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Western University
Pharmacology 2060A/B

Module 1 1/25/2013 2:22:00 PM INTRODUCTION  What is Pharmacology? o Derived from the Greek words “pharmakon” meaning remedy and logos meaning study. o Generally pharmacology is considered the study of drugs. o The study of drugs can include various aspects, some of which include:  1) How a drug is delivered (it‟s route of administration).  2) How a drug works (it‟s mechanism of action).  3) The therapeutic effect of drugs on patients.  4) The adverse effects of drugs on patients.  Classification of Therapeutics o 1) Drugs – Traditional drugs (i.e. chemical agents). o 2) Biologics – antibodies, hormones. o 3) Natural Health Products – herbals, vitamins, minerals.  Canadian Drug Legislation o 1. Food and Drugs Act/Regulations o 2. Health Canada o 3. Health Canada Products and Food Branch o 4. Therapeutic Products Directorate, Biologics and Genetic Therapies Directorate and Natural Health Products Directorate  Approval of typical drugs  Approval of hormones/antibodies  Approval of natural source medicine products  What is a Drug? o Drugs are actually chemicals. o Within every pill are many molecules of a chemical. It is the chemical that actually produces the pharmacological effect.  Naming of Drugs o Drugs have three types of names:  1. Chemical Name – Describes the chemical structure of the molecule.  2. Generic Name – A unique name that identifies a drug.  Most often used in Pharmacology.  3. Trade name – The name assigned by a drug company.  Major problem with trade names is many companies may make the same drug, therefore it may have many different trade names.  Approval of Marketed Drugs in Canada o 1. o 2. o 3. o 4. o 5. o 6. o 7. BASIC PHYSIOLOGY AND THE CELL MEMBRANE  Physiological Barriers to Drug Transport o Intestinal villi form a barrier against ingested drugs, toxins and nutrients. o Some cells have tight junctions which prevent molecules from passing between cells.  i.e. brain cells o In order to exert its effect, a drug must have the right chemical properties to pass through these barriers.  Components of the Cell o Nucleus – Contains genetic material. o Smooth Endoplasmic Reticulum – Metabolizes drugs, carbohydrates and steroids. o Rough Endoplasmic Reticulum – Synthesizes proteins. o Golgi Apparatus – Processes and packages proteins and lipids. o Mitochondria – Produces ATP. o Cell membrane – Separates the intracellular and extracellular environments. o The Cell Membrane  Composed of phospholipids which have a polar (water soluble), phosphate containing head and two fatty acid (lipid soluble) tails.  The cell membrane is often called a lipid bilayer because of the arrangement of the phospholipids.  “Fluid” because the phospholipids are flexible allowing them to undulate back and forth.  Contains proteins embedded in the phospholipids. HOW DO DRUGS CROSS THE CELL MEMBRANE  1) Direct penetration of the cell membrane. o To directly penetrate cell membranes, drugs must be lipid soluble (lipophilic). o Cell membranes are composed of primarily lipid  Therefore drugs must be able to dissolve into the lipids of the cell membrane in order to pass through it. o Molecules that are not lipophilic cannot pass through cell membranes.  2) Through ion channels and pores. o The channels and pores in cell membranes are very small.  Only very small compounds (molecular weight < 200) can pass through channels and pores. o Channels are selective meaning only certain small compounds can fit through them.  Charge can also be a factor o Examples of compounds that cross membranes through channels include ions like sodium, potassium and lithium  3) Specific transport proteins (drug transporters). o Are carrier proteins that move drugs from one side of the cell membrane to the other. o Two types:  Uptake transporters move drugs from outside the cell to inside.  Important in mediating intestinal absorption, renal excretion and reaching target sites of action inside cells.  Efflux transporters move drugs from inside the cell to outside.  Important for protecting cells and are present in the intestine, placenta, kidney and at the blood brain barrier. THE CHEMISTRY OF PHARMACOLOGY  Types of Drug Molecules o 1) Polar Molecules  Water soluble.  Have an uneven distribution of electrical charge and have no net charge.  Examples of polar molecules include water, glucose and kanamycin. o 2) Ions  Atoms or molecules where the total number of electrons is not equal to the total number of protons.  