Adverse drug reactions and drug interactions

ADVERSE DRUG REACTIONS AND DRUG INTERACTIONS USEFUL FOR PharmD, Bpharm and other medical professionals

1. MADE BY: Dr. S P SRINVAS NAYAK Assistant Professor, Dept of Pharmacy Practice Sultan- ul - Uloom college of Pharmacy, hyd . ADVERSE DRUG REACTIONS & DRUG INTERACTIONS

2. overview INTRODUCTION OF ADR Statistics and factors of ADR Classifications OF ADR ADR MONITORING MANAGEMENT OF ADR. DRUG INTERACTIONS METHODS OF DETECTING DRUG INTERACTIONS

3. WONDER DRUG DISASTER

4. THALIDOMIDE

5. ADR DEFINITION WHO, (1972) 'A response to a  drug  which is noxious and unintended , and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function‘ ADRs may lead to organ damage, prolong hospitalization, may lead to ADE and sometimes death.

6. W HAT ARE A DVERSE D RUG R EACTIONS ( ADR S )? Any noxious change which is suspected to be due to a drug , occurs at doses normally used in man , requires treatment or decrease in dose or indicates caution for in future use of the same drug .

7. Adverse drug event – Any untoward medical occurrence that may present during treatment with medicine , but which may not have causal relationship with the treatment.

8. Difference b/t ADR and ADE ADR It’s a drug reaction Eg : sedation by antihistamine. ADE its an event Eg : accident by seadation caused due to antihistamine

9. S TATISTICS ADR to drugs are most common cause of iatrogenic disease. 3-5% hospitalisations due to adverse reactions results in 3,00,000 hospitalisations annually in US. Once hospitalised → 30% chance of ADR → Risk of each course is 5% 3% chance of life threatning reactions → Risk of each course is 0.4 %

10. C OMMON CAUSES OF ADR S Failing to take the correct dosages at the correct times. Overdosing. Allergies to chemical components of the medicine. Combining the medicine with alcohol. Taking other drugs or preparations that interact with the medicine. Taking a medicine that was prescribed for someone else.

11. F ACTORS AFFECTING A DVERSE D RUG R EACTIONS : Patient-related factors Age Sex Genetic influences Concurrent diseases (renal ,liver , cardiac) Previous adverse drug reactions Compliance with dosing regimen Total number of medications Misc. (diet, smoking, environmental exposure)

12. A GE Children are often at risk because their capacity to metabolize drugs is usually not fully developed Children younger than 18 may be at risk of developing Reye’s syndrome if given acetylsalicylic acid (aspirin) while infected with chickenpox or influenza.

13. E L D E R L Y ADRs, including drug interactions, are a common cause of admission to hospitals in the elderly Reasons for ADRs in the elderly: Concomitant use of several medications Decreased drug ADME activity due to age These conditions are exacerbated by malnutrition and dehydration, common in the elderly

14. P R E GNA N CY Sulfonamides → Jaundice and brain damage in the fetus Warfarin → Birth defects, and increased risk of bleeding problems in newborns and mothers Lithium → Defects of the heart (Ebstein’s Anomaly), lethargy, reduced muscle tone, and underactivity of the thyroid gland

15. B REAST FEEDING → Many drugs can be passed from mother to infant via breast milk Amantadine (antiviral) Cyclophosphamide (antineoplastic) Cocaine (Schedule 2 FDA drug) Carisoprodol (skeletal muscle relaxant)

16. Drug-related factors Dose Duration Inherent toxicity of the agent Pharmacodynamic properties Pharmacokin e tic properties F ACTORS AFFECTING A DVERSE D RUG R EACTIONS :

17. GENE T IC BASIS Atypical pseodocholinesterase → Faulty hydrolysis: AR, normal action of succinylcholine hydrolysis takes 5 min ,here it takes 1-2 hours, results in prolonged respiratory failure. Hydroxylase polymorphism → Faulty oxidation, AR , Phenytoin toxicity ↑ in slow hydroxylators.

18. G ENETIC BASIS Acetylator status → AR In fast acetylators → INH → Acetyl hydrazine → Hepatotoxicity In slow acetylators → INH → peripheral neuritis In slow acetylators → Dapsone → hemolysis. G6PD deficiency → X linked recessive → Primaquine , sulfonamides, nitrofurantoin causes hemolytic anemia.

