1 Variability of drug response Dr. Martha Nowycky Dec. 4, 2017

2 Lecture outline I. Sources of variability in population – – A. Body weight and composition – B. Gender – C. Age – Elderly and infants – D. Pregnancy II. Sources of variability in individual – – A. General state of health – disease and allergy – B. Drug Tolerance – C. Drug Resistance – D. Drug-Drug interactions – E. Food and drugs III. Inherited characteristics - Pharmacogenetics – A. Variability in receptors - Pharmacodynamics – B. Variability in drug disposition - Pharmacokinetics

3 Goals and Learning Objectives Describe the main contributors to drug variability between individuals in a population Describe how the pharmacokinetics of the a) elderly and b) infants differ from average adult ADME and how this affects their drug responses Know the special properties of drug pharmacokinetics in pregnancy What is unusual about pharmacology of drugs in developing fetus? What are the differences between tolerance due to pharmacodynamic vs pharmacokinetic changes? Describe different types and mechanisms of drug resistance What are the different types of drug-drug and food-drug interactions? Describe pharmacogenetic causes of variability in the population due to a) pharmacodynamic and b) pharmacokinetic processes

4 Variability of response Definition of variability: – Individuals in a population respond differently to drugs – One individual responds differently to a drug at two different times Goal: – Understand sources of variability so as to predict how an individual will respond to a drug

5 Quantal Dose-Response Relationship Courtesy of R. Howland ED 50 FROM: Dr. Berlin, Pharmacodynamics, Slide 35 Problem 1: The quantal dose-response relationship only describes responders

6 Problem 1: For many drugs, individual patients may be ‘non-responders’ % Responders Disease Alzheimer ’ s Pain Asthma Cardiac Arrhythmias Depression Diabetes Incontinence Migraines Cancer Osteoporosis Rheumatoid Arthritis Schizophrenia 30 80 60 62 57 40 52 25 48 50 60 Example for illustration only. Do not memorize!

7 Problem 2: Not all drug activity can be described with a single quantal dose-response distribution Sensitivity of a population of patients to a cancer drug, 6-MP, depends on the activity of a drug metabolizing enzyme, thiopurine S-methyl transferase (TPMT).

8 Variability in response influences decisions in pharmacotherapeutics Should this person be receiving the drug? – Responsiveness to drug – Allergy – Drug resistance – Adverse Drug Reactions (ADR) – Interactions with other drugs, food, or environmental factors How much drug should be given? – Pharmacokinetics: Absorption, Distribution, Metabolism, Excretion (ADME) – Pharmacodynamics: Is the drug ‘receptor’ identical to receptor in all individuals? – Interactions with other drugs, food, or environmental factors

9 Lecture outline I. Sources of variability in population – – A. Body weight and composition – B. Gender – C. Age – Elderly and infants – D. Pregnancy

10 I. Sources of variability in population: A. The average adult dose Average adult dose (definition) – quantity that produces a particular effect in 50% of population between 18 and 65 years old and weighing about 70 kg (150 lbs) Individual Dose – For most drugs, use the average adult dose – For a few drugs, for adults within normal weight range, calculate dose based on weight: Avg adult dose x weight of individual (kg) 70 kg ED 50

11 I.A. Body composition Extremely obese or lean individuals may need lower/higher doses of particular drugs Table from: Walsh & Schwartz-Bloom, Levine ’ s Pharmacology, 7ed, pg. 261, 2005 1)The Vd (volume of distribution) varies between lean & obese individuals 2)Lean individuals may metabolize drugs more rapidly (99% of drug metabolism is in lean tissue) 3)Dosage should be adjusted for drugs with narrow safety margin (case by case) Avg adult

12 I.B. Gender Women Smaller than men (size issue) Adult women have greater % adipose tissue, smaller % water Smaller plasma volume. Women tend to have slower metabolism than men Result:women may have faster onset, prolonged action for lipid soluble drugs and increased effects of water soluble drugs. Dosage should be adjusted for drugs with narrow safety margin.

