Pharmacology, Statistics

Question 1

Pharmacokinetics - definition

Answer 1

Movement of a drug throughout the body (what the body does to the drug)

Question 2

Pharmacodynamics - definition

Answer 2

Relationship between drug dosage/ concentration and response (what the drug does to the body)

Question 3

Idiosyncrasy - definition

Answer 3

The principle by which people react differently to different drugs

Question 4

Concentration-time curve

Answer 4

• This graph represents drugs that exhibit first order kinetics
• Ascending curve represents liberation of drug/ dissolution and absorption
• After Tmax (= time that the maximum concentration of drug occurs), metabolism and elimination become rate limiting

• AUC = area under the concentration-time curve
o Reflects degree of systemic exposure from a given drug dosage
o Can be worked out by integrating plasma concentration
o Concentration and time dependent
o Unit g/l/hour

• IV bolus – plasma concentration maximum at T = 0 then rapid fall due to redistribution, then falls slowly due to elimination – E.g. IV diazepam distributes to maximum concentration in brain same as plasma
• Oral medications / some IV – delayed action due to slow distribution to site of action – E.g. IV digoxin distribution to cardiac muscle, no advantage on IV over oral due to delayed effect/distribution
• Once redistribution complete, effects/concentrations related to plasma concentration

Question 5

Absorption - definition

Answer 5

• Definition = extent to which intact drug is absorbed from the gut lumen into the portal circulation
• Expressed as fraction of the dose which is absorbed from the gut

Question 6

First pass metabolism

Answer 6

• Definition = extent to which drug is removed on initial passage through the liver during the first passage of portal blood through the liver into the systemic circulation

• Avoiding 1st pass metabolism
o IM = often faster and more complete than oral
o SC = slower absorption than IM
o Buccal/sublingual = direct absorption into systemic circulation (bypass hepatic portal circuit)
o Rectal = 1/3 systemic (partial avoidance of 1st pass effect)
o Inhalation
o Topical = local effect only
o Transdermal = systemic effect, but slow absorption

Question 7

Bioavailability and bioequivalence

Answer 7

Bioavailability
• Definition = fraction of a drug dose administered by an extravascular route (eg oral/ IM/ SC) that is absorbed into the systemic circulation
o Defined by comparison of AUC following oral dose compared to IV dose
o High bioavailability = 1, low bioavailability = 0
• Affected by
o Absorption
o First pass metabolism
Example
• 100mg dose
• 80mg absorbed intact into portal circulation (fraction 0.8)
• 60mg extracted first pass metabolism (hepatic extraction ratio 0.75), 20mg escapes
• Therefore bioavailability = fraction absorbed x fraction escaping first pass metabolism
o 0.8 x 0.25 = 0.2 = 20%

Bioequivalence
• Definition = clinical definition referring to two formulations of a drug
o Considered to be bioequivalent if the bioavailability means likely to be no clinical difference between effects
o Extent and rate of absorption are not significantly different from that of a standard reference drug administered at the same dose
o Indicates that two drug products, when given to the same patient in the same dosing regimen, results in equivalent concentrations of drug in plasma and tissues.
• Utility
o Compare bioavailability of one drug vs another (eg for generic brands)
• NOTE
o Does NOT work for prodrugs
o Deviation allowed is +/- 20% (for both AUC + Cmax) - log transformed therefore 80%-125% for AUC + Cmax
 This 20% difference may be clinically significant for those with a narrow therapeutic range

Question 8

Volume of distribution

Answer 8

• Definition = the hypothetical volume that would be required to dissolve the total amount of drug at the same concentration as found in the blood
o Relates plasma drug concentration to total amount of drug in the body
o E.g. if drug has plasma concentration 10mg/L when there is 1000mg drug in the body, Vd is 100L

• Factors affecting volume of distribution
o Relative strength of binding of the drug to tissue components compared with plasma proteins
o Molecule size – E.g. monoclonal antibodies and IVIG unable to enter cells due to large molecular size

• Low vs high Vd
o Low
 Suggests drug is confined to intravascular space (high blood concentration)
 Occurs if poorly lipophilic and highly plasma bound
 E.g. heparin, warfarin, aspirin, gentamicin
o High
 Suggests that drug is distributed to tissue/fat widely
 Occurs if bound to tissues and not blood, most of drug in tissues and little in plasma
 Usually highly lipophilic
 E.g. nortriptyline, imipramine, chlorpromazine

• Utility
o Calculating loading dose to get to therapeutic range quicker (i.e. same as steady state concentration)
o Clearance determines steady state concentration
o If there is higher VD then will require higher loading dose to reach steady state and fill up the volume of distribution

Example
• A bolus dose 200mg given
• At Time 0s concentration was 10mg/L
• Therefore VD = 200mg / 10mg/L = 20L

Question 9

Compartment models

Answer 9

• Compartments are hypothetical space that quantitates the relationship between drug dosage and the amount of drug in the body at a given time
• 1 compartment model = treats all body fluids and tissues as one space with definable rates of in and out
• 2+3 compartment models = separate fluid/ organ/ tissue spaces
o Recognizes that some drugs get taken up into certain organs first, then eliminated into a second compartment
o Gradients will change as drug passes into another compartment

Question 10

Protein binding drugs

Answer 10

• When a drug combines with plasma/ extracellular / tissue proteins to form a reversible drug-protein complex
• These complexes are inactive, cannot be readily metabolized/ excreted
• If a drug is highly protein bound:
o Vd will be large
o Elimination half-lives will be long
o Susceptible to increased Vd in conditions with extravascular protein leak (eg nephrotic syndrome)

Question 11

Hepatic extraction ratio

Answer 11

• Hepatic extraction ratio = amount of drug cleared by liver metabolism on first passage through

Example
• Propranolol 80% blood entering liver is extracted (extraction ratio 0.8)
• Liver blood flow is 90L/hour
• Therefore 0.8 x 90L = hepatic clearance of 72L/hour

Determinants of the hepatic extraction ratio

1. Liver blood flow
2. Unbound fraction – ability of liver to remove drug depends on protein binding as it is only the free (unbound) drug that is available for diffusion from blood into liver where metabolism occurs
3. Intrinsic clearance – ability of liver to remove (metabolise) drug (it is what hepatic clearance would be without restrictions of blood flow and protein binding)
   a. Cannot exceed hepatic blood flow

When very low enzyme activity – SYSTEMIC CIRCULATION affecting clearance
• I.e. LOW hepatic ability to remove drug = low hepatic ER
• DEPEDENT on unbound fraction or intrinsic clearance
• Not much influence on blood flow and extraction low anyways
• Example – diazepam, warfarin, theophylline, phenytoin, carbamazepine

When very high enzyme activity
• I.e. HIGH hepatic ability to remove drug = HIGH hepatic ER
• DEPENDENT on blood flow
• Not much influence on unbound fraction or intrinsic clearance as already high
• Example – GTN, propranolol, verapamil, lignocaine, morphine

