Week 1 Flashcards

Question

Describe how METABOLISM affects drug movement throughout the body.

Answer 1

i) Transformed into a molecule that is: (1) More easily excreted (a) Usually becomes more water soluble (less lipid soluble) (2) Increased or decreased therapeutic action (3) Increased or decreased toxicity ii) Phase I and Phase II Metabolism (1) Phase I metabolism: Oxidation, reduction, and hydrolysis (a) Cytochrome P450 (CYP 450) system (2) Phase II metabolism: Conjugation reactions (a) E.g. glucuronidation, sulfation iii) Prodrugs (1) Inactive compounds that rely on metabolism to become active (2) Example: codeine is not active as codeine, but is metabolized to morphine by CYP2D6 iv) First pass metabolism (1) When oral drugs are absorbed by the GI tract they are carried directly to the liver (a) Some drugs can be completely inactivated on first pass if liver is able to metabolize (2) For this reason some medications cannot be given orally (a) E.g. nitroglycerin v) Hepatic Dose Adjustments (1) For medications metabolized in the liver, may need to adjust the dose in patients with liver dysfunction. (2) Stages of liver disease: Child’s Pugh Score (a) Given points for ascites, encephalopathy, bilirubin, albumin, and prothrombin time (b) Higher points value = worsening liver function

Answer 2

i) Most commonly occurs in the kidneys ii) Steps in renal excretion: (a) Glomerular filtration to passive and active tubular reabsorption to active tubular secretion iii) Renal function (1) Methods of assessing renal function: (a) Estimated glomerular filtration rate (eGFR) (b) Creatinine clearance (CrCl) iv) Renal dosing (1) If patient’s kidneys are not working properly, may need to adjust dose based on renal function to prevent toxicity.

Answer 3

a) Cytochrome P450 (CYP450) enzymes i) Primarily found in the liver ii) Account for 70-80% of the enzymes involved in drug metabolism iii) Examples: (1) CYP3A4 – 50% of drug metabolism (2) CYP2D6 – 25% of drug metabolism (a) Selective serotonin reuptake inhibitors (SSRIs), Tricyclic antidepressants (TCAs), Beta blockers, codeine (3) CYP2C9 (a) Warfarin, antiepileptic drugs (phenytoin), glipizide

Answer 4

i) Children are NOT just small adults ii) Absorption (1) Normal pH around age 2 (2) Normal motility around 6-8 months iii) Distribution (1) Decreased protein binding (2) Adult values between 7 – 12 years (3) More lipid soluble meds may cross BBB iv) Metabolism (1) Increased metabolic rate and clearance for first 2 years (2) Decreased metabolic rate and clearance until puberty v) Elimination (1) Kidney matures around 6 – 12 months

Answer 5

i) absorption (1) May have decreased acid secretion, increased gastric pH, decreased first pass effect leading to increased bioavailability (2) Medications (a) Proton pump inhibitors (b) H2 receptor antagonists (3) Drug interactions (a) Drug-drug (e.g. sucralfate) (b) Drug-food (e.g. tetracyclines with milk) (c) Drug-disease state (e.g. s/p bariatric surgery) ii) distribution (1) Decrease in lean body mass (a) Impact drug volume of distribution (i) Fat soluble medications: duration of action frequently prolonged (e.g. benzodiazepines) (ii) Water soluble drugs: e.g. acyclovir dosed based on ideal or adjusted body weight (2) Decreased blood flow and tissue perfusion (3) Decrease in serum albumin and protein binding iii) Metabolism (1) Changes in hepatic function with aging (a) Decreased hepatic blood flow (especially in heart failure, etc..) (b) Decreased ability to recover from injury (alcohol, hepatitis, etc..) (c) Decreased CYP450 activity with decreasing hepatic function iv) Elimination/Excretion (1) Decreased renal function associated with aging (a) Age-related decrease in creatinine clearance (b) Estimates for renal function based on various equations (i) E.g. eGFR, Cockcroft-Gault (c) Drugs doses and recommendations based on renal function to avoid toxicity

Answer 6

i) Most drugs taken by pregnant women will cross the placenta and expose the developing embryo and fetus to pharmacologic and teratogenic effects ii) Critical factors include: (1) Properties of the drug (2) Rate and amount that crosses placenta (3) Duration of exposure (4) Distribution characteristics in fetal tissues (5) Stage of placental and fetal development iii) Pregnancy Categories (1) Pregnancy categories are being taken away – in future will just have a description of risks/studies

Answer 7

time required for the amount of drug in the body to decrease by 50%

Answer 8

(1) Clearance (2) Volume of distribution (3) Steady state

Answer 9

Takes ~5 half-lives to reach steady state and to get rid of drug from system

Answer 10

Proportion of drug in body to the serum concentration; The volume that the drug would occupy if it were present throughout the whole body at the serum concentration i) Vd= (Amount of drug)/(Serum concentration) ii) High volume of distribution = higher concentrations in tissue iii) Low volume of distribution = higher concentrations in the vascular component