Have a net charge.  Due to their charge, ions cannot directly pass through the cell membrane.  Very small ions pass through ion channels or pores. o 3) Quaternary Ammonium Compounds  Have at least one nitrogen atom that has a positive charge at all times.  Due to the positive charge, these molecules are unable to cross cell membranes. o 4) Ionizable Molecules  Can exist in charged or uncharged form.  Weak acids or weak bases.  Determination of whether a weak acid or a weak base carries a charge depends on the pH of the surrounding medium.  The 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 membranes more easily in an alkaline medium (intestines) o Example: Medium = stomach (acidic)  The acidic drug is unionized and can therefore cross the cell membrane.  The basic drug is ionized and therefore can‟t cross the cell membrane. o Acidic Medium (stomach)  + weak acid = non ionized  + weak base = ionized o Alkaline Medium (small intestine)  + weak acid = ionized  + weak base = non ionized  Ion Trapping o Occurs 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. o Ion trapping can be put into use clinically in some cases of drug overdose o Example: an acidic drug is placed into an acidic environment.  Since acidic drugs are unionized in acidic environments, the drug is able to cross the membrane.  The other side of the membrane is basic, therefore when the drug crosses the membrane is becomes ionized.  Since ionized drugs are unable to cross cell membranes, the drug is now “trapped” on the basic side of the membrane. DRUG MOVEMENT OUT OF CAPILLARIES  Capillaries o The smallest blood vessels in the body. o Blood supply from the heart travels through the arteries into narrower arterioles which narrow further into capillaries. o Capillary beds supply tissue with oxygenated blood and allow the drugs and other molecules to move from the blood to the tissue.  Movement o Capillaries have large gaps between them called fenestrations. o Hydrophilic drugs can pass between fenestrations to leave the blood only o Lipophilic drugs can either pass between fenestrations or directly through capillary endothelial cells. o Capillaries at the blood brain barrier have tight junctions.  They do not have fenestrations.  In order to penetrate the brain, drugs must either be lipophilic or have a specific transport protein that carries them into the brain. Module 2 1/25/2013 2:22:00 PM INTRODUCTION  Pharmacokinetics o The study of drug movement in the body. o It‟s what the body does to the drug. o Composed of four basic processes:  Absorption  The movement of the drug from the site of administration into the blood.  Rate determines how quickly the drug effect will occur  The amount of absorption determines how intense the effect will be  Distribution  Metabolism  Excretion FACTORS AFFECTING ABSORPTION  1) Rate of Dissolution o Dissolution means 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 than drugs with slow dissolution. o When we swallow a medication, the tablet undergoes disintegration and the medication dissolves in our stomach contents.  2) Surface Area o Surface area is a major determinant of drug absorption. o The larger the surface area, the faster drug absorption is. o Which has the greater surface, the stomach or the small intestine?  While the stomach has folds called rugae, the intestine has thousands of finger like projections called villi.  The villi that line the intestine make the surface area very large.  3) Blood Flow o Drug absorption is fastest in areas with high blood flow. o Areas with a high blood flow maintain a concentration gradient which drives absorption. o Areas with low blood flow do not maintain as great of a concentration gradient. o Exercise increases blood flow and can increase drug absorption. o Blood flow is decreased in heart failure, severe hypotension, hypothermia and circulatory shock.  4) Lipid Solubility o Drugs with high lipid solubility (i.e. lipophilic drugs) are absorbed more rapidly than water soluble (i.e. hydrophilic) drugs. o Lipophilic drugs are able to cross the cell membrane whereas hydrophilic drugs can‟t.  5) pH Partitioning o Drug absorption is greater when there‟s a difference between the pH at the site of administration and the blood such that the drug is ionized in the blood.  