13 I.C. Age – Life stage Age much more important than size for infant, young child, and elderly. – Both infants and elderly are often unusually sensitive to drugs, but for different reasons – Many differences in sensitivity due to differences in Pharmacokinetics or “ADME:” Absorption, Distribution, Metabolism (biotransformation) or Excretion

14 Elderly Pharmacokinetic changes (ADME) Absorption: ê sensitivity to oral drugs because of ê absorption GI tract has increased pH (alkaline) and decreased peristalsis and absorption Distribution: é sensitivity: decreased body weight and decreased Vd (loss of muscle mass) Metabolism é sensitivity: ê ability to biotransform and excrete drugs Liver decreased production of enzymes-decreased metabolism decreased blood flow Excretion é sensitivity: decline in renal function – decreased renal clearance NET RESULT: Elderly generally should take lower dosage than adult average

15 Elderly often suffer from additional problems and experience more severe side effects (ADR) Increased incidence of disease Risk of polypharmacy induced drug reactions - interaction with other drugs (alcohol, nicotine, caffeine, laxatives, analgesics). Complications from poor nutrition, hoarding & sharing, adherence issues, visual dysfunction, inadequate patient education. More severe adverse drug reactions (ADR): Decline in homeostatic mechanisms: orthostatic hypotension, posture/balance, cognitive function, muscle strength/endurance Example: beta-blockers (inhibit NE stimulation of heart) have more severe ADR in elderly Cold sensitivity Dizziness Respiratory effects Psychiatric effects Incontinence

16 Infants: Pharmacokinetic differences from adults (ADME) Absorption: ê sensitivity to oral drugs because of ê absorption GI tract has increased pH (alkaline) and decreased peristalsis, absorption Distribution: é sensitivity: small body weight but large Vd ***Diffusion barriers are not well defined ***Blood-brain barrier is more permeable Metabolism: é sensitivity: Enzyme systems for normal metabolic conversions and biotransformation are underdeveloped. Most enzymes reach adult levels 1-8 weeks after birth; maximally active by first year Microsomal enzymes for oxidation and glucuronide conjugation are lacking or present in low quantities. Decreased first pass effect Elimination: é sensitivity: Renal excretion low: Decreased perfusion to the kidney, decreased filtering through the kidney, less developed active transport NET RESULT: Infants generally much more sensitive to drug dosage than adult

17 Infants – Drug Pharmacokinetics Rapid drug delivery usually accompanied by slow elimination Slow drug delivery usually results in higher peak concentrations as well as slow elimination Levine, ed 7. Fig 11-1MEC: minimum effective concentration in blood

18 Increased absorption and/or decreased excretion = higher peak concentrations. Can lead to drug toxicity Toxic Effective No effect Effect on differences in absorption rate on Cmax ©2005 Gus Rosania

19 Infants Summary: Elimination is slower and drug levels may build Drug actions heightened or prolonged even after adjusting dosage to body size e.g. rate of elimination of insulin is 3x slower than in older child, even after correcting for Vd Combination of low renal function and ê rate of biotransformation accounts for many drug toxicities in newborn infant – Drugs may accumulate to toxic levels – need to keep spacing between doses long E.g. in adult, chloramphenicol (antibiotic) is conjugated with glucuronic acid, excreted rapidly by renal tubular secretion and glomerular filtration In newborn, most of chloramphenicol is free, poorly eliminated in urine

20 Some drugs are more toxic : Phenobarbital, morphine Opioids, barbiturates penetrate brain in much higher concentrations because of poorly developed blood-brain barrier Aspirin May causes Reye’s syndrome: a rare, but frequently fatal disease Some drugs are “ contraindicated ” because they affect growing systems: Tetracycline, a common antibiotic, can cause birth defects in fetus if taken by pregnant woman Additional complications of drugs in children

21 I. D. Pregnancy and Drug Response Pregnancy is a very complex state for analyzing drug pharmacology and requires consideration of: – Physiological changes in the mother – Physiological differences in fetus during gestation – Possible gestational (developmental) abnormalities in fetus

