Wk11 ADR Flashcards
What is ‘adverse drug reaction’?
- a response to a drug which is noxious and unintended, and which occurs at therapeutic use/dosage
- different to side effect (undesired effect that occurs when the medication is administered regardless of the dose)
What is the role of Therapeutic Good Administration (TGA) in the regulation of medicines?
- regulatory authority for therapeutic goods
- maintains the Australian Register of Therapeutic Goods
- Carries out assessment and monitoring of therapeutic goods in AU
> evaluate and regulate the therapeutics before they reach the market
> monitor safety/efficacy after they reach the market - continue post marketing surveillance: monitoring the drug after it’s on the market (phase IV of clinical trial)
- Regulatory decisions are made based on risk-benefit analysis, eg ACEi and cough
How TGA works?
> medicines are registered: with established quality, safety and efficacy evaluation, and medical benefits outweigh risks
> products are listed: quality and safety established, but not efficacy*, ie complementary medicines
What are the processes by which ADR is reported to the TGA?
- Anyone can report an adverse reaction to the TGA via the TGA website
- Any adverse reaction/interaction of registered/listed medicines, vaccines, medical devices should be reported regardless of whether you’re certain/suspicious
- Community and sponsor (drug company) monitors safety and reports ADR
How the ADRs are categorised (A)?
A: augmented (related to the drug)
Characteristics: common, predictable, related to the pharmacological action of the drug - long half-life, dose-related
Example: digoxin toxicity, β-agonists and tachycardia, β-blockers and hypotension
Management: reduce dose, withhold treatment, consider effects of concomitant therapy e.g. other drugs the patient is taking contributing to the reaction?
Example - digoxin toxicity
> treatment of AF - slows HR, slows the conduction rate through the AV node + increases the refractory period of AV node
> low therapeutic index [A high therapeutic index is desirable, a low therapeutic index means that the dose which causes
therapeutic effect is close to the threshold dose at which adverse effects occur]
> S/S of digoxin toxicity:
- N/V, worsen arrhythmia, visual disturbance
- At high doses – can lead to AV node block
> Eliminated unchanged via kidneys as substrate of P-glycoprotein – be careful in those with renal impairment
> Drugs which ↓ digoxin elimination (inhibit P-glycoprotein), leading to ↑ digoxin concentration:
amiodarone, verapamil, diltiazem, erythromycin, sertraline
① Digoxin Toxicity（Type A）：考虑病人肾功能/测浓度/Clinical Response/Hypokalaemia，浓度>2危险，需Digifab解毒
② Digoxin MOA：帮Afib降AV node降心率，帮心衰堵住NaK pump留盐
How the ADRs are categorised (B)?
B: bizarre (related to the person)
Characteristics: uncommon, unpredictable, not related to pharmacological action of the drug, may be caused by genetic factors
Examples: immunological/allergic reactions, eg penicillin hypersensitivity
Management: withhold treatment, avoid in future
Example: sulfonamide hypersensitivity (antibiotics)
o Describe immediate (type I) and delayed (type IV) hypersensitivity reactions
Type I reactions/immediate ADR: less common, hives, anaphylaxis
Type IV reactions/delayed ADR: more common, cutaneous rashes (can appear days after treatment), steven-johnson syndrome
o List symptoms of sulfonamide hypersensitivity reactions
> Sulfonamide hypersensitivity: fever, dyspnoea, cough, rash, anaphylaxis
o Describe and relate the structure of sulfonamide antibiotics and non-sulfonamide antibiotics to sulfonamide hypersensitivity reactions
o Discuss the likelihood of cross-reactivity in sulfonamide hypersensitivity reactions
There are associations between sulfonamide antibiotics/non-antibiotics and subsequent hypersensitivities. However, these associations appear to be predispositions to allergic reactions rather than to cross-reactivity with sulfonamide-based drugs.
How the ADRs are categorised (C)?
C: Chronic (chronic use of a drug)
Characteristics: uncommon, related to the cumulative dose
Examples: corticosteroid-induced adrenal suppression, NSAIDs + peptic ulcers
Management: ↓ dose, withhold treatment, withdraw over prolonged time
Example: chronic corticosteroid use + adrenal suppression (prednisone, cortisone)
o Recall the mechanism of action and clinical uses of corticosteroid drugs
o List adverse reactions which may occur following chronic corticosteroid administration
> ADR: osteoporosis, hyperglycaemia, diabetes, inhibition of growth in children, adrenal suppression
o Describe how chronic inhaled corticosteroid use can lead to oral candidiasis
> Inhaled corticosteroids lead to local
immunosuppressive effects
o Describe how chronic corticosteroid use can lead to adrenal suppression
> Glucocorticoid release is controlled by a negative feedback mechanism
> Administration of glucocorticoids reduces the patient’s ability to synthesise corticosteroids due to suppression of feedback mechanism
> Glucocorticoid drugs mustn’t be withdrawn suddenly – can lead to adrenal insufficiency – crossover with category E
How the ADRs are categorised (D)?
