Diagnostics/Therapeutics

Question 1

Difference between pharmacodynamics and pharmacokinetics

Answer 1

Pharmacodynamics - what the drug does to your body e.g. at site of action (Efficacy, toxicity)

Pharmacokinetics - what your body does to the drug (absorption, distribution, elimination)

Question 2

Describe the following relationship between drug-receptor binding and pharmacologic response: 
1. Agonism 
2. Partial Agonism
3. Antagonism 
A. Competitive
B. Noncompetitive

Answer 2

1. Agonism: drug binds receptor and induces response –> mimics the action of endogenous compound to produce response
2. Partial agonism: drug binds receptor and induces only a partial (not maximal) response
3. Antagonism: drug binds to receptor and acts as blocker –> blocks actions of endogenous agonists –> does not produce response
   A. Competitive - competes with agonist for reversible binding; depends on plasma level of antagonist and affected by changes in endogenous agonist levels
   B. Noncompetitive - irreversible binding; bound receptors are inactive; not affected by endogenous agonist levels but overdose is v dangerous

Question 3

What are the axes of the graded dose-response curve?

How does the curve change with respect to:

1. Competitive antagonist
2. Noncompetitive antagonist

Answer 3

X-axis: log of concentration of the drug [D]
Y-axis: Effect of the drug, influenced by the total number of receptors
plateaus at Emax - maximal effect of drug
inflection point is EC50 - [D] to give 50% of Emax

1. Competitive: higher EC50, unchanged Emax
2. Noncompetitive: unchanged EC50, lower Emax

Question 4

What is the difference between potency and efficacy?

Which concept influences drug selection and which influences amount of drug administered?

Answer 4

Potency - how much drug is required to elicit a response; lower EC50 –> higher potency

Efficacy - maximal effect, determined by Emax; partial agonists are always less efficacious (lower Emax) than agonists

Drug selection based on efficacy (Emax) and potential side effects
Amount of drug administered based on potency (EC50)

Question 5

Describe other mechanisms of antagonism:

1. Chemical
2. Physiologic
3. Pharmacokinetic

Answer 5

1. Chemical - one drug antagonizes by binding and inactivating second drug
2. Physiologic - prescribe second drug to oppose the effects of the first (e.g. insulin to combat increased blood sugar of glucocorticoids)
3. Pharmacokinetic - one drug antagonizes or promotes the elimination of the second

Question 6

1. What are spare receptors?
2. Specify whether a tissue contains spare receptors for an agonist based on the impact of an irreversible antagonist on the graded dose-response curve of the agonist

Answer 6

1. Spare receptors - more receptors than are needed for a maximal response –> increase likelihood of drug being bound even at low concentrations –> increase tissue sensitivity to drug
2. When antagonist is added - first appears to be noncompetitive (EC50 increases, Emax the same) bc spare receptors are getting used up; once spare receptors are used –> Emax declines, EC50 unaffected

Question 7

What are quantal dose-response curves?

Answer 7

quantal - either/or, Y/N outcome
quantal dose response curve - plot of % individuals responding vs log[D]
ED50 - effective dose at which 50% of individuals exhibit quantal (Y/N) response

work around the limitations of graded E vs log[D] dose
response curves; can get information on TI through Phase I and II Clinical trials

Question 8

What is the therapeutic index?

Answer 8

Therapeutic index (TI) - margin of safety of a drug; ratio of dose required to produce toxic effect / effective dose

TI = TD50/ED50 (Toxic dose in 50% of case / effective dose in 50% of cases)

want wide TI - at least 10x

Question 9

What are the major routes by which drugs are eliminated from the body?