22 Pregnancy and Drug Response (cont) Pregnancy causes physiological changes in mother Absorption -blood flow due toblood volume resting ventilation rate Distribution -total body water body fat protein binding Biotransformation - enzyme levels Excretion -glomerular filtration

23 Cardiovascular: plasma volume expansion, and increase in cardiac output, changes in regional blood flow Decreased plasma proteins Variable changes in biotransformation: – Increased CYP3A4: methadone (an opiate agonist) and nifedipine (calcium channel blocker) are substrates for CYP3A4 and undergo increased clearance. – Decreased CYP1A2: Caffeine is metabolized by CYP1A2 and undergoes decreased clearance Renal excretion increases because renal blood flow increases glomerular filtration rate NET RESULT: drug effects unpredictable largely due to changes in pharmacokinetics – evaluate drug by drug Pregnancy and Drug Response (cont) Physiological changes in mother

24 – Most drugs in maternal blood can cross placental barrier – Blood-brain barrier is not formed in fetus or newborn. Drugs (e.g. opiates) reach fetal brain quickly and in high concentrations – Drugs with little effect in mother may be very harmful to developing fetus because of teratogenic effects – Drugs given to mother may have long-lasting and/or profound effects in newborn Newborn may not have metabolizing enzymes. At moment of birth, newborn loses protective effect of mother’s metabolizing systems and any drugs present in bloodstream may clear very slowly Pregnancy and Drug Response (cont) Effects on fetus

25 Pregnancy and Drug Response (cont) Teratogenic effects on fetus Medications may be teratogenic, mutagenic, or carcinogenic to the fetus. Most dramatic effects when fetus is exposed during period of first 2 weeks of rapid cell proliferation and the 3rd-10th week when the axial skeleton, muscles, limbs and organs are developing. Example: Thalidomide – over-the-counter medication used as tranquilizer, painkiller, and for morning sickness in Europe (1957-1961). Babies were born with missing or badly malformed limbs.

26 FDA Pregnancy Safety Categories During drug testing phase prior to marketing, special categories are designated for use in pregnancy A: adequate studies indicate no risk to fetus in first or later trimesters B: animal reproduction studies have not demonstrated risk to fetus but no controlled studies in pregnant women C: animal studies have reported adverse effect on fetus but no studies in humans—benefits may be acceptable in pregnant women (anti-hypertensive meds) D: evidence of fetal risk but this risk may be acceptable if there are no other safer drugs X: no justification for use. Animal and human studies show fetal risk. Risks outweigh benefits Because animal reproductive studies are not always predictive of human response, most drugs should be used during pregnancy only if clearly needed

27 Lecture outline II. Sources of variability in individual – – A. General state of health – disease and allergy

28 II. Sources of variability in individual A. Disease state and allergic responses Pharmacokinetic (PK) measurements are developed from data collected in normal healthy subjects Disease states can have significant effects on PK – Body temperature (e.g. fever) – Water content – e.g. Overhydration (edema) or dehydration affects Vd – pH – acidosis or alkalosis – Altered rate of distribution or excretion

29 Disease state Renal disease – affects excretion Liver disease – decreases drug metabolism – Cirrhosis – Alcoholic ‘Non-alcoholic fatty liver disease’ – obesity Hepatitis

30 Allergic responses to drugs Allergy – – Adverse responses to foreign chemical resulting from previous exposure to substance – Manifested only after second or later exposure – Reaction is different from usual pharmacologic effect

31 Drug allergy A tiny amount of otherwise safe drug can elicit the allergic response Allergic reactions – Minor: immediate response to histamine release Similar to hay fever or food allergy; Respiratory and GI, blood vessels, skin, skin rash – Intermediate: Difficulty breathing, swelling of mucous membrane, fall in blood pressure – Major: Anaphylaxis Anaphylactic shock – death can occur within few minutes from complete obstruction of respiratory passages and precipitous drop in blood pressure

32 Frequency of allergic reaction to most drugs is low – Caffeine – no known allergic response – Penicillin One of most common offenders Allergic response in 5-10% of patients Allergy to penicillin can be produced by exposure to moldy foods (bread, cheeses) or milk from penicillin-treated cows – Allergies often develop to components of drug solutions Local anesthetics – users may develop reaction to paraben derivatives which are common preservatives Glaucoma eye drops – many users develop reaction to benzalkonium chloride, a preservative

