Lecture 25 - adverse drug reactions mechanisms Flashcards
what is the WHO definition fOR an ADR?
this is any “response to a drug which is noxious, unintended and occurs at doses used for prophylaxis, diagnosis, or therapy”
Excludes:
- Intentional or accidental poisoning (i.e. overdose)
- Therapeutic failures
- Drug abuse
- Errors in drug administration
What is the incidence of adverse drug reactions in hospitalised patients?
Incidence of serious ADRs 6.7%
- In 1994 2.2 million patients
Incidence of fatal ADRs 0.32%
- In 1994 0.1 million patients
~ 5th leading cause of death
1225 admissions related to ADR (6.5%)
28 patients died (0.15%)
Patients hospitalised for 8 days
Cost NHS £466 million
what are examples of ADRs in respsoen to medications ?
Allergic response to penicillin
Toxic epidermal necrolysis (TEN) due to antibiotic
Stevens-Johnson syndrome (SJS) in conjunctiva and mouth due to antibiotic
Tetracycline-induced “black hairy tongue” and teeth staining
Slate-grey pigmentation due to amiodarone
Phocomelia caused by thalidomide
what is the incidence and symptoms of SJS and TEN
Rare: 1 case per million per year for TEN, 30% mortality
Symptoms: fever, sore throat, skin rash that tends to form blisters (occur almost immediately on drug exposure, or can be several weeks later)
Skin sloughs off when pressure is applied
SJS <10% of epidermis affected; TEN >30% of epidermis affected
Mucous membranes (crusty haemorrhage) and eyes (conjunctivitis) affected as well
Immune based reaction to foreign antigen (drug)
what are Limitations of clinical trials?
Small number of patients studied
Restricted populations (age, sex, ethnicity)
Narrow indications
Short duration of drug exposure
why was VIOXX withdrawn ?
COX-2 Inhibitor used in treatment of arthritis.
Cardiovascular side effects: heart attack, stroke. WITHDRAWN FROM USE IN 2004
what are type (Bizarre) B classification of adverse drug reactions?
Includes: Hypersensitivity reactions
Idiosyncratic reactions
20-25% Incidence
Occur in some people
Not Predictable from normal Pharmacology
Not dose related
High mortality
Low morbidity
e.g. Allergic reaction to penicillin
what are type A classification of adverse drug reactions?
75-80% Incidence
Occur in everyone if enough drug given
Predictable from known Pharmacology
Dose related
Low mortality
High morbidity
e.g. Postural hypotension caused by antihypertensive treatment with prazosin
what is typical C continuous reactions?
Effects occur following long term use. e.g. Chloroquine induced retinopathy
e.g. Chloroquine induced retinopathy
what are type D and Type E ADR?
Type D (Delayed) Reactions
May not require long-term use but are evident some time after exposure eg e.g. Cancer following treatment with ciclosporin
Type E (End of use) Reactions. Effects that occur when discontinuation is too abrupt - e.g. Rebound adrenocortical insufficiency
what are cardiotoxcity symptoms of anti-cancer therapy that can be caused ?
Cardiac dysfunction and heart failure
Arterial hypertension
Vasospastic and thromboembolic ischaemia
Arrhythmia / QT prolongation
what is the effect of doxorubicin on cardiomycoytes ?
Loss of myofibrils
Vacuolar degeneration
Interstitial fibrosis
what is the mechanism of action of doxorubicin?
Lipid peroxidation at the cell and mitochondrial membranes
Mitochondrial DNA damage and energy depletion through production of reactive oxygen species (ROS)
Impairs Ca2+ handling in the SR
Inhibits transcription of muscle proteins
Downregulates adrenoceptors and impairs signalling
Induces apoptosis
what are the two types of cardiotoxicity: irreversible (Type I) and reversible (Type II), often associated with cancer therapy?
Irreversible (Type I) Cardiotoxicity:
Pathophysiology: Damage is due to cell loss (necrosis/apoptosis).
Manifestation: Can result in cardiomyopathy/heart failure, myocardial infarction, and thrombosis.
Diagnosis: Detected by injury marker release, progressive contractile dysfunction, and cardiac remodeling.
Leads to progressive cardiovascular disease.
Reversible (Type II) Cardiotoxicity:
Pathophysiology: Damage is due to mitochondrial/protein dysfunction causing cellular dysfunction.
Manifestation: Causes temporary contractile dysfunction, vasospastic angina, and arterial hypertension.
Diagnosis: There is no injury marker release; instead, reversible contractile dysfunction and reversible arterial hypertension are noted.
Can lead to normalization of cardiovascular function if addressed.
what are risk factors for doxorubicin and cardiotoxicty ?
Cumulative dose
Pre-existing heart disease
Age (young children and >65 years)
Mediastinal (chest) radiation
Combination therapy
