Adverse Drug Reactions.pptx 7th sem bpharm pharmacy practice

pharmacy practice unit 1 adverse drug reaction note bpharm 7th semester

1. Adverse Drug Reaction s

2. Definition - WHO “Any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or therapy.”

3. Importance Category Statistic Source Prevalence and Impact ADRs responsible for 6.7% of hospital admissions in the US (over 2.2 million admissions annually). Journal of the American Medical Association (JAMA), 2023 ADRs are among the top 10 leading causes of mortality and morbidity globally (10% of hospitalized patients). World Health Organization (WHO), 2023 Economic Burden ADRs contribute to $30 billion in additional healthcare costs in the US annually. Institute for Safe Medication Practices (ISMP), 2023 Specific Drug Examples Opioid ADRs lead to more than 40,000 emergency department visits and 5,000 deaths annually in the US. The Lancet, 2023 Anticoagulant ADRs cause over 15,000 hospitalizations and 1,000 deaths per year due to bleeding complications. The Lancet, 2023 Genetic Factors Up to 30% of ADRs have a genetic basis . Variations in the CYP2D6 gene can cause severe ADRs with drugs like codeine and tramadol. Nature Genetics, 2023 Emerging Concerns ADRs from COVID-19 treatments, including remdesivir and dexamethasone, have led to significant liver and renal toxicity in some patients. The New England Journal of Medicine, 2023

4. Managing ADRs Management Strategy Description Monitoring Regular monitoring of patients for early detection of ADRs. Genetic Testing Screening for genetic variations that may predispose patients to ADRs. Patient Education Educating patients about potential ADRs and the importance of reporting symptoms immediately. Alternative Therapies Considering alternative medications with a lower risk of ADRs. Dose Adjustment Adjusting drug dosages based on patient-specific factors such as renal function and genetic makeup. Anticoagulant ADRs cause over 15,000 hospitalizations and 1,000 deaths per year due to bleeding complications. Genetic Factors Up to 30% of ADRs have a genetic basis. Variations in the CYP2D6 gene can cause severe ADRs with drugs like codeine and tramadol. Emerging Concerns ADRs from COVID-19 treatments, including remdesivir and dexamethasone, have led to significant liver and renal toxicity in some patients.

5. Classification of Adverse Drug Reaction (ADR) DOS E -REL A T E D AD V ERSE DR U G REACTIONS Pharmaceutical Variation Pharmacokinetic Variation Pharmacodynamic Variation 2. NON-DOS E REL A T E D AD V ERSE DR U G REACTIONS a) b ) Immunological Reactions Pseudo Allergic Reactions Pharmacogenetic Variation 3. Long-term adverse drug reactions Adaptive Changes Rebound Phenomenon Delayed adverse drug reactions Carcinogenesis Effects Concerned With Reproduction Impaired infertility Teratogenesis Drugs in breast milk

6. Classification of ADRs.... Wills and brown Type A (Augmented) Type B (Bizarre) Type C (Chemical) Type D (Delayed) Type E (Exit/End of treatment) Type F (Familial) Type G (Genotoxicity) Type H (Hypersensitivity) Type U (Un classified)

7. Classification of Adverse Drug Reactions Type Description Examples Type A (Augmented) Dose-dependent and predictable reactions based on the known pharmacology of the drug. Bradycardia with beta-blockers, bleeding with anticoagulants Type B (Bizarre) Dose-independent, unpredictable reactions not related to the drug's pharmacological action. Anaphylaxis with penicillin, Stevens-Johnson syndrome with sulfonamides Type C (Chronic) Reactions that occur as a result of long-term use of a drug. Osteoporosis with corticosteroids, tardive dyskinesia with antipsychotics Type D (Delayed) Reactions that become apparent some time after the use of the drug. Carcinogenesis, teratogenesis Type E (End of use) Reactions that occur when a drug is stopped, especially if it has been used for a long time. Withdrawal symptoms from opioids, rebound hypertension from clonidine Type F (Failure) Unexpected failure of therapy, often due to drug interactions or genetic differences in metabolism. Failure of oral contraceptives when taken with antibiotics

8. Classification of Adverse Drug Reactions Drug Adverse Reaction Type Adverse Reaction Penicillin Type B Anaphylactic shock Warfarin Type A Bleeding Aspirin Type A Gastric ulcer Chloramphenicol Type D Aplastic anemia Thalidomide Type D Phocomelia (limb deformities in newborns) Clozapine Type B Agranulocytosis