33 Lecture outline II. Sources of variability in individual – – B. Drug Tolerance – C. Drug Resistance (When Drugs that used to Work Stop Working)

34 Tolerance is a subject ’ s diminished response to a drug when the drug is given to that subject repeatedly requiring larger doses to achieve same effect. Resistance is a property of the drug target. It is the ability of pathogens, cancer cells, or organisms to withstand the effects of drugs or pesticides usually effective against them. Drug Tolerance vs Drug Resistance

35 II. B. Drug Tolerance Tolerance = condition of decreased responsiveness after prior or repeated exposure Successive doses have to be increased to produce equal effects or durations Tolerance is striking for narcotic analgesics (opioids) and general CNS depressants (e.g. benzodiazepines), and CNS stimulants (e.g. amphetamine) Tolerance disappears when administration is discontinued

36 Pharmacokinetic or “Drug-disposition” tolerance – Decrease in effective concentration of agonist at site of action – Drug may reduce its absorption or transfer across biologic barrier or increase its rate of elimination Phenobarbital, ethanol, opioids increase their own rates of biotransformation through stimulation of microsomal enzyme systems, particularly of CYP family Alcohol induces synthesis of alcohol dehydrogenase

37 Pharmacodynamic or “cellular” tolerance Reduction in normal reactivity of the receptor Usually develops more slowly – Accounts for most tolerance in CNS mood-behavior Probably caused by adaptation in neurons which makes them insensitive – Morphine addict may tolerate doses many times greater than would be lethal for naïve person. Cross-tolerance – Individual who develops tolerance to one drug may be tolerant to drugs acting on same receptor or same system – E.g. Individual tolerant to opioids is cross-tolerant to heroin, oxycodone, etc but not alcohol or barbiturates – E.g Alcoholic is partially tolerant to barbiturates, but not to opioids

38 Pharmacokinetic Tolerance can be overcome by more drug – Pharmacodynamic tolerance usually cannot Log (Dose) Response Log (Dose) Response Pharmacodynamic Pharmacokinetic

39 II.C. Drug Resistance Resistance is a change in the target (e.g cancer cell, microorganism) that makes the target unresponsive. Resistance develops after prior administration of same or related drug to the individual patient or to the infectious organisms. Resistance may develop in patient - e.g. Cancer cells may become resistant to a drug Resistance may develop in microorganism: Anti-microbial resistance – Microorganism strain may become drug-resistant within a patient – Strain may become drug-resistant after drug was given to another individual or even animal.

40 Drug resistance in patient cells – decreased intracellular availability Changes due to decreased entry – Cancer cells actively transport methotrexate into cell - resistance is due to decreased affinity of carrier for drug Changes due to increased efflux – Usually due to increased expression of a drug (efflux) transporter – ATP-binding cassette (ABC) family Facilitate export of drugs from cell Very broad substrate specificity Examples: – Pgp efflux transporter (MDR1) – Breast cancer resistance protein (BCRP) – Multidrug resistance protein 2 (MRP2) PGP efflux transporter From: Dr. K lecture ‘Drug Design’ – Slide 46.

41 Anti-microbial Drug Resistance Definition: Microorganisms (not patient) become resistant. Changes can be in genome of microorganism Drug-resistant strains can spread within human or animal population. Examples: – In 1940, 70% of patients with gonorrhea responded to sulfa drugs. In 1945, 70% were resistant. Now use penicillin. – MRSA: Methicillin-resistant Staphylococcus aureus. A form of Staphylococcus bacterium that is resistant to family of penicillins and cephalosporins. Develops through natural selection – Multi-drug-resistant tuberculosis (MDR-TB)

42 Causes of drug resistance in microorganisms Decreased intracellular drug availability – Decrease rate of entry – Increase in efflux transporters Increase of specific inactivating enzymes – Resistance to penicillin: organism (bacteria) produces enzyme penicillinase which hydrolyzes penicillin to inactive metabolite Decreased affinity of drug for its target – Genetic modification that alters protein which is specific target of drug TB resistance to Rifampin - mutations in  -subunit of RNA polymerase TB resistance to Isoniazid - mutations in enzyme that builds cell wall