19. 5. Uroporphyrinogen Synthetase Enzyme deficiency → AD ,required for haem synthesis → Barbiturates , phenytoin , carbamazepine give rise to acute intermittent porphyria. G ENETIC BASIS

20. Type A - ( A ugmented) Type B - ( B izarre) Type C - ( C ontinuous) Type D - ( D elayed) Type E - ( E nding of Use) Type F - ( F ailure of Efficacy) T YPES OF ADR

21. Type A (Augmented) Predictable Type B (Bizzare) Unpredictable Expected- Undesirable Unexpected- Undesirable Based- Pharmacological properties of drug Based- Peculiarities of patient More common Less common Dose related Non dose related Mostly preventable and reversible More serious, requires drug withdrawl Includes- Side effects , Secondary effects , Toxic effects, Consequences of drug withdrawal Includes-Hypersensitivity/allergy , Idiosyncrasy ADR C LASSIFICATION

22. T YPES BASED ON ONSET Onset of event: Acute - within 60 minutes Sub-acute - 1 to 24 hours Latent - > 2 days

23. S EVERITY OF ADR Minor Moderate Severe Lethal No Requires Requires Directly/ treatment/ treatment/ intensive Indirectly Antidote/ Change in treatment , contributes Prolongation treatment/ Life to the death of Prolongation threatening, of the hospit a lis a ti on by at least 1 day Perm a n e nt damage patient

24. FDA defines Serious ADR as which Results in death Life-threatening Require hospitalization Prolong hospitalization Cause disability Cause congenital anomalies Require intervention to prevent permanent injury

25. Pharmacological properties of a drug Extension effects Predictable Dose - Related responses Prevention - Adjustment of dosage regimen Examples Benzodiazepines - Sedation Furosemide - Water and electrolyte imbalance Heparin, warfarin - Spontaneous bleeding Insulin - Hypoglycemia T YPE A R EACTIONS OR A UGMENTED

26. A DVERSE E FFECTS Predictable, dose-dependent reactions unrelated to the goal of therapy Often produced by the same drug-receptor interaction responsible for the therapeutic effect, differing only in the tissue/s or organ/s affected

27. E XAMPLES OF A DVERSE E FFECTS INH, Rifampicin, PZA – Hepatotoxicity Streptomycin - Ototoxicity, nephrotoxicity Captopril - Cough Simvastatin – Rhabdomyolysis Nitrates – Headache Propranolol – Bronchial asthma Tetracycline – Hypoplasia of the teeth

28. T YPE B R EACTIONS OR B IZARRE Abnormal effects Unrelated from the drug’s known pharmacological actions

29. E XAMPLE S OF B IZARRE R EACTIONS Hypersensitivity reactions Stevens-Johnson’s Syndrome Hemolytic anemia

30. Long term effects are usually related to the dose and duration of treatment Examples Ethambutol - Retinopathy NSAIDs - Nephrotoxicity T YPE C R EACTIONS OR C ONTINUOUS

31. Carcinogenesis Teratogenesis Examples: Thalidomide T YPE D R EACTIONS OR D ELAYED

32. Withdrawal Syndromes Examples: Benzodiazepines – Rebound insomnia, agitation Clonidine – Rebound hypertension Corticosteroids – Acute adrenal insufficiency T YPE E R EACTIONS OR E NDING OF U SE

33. T YPE F R EACTIONS OR F AILURE OF E FFICACY Counterfeit medicines Underdosing of medications Drug interactions

34. DRUG INTERACTION Warfarin which is highly protein bound is displaced by valproic acid leading to bleeding Aspirin inhibit platelet aggregation together with heparin an anticoagulant leads increased risk of bleeding.