Remember the effect of pH dependent ionization*  If the drug becomes ionized, it will become „trapped‟ in the blood  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 the absorption of drugs. o Efflux drug transporters decrease the absorption of drugs. ROUTES OF ADMINISTRATION  8 major routes of drug administration o 1) Oral (PO = per os which is latin for by mouth) o 2) Sublingual o 3) Transdermal o 4) Rectal o 5) Intravenous (IV) o 6) Subcutaneous (SubQ or SC) o 7) Intramuscular (IM) o 8) Pulmonary  Routes of administration are often referred to as enteral or parenteral. o Enteral – Routes of administration that involve the gastrointestinal tract.  Oral  Rectal o Parenteral – Routes of administration that do not involve the gastrointestinal tract.  Intravenous  Subcutaneous  Intramuscular o Other  Sublingual  Transdermal  Pulmonary  1) Oral o Intestine vs. Stomach  Drug absorption would be greater in the intestine than the stomach.  What about drugs that are weak acids, wouldn‟t they be better absorbed in the stomach?  Based on the pH effects weakly acidic drugs should be better absorbed in the acidic environment of the stomach because they would unionized.  However, the surface area of the stomach is small and the stomach is covered with a thick layer of mucous.  Therefore the rate of drug absorption in the intestine will be greater than the stomach, even if the drug is ionized! o Pharmaceutical Phase  Occurs after the patient swallows a tablet.  It involves the disintegration of the tablet and the dissolution of the drug.  If the drug does not completely disintegrate or does not go into solution, absorption is reduced. o Gastric Emptying  The movement of the stomach contents into the intestine.  Since the rate of drug absorption is greater in the intestine, things that increase gastric emptying also increase the rate of drug absorption.  Factors Affecting Gastric Emptying  Enteric Coating  Drugs with enteric coating are covered with a special coating that prevents their dissolution in the acidic environment of the stomach.  Once the drug passes into the more alkaline duodenum, the enteric coating dissolves.  Bioavailability  The fraction of a dose of drug that reaches the systemic circulation unchanged.  Can be influenced by: o 1) Drug formulation o 2) Route of Administration o 3) Degree of Metabolism  Aqueous solutions have high bioavailability while tablets have low bioavailability  2) Sublingual o Involves placing a drug under the tongue. o The drug dissolves and is absorbed across the oral mucosa. o Venous drainage from the oral mucosa is to the superior vena cava.  Superior vena cava takes blood to the heart. o Drugs administered sublingually avoid first pass metabolism through the liver. o In order to be absorbed drugs must be lipophilic and uncharged.  3) Transdermal o Not all drugs penetrate the skin. o The epidermis provides a lipid barrier, therefore drugs must be lipophilic enough to penetrate the skin. o Drugs must also be relatively hydrophilic in order to dissolve in the extracellular fluid.  Ideal transdermal preparations have some degree of lipophilicity and some degree of hydrophilicity and are usually small (< 600 Da) molecules. o Transdermal drugs are typically administered as patches, ointments, sprays or lotions. o Transdermal administration provides constant plasma drug levels with minimal peaks and troughs. o Tolerance may develop unless drug‐free period‟s are enforced.  Typically patches are removed for 6 – 10 hours per day to avoid tolerance. o Factors Affecting Transdermal Absorption  1) Thickness of the skin – Transdermal absorption is inversely proportional to skin thickness.  Increasing thickness = decreased absorption  2) Hydration – Transdermal absorption is increased when the skin is well hydrated.  3) Hair follicles – Provide routes for drugs to bypass the barrier function of the epidermis.  In general the greater the number of hair follicles, the greater the transdermal absorption is.  4) Application Area – The greater the application area, the greater the transdermal absorption.  5) Integrity of the barrier – In conditions such as psoriasis, burned or abraded skin, transdermal absorption is increased.  4) Rectal o Useful when the patient is unconscious or vomiting. o Approximately 50% of rectally administered drugs bypass the liver (an important site for drug metabolism). o Administration:  The drug is inserted into the rectum as a suppository.  The suppository dissolves and the drug crosses the rectal mucosa into the blood. o Disadvantages:  Incomplete absorption  Some drugs may irritate the rectal mucosa  5) Intravenous (IV) o Drug is injected directly into a peripheral vein. o Most commonly used veins are those on the back of the hand or the median cubital vein at the elbow although any visible vein may be used. o Intravenous drugs can be given as a bolus or by an IV drip.  