Answer 11

Ratio of LD50 (amount of drug that produces toxicity in 50% of the people taking it) to ED50 (amount of drug that produces the desired effect in 50% of the people taking it) i) Drugs with narrow therapeutic index have a very narrow range between the dose that is effective and the dose that is toxic (1) E.g. phenytoin, warfarin

Answer 12

increase the action of the receptor (1) Reversible or irreversible

Answer 13

decrease the action of the receptor (1) Competitive or noncompetitive (allosteric)

Answer 14

competes with the normal ligand for the receptor, and causes a smaller action/response at the receptor

Answer 15

i) Ion channel receptors (1) Binding changes ion movement (2) E.g. acetylcholine, GABA

Answer 16

ii) G protein coupled receptors (1) E.g. Hormones and slow transmitters e.g. dopamine

Answer 17

iii) Transmembrane Receptors/Enzyme linked receptor (1) Extracellular binding with intracellular enzyme (a) E.g. insulin receptors, platelet-derived growth factor

Answer 18

iv) Intracellular receptors (1) Located in cytosol (2) Migrates to nucleus after binding to signaling molecule to then move to nucleus and control transcription (a) E.g. thyroid hormone and steroids

Answer 19

Agonist: enhances cellular activity; Antagonist: blocks cellular activity

Answer 20

(1) Competitive Inhibitor – binds to same site as substrate (2) Noncompetitive inhibitor – binds to a different site

Answer 21

i) Pharmacological (intrinsic): predictable based on drug’s mechanism of action and is typically dose-related (1) E.g. hypotension from a blood pressure medication; diarrhea from metformin (2) 85-90% of adverse drug reactions ii) Idiosyncratic: unpredictable; mediated by immune system, receptor abnormalities, drug-drug interactions, abnormalities in drug metabolism, pharmaceutical variations, etc. (1) E.g. anaphylaxis, drug rash (2) 10-15% of adverse drug reactions

Answer 22

a) National Institutes of Health – Office of Dietary Supplements (https://ods.od.nih.gov/) i) Dietary Supplement Fact Sheets b) National Center for Complementary and Integrative Health (https://nccih.nih.gov/) c) Natural Medicines Database (https://naturalmedicines.therapeuticresearch.com/) i) Monographs ii) Drug Interaction checker

Answer 23

i) Some supplements can inhibit or induce the CYP450 system, same as prescription medications (1) Example: CYP1A2, 2C9, and 3A4 are responsible for the metabolism of progestins and estrogens in oral contraceptives; St. John’s Wort is an inducer of these CYP450 enzymes= reduces the effectiveness of oral contraceptives by increasing inactive metabolites

Answer 24

i) Some supplements, especially divalent cations (e.g. Ca2+, Mg2+), can slow absorption of certain medications (1) Example: calcium can bind to tetracyclines in the gut, so doxycycline should be taken 2 hours before or 4 hours after calcium supplements

Answer 25

a) The Federal Food, Drug, and Cosmetic Act defines a dietary ingredient as: i) “A vitamin; mineral; herb or other botanical; amino acid; dietary substance for use to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of the preceding substances.”

Answer 26

b) Regulations i) Dietary supplements do not require premarket review or approval by the FDA. ii) Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), manufacturers and distributors of dietary supplements are prohibited from marketing products that are adulterated or misbranded. (1) The manufacturers are responsible for evaluating the safety and labeling of their products before marketing iii) The FDA can remove products from the market, but must first establish that such products are either: (1) Adulterated (the product is unsafe) (a) E.g. contain a potentially unsafe ingredient (2) Misbranded (the labeling is false or misleading) (a) E.g. the label claims that the supplement can cure a disease

Answer 27

c) Good Manufacturing Practices i) The FDA has established good manufacturing practices (GMPs) for dietary supplements to help ensure their identity, purity, strength, and composition. ii) These GMPs are designed to prevent: (1) The inclusion of the wrong ingredient (2) The addition of too much or too little of an ingredient (3) The possibility of contamination (4) The improper packaging and labeling of a product.

Answer 28

d) Independent testing laboratories i) Several independent organizations offer quality testing and allow products that pass these tests to display their seals of approval. (1) Provide assurance that the product was properly manufactured, contains the ingredients listed on the label, and does not contain harmful levels of contaminants. (2) Does not guarantee that a product is safe or effective. ii) Organizations that offer this quality testing include (1) U.S. Pharmacopeia (USP), Consumerlab.com, NSF International

Answer 29

e) Dietary Supplement label i) The FDA requires that dietary supplement labeling include: (1) Name of the product stating that it is a "dietary supplement“ (2) Name and place of business of the manufacturer (3) List of ingredients (4) Net contents

Answer 30

helps determine the likelihood that a adverse reaction is related to a drug

Answer 31

i) FDA Adverse Event Reporting System (FAERS): computerized database of adverse events, medication error reports, and product quality complaints resulting in adverse events (1) Post marketing surveillance system ii) MedWatch (1) How healthcare professionals, consumers, and manufacturers submit reports of adverse drug events (2) https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program

Answer 32

i) If drugs have similar side effects/toxicity, their adverse effects may be compounded if taken together (1) E.g. taking aspirin and warfarin together increases risk of bleeding ii) Some drugs can change the metabolism of other drugs (1) Some drugs can induce enzymes – increase metabolism (2) Some drugs can inhibit enzymes – decrease metabolism

Answer 33

i) Can be inhibited or induced by drugs (1) May change the levels of the drugs that are normally found in the body

Answer 34

i) Understanding how genetic variation contributes to variability in drug pharmacokinetics, pharmacodynamics, and toxicity ii) Enhance drug therapy to maximize efficacy based on individual’s genomic variants iii) Identify optimal doses based on individual’s genomic variants iv) Avoid ADRs

Answer 35

b) Genetic variants i) Allele – one of two or more alternative forms of a gene that arise by mutation ii) Genetic polymorphism: if an allele is common in a population, that gene is considered to be polymorphic iii) Variants of specific genes are numerically and sequentially named (1) Normal/nonmutated copy: “wild-type” (2) Example: (a) Wild-type: CYP2D6 (b) Mutant copy: CYP2D6\*1 iv) Phenotypes: (1) May contribute to pharmacokinetics and pharmacodynamics (2) Variations in drug metabolizing enzymes (e.g. CYP450 enzymes) and drug transporters (e.g. P-gp) affect drug disposition (3) Can have different phenotypes of CYP enzymes: (a) Poor metabolizers (b) Intermediate metabolizers (c) Extensive metabolizers (d) Ultra-rapid metabolizers

Answer 36

c) Warfarin example i) CYP2C9 metabolizes \>90% of active warfarin (1) Variant alleles associated with increased sensitivity to Warfarin (CYP2C9\*2,\*3 - most common variants) ii) Studies have demonstrated how to adjust warfarin dose based on SNP type iii) August 2007, FDA label now provides info regarding altered metabolism in CYP2C9 genetic variants (1) Pharmacogenetic dosing based on testing may help determine initial dose and titration although still a long way off (2) Package insert has recommendations for dosing for specific alleles: https://www.accessdata.fda.gov/drugsatfda\_docs/label/2017/009218s118lbl.pdf

Answer 37

Drugs with FDA label for genetic testing i) 120 drugs identify genetic variability in labeling ii) FDA Table of Pharmacogenomic Biomarkers in Drug Labeling iii) https://www.fda.gov/drugs/scienceresearch/ucm572698.htm iv) Infectious disease (voriconazole) v) Cardiology and hematology (warfarin) vi) Neurology (carbamezapine) vii) Psychiatry (atomoxitine) viii) Oncology (azathioprine)

Answer 38

i) Most pharmacy benefit groups select a drug with the lowest acquisition cost regardless of generic or brand-name status (1) Most insurances have formularies that include “tiers” of coverage, with cheaper medications at lower tiers and more expensive at higher tiers, in general (2) Generic medications are often cheaper (but not always) ii) The FDA Orange Book specifies which mediations are rated as therapeutic equivalents (1) Pharmacists may dispense a generic equivalent for a brand name unless the prescriber specified “Dispense as Written” on the prescription

Answer 39

i) Direct costs – directly attributed to the treatment or disease (1) Medical (e.g. price of medications, health care provider time, diagnostic tests) (2) Nonmedical (e.g. transportation) ii) Indirect costs – derived from morbidity and mortality (1) E.g. loss of income iii) Intangible costs – nonfinancial outcomes (1) E.g. pain, suffering, grief

Answer 40

i) Economic outcomes: costs/benefits ii) Clinical outcomes: medical events iii) Humanistic outcomes: quality of life iv) Can be positive or negative

Answer 41

d) Cost of Illness i) Does NOT include intangible costs – difficult to quantify ii) Example: per the American Diabetes Associate (2013), the cost of diabetes in the US is $327 billion (2017), a 26% increase from previous estimate of $245 billion (in 2012 dollars) ![]()

Answer 42

e) Cost-Minimization (CMA) i) Assumes that evidence supporting efficacy of each alternative already exists and strictly looks at which would be least costly to administer ii) E.g. generic lamotrigine vs. brand name Lamictal ![]()

Answer 43

f) Cost-Effectiveness i) Compares two or more treatments that are NOT therapeutically equivalent ii) Example: lisinopril versus olmesartan ![]()

Answer 44

![]()g) Cost- Benefit (CBA) i) Looks at two separate interventions or programs and determines which produces a greater benefit for the money; often for budgeting purposes ii) Example: determining if an existing anticoagulation program is worth keeping or whether that money would be better spent on a new hypertension clinic or diabetes education program

Answer 45

h) Cost- Utility i) Can be very subjective, so best use if when quality of life is considered the most important factor ii) Example: cancer treatment options ![]()