Answer 9

Excreted through kidney (renal) unchanged, but not lipophilic drugs bc they get reabsorbed

Metabolism / Biotransformation of drugs into hydrophilic/polar metabolites by the same pathways that we deal with foreign invaders
-metabolism alters pharmacodynamic (inactivates) and pharmacokinetic (increases clearance) properties of drugs, detoxifies

Question 10

Describe the major phase I and phase II drug metabolic reactions and the principal classes enzymes involved in catalyzing these reactions

Answer 10

Phase I - functionalization rxns, exposure polar functional group on parent compound
Enzymes: cytochrome P450 CYP; high lipid solubility and low substrate specificity

Phase II - conjugation rxns, join endogenous compounds to Phase I products to yield polar and chemically inactive conjugates
Enzymes: transferase - most common UGT (glucuronidation) and GST (glutathione conjugation)

liver is primary site of drug metabolism, also the kidneys, skin, lungs, and GI tract

Question 11

What is the first pass effect?

Answer 11

After being taken orally, drugs are transported via portal system to the liver –> metabolized in liver –> systemic circulation

limits oral bioavailability of drugs that are highly metabolized and therefore inactivated by the liver –> need to be administered parenterally (IV)

Question 12

Describe how the metabolism of acetaminophen (Tylenol®) can result in hepatotoxic metabolites as well as the metabolic pathway that detoxifies these metabolites.

Answer 12

Acetaminophen has different possible pathways - 2 phase II and 1 phase I hydroxylation into a reactive electrophilic compound - hepatotoxic (can react with liver proteins and shut down liver)

Glutathione conjugation shuts neutralizes - pee out as sulfur-containing mercapturate compound

tylenol OD is so dangerous bc even if you pump out the drug, still hepatotoxic metabolite in your system; antidotes are glutathione analogs cysteamine or N-acetylcysteine

Question 13

Using the anti-tubercular drug isoniazid as an example, describe how genetic differences amongst individuals can influence drug metabolism.

Answer 13

Metabolism of INH: 1) Phase II reaction first - acetylation; 2) Then Phase I - hydrolysis

leads to harmless product and an electrophilic metabolite that reacts with proteins in hepatocytes –> hepatoxicity; metabolite is neutralized by glutathione

individual differences in metabolic rate e.g. polymorphism of NAT2 gene –> NAT2 enzyme used in 1st step of metabolism

2 alleles of slow NAT2 –> slow acetylators –> need lower dosage or higher dosing interval; MUST do genetic screen before prescribing INH

Question 14

Describe the factors that can affect drug metabolism and how these factors influence therapeutic choice

Answer 14

Genetic factors: defects, polymorphisms
Non-genetic factors: Age and gender, disease
Environmental: dietary e.g. drinking/smoking, environmental e.g. pollutants, drug-drug e.g. inhibition or induction

Question 15

Describe metabolic enzyme induction and inhibition

Answer 15

Induction - induces CYP genes –> increases amount of CYP enzymes –> increases metabolism rates e.g. cigarettes, alcohol, broccoli, chargrilled food

Inhibition - inhibits CYP enzymes –> decreases metabolism rates e.g grapefruit juice

Question 16

What is the effect of the following on drug metabolism:

1) Drug-drug interactions
2) Disease
3) Gender and age

Answer 16

1) Drug-drug interactions - can inhibit or induce metabolizing enzymes

2) Disease: liver diseases (hepatitis, cirrhosis, cancer) + cardiac disease (through limited blood flow) –> diminish metabolism of some drugs
heavy metal poisoning + porphyria –> impair activity of metaboliz enzymes –> impair hepatic drug metabolism

3) Gender and age: very young and very old patients metabolize more slowly; some OCPs are irreversible inhibitors of CYPs

Question 17

Herbal Supplement: Echinacea

1) Uses
2) Adverse effects
3) Drug interactions

Answer 17

Echinacea
1) Uses: boosts immune system antibacterial//fungal/viral –> decreases duration and symptoms of common cold

2) Adverse effects: flu-like symptoms, GI upset, rash
3) Drug interactions: avoid if immunosuppressed (AIDS, cancer, TB, or transplant drugs)

Question 18

Herbal Supplement: Garlic

1) Uses
2) Adverse effects
3) Drug interactions

Answer 18

Garlic
1) Uses: inhibits HMG COA reductase –> cholesterol reduction, BP, triglycerides; reduced vascular plaque accumulation/antiplatelet

