Lecture 10.1: Adverse Drug Reactions and Pharmacovigilance Flashcards
What is an Adverse Drug Reaction?
Unwanted or harmful reaction following administration of a drug or combination of drugs under normal conditions of use suspected to be related to the drug
How can ADRs be catagorised?
- Those that occur at concentrations within therapeutic
range (side effects) - Those that occur beyond the therapeutic range (toxic
effects)
What are the 2 classifications of adverse drug reactions?
- Adverse affects related to the known pharmacological
action of the drug - Adverse affects unrelated to the known
pharmacological action of the drug
Type A: Augmented Reactions
- Predictable from knowledge of how a medication
works - Dose related
- Reversible
- Adjust dose
Examples of Type A (Augmented Reactions) (4)
- Opioid induced constipation: predictable consequence
of opiate action on opioid receptors in the gut - Postural hypotension with alpha antagonists
- Bleeding with anticoagulants
- Hypoglycaemia with insulin
Type B: Bizarre Reactions or Idiosyncratic Reactions
- Not related to the pharmacological action of the drug
- Not predictable, uncommon, often fatal
- Not dose dependent in the therapeutic range
- Often immunological
- Often linked to genetic variation
Examples of Type B (Bizarre Reactions or Idiosyncratic Reactions) (5)
- Anaphylaxis and penicillin
- Aplastic anaemia and chloramphenicol
- Peripheral neuropathy and isoniazid
- Agranulocytosis and carbimazole
- Malignant hyperthermia and hepatitis from
anaesthetic agents
Type C: Continuous Reactions
- Persist relatively long time
- Steroid therapy and osteoporosis
- Prolonged steroid use and adrenal suppression
Type D: Delayed Reactions
- Apparent sometime after use of a medicine
- Azathioprine immunosuppression and malignancy
Type E: End of Use Reactions
E.g insomnia, anxiety, perceptual disturbances following
benzodiazepine withdrawal
Type F: Failure
Failure of oral contraceptive and enzyme inducer
What is the DoTS System?
- Dose
- Timing
- Susceptibilities
What is Hypersusceptibility?
ADR at much lower than therapeutic doses
What are Collateral Effects?
ADR at therapeutic doses
What are Toxic Effects?
ADR at doses higher than therapeutic
Types of Time Dependent Reactions (6)
- Rapid Reactions
- Early Reactions
- First Dose Reactions
- Intermediate Reactions
- Late Reactions
- Delayed Reactions
What are Rapid Reactions? Example?
- Occur when a drug is administered too rapidly
- Red man syndrome following rapid infusion of
vancomycin
What are Early Reactions? Example?
- Occur early in treatment and then abate with time
(tolerance) - Nitrate induced headache
What are First Dose Reactions? Example?
- Occur after first dose
- Hypotension after ACEI
What are Intermediate Reactions? Example?
- Occur after some delay, if reaction does not occur
after a certain time then little or no risk is posed - Some allergic reactions
What are Late Reactions? Example?
- Risk of ADR increases with continued repeated
exposure, including withdrawal symptoms - Withdrawal reactions following long-term
corticosteroids
What are Delayed Reactions? Example?
- Occur sometime after exposure, even if drug
withdrawn - Teratogens (thalidomide)
Drug Development Process (5)
- Drug Discovery (2-5 yrs)
- Preclinical Development (1.5yrs)
- Clinical Development (3 Phases) (5-7yrs)
- Regulatory Approval (1-2yrs)
- Post Marketing Surveillance
What are the Stages of Clinical Trials/Development (3)
- Phase 1 (human volunteers)
- Phase 2 (few hundred patients with target disease)
- Phase 3 (controlled clinical trial – several thousand
patients with target disease)
Medical Product Characteristics (SPC): What are Contraindications?
Defines the patient populations who must not take the medicine
Medical Product Characteristics (SPC): Undesirable Effects
Summary of safety profile of the medicine informing on the most serious and/or most frequently occurring adverse reactions. A tabulated list of all adverse reactions with their respective frequency
What does it mean when the Frequency of Side-Effects is Very Common?
Greater than 1 in 10 (10% +)
What does it mean when the Frequency of Side-Effects is Common?
1 in 100 to 1 in 10 (1-10%)
What does it mean when the Frequency of Side-Effects is Uncommon?