9. Dose related adverse reactions This has led to the concept of the THERAPEUTIC INDEX , or the TOXIC:THERAPEUTIC RATIO . This indicate the margin between the therapeutic dose and the toxic dose. The bigger the ratio, the better. Examples of drugs with a low TOXIC:THERPEUTIC RATIO - Anticoagulants (warfarin, heparin), Hypoglycemic drugs (insulin, sulfonylurea), Antiarrythmic drugs (lidocaine, amiodarone) It can occur because of variations in the Pharmaceutical, Pharmacokinetic, Pharmacodynamic properties of a drug

10. Dose related adverse reactions Drug Adverse Reaction Description Warfarin Bleeding Due to its anticoagulant effect, especially at higher doses. Insulin Hypoglycemia Excessive insulin can lower blood sugar levels too much. Aspirin Gastric Ulcers High doses can irritate the stomach lining, causing ulcers. Digoxin Bradycardia Excessive doses can slow the heart rate excessively. Theophylline Seizures High doses can cause central nervous system stimulation. Beta-blockers Hypotension Excessive doses can lower blood pressure too much.

11. PHARMACEUTICAL VARIATION ADR occur because of alterations in the systemic availability of a formulation EX: Phenytoin Intoxication presence of a contaminant EX: Pyrogens or even B a cteria i n i n t r a v enous f orm u l a tio n s. Out of date formulations (expiry date) - degradation products. EX: out-dated Tetracycline c an c ause F a nconi ’ s S y n d r om e .

12. Type of Variation Description Examples of ADRs Formulation Variation Differences in drug composition affecting release, stability, or bioavailability. A reformulated drug with different excipients causing allergic reactions in sensitive patients. Manufacturing Variation Differences in manufacturing process affecting drug quality and efficacy. Variations in particle size leading to different absorption rates and unexpected side effects. Storage Variation Differences in storage conditions affecting drug stability and potency. Degraded active ingredients due to improper storage causing reduced efficacy and adverse effects. Packaging Variation Differences in packaging materials/methods affecting stability and compliance. Packaging changes leading to medication errors and subsequent ADRs. Batch-to-Batch Variation Quality and consistency differences between batches. Variation in drug concentration between batches causing inconsistent therapeutic effects. Route of Administration Variation Differences in administration route affecting absorption and effect. Oral versus intravenous administration causing differences in onset of action and potential ADRs.

13. Pharmacokinetic Variation There is much variation among normal individuals in the rate of elimination of drugs. This variation is most marked for drugs that are cleared by hepatic metabolism. It is determined by several factors, which may be Genetic Environmental Hepatic.

14. Pharmacokinetic Variation Drug Pharmacokinetic Variation Adverse Reaction Warfarin Metabolism Variation Increased bleeding risk Phenytoin Absorption Variation Toxicity or subtherapeutic effect Morphine Excretion Variation Prolonged sedation and respiratory depression Diazepam Protein Binding Variation Enhanced sedation or toxicity Omeprazole Enzyme Inhibition Drug-drug interactions leading to increased levels of drugs metabolized by CYP2C19, such as clopidogrel Carbamazepine Enzyme Induction Reduced efficacy of co-administered drugs

15. G e n e tic Acetylation Depending on genetics individuals are Fast and Slow acetylators. Ex: Isoniazid, Hydralazine, Procainamide, Dapsone, Some sulfonamides. Increased incidence of PERIPHERAL NEUROPATHY is observed in slow acetylators of Isoniazid Oxidation Oxidation also shows genetic variability. There are individuals with impaired oxidation and with normal oxidation. Impaired oxidation ones are called as POOR METBOLIZERS and the ones with normal are called EXTENSIVE METABOLIZERS Succinylcholine hydrolysis: Succinylcholine is hydrolyzed by PSEUDOCHOLINESTRASE. In some individuals pseudocholinestrase is abnormal and does not metabolize succinylcholine rapidly. In such cases drug persist in blood and continue to produce neuro muscular blockade for several hours. This result in respiratory paralysis called SCOLINE APNOEA .