2) Adverse effects: naseau, hypotension, allergy, bleeding
3) Interactions: Avoid if on anti-clotting medications (warfarin, ibuprofen) - can cause bleeding; monitor BP

Question 19

Herbal Supplement: Gingko

1) Uses
2) Adverse effects
3) Drug interactions

Answer 19

Gingko
1) Uses: Increased blood flow and tissue perfusion –> reduction in peripheral vascular disease

2) Adverse effects: avoid in those with seizures
3) Interactions: Avoid if on anti-clotting medications (warfarin, ibuprofen); monitor BP

Question 20

Herbal Supplement: Ginseng

1) Uses
2) Adverse effects
3) Drug interactions

Answer 20

Ginseng
1) Uses: anti platelet, boost immune system and glucose homeostasis, anticancer, cardioprotective

2) Adverse effects: vaginal bleeding, CNS overstimulation, HTN with high doses
3) Interactions: Avoid if on anti-clotting medications, immunocompromised, immunosuppressants

Question 21

Herbal Supplement: Milk Thistle

1) Uses
2) Adverse effects
3) Drug interactions

Answer 21

Milk Thistle:
1) Uses: hepatic repair, induce lactation in mothers, inhibit cancer cell growth, mushroom poisoning

2) Adverse effects: rare; laxative at high doses
3) Interactions: None

Question 22

Herbal Supplement: St. John’s Wort

1) Uses
2) Adverse effects
3) Drug interactions

Answer 22

St. John’s Wort
1) Uses: antidepressant

2) Adverse effects: photosensitization, mania, autonomic arousal
3) Interactions: Don’t use with antidepressants, induces CYP enzymes (leads to low levels of digoxin, OCP, etc)

Question 23

Herbal Supplement: Saw Palmetto berries

1) Uses
2) Adverse effects
3) Drug interactions

Answer 23

Saw Palmetto Berries
1) Uses: benign prostate hyperplasia (lowers DHT levels)

2) Adverse effects: decreased libido, abdominal pain, nausea
3) Interactions: None

Question 24

Herbal Supplement: Coenzyme Q10

1) Uses
2) Adverse effects
3) Drug interactions

Answer 24

Coenzyme Q10
1) Uses: antioxidant; treat HTN and heart failure, ischemic heart disease; BP reduction

2) Adverse effects: GI upset, diarrhea, nausea, heartburn, anorexia
3) Interactions: can reduce effects of warfarin (similar to Vitamin K)

Question 25

Herbal Supplement: Glucosamine 1) Uses 2) Adverse effects 3) Drug interactions

Answer 25

Glucosamine 1) Uses: pain associated with knee arthritis 2) Adverse effects: cannot be tolerated by those with shellfish allergies 3) Drug interactions: increase INR for those on warfarin --> increased bruising/bleeding

Question 26

Herbal Supplement: Melatonin 1) Uses 2) Adverse effects 3) Drug interactions

Answer 26

Melatonin 1) Uses: induce sleep, jet lag, contraceptive 2) Adverse effects: drowsiness, fatigue, headache 3) Interactions: careful with antiHTN meds and may reduce warfarin

Question 27

List the mechanism, common uses, utility, and toxicity of the following imaging modalities: 1) X-ray 2) Ultrasound