35. 1. Side Effects - Undesirable effects at therapeutic doses e.g a)Atropine → Preanaesthetic medication → (undesirable ) dry mouth b) Codiene → Suppresses Cough (desirable) → Constipation (undesirable) Making Use of side effects - Minoxidil → Antihypertension → Hypertrichosis → Male pattern baldness Codeine → used in travellers diarrhoea A DVERSE DRUG EFFECTS MAY BE CATEGORISED INTO

36. Secondary Effects - Indirect consequence of primary action of drug Examples - Corticosteroids → ↓ Immunity → Latent T.B. activated Tetracyclines → ↓ Bacterial flora → Super-infection. Toxic Effects - Exaggerated form of side effects due to overdosage/prolonged use Examples - High dose heparin → Bleeding Prolonged use of streptomycin → Ototoxicity, nephrotoxicity

37. 4. Allergy/Hypersensitivity- Immunologically mediated allergic responses occurs when sensitised individuals are re-exposed to same drug again Humoral-Type I,II,III Cell mediated-Type IV

38. Type I - Anaphylactic reactions due to IgE antibodies, min → 2-3 hours Examples - urticaria ,angioedema , anaphylactic shock Type II - Cytolytic reactions due to antigen antibody complex , within 72 hours Examples - hemolytic anemia , SLE.

39. Type II I – R e t a rde d or Arthu s reactio n - Immune complex mediated reactions, 72 hours → 1-2 weeks Examples - serum sickness (fever, arthralgia, lymphadenopathy),PAN , Steven Johnson syndrome , procainamide induced systemic lupus erythematous. Type IV - Delayed hypersensitivity reaction Examples - Contact dermatitis

40. Idiosyncrasy - Genetically determined abnormal reactivity to a chemical. Here drug interacts with some unique features of individuals , not found in majority of subjects , produces uncharacteristic reaction . Examples - Barbiturates → excitement and mental confusion in some patients. Chloramphenicol → Aplastic anemia in some patients. Quinine/ quinidine → cramps, diarrhoea , purpura , asthma & vascular collapse.

41. Drug Intolerance - Characteristic toxic effects at therapeutic dose Converse of tolerance ↑ sensitivity to low doses Examples - Single dose triflupromazine → muscular dystonia

42. Photosensitivity - Cutaneous reactions → sensitized skin → UV radiation. Two types: Phototoxicity Photoallergicity

43. Phototoxicity Photoallergy Drug/ metabolite accumulates in skin → absorbs light → photochemical and photobiological reaction → local tissue damage i.e.erythema,edema,blistering, hyperpigmentation Drug/metabolite → cell mediated immune response → UV light → papular or eczematous contact dermatitis like picture Short wavelengths (290-320nm) UV-B Longer wavelengths (320-400nm) UV-A More common e.g. Tetracyclines Less common e.g. Sulfonamides,Griseofulvin

44. Drug withdrawal reactions - Sudden interruption of drug → worsens clinical condition for which previously drug was used. Examples - Corticosteroids in asthma → precipitates acute attacks , myalgia, depression Beta Blockers → worsening of angina , precipitates myocardial infarction

45. 9. Teratogenicity – Drug → pregnant mother → foetal abnormalities Examples- Thalidomide → Phocomelia. Diethylstilbesterol → Vaginal adenocarcinoma. Valproic acid → Neural tube defects. Antithyroid drugs → Foetal goiter, hypothyroidism. Phenytoin → Cleft lip , microcephaly.

46. D RUGS CAN AFFECT THE FOETUS AT 3 STAGES 1)Fertilization & implantation (blastocyst formation) Conception to 17 days - failure of pregnancy - Cytotoxic drugs , alcohol . 2) Organogenesis - 18-55 days of gestation - most vulnerable period - deformities are produced – teratogens. 3 ) Growth and development - Developmental & functional abnormality ACE inhibitors - Hypoplasia of organs NSAIDS- Premature closure of ductus arteriosus

47. R ISK CATEGORY OF DRUGS DURING PREGNANCY Pr e gnancy Category Description A No risk : Ad e quat e and w e l l - controlled h uma n studies - F a iled to demonstrate a risk to the foetus e.g. inj magnesium sulphate , thyroxine

48. Cate g ory Description B No evidence of risk in humans : Animal reproduction studies - Failed to demonstrate a risk to the foetus & no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the foetus in any trimester. E.g. Penicillin V, amoxicillin , cefaclor, erythromycin paracetamol , lidocaine

49. Category Description C Risk cannot be ruled out: Animal reproduction studies have shown an adverse effect on the foetus and there are no adequate and well-controlled studies in pregnant women, But potential benefits may warrant use of the drug in pregnant women despite potential risks. E.g morphine , codeine , atropine , corticosteroids ,adrenaline , thiopentone, bupivacaine

50. category Description D Benefit may outweigh potential risk: Posit i v e e vide n ce of h uma n foeta l ris k - on adverse reaction data from investigational or marketing experience or studies in humans, But potential benefits may warrant use of the drug in pregnant women despite potential risks . E.g. aspirin , phenytoin , carbamazepine, valproate, lorazepam , methotrexate

51. Category Description X Contraindicated in Pregnancy: Studies in animals or humans have demonstrated foetal abnormalities and/or There is positive evidence of human foetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. E.g oestrogens , isotretinoin , ergometrine, thalidomide.

