often contains lipid soluble drugs o Muscle – some drugs bind tightly to muscle tissue o Bone – some drugs absorb onto crystal surface of bone with eventual incorporation into the crystal lattice. This causes bone to be a reservoir for the slow release of some drugs o Other tissues • Distribution • The more drug that distributes out of blood, the lower the concentration of the drug in the blood • Distribution is determined by: o Blood flow to tissues ▪ Blood flow to tissues is a key determinant of drug distribution ▪ In well perfused tissues such as the liver, kidney, and brain, the drug distribution while distribution to skin, fat, and bone is much slower ▪ Neonates have limited blood flow therefore may have limited drug distribution ▪ Solid tumours have low regional blood flow therefore it is difficult to attain high drug concentration with solid tumours ▪ Abscesses which are infections filled with puss have no blood supply and therefore are difficult to treat with antibiotics, often must be drained before treatment with antibiotics can occur o Ability of drug to move out of capillaries ▪ With exception of brain, drug movement out of capillaries into the interstitial space occurs rapidly due to the permeable nature of the capillary wall ▪ Drugs move out of capillaries through fenestrations o Ability of drug to move into cells ▪ Once drugs leave the vasculature they must enter their target organ cells to have an effect ▪ The cell membrane is a significant barrier to drugs reaching their targets ▪ In order for drugs to enter cells they must be sufficiently lipophilic to cross membrane ▪ Some drugs are extruded by efflux transporter P-Glycoprotein (P-GP) • P-GP is an efflux transporter • P-GP plays a role in the distribution of drugs, the P stands for permeability but it is important to remember that P-GP is Protective • It facilitates drug efflux from cells, promotes drug excretion, and protects the body from exposure to drugs and other toxins • P-GP is an active transporter (using ATP) • In the liver, it pumps drugs from hepatocytes into the bile for excretion • In the intestine, P-GP is in enterocytes intestinal lumen and pumps drugs into the lumen from cells to avoid absorption into the blood. • In the kidneys, it pumps drugs into the lumen in order to facilitate excretion • In the brain, it pumps the drugs into the blood to limit the brains exposure Plasma Protein Binding • In the plasma, drugs can be bound to plasma proteins or free • Only free drug is available to elicit a pharmacological response • Proteins are large and therefore drugs that are bound to proteins cannot pass through capillary fenestrations • There are two major plasma proteins: o Albumin – has high affinity for lipophilic and anionic (weakly acidic) drugs. Responsible for the majority of protein binding. o Alpha 1 Acid glycoprotein – binds primarily hydrophilic and cationic (weakly basic) drugs • Plasma protein binding is reversible o If some of the free drug in the plasma is removed, some of the plasma bound drug will dissociate and become free • Conditions affecting plasma protein binding o Alpha 1 Acidic Glycoprotein ▪ Aging, trauma, hepatic inflammation, often hepatitis, results in decreased free drug concentration which may lead to ineffective therapy ▪ Less free drug to induce pharmacological effects o Albumin ▪ Malnutrition, aging, trauma, liver, and kidney disease decrease plasma albumin concentration. This results in increased free drug and possible toxicity Volume of Distribution • Volume of distribution (Vd) represents the apparent volume that a drug distributes into • Vd is the ratio of total amount of drug in body (D) to the plasma concentration of the drug (C) (Vd=D/C) • This is not a physical, anatomical space, but rather the calculated volume that helps determine the relative distribution that has occurred • Some drugs have Vs much larger than the volume of the body due to extensive binding to tissue (very small plasma volume) • Plama – non-cell portion blood 4 litres • Interstitial Fluid – fluid that surrounds the cells 10 Litres • Intracellular fluid – fluid inside the cells 28litres • Total body water – 42 litres • Small Vd: o Highly protein bound is retained in plasma o Large molecular weight and is unable to pass through fenestrations o These drugs are unable to pass through vascular space o Therefore these drugs tend to distribute into the plasma volume which is approximately 0.057L/kg • Intermediate Vd: o Low molecular weight and are unable to pass through fenestrations o Very hydrophilic and cant cross the membrane o Intermediate protein binding o These drugs are able to leave the vascular space and enter the interstitial space but cannot enter the cells o Extracellular space is where they distribute o.2L/kg • Large Vd: o Low molecular weight and can pass through capillary fenestrations o Lipophilic and can cross membrane o Minimal protein binding o Distribute into muscle tissues o Greater than 0.2 L/Kg o Distributes into intracellular fluid o NOT ACTUAL MEASUREMENT Drug Displacement from Protein • It is reversible • If two drugs are present in the blood, one may displace the other • The fate of the drug depends on its volume of distribution • Small Vd - displaced drugs to not distribute into tissue and stay in plasma • Large Vd – leaves the plasma and distributed into the tissues and apparent Vd to increase even further Body Composition and Drug Distribution • As we age the body composition changes • Older people have more fat mass and so do obese people • As people age muscle decreases, and infants do too • As people age they have less total body water • Lower muscle, lower muscle there is a lower Vd Module 4: Pharmacokinetics Metabolism • Metabolism is the enzyme mediated alteration of a drugs structure • Metabolism is also referred to as biotransformation • Sites of drug metabolism: o Liver – primary site of metabolism o Intestine – enterocytes that line the gut are able to metabolize drugs o Stomach – Site for metabolism of alcohol o Kidney – underappreciated as a metabolic organ o Intestinal bacteria – normal bacterial flora play an important role in drug metabolism • Importance: o Drug metabolism is important in humans to protect us from a number of environmental toxins well as synthesize essential endogenous molecules o A summary of common exogenous toxins that drug metabolism protects us from are alcohol, cigarettes, caffeine, drugs, green onions, red meat o Engenous molecules synthesized by drug metabolizing enzymes are vitamin D, bile acid, steroid hormones, cholesterol, and bilirubin o Even vegetables would be toxic without enzymes too process them • Therapeutic Consequences of Drug Metabolism o Drug metabolism can have several different consequences o Increase water solubility of drugs to promote their excretion (lipophilic  hydrophilic) o Inactivate drugs o Increase drug effectiveness o Activate Prodrugs o Increase Drug toxicity Kinetics of Drug Metabolism • First Order o In most clinical situations the concentration of drug is much lower than the metabolic st capacity of the body. In these situations drug metabolism displays 1 order kinetics. o Drug metabolism is directly proportional to the concentration of free drug o This means a constant fraction of drug is metabolized per unit time o Concentration decreases faster when there is more drug present • Zero Order o The plasma drug concentration is much higher than the metabolic capacity of the body o Drug metabolism is constant over time o Metabolism is independent of concentration of the drug First Pass Metabolism • PO (oral) drugs may undergo significant metabolism prior to entering systemic circulation st • The result of 1 pass metabolism is a decreased amount of parent drug that enters systemic circulation • First pass metabolism: o Hepatocytes in the liver o Intestinal Enterocytes o Stomach o Intestinal Bacteria Extraction Ratio • The amount of metabolism on the first pass through the liver can greatly determine a drugs bioavailability • Drugs are characterized as having high or low extraction ration depending on how much metabolism occurs on the first pass through the liver • Low ER Drugs o Have high oral bioavailability >80% o PO doses are usually similar to IV doses o Small changes in hepatic enzyme activity have little effect on bioavailability o Not very susceptible to drug-drug interactions o Take many passes through the liver to be completely metabolized • High ER drugs: o Have low bioavailability (1-20%) o Oral doses are usually much higher than IV doses because of first pass metabolism o Small changes in hepatic enzymes activity produce large changes in bioavailability o Very susceptible to drug-drug interactions Types of Drug Metabolism • Phase I Metabolism o Covert lipophilic drugs to more polar molecules by introducing or unmasking more functional groups o Involves oxidation, reduction, and hydrolysis reactions o Mediated by cytochrome p450 enzymes, esterases and dehydrogenases o Metabolites can be more active, less active, or equally active as the parent drug • Phase II Metabolism o Increase the polarity of lipophilic drugs by conjugation reactions (addition of large water soluble molecule to drugs) o Conjugates include glucoronic acid (sugar), sulphate, acetate, or amino acids o Metabolites are less than the parent drug • Intracellular site of drug metabolizing Enzymes o Phase I – drug metabolizing enzymes are localized to the smooth endoplasmic reticulum ER o Phase II – drug metabolizing enzymes are localized in the cytosol with glucuronidation which is localized to the ER Cytochrome P450 • Large family of drug metabolizing enzymes • Performs most of the drug metabolism in the body • Do a lot of Phase I metabolism • CYP oxidize drugs by inserting one atom of oxygen into the drug molecule and producing water as a by product • 12 families CYP with 3 accounting for the majority of drug metabolism • Malnutrition can decrease CYP activity as these enzymes require dietary protein, iron, folic acid, and zinc for full activity. • Nomenclature: family is first number, sub family is second letter, second number is isozyme • CYP3A4 is 50% of the enzymes Phase II Drug Metabolizing Enzymes • UDP-glucuronosyltransferases UGTs o Localized to the SER o Catalyze the transfer of a glucuronic