Question 12

Phase 1 metabolism

Answer 12

• Goal = designed to make drug more water soluble + less toxic
• Introduce/ reveal a functional group within the substrate drug molecule that serves as a site for a phase II reaction
• Non-synthetic, simple changes are made to the molecule

• Reactions
o Oxidation = CYP450
o Reduction = flavin
o Hydroylses = esterase

Question 13

Cytochrome P450 enzymes

Answer 13

• Group of related isoenzymes involved in phase I drug metabolism reactions
• Present in large quantities in ER of liver, but also lung, kidney and intestinal wall
• Involved in the hydroxylation +/- oxidation of drugs and lipophilic endogenous substances
• Cytochrome activity varies with age, race, genetic factors
• The most important CYPs in humans are the groups 1, 2 and 3

Inducers
•	Anti-epileptics 
o	Phenobarbitone 
o	Carbamazepine 
o	Oxcarbazepine 
o	Phenytoin 
•	Rifampicin 
•	Ethosuxamide
•	Steroids
•	Topiramate 
•	St John’s wort 

Inhibitors
• Azole antifungals = voriconazole, posaconazole
• Macrolide antibiotics = clarithromycin, erythromycin
• Cimetidine
• Valproate
• CCBs = verapamil, diltaizem
• Grapefruit juice

Question 14

Phase 2 metabolism

Answer 14

• Goal = add onto drug molecule for elimination
• Conjugation with acetate, glucuronic acid, glycine and sulfate
• These processes increase the polarity of an intermediate metabolite  more water solubility
• Enzymes involved: NAT1/NAT2 arylamine N-acetylransferases, glucoronosyl transferases (UGTs), epoxide hydrolase, glutathione S-transferases (GSTs), sulfotransferases (SULTS) and methyltransferases

• Examples

o Gluocronosyl transferases
 Catalyze conjugation of glucuronic acid with several drugs: morphine, paracetamol, NSAIDS, benzodiazepines
 Immature processes in neonates -> hyperbilirubinemia, grey baby syndrome, INCREASED clearance of morphine
 UGT1A1: the major ugt gene product responsible for bilirubin glucoronidation. Mutations (usually involving a TA repeat in the atypical TATA box of the UGT1A1 promoter) cause Crigler-Najjar syndrome and Gilbert syndrome

o NAT-2 polymoprhisms (arylamine N-acetyl transferases)
 High level of slow metabolisers
 Involved in metabolism of sulfasalazines, procainamide + isoniazide induced lupus + SJS/ TENS

o TPMT
 Catalyses S-methylation of sulfur containing compounds – 6-MP, azathioprine and 6-thioguanine
 1/300 people have TPMT deficiency (AR trait)
 Risk of increased myelosuppression with above drugs

Question 15

Phase 3 metabolism

Answer 15

• Transport of conjugated drug into bile – transporters are part of ATP binding cassette (ABC) superfamily

Question 16

Clearance and elimination

Answer 16

o Clearance
 Definition
• Irreversible elimination of drug from the systemic circulation – either by excretion of the unchanged drug (into urine, gut, expiration) or the metabolic conversion of the drug into a different chemical compound
• Volume of blood from which a certain amount of unmetabolized drug is removed per unit time
 Usually constant over the therapeutic range (except drugs with zero order kinetics such as phenytoin and ethanol)
 Clearance is the parameter which relates elimination to concentration

o Elimination
 Definition = irreversible removal of the drug from the body
 Divided into two components
• Excretion = removal of the intact drug
o Kidneys = renal (correlates to renal function)
o Liver = biliary excretion (parent compounds or metabolites)
o Lungs = pulmonary (MINOR)
• Biotransformation = chemically converted into a metabolite
o Enzymatic process
o Mostly occurs in the liver, but does NOT correlate with LFT
o Other site = intestine, lung, kidney

• Clearance + Elimination
o Therefore, clearance will remain constant as it is a characteristic of particular drug and patient, so that the elimination varies directly with plasma drug concentration
o At steady state elimination dictates maintenance dose in order to keep drug plasma concentrations same
o Another definition for clearance is the constant relating rate of elimination of a drug to plasma drug concentration

Clearance is defined as ‘the volume of blood cleared of drug per unit time’. … Drug elimination rate is defined as ‘the amount of drug cleared from the blood per unit time’ In first order kinetics, elimination rate is proportional to dose, while clearance rate remains independent of the dose.

Question 17

Renal elimination

Answer 17

• Principles of renal clearance
o Equivalent to filtration + secretion – reabsorption
o Can only be quantified by measuring urine
o Classic drugs excreted renally = vancomycin, beta-lactams
o For most drugs GFR is most important – secretion/ reabsorption not relevant
o Usually correlates with renal function
 Eg. halving of renal function  half clearance of drug

• Dependent on three processes
o Filtration – determined by:
 GFR – determined by renal function
 Fraction unbound (bound drug unable to be filtered)
o Secretion – active, determined by:
 Fraction unbound
 Availability of active transport systems (one for weak acids one for weak bases) -> can be subject to competitive drug interactions and saturatable kinetics
o Reabsorption – passive reabsorption of water in distal tubule means drug reabsorption depends on:
 Concentration gradient – determined by urine flow rate, the higher the urine flow rate the higher the drug clearance (as less concentration gradient pulling the drug out of renal tubule)
o Ion trapping - pKa of the drug +/- pH urine
 Non-ionised drugs pass through the cell membrane
 Ionized drugs stay in water (and get trapped as they do not pass through the membrane)
 This principle can be used by alkalizing/ acidifying urine
• Weak acid drugs are ionized in basic solution
• Weak basic drugs are ionized in acidic solution
 Alkalinization of urine
• Helps to excrete weak acids that are renally excreted (eg aspirin)
• This can be achieved by administering bicarbonate

Question 18

Dose adjustment in renal failure

Answer 18

• Renal clearance reduced in proportion with reduction in GCF (Cr clearance)
• Adjustment of drug doses only necessary when drug is >50% cleared by renal elimination and renal function is reduced to half or less
• Dose rate is reduced proportional to reduction in creatinine clearance either by –
o Reducing the dose
o Increasing the dose interval
o E.g. if a drug is 50% renally cleared, and Cr clearance is 10% usual (90% reduction), then renal clearance reduced from 50% to 5% and total clearance is 55%, therefore dose rate should be decreased to 55% normal
• Factors to consider
o Therapeutic index – if wide may not need dose adjustment
o Metabolites renally cleared

Example
• Dose renally cleared = usual dose x new GFR/old GFR
• Eg – if the dose is usually 100mg for a drug which is 20% hepatically cleared and the GFR is 25%
• Renal dose = 80 x 0.25 = 20, liver dose = 20 x 1 = 20 – therefore dose = 40mg

Question 19

Elimination kinetics

Answer 19

• Zero order kinetics
o Definition = elimination occurs at the same irrespective of the concentration
o Amount of drug in the body determined by volume  a constant amount of drug is eliminated per unit time
o Examples = alcohol, phenytoin, aspirin (high dose), theophylline
o NO half life
o Consequences
 Large increases in drug concentration with small increases in drug doses
 High risk of drug toxicity

