Adverse Drug Reactions-harm

associated with the use of given medications at a

3) OTHERS

normal dose.

a) Liver Disease
-Halothene acute hepatic necrosis - Chlorpromazine intrahepatic cholestasis.

Type A- Augmented Pharmacologic effects

1. Dose dependant and predictable harm. 2. Known to occur from pharmacology of the drug, or due to drug interactions. 3. Seldom fatal. 4. Relatively common. 5. Most relevant for drugs with low therapeutic index (levels must be monitored) . Examples: 1) Warfarin- Bleeding. 2) Insulin- hypoglycaemia due to insulin injection. 3) Digoxin- heart block, ventricular tachycardia. 4) Beta-adrenergic blockersbronchospasm/asthma. 5) Alpha- adrenergic blockers- postural hypotension. 6) Opiates- respiratory depression. 7) NSAIDs- gastric ulcers, bleeding and perforation. -

b) Kidney disease
- NSAIDs acute interstitial nephritis.

c) Bone marrow damage

Antithyroid drugs (Carbimazole) aggranulocytosis

d) Teratogenicity
Antiepileptic drugs Reninangiotensin system blockers, cytotoxic drugs

Type B- Bizzare adverse drug reactions

1) 2) 3) 4) Occur unpredictably. Unrelated to pharmacological effect of a drug. High rate of morbidity and mortality. Uncommon.

TYPE C- Chronic/ Long-term effects

Occur only during prolonged treatment (not with single dose) associated with long term drug theraphy.

Examples: 1) Phenothiazine tranquilizers orofacial dyskinesia 2) Chloroquine retinopathy 3) Rofecoxib (selective COX2 inhibitor) thromboembolic events 4) Amiodarone eye, thyroid, lung and skin

Examples: 1) HYPERSENSITIVITY- Allergies and anaphylaxis Penicillins, foreign proteins such as streptokinase, iodinated contrast media. 2) ANAPHYLACTOID REACTIONSi- Type 1 hypersensitivity reaction ACE-inhibitors angioedema

toxicity.

TYPE D- DELAYED EFFECTS

Occur remote from treatment either in children of treated patients or patient themselves years after treatment. These refer to carcinogenic and teratogenic effects. These reactions are delayed in onset and are very rare since extensive mutagenicity and carcinogenicity studies are done before drug is licensed Symptomatic but not serious 1) Minoxodil hirsutism 2) Ca2+ channel blockers headache 3) - Adrenergic blockers nightmares WARN PATIENTS ABOUT THESE Initially Asymptomatic eventually serious 1) Aminoglycoside renal failure 2) Amiodarone pulmonary fibrosis 3) Chloramphenicol aplastic anaemia WE BOTH WARN PATIENTS AND CAREFULLY MONITOR FOR THEM

Examples: 1) Alkylating agents (for treatment of Hodgkins disease or lymphoma) second cancers in patients. 2) Diethylstilbestrol (taken during pregnancy by their mothers) Clear cell vaginal carcinoma

WHO ARE AT RISK?? Those with:- Renal disease, liver disease, older patients, very young patients and genetically predisposed patients.

TYPE E- END OF TREATMENT EFFECTS

End of treatment effects occurs when the
treatment is stopped.

ENZYMES POLYMORPHISM AND DRUG INTERACTION

1) Cytochrome P450 (CYP)
CYP 2D6 and CYP 2C9 display significant polymorphisms. CYP 2D6 metabolises Antidepressants, blockers and Codeine. CYP 2C9 metabolises Warfarin and Phenytoin. Individuals can be grouped by their CYP enzyme activity poor, intermediate, extensive (normal) and untrarapid.

Withdrawal effects !!!!

Example: If these drugs are stopped then... 1) Beta- Blockers unstable angina 2) Clonidine Rebound hypertension

Poor metabolisers Risk using drugs due to high plasma drug concentrations Drugs can have adverse drug reactions that are either related or unrelated to pharmacology. Related Unrelated Hyperkalaemia Angioedema Drowsiness, dry mounth Syncope (Torsade De pointes) a) Nortriptyline (a tricyclic antidepressant) b) Venlafaxine (selective serotonin reuptake inhibitor) Also CYP 2D6 poor metabolisers will not get a good analgesic effect with codeine as codeine will not be metabolised to its active form morphine! Ultrarapid metabolisers may require higher doses of drugs to benefit from therapy.

ACE inhibitors Terfenadine

2) Thiopurine methyltransferase (TPMT) metabolises the cytotxic drugs azathioprine and 6-mercaptopurine. These drugs have low therapeutic index, used to treat acute lymphoblastic leukaemia , inflammatory bowel disease. TMPT deficient patients risk of fatal myelosuppression when given normal doses of azathioprine and require only 1/10th the normal dose for effective treatment. (as the drug is not broken down by TMPT thats absent)

3) N- Acetyltransferase 2 (NAT2)
Acetylates antituberculous drug Isoniazid Slow acetylators show neurological side effects

ALLERGIES
1) Type 1 Allergy (IgE dependant) Urticaria Atopic dermatitis Asthma Rhinitis Anaphylaxis 2) Type 2 Allergy (IgG and IgM dependant) Methyldopa haemolysis Heparin or Clopdogrel thrombocytopenia Sulphonamides granulocytopenia 3) Type 3 Allergy (immune complex) Streptokinase serum sickness Anti-bacterial drugs like Sulphonamides Stevens Johnson syndrome drug-induced toxic epidermal necrolysis desquamating skin disorder. 4) Type 4 Allergy (Celullar) Procainamide (class 1a antiarrhythmic) systemic lupus erythmatosis.

Nonimmunogenic reactions resembling anaphylaxis but can occur without prior exposure or after prolonged event free exposure.