acid to a drug o Glucuronidated drugs are more polar and there more easily extracted o 19 UGT enzymes • Sulfotranferases SULTS o Cystosolic phase II drug metabolizing enzymes o Catalyse the transfer of a sulphate o Sulphated drugs are more polar and therefore more easily extracted o 11 sults • Glutathione S Transferases GSTs o Transfer of a glutathione into a reactive drug renders the metabolite less toxic o There are 20 human GST enzymes • N-acetyltransferases NAT o Transfer an acetyl group from acetyl coA to a drug o Subject to genetic polymorphism which is a major cause in variability to drug response o 2 NAT • Thiopurine Methyltransferase TPMT o Transfer a methyl group from s-adenosylmethionine to a drug o Subject to genetic polymorphisms • Equal Split between the first 4 types Factors effecting drug metabolism • Age o Infants have no CYP activity, it takes 1 year before they get a reasonable amount o Young and adult people have the same amount of enzymes but it is reduced in elderly adults • Drug interactions o Enzyme Induction ▪ Induction Is where a cell synthesizes an enzyme in response to a drug or other chemical ▪ Isozymes are susceptible to induction by drugs ▪ The consequence of the CYP induction is increased drug metabolism ▪ Enzyme induction plays an important rile in drug interaction ▪ Consequences of increased drug metabolism includes decreased plasma concentration, decreased drug activity, increased drug activity if prodrug o Enzyme Inhibition ▪ Some drugs and natural compounds can inhibit CYPs ▪ The consequences of CYP inhibition is decreased drug metabolism ▪ Results in higher plasma concentration, increased therapeutic effect of drugs, increased drug toxicity • Disease State o Disease can play a critical role in determining CYP activity o Diseases that decrease CYP activity include liver, kidney, inflammatory, infection • Genetic Polymorphisms o SNP can change metabolism SNP is single change in DNA o Affect the protein that is produced, this can cause a pronounced difference in response to a drug o Phase I: ▪ CYP2C9 • Metabolizes the anticoagulant drug warfarin • Polymorphism of CYP2C9 results in an enzyme with decreased metabolism • Lower dose of warfarin • If dose is not lowered patients will bleed ▪ CYP2D6 • Metabolizes codeine to morphine, morphine is a more potent analgesic • Results in 4 distinct phenotypes, Ultra Rapid UR, extensive metabolizer EM, Intermediate, and Poor • Extensive metabolizers are considered to have normal enzymatic activity • UR have increased CYP2D6 o Phase II: ▪ UGT1A1 • UGT family • It gluguronidates the anti cancer compound SN 38 • Polymorphism decreases its activity With polymorphism increased risk of diarrhea and hose limiting bone marrow suppression ▪ NAT2 • Acetylates the drug isoniazid for turboculosis, caffeine, and cancer causing chemicals • There are over 23 different SNPs in the NAT2 gene • Rapid or slow acetylators • Slows are more susceptible to toxicity • Slows are at risk of cancer Module 5: Pharmacokinetics Excretion • Drug Excretion: the removal of the parent drug and drug metabolites from the body • Renal Drug Excretion: o The kidneys account for the majority of drug excretion o Healthy kidneys serve to limit the duration and intensity of drug effects o Decreased kidney function prolongs the duration of action and intensity of drug effects • The Nephron o The basic structural and functional unit of the kidney o Regulates water, electrolyte, and drug excretion o Controls blood volume, blood pressure, blood pH and solute (including drug) excretion o Afferent – to glomerulus, glomerulus – filter, efferent – away from • Factors Affecting Renal Drug Excretion o Glomerulus o Tubular secretion o Tubular reabsorption • Glomerular Filtration o Drug enter the kidney from the renal artery o Hydrostatic pressure within glomerular capillaries forces low molecular weight drug into the renal tubules o Glomerular filtration rate is ~120 ml/min/1.73m^2 or about 20% of total renal plasma flow o Lipid solubility and pH do not affect glomerular filtration of drugs o Only non-protein bound free drugs are filtered at the glomerulus • Tubular Secretion o Drugs not filtered by the glomerulus leave the glomerulus by the efferent arteriole o The efferent arterioles divide to form capillaries that surround the proximal tubule o Drugs can be secreted from the blood surrounding the tubules into the lumen of the proximal tubule o Drug secretion in the kidney primarily occurs by two transport systems, one for weak acids and one for weak bases • Tubular Reabsorption o As drugs move towards the distal tubule their concentration increases o This is primarily due to the actions of the loop of henle which functions to concentrate tubular solutes o Once in the distal tubule the drug concentration often exceeds the concentration in the blood that immediately surrounds the distal tubule o If the drug is uncharged or lipid soluble, it is able to leave the tubule and be reabsorbed back into the blood • Effect of Age o Kidney function is low in newborns o It increases to be high in adults o Decreases slowly decreases as you age Biliary Drug Excretion • Some frugs are eliminated into the bile and ultimately excreted in the feces • Characteristics of drugs eliminated in the bile: o Molecular weight >300Da (large) o Have both polar and lipophilic groups (amphipathic molecule) o Are glucuronidated (phase II) • Transporters on the canalicular membrane of hepatocytes transport drugs and metabolites from liver into the bile • P-glycoprotein transports a variety of amphipathic drugs into bile and MRP2 transports glucuronidated metabolites into bile • Drugs released into the bile are ultimately released into the intestine during digestive processes • Drugs released into the intestine may be excreted into the feces or undergo enterohepatic recycling Enterohepatic Recycling • Drugs and drug conjugates excreted in the bile enter the intestinal lumen • Intestinal bacteria can cleave conjugate metabolites leaving the original drug • The original drug may be reabsorbed in the intestine to re-enter the body • This process is known as enterohepatic recycling • Drugs that undergo enterohepatic recycling persist in the body for substantially longer • Bile canaliculus small tube collecting drugs and bile Pulmonary Drug Excretion • Drugs eliminated by pulmonary excretion are usually gaseous and highly volatile • The best examples are general anesthetics • Pulmonary drug excretion is not heavily reliant on drug metabolism • Factors affecting pulmonary drug excretion include: o Rate of respiration o Cardiac output o Solubility of Drug in blood o High drug blood solubility  low pulmonary excretion o Low blood drug solubility  high pulmonary excretion Drug Excretion in Breast Milk • >90% of women take at least one drug in the first week post-partum • Drug excretion in breast milk is important because breast-fed infant may be inadvertently exposed to drugs • Drug excreted in breast milk usually have o Low protein binding o Low molecular weight o High lipophilicity • The drug transporter breast cancer resistance protein (BCRP) transports drugs into breast milk • Breast milk has a lower pH and higher lipid content than plasma • It is important to note that while drug exposure via breast milk is an important concern, only relatively few drugs pose a clinically relevant risk to infants. Consultation is important for dosing. Other Routes of Drug Excretion • Hair – drugs may be excreted into hair follicles. Drugs can be measured in hair to determine how long a person has been exposed. This is especially useful in forensics. Hair grows ~1cm/month • Saliva – drug excreted in saliva is usually swallowed and then subject to either intestinal absorption or fecal excretion • Sweat – Drugs excreted in sweat are mostly washed away although a minor amount of dermal reabsorption may occur. • These are minor Module 6: Clinical Pharmacokinetics • Relationship between the effects of drug and concentration of the drug in the body • Clinical Pharmacokinetics provides: o Quantitative relationship between drug dose and effect o A framework to interpret measurements of drug concentration in biological fluids to benefit of patient drug therapy • Most Important parameters determining drug disposition: o Clearance - body’s efficiency at elimination o Volume of distribution – apparent space in the body available o Elimination half life – rate of removal o Bioavailability – fraction of drug that even reaches systemic circulation Plasma Concentration: o Ideally all drugs would be measured from site of action but this isn’t feasible because of barriers and importance of sites of action o Instead they are measured in the plasma which is good because it is non-invasive and there is a good correlation between plasma concentration and therapeutic/toxic effects of the drug o Only the free drug is able to elicit pharmacological effects but since separating protein bound and free protein is difficult, total plasma concentration is used Drug Concentration Time Curve: o Oral Administration o Oral Administration must be absorbed into the blood o At the beginning, rate of absorption is greater than rate of elimination so plasma drug concentrations are high o Rate of absorption equals elimination and therefore it is the peak o Rate of absorption is less than elimination and over time declines from the peak o Characteristics of Plasma Concentration Time Curves ▪ Plasma drug concentrations must be high enough to have therapeutic effect but not in the toxic level ▪ Minimum Effective Concentration (MEC) - The minimum concentration to show therapeutic effects ▪ Duration – length of time that the drug is over MEC ▪ Toxic concentration – plasma concentration too high and causes toxic effects ▪ Therapeutic range - drug concentrations below toxic but above MEC (AKA therapeutic window) o If narrow the drug must undergo more therapeutic monitoring in order to stay within target range o The larger the therapeutic range, the safer the drug is Onset of Action o Drug given orally often have a lag time before they reach MEC o Lag time varies between drug dependant on rate and extent of absorption o The onset of action determines how soon the drugs effec
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