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
What’s the overall effect of phase I and II metabolism reactions on drugs?
More polar - easier to excrete by kidneys
How can co-administration of drugs affect drug metabolism?
Drug metabolism interactions may be inhibited or enhanced by co-administration of other drugs
Do most drugs undergo metabolism by a single or multiple isozymes (CYP450 substrates)?
- Multiple isozymes
* If co-administered with CYP450 inhibitor, the other isozymes increase activity to compensate
Over half of drug metabolism is done by which CYP450 isozymes?
CYP2D6 and CYP3A4
Give examples of CYP450 inhibitors
- Cimetidine (peptic ulcer treatment)
- Erythromycin
- Ketoconazole
- Ritonavir
- Fluoexetine (SSRI)
- Grapefruit juice
Give examples of CYP450 inducers
- Rifampicin (antibiotic)
- Carbamazepine
- St John’s Wort (hypericin)
How long does CYP450 inhibition and induction take?
- Inhibition - rapid
* Induction - hours/days
Where do drug elimination interactions almost always take place?
Renal tubule
e. g. probenecid reduced elimination of penicillin (good)
e. g. thiazides reduce clearance of lithium (toxic)
Give examples of deliberate interactions that are commonly prescribed?
- Levadopa and carbidopa
- ACEi and thiazides
- Penicillins and gentamicin
- Salbutamol and ipratropium (beta-2 antagonist + anticholinergic) - in asthma to bronchodilate