• First order kinetics
o Most common
o Definition = elimination rate proportional to the concentration of drug in body
o If more drug is present, elimination is more rapid  a constant proportion of the drug is eliminated per unit time
o The elimination rate can be represented by a constant k
o Drugs will have a consistent half life
o Time to steady state (or >95% drug elimination) = five half lives
o Most drugs are first order kinetics - do not saturate the elimination pathway

• Saturable kinetics
o Some drugs will demonstrate first order kinetics at low doses, and zero order kinetics at higher doses
 Renal elimination theoretically uncapped
 Hepatic metabolism – eventually reach maximum metabolic pathway
• Only when enzyme pathway is saturated – zero order kinetics
• Michaelis-Mentin kinetics = low dose 1st order, high dose zero order kinetic
o Examples = phenytoin, theophylline, aspirin

Question 20

Half life

Answer 20

• Definition = the time for post-absorption blood/ plasma concentration to be reduced by 50%
o There will be < 5% of drug left after 5 half lives

• Plasma half-life determines
o Duration of action after a single dose
 The longer the half-life, the longer the drug will stay in therapeutic range
 Increasing the dose is an ineffective way of increasing duration of action as log scale therefore proportionate clearance (not constant)
o Time required to reach steady state with repeated dosing
 5 half-lives until steady state
 5 half-lives until elimination
 Loading dose will not change time until steady state, will only increase starting concentration closer to steady state
o Dose frequency required to avoid large fluctuations in concentration in the dosing interval
 If drug given every half-life, the concentration falls to half the peak concentration – peak concentration double the trough (pre-dose)
 Drug given more frequently than half-life then there will be minimal fluctuation in dose in interval

Question 21

Steady state

Answer 21

• Definition
o Level of drug accumulation in the blood and tissue after multiple doses where the rate of input and output are at equilibrium; therefore, the plasma drug concentration remains constant
o If a drug follows first order kinetics, this will be reached after five half lives
• NOTE:
o This is NOT the same as a therapeutic level
o Dosing interval does NOT influence steady state
o Loading dose does NOT influence steady state – reduces the amount of time until in therapeutic range

• Clearance determines the maintenance dose rate required to achieve a desire plasma concentration at steady state

 More frequent dosing = more time in the therapeutic range
 Amount of time to reach steady state does NOT change based on dosing interval
 Half-life does NOT relate to dosing interval

Question 22

Affinity

Answer 22

• Affinity – Kd
o Concentration of drug required to bind 50% of receptor sites
o The lower the Kd, the lower the drug concentration needed to bind 50% receptor sites correlating with increased affinity for receptor

• Spare receptors
o Maximal response obtained at less than maximal occupation of receptors
o Work this out by comparing EC50 with Kd
o If Kd > EC50 = less than 50% of receptors must be activated to achieve EC50 therefore there are some spare receptors

The parameter EC50 abbreviates for ‘half maximal effective concentration’. In a pharmacological context, this can be the concentration of a drug that is necessary to cause half of the maximum possible effect.

Question 23

Efficacy and potency

Answer 23

• Definitions
o Emax = the maximal effect that a drug produces irrespective of drug concentration
o EC50 = dose at which a drug achieves 50% of its maximum effectiveness
• Efficacy = defined by maximum effect

• Potency = defined by EC50
o The amount of drug needed to produce a given effect
o Usually this is defined as the amount of drug dose that produces a quantal effect in 50% of the population OR the amount of drug required to produce 50% of its maximal drug effect
o A highly potent drug: larger response at lower concentrations

Question 24

Agonists and antagonists

Answer 24

• Full agonist = affinity and efficacy
o Can produce a maximal response at low occupancy

• Partial agonist = affinity and less efficacy
o Response at a given receptor occupancy always less than that of a full agonist
o ALSO have the capacity to act as antagonists if in the presence of the full agonist
 At low concentrations acts as an agonist
 At high concentrations occupies receptors preventing full agonist binding – therefore acts as antagonist

• Antagonist = affinity but no efficacy (efficacy of 0)
o Requires the presence of an agonist to exert an effect
o Competitive = reversible
 Competitive inhibition does not change the maximum response of the tissue
 Surmountable (ie. no depression of the maximum response)
 Parallel shifts in log CR curves
o Non-competitive antagonist = irreversible (eg. aspirin)
 Essentially insurmountable
 Essentially irreversible – receptors have been blocked by antagonist molecules OR bind at a different site and cannot be displaced by the agonist
 Unable to reach maximum effect
 Lowers maximum response in log CR curve

Question 25

Therapeutic range and index

Answer 25

Therapeutic range • Range of effect between minimal effective concentration and minimally toxic concentration • Increasing the dose does NOT necessarily increase time spent in the therapeutic window • Increasing the frequency of dosing increases time in therapeutic range Therapeutic index • Definition margin of safety of a drug • Ratio of lethal or toxic dose to the therapeutically effective dose. • In animal experiments, TI is the ratio of LD50 (dose at which lethal to 50% of the animal population) to ED50 (effective dose in 50% of animal population) • Examples o Broad = penicillins, beta 2 agonists, and thiazide diuretics o Narrow = digoxin, theophylline, lithium and phenytoin The therapeutic index is an important ratio to determine how close a toxic dose is to an effective one. The therapeutic window (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects.

Question 26

Adverse drug reactions - classification

Answer 26

a. Type A = predictable (85-90%) i. Dose dependent ii. Can be related to known pharmacological actions of the drug iii. Occur in patients with susceptibility – can occur in any individual given sufficient dose and exposure iv. Include 1. Drug toxicity/ overdose 2. Drug interactions 3. Adverse effects b. Type B = unpredictable (10-15%) i. Dose independent ii. Often not related to pharmacological actions of the drug iii. Occur in patients genetically predisposed iv. Include 1. Idiosyncratic reactions 2. Allergic reactions 3. Pseudoallergic reactions - caused by non-IgE release of mediators from mast cells and basophils (eg. anaphylactoid reaction after radiocontrast media)