In IV bolus a single dose is administered over a short time period.  In an IV drip a drug is administered under continuous infusion over a prolonged period.  Drugs are typically diluted in a “vehicle” such as saline in an IV bag. o Advantages:  No barriers to absorption, bioavailability is 100%.  Allows precise control of the drug dosage and duration of action.  Allows administration of poorly soluble drugs that must be diluted in a large volume.  Allows the injection of drugs that are irritants (i.e. many chemotherapeutic drugs) as they can be injected slowly so they are diluted in the blood. o Disadvantages:  Expensive, invasive and inconvenient.  Drug cannot be removed once injected.  Risk of infection and fluid overload.  Risk of injecting wrong formulation (IM formulation sometimes injected IV by accident).  6) Subcutaneous o Drug is injected beneath the skin into the subcutaneous tissue. o The only barrier to absorption is the capillary wall. o Irritant drugs must not be injected subcutaneously as this will cause severe pain and/or tissue sloughing. o The primary determinants of rate of absorption are blood flow and water solubility.  7) Intramuscular (IM) o Drug is injected directly into muscle tissue. o Absorption is determined by the ability of the drug to pass through fenestrations in the capillary wall. o The primary determinants of rate of absorption are blood flow and water solubility. o Advantages:  1. Can be used for poorly soluble drugs.  2. Can use it to administer depot preparations  Preparations in which the drug is absorbed slowly over time o Disadvantages:  1. Pain/discomfort  2. May cause local tissue and/or nerve damage if the injection is done improperly. o Factors Affecting Intramuscular Absorption  Blood flow is different depending on which muscle is used for injection.  In general blood flow is deltoid > vastus lateralis> gluteal.  Exercise increases blood flow and may therefore increase absorption for IM drugs.  Blood flow may be decreased in heart failure, severe hypotension and hypothermia.  8) Pulmonary o Gaseous and volatile drugs can be inhaled and absorbed into the blood through the pulmonary epithelium. o Absorption is very rapid (almost instantaneous) due to the large surface area of the lung. o In the case of pulmonary disease (i.e. asthma), the drug is delivered 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 1/25/2013 2:22:00 PM BODY COMPARTMENTS  Drugs distribute into compartments in the body where they may be stored, metabolized, excreted or exert their pharmacological effect.  The bodies compartments include: o 1. Interstitial Space – The extracellular fluid that surrounds cells.  Low molecular weight, water soluble drugs distribute in the interstitial space. o 2. Total body water – Includes the interstitial space, intracellular fluid and the plasma. o 3. Plasma – The non‐cell containing component of blood.  Drugs strongly bound to plasma protein and high molecular weight drugs typically distribute in plasma. o 4. Adipose Tissue – The bodies fat.  Lipid soluble (lipophilic) drugs distribute into adipose tissue. o 5. Muscle – Some drugs bind tightly to muscle tissue. o 6. Bone – Some drugs adsorb 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. o 7. Other tissues DRUG DISTRIBUTION  Determined by: o 1. Blood flow to tissues.  The more drug that distributes out of the blood, the lower the concentration of drug in the blood.  Blood flow to tissues is a key determinant of drug distribution.  In well perfused tissues such as the liver, kidney and brain, drug distribution is rapid.  Distribution to tissues with lower blood flow such as skin, fat and bone is much slower.  Implications for Altered Blood Flow  Neonates have limited blow flow and therefore may have limited 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 altered drug distribution.  Solid tumors have low regional blood flow.  The outer portion of tumors has a high blood flow but the blood flow progressively decreases towards the middle.  Therefore it is difficult to attain high drug concentrations within solid tumors.  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. o 2. Ability of drug to move out of capillaries.  With the exception of the brain, drug movement out of the capillaries into the interstitial space occurs rapidly due to the permeable nature of the capillary wall.  