43 Multi-drug resistant tuberculosis (MDR-TB) Definition of MDR-TB: TB that is resistant to one of 2 front-line drugs: rifampin (rifampicin) and isoniazid – Example: Rifampin resistance is due to mutation in  subunit of bacterial RNA polymerase. Isoniazid interferes with cell wall synthesis. At least two separate mutations make up MDR-TB The frequency of resistance to multi drugs, varies geographically based on populations of Mycobacterium tuberculosis. – High rates of acquired MDR-TB in Nepal (48%), India (33.8%), and New York City (30%).

44 Drug resistance of micro-organisms can occur by natural selection or by gene transfer between organisms Natural selection Infectious drug resistance

45 How a resistance gene moves between bacteria

46 Avoidance of drug resistance of micro- organisms Best: avoid development of resistance in first place Avoid unnecessary, promiscuous drug use Begin drug treatment early and continue until all infections organisms are eradicated Use multi-drug therapy from start when feasible Antibiotics in livestock feed are major problem for infectious resistance

47 Lecture outline II. Sources of variability in individual – – D. Drug-Drug interactions

48 Poly-drug use is common in many conditions ‘Polypharmacy’ – 5 or more drugs taken simultaneously ‘Pill Burden’ – number of drugs taken regularly Many chronic diseases require multiple drug regimens – Epilepsy, diabetes, heart disease, hypertension, high cholesterol – Elderly may have multiple medical problems – If patient gets another illness, conjoint administration of several drugs may be mandatory Average hospital patient gets 6-10 different drugs Childhood cancers, AIDS, organ transplants – conditions with such high pill burdens that a dedicated pharmacist is part of management team

49 Drug-drug interactions Two drugs may act completely independently – Aspirin to lower fever, antibacterial for killing organism OR: One drug may act in enhancement or opposition to action or effects of another drug (pharmacodynamic interaction) OR: One drug can affect the absorption, distribution, biotransformation or excretion (pharmacokinetic interaction)

50 Drug-drug interactions Interactions can be beneficial, deleterious, or disastrous – Beneficial (aspirin & antibacterial drug) – Disastrous: A MAO inhibitor antidepressant with a serotonin- uptake inhibitor antidepressant (e.g. imipramine) MAO (Monoamine oxidase) metabolizes monoamines (dopamine, norepinephrine, serotonin (5HT)) Anti-depressant uptake inhibitors block monoamine reuptake through transporters Together: excessive DA / NE/ 5HT neurotransmitters at synapses in CNS –> convulsions, delirium, and death

51 Drug-Drug Interactions: Enhancement of beneficial effect Additive or summation effects – Codeine and aspirin – both relieve pain, 2 different mechanisms – Aspirin and acetaminophen (Tylenol) – both reduce fever, same mechanism Synergism – joint effect greater than algebraic sum – Usually 2 drugs acting at different sites and one drug, the synergist, increases the effect of the second drug by altering its pharmacokinetics – E.g. probenecid (reduces renal excretion) and tamiflu (anti-flu drug)

52 Drug-Drug Interactions: Antagonism 1. Pharmacologic antagonism—at receptor level 2. Physiological antagonism—drugs act at different sites and produce opposite effects on the same physiologic function 3. Chemical antagonism 4. Biochemical antagonism

53 1. Pharmacological antagonism – Drugs compete for binding at a receptor Naloxone reverses effects of opioids by binding to opioid receptor – naloxone is a pure antagonist of agonist opioids 2. Physiologic antagonism – Two agonists, acting at different sites, produce opposite effects on same physiologic function Histamine lowers blood pressure by dilating blood vessels; NE increases blood pressure by constricting vessels. Each agent acts on own receptor and produces its own characteristic response Drug-Drug Interactions (cont.)