Question 27

Types of hypersensitivities

Answer 27

``` Type 1 - IgE-mediated, immediate-type hypersensitivity • Mechanism: Antigen exposure causes IgE-mediated activation of mast cells and basophils, with release of vasoactive substances, such as histamine, prostaglandins, and leukotrienes - IgE against soluble antigen Features: • Anaphylaxis • Angioedema • Bronchospasm • Urticaria (hives) • Hypotension Drugs: • Beta-lactams • Neuromuscular blocking agents • Quniolones • Carboplatin • Immunologics – rituximab ``` Type 2 - Antibody-dependent cytotoxicity • Mechanism: An antigen or hapten that is intimately associated with a cell binds to antibody, leading to cell or tissue injury - IgG/IgM against cell surface antigen • Hemolytic anemia – cephalosporins, penicillins, NSAIDs, quinine-quinidine • Thrombocytopenia - heparin, abciximaab, quinine, quinidine, sulphonamides, vancomycin, gold, beta-lactams, carbamazepine, NSAIDs • Neutropenia – PTU, antimalarial, flecainide Type 3 - Immune complex disease • Mechanism: Damage is caused by formation or deposition of antigen-antibody complexes in vessels or tissue. Deposition of immune complexes causes complement activation and/or recruitment of neutrophils by interaction of immune complexes with Fc IgG receptors - IgG to soluble antigen Examples: • Serum sickness – antitoxins • Vasculitis – penicillins, cephalosporins, sulphonamides, phenytoin, allopurinol • Arthus reaction- tetanus, diphtheria, hepatitis B Type 4 - Cell-mediated or delayed hypersensitivity • Mechanism: Antigen exposure activates T cells, which then mediate tissue injury • Depending upon the type of T cell activation and the other effector cells recruited, different subtypes can be differentiated (ie, types IVa to IVd). - T cells against soluble/cellular antigen Examples: • Contact dermatitis – opcial antihistamine • Some morbilliform reactions • Severe exfoliative dermatoses (eg, SJS/TEN) • AGEP • DRESS/DiHS • Interstitial nephritis • Drug-induced hepatitis

Question 28

Adverse drug reaction - assessment and rx

Answer 28

6. Assessment a. History = underlying illness, time course, systemic involvement b. Investigations i. Skin prick test (often negative in setting of drug allergy) ii. Intradermal tests 1. Intradermal injection of drug, measure wheal 2-3 minutes later 2. Much more painful than skin prick testing, risk of anaphylaxis 3. Penicillin intradermal testing useful for IgE mediated reactions due to its NPT value a. 1-3% of patients with negative skin test have a reaction (which is mild) when re-exposed to penicillin b. Skin testing for penicillin should be performed using the major determinant (penicilloyl polysine) and minor determinants (penicilin G, penicilloate and penilloate) c. Skin prick testing to penicillin does NOT predict non-IgE mediated reactions iii. Drug provocation test 1. Gold standard 2. Graded exposure in hospital UNLESS hx of SJS/ TENS/ DRESS iv. NOTE: 1. Serum sIgE  not adequately validated, rarely used for drug allergy 2. Basophil activation assay  poor sen/ spec compared to skin testing (uses flow cytometry to quantify expression of activation markers after stimulation with allergen) 3. Patch testing – more relevant for non IgE mediated disease, may be useful for AGEP etc 7. Management = drug desensitization a. Amount of drug tolerated by patient determines safe initial dose b. Double dose every 15 minutes c. Requires regular administration to maintain desensitization d. Contraindications = history of DRESS, SJS/TEN e. Indications i. Drug allergy – when no alternative treatment for temporary tolerance during course of treatment – E.g. penicillin and vancomycin ii. Anaphylaxis – bee sting iii. Allergic rhinitis and asthma – refractory – dustmite, pollens, animal

Question 29

DRESS - general

Answer 29

"drug rash with eosinophilia and systemic symptoms" 1. Key points a. Rare, potentially life-threatening drug reaction b. In 10-20% of cases drug cannot be identified 2. Aetiology a. Anticonvulsants – phenytoin, phenobarbital, carbamazepine, lamotrigine i. 75% cross reactivity b. NSAIDs c. Sulphonamides d. Dapsone e. Allopurinol f. Penicillin g. Minocycline 3. Risk factors a. HLA-B*58:01 (Han Chinese) strongly associated with allopurinol associated DRESS 4. Clinical manifestations a. Timing = 2-8 weeks between drug exposure and disease onset i. Usually begins with high fevers and lymphadenopathy b. Skin i. Eruption; diffuse, confluent, and infiltrated erythema ii. Facial edema common iii. Can have erythema multiforme c. Systemic: Fever, Malaise, Lymphadenopathy d. Haematological i. Atypical lymphocytosis – early ii. Eosinophilia iii. Pancytopaenia less common e. Internal organ involvement (hepatitis, nephritis, pneumonitis, encephalitis, carditis, hypothyroidism) 5. Investigations a. Eosinophilia b. Atypical lymphocytosis c. UEC, urine microscopy, LFT, CXR, ECG d. If symptoms – TSH, echo, LP 6. Natural history a. Skin eruption and visceral involvement resolve gradually after drug withdrawal b. Average time 6-9 weeks c. Up to 20% of cases disease persists for several months - 10% mortality 7. Management a. Removal of drug b. Systemic corticosteroids c. Topical corticosteroids

Question 30

AGEP - general

Answer 30

"Acute generalized exanthematous pustulosis" - pustules** 1. Key points a. Rare, acute eruption 2. Aetiology a. Drugs i. Antibiotics – aminopenicillins, macrolides ii. Antifungals iii. CCB iv. Anti-malarials b. Other i. Viral infection – parvovirus B19, CMV, coxsackie ii. Mycoplasma iii. Spider bite 3. Clinical manifestations a. Timing = few days after administration b. Numerous non-follicular sterile pustules on a background of edematous erythema i. Prominent in flexures ii. Usually begins on the face and intertriginous areas and rapidly extends c. Fever d. Leukocytosis e. Organ involvement uncommon 4. Natural history a. Skin symptoms resolve without treatment in one to two weeks after discontinuation of the offending drug b. Pustular eruption is followed by desquamation with characteristic collarettes of scale c. Courses >2 weeks are rare 5. Treatment a. Cessation of drug b. Supportive

Question 31

SJS/TEN - bg

Answer 31

1. Key points a. Severe mucocutaneous reactions b. Most commonly triggered by medications c. Characterised by extensive necrosis and detachment of the epidermis (full thickness) d. Mucous membranes are affected in >90% of patients e. NOTE = erythema multiforme is a SEPARATE condition - Similar histology, Typically target lesions only – no widespread coalesce 2. Definitions a. SJS = skin detachment <10% BSA b. TEN = skin detachment >30% BSA c. All TEN will start as SJS 3. Epidemiology a. F>M, any age c. Mortality 30% - 10% for SJS to >30% for TEN 4. Pathogenesis a. Drug specific CD8+ cytotoxic T cells and NK cells major inducers of keratinocyte apoptosis 5. Atiology a. Drugs = most common i. Allopurinol ii. Aromatic anticonvulsants = phenobarbital, carbamazepine, lamotrigine iii. Antibacterial sulphonamides = commonest in adults v. NSAIDs vi. Penicillins b. Mycoplasma pneumoniae infection = second most common trigger, particularly in children c. Other (after BMT, vaccinations, AI) 6. Risk factors a. HIV b. Genetic factors e.g. HLA-B*15:02 and 11 c. Underlying immunological disease or malignancies

Question 32

SJS/TEN - sx

Answer 32

7. Natural history a. Acute phase lasts 8-12 days b. Characterised by persistent fever, severe mucous membrane involvement and epidermal sloughing c. Re-epithelialization begins after several days and typically takes 2-4 weeks 8. Clinical manifestations a. Prodrome = 2 days to 2 weeks i. Fever and influenza like symptoms ii. Photophobia, conjunctival itching or burning and pain with swallowing iii. Mild to moderate skin tenderness or burning iv. May have oral mucositis b. Cutaneous lesions i. Ill-defined, coalescing, erythematous macules with purpuric centres ii. Skin tender to touch iii. Lesions start on face and thorax before spreading iv. Symmetrically distributed v. Scalp, palms and soles rarely involved vi. Bullae begin to form which then slough vii. Nikolsky sign (ability to extend the area of superficial sloughing by applying gentle lateral pressure on the surface of the skin at an apparently uninvolved site) viii. Bullae spread sign (lateral extension of bullae with pressure) c. Mucosal lesions i. Occur in 90% of cases ii. Can proceed or follow skin eruption iii. Oral = almost invariably involved; painful haemorrhagic erosions with grayish-white membrane iv. Ocular = present in 80%; most commonly severe conjunctivitis with purulent discharge 1. Eye changes may regress completely 2. At least 50% of patients have late eye seqeuale includeing pain, dryness and scarring with development of synechiae between eyelids and conjunctiva v. Urogenital = 2/3 of patients 1. Vulvovaginal involvement may lead to long-term anatomical sequelae