1 in 1000 to 1 in 100 (0.1 – 1%)
What does it mean when the Frequency of Side-Effects is Rare?
1 in 10 000 to 1 in 1000 (0.01 – 0.1%)
What does it mean when the Frequency of Side-Effects is Very Rare?
Less than 1 in 10 000 (0.01% or less)
What does it mean when the Frequency of Side-Effects is Frequency Not Known?
Frequency is not defined by product literature or the side-effect has been reported from post-marketing surveillance data
What is Pharmacovigilance?
The practice of monitoring the effects of medical drugs after they have been licensed for use, especially in order to identify and evaluate previously unreported adverse reactions
What is the Yellow Card Scheme?
Report suspected side effects to medicines, vaccines, e-cigarettes, medical device incidents, defective or falsified (fake) products to the Medicines and Healthcare products Regulatory Agency to ensure safe and effective use
What does a Black Triangle indicate about a medication?
- Highlight medicines that are subject to intensive safety
monitoring - The black triangle alerts both patients HCPs that the
medicine is being closely monitored by European
regulatory authorities
How is Toxicity Testing carried out? (6)
- Animals: assumption is toxicity similar in humans but
may be interspecies differences in drug metabolising
enzymes - Biochemistry, post mortem
- Doses well above therapeutic: target organs for
toxicity - Reversible or irreversible carcinogenesis/
neurodegeneration) - Liver: hepatocytes exposed to metabolites
- Kidney: renal tubule
What drugs can cause altered intraglomerular haemodynamics? (3)
- Non-steroidal anti-inflammatory drugs (NSAIDs)
- Angiotensin-converting enzyme inhibitors (ACEi)
- Angiotensin receptor blockers (ARB)
What is Tubular Cell Toxicity?
- Tubular cells exposed to high levels of toxins
(concentrating reabsorbing) - Metabolically active
- Toxins impair mitochondrial function and tubular
transport
What drugs can cause Tubular Cell Toxicity? (4)
- Gentamicin
- Iodinated contrast agents
- Antiretrovirals
- Cisplatin
What drugs can cause Inflammatory Changes in the renal system? (7)
- Allopurinol
- Antibiotics (beta lactams, quinolones, sulfonamides,
and vancomycin) - Antivirals (acyclovir)
- Diuretics (loop, thiazides);
- NSAIDs
- Phenytoin
- PPIs (lansoprazole)
What drugs can cause Crystal Depositions in the renal system? (5)
- Ampicillin
- Ciprofloxacin
- Acyclovir
- Methotrexate
- Chemotherapy for lymphoproliferative disease -
tumour lysis syndrome - uric acid and calcium
phosphate crystal deposition
What drugs can cause Rhabdomyolysis? (2)
- Statins
- > 150 medications and toxins have been implicated -
cocaine, heroin)
What drugs can cause Thrombotic Microangiopathy? (5)
- Platelet thrombi in the microcirculation
- Antiplatelet agents (clopidogrel)
- Cyclosporine
- Mitomycin-C
- Quinine
What is Thrombotic Microangiopathy?
Clinical syndromes defined by the presence of hemolytic anemia (destruction of red blood cells), low platelets, and organ damage due to the formation of microscopic blood clots in capillaries and small arteries
Mutagenesis
- Modification of DNA bases
- Chromosomal damage
- Mutation in proto-oncogenes and tumour suppressor
genes
Teratogenesis
A process that causes birth defects or malformations in an embryo or foetus
Taking what supplement can reduce spontaneous and drug induced neural tube defects?
Folate/Folic Acid
Effects of Antiepileptic Drugs in Pregnancy
- Congenital malformations 2-3 X in mums with epilepsy
- Phenytoin – cleft lip and palate
- Valproate – neural tube defects
- Valproate rate of congenital abnormality 10% and a
30% to 40% chance of a wide range of early.
developmental problems that can lead to learning
disabilities - Carbamazepine - spina bifida
Rifampin, antituberculosis drug is an inducer of isoenzyme CYP2C9 which leads to…?
Decreased plasma levels of HIV protease inhibitors, disabling suppression of HIV replication
Omeprazole is an inhibitor of CYP2C9 which may lead to increased warfarin plasma levels leading to …?
Bigger anticoagulant effect and greater risk of
bleeding
