21. Adverse drug reactions Flashcards
What percentage of adverse drug reactions are preventable?
30-60%
How are ARDs classified (3 ways)?
- Onset
- Severity
- Type
How is the onset of ARDs categorised?
- Acute: within 1 hour
- Sub-acute: 1-24 hours
- Latent: >2 days
How is the severity of ARDs categorised?
- Mild: no change in therapy required
- Moderate: change in therapy required, maybe additional treatment, possible hospitalisation
- Severe: disabling, life-threatening, causes damage to foetus, requires intervention to prevent permanent injury
How is the type of ARDs categorised?
- Type A - augmented pharmacological effect (majority)
- Type B - bizzare
- Type C - chronic
- Type D - delayed
- Type E - end-of-treatment
Outline type A reactions
- Augmented pharmacological effect of known drug
- Usually predictable and often dose dependent
- Responsible for 2/3 of ADRs
How dose the toxicity of paracetamol and digoxin increase with dose?
- Paracetamol slowly increases toxicity through the therapeutic affect, then sharply increases just after
- Digoxin increases more than initial paracetamol rise, but is consistent
Outline type B reactions
- More dramatic
- Idiosyncratic (particular to given individuals) or immunologic reactions
- Include allergy and pseudo-allergy
- Very rare and unpredictable
- e.g. ACEi and angioedema (pseudo-allergy)
Outline type C reactions
- Associated with long-term use of drugs
- Involve dose accumulation
- e.g. methotrexate (chemotherapy/immunosuppressant) and liver fibrosis
Outline type D reactions
• Delayed effects (sometimes dose dependent, but not strongly linked)
• e.g. carcinogenicity (immunosuppressants)
• e.g. teratogenicity (thalidomide)
•
Outline type E reactions
- Withdrawal reactions - opiates, benzodiazepines, corticosteroids
- Rebound reactions - clonidine, beta-blockers, corticosteroids
- Adaptive reactions - neuroleptics
Describe the rebound reaction of clonidine withdrawal
- Used to be used as an anti-hypertensive
- Alpha-2 agonist - reduced release of NA - drop in BP
- If you miss 1 or 2 doses, substantial rise in BP
- Long-term use of clonidine causes long-term suppression of NA production
- Leads to compensatory up-regulation in adrenergic receptors on post-synaptic neurone
- NA has more receptors to act one when inhibition is removed
What are the 4 classifications for allergies and give an example for each?
- Type I - immediate, anaphylactic (IgE) e.g. anaphylaxis with penicillin
- Type II - cytotoxic antibody (IgG, IgM) e.g. methyldopa and hemolytic anaemia
- Type III - serum sickness (IgG, IgM): antigen-antibody complex e.g. procainamide-induced lupus
- Type IV - delayed hypersensitivity (T cell) e.g. contact dermatitis
Are pseudoallergies related to the immune system?
No
Why are aspirin/NSAIDs associated with bronchospasm?
Pseudoallergy
• Inhibition of COX
• Reduction of prostanoid synthesis (bronchodilators)
• Body makes more leukotrienes instead (pro-inflammatory and bronchoconstrictors)
• Pharmacological reaction
What are the signs and symptoms of angioedema similar to?
Anaphylaxis, but much less severe
What are the most common causes of ADRs?
- Antineoplastic drugs (as they are given to so many people)
- Cardiovascular drugs
- NSAID/analgesics
- CNS drugs
(also antibiotics, anticoagulants, antihypertensives)
How do we detects ARDs (problem with disease or drugs)?
- Subjective report - patient complant
- Objective report - direct observation
- Sometimes need a larger number of events if e.g. 1/100 chance
What is the yellow card scheme?
- Public way of detecting adverse reactions (introduced in 1964 after thalidomide)
- No system of checking safety before then
- Scheme is voluntary and can be used by doctors, coroners, pharmacists, members of the public etc.
- Included blood products, vaccines, contrast media
- Only report serious ADRs for established drugs
- Black triangle drugs (newly licensed <2 years) - report any suspected adverse reaction
What are the 3 varieties of drug interactions?
- Pharmacodynamic - related to drug’s effects in the body
- Pharmacokinetic - related to body’s effect on the drug (e.g. metabolism)
- Pharmaceutical interactions - drugs interacting outside the body (mostly IV infusions)
Describe the 3 types of pharmacodynamic drug interactions
- Additive - 2 drugs producing an effect of the sum of the drugs - overlapping toxicities e.g. ethanol + benzodiazepines
- Synergistic actions of antibiotics - 2 drugs potentiate each others actions for a greater effect than expected
- Antagonistic effects e.g. anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)
What are the 3 types of pharmacokinetic drug interactions?
- Alterations in absorption (chelation)
- Protein binding interactions
- Drug metabolism and elimination
What does alterations of absorption (chelation) involve in ‘pharmacokinetic interactions’?
- Irreversible binding of drugs in the GIT
- Tetracyclines and quinolone antibiotics can be involved
- They form a stable chelate with mineral ions e.g. ferrous sulphate, dairy products and antacids
- Therefore you don’t absorb the ion or antibiotic
What do protein binding interactions (pharmacokinetic) involve?
- Competition between drugs for protein or tissue binding sites
- Increase in free (unbound) concentration - enhanced pharmacological effect
- Most are not usually clinically significant, few are (mostly warfarin)
- Warfarin is tightly bound to proteins - small displacement has drastic effects