Question 33

SJS/TEN - ix, cx

Answer 33

9. Complications/ Systemic Manifestations a. Acute i. Loss of fluid through denuded skin -> Electrolyte imbalance, Hypovolaemic shock, pre-renal AKI iv. Bacteraemia + septic shock – most commonly S. aureus and P aeruginosa v. Insulin resistance vi. Multiple organ dysfunction (pulmonary, renal, GI, liver) vii. Complications of erythroderma – fluid, temp, HF, nutrition, DVT b. Long-term i. Cutaneous sequelae = post-inflammatory hypo- or hyperpigmentation, scarring, eruptive nevi, abnormal regrowth of nails, telogen effluvium, chronic pruritis ii. Ophthalmic = 50-90% of patents; include dry eye, photophobia, ingrown eyelashes, neovasculatirsation of the cornea, keratitis, symblepharon, corneal scarring (rarely reslting in blindness) iii. Oral and dental sequelae iv. Vulvovaginal sequelae = vaginal adhesions, obstructed urinary stream, urinary retention, recurrent cystitis, hematocolpos v. Psychiatric 10. Investigations a. Anaemia and lymphopenia b. Neutropenia present in 1/3 and correlates with poor prognosis c. Biopsy = partial to full thickness necrosis of the epidermis

Question 34

SJS/TEN - rx, prevention

Answer 34

11. Treatment a. Withdrawal of culprit drug b. Burns unit management c. Supportive care i. Manage temperature, oxygenation ii. Wound care – silver impregnated hydrocolloid dressing iii. Fluids and nutrition – NG or TPN iv. Pain control v. Prevention of infections 1. Reverse barrier nursing 2. Daily swabs 3. Antibiotics only for suspicion of sepsis 4. GMCSF useful if neutropenic vi. Prevention of vulvovaginal and ocular sequelae d. Adjunctive therapies = little evidence to guide treatment i. Sepsis leading cause of death – must be used with caution ii. Early treatment may be beneficial whereas late treatment may be contra-indicated iii. Include 1. Cyclosporine 2. Systemic corticosteroids 3. IVIG – standard therapy at RCH 4. New study suggesting etanercept (anti-TNF fusion protein) 12. Prevention a. Genetic screening of patients of Asian and South Asian ancestry

Question 35

Penicillin immediate hypersensitivity - general

Answer 35

1. Key points a. Most common medication related allergy b. 10-15% of patients report penicillin allergy c. Many of these patients are NOT allergic d. Multiple different allergenic components (e.g. peniciloyl, R-chain (in amoxicillin)) 2. Risk factors a. Age, hereditary factors, other allergic disease b. Frequent, repeated exposure c. Route of administration – IV results in more rapid sensitisation d. Multiple antibiotic allergy syndrome 3. Natural history a. Penicillin allergy resolves in many (not all) patients who avoid penicillin i. 50% of patients have lost the sensitivity 5 years after their last reaction. 80% after 10 years 4. Antibiotic choices a. Avoidance of all penicillins b. Use of related drugs i. Cephalosporins – most closely related to penicillins 1. Share beta lactam AND R1 side chain 2. 1st generation more likely to cross react 3. 2% rate of cross reactivity - AVOID ii. Carbapenems – also related 1. <1% rate of cross-reactivity – AVOID 5. Testing a. Can be performed for classical penicillin reagents b. Semisynthetic penicillins can test for side chain allergies c. Only 1-3% of skin test negative patients develop reaction when challenged with a drug

Question 36

Vancomycin allergies - general

Answer 36

1. Red man syndrome o Most common reaction o Not true IgE mediated reaction o Pseudoallergic reaction where vancomycin directly activates mast cells – release of histamine and other vasoactive mediators o May develop with first administration of vancomycin, occurs with IV route o Rate-dependent infusion reaction o All patients will get reaction if fast enough o Suggested that infusion rate no higher 10mg/min o Clinical features - flushing, erythema, pruritus affecting upper body/face > lower, pain/muscle spasm in back and chest, dyspnea, hypotension. o Rarely life threatening, but same clinical presentation as anaphylaxis o Management o Antihistamine premedication if rapid infusion required o Mild-moderate acute reaction – stop infusion, give antihistamine (H1 and H2), restart infusion half the rate o Severe reaction (cardiovascular) – stop infusion, give antihistamine, fluid resuscitation, slow infusion further / stop 2. Anaphylaxis o IgE mediated o Requires previous exposure o True anaphylaxis is rare, but reactions involving angioedema, respiratory distress/bronchospasm more common o Clinical manifestations – skin, GIT, resp, cardiovascular o Very similar to red man syndrome - Wheeze/resp distress more common in anaphylaxis - Angioedema only in IgE mediated response o Management: Stop infusion, IM adrenalin

Question 37

Grey baby syndrome

Answer 37

Chloramphenicol -> grey baby syndrome • Lack of glucoronidation -> accumulation of toxic chloramphenicol metabolites • The udp-glucuronyl transferase enzyme system of infants, especially premature infants, is immature and incapable of metabolizing the excessive drug load • Insufficient renal excretion of the unconjugated drug • Toxic levels of chloramphenicol after 2–9 days result in vomiting, grey skin colour, hypotonia, hypotension, cyanosis, hypothermia, cardiovascular collapse

Question 38

Rifambutin and red/orange skin discoloration

Answer 38

* Anti-mycobacterium agent – used primarily in prophylaxis of M. avium-intracellulare * Complex (MAC) infections in HIV * Causes discoloration skin/tears/urine and can cause liver and haematological abnormalities

Question 39

Sulphonamide adverse drug reactions

Answer 39

* (Bactrim) – the major drug implicated * Non-antibiotic sulphonamides (acetazolamide, chlorpromazine, chlorothiazide) do NOT tend to be cross reactive * Bactrim usually caused by a different component * T cell mediated hypersensitivity – rather than IgE or IgG mediated * Clinically – generalized erythematous rash + fever * Structure = Sulfonamide moiety + N4 aromatic amine + N1 substituted ring * N4 aromatic amine + N1 substituted ring responsible for IgE mediated reaction

Question 40

Perioperative anaphylaxis

Answer 40

* 1/1,250 – 10,000 * Most commonly NMJ blocking agent 50-70%, then latex allergy, then antibiotic allergy • Aetiology o Neuromuscular blocking agents  50-70% caused by neuromuscular blocking agents  Usually in induction phase of anaesthesia  Succinylcholine most common cause  Cross reactivity is common o Latex allergy  Occurs in maintenance phase of anaesthesia  Risk factors = multiple operations, particularly bladder + those with atopic reactions, spina bifida  Ix = SPT, specific IgE, latex glove challenge o Antibiotics  Contact urticaria  Anaphylaxis during maintenance phase of anaesthesia

Question 41

Radiocontrast media adverse reaction

Answer 41

* Are not IgE mediated, are more ‘anaphylactoid reactions’ * Occur in 1-3 % * Due to direct activation of mast cells

Question 42

Pharmacogenomics examples

Answer 42

o Carbamazepine  High risk of SJS within first four weeks  T cell mediated disease  Associated with HLA-B 15-02 (odds risk ratio of 80) • 98.3% sensitivity, 97% specificity, 7.7% PPV, 100% NPV  Most common in Han Chinese and Singaporean  Allele frequency of 0% in Europeans  Should be tested in ALL Asian individuals prior to commencing therapy  NOTE: also have recurrent risk of phenytoin + phenobarbitone (cross reactivity) • HOWEVER genotype does not predict risk of SJS for phenytoin + phenobarbitone o Flucloxacillin  HLA-B1501  Increased risk of hepatotoxicity o Gentamicin  ↑ risk of deafness with mitochondrial mutation m.1555A  G (mostly homoplasmic mutation)  May account for 33-59% of aminoglycoside induced deafness o Allopurinol increased risk of cutaneous reactions in HLA-B5801 o Abacavir – high rates of toxicity in HLA- B5701