54 3. Chemical Antagonism: – Agonist and antagonist react with each other to form an inactive product – Example 1: Neutralization of gastric secretions by antacid drugs such as bicarbonate – Example 2: Heparin and protamine Heparin is an anticoagulant. It’s a macromolecule (glycosaminoglycan) with a strong, negative charge. Used before surgery to prevent blood clot formation Protamine, a positively charged protein, antagonizes heparin. Protamine sulfate is antidote if there if heparin is results in excessive bleeding (’heparin overdose’) Drug-Drug Interactions (cont.)

55 4. Biochemical Antagonism: – Opposite of synergism: one drug reduces the amount of a second drug so less available at the target site. – Modifies Pharmacokinetics - ADME – Example 1: Phenobarbital & the antibiotic rifampin induce drug-metabolizing enzymes in liver. Increase metabolism of unrelated drugs: e.g. birth control pills, steroids. – Example 2: Laxatives increase GI motility & result in decreased absorption of other drugs

56 Lecture outline II. Sources of variability in individual – – E. Food and drugs

57 II. E. Food-Drug Interactions Food can affect drug absorption – Presence of food often decreases drug bioavailability – Co-administration of some drugs with acidic beverages such as coke (pH

58 Food-Drug Interactions Foods can affect drug metabolism by increasing or decreasing metabolizing enzymes – Cruciferous vegetables (broccoli, bok choy family) are powerful inducers of the microsomal cytochrome P450 enzyme, CYP1A2 – Grapefruit juice contains bergamottin (a furanocoumarin), which inhibits CYP450 family and potentiates activity of various drugs (statins, calcium channel blockers, tetrahydrocannabinoid). – Cigarette smoking (nicotine) induces CYP2A6, a member of CYP450 family

59 Food-Drug Interactions Foods rich in tyramine can have toxic, potentially lethal, effect when eaten while taking MAO inhibitors for depression – MAO (Monoamine oxidase) metabolizes norepinephrine and serotonin – Tyramine rich foods include: Certain cheeses (Camembert, cheddar, Stilton, Roquefort) Pickled herring, red wine, chicken liver – Tyramine normally metabolized by MAO. Levels increase in presence of MAO inhibitors, cause sharp rise in blood pressure, including fatal cerebral hemorrhage

60 III. Pharmacogenetics: Inherited characteristics as source of variability

61 Genetic Factors affecting Variability of Drug Response Pharmacogenetics – branch of pharmacology that deals with genetic modifications that affect drug response Used to be called ‘idiosyncratic response’ (definition: unique to individual) Now called a ‘genetically determined abnormal response’

62 Pharmacogenetics has potential to allow prediction of an individual’s response to a drug – greatly benefiting patients Drug responsiveness – Each antidepressant has to be tried for 2 weeks Drug safety – ADR (adverse drug reactions) are responsible for 2.2 million serious medical events in US per year – 5-7% of hospital admissions are due to ADR Drug trials – A few patients with serious reactions can stop a drug trial

63 SNPs: Single Nucleotide Polymorphisms –A SNP is a site of the DNA in which a single base-pair varies from person to person –SNPs are most common form of genetic variation in human genome (frequency of >1%) –Easy to identify and analyze –Responsible for a large number of variations in drug responsiveness

64 Genetic mutations important in pharmacology Proteins with genetic mutations can be – Receptors – Transporters – Drug metabolizing enzymes – Alteration of a receptor protein may lead to increased or decreased intensity of drug effect – Abnormalities to transporters may result in prolonged effect or manifest as a novel drug response – Modification of enzyme responsible for drug biotransformation can prolong or shorten the duration of action

65 III. A. Pharmacodynamics: Abnormalities in receptors or associated proteins Many African-Americans are less responsive to  -blockers (antagonists of a class of NE receptors) in cardiovascular disease than Caucasian or Chinese patients 40% of African Americans in a study had a SNP (mutation) at Leu41 in GRK5. Only 2% to 3% of participants of European or Chinese descent had this variant. The  -receptors of the individuals were normal, but G- protein receptor-coupled kinase 5 (GRK5), a terminator of  - receptor activity, had a polymorphism which affected drug response