52. 10. Carcinogenecity and mutagenecity Carcinogenecity - Oxidation → reactive metabolites → structural gene damage e.g. Anticancer drugs , estrogens .

53. M UTAGENICITY Structural changes in DNA Oxidation of the drugs produces reactive metabolites Covalent interaction with DNA Inheritable Takes 10-40 years to develop Anti cancer drugs, radioisotopes Usually marketed for life threatening conditions

54. Iatrogenic (Drug induced diseases) - Examples - NSAID'S → Peptic ulcers Hydralazine → DLE Phenothiazines → Parkinsonism INH → Hepatitis

55. 12. Drug Dependence - Use of drug produces a state in which person believes that continuous use is necessary for state of well being ( psychic dependence) or to avoid withdrawal symptoms ( physical dependence.) Psychological Physical Here person believes Here repeated administration that state of wellbeing of drug required to maintain achieved only with action physiological equilibrium of drugs. Discontinuation → withdrawl e.g. Opiods , B e nzo d iaz e pins e.g. Alcohol , Barbiturates , Benzodiazepins

56. P REVENTION OF ADR Avoid all inappropriate use of drugs. Use of appropriate dose , route & frequency of drug administration. Elicit & take into consideration previous history of drug reactions. Elicit h/o allergic diseases & exercise caution. Rule out possibility of drug interaction. Adopt correct drug administration technique. Carry out appropriate laboratory investigation. Be aware of interactions with certain foods, alcohol and even with household chemicals.

57. M ANAGEMENT OF ADR Discontinue the offending agent if - It can be safely stopped The event is life-threatening or intolerable There is a reasonable alternative Continuing the medication will further exacerbate the patient’s condition Continue the medication (modified as needed) if - It is medically necessary There is no reasonable alternative The problem is mild and will resolve with time

58. Discontinue non-essential medications Administer appropriate treatment - e.g., atropine,protamine sulfate ,digibind antibodies, flumazenil. Provide supportive or palliative care - e.g., hydration, glucocorticoids, warm / cold compresses, analgesics or antipruritics Consider rechallenge or desensitization

59. P RINCIPLES OF D ESCRIPTIVE TOXICITY TESTING IN ANIMALS Effects of chemicals produced in laboratory animals when properly quantified apply to human beings. Exposure of experimental animals to toxic agents in high doses – necessary & valid method to discover possible hazards to human beings.

60. M ANAGEMENT OF POISONING Maintain vital & physiological functions from impairment Termination of exposure (decontamination) Prevention of absorption of ingested poison.(activated charcoal) Hastening elimination Urinary alkanlization Multidose activated charcoal Extracorporeal drug removal Antidote therapy

61. P HARMACOVIGILANCE Definition – Science and activities relating to the detection ,assessment , understanding and prevention of adverse effects or any other drug related problems . Activities involved in it Postmarketing surveillance Dissemination of ADR data Changes in labelling of medicines

62. A DR REPORTING FORM

63. C AUSALITY ASSESSMENT Routine procedure in Pharmacovigilance Relationship of cause & effect Most outcomes : multiple interacting causes Aim : to define contribution due to drugs Problems : ADRs rarely specific Diagnostic tests usually absent Re challenge rarely ethically justified Various methods : None is precise, reliable

64. Causality Assessment Methods Algorithmic : (algorithm - specify how to solve problem) Series of questions Answers are weighted Overall score determines causality category e.g. Naranjo’s scale Probalistic : (based on probability) Set of explicitly defined causality categories e.g. WHO UMC method Uses of causality assessment Initial review of report Signal detection Scientific publications

