Lecture 12 Adverse Drug Reactions and Interactions Flashcards
Why may patients lost confidence after an ADR?
It may mimic disease and so leads to unnecessary investigations or treatment.
- In BCH study 2001 what were the commonest classes of drugs causing ADRs?
- What were the drugs most commonly involved in SEVERE ADRs?
- Antibiotics, analgesics and anticoagulants.
2. Hypoglycaemic agents (insulin) and NSAIDs.
Describe the nature of ADRs
- Nausea and vomiting
- Excessive sedation
- Rash
- Bleeding
- Renal failure/ electrolyte abnormalities
- Abnormal liver enzymes
Describe 4 categories of drugs which commonly cause ADRs and give examples in each class
ANTIBIOTICS:
- Flucloxacillin/ Co-amoxiclav
- Clarithromycin
- Ceftazidine
ANTICOAGULANTS:
- Warfarin/ LMWH
ANALGESICS:
- Morphine/ Tramadol/ Co-codamol 30/50
- Ibuprofen or other NSAIDs
ANTIHYPERTENSIVES:
- ACEis/ ARBs
- Diuretics
- Alpha blockers
How are ADRs classified?
Type A - augmented/ accentuated Type B - bizarre Type C - chronic Type D - delayed Type E - end of use Type F - failure
Describe TYPE A (Augmented) ADRs
Give an example
- Dose dependent
- Predictable from the pharmacology of the drug
- Host independent
- Common
- Usually mild
- Low morbidity and mortality
- Reproducible in animal studies
- Reduce dose or withhold the drug
e.g. bleeding/ bruising on warfarin or aspirin.
- Describe the pharmacokinetic, pharmacodynamic and pharmaceutical mechanisms of Type A ADRs
- Explain pharmacogenetics in Type A ARDs
- Pharmacokinetic:
- renal excretion
- hepatic metabolism
- extremes of age
- genetic variations
Pharmacodynamic:
- genetic variations
- extremes of age
Pharmaceutical:
- excipients
- bioequivalence
- Poor metabolisers or extensive metabolisers
- CYP2D6
- CYP2C19
- Acetylation ‘fast’/’slow’
- Methylation
- Non-hepatic metabolism (pseudocholinesterase)
Describe TYPE B (Bizarre) ADRs.
Give an example
- Dose independent
- Unpredictable
- Host dependent
- Uncommon
- Can be severe
- High morbidity and mortality
- No animal models
- Withhold and avoid in future/ put in notes
Anaphylaxis to penicillin
What are the mechanisms of Type B ADRs?
- Allergic reactions
- Pseudoallergie reactions
- Genetic factors
What are the types of hypersensitivity (allergic) reactions?
Type I (immediate) - IgE –> mast cell release –> anaphylaxis
Type II (antibody-mediated cytotoxic) - drug induced haemolysis
Type III (immune complex) - fever, rash, arthropathy, glomerular damage
Type IV (delayed/ cell mediated) - drug acts as hapten, rash common
What are the types of rash?
- Typical drug-induced rash. Most common is palpable purpura around 1-3mm which may coalesce to form plaques or ulcerate. More commonly found on the legs.
- Rare and severe Stevens-Johnson syndrome.
- Photosensitivity reaction. Metabolite deposition in the skin/ enhanced melanin production/ drug induced post-inflammatory changes in the skin.
What drugs are involved in drug-induced photosensitivity?
- ANTIMALARIALS
- Chemotherapeutic agents
- Psychotropic drugs
- Heavy metals
- Miscellaneous medications (e.g. amiodarone, zidovudine, minoclycline, psoralens)
What are pseudo allergic drug reactions?
Name a drug that is particularly associated with this anaphylactoid reaction.
- Mimic allergic reactions, especially type I, similar clinical features but NO EVIDENCE OF IMMUNE RESPONSE
- If severe may be termed anaphylactoid
N-Acetylcysteine.