Drugs move out of the capillary through fenestrations. o 3. Ability of drug to move into cells.  Once drugs leave the vasculature they must enter their target organ 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 the cell membrane or be carried by an uptake transporter into the cell.  Some drugs are extruded (removed) from cells by efflux transporters. P‐GLYCOPROTEIN (P‐GP)  The most widely studied efflux transporter.  Plays an important role in the distribution of drugs.  Although the “P” in P‐gp stands for permeability, it is helpful to remember the word Protective when you think of P‐gp.  Protective because it facilitates drug efflux from cells, promotes drug excretion and protects the body from exposure to drugs and other toxins.  An active transporter which means that it requires energy (ATP) in order to transport drugs against a concentration gradient.  In the liver pumps drugs into the bile to facilitate excretion.  In the intestine, P‐gp pumps drug into the lumen preventing absorption into the blood.  In the kidney P‐gp pumps drugs into the lumen facilitating excretion.  In the brain P‐gp pumps drugs into the blood limiting exposure in the brain PLASMA PROTEIN BINDING  In 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 that are bound to plasma proteins are unable to pass through capillary fenestrations.  There are two major plasma proteins that bind drugs in plasma: o 1. Albumin – Has a high affinity for lipophilic and anionic (i.e. weakly acidic) drugs.  Responsible for the majority of protein binding. o 2. Alpha 1 acid glycoprotein – Binds primarily cationic (i.e. weakly basic) and very hydrophilic drugs.  Plasma Protein Binding is Reversible o The binding of drugs to plasma proteins is reversible. o If some of the free drug is removed, some of the protein bound drug will dissociate from the protein and become free.  Conditions Affecting Plasma Protein Binding o The following decrease plasma albumin concentration  Malnutrition  Trauma  Aging  Liver and kidney disease  This results in an increase in free drug concentration which may result in toxicity. o The following increase alpha-1-acidic glycoprotein concentration  Aging  Trauma  Hepatic inflammation (i.e. in hepatitis)  This results in decreased free drug concentration which may lead to ineffective therapy. 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: o Vd = D/C  It is important to note that Vd is NOT a physical, anatomical space, rather it is 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. (~4 L) o Interstitial Fluid – The fluid that surround the cells of the body. (~10 L) o Intracellular Fluid – The fluid inside cells. (~28 L)  Drugs with a Small VD o Have the following characteristics:  Highly protein bound (retained in plasma).  Large molecular weight (unable to pass through capillary fenestrations). o Unable to leave the vascular space (plasma). o When displaced from plasma proteins, free drug concentration increases o Distribute into the plasma volume which is approximately 0.057 L/kg or 5.7% of total body weight (~4 L in a 70 kg person).  Drugs with an Intermediate VD o Have the following characteristics:  Low molecular weight (able to pass through capillary fenestrations).  Very hydrophilic (can‟t cross cell membranes).  Intermediate protein binding. o Able to leave the vascular space and enter the interstitial space  Unable to enter cells. o Distribute into the extracellular fluid (plasma + interstitial space).  The extracellular space is ~0.2 L/kg or 20% of total body weight (~14 L in a 70 kg person).  Drug with a Large VD o Have the following characteristics:  Low molecular weight (able to pass through capillary fenestrations).  Lipophilic (able to cross cell membranes).  Minimal protein binding. o Able to leave the vascular space and the interstitial space. o When displaced from plasma proteins, drug moves into the tissue, decreasing drug concentration in the blood and further increasing Vd o Distribute into body compartments such as fat, bone, muscle and other tissues. o Distribute into greater than 0.2 L/kg. o Keep in mind that these drugs may have a Vd larger than total body water!  How is this possible?  Remember that Vd is mathematically derived and 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 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.  This means the free drug concentration increases. o Large Vd  When the Vd of the displaced drug is large, displaced drug leaves the plasma and distributes into the tissues.  