Question 43

Study designs - broad/list

Answer 43

• Observational = WATCH - investigators do not assign exposure o Can only support an association not causality o Includes  Case control  Cohort studies  Correlation (ecological)  Cross-sectional = survey, census  Ecological (correlational) – aggregated data ``` • Experimental = INTERVENE - investigators assign exposure o Demonstrate causality o Includes  RCT only  Non-randomised control trial ```

Question 44

Correlation/ecological study

Answer 44

Observational Compare different groups or at different time periods • Often used to measure prevalence and incidence of disease, particularly when the disease is rare • Types o Geographical o Longitudinal o Migration Advantages • Fast/cheap • Generate hypothesis Disadvantages • High risk of bias • Suggest associations not causations

Question 45

Cross sectional study

Answer 45

Observational Assess frequency of disease and related RF at a certain time point (single time point) • Examples = survey, census o Measure outcome + exposure at the same time Measures: Prevalence Advantages • Show risk factor associations Disadvantages • No causality o Cannot evaluate causation as it doesn’t take into account how TIMING of exposure to a risk relates to development of disease

Question 46

Case control study

Answer 46

Disease vs no disease (case vs control) Prior exposure or risk factor Retrospective (always!) o Start with disease outcome  look back to examine risk factors o Validity of this type of study depends on how appropriate selection of controls was Measures: Odds Ratio Advantages • Rare outcomes and common exposures • Possible with small numbers Disadvantages • Recall & selection bias (need to select controls appropriately) • Measurement error

Question 47

Cohort study

Answer 47

Group with given exposure/RF to group without See if exposure = risk of disease Prospective or retrospective • Prospective o Description = observational study of a group of subjects with a specific disease or exposure who are followed up over a period of time to detect complications or new events; may be compared with a control o Key points  Start with exposure  outcome  Follow a group with a certain behaviour/ risk factor  Look to see development of disease outcome • Retrospective o Description = 2 groups but based on exposure– exposed vs non exposed – but medical records are used retrospectively to compare for a particular outcome and to follow up over ensuring time period Measures: Relative Risk Advantages • Good for rare exposure and common outcome Disadvantages • Subjects and controls may differ on important predictors of outcome • Expensive and time-consuming • Loss to follow-up – affects validity

Question 48

Randomised controlled trial

Answer 48

Randomly allocated to treatment/control Interventional • Key elements o Comparison group that receives current best practice or inactive treatment (placebo) o Randomizing to ensure both groups the same  removes confounding o Minimise allocation bias o Allocation concealment  removes bias o Blinding = double or single ``` Measures: Confidence intervals, Causality • Statistics generated o Absolute risk difference o Relative risk difference o NNT ``` • Important principles in RCT o Confounding  Variable that interacts with the exposure AND outcome o Intention to Treat Analysis  Gold standard  Patients included in the groups to which they were randomised  Avoids issues of patient factors affecting drop-out (eg. if all individuals with a side effect dropped out)  Most closely resembles “what would be the event seen in practice”  Adherence to protocol not accounted for  May underestimate the effect of intervention o Per Protocol Analysis  ONLY analyse those who comply with protocol  Estimates intervention effect  Does NOT maintain randomisation – risk of biases Advantages • Gold standard test Disadvantages • Time consuming • Ethics required

Question 49

Twin concordance / adoption study

Answer 49

Compare twins/siblings Measures: Heritability and influence of environmental factors

Question 50

Meta analysis

Answer 50

Summates multiple studies together which meet strict criteria • Systematic method that uses statistical techniques for combining results from different studies to obtain a quantitiave estimate of the overall effect of a particular intervention or variable on a defined outcome • Produces a stronger conclusion than can be provided by any individual study Measures: Forrest plots • Size of square relates to weight given to the study in the meta-analysis • Placement of square gives you the odds ratio OR relative risk (mean effect of intervention) • Horizontal lines = 95% CI for that study • Black diamond = overall meta-analysis findings o Peak of the diamond  point estimate/ overall result o Edges of the diamond  confidence interval  If crosses the line there is NO statistical significance • Heterogeneity o Amount of variability between studies o Two types of variability Clinical heterogeneity = always present  differences in patients, location, intervention, study design  and quality  Statistical heterogeneity = not always present o Tests to measure heterogeneity  Chi2  I2 = <50% - if any higher the papers could be inconsistent due to a reason OTHER than chance Advantages • Highest level of evidence Disadvantages • Time consuming

Question 51

Odds ratio versus relative risk

Answer 51

* Odds ratio is the number of participants in the group who achieve a stated end-point divided by the number of patients who do not * Risk ratio, as opposed to odds ratio, is the number of participants in the group who achieve the stated end-point divided by the total number of patients in the group * Main measures of association derived from observational studies * Both measures compare the likelihood of an event between two groups * IF CI for OR does not include 1, CI for RR will not include 1 * More likely to be similar if the disease is rare

Question 52

Clinical trials - phases

Answer 52

Preclinical • In vitro/ animal Phase 0/ Pilot • Preliminary PK/PD • Micro dosing • Very small population/patient numbers ``` Phase I • SAFETY • Dosage, side effects • Further PK/PD information • Small groups (20-80) • Healthy volunteers ``` ``` Phase II • EFFICACY • Dose response • Larger groups, several hundred (100-300) • Case series/ small RCT ``` Phase III • Efficacy COMPARED TO CURRENT STANDARD RX • Monitor adverse effects • Several hundred to thousands (300-5000) • Individuals with disease ``` Phase IV • Surveillance • Cost efficacy • Longer term / rare effects • After marketing • Effectiveness in general population ```

Question 53

Intention to treat analysis

Answer 53

• Forms the basis for analysis in RCTs • Study participants are analysed as members of the treatment group they are randomized regardless of their adherence to, or whether they received the intended treatment o Without intention to treat analysis, the randomness is reduced and bias may increase (drop out may affect one arm of a study more than another • E.g. in a trial where patients randomized to treatment A or B, a patient may accidentally receive the wrong treatment, never receive any treatment, or not adhere to treatment – in all situations the participant and outcomes would be analysed according to original randomization • Eliminating study participants who were randomized or not treated or moving them between groups would violate ITT principle • Effectiveness of therapy not only determined by biological effect, but also by patients adherence to treatment – only by retaining all patients as originally randomized, means unbiased estimate of effect • Limitations o Non-inferiority studies o Not useful for safety studies o Can decrease power and decrease effect size

Question 54

Risk factor stratification

Answer 54

• ‘Randomisation after the event’, done at the completion of the study rather than at the beginning/design phase

Question 55

Dependent versus independent variables

Answer 55

o Independent variable is the variable that is changed or controlled in a scientific experiment to test the effects on the dependent variable o A dependent variable is the variable being tested and measured in a scientific experiment

Question 56

Continuous versus categorical variables/data

Answer 56

