Diagnostics/Therapeutics Flashcards
Difference between pharmacodynamics and pharmacokinetics
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)
Describe the following relationship between drug-receptor binding and pharmacologic response: 1. Agonism 2. Partial Agonism 3. Antagonism A. Competitive B. Noncompetitive
- Agonism: drug binds receptor and induces response –> mimics the action of endogenous compound to produce response
- Partial agonism: drug binds receptor and induces only a partial (not maximal) response
- 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
What are the axes of the graded dose-response curve?
How does the curve change with respect to:
- Competitive antagonist
- Noncompetitive antagonist
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
- Competitive: higher EC50, unchanged Emax
- Noncompetitive: unchanged EC50, lower Emax
What is the difference between potency and efficacy?
Which concept influences drug selection and which influences amount of drug administered?
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)
Describe other mechanisms of antagonism:
- Chemical
- Physiologic
- Pharmacokinetic
- Chemical - one drug antagonizes by binding and inactivating second drug
- Physiologic - prescribe second drug to oppose the effects of the first (e.g. insulin to combat increased blood sugar of glucocorticoids)
- Pharmacokinetic - one drug antagonizes or promotes the elimination of the second
- What are spare receptors?
- 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
- 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
- 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
What are quantal dose-response curves?
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
What is the therapeutic index?
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
What are the major routes by which drugs are eliminated from the body?
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
Describe the major phase I and phase II drug metabolic reactions and the principal classes enzymes involved in catalyzing these reactions
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
What is the first pass effect?
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)
Describe how the metabolism of acetaminophen (Tylenol®) can result in hepatotoxic metabolites as well as the metabolic pathway that detoxifies these metabolites.
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
Using the anti-tubercular drug isoniazid as an example, describe how genetic differences amongst individuals can influence drug metabolism.
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
Describe the factors that can affect drug metabolism and how these factors influence therapeutic choice
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
Describe metabolic enzyme induction and inhibition
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
What is the effect of the following on drug metabolism:
1) Drug-drug interactions
2) Disease
3) Gender and age
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
Herbal Supplement: Echinacea
1) Uses
2) Adverse effects
3) Drug interactions
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)
Herbal Supplement: Garlic
1) Uses
2) Adverse effects
3) Drug interactions
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
Herbal Supplement: Gingko
1) Uses
2) Adverse effects
3) Drug interactions
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
Herbal Supplement: Ginseng
1) Uses
2) Adverse effects
3) Drug interactions
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
Herbal Supplement: Milk Thistle
1) Uses
2) Adverse effects
3) Drug interactions
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
Herbal Supplement: St. John’s Wort
1) Uses
2) Adverse effects
3) Drug interactions
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)
Herbal Supplement: Saw Palmetto berries
1) Uses
2) Adverse effects
3) Drug interactions
Saw Palmetto Berries
1) Uses: benign prostate hyperplasia (lowers DHT levels)
2) Adverse effects: decreased libido, abdominal pain, nausea
3) Interactions: None
Herbal Supplement: Coenzyme Q10
1) Uses
2) Adverse effects
3) Drug interactions
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)
Herbal Supplement: Glucosamine
1) Uses
2) Adverse effects
3) Drug interactions
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
Herbal Supplement: Melatonin
1) Uses
2) Adverse effects
3) Drug interactions
Melatonin
1) Uses: induce sleep, jet lag, contraceptive
2) Adverse effects: drowsiness, fatigue, headache
3) Interactions: careful with antiHTN meds and may reduce warfarin
List the mechanism, common uses, utility, and toxicity of the following imaging modalities:
1) X-ray
2) Ultrasound
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
List the mechanism, common uses, utility, and toxicity of the following imaging modalities:
3) Angiography, contrast
4) Nuclear medicine
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)
List the mechanism, common uses, utility, and toxicity of the following imaging modalities:
5) CT +/- contrast
6) MRI +/- gadolinium
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
- Estimate the magnitude of the risk of malignancy from radiation and list its influences
- Which populations are at higher risk from imaging?
- link between low/moderate radiation exposure and cancer
20 mSv yearly recommended occupationally
chest X-ray 0.02 mSv
CT 7-20 mSv - Age is biggest influence - young people more at risk for radiation
Define and describe importance of indicentaloma.
Define overdiagnosis
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
Define:
1) Gold standard
2) Accuracy vs Precision
3) Reference range
4) ROC Curve
5) POC testing
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
What is the difference between diagnostic and screening tests?
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
Describe the 3 phases of diagnostic testing
- Pre-analytic phase
- Analytic phase
- Post-analytic phase
- Pre-analytic phase: develop question, select and order test, collect specimen 70% errors in this phase e.g. labeling, incorrect collection tube
- Analytic phase: prepare, analyze sample + verify result
- Post-analytic phase: report and analyze result
Autopsy: When, how, and why are autopsies performed?
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
Describe the limitations of different study types and how they affect results:
I. Observational
II. RCT
III. Meta-analysis
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)
What are the following studies best used for?
- Bench/animal research
- Case series
- Case-control
- Cohort
- Big data
- RCT
- Systematic review/meta-analysis
- Bench/animal research –> hypothesis generating
- Case series (tracks exposure) –> hypothesis generating; pointing out new threats e.g. Zika
- 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
- 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
- Big data –> retrospective cohort, good for hypothesis generation or testing; only have data available so potensh missing info
- 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
- Systematic review/meta-analysis –> hypothesis testing; cheaper but dependent on quality of data
Describe the factors involved in absorption of an orally administered drug from across GI epithelial membrane (stomach lumen –> plasma)
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
- 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
What is the pH partition hypothesis? Explain for weak acid and weak base (pKa=3) between stomach lumen (pH=1) and plasma (pH=7)
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
Define and describe the inter-relationship between drug bioavailability, bioinequivalence, therapeutic inequivalence, and therapeutic index.
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)
When can use of generic drug be problematic?
1) The two preparations are bioinequivalent (different bioavailabilities)
2) Drug has low therapeutic index
What are the main reasons for administering a drug through IV (parenterally)?
- 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
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
Total body water = Extracellular fluid (plasma + interstitial fluid IF) + Intracellular fluid ICF
- 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 - Total Body Water
- gender - males have more water than females
- age - age decreases % of water
- body composition - more lipid e.g. obesity decreases % water
What is volume of distribution Vd? What factors affect it?
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
Describe methods of drug elimination and role of the kidneys.
How can you affect reabsorption step?
Clearance is parameter of drug elimination
- Drug metabolism - liver reduces lipid solubility –> promotes bile/renal excretion
- 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
Describe the interactions between the following:
- St John’s wort and cyclosporine
- Grapefruit juice and oxycodone
- NNRTI and itraconazole
- Sucralfate and cipro
- Genetic allele SLCO1B1 on pitavastatin
- 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
- Grapefruit juice and oxycodone: Grapefruit juice inhibits CYP3A4 –> affects pharmacodynamics –> negative effects from prolonged exposure to oxycodone
- NNRTI and itraconazole: NNRTIs induce CYP3A4 –> lower concentration itraconazole to treat fungal infections; meanwhile, protease inhibitors inhibit CYP3A4
- Sucralfate and cipro: Sucralfate is aluminum-containing antacid –> binds cipro and makes it impermeable –> cannot be absorbed across membrane –> Reduces bioavailability
- Genetic allele SLCO1B1 on pitavastatin: people homozygous for this allele –> less hepatic absorption –> higher plasma concentrations of pitavastatin –> skeletal toxicity/muscle damage
Describe the drug discovery and development process
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
Describe the goals and designs of the following phases of clinical trials: Phase 0 Phase 1 Phase 2 Phase 3 Phase 4
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)
- Define the placebo/nocebo effect.
- Which types are most effective?
- What outcomes do they influence the most?
- 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
- Pill placebos less effective than placebo surgery, injections, topicals, and acupuncture
- Placebos influence graded, subjective outcome (e.g. pain, depression on 1-10 scale) more than dichotomous, objective outcomes
Describe the magnitude of the placebo effect
Describe mechanisms and influences
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
- Which studies need a placebo arm in order to be valid? 2. In which studies would placebo arm be unethical?
- Outcome-based
studies with graded, subjective outcome need placebo arm (vs an untreated arm) to be valid - 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