This causes the total plasma drug concentration to decrease, and the apparent Vd to increase even further. BODY COMPOSITION AND DRUG DISTRIBUTION  As we age our body composition changes. o Total body water decrease with age o Muscle mass increases and then decreases  Elderly people have an increased proportion of body mass as fat. o Similarly, obese people have a larger proportion of body mass as fat. o Drugs that distribute in fat will have a larger Vd in obese or elderly people than young healthy adults.  As people age they have a decreased percentage of muscle per total body mass. o Therefore drugs that distribute into muscle will have a lower Vd. Module 4 1/25/2013 2:22:00 PM DRUG METABOLISM  Metabolism is the enzyme mediated alteration of a drug‟s structure. o Also referred to as biotransformation.  Sites of drug metabolism include: o Liver – primary site o Intestines – enterocytes that line the gut are responsible  Bacterial flora play an important role o Stomach – alcohol metabolism o Kidney  Drug metabolism evolved in humans to protect us from a number of environmental toxins as well as synthesize essential endogenous molecules. o Exogenous – substances that are not naturally in our body to begin with  i.e. wine, cigarettes, steak, coffee, vegetables and drugs  They have the potential to be toxic and drug metabolism helps prevent this o Essential endogenous molecules synthesized by drug metabolizing enzymes  i.e. vitamin D synthesis, bile acid synthesis, cholesterol metabolism, synthesis and metabolism of hormones, bilirubin  Therapeutic Consequences of Drug Metabolism o 1) Increase water solubility of drugs to promote their excretion  Lipophilic  Hydrophilic  Most important consequence because this allows excretion o 2) Inactivate drugs.  Active  Inactive  Metabolite does not have activity o 3) Increase drug effectiveness  Active  More active o 4) Activate prodrugs (inactive until metabolized)  Prodrug (inactive)  Active drug o 5) Increase drug toxicity  Non‐toxic  Toxic  Less favorable consequence KINETICS OF DRUG METABOLISM  First Order o In most clinical situations the concentration of drug is much lower than the metabolic capacity of the body  Concentration of drug < drug metabolizing enzymes  In these situations drug metabolism displays 1st order kinetics. o Drug metabolism is directly proportional to the concentration of free drug.  This means a constant fraction of drug is metabolized per unit time. o The concentration decreases faster when there are higher drug concentrations than at the end when the drug concentrations are low.  High concentration = high metabolism  Low concentration = low concentration  Zero Order o The plasma drug concentration is much higher than the metabolic capacity of the body.  Drug concentration > drug metabolizing enzymes o Drug metabolism is constant over time.  This means a constant amount of drug is metabolized per unit time.  Rate of drug metabolism is same throughout o One of the best examples of zero order kinetics is ethanol. o A constant amount of drug is eliminated over time.  Metabolism is independent of drug concentration FIRST PASS METABOLISM  PO (orally administered) drugs may undergo significant metabolism prior to entering the systemic circulation. o This is called 1st pass metabolism.  First pass metabolism can occur via: o 1. Hepatocytes in the liver o 2. Intestinal enterocytes o 3. Stomach o 4. Intestinal bacteria  The result of 1st pass metabolism is a decrease amount of parent drug that enters systemic circulation.  Example: Oral administration of alcohol o Stomach = first site  Alcohol dehydrogenase metabolizes alcohol o Moves into the intestines  CYP enzymes metabolize into metabolites o Moves into the liver  Primary site  CYP enzymes + many others  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.  Almost none of the drug will reach the systemic circulation and act in our body if extensively metabolized in the liver o High ER Drugs  Have 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 produce large changes in bioavailability.  Very susceptible to drug‐drug interactions  Will be extensively metabolized in its first pass through the liver  Significantly metabolized o Low ER Drugs  Have high oral bioavailability ( > 80%)  PO doses are usually similar to IV doses.  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.  