66 From: Dr. K’s lecture #4 on GPCR, slide 49 GDP P P GRK E E E E GP GDP GP GTGPDP GP GTP GP GTP E GP GDP P P E Arrestin GP GDP PiPi G-protein receptor kinase/  -arrestin mediated termination of signaling G-protein receptor kinase (GRK)

67 III.B. Pharmacokinetics: Abnormalities in biotransformation processes Abnormalities – SNP mutations can be at any stage of biotransformation process Examples: 1.6-MP 2.Alcohol 3.Adverse drug reactions to Cyp-450 family of enzymes 1.Calcium channel blockers 2.Isoniazid ©2005 Gus Rosania

68 1. SNP Mutation in TPMT, an enzyme involved in 6MP (6-mercaptopurine) metabolism, affects apparent quantal dose-response distribution 6MP is an immunosuppressive drug also used for leukemia and cancer treatment TGN is active metabolite; MeMP is inactive TPMT: thiopurine S-methyltransferase converts 6MP to inactive metabolite Normal (‘WT’) TPMT has high activity. Mutated TMPT has very low activity. Individuals who are heterozygotes (1 WT, 1 mutant gene) have intermediate activity

69 6-MP dose is adjusted based on TPMT Genetic Polymorphism 5-10% of normal dose Evans, SJCRH, 2000.

70 2. An SNP causes variability in alcohol metabolism ALDH2 maintains low blood levels of acetaldehyde. Acetaldehyde produces “hangover” symptoms, sometimes called “Asian Flush” or “Oriental Flushing Syndrome”. ALDH2*2, a mutant form of aldehyde dehydrogenase, has a lysine E482K replacement. Homozygous individuals have almost no ALDH2 activity, and heterozygous individuals have reduced activity. Mutation is common in Japan, where 41% are ALDH2 deficient; Taiwan with 30%. AlcoholAldehyde dehydrogenase (ADH) dehydrogenase (ALDH2)

71 3. Pharmacokinetics: Abnormalities in CYP450 family Cytochrome p450s (CYP) enzymes alter the chemical structure of many drugs for elimination. Over 50 cyp450 genes expressed in different tissues of the body Genetic differences in cyp450 structure, expression and function lead to differences in drug and nutrient absorption and clearance. Genetic differences in cyp450 are responsible for some of the variability of ADR among ethnic groups

72 Individual Cyp450 enzymes vary in expression, induction, and SNP Zanger & Schwag. Pharmacology & Therapeutics. Vol 138, 103–141, 2013. Do not memorize

73 Example: CYP3A4 SNP determine blood levels of nifedipine (calcium channel blocker) in different ethnic groups after same dose ©2005 Gus Rosania Slow metabolizers, CYP3A4 gene

74 Example: Blood levels of isoniazid (TB medication) vary 100-fold in population of individuals receiving same dose. Patients with high levels likely to develop toxic effects Levine, Fig 11-4

75 Isoniazid can be metabolized through two pathways ©2005 Gus Rosania – Isoniazid acetylated by NAT2 enzyme results in non-toxic metabolites – Isoniazid metabolized through Cyt p450 results in toxic metabolites

76 Blood levels of isoniazid are determined by enzymes found in individuals – which vary by population CaucasianAfrican-AmericanAsian NAT40-70%50-60%10-15% CYP2D6 poor metabol.6-10%5%1% CYP2C19 poor metabol.2%4-18%12-23% CYP2C9 poor metabol.14-37%0-8%0-1% ©2005 Gus Rosania – ADR to isoniazid vary in geographic groups: 44-54% of American Caucasians and African Americans 60% of Europeans 5% of Eskimos

77 Future trends in Pharmacogenetics – Investigation and identification of genetic basis for unusual drug responses – Development of methods for predicting who will react abnormally – Check family members and relatives – Tailor drug prescriptions to individuals

78 End goal of pharmacogenetics is ‘personalized medicine’ – each individual’s genome will be sequenced and drugs type and dose can be adjusted for that individual

79 THE END Hope you find what you learned here helpful no matter what career you pursue! Thanks for being a great class!!!