16. Type of Genetic Variation Description Examples of ADRs Polymorphisms in Drug-Metabolizing Enzymes Genetic variations in enzymes responsible for drug metabolism. Example: Variations in CYP2D6 leading to differences in drug metabolism rates. HLA Alleles Variations in human leukocyte antigen (HLA) genes affecting immune responses. Example: HLA-B*5701 variant leading to hypersensitivity reactions to abacavir . Transporter Gene Polymorphisms Genetic differences in drug transporter proteins affecting drug distribution. Example: Variations in SLCO1B1 affecting statin uptake and risk of myopathy. Receptor Gene Variants Variations in genes encoding drug target receptors affecting drug efficacy and safety. Example: VKORC1 variants affecting warfarin sensitivity and risk of bleeding. G e n e tic

17. G e n e tic Drug Genetic Variation Adverse Reaction Abacavir HLA-B*5701 Hypersensitivity Reaction Warfarin CYP2C9 and VKORC1 Increased Bleeding Risk Codeine CYP2D6 Respiratory Depression Simvastatin SLCO1B1 Myopathy

18. Hepatic Disease Hepatocellular dysfunction , as in several hepatitis or advanced cirrhosis , can reduce the clearance of drugs like phenytoin, theophylline and warfarin . A reduction in hepatic blood flow , as in heart failure, can reduce the hepatic clearance of drugs that have an high extraction ratio for e.g. propranolol , morphine and pethidine . Reduced production of plasma proteins (for e.g. albumin) by the liver in cirrhosis can lead to reduced protein binding of drugs. Hepatic congestion and reduced liver blood flow may impair the metabolism of some drugs (e.g. Lidocaine ).

19. Types and Examples of Hepatic ADRs Type of Hepatic ADR Description Examples of ADRs Hepatocellular Injury Damage to liver cells, often indicated by elevated liver enzymes (ALT, AST). Acetaminophen overdose causing severe liver cell damage. Cholestatic Injury Impairment of bile flow, leading to elevated bilirubin and alkaline phosphatase. Chlorpromazine-induced cholestasis. Mixed Hepatocellular- Cholestatic Injury Combination of hepatocellular and cholestatic damage. Amoxicillin- clavulanate causing mixed-pattern liver injury. Granulomatous Hepatitis Inflammatory reaction in the liver forming granulomas. Allopurinol-induced granulomatous hepatitis.

20. Examples of Drugs Causing Hepatic ADRs Drug Type of Hepatic ADR Adverse Reaction Acetaminophen Hepatocellular Injury Acute Liver Failure Chlorpromazine Cholestatic Injury Cholestasis Amoxicillin- Clavulanate Mixed Hepatocellular-Cholestatic Injury Mixed Liver Injury Allopurinol Granulomatous Hepatitis Granulomatous Hepatitis

21. Renal Disease If a drug or active metabolite is excreted by glomerular filtration or tubular secretion, it will accumulate in renal insufficiency and toxicity will occur. Poor renal perfusion may result in reduced renal elimination (e.g. Procainamide ). Type of Renal ADR Description Examples of ADRs Acute Kidney Injury (AKI) Sudden decline in kidney function, leading to decreased urine output and elevated serum creatinine. NSAIDs causing reduced renal perfusion and acute kidney injury. Chronic Kidney Disease (CKD) Gradual loss of kidney function over time. Long-term use of lithium causing chronic interstitial nephritis. Nephrotic Syndrome Damage to the kidney’s filtering units, leading to proteinuria and edema. Gold salts causing membranous nephropathy. Tubulointerstitial Nephritis Inflammation of the kidney tubules and surrounding interstitial tissue. Methicillin causing acute interstitial nephritis.

22. Cardiac Disease Ca r d i ac f ailu r e, particula r l y c o n g est i v e c ardiac failure , can alter the pharmacokinetic properties of drugs by several mechanisms Impaired absorption, due to intestinal mucosal edema Poor splanchnic circulation , can alter the efficacy of some oral diuretic, such as FUROSEMIDE Reduction in the apparent volumes of distribution of some cardio active drugs e.g. Procainamide, Lidocaine, Quinidine

23. Pharmacodynamic Variation Various factors influences body’s reaction on drugs. It may be due to Hepatic Disease Reduced blood clotting Hepatic encephalopathy Sodium and water retention Altered fluid and electrolyte balance

