1.4 ADR Flashcards
Please explain the different definitions of ADR, side effects, and adverse drug events.
ADR: (Adverse drug reactions) any untoward medical occurence associated with the use of a drug in humans for which there is a reasonable possibility the drug caused the adverse event.
Side effects: any intended effect of a drug (wheather therapeutical or adverse), may even be beneficial
Adverse drug events: any injury at the time the drug is used, irrespectively of causal relationship
What is the EMA standard nomenclature of ADR frequency?
very common: >10% common: 1-10% uncommon 0,1-1% rare: 0,01-0,1% very rare: <0,001%
Please explain mechanistically and give examples for the different ADR types.
Type A: augmented = dose-dependent, predictable, very common (80% of all ADR) –> Management: dose adjustment (e.g. in orthostatic hypertension from antihyptertensives)
Type B. Bizzare = dose-independent, unpredictable, very rare, occasionally fatal,
eg. anaphylaxis from penecillin
- -> Management: anamnesis, no re-challenge
Type C: chronic = time+ dose-dependent, predictable, common (e.g. hypocalemia from diuretics or analgesic nephropathy)
–> Management: dose reduction, shorter duration
Type D: delayed = dose (in)-dependent, predictable, rare, occur after months/years (eg tardive dyskinesia of antipsychotics/fetal toxicity in pregnancy) –>Management: not possible if indication is given
Type E: end-of-use = withdrawl, rebound, common, predictable (e.g. sleeping disorders or rebound hypertension after stopping antihypertensive
medication) –> management: Slow reduction of dose, no immediate stopping
Please give an overview of ADR risk factors and explain the respective mechanistic and pathophysiological background.
Crtitical drugs: could have very common and/or severe ADR (NSAIDs, diuretics, anticoagulants), narrow TI (lithium), extensive toxicity (chemotherapy)
predisposing immunological diseases as well as predisposing allergic diseases
being female: Women take more drugs and are more likely to tell about ADR; different physioloy (height, weight, hormones)
polymedication: risk of drug interactions when taking (>5 drugs per day) –> cascade of prescription
renal/hepatic insufficiency: decreased metabolism (increased toxicity)
standard doses (for non standard people)
individual pharmacogenetics: Like HLA-haplotype
Which drug classes are most relevant for ADR manifestation in elderly patients? Which precautions are appropriate to reduce the ADR risk?
- Antihypertensive drugs
- Psychotropic drugs
- Diuretic drugs
- -> most common cause: relative drug overdose (due to neglecting weight loss/renal impairment)
Strict indictions for all groups, start low, go slow, therapy control and surveillance of K+ and Na+ in blood (diuretics)
Which tools can be used to increase drug safety in geriatric pharmacotherapy?
Beers criteria: comprehensive + systematic review of potentially inappropriate medication in older adults, grading of evidence on drug-related problems, gives information in which drugs dose modification is needed in patients with renal impairment, but does not always give an alternative/sugestion of the reduction
START/STOPP criteria: START = screening tool to alert the right treatment –> prevention of undertreatment
STOPP = screening tool to older peoples prescriptions –> prevention of overtreatment + ADR
What is the mechanistic background of an analgesic-associated nephropathy?
Kidney injury induced by excessive NSAID use –> decreased renal blood flow due to inhibition prostaglandin E2 production (by COX-1 inhibition)–> renal papillary necrosis, interstitial nephritis
Most common with NSAIDs that inhibti COX1 (as well as COX2 production) like phenacitin (not available anymore), very rare with paracetamol
AAN ist common for NSAIDs when high-dose, long-term use and combinations of different NSAIDs, pre-existing renal impairment, dehydration
Please explain the different DILI types and provide specific examples.
Direct hepatotoxicity: dose-dependent, rapid onset (predictable and preventable), occurs with overdose in only a few drugs (paracetamol, MTX, aspirin) –> Accumulation of toxic metabolites
Idiosyncratic/indirect hepatotoxicity: non dose-related (may occur with standard dose), can occur with almost every drug, Partially or not predictable, in some cases association with HLA type (flucoxacillin)
What is the pathophysiological role of pyrrolizidine alkaloids in the context of HILI?
Produced by plants for herbivore defense.
Exhibit acute hepatotoxicity and are cancerogenic, eg. retronecine
Contamination of organic teas
enzymatic cleavage –> Dehydropyrrolizidine alkoloids react with cell protein and DNA
