Adverse drug reaction

Definition, Reasons for adverse drug reaction, Classification,
ADR Reporting and Management

1. Adverse Drug Reaction Dr. Subhash R. Yende Asst. Professor, Gurunanak College of Pharmacy, Nagpur 1 Dr. Subhash R. Yende, GNCP, Nagpur

2. Definition Any undesirable or unintended consequence of drug administration Any noxious change which is suspected to be due to a drug, occurs at doses normally used in man, for treatment, prophylaxis, diagnosis of disease. Adverse effects are more common with multiple drug therapy, after prolonged medication or even after stoppage of the drug and in the elderly patients an incidence of 10–25% has been documented 2 Dr. Subhash R. Yende, GNCP, Nagpur

3. Reasons for adverse drug reaction Dispensing and medication error Failure to set therapeutic endpoint Bioavailability differences Patients factors 3 Dr. Subhash R. Yende, GNCP, Nagpur

4. Classification Predictable (Type A or Augmented) reactions Excessive pharmacological effects Secondary pharmacological effects Rebound effect on discontinuation Unpredictable (Type B or Bizarre) reactions Allergic drug reactions Idiosyncrasy Genetically determined toxicity 4 Dr. Subhash R. Yende, GNCP, Nagpur

5. Excessive pharmacological Effects (Toxic effects) Due to overdosage or prolonged use Overdosage may be absolute (accidental, homicidal, suicidal) or relative (i.e. usual dose in presence of renal failure, age range, lower albumin level etc) Examples- Coma by barbiturates Complete A-V block by digoxin Bleeding due to heparin Morphine (analgesic) causes respiratory failure in overdosage Phenytoin (anticonvulsant) cause memory impairment after prolong used 5 Predictable reactions Dr. Subhash R. Yende, GNCP, Nagpur

6. Secondary pharmacological effects (Side effects) Unwanted but often unavoidable pharmacodynamic effects that occur at therapeutic doses can be predicted from the pharmacological profile of a drug Reduction in dose, usually ameliorates the symptoms Examples- postural hypotension caused by prazosin ; promethazine produces sedation Sometime side effect may be based on the same action as the therapeutic effect, e.g. atropine is used in preanaesthetic medication for its antisecretory action; codeine used for cough produces constipation as a side effect, but the latter is its therapeutic effect in traveller’s diarrhoea 6 Predictable reactions Dr. Subhash R. Yende, GNCP, Nagpur

7. Rebound effect on discontinuation Chronic use of certain drugs produces drug dependence and addiction Drugs producing dependence are- opioids , barbiturates and other depressants including alcohol and benzodiazepines Amphetamines, cocaine, cannabis are drugs which produce addiction Sudden interruption of therapy with certain other drugs also results in adverse consequences (Withdrawal effects) Severe hypertension, restlessness and sympathetic over activity may occur shortly after discontinuing clonidine ; Frequency of seizures may increase on sudden withdrawal of an antiepileptic 7 Predictable reactions Dr. Subhash R. Yende, GNCP, Nagpur

8. Allergic drug reactions An immunologically mediated reaction producing stereotype symptoms which are unrelated to the pharmacodynamic profile of the drug occur only in a small proportion of the population exposed to the drug The drug or its metabolite acts as an antigen (AG), or more commonly a hapten (incomplete antigen: drugs have small molecules which become antigenic only after binding with an endogenous protein) and induce production of antibody (AB)/sensitized lymphocytes Eg . Drugs like Penicillins , Aspirin, Sulfonamides – urticaria , itching, rashes on skin Tetracyclin cause dermatitis Penicillins , LA causes respiratory difficulties Methyldopa, quinidine cause anemia 8 Unpredictable reactions Dr. Subhash R. Yende, GNCP, Nagpur