Answer 27

``` 1) X-ray A. Mechanism: X-ray, 2D B. Common uses: chest, abdomen, bone C. Utility: fairly cheap; air is dark and bone is white but not good at differentiating between organs and fluid D. Toxicity: radiation, minimal ``` 2) Ultrasound A. Mechanism: sound wave reflection, 2D - sound is reflected back by air and hard objects but travels through fluid B. Common uses: heart, gallbladder, pregnancy C. Utility: differentiating fluid vs solid; problem is visualizing lots of bone (skull) or air (lungs); fairly cheap D. Toxicity: thought to be none

Question 28

List the mechanism, common uses, utility, and toxicity of the following imaging modalities: 3) Angiography, contrast 4) Nuclear medicine

Answer 28

3) Angiography A. Mechanism: X-ray with intravascular contrast (dye added into blood vessel), can be 2D or 3D B. Common uses: atherosclerosis (dilate narrowed artery), bleeding (can inject clotting substance) C. Utility: differentiates blood in vessel from rupture from surrounding tissues; v expensive D. Toxicity: high radiation; potential contrast allergy, vessel puncture 4) Nuclear Medicine A. Mechanism: give radiation emitting material and then can for emission, 2D B. Common uses: myocardium, PE, cancer/inflammation; V/Q perfusion C. Utility: differentiates tissues with more vs less uptake, fairly expensive D. Toxicity: high radiation (though less than CT)

Question 29

List the mechanism, common uses, utility, and toxicity of the following imaging modalities: 5) CT +/- contrast 6) MRI +/- gadolinium

Answer 29

5) CT A. Mechanism: X-ray slices to give 3D image B. Common uses: trauma, brain ,tumors C. Utility: differentiates tissues with more gradations of density --> clearer pictures; contrast can pick up increased blood flow/inflammation, but v expensive D. Toxicity: v high radiation 6) MRI A. Mechanism: 3D magnetic resonance imaging B. Common usesL brain, spinal cord C. Utility: differentiates tissues by water content and arrangement (NOT density); gadolinium highlights areas of inflammation D. Toxicity: long-term thought to be N/A

Question 30

1. Estimate the magnitude of the risk of malignancy from radiation and list its influences 2. Which populations are at higher risk from imaging?

Answer 30

1. link between low/moderate radiation exposure and cancer 20 mSv yearly recommended occupationally chest X-ray 0.02 mSv CT 7-20 mSv 2. Age is biggest influence - young people more at risk for radiation

Question 31

# Define and describe importance of indicentaloma. Define overdiagnosis

Answer 31

Imaging studies show abnormalities that have nothing to do with reason test was performed and would not have caused problems in patient's lifespan --> Receive lot more imaging and radiation and also invasive testing related concept is overdiagnosis - diagnosis and treatment of illness that would never have caused symptoms or death in that patient

Question 32

# Define: 1) Gold standard 2) Accuracy vs Precision 3) Reference range 4) ROC Curve 5) POC testing

Answer 32

1) Gold standard - diagnosis test or benchmark that is best available under reasonable conditions e.g. mass spec for Vitamin D 2) Accuracy vs Precision A. Accuracy - correctness B. Precision - reproducibility 3) Reference range - normal range (+/- 2 SDs i.e. 95% of normal health individuals results) or less than/greater than certain value --> more tests you run, more likely one will return abnormal result e.g. 3 tests --> 1-(0.95^3) --> 15% chance that at least one test is out of reference range 4) ROC curve - curve to compare diagnostic test performance at different cut off points --> illustrates tradeoff between sensitivity and specificity (increase in sensitivity --> increase in FP --> decrease in specificity) 5) Point of Care testing - medical testing at/near site of patient care; usually involve blood/urine testing and can be done in short period of time BUT need to do it correctly to get accurate and reliable results

Question 33

What is the difference between diagnostic and screening tests?

Answer 33

Screening test - IDing asymptomatic individuals who may have disease --> V sensitive (ability of test to detect disease, so its okay to have false positives) Diagnostic test --> determine presence/absence of disease when subject shows signs/symptoms --> V specific (ability to detect absence of disease --> only want to get the people who actually have disease) -performed after positive screening to establish definitive diagnosis e.g. Pap smear --> biopsy; quad screen --> amniocentesis; fasting blood sugar --> glucose tolerance

Question 34

Describe the 3 phases of diagnostic testing 1. Pre-analytic phase 2. Analytic phase 3. Post-analytic phase

Answer 34

1. Pre-analytic phase: develop question, select and order test, collect specimen *70% errors in this phase e.g. labeling, incorrect collection tube* 2. Analytic phase: prepare, analyze sample + verify result 3. Post-analytic phase: report and analyze result

Question 35

Autopsy: When, how, and why are autopsies performed?