Will be minimally metabolized in its first pass through the liver  Barely metabolized TYPES OF DRUG METABOLISM  Drug metabolism is broadly divided into 2 phases: o Phase I metabolism  Convert lipophilic drugs to more polar molecules by introducing or unmasking polar functional groups such as hydroxyl (‐OH) or amine (‐NH2).  Making a drug more hydrophilic/water soluble in order to facilitate excretion  Involves oxidation, reduction and hydrolysis reactions.  Mediated by cytochrome P450 enzymes, esterases and dehydrogenases.  Metabolites formed can be more active, less active or equally active as the parent drug. o Phase II Metabolism  Increase the polarity of lipophilic drugs by conjugation reactions (addition of large water soluble molecule to drug).  Making a drug more hydrophilic/water soluble n order to facilitate excretion  Conjugates include glucuronic acid (a sugar), sulfate (‐ SO4), acetate or amino acids (i.e. glycine).  Metabolites are less active than the parent drug.  Exception: Morphine 6‐glucuronide (metabolite) is a more potent analgesic (pain reliever) than morphine. o Intracellular Site of Drug Metabolizing Enzymes  Phase I – enzymes are localized to the smooth endoplasmic reticulum.  Phase II –enzymes are localized predominantly in the cytosol of the cell  Exception of glucuronidation which is localized to the smooth endoplasmic reticulum. CYTOCHROME P‐450 DRUG METABOLIZING ENZYMES  CYPs are a large family of drug metabolizing enzymes.  CYPs are the predominant phase I drug metabolizing enzyme system.  The majority 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. o Drug + O2 + NADPH + H+ → Drug (oxidized) + H20 + NADP+  There are 12 families of CYPs 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: o Example: CYP3A4 where 3 = family, A = subfamily and 4 = isozyme  CYP3A4 metabolizes the largest fraction of currently marketed drugs. PHASE II DRUG METABOLIZING ENZYMES  1. UDP‐glucoronosyltransferases (UGTs) o Are localized in the smooth endoplasmic reticulum o Catalyze the transfer of a glucuronic acid (sugar) to a drug. o Glucuronidated drugs are more polar and therefore more easily excreted. o There are 19 human UGT enzymes. o Drug + UDP‐glucuronic acid → drug‐glucuronide + UDP  2. Sulfotransferases (SULTs) o Are cytosolic phase II drug metabolizing enzymes. o Catalyze the transfer of a sulfate group to a hydroxyl group of drugs. o Sulfated drugs are more polar and therefore more easily excreted. o There are 11 human SULT enzymes. o Drug + sulfate → drug‐sulfate  3. Glutathione S Transfreases (GSTs) o May be cytosolic or microsomal. o Catalyze the transfer of a glutathione molecule to a drug.  Glutathione (GSH) is an intracellular anti‐oxidant.  Transfer of a glutathione molecule onto a reactive (i.e. toxic) drug renders the metabolite less toxic. o There are over 20 human GST enzymes. o Reactive Drug + GSH → drug‐GSH  4. N‐acteyltransferases (NATs) o Are cytosolic metabolizing enzymes. o Catalyze the transfer of an acetyl group from acetyl CoA to a drug. o Subject to genetic polymorphisms which is a major cause in variability to drug response. o There are 2 human NAT enzymes: NAT 1 and NAT2. o Drug + Acetyl CoA → Acetylated Drug + CoA  5. Thiopurine Methytransferase (TPMT) o Are cytosolic metabolizing enzymes. o Catalyze the transfer of a methyl group from S‐ adenosylmethionine to a drug. o Subject to genetic polymorphisms.  Although rare, these polymorphisms have dramatic effect on drug safety. o Drug + S‐adenosylmethionine → Drug‐CH3 + Methionine  The fraction of drugs metabolized by phase II enzymes is relatively equally split between UGTs, SULTs, GSTs and NATs. FACTORS AFFECTING DRUG METABOLISM  1. Age o The expression and activity of drug metabolizing enzymes changes as we age.  For example, infants have almost no CYP activity. It takes babies approximately 1 year after birth until they have a reasonable level of drug metabolizing enzymes.  By age 2, babies have the same amount of drug metabolizing enzymes as adults do.  2. Drug interactions (enzyme inducers and enzyme inhibitors). o Enzyme Induction  Induction is a process where a cell synthesizes an enzyme in response to a drug or other chemical.  Certain CYP isozymes are susceptible to induction by drugs.  The consequence of CYP induction is increased drug metabolism.  Enzyme induction plays an important role in drug interactions.  Consequences of increased drug metabolism may include:  1. Decreased plasma drug concentration.  2. Decreased drug activity (if metabolite is inactive).  3. Increased drug activity (if metabol
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