9. Idiosyncrasy Genetically determined abnormal reactivity to a chemical The drug interacts with some unique feature of the individual, not found in majority of subjects, and produces the uncharacteristic reaction The type of reaction is restricted to individuals with a particular genotype e.g.: Barbiturates cause excitement and mental confusion in some individuals Quinine/ quinidine cause cramps, diarrhoea , asthma, angioedema of face and hypotension in some patients Analgesics may induced tumors of kidney in patients with renal disease 9 Unpredictable reactions Dr. Subhash R. Yende, GNCP, Nagpur

10. Genetically determined toxicity In case of patients with special genotype or genetic make up, there is risk of drug toxicity Example – Hereditary deficiency of pseudocholinestrase are unable to metabolize the succinyl-choline and may develop prolonged paralysis and apnoea following its use Glucose 6 phosphate dehydrogenase is an enzyme which is involved in the degradation of glucose. Such patients can develop hemolytic anemia after use of primaquine , quinidine , sulfonamide and nitrofurantoin Isoniazid metabolised in the l iver by the enzyme N -acetyl transferase . In the population, some 1ndividuals are slow acetylators and some fast acetylators . Slow acetylators of isoniazide may suffer from peripheral neuropathy. 10 Unpredictable reactions Dr. Subhash R. Yende, GNCP, Nagpur

11. ADR Reporting and Management ADR detection: Adverse effects resulting from excessive pharmacological activity are well documented. But unpredictable adverse effects are not identified, until it has been subjected to much more widespread use. Collection of Patients data either by- Patient interview Reviewing prescriptions containing drugs Checking for abrupt cessation of any medications Obtaining previous medical history 11 Dr. Subhash R. Yende, GNCP, Nagpur

12. Data to be collected includes- Patient’s demographic data; presenting complaints; past medication history; drug therapy details including over‐the‐counter drugs, current medications and medication on admission; and lab data such as hematological, liver and renal function tests Details of the suspected adverse drug reaction such as time of onset and duration of reaction, nature and severity of reaction; Details of the suspected drug including dose, frequency, time of administration, duration of treatment, plasma concentration of drug; Previous reports on reported reactions; 12 Dr. Subhash R. Yende, GNCP, Nagpur

13. ADR Reporting: What to report ? Serious and or life threatening reactions Fatal reactions Reactions resulted in disabilities/ permanent harm Reactions resulted in increased healthcare costs Severe reactions of any type Any reactions to newer drugs Newer reactions to any drugs in the market Rare and uncommon adverse reactions 13 Dr. Subhash R. Yende, GNCP, Nagpur

14. Different approaches for ADR reporting are- 1. Cohort study: This study involve short term and long term clinical trials and post marketing surveillance of established and new drug. 2. Spontaneous reports of suspected adverse drug reaction occurs when prescribers report suspected reaction to investigator agency 3. Review of vital statistics : Regular review of national and regional vital statistics 4. Case-control studies : patients with suspected drug induced disease are compared with a reference population 14 Dr. Subhash R. Yende, GNCP, Nagpur

15. Management of ADR: Decisions are made by considering Seriousness / severity of ADR Seriousness of disease Benefit / harm assessment If the reaction is serious - Withdraw suspected (all?) drugs Treat urgently 15 Dr. Subhash R. Yende, GNCP, Nagpur

16. If the disease is serious - Consider the effect of not having treatment Continue treatment and treat symptoms of reaction if necessary Consider an alternative drug Stop unnecessary drugs If the reaction is mild – Continue treatment if necessary Stop unnecessary drugs Consider dose reduction Reassure and do nothing Symptomatic treatment if warranted 16 Dr. Subhash R. Yende, GNCP, Nagpur

17. Management of ADR (Summary) 17 Dr. Subhash R. Yende, GNCP, Nagpur

18. Reference K.D. Tripathi , Essentials of Medical Pharmacology, Eighth Edition, Jaypee Brothers Medical Publishers (P) Ltd A.R. Paradkar and S.A. Chunawala Hospital and clinical pharmacy, Nirali Prakashan . https://www.slideshare.net/KatlaSwapna/detection-reporting-and-management-of-adverse-events 18 Dr. Subhash R. Yende, GNCP, Nagpur