Answer 35

I. When Hospital autopsy post hospital death, upon request of kin Medical Examiner autopsy when death is unusual, w/in 24 hrs, violent, public health concern; no consent needed II. How Virchow: organs removed one by one Rokitansky: organs removed en masse ``` III. Why quality assessment (was diagnosis of death correct?), instruction, investigation, discovery ``` *autopsy rate has declined due to new diagnostic tools, concern of malpractice, lack of interest, no longer a requirement

Question 36

Describe the limitations of different study types and how they affect results: I. Observational II. RCT III. Meta-analysis

Answer 36

I. Observational - confounding by indication - did drug itself cause bad side effect or do doctors prescribe drug to sick people? - selection bias - people with exposure different in some ways from people without exposure - recall bias - ascertainment - patients who are sicker have more tests --> more likely to find a disease - lead time bias - people live longer with screening bc disease found earlier; if screening is associated with disease risk factor, can influence results II. RCTs - expensive and time-consuming - not enough power --> more likely to make Type II (FN) error - randomization/concealment issues - inadequate blinding/placebo - early stopping for benefit/harm - intention to treat is better than per protocol analysis *except for non-inferiority RCT III. Meta-analysis - garbage in= garbage out - smaller trials have larger effect sizes than larger trials (only publish if they have good results)

Question 37

What are the following studies best used for? 1. Bench/animal research 2. Case series 3. Case-control 4. Cohort 5. Big data 6. RCT 7. Systematic review/meta-analysis

Answer 37

1. Bench/animal research --> hypothesis generating 2. Case series (tracks exposure) --> hypothesis generating; pointing out new threats e.g. Zika 3. Case-control (comparison groups based on outcome)--> hypothesis generating or testing; most subject to confounding/bias, good for uncommon outcomes; do only if you have no other options 4. Cohort (comparison groups based on exposure)--> (retrospective) diagnosis or prognosis questions; good for risky exposures but subject to LTFU and confounding; (prospective) diagnosis or prognosis - determining test characteristics e.g sensitivity, specificity, or how good a prognostic marker is; more expensive/timely but more complete data e.g. Framingham heart study 5. Big data --> retrospective cohort, good for hypothesis generation or testing; only have data available so potensh missing info 6. RCT --> hypothesis testing best for looking at any type of interventions (whether treatment or screening) --> what course of action will lead to better outcomes?; least confounding but expensive/timely, limits to therapeutic equipoise 7. Systematic review/meta-analysis --> hypothesis testing; cheaper but dependent on quality of data

Question 38

Describe the factors involved in absorption of an orally administered drug from across GI epithelial membrane (stomach lumen --> plasma)

Answer 38

1) Active transport - Hydrophilic/charged drugs pass via protein carrier (ATP consumed) 2) Passive transport - more common, less selective; hydrophobic drugs can pass since they are not charged; small hydrophilic drugs can pass through protein pores 3) Higher P value (lipid-to-water partition coefficient) --> more readily drug passes through GI membrane 4. pKa of a drug - weak acids/bases can only go across if uncharged --> protonated (acid) or unprotonated (base) * drug accumulates in whichever compartment it is ionized the most Oral drug most often absorbed in intestine and NOT stomach - bc more blood flow + greater surface area; absorption slowed by presence of food

Question 39

What is the pH partition hypothesis? Explain for weak acid and weak base (pKa=3) between stomach lumen (pH=1) and plasma (pH=7)

Answer 39

I. Weak Acid: Distribution of drug will proceed until uncharged form of drug achieves equal concentration in both water components of the body In stomach lumen, drug is in form HA and is pulled into plasma --> in the high pH, it becomes ionized into A- and cannot leave II. Weak Base: Mostly in BH+ form in lumen, small amount in form B pulled into plasma --> weak bases not absorbed from stomach, but rather from intestine where pH is higher

Question 40

Define and describe the inter-relationship between drug bioavailability, bioinequivalence, therapeutic inequivalence, and therapeutic index.

Answer 40

Oral bioavailability - % of drug that gains access to systemic circulation in chemically unaltered form Decreased by A. first pass hepatic transformation - oral drugs absorbed in intestine --> portal circulation --> altered and inactivated in the liver B. hydrophilicity C. Altered by enzymes/low pH of GI tract D. Bioinequivalence - drug preparations differ to the point that their bioavailabilities also differ; common in hydrophobic steroids Therapeutic inequivalence - bioinequivalence of 2 drug preparations leads to difference in therapeutic outcome Whether bioinequivalence will be a problem is based on therapeutic index (TI = TD50/ED50)