``` Continuous o Discrete (HR, minutes) o Continuous = height, weight temperature, QAL o Analysis  Mean = sum of all values/ number of cases  Median = middle observation/ 50th centile  IQR = spread of middle 50% of the distribution  Range = maximum vs minimum  Standard deviation = average distance/ deviation of the observations from the mean ``` Categorical o Nominal = binary (dead/ alive, married/ single) o Ordinal = stratified age groups, social class o Analysis  Frequencies (rates)/ percentages/ proportions  Contingency table • Risk difference • Relative risk • Odds ratio Broad/simple principle - the above affects the statistical analysis used to analyse the data. If continuous, use t test, if categorical, use chi square test.

Question 57

Prevalence and incidence

Answer 57

• Prevalence = PROPORTION o Number of individuals with a given disease at a given point in time o Influenced by disease duration o Prevalence > incidence for chronic disease o NOTE: can also have prevalence over a defined period of time • Incidence = RATE o Number of new events that have occurred in a specific time interval o Likelihood of developing a new event in that time interval – time interval is the denominator

Question 58

Standard deviation

Answer 58

= measures the amount of variability in the population o Assumes a normal curve (mean/ mode/ median are the same, data is symmetrically distributed) o 68% in a sample population are within 1 standard deviation of the mean o 95% are within 2 standard deviations o 99.7% are within 3 standard deviation

Question 59

Normal distribution

Answer 59

= mean is the middle

Question 60

Parametric vs non-parametric

Answer 60

o Parametric tests are generally used when data is normally distributed

Question 61

Null hypothesis

Answer 61

= there is NO difference between the two interventions

Question 62

P value

Answer 62

= the probability, if the null hypothesis were true, of getting a difference between the two group means as large or larger than the difference that we observed • The smaller the p value the stronger the evidence against the null hypothesis • Therefore o If p <0.05 = we reject the null hypothesis o If p >0.05 = we accept the null hypothesis • If the 95% CI does not contain the null value (ie. no difference between the groups) then the p value must be <0.05

Question 63

Type 1 and 2 errors

Answer 63

• Type 1 and 2 errors occur when there is incorrect rejection/ acceptance of the null hypothesis • Type 1 error (alpha, p values) = FALSE POSITIVE o Definition  Test REJECTS a null hypothesis when it is true (ie. false positive – finding a difference that did NOT exist)  Test suggests a population effect exists when it does not o Probability of incorrectly concluding that there is a statistically significant difference in a data set o May be due to bias, confounding or chance o Most commonly due to SAMPLING ERROR o Reduce risk  Randomizing  Blinding  ITT  Risk factor stratification  Sample size – MOST IMPORTANT o The lower the p value the less likely it is to be a false positive o P value of < 0.05: < 1/20 chance that the difference could have occurred by chance • Type 2 error (beta) = FALSE NEGATIVE o Definition  Test fails to a reject a null hypothesis that is false (ie. false negative – did not see a difference that existed)  Test result is non-significant even though a population effect actually exists o Most commonly due to insufficient POWER o Reduce risk by INCREASING power  ↑ Sample size  ↑ Expected effect size + precision

Question 64

Power

Answer 64

* 1-beta = the ability of a study to detect a true difference * Usually set at 0.20: so that there is an 0.8 chance (80% power) to detect a specified degree of difference * Power calculation prior to study calculates how many observations required to detect a desired degree of difference * The larger the anticipated difference, fewer number of observations will be required

Question 65

Confidence interval

Answer 65

• CI = type of interval estimate, computed from the statistics of the observed data, that might contain the true value of an unknown population parameter • Aim to give a measure of variability to give an idea of how confident about a study’s estimate of treatment effects and not due to chance o A range provided that is likely to include the true value • The narrower the range the more precise the study’s estimates and the more confidence that study results represent true findings and not due to chance • Usually expressed in terms of 95% CI – range of results within which we can be 95% certain that true answer (ie. true mean of the population) • Interpretation o If the confidence interval includes 1 = findings are not significant o If the confidence interval is narrow = there are ↓ variance in results or ↑ observations o If the confidence interval is large = there is ↑ variance or ↓ observations

Question 66

Bias

Answer 66

1. Selection bias a. Occurs when there is a difference between the people enrolled and the ‘whole’ population b. Aim to sample randomly, whole population (not voluntarily), aim to minimise refusal, and minimise loss to follow up c. Minimise by: i. RCT: defined study population with specific inclusion/ exclusion criteria ii. Cohort: similar groups except intervention/ exposure status, limit loss to follow up iii. Case: controls representative of whole population 2. Measurement bias a. Occurs when there is inaccurate measurement of data, classification of disease/ risk factors b. Minimise by: i. Measurement bias – accurate and validated tools ii. Observer bias – blinding, objectivity iii. Responder – blinding, comprehension language/ instructions 3. SUMMARY a. Blinding and the use of coded samples = MOST IMPORTANT b. Randomisation of sampling of participants c. Randomisation of the participants to control/intervention d. Randomisation of the order in which measurements are made