- Anaphylactoid reaction relatively common
- giving drug too fast results in vasoreactive histamine release
- therefore ALWAYS check your calculations with someone else
Explain the pharmacogenetics of Type B ADRs.
- Glucose-6-phosphate dehydrogenase deficiency - leads to haemolysis of RBCs with oxidising agents
- Porphyria
- Malignant hyperthermia - 1:20,000 abnormal response to GA
- Coumarin (warfarin) resistance
- Aminoglycoside induced deafness
- Long QT syndrome
Describe TYPE C (Chronic/ cumulative) ADRs.
Give an example.
- Uncommon
- Related to cumulative dose
- Withdrawal may need to be carried out slowly
e.g. Adrenal suppression with long term corticosteroids.
Describe TYPE D (Delayed) ADRs.
Give an example.
- Uncommon
- Occurs some time after the drug has been started
- Often dose and time related
- Often intractable
e.g. Carcinogenesis or Tardive dyskinesia
Describe TYPE E (End-of-use) ADRs.
Give an example.
- Uncommon
- Withdrawal effect
- Re-introduce drug and wean down slowly
e. g. Opiate withdrawal syndrome
e. g. MI coming off B blockers
Describe TYPE F (Failure) ADRs.
Give an example
- Usually dose related
- May be due to drug interactions
- Increase dose and consider potential drug interactions
e.g. failure of OCP due to enzyme induction
How do you identify an ADR?
What is the algorithm used to assess causality of an ADR?
- Timing of administration
- Previous evidence in literature
- Absence of alternative explanation
- Effects of re-challenge
The Naranjo algorithm.
- How do you report ADRs?
2. Which ADRs do you report?
- Report to Committee on Safety of Medicines (MRHA) by Yellow card scheme
- For established drugs report ‘ALL serious suspected reactions’ i.e. fatal, life threatening or disabling which prolong hospital stay even if the effect is well recognised.
New drugs - report ALL suspected reactions i.e. any adverse or unexpected event however minor which could conceivably be attributed to the drug.
How do you manage a suspected ADR?
- Identify problem as an ADR
- Remove offending drugs
- Provide supportive treatment as required
- Check no error has occurred
- Report ADR to MHRA (yellow card) if appropriate
- Write in Kardex/ medical notes and inform GP
What percentage of ADRs are accounted for by Drug Interactions?
15%
What are the mechanisms of drug interactions?
- Pharmaceutical
- phenytoin and dextrose
- Calcium salts and sodium bicarbonate - Pharmacokinetic
- Absorption: pH, chelation, rate of gastric emptying
- Distribution: protein binding
- Metabolism: phase 1 and phase 2 reactions
- Excretion: pH, competition - Pharmacodynamic
- Receptor interactions (agonists, antagonists and partial agonists)
- Physiological interactions (potentiation, summation, antagonism)
Describe the pharmacokinetic aspects of drug interactions including:
Absorption
Distribution
Metabolism
Elimination
ABSORPTION
- pH
- Surface area (activated charcoal)
- Chelation (tetracyclines and charcoal)
- Gastric emptying (metoclopramide)
DISTRIBUTION
- Displacement from plasma protein binding sites. Theoretical effect for highly protein bound drugs e.g. warfarin and phenytoin but as system is dynamic increased free drug leads to increased clearance.
- Displacement from tissue binding sites e.g. increased digoxin level with amiodrone therapy.
METABOLISM
- Enzyme inducers PC BRAGS
- Enzyme inhibitors
(see the prescribing in liver failure lecture)
EXCRETION
- Inhibition of renal tubular secretion e.g. verapamil decreases the renal secretion of digoxin, salicylate decrease the renal tubular secretion of methotrexate.
- Induced renal tubular absorption e.g. diuretics decrease sodium reabsorption producing a compensatory rise in lithium reabsorption
- Reduced renal tubular absorption - change in pH can alter reabsorption of drugs.