Question 41

When can use of generic drug be problematic?

Answer 41

1) The two preparations are bioinequivalent (different bioavailabilities) 2) Drug has low therapeutic index

Question 42

What are the main reasons for administering a drug through IV (parenterally)?

Answer 42

- hydrophilic drugs that are not well absorbed in GI tract - also bases with pKa > 2 units from the pH (stomach = 1, small intestine = 5.3) - metabolically labile drugs e.g. insulin that would be degraded by the GI tract - drugs that have high metabolism by liver (first pass effect) - increased speed of action e.g. anti-arrhythmic agents - maximal control of plasma concentration - can reach peak plasma concentration and maintain

Question 43

Describe the factors that affect distribution of drug throughout the body (when in general circulation, whether through IV or oral) Describe factors that affect total body water

Answer 43

Total body water = Extracellular fluid (plasma + interstitial fluid IF) + Intracellular fluid ICF 1. Drug distribution - high molecular weight drugs - trapped in plasma - low molecular weight drugs - small hydrophilic can enter interstitial fluid but not intracellular fluid; small hydrophobic can enter all three (plasma, IF, and ICF) - hydrophobic drugs (weak acids) that bind to plasma proteins e.g. albumin - inert and cannot enter IF or ICF 2. Total Body Water - gender - males have more water than females - age - age decreases % of water - body composition - more lipid e.g. obesity decreases % water

Question 44

What is volume of distribution Vd? What factors affect it?

Answer 44

Vd- volume constant that describes how drugs partition into volumes different in size than body's water compartments (~42L) - movement from plasma to elsewhere in the body Vd (in L)= Ab/Cpl where Ab=total amount of drug in body and Cpl = plasma concentration of the drug (Free + bound) Affected by: - body composition - lipophilic drug has higher Vd in obese person - pathological hemodynamics - preferential distribution into well perfused areas - polypharmacy - use of several drugs concurrently --> competition for albumin --> altered distribution displacing plasma proteins will increase Vd because Cpl decreases

Question 45

Describe methods of drug elimination and role of the kidneys. How can you affect reabsorption step?

Answer 45

Clearance is parameter of drug elimination 1. Drug metabolism - liver reduces lipid solubility --> promotes bile/renal excretion 2. Renal elimination - unmetabolized drugs through renal system A. glomerulus filtration into urine - only free drugs, max GFR=125 mL/min B. proximal tubule into urine - active process --> protein carriers can filter out free or previously protein-bound drugs; separate carrier systems for acids and bases C. distal tubule reabsorption into blood (of lipophilic drugs) - passive diffusion of free, unionized drugs back into the blood Increasing clearance in reabsorption step: A. Administer bicarbonate (HCO3-) --> alkalinizes urine --> more acid in form A- --> cannot cross back into the blood B. Administer ammonium chloride (NH4Cl) --> acidifies urine --> more base in form BH+ --> cannot cross back into blood

Question 46

Describe the interactions between the following: 1. St John's wort and cyclosporine 2. Grapefruit juice and oxycodone 3. NNRTI and itraconazole 4. Sucralfate and cipro 5. Genetic allele SLCO1B1 on pitavastatin

Answer 46

1. St John's wort and cyclosporine: SJW induces CYP3A4 and stimulates P-gp pump --> more metabolism and drug efflux --> reduces plasma concentration and bioavailability of cyclosporine 2. Grapefruit juice and oxycodone: Grapefruit juice inhibits CYP3A4 --> affects pharmacodynamics --> negative effects from prolonged exposure to oxycodone 3. NNRTI and itraconazole: NNRTIs induce CYP3A4 --> lower concentration itraconazole to treat fungal infections; meanwhile, protease inhibitors inhibit CYP3A4 4. Sucralfate and cipro: Sucralfate is aluminum-containing antacid --> binds cipro and makes it impermeable --> cannot be absorbed across membrane --> Reduces bioavailability 5. Genetic allele SLCO1B1 on pitavastatin: people homozygous for this allele --> less hepatic absorption --> higher plasma concentrations of pitavastatin --> skeletal toxicity/muscle damage

Question 47

Describe the drug discovery and development process

Answer 47

Can take 15+ years and 1.2B+ dollars Discovery: develop assays --> ID lead compound --> optimize drug properties to give "proof of concept" molecule Preclinical: safety assessment, toxicology, pharmacology --> R&D --> regulatory affairs In vitro studies to determine drug's pharmacology In vivo studies to determine efficacy, toxicology, and dose/escalations/schedule Development: ONLY after filing IND with FDA and receiving approval --> can now start phased clinical trials

Question 48

``` Describe the goals and designs of the following phases of clinical trials: Phase 0 Phase 1 Phase 2 Phase 3 Phase 4 ```

Answer 48

Phase 0: tells you likelihood of drug reaching actual target; NO therapeutic benefit Phase 1: 20-100 patients; goal - determine MTD (maximum tolerated dose) --> NO therapeutic goal; tells you about ADME (absorption, distribution, metabolism, excretion); normal healthy volunteers, patients in subpopulations or with target disease, in common clinical settings Phase 2: 100-1000 patients; hypothesis generating, explore endpoints, methodologies for definitive later studies; patients with target disease Phase 3: >1000 patients; confirm efficacy and safety population in broader patient population; generate evidence on benefit/risk relationship for FDA approval Phase 4: pharmacovigilance, postmarket surveillance after FDA NDA approval; to see if drug is safe over time e.g. Vioxx (COX2 inhibitors --> increased thromboxane --> cardiac problems --> drawn from market)

Question 49

1. Define the placebo/nocebo effect. 2. Which types are most effective? 3. What outcomes do they influence the most?

Answer 49

1. Placebo/nocebo effect - non-specific or contextual effects of therapy; placebo=positive, nocebo=negative Total effect = natural history (regression to mean, hawthorne effect, etc) + placebo effect + treatment effect 2. Pill placebos less effective than placebo surgery, injections, topicals, and acupuncture 3. Placebos influence graded, subjective outcome (e.g. pain, depression on 1-10 scale) more than dichotomous, objective outcomes

Question 50

Describe the magnitude of the placebo effect Describe mechanisms and influences

Answer 50

Magnitude: placebo effect can be 50%+ of medication benefit esp with pain and depression outcomes; 30% of subjects discontinue placebo due to side effects (nocebo) --> means that side effects have nothing to do with the medication Mechanisms: - activation of brain areas e.g. Parkinson pill placebos, sham surgery - changes in neurotransmitters - response to pain placebos blocked by naloxone - expectations, experiences, conditioning - e.g. open vs hidden IV pain meds - genetic predisposition - contextual (color, cost, setting) - eg blue vs pink pills - provider-patient relationship

Question 51

1. Which studies need a placebo arm in order to be valid? 2. In which studies would placebo arm be unethical?

Answer 51

1. Outcome-based studies with graded, subjective outcome need placebo arm (vs an untreated arm) to be valid 2. Studies without therapeutic equipoise - where you know no treatment will lead to bad outcome - established treatment exists - in that case compare new therapy can be compared to placebo as add-on therapy