Adverse Drug Reactions and Drug Safety Department of Pharmacology

Adverse reactions to drugs Adverse effect = Unwanted effect Due to either toxic or side effect Toxic effect = exaggeration of the same pharmacological effect e.g.,hypokalaemia due to certain diuretics like furosemide ( dose related )

A side effect is an adverse effect that arises through some pharmacological action other than which produces the therapeutic effect; such effect may be dose related or not dose related. Dose related side effect = toxic effect e.g., propanolol causes lowering of blood pressure and Bronchoconstriction (asthma) while taking therapeutic dose Better avoid side effect/toxic effect and instead better Use ADVERSE EFFECT which covers all unwanted effects

History 1870 – 1890  sudden deaths due to chloroform anaesthesia 1922  jaundice while treating syphilis with organic arsenic 1937  107 people died after taking sulphanilamide elixir containig diethylene glycol (USA) After that incident,FDA was established to enquire safety of new drugs before marketing

1961  thalidomide disaster Phocomelia in the newborn babies whose mothers took thalidomide during the first 3 months of pregnancy (hypoplastic or aplastic limb deformities)

Teratogenicicity testing for the new drugs was not a routine at that time  awareness of the adverse effects of drugs had greatly increased and much more sophisticated approach was done in preclinical testing and clinical evaluation of drugs before marketing was done.

1982  benoxaprofen ( anti-inflammatory drug ) Fatal liver failure in old age group (reason – dose recommendation based upon young and healthy volunteers) 1995  oral contraceptives containing 3 rd generation progestogen causes thromboembolism Therapeutic abortion rate among reproductive age group was increased due to the “pill scare”.

Adverse drug reaction is common in : 1.patients taking several drugs because of drug interactions or drug- disease interaction. 2. elderly patients because of organ dysfunction/failure, concomittent disease and drug interaction.

Classification of ADRs 1)Dose - related 2)Non - dose related 3)Long - term and withdrawal effects 4)Delayed effects

1)Dose - related ADR Commonest type of ADR (about 80%) of the case Predictable Avoidable with attention to detail and appropriate Knowledge Can be divided into a)Pharmaceutical variations b)Pharmacokinetic variations c)Pharmacodynamic variations

a)Pharmaceutical Changing drug formulation causes changing Bioavailability of the drug  phenytoin toxicity in epileptics in Australia after changing excipient from calcium sulfate to lactose Contamination of IV fluids with pyrogen or bacteria Out-of-date formulation can produce degradation products

b) Pharmacokinetic variations:  Pharmaco genetic variation  Liver disease  Renal disease  Cardiac disease  Thyroid disease  Drug interaction

Pharmacogenetic variation –  slow acetylator of Isoniazid (anti TB drug )  peripheral neuropathy  Suxamethonium apnoea  abnormal drug metabolizing enzyme due to abnormal gene

Liver disease  Impaired metabolism of the drugs that are mainly metabolized in the liver.  Drugs with low toxic : therapeutic ratio  Drugs with extensive first-pass elimination  Drugs with great affinity to the plasma protein (albumin)

Renal disease  Drug or active metabolite excreated by the glomerular filtration or tubular secreation will be accumulated if the renal function is impaired.  Direct nephrotoxic drugs should be avoided.

Cardiac disease Congestive cardiac failure can alter the pharmacokinetic properties of the drug by  Impaired absorption  Hepatic congestion  Poor renal blood flow

Thyroid disease Metabolism of some drugs are :  Increased in hyperthyroidism so need to give higher dose to get same therapeutic effect  Decreased in hypothyroidism even the therapeutic dose of the drug can produce coma.

c) Pharmacodynamic variations Hepatic disease  Reduced blood clotting due to insufficient liver function cause bleeding peptic ulcers  Hepatic encephalopathy Opoids, barbiturates must be avoided Diuretics  hypokalemic alkalosis  ammonia production  can precipitate encephalopathy

Altered (abnormal) body fluid and electrolyte status  Increased risk of digitalis toxicity in hypokalaemia (potassium ion level is lower than normal in the plasma )  Enhanced hypotensive effect of the drugs in patients with hypovolemia

2)Non-dose-related reactions Drugs -- >Immunological reactions Macromolecules such as,  proteins (vaccines, streptokinase enzyme)  Polypeptides ( insulin )  Dextrans are themselves immunogenic. Patients with atopic disease, angio-edema are prone to get allergic action.

3) Long-term and withdrawal effects :  Adaptive changes of the body Tolerance to opoids : need increasing dose to get the same effect  Rebound and withdrawal phenomena Rebound insomnia after withdrawal of diazepam  Others – chloroquine  retinopathy analgesic nephropathy

4) Delayed effects causing ADRs  Carcinogenesis Increased risk of breast cancer risk in postmenopausal patients taken HRT with oestrogen  Gene toxicity in those treated with anticancer drugs ( cytotoxic drugs like antifolate)  Suppression of immune response Those taken immunosuppressents after organ transplants

 Impaired fertility both in males and females after cytotoxic drug therapy  Teratogenisis  ADRs in the baby due to drugs secreted in breast milk

Drug safety Before FDA approval,all adverse events (serious,life-threatening,reasonably drug related or unexpected) must be reported. Following FDA approval to market, surveillance, evaluation,reporting must continue for any adverse events in patients that are related to use of drugs including overdose, accidents,failure of expected effects, withdrawal effects and events not listed in labelling.

Drug safety Methods of surveillance : a)Anecdotal reporting b)Voluntary but organized reporting c)Post-marketing surveillance  Intensive event recording (hospital based)  Cohort studies ( prospective )  Case - control studies ( retrospective )  Use of population statistics  Record linkage

Learning outcome: 1. What is the adverse drug reaction? 2. Classification of ADRs.  Dose-related  Non-dose-related  Long term and withdrawal effects  Delayed effects 3. Surveillance methods used to detect ADRs