65. T HE N ARANJO ADR P ROBABILITY S CALE Questions Y es No Don’t Know 1) Are there previous conclusive reports on this reaction? +1 2) Did the ADR appear after the suspected drug was administered? +2 -1 3) Did the ADR improve when the drug was discontinued? +1 4) Did the ADR appear with re-challenge? +2 -1 5) Are there alternative causes for the ADR? - 1 +2 6) Did the reaction appear when placebo was given? - 1 +1 7) Was the drug detected in blood at toxic levels? +1 8) Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 9) Did the patient have a similar reaction to the same or similar drug in any previous exposure? +1 10) Was the ADR confirmed by any objective evidence? +1

66. T HE N ARANJO P ROBABILITY S CALE The score :- ≥ 9 = Definite 5-8 = Probable 1-4 = Possible 0 = Doubtful Naranjo CA et al. Clin Pharmacol Ther 1981;30:239-45.

67. DRUG INTERACTIONS PHARMACOKINETIC DRUG INTERACTIONS 1 ) DRUG –DRUG interaction Drug interaction (more precisely 'drug-drug interaction') refers to modification of response to one drug by another when they arc adminis-tered simultaneously or in quick succession . 2) Drug – food 3) Drug – chemical 4) Drug – disease.. etc

68. Regular medication drugs (Likely to be involved drug teract1ons ) 1 . Antidiabetics 2 . Antihypertensives 3. Antianginal drugs 4 . Antiarthritic drugs 5. Antiepileptic drugs 6. Antiparkinsonian drugs 7. Oral contraceptives 8 . Anticoagulants 9. Antiasthmatic drugs 10 . Psychopharmacological agents 11 . Antipeptic ulcer/reflux drugs 12 . Corticosteroids 13. Antitubercular drugs 14 . Anti-HIV drugs

69. Drug interactions at ABSORBTION Absorption of an orally administered drug can be affectcd by other concurrently ingested drugs. This is mostly due to formation of insoluble and poorly aborbed complexes in the gut lumen, as occurs between tetracyclines and calcium/iron salts, antacids or sucralfate . Phcnytoin absorption is decreased by sucralfate due to binding in the g.i . lumen.

70. Ketoconazole absorption is reduced by H 2 blockers and PPIs because they decrease gastric acidity which promotes dissolution and absorption of ketoconazole . Antibiotics like ampicillin , tetracyclines , cotrimoxazole markedly reduce gut flora that normally deconjugates oral contraceptive steroids secreted in the bile as glucuronides and permits their enterohepatic circulation . contraceptive failure have been reported with concurent use of these antibiotics due to lowering of the contraceptive blood levels. AIteration of gut motility by atropinic drugs, tricyclic antidepressants, opioids and prokinetic drugs like metoclopramide can also affect drug absorption.

71. Distribution Interactions drug distribution are primarily due to displacement of one drug from its binding sites on plasma proteins by another drug. Drugs highly bound to plasma proteins that have a relatively small volume of distribution like coumarine anticoagulants, sulfonylureas , certain NSAIDs and antiepileptics are particularly liable to displacement interactions . Displacement of bound drug will initially raise the concentration of the free and active form of the drug in plasma that may result in toxicity.

72. Quinidine has been shown to reduce the binding of digoxin to tissue proteins as well as its renal and biliary clearance by inhibing the efflux transporter P-glycoprotein, resulting in nearly doubling of digoxin blood levels and toxicity .

73. Metabolism interaction Certain drugs reduce or enhance the rate of metabolism of other drugs . Macrolide antibiotics, azole anti fungals , chloramphenicol , omcprazole , SSRls , HIV-protease inhibitors, cimctidine , ciprofloxacin and metronidazolc are some important inhibitors of metabolism of multiple drugs . Risk of statin induced myopathy is increased by fibrates , niacin, erythromycin , azole antifungals and HIV-protease inhibitors, probably due to inhibition of statin metabolism.

74. Barbiturates, phenytoin , carbamazepine , rifampin , cigarelle smoking, chronic alcoholism and certain pollutants are important microsomal enzyme inducers . Contraceptive failure and loss of therapeutic effect of many other drugs have occurred due to enzyme induction. On the other hand, paracetamol toxicity occurs in chronic alcoholics and in those on enzyme inducing medication, because one of the metabolites of paracetamol is responsible for its overdose hepatotoxicity .

75. Excretion interactions lnteraction involving excretion are important mostly in case of drugