Study Guides (238,612)
Canada (115,252)

Pharm 2060 Midterm Notes

58 Pages
Unlock Document

Western University
Pharmacology 2060A/B
Angela Nissen

PHARMACOLOGY 2060B 1 Module 1 1.1 Introduction  What is Pharmacology? o Study of the drugs o Derived from greek word pharmakon meaning remedy and logos meaning study  Classification of therapeutics o Drugs – Traditional drugs (ie. Chemical agents) o Biologics – antibodies, hormones o Natural health products – herbals, vitamins, minerals  Canadian drug legislation o Food and Drugs Act and Regulations  Health Canada  Health Canada products and food branch  1. Therapeutic products directorate 2. Biologics and Genetic therapies directorate 3. Natural health products directorate o Important to note that we know have three directorates  Therapeutic = pills were used too  Biologics and genetic therapies – evaluate and approve hormone and antibody type therapies  Natural health products – approves and evaluates natural health products  What is a drug? o When we think of drugs we have to think of them as chemicals that produce a pharmacological effect  Naming drugs o Three different ways to name: 1. Chemical name – describes the chemical structure of the molecule; used by chemists 2. Generic name – unique name that identifies the drug, most often used in pharmacology, easier to say; the name that should be used by health care professionals 3. Trade names – names assigned by companies that make them (eg. Valium)  Usually easy to remember and marketable  The problem is that when more than one company makes the drug we get extra names  Valium has more than 20 trade names, therefore pharmacologists usually use the generic name Approval of Marketed Drugs in Canada o Approval in Canada takes approximately 15 years o Drug development has several different levels o Total cost of a new drug can be as high as $800,000,000 2 o 1. Preclinical Testing - Drug Discovery  Can take up to 6.5 years  In cultured cells, living tissue or experimental animals  Evaluate biological effects, pharmacokinetics and toxicity o 2. Clinical trial Application  A lot of paperwork  Submitted to health Canada, responds within 30 days  Must be submitted to Health Canada prior to any human studies o 3. Phase I  20-100 Healthy volunteers  Pharmacokinetics and dynamics investigated  Phase takes approx. 1 year to complete o 4. Phase II  300-500 patients with target disorder  Effectiveness, side effects and dosing info is gathered  Takes about 2 years o 5. Phase III  500-5000 patients with target disorder  Effectiveness verified, long term side effects assessed  Takes about 4 years o 6. NDS (New Drug Submission) to Health Canada  Report that details how well the drug works and the safety profile of the drug  Results of all preclinical studies  If approved, Health Canada issues a Notice of Compliance (NOC) and a Drug Information Number (DIN) issued – both required for marketing the drug in Canada  Takes about 1.5 years o 7. Phase IV  Post marketing surveillance  Efficacy and safety of the drug  Continues after drug has been marketed  Drugs can be pulled from the market  What the body does to the drug encompasses drug Absorption, Distribution, Metabolism and Excretion (ADME) 1.3 Basic Physiology and the Cell Membrane  Administration o Enteral – Gastrointestinal tract  Oral  Rectal o Parenteral  Intraveneous 3  Intramuscular  Subcutaneous o Topical  Creams  Patches  Pharmacokinetics o When given orally, patient swallows and it enters small intestine and is carried by portal blood supply to liver (primary site of drug metabolism in the body), then can enter systemic circulation (for heart, brain, muscle or kidney) or can enter the bile ducts  Kidney is the primary excretion organ in the body  Bile is another route of excretion of drugs that go back into the intestine and leave the body in the feces o Other routes:  Following parenteral it is absorbed directly into systemic  Therefore they don’t go to the liver before it goes to systemic  Distributed to heart, brain, muscle or excretion in the kidneys  Also goes to the liver  Barriers to drug transport o Our body has developed barriers to help protect us o When we ingest something orally  intestinal villi o Tight junctions  prevent molecules from passing between cells o Drug needs right chemical and physical properties to pass through barriers  Components of the cell o Nucleus – contains genetic material o Smooth ER - metabolizes drugs, carbs and steroids o Rough ER – synthesizes proteins o Golgi apparatus – processes and packages proteins and lipids o Mitochondria – produces ATP (cell’s source of energy) o Cell membrane – separates the intracellular and extracellular environments  The Cell Membrane o Important barrier o Phospholipids with a polar hear and two fatty acids o Fluid because phospholipids are flexible o Has embedded proteins – can be receptors or channels 1.4 How Drugs Cross the Cell Membrane  1. Direct penetration of membrane o Drug must be lipid soluble (lipophilic) o Hydrophilic drugs don’t cross the cell membrane  2. Through ion channels and pores o Only small drugs can pass through, typically only ions 4 o Channels are selective o Eg. Sodium, potassium and lithium  3. Specific transport proteins o Carrier proteins that move drugs from one side to another o Uptake transporters move drugs from outside the cell to the inside  Allow drug absorption into the body across the intestines and important in renal excretion o Efflux move drugs from outside to inside  Important for protecting cells  Present in intestine, placenta, kidney and blood brain barrier 1.5 The Chemistry of Pharmacology  Types of Drug Molecules o Polar molecules  Water soluble  Uneven distribution of electrical charge and have no net charge  Ex. Water, glucose and kanamycin o Ions  Total number of electrons is not equal to the total number of protons  Ions have a net charge  Because of their charge they cannot directly pass through the cell membrane  Usually pass through ion channels or pores o Quaternary ammonium compounds  Have at least one nitrogen atom that has a positive charge at all times  Due to the positive these molecules are unable to cross cell membranes o Ionizable molecules  Charged or uncharged  Weak acids or weak bases  Charge is determined by the pH of surrounding medium  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 the membrane most easily in alkaline medium (eg. Stomach medium)  Ion Trapping 5 o When there is a difference in pH on different sides of a membrane o Drugs accumulate on the side of the membrane where they are ionized – because they cannot cross back over to other side of the membrane o Can be put into use clinically in some cases of drug overdose 1.6 Drug Movement out of Capillaries  Capillaries o Smallest blood vessels in the body o Blood supply from heart comes from arteries and narrows to arterioles then to capillaries o Supply tissue with oxygenated blood and allow the drugs and other molecules to move from the blood to the tissue o Capillaries have large gaps between them, fenestrations o Add hydrophilic Drug  Unable to directly pass across capillary cell but can pass through fenestrations and be exposed to tissue to act o Lipophilic drug  Move through capillaries directly and through fenestrations  Drug movement out of capillaries – Blood Brain Barrier o Capillaries at blood brain barrier have tight junctions, not fenestrations o To penetrate the brain, drugs must either be lipophilic or have a specific transport protein 6 Module 2: Pharmacokinetics – Absorption 2.1 Introduction  Study of drug movement in the body  Is what the body does to the drug  Composed of 4 basic processes 1. Absorption 2. Distribution 3. Metabolism 4. Excretion  Absorption o Movement of the drug from the site of administration into the blood o The rate of absorption determines how quickly the drug effect will occur o Amount determines how intense the effect of the drug will be 2.2 Factors affecting absorption  1. Rate of dissolution o Dissolving in solution o Drugs must dissolve before they can be absorbed o Drugs with a fast rate of dissolution will have a faster onset of action 7  2. Surface Area o Major determinant of drug absorption, larger = faster absorption o Intestines have thousands of folds, villi, that increase the surface area, the stomach just has folds (rugae)  3. Blood flow o Fastest in areas with high blood flow o High blood flow areas maintain a concentration gradient which drives absorption o Exercise increases blood flow and can increase absorption o Blood flow is decreased in heart failure, severe hypotension, hypothermia and circulatory shock  4. Lipid Solubility o Drugs with high lipid solubility (lipophilic) are absorbed faster than hydrophilic drugs  Because it can cross the membrane  5. pH Partitioning o Faster when there’s a difference between the pH at the site of administration and the blood so the drug is ionized in the blood o A Weak acid, non-ionized drug in the stomach (acidic environment) isn’t ionized and easily crosses the membrane, once it crosses into the blood it becomes charged is unable to cross the membrane, increased absorption because it can’t go back into the stomach  6. Activity of Drug Transport Proteins o The rate and extent of drug absorption can be significantly impacted by drug transporters o Uptake drug transporters increase absorption o Efflux drug transporters decrease absorption of drugs by pumping drugs out of the cell 2.3 Routes of Administration  8 major routes of drug administration o Oral (PO = per os; latin for mouth) o Sublingual o Transdermal o Rectal o Intravenous (IV) o Subcutaneous (SubQ or SC) o Intramuscular (IM) o Pulmonary  Enteral – routes involving the GI tract o Oral and Rectal  Parenteral – routes that do not involve the GI tract o Intravenous, Intramuscular or Subcutaneous  Other – sublingual, transdermal, pulmonary 8 o Would be classified as parenteral due to the definition but in the clinic they are not  Oral Absorption o Most common due to a number of advantages like safety, convenience and economical o Disadvantages: incomplete and variable absorption o Intestine vs stomach  The drug enters the stomach first  The intestine has a larger surface area than the stomach, so drug absorption is greater in the intestine  Weakly acidic drugs should be better absorbed in acidic environments like the stomach because they would be unionized and more likely to cross the cell membrane  But, the surface area of the stomach is small and is covered with a thick layer of mucous, so the rate is greater in the intestine even if it’s ionized  Generally, for most drugs oral absorption is greatest in the intestine o Pharmaceutical Phase  After the tablet is swallowed  2 Phases: disintegration of the tablet and dissolution of the drug  If the drug isn’t completely disintegrated or doesn’t go into solution, absorption is reduced o Gastric Emptying  The movement of the stomach contents into the intestines  Since rate of absorption is greatest in the intestines, Things that increase gastric emptying also increase the rate of drug absorption  Factors affecting: Increase Emptying Decrease Emptying Taking medication on an empty High fat meal stomach Taking medication with cold water Heavy exercise Laying down on the right side Laying down on the left side High osmolality feeding (tube Taking a drug that inhibits the vagus feeding) nerve (ie. Anticholinergic drugs) Taking a prokinetic drug (drug that increases GI motility) 9 o Enteric Coating  Special coating that prevents their dissolution in the acidic environment of the stomach  Once the drug passes into the more alkaline duodenum, enteric coating dissolves  Allows drug to pass through stomach without undergoing pharmaceutical phase o Bioavailability  Fraction of a dose of drug that reaches the systemic circulation unchanged  Especially important for orally administered drugs because some have a low bioavailability  Influenced by: 1. Drug formulation 2. Route of administration 3. Degree of Metabolism  Drug formulation o Compressed tablets, enteric coated tables and time release capsules have low bioavailability because formulation involves significant differences in drug disintegration and dissolution o Capsules, granules and chewable tablets have medium bioavailability o Suspension, syrup and aqueous solution have higher  Suspensions – drug doesn’t have disintegrate at all  Syrups and aqueous are already in solution so absorption is enhanced  Sublingual o Placing a drug under the tongue o Drug dissolves and is absorbed across oral mucosa o Venous drainage from the oral mucosa is to the superior vena cava. Superior vena cava takes blood to the heart o Avoid first pass metabolism through the liver, unlike orally administered o In order to be absorbed, must be lipophilic and uncharged  Transdermal o Not all drugs are able to penetrate the skin o Epidermis is a lipid barrier, so drugs must be lipophilic o Must also be relatively hydrophilic in order to dissolve in the extracellular fluid o Ideally have some degree of lipophilicity and hydrophilicity o Large molecules do not typically penetrate the skin 10 o Preparations  Typically administered as patches, ointments sprays or lotions  Administration provides constant plasma drug levels with minimal peaks and troughs  Tolerance may develop unless drug-free period’s enforced  Patches are typically removed for 6-10 hours per day o Factors affecting absorption 1. Thickness of the skin – absorption is inversely proportional to skin thickness 2. Hydration – absorption is increased when the skin is hydrated 3. Hair follicles – routes for drugs to bypass the barrier function of the epidermis, greater number of follicles = greater absorption 4. Application area – greater the area, greater absorption 5. Integrity of the barrier – in conditions such as psoriasis, burned or abraded skin, transdermal absorption is increased  Rectal o Useful when the patient is unconscious or vomiting o Approx. 50% bypass the liver o Drug is inserted into rectum as a suppository which dissolves and the drug crosses the rectal mucosa into the blood o Disadvantages: incomplete absorption and some drugs may irritate the rectal mucosa  Intravenous o Injected into peripheral vein o Most commonly used veins are those on the back of the hand or the median cubital vein at the elbow, but any visible vein could be used o Can be given as a bolus or by an IV drip o IV bolus: single dose is administered over a short time period o IV drip: drug is administered under continuous infusion over a prolonged period  Drugs are typically diluted in a vehicle, eg. Saline Advantages Disadvantages No barriers to absorption, bioavailability is 100% Expensive, invasive and inconvenient Allows precise control of the drug dosage and Drug cannot be removed once duration of action injected Allows Administration of poorly soluble drug that Risk of infection and fluid overload must be diluted in a large medium Allows the injection of drugs that are irritants (ieRisk of injecting wrong formulation Many chemotherapeutic drugs) as they can be (IM instead of IV) injected slowly so they are diluted in the blood 11  Subcutaneous o Drug is injected beneath the skin into the subcutaneous tissue o Only barrier is capillary wall o Irritant drugs can’t be injected this way because it’ll cause local tissue damage causing pain and/or tissue sloughing o Primary determinants of absorption are blood flow and water solubility  Intramuscular (IM) o Injected directly into muscle tissue o Absorption determined by ability of the drug to pass through fenestrations in capillary wall o Primary determinants of rate are blood flow and water solubility o Advantages:  Can be used for poorly soluble drugs  Can use it to administer depot preparations (preparations in which the drug is absorbed slowly over time) o Disadvantages:  Pain/discomfort  May cause local tissue and/or nerve damage if injection is done improperly o Factors affecting absorption  Blood flow is different depending on which muscle is used for injection  In general: deltoid > vastus lateralis > gluteal  Exercise increases blood flow and may increase absorption for IM drugs  Blood flow may be decreased in heart failure, severe hypotension and hypothermia  Pulmonary o Gaseous and volatile drugs can be inhaled and absorbed into the blood through pulmonary epithelium o Rapid absorption due to large surface area in the lungs o In the case of pulmonary disease (ie. Asthma), the drug is delivered directly to its site of action which is a major advantage o Drugs such as general anesthetics used in surgery are also often administered by the pulmonary route of administration Module 3: Pharmacokinetics – Distribution 3.1 Body compartments  Drugs distribute into compartments in the body where they may be stored, metabolized, excreted and exert their pharmacological effect  The bodies compartments include: 1. Interstitial Space - extracellular fluid that surrounds cells. Low molecular weight, water soluble drugs distribute in the interstitial space 2. Total body water – includes the interstitial space, intracellular fluid and the plasma 12 3. Plasma – non-cell containing compartment of blood. Drugs strongly bound to plasma protein and high molecular weight drugs typically distribute in plasma 4. Adipose Tissue – the bodies fat. Lipid soluble (lipophilic) drugs distribute into adipose tissue 5. Muscle – some drugs bind tightly to muscle tissue 6. Bone – some drugs absorb onto the crystal surface of bone with eventual incorporation into the crystal lattice. Bone can be a reservoir for the slow release of some drugs 7. Other tissues  Drug is inserted parentally o Following absorption the drug enters the plasma as the free form o Once in the plasma as the free form a lot of drugs become highly protein bound  Typically not able to leave the plasma, because proteins can’t fit through fenestrations in capillary wall o The free drug is able to leave the plasma, the protein bound drug is held in the plasma  Orally administered drug o Similar to parental o Except following absorption the drug goes to the liver before the plasma o From the liver, the drug or the metabolite may enter the plasma as the free drug and can then become protein bound 13 3.2 Drug Distribution  Determined by: o Blood flow to tissues o Ability of drug to move out of capillaries o Ability of drug to move into cells  The more drug that distributed out of the blood, the lower the concentration of drug in the blood  Blood flow to tissues o Key determinant of distribution o In well perfused tissues such as the liver, kidney and brain, drug distribution is rapid o Distribution in tissues with lower blood flow, skin, fat and bone and some degree muscle, is much slower o Implications of altered blood flow  Neonates (newborns) have limited blood flow and therefore may have limited or unpredictable drug distribution  Poor blood flow rarely limits drug distribution in adult patients however some exceptions do exist  Patients with heart failure or shock may have reduced blood flow and therefore have slow and altered drug distribution  Solid tumours have low regional blood flow. The outer portion of tumours has a high blood flow but the blood flow progressively decreased towards the middle. Therefore it is difficult to attain high drug concentrations within solid tumours  Abscesses (infection filled with pus) have no blood supply and are therefore difficult to treat with antibiotics. They are often drained prior to drug therapy  Ability of drug to move out of capillaries o With the exception of the brain, drug movement out of capillaries into the interstitial space occurs rapidly due to the permeable nature of the capillary wall o Drugs move out of the capillary through fenestrations  Ability of drug to move into cells o Once drugs leave the vasculature they must enter their target organ to have an effect o The cell membrane is a significant barrier to drugs reaching their targets o In order for drugs to enter cells they must be sufficiently lipophilic to cross the cell membrane or be carried by an uptake transporter into the cell o Some drugs are extruded (removed) from cells by efflux transporters 3.2 Glycoprotein (P-GP)  P-glycoprotein is the most widely studied efflux transporter  P-gp plays an important role in the distribution of drugs 14  Although the P in P-gp stands for permeability, it’s helpful to remember the word Protective when you think of P-gp  P-gp is protective because it facilitates drug efflux from cells, promotes drug excretion and protects the body from exposure to drugs and other toxins  P-glycoprotein is an active transporter which means that it requires energy (ATP) to transport drugs against a concentration gradient  In order for a drug to get into the cell it has to overcome P-gp  P-gp in the liver pumps drugs into the bile from the hepatocyte to facilitate excretion  In the intestine, it pumps drug from enterocyte back into the lumen preventing absorption into the blood  In the kidney it pumps drugs from proximal tubule cells into the lumen of the nephron to facilitating excretion  In the brain it pumps drugs into the blood limiting exposure to the brain 3.4 Plasma Protein Binding  In the plasma, drugs can be bound to plasma proteins or free (unbound)  Only free drug is available to elicit a pharmacological response  Proteins are large and therefore drugs bound to plasma proteins are unable to pass through capillary fenestrations and keep drugs in the blood  There are two major plasma proteins that bind drugs in plasma: 1. Albumin: has a high affinity for lipophilic and anionic (ie. Weakly acidic) drugs. Responsible for the majority of protein binding 2. Alpha 1 acid glycoprotein: binds primarily cationic (ie. Weakly basic) and very hydrophilic drugs 15  Plasma protein binding is reversible o The free drug (yellow dots) is in equilibrium with plasma protein o If some of the free drug is removed, some of the protein bound to the drug will dissociate from the protein and become free  Conditions affecting plasma protein binding o Albumin  Malnutrition, trauma, aging, liver and kidney disease decrease plasma albumin concentration  Results in an increase in free drug concentration which may result in toxicity  In the example, the malnourished patient has less albumin in their blood and therefore a higher free concentration of the drug o Alpha 1 Acidic Glycoprotein  Aging, trauma and hepatic inflammation cause increased alpha-1- acidic glycoprotein concentration  This results in decreased free drug concentration which may lead to ineffective therapy  In the example, the trauma patient has more alpha 1 acidic glycoprotein in their blood and therefore a lower free drug concentration 3.5 Volume of Distribution (Vd)  Represents the apparent volume that a drug distributes into  Vd is the ratio of the total amount of drug in the body (D) to the plasma concentration of the drug (C), therefore: Vd = D/C  Vd is not a physical, anatomical space, but rather a calculated volume that helps determine the relative distribution of a drug within the body  Some drugs have a Vd much larger than the volume of the body due to extensive binding to tissue  Water compartments in the body o Plasma – the liquid portion of blood o Interstitial Fluid – the fluid that surrounds the cells of the body o Intracellular fluid – the fluid inside cells 16 o Total body water = Plasma + Interstitial Fluid + Intracellular Fluid o For the average person (70Kg) their total body water is typically 42 liters.  Drugs with a small Vd o Have the following characteristics:  Highly protein bound (retained in plasma)  Large molecular weight (unable to pass through capillary fenestration) o Unable to leave the vascular space (plasma). Therefore these drugs tend to distribute into the plasma volume, which is approximately 0.057L/Kg  Drugs with an intermediate Vd o Have the following characteristics:  Low molecular weight (able to pass through capillary fenestrations  Very hydrophilic (can’t cross the cell membrane)  Intermediate protein binding o These drugs are able to leave the vascular space and enter the interstitial space, however are unable to enter cells o Tend to distribute into the extracellular (plasma + interstitial space) o The extracellular space is ~0.2 L/Kg  Drugs with a large Vd o Have the following characteristics:  Low molecular weight (able to pass through capillary fenestrations)  Lipophilic (able to cross cell membrane)  Minimal protein binding o These drugs are able to leave the vascular space and the interstitial space, so they can distribute into body compartment such as fat, bone, muscle and other tissues o Typically distribute into greater than 0.2 L/Kg o Vd Can be larger than total body water because it is NOT an actual physical volume  Drug Displacement from Protein o Drug binding to protein is reversible o If two drugs are present in the blood, one drug may displace the other drug from plasma protein o In the example, the purple drug displaces the yellow drug from protein o The fate of the displaced drug depends on its volume of distribution o Small Vd  When the Vd of the displaced drug is small, displaced drug does NOT distribute into tissues, it stays in the plasma 17  The free drug concentration increases o Large Vd  Displaced drug leaves the plasma and distributes into the tissues  Causes the total drug concentration to decrease and the Vd to increase 3.6 Body composition and Drug distribution  As we age our body composition changes  Elderly have an increased proportion of body mass as fat  Obese people have a larger proportion of body mass as fat  Drugs that distribute in fat will have a larger Vd in obese or eldery people than young healthy adults  As people age, they have a decreased % of muscle per total body mass, therefore drugs that distribute into muscle will have a lower Vd  As we age total body water decreases  Yellow summarizes fraction of lipophilic drugs in tissue Module 4: Pharmacokinetics – Metabolism 4.1 Drug Metabolism  Metabolism is the enzyme mediated alteration of a drugs structure  Metabolism is also referred to as biotransformation  Sites of drug metabolism include:  Why do we need drug metabolism: o Drug metabolism evolved in humans to protect us from a environmental toxins and synthesize essential endogenous molecules o The same family of enzymes responsible for metabolizing drugs is also important for endogenously regulated processes o Even things like vegetables could be toxic if we didn’t have enzymes to process them 18  Therapeutic consequences of Drug metabolism o Increase water solubility of drugs to promote their excretion (lipophilic  hydrophilic) o Inactive drugs (active  inactive) o Increase drug effectiveness (active  more active) o Activate prodrugs (prodrugs are inactive until metabolized) (inactive  active) o Increase drug toxicity (non toxic  toxic) 4.2 Kinetics of Drug Metabolism  First order o What most drugs exhibit o In most clinical situations the concentration of drug is much lower than the metabolic capacity of the body o More drug metabolizing enzymes then drugs o In 1 order kinetics 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 Top image shows how the plasma concentration changes over time  Concentration decreases faster when there are higher drug concentrations than at the end when [] is low o Bottom image shows the amount of drug and the amount of enzyme  There is much more enzyme than there is drug  Zero order o Plasma drug concentration is much higher than the metabolic capacity of the body o Drug metabolism is constant over time o Constant amount of drug is metabolized per unit time o Eg. Ethanol o Top figure shows how plasma concentration changes over time  Metabolism is independent of drug concentration o Bottom figure shows the amount of drug and amount of enzyme  More drug than there is enzyme 4.3 First Pass Metabolism  PO drugs may undergo significant metabolism prior to entering systemic circulation 19  Can occur via 1. Hepatocytes in the liver 2. Intestinal enterocytes 3. Stomach 4. Intestinal bacteria  The net result of first pass metabolism is a decrease amount of parent drug that enters systemic circulation  Extraction Ratio o The amount of metabolism on the first pass through the liver can greatly determine a drugs bioavailability o Drugs are characterized as having high or low extraction ratio (ER) depending on how much metabolism occurs on the first pass through the liver o Higher ER  Significantly metabolized when they pass through the liver  Low oral bioavailability (1-20%)  PO doses are usually much higher than IV doses (to compensate for high first pass metabolism)  Small changes in hepatic enzyme activity to produce large changes in bioavailability  Very susceptible to drug-drug interactions o Low ER  High oral bioavailability (>80%), PO doses are usually similar to IV  Small changes in hepatic enzyme activity have little effect on bioavailability  Not very susceptible to drug-drug interactions  Take many passes through the liver via the systemic circulation before they are completely metabolized 20 4.4 Types of Drug Metabolism  Phase I metabolism o Convert lipophilic drugs to more polar molecules to facilitate excretion by introducing or unmasking polar functional groups such as hydroxyl (OH) or amine (NH2) o Involves oxidation, reduction and hydrolysis reactions o Mediated by cytochrome P450 enzymes (dominant), esterases and dehydrogenases o Metabolites formed can be more active, less active or equally active as parent drug  Phase II metabolism o Increases the polarity of lipophilic dugs by conjugation reactions (addiction of large water soluble molecules to drug) o Conjugates include glucuronic acid (a sugar), sulfate (SO4), acetate or amino acids o Metabolites are less active than the parent drug  EXCEPT: morphine-6-glucuronide is a more potent analgesic than morphine  Some drugs can bypass phase I  Intracellular Site of Drug Metabolizing Enzymes o Phase I: localized to the smooth ER o Phase II: localized predominantly in the cytosol of the cell  With the exception of glucuronidation which is localized to the smooth ER 4.5 Cytochrome P-450 Drug Metabolizing Enzymes  CYPs are a large family of drug metabolizing enzymes  Predominant phase I drug metabolizing enzyme