24. Hepatic Disease Hepatic disease can alter pharmacodynamic responses to drugs in several ways; R e d u c e d Blo o d Clot t ing: In cirrhosis and acute hepatitis , production of clotting factor is impaired and patients bleed more readily. Drugs that impair blood clotting, homeostasis, or that predispose to bleeding by causing gastric ulceration should be avoided or used with care Ex: Anticoagulants and NSAIDS . H e pat ic Ence p halopath y : In patients with, or on the border line of, hepatic encephalopathy, the brain is more sensitive to the effects of drugs with sedative actions. If such drugs are used, coma can result. Opioids , other Narcotic Analgesics and Barbiturates . So d i u m a nd Wate r R e t e n t i o n In hepatic cirrhosis, sodium and water retention can be exacerbated by certain drugs. NSAIDS , Corticosteroids , Carbamazepine and formulations containing large amount of sodium.

25. Altered Fluid and electrolyte balance The pharmacodynamic effects of some drugs are altered by changes in fluid and electrolyte balance. Example: The toxic effect of cardiac glycosides are potentiated by both Hypokalaemia and Hypercalcaemia . The Class1 of Antiarrhythmic drugs such as Q u inidin e , Procain a mi d e and D i s o p y r a m ide a r e more arrhythmogenic if there is hypokalaemia.

26. NON-DOSE RELATED ADVERSE DRUG REACTIONS It may proceed in either of this procedure IMMUNOLOGICAL REACTIONS PSEUDO ALLERGIC REACTIONS PHARMACOGENETIC VARIATION

27. IMMUNOLOGICAL REACTIONS There is no relationship to the usual pharmacological effects of the drug; There is often a delay between the first exposure to the drug and the occurrence of the subsequent adverse reaction; There is no formal dose-response curve; The illness is often recognizable as a form of immunological reaction like rash, serum sickness, urticaria etc

28. IMMUNOLOGICAL REACTIONS Factors involved in drug allergy are: Drug and Patients THE DRUG: – Macromolecules such as PROTEINS ( vaccines and enzymes such as streptokinase), POLYPEPTIDES ( insulin and dextrans ) can themselves be immunogenic. THE PATIENTS: There are genetic factors that make some patients more likely to develop allergic reactions than others: A history of allergic disorders HLA status(antigens on human lymphocytes)

29. PHARMACOGENETIC VARIATION It may involve Red cell enzyme defects Porphyria Malignant hyperthermia

30. RED CELL ENZYME DEFECTS Unusual drug reaction occur in individuals whose erythrocytes are deficient in any one of three different but functionally related enzymes. Glucose-6-phosphate dehydrogenase Glutathione reductase Methaemoglobin reductase

31. Porphyria Porphyrias constitute a group of disorders of haem- biosynthesis. Different types of porphyrias are: Acute intermittent porphyrias Variegate porphyria Porphyria cutanea tarda Erythropoietic Porphyria Each type of Porphyria is associated with a different abnormality of an enzyme in haem-biosynthetic pathway. Drugs to be avoided in porphyria : Barbiturates, Dapsone, Chloramphenicol, Diclofenac etc.

32. Malignant hyperthermia It is an autosomal dominant generic disorder of skeletal muscles that occurs in susceptible individuals undergoing General Anesthesia with inhaled agents (halogenated) and muscle relaxants like Succinylcholine . This rare condition of uncontrolled release of calcium by sarcoplasmic reticulum of skeletal mus c l e s l e ads t o muscles spas m , h yp e rth e rmia and autonomic liability . Dantrolene is indicated in life threatening situations.

33. Long Term Effect Adaptive changes Examples include development of tolerance to and physical dependence on the NARCOTIC ANALGESICS and the occurrence of TARDIVE DYSKINESIA in some patients receiving long term neuroleptic drug therapy for schizophrenia . Rebound and withdrawal phenomena During long term therapy sudden withdrawal of the drug can result in rebound reactions. Examples : Barbiturates - restlessness , mental confusion and convulsions. β-adrenoceptors antagonists - rebound tachycardia which can precipitate myocardial ischemia . Corticosteroids - adrenal insufficiency.

34. Delayed adverse drug reactions It involves CARCINOGENESIS Hormonal Gene toxicity Suppression of immune response EFFECTS CONCERNED WITH REPRODUCTION Impaired infertility Teratogenesis Drugs in breast milk

35. There are three major mechanisms of carcinogenesis: Hormonal: Incidence of VAGINAL ADENOCARCINOMA is increased in daughters of women who have taken STILBOESTROL during pregnancy for the treatment of threatened abortions. Increased risk of BREAST CANCERS is about 50% and woman taking HORMONE REPLACEMENT THERAPY (HRT) for more than five years.

36. Gene Toxicity Occurs when certain molecules bind to nuclear DNA and produce changes in gene expressions. Examples: BLADDER CANCER in patient taking long term CYCLOPHOSPHAMIDE Carcinomas of RENAL PELVIS associated with PHENACETIN abuse. Non lymphocytic LEUKEMIA in patients receiving ALKYLATING AGENTS such as melphalan, chlorambucil etc.

37. Suppression of immune responses Patients taking immunosuppressive drugs such as AZATHIOPRINE with CORTICOSTEROIDS have increased risk of developing LYMPHOMAS .

38. Effects Concerned With Reproduction: Impaired Fertility Cytotoxic drugs can cause female infertility through ovarian failure with amenorrhea. Male fertility can be reduced by impairment of spermatozoal production or function and can be either REVERSIBLE IMPAIRMENT can be caused by sulfasalazine, nitrofurantoin, MAO inhibitors and antimalarial drugs; IRREVERSIBLE IMPAIRMENT , due to azospermia, can be caused by cytotoxic drugs, such as alkylating agents cyclophosphamide and chlorambucil.

39. Effects Concerned With Reproduction: Teratogenesis Teratogenesis occurs when a drug taken during early stages of pregnancy causes a developmental abnormality in a fetus. Drugs can affect fetus at 3 stages: FERTILIZATION AND IMPLANTATION Conception to 17 days Failure of pregnancy which often goes unnoticed. ORGANOGENESIS 18 to 55 days of gestation Most vulnerable period, deformities are produced GROWTH AND DEVELOPMENT development and functional abnormalities can occur ACE inhibitors can cause HYPOPLASIA of organs NSAIDs may induce PREMATURE CLOSURE OF DUCTUS ARTERIOSUS Different teratogenic drugs are: Thalidomide, Methotrexate, Warfarin, Phenytoin, Phenobarbitone, Valproate Sod.,Lithium, etc.

40. Factors predisposing to ADRS Drug Related Factors Dose Dosage form and delivery system Interactions between drugs Patient Related Factors Age - Geriatrics Age – Pediatrics Concurrent diseases Hepatic disease Renal disease Other diseases Genetic factors Gender Nutrition

41. Prevention of ADR Avoid all inappropriate use of drugs Use appropriate dose, route & frequency Consider previous history of Drug reaction Rule out possibilities of Drug interference Carry appropriate laboratory monitoring

42. Clinical Manifestation of ADR Side Effects Unwanted, unavoidable pharmacological effects occurring at therapeutic doses of drug predicted from pharmacological effects of drug Ex: Atropine – dryness in mouth, Promethazine – sedation • Secondary Effects – – Indirect consequences of primary action of drug Ex: Tetracycline – super infections • Toxic Effects Result of excessive pharmacological action of drug due to over dosage or prolonged use Ex: Morphine – respiratory depression, Amino glycosides – ototoxicity Untoward effects Occurs at therapeutic dose but if severe necessitate cessation of treatment Vomiting and diarrhea with Para-amino salicylic acid

43. Clinical Manifestation of ADR Idiosyncrasy Genetically determined abnormal reaction to a drug or chemical Salicylates and sulfonamides produce haemolysis in individuals whose RBC lack glucose-6-phosphate dehydrogenase Drug allergy Immunologically mediated reactions producing symptoms which are unrelated to pharmacodynamic profile of drug independent to dose Photosensitivity Drug or its metabolite accumulates in the skin, absorb light and undergo photochemical reaction to cause local tissue damage Tetracycline, fluoroquinolones, sulfonamides

44. References Basic & Clinical Pharmacology Bertram G. Katzung Twelfth Edition Essential of medical pharmacology - K.D. Tripathi 6 th edition Lippincott - Modern Pharmacology With Clinical Applications 6E Color Atlas Of Pharmacology, 2Nd Ed (Lüllmann, Thieme 2000)