Question 67

Confounders

Answer 67

* A cofounding factor is associated with exposure (risk) under study and independently affects risk of developing disease * May affect observed outcome if unequally distributed between study groups / offer an alternative explanation for any association found • Criteria for confounding o Associated with risk factor under study o A risk factor for the disease being investigated • Controlling for confounding o Randomization = equal distribution of potential counfounders between control and intervention groups o Restriction = of confounding factor so not include in study o Matching = subjects on confounding variables o Analysis = stratification of groups according to variable OR statistical regression (allows multiple confounding simultaneously)

Question 68

Odds ratio

Answer 68

• The odds that an individual with a specific condition has been exposed compared to the odds that a control has been exposed • Used in case control studies • Interpretation o OR >1 = positive association o OR = 1 = no association o O <1 = negative/ inverse association • Example = OR 4.89 – those with a headache were 4.89x more likely to have had McDonalds

Question 69

Relative risk

Answer 69

• Proportion of disease in exposed / unexposed • Can only be used in cohort studies (need to be able to calculate the proportion of unexposed with disease) • Interpretation o RR > 1 = risk is greater in exposed than unexposed (?causal) o RR < 1 = risk is less in exposed than unexposed (?protective) o This has relative effect - a RR of 3 could mean a change from risk of 10 -> 30% of 0.1 -> 0.3 % • Example = RR 1.1 – those that attended lecture series 10% more likely to pass

Question 70

Number needed to treat

Answer 70

• Reciprocal of risk difference • Allows comparison of relative benefit/ harm of interventions • CAN be misleading o NNT from different studies CANNOT be compared unless the methods used to determine them are identical o Calculation of NNT depends upon the control rate (which can be variable especially in small trials) • Example: o ie placebo-controlled trial involving 100 patients (50 each group) o 30 patients died (10 receiving active drug and 20 receiving placebo) o = mortality rate of 20% with active drug vs 40% with placebo o RD = 40-20 = 20% (0.2) o NNT = 1/0.2 = 5 Absolute Risk Reduction (= Attributable risk/ Risk difference) • Absolute difference in occurrence of an outcome in the exposed vs unexposed • NOT a proportion Absolute Risk Difference • Rate of occurrence of a disease in the exposed population

Question 71

Hazard ratio

Answer 71

• Hazard ratio is kind of like a relative risk, but provides a time-to-event analysis • Interpretation o HR = 1  event rate is the same in treatment arm compared to control arm o HR = 2  event rate is twice the number of patients in treatment group o HR = 0.5  event rate is half as frequent as patients in control group * E.g. hazard ratio = 0.64 for people given Atorvastatin vs people given placebo. This means people given Atorvastatin are 36% less likely to experience an event than the placebo group. * Often portrayed with Kaplan Meier curve, analysed using Cox proportional regression model

Question 72

T test

Answer 72

Compares the means between 2 groups

Question 73

Chi square test

Answer 73

Compares difference between 2+ % / proportions of categorical outcomes

Question 74

Multi variate analysis

Answer 74

= form of analysis that accounts for multiple variables, o Multiple regression = models used when the outcome is continuous o Logistic regression = used when the outcome is dichotomous

Question 75

Sensitivity, Specificity, PPV, NPV

Answer 75

Sensitivity (A/A +C) • Ability to detect the disease • Proportion of true positives (ie. proportion of individuals with disease that the test identifies) • A sensitive test has a low number of false negatives (Sensitive – Negatives – Rules Out disease) Specificity (D/B+D) • Ability to identify those without the disease • Proportion of true negatives (ie. proportion of individuals without the disease that the test identifies) • A specific test has a low rate of false positives (Specific – Positives – Rules In disease) Sensitivity and specificity do NOT rely on disease prevalence Positive predictive value (A/A +B) • The likelihood of having a disease if a test is positive • Proportion of tests the at are truly positive • True positive/ total positive results • *** PPV always drops if low prevalence Negative predictive value • The likelihood that a patient with a negative test is free from disease • Proportion of tests that are truly negative • True negative/ total negative • *** Usually negative predictive value is the largest percentage

Question 76

Pre test probability

Answer 76

* Probability of a patient having a disease before the diagnostic test is known – essentially prevalence within the subject population * Calculated by proportion of patients with the target disorder/all patients with the symptoms (with and without disorder)

Question 77

Likelihood ratios

Answer 77

• Measures the odds of having a disease relative to the prior probability of disease • This is INDEPENDENT of the disease prevalence • Interpretation o LR = 1  useless test o L >10  large increase in post test probability Positive likelihood ratio = probability of +ve test in those with disease/ probability of +ve test in those without the disease [‘a positive test result is n times more likely in someone with disease’] Negative likelihood ratio = probability of -ve test in those with disease/ probability of -ve test in those without disease [‘a negative test is n times more likely in those without disease’] – the smaller the negative LR the better the test to rule out disease

Question 78

Morbidity and mortality

Answer 78

• Mortality = death rate = number dead / number at risk • Morbidity = illness rate = number sick / number at risk o Case fatality = number dead / number sick

Question 79

Types of cognitive bias

Answer 79

• Affective bias/outcome bias o Effects of emotional influences on thinking, including feelings toward patients, both positive and negative  believing the diagnosis you want to be true for that particular patient (e.g. headache in friend  migraine over SAH) • Aggregate bias/ecological fallacy o Not applying clinical decision instruments to the patient in front of you, who is seen as different • Ambiguity effect o Select options/diagnoses for which the probability is known, rather than the diagnosis for which probability is unknown (regardless of whether it is actually more likely) • Anchoring/premature closure o Accepting a diagnosis before it is fully verified, based on a single/few features – despite other features refuting this hypothesis o Related to, and made worse by, confirmation bias • Ascertainment bias o Decision making is shaped by prior expectations e.g. stereotyping, gender bias • Availability bias o Recent experience with a particular diagnosis increasing the chance that the same diagnosis will be made again o  Rare disease under-diagnosed, and common diseases overdiagnosed • Commission and omission bias o The tendency towards action (commission) or inaction (omission) • Confirmation bias o Once an opinion is formed, the tendency to only notice evidence that supports the diagnosis, and ignore contrary evidence

Question 80

WHO principles of screening

Answer 80

• Condition o The condition should be an important health problem o There should be a recognisable latent or early symptomatic sage o The natural history of the condition, including development from latent to declared disease, should be adequately understood • Test o There should be a suitable test or examination o The test should be acceptable to the population • Treatment o There should be an accepted treatment for patients with recognized disease • Screening program o There should be an agreed policy on whom to treat as patients o Facilities for diagnosis and treatment should be available o The cost of case-finding (including diagnosis and treatment of patients) should be economically balanced in relation to possible expenditure on medical care as a whole o Case-finding should be a continuing process and not a ‘once and for all’ project

Question 81

Lead and length time biases

Answer 81

• Lead time o Screening picks up disease earlier than clinical diagnosis o Seems like prognosis is better since living longer, actually just living longer with knowledge of disease – also less aggressive forms are picked up (with better prognoses) • Length time o Screening picks up people with less aggressive form of disease o Makes prevalence seem lower – people have died already o Miss people with very aggressive disease