system  Majority of drug metabolism in the body is performed by hepatic CYP enzymes  CYPs oxidize drugs by inserting one atom of oxygen into the drug molecule producing water as a by product  There are 12 million families of CYPs with 3 accounting for the majority of drug metabolism 21  Malnutrition can decrease CYP activity as these enzymes require dietary protein, iron, folic acid and zinc for full activity  Nomenclature: o  CYP3A4 metabolizes the largest fraction of currently marketed drugs 4.6 Phase II Drug Metabolizing Enzymes  Phase II drug metabolizing enzymes include: 1. UDP –glucoronosyltransferase (UGTs)  Localized in the SER  Catalyze the transfer of a glucuronic acid (Sugar) to the drug  Glucuronidated drugs are more polar, so they are more easily excreted  There are 19 human UGT enzymes 2. Sulfotransferases (SULTs)  Cytosolic metabolizing enzymes  Catalyze the transfer of a sulfate group to a hydroxyl group of drugs  Sulfated drugs are more polar = more easily excreted  There are 11 human SULT enzymes 3. Glutathione S transferases (GSTs)  Cytosolic or microsomal drug metabolizing enzymes  Catalyze the transfer of a glutathione molecule to a drug  Glutathione is an intracellular anti-oxidant  Transfer of a glutathione molecule onto a reactive (ie. Toxic) drug renders the metabolite less toxic  There are over 20 human GST enzymes 4. N-acteyltransferases (NATs)  Cytosolic drug metabolizing enzymes  Catalyze the transfer of an acetyl group from acetyl CoA to a drug = more water soluble  Subject to genetic polymorphisms which is a major cause of variability to drug response  There are 2 human NAT enzymes, NAT1 and NAT2 5. Thiopurine Methyltransferase (TPMT)  Cytosolic metabolizing enzymes  Catalyze the transfer of a methyl group from S-adenosylmethionine to a drug 22  Subject to genetic polymorphisms – although rare, these can have a dramatic effect on drug safety  Unlike CYPs, the fraction of drugs metabolized by phase II enzymes is relatively equally split between UGTs, SULTs, GSTs and NATs 4.7 Factors Affecting Drug Metabolism  There are many factors that affect drug metabolism: a. Age  Infants have almost no CYP activity – crucial in determining the right amount of drug to give an infant  Takes babies about a year to have a reasonable level  By age 2, babies have the same amount as adults do b. Drug interactions (enzyme inducers and enzyme inhibitors)  Enzyme Induction  Induction is a process here a cell synthesizes an enzyme in response to a drug or other chemical  Certain CYP isozymes are susceptible to induction by drugs  Consequence of induction is increased drug metabolism  Enzyme induction plays an important role in drug interactions  Consequences of increased drug metabolism: o Decrease in plasma concentration o Decreased drug activity (if metabolite inactive) o Increased drug activity (if metabolite is active)  Enzyme inhibition:  Some drugs and natural compounds can inhibit CYPs  The consequence of inhibition is decreased drug metabolism  Decreased drug metabolism may result in 1. Higher plasma drug concentration 2. Increased therapeutic effect of drugs 3. Increased drug toxicity c. Disease state  Disease can play a critical role in determining CYP activity  Diseases that decrease CYP activity include:  Liver disease  Kidney disease  Inflammatory diseases  Infection d. Genetic polymorphisms 23  Genes for some drug metabolizing enzymes have genetic polymorphisms known as SNPs  SNP is a change of a single nucleotide in our DNA  SNPs often affect the protein that is produced  There are a number of SNPs in drug metabolizing enzymes that cause pronounced differences to the response of drugs  Phase I SNPs o CYCP2C9  Metabolizes the anticoagulant drug warfarin  Polymorphism of CYP2C9 results in an enzyme with decreased activity  Patients with this require a lower dose of warfarin  If the does isn’t lowered, patients may experience extensive bleeding, side effect of warfarin o CYP2D6  Metabolizes codeine to morphine (more potent analgesic)  Has many genetic polymorphisms that can result in 4 distinct phenotypes:  Ultra rapid metabolizer (UM), extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM)  EM are considered to have normal enzymatic activity  IM have reduced activity, and poor have almost none  UM have significantly increased activity  Possess multiple copes of the gene  Can be subject to side effects of drugs  Phase II SNPs o UGT1A1  Part of the UGT family of enzymes  Glucuronidates the anti cancer compound SN-38 (active metabolite of irinotecan)  Polymorphisms decrease its activity  Patients with this are at increased risk of diarrhea and dose limiting bone marrow suppression (potentially fatal) o NAT2  Acetylates the drug isoniazid (used to treat TB), caffeine and various cancer causing chemicals  There are over 23 different SNPs  Patients are classified as either rapid or slow acetylators based on their genotype  Slow acetylators are more susceptible to isoniazid toxicity (neuropathy, hepatotoxicity) than rapid  Slow have a higher risk for developing certain types of cancer  Case Study o Methotrexate side effects 24  Liver damage resulting in  Nausea  Tiredness and lack of energy  Loss of appetite and flu like symptoms  Can cause decrease in the number of blood cells made in the bone marrow o Mercaptopurine side effects  Abdominal or stomach pain or tenderness  Decreased appetite  Fever or chills  Headache  Loss of appetite  Unusual tiredness or weakness o Mercaptopurine might be the reason for the worsening condition  Explain side effects that are not secondary to other issues  It is metabolized by TPMT which is subject to genetic polymorphisms o Pharmacokinetics:  Methotrexate: enters cells through active transport and facilitate diffusion and is then converted to polyglutamate MTX - glutamate, polar amino acid, conjugated to MTX making the drug more water soluble  Because added through conjugation, implies a phase 2 reaction  Mercaptopurine: bioavailability is limited by extensive first pass metabolism in the liver and intestinal mucosa. Prodrug that must be converted to exert cytotoxic effect. Metabolism occurs in the liver where the reaction is catalyzed by xanthine oxidase. Inactivated by TMPT which can be highly variable due to polymorphisms in the TPMT gene o Reasons for altered absorption, distribution and/or metabolism:  Genetic variation in the way the drug was metabolized  TMPT if it has a SNP could explain o Lab testing  TPMT testing: TPMT genotyping or phenotyping can identify patients who are homozygous deficient or have low or intermediate TPMT activity  Genotypic testing can determine the allelic pattern of a patient  Individuals homozygous for these alleles are TPMT deficient and those heterozygous have variable TPMT activity o Intervention  When standard doses of mercaptopurine are administered, TPMT-deficient patients can accumulate excessive thioguanine nucleotides which can be toxic and fatal  They can be treated by using a lower dosage of medication 25 Module 5: Pharmacokinetics – Excretion 5.1 Routes of Drug Excretion  Drug excretion: removal of parent drug and drug metabolites from the body  The most common sites are in the kidney and in the bile  Renal o 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  Especially important in end stage kidney disease when the require dialysis, drug excretion in the urine is almost negligible, drug dosage must be decreased o Nephron  Basic structural and functional unit of the kidney  Regulates water, electrolyte and drug excretion  Controls blood volume, BP, blood pH and solute (including drug) excretion 5.2 Factors affecting renal drug excretion 1. Glomerular Filtration a. Drugs enter the kidney from the renal artery and the afferent arteriole b. Proteins are not filtered at the glomerulus c. Hydrostatic pressure within glomerular capillaries forces low molecular weight drugs to leave the blood supply into the renal tubules d. The major determinant to what leaves the glomerulus is the size of the molecule e. Glomerular filtration rate is ~120ml/min/1.73 m2 or about 20% of total renal plasma flow. f. Lipid solubility and pH do not affect glomerular filtration of drugs g. Only non-protein bound drugs are filtered at the glomerulus 2. Tubular Secretion a. Drugs not filtered by the glomerulus leave the glomeruli by the efferent arteriole b. The efferent arterioles divide to form capillaries that surround the proximal tubule c. Drugs can be secreted from the blood surrounding the tubules into the lumen of the proximal tubule d. Drug secretion in the kidney primarily occurs by two transport systems, one for weak acids and one for weak bases e. Secreting is a rapid and high capacity process f. Occurs at the proximal tubule g. Transporters on the basolateral membrane 26 h. When drugs come into efferent arteriole, the transporter flips them into the tubule lumen so they can be eliminated in the urine 3. Tubular Reabsorption a. As drugs move toward the distal tubule, their concentration within the tubule increases b. This is primarily due to the actions of the loop of Henle which functions to concentrate tubular solutes c. Once in the distal tubule the drug concentration often exceeds the concentration in the blood that immediately surrounds the distal tubule d. 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 on renal function o Kidney function is low in newborns  Typical GFR is 40 mL/min/1.73m 2  By two years old the GFR reaches that of a healthy adult (120 mL/min/1.73m ) 2 o As we age renal function decreases o If renal function is decreased, renal drug excretion is decreased 5.3 Biliary drug excretion  Some drugs are eliminated into the bile and ultimately excreted in the feces  Characteristics of drugs eliminated in the bile include: o Larger drugs, Molecular weight > 300 Da o Have both polar and lipophilic groups (amphipathic) o (Phase II) Are glucoronidated  Transporters on the canalicular membrane of the hepatocytes transport drugs and metabolites from the 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  Portal Vein – carries blood from the intestine to the liver o At this stage where a drug is absorbed in the body, it is in solution and not in a capsule  Hepatocyte – major cell in the liver, contain phase I and II drug metabolizing enzymes  Bile canaliculus – hollow tubes that collects bile and drugs excreted in the liver  Hepatic duct – carries bile and drugs from liver to gall bladder so they can then be excreted back into the intestine 27  Enterohepatic recycling o Drugs and drug conjugates excreted in the bile enter the intestinal lumen o Intestinal bacteria can cleave conjugate metabolites leaving the original drug o The original drug may be reabsorbed in the intestine to re-enter the body o This process is known as enterohepatic recycling o Drugs that undergo this persist in the body for substantially longer periods 5.4 Pulmonary Drug Excretion  Drugs eliminated by pulmonary excretion are usually gaseous and/or highly volatile so they can be eliminated in the breathe  The best example are general anesthetics  Pulmonary drug excretion is not heavily reliant on drug metabolism o Drugs don’t have to be metabolized to be excreted  Factors affecting pulmonary drug excretion include: o Rate of respiration o Cardiac output o Solubility of drug in blood  High drug solubility  low pulmonary excretion  Low blood drug solubility  high pulmonary excretion 5.5 Drug Excretion in Breast Milk  Breast-fed infants may be inadvertently exposed to drugs as 90% of women take at least one drug in the first week post-partum  Drugs excreted in the breast milk usually have low protein binding low molecular weight and highly lipophilic  There’s a difference in pH between maternal plasma and breast milk  The transporter Breast Cancer Resistance Protein (BCRP) transports drugs into the milk o Substrates are actively pumped into the breast milk from the plasma  Breast milk has a lower pH and higher lipid content than plasma o When uncharged weak base able to cross into the breast milk and then becomes ionized and therefore trapped  Only relatively few drugs pose