D: delayed
Characteristics: uncommon, usually dose-related, occur sometime after taking the drug
Examples: teratogenetic effects (birth defects), carcinogenesis (cause cancer)
Management: reduce dose, withhold treatment
Example: thalidomide + teratogenesis
o Define “teratogen” and list some examples of drugs which can have teratogenic effects
> Teratogenesis: congenital malformation from a drug/agent (teratogen)
o Describe the thalidomide tragedy
> Thalidomide → morning sickness(antiemetics) → “seal limbs”
o Describe the categorisation of drugs for use in pregnancy
> Drugs were categorised based on their risk when used during pregnancy
> Categories only valid at recommended therapeutic doses
o Recognise examples of drugs belonging to category A, B, C, D, X
A - no evidence, B - limited human evidence/0 or little evidence in animal, C - suspected but reversible damage, D - suspected but irreversible damage, X - high risk (Thalidomide)
o Understand limitations of and common misconceptions relating to the categorisation of drugs for pregnancy
– A, B, C, D implies a hierarchy of risk - category C is worse than category B NO
– Drugs within the same category carry a similar risk NO
– Sodium valproate (significantly increased risk defects) vs. paroxetine (slightly increased risk of heart defects)
– Category D drugs are unsafe to use throughout the whole pregnancy NO
> Some drugs may only cause defects in the early stages of pregnancy
– Category D drugs are unsafe no matter the dose or route of administration NO
> Fluconazole single oral dose for thrush vs. IV for systemic fungal infection
– Animal data is directly translatable to humans NO
How the ADRs are categorised (E)?
E: end of use (withdrawal)
Characteristics: uncommon, occurs soon after withdrawal of drug
Examples: opioid withdrawal, benzo withdrawal, SSRI withdrawal
Management: reintroduce and withdraw slowly
Example: opioid withdrawal syndromes
o Define “physical dependence”
> Physical dependence: withdrawal leads to adverse physiological effects (sweating, nausea, shivering, piloerection, muscle aches, tachycardia, increased BP, diarrhoea)
o List examples of drugs which, upon cessation, may produce withdrawal symptoms
> Withdrawal effects can be experienced when administering an agonist e.g. heroin + naloxone
o List symptoms which may occur following cessation of opioids and benzodiazepines
Withdrawal opioid/benzo: anxiety, irritability, tremor, hallucination/psychosis
o Describe how withdrawal is managed
> Naloxone - opioid antagonist
> withdrawal can be managed using a benzodiazepine with a longer t1/2
e.g. diazepam
How the ADRs are categorised (F)?
F: failure
Characteristics: common, dose-related, often caused by drug interactions (metabolism-related e.g. drugs inhibiting/inducing CYP enzymes)
Examples: oral contraceptive failure
Management: ↑ dosage, consider effects of concomitant therapy
Example: oral contraceptive failure
o Understand the role of Cytochrome P450 enzymes in drug metabolism
> Metabolism of the pill by CYP3A4 reduces
the plasma concentration of active drug
o Identify drugs which are CYP3A4 substrates/inhibitors/inducers
> CYP3A4 substrates:
> CYP3A4 inhibitors: clarithromycin, erythromycin, verapamil, diltiazem
> CYP3A4 inducers: St John’s Wort, glucocorticoids, rifampicin, phenytoin, carbamazepine
o Understand how CYP3A4 induction may cause oral contraceptive failure
o Understand how the induction or inhibition of metabolic enzymes may affect the plasma concentration of drugs
> If taking another drug that INDUCES CYPA3A4 → this increases the rate of pill metabolism → reduces plasma concentration of pill → reduces efficacy = pregnancy
What are the risk factors that contribute to ADR?
- age: children, elderly
- gender: females
- genetics: the efficacy of human immune response
- polypharmacy: drug interactions
How genetic polymorphisms may contribute to the flushing response following alcohol ingestion?
– ALDH2*2 polymorphism = decreased activity of ALDH
– Cannot metabolise acetaldehyde/alcohol effectively
– Accumulation of acetaldehyde/alcohol → Flushing response