a clinically relevant risk to infants 28 5.6 Other Routes of Drug Excretion  Hair - drugs may be excreted into the hair follicle o Exposure rates and lengths can be determined by looking at the hair as the growth rate of ~1cm/month is used  Saliva – drug excretion through saliva is usually swallowed back and then subject to either intestinal absorption or fecal excretion  Sweat – mostly washed away although a minor amount of dermal reabsorption may occur Module 6: Clinical Pharmacokinetics 6.1 Clinical Pharmacokinetics  Relationship exists between the effect of the drug and the concentration of the drug in the body o The higher the concentration the greater the effect  Provides a quantitative relationship between the drug dose and the effect  Provides a framework to interpret measurements of drug concentrations in biological fluids to benefit drug therapy  The most important parameters determining drug disposition in humans are: i. Clearance – the body’s efficiency in drug elimination ii. Volume of distribution – the apparent space in the body available to contain the drug iii. Elimination Half Life1/2 ) – a measure of the rate of removal of the drug from the body iv. Bioavailability – the fraction of drug that reaches the systemic circulation 6.2 Plasma Drug Concentration Measuring Drug Concentrations  Ideally drug concentrations would be measured from the site of action – in reality this is not feasible o Taking a sample of the brain to determine drug concentration for a drug treating a psychological disorder would clearly do more harm than good  Concentrations are usually measured in plasma o Ideal site because  It’s relatively non-invasive, take a sample by phlebotomy  For most drugs, there’s a good correlation between plasma concentration and therapeutic and toxic drug effects o Take a Phlebotomy (blood taken from patient – centrifuge blood sample to eliminate cellular components 29 Free vs. Total Plasma Drug Concentrations  Drugs in plasma exist as bound plasma proteins or in free state  Only free form can elicit a pharmacological response o In theory measuring free concentration would be ideal, however this is tedious therefore total concentration is usually taken (free + protein bound concentration)  For most drugs measuring total plasma concentration provides enough information to guide dosing 6.3 Drug Concentration Time Curves Oral Administration  In beginning rate of absorption is greater than elimination therefore plasma concentrations increase (A >>E)  At later time the rate of absorption is equal to eliminations – this is peak/rounded top of curve and is called MAX  After peak the rate of elimination is greater than absorption so plasma concentration declines Characteristics of Plasma Concentration Time Curves  Plasma drug concentrations must be high enough to have a therapeutic effect but not so high as to induce toxicity  Minimum effective concentration (MEC) – the minimum concentration required to have a therapeutic effect – drug concentrations below this do not have a therapeutic effect  Duration – the length of time the drug concentration is above the minimum effective concentration, determine the time frame a drug is effective for  Toxic Concentration – plasma concentrations are too high and toxic side effects will occur  Therapeutic Range (therapeutic window) – Drug concentrations below toxic concentrations yet above the minimum effective level – the goal of pharmacotherapy is to attain concentrations in this range (The white space on the image) o The width is an index for how safely a drug can be used o Drugs with narrow range are difficult to administer safely since there is only a narrow window where the drug will be effective and not toxic  Often monitored to ensure concentrations are safe by using therapeutic monitoring – sampling blood prior to secondary dosage 30 Onset of Action  Orally administered drugs are subject to lag time before the reach the minimum effective level (must be absorbed into the body first) o Lag time varies between drugs  The rate and extent of absorption affect the onset of action  The onset of action determines how soon a drug effects will occur  Figure on the right shows three different drugs, the drug with the black line has a faster onset of action – could be a therapeutic benefit to have quicker effect Drug Concentration Time Curve – Continuous Intravenous Infusion  Rate of drug entry into the body is constant  There is no absorption phase, as the drug enters directly into the systemic circulation  After initiation of the infusion the plasma concentration rises until the rate of infusion equals the rate of elimination o Drug levels do not change over time – steady state  When the infusion is stopped plasma drug concentrations decrease Drug Concentration Time Curve – Intravenous Bolus  The drug is rapidly injected directly and quickly distributes and is eliminated over time  The elimination of a drug usually follows first order kinetics o Rate of elimination is dependent of the blood concentration – the higher the concentration the greater the rate of elimination Drug Concentration Time Curve – Repeated Doses  When patients take repeated dosing of drugs accumulation occurs until a plateau is reached – called steady state  When repeatedly administered orally or through IV bolus drug concentrations fluctuate o The high level is referred to as the peak and the low referred to as the trough o The goal of drug therapy is for the fluctuations at steady state to be within the therapeutic range
More Less

Related notes for Pharmacology 2060A/B

Log In


Don't have an account?

Join OneClass

Access over 10 million pages of study
documents for 1.3 million courses.

Sign up

Join to view


By registering, I agree to the Terms and Privacy Policies
Already have an account?
Just a few more details

So we can recommend you notes for your school.

Reset Password

Please enter below the email address you registered with and we will send you a link to reset your password.

Add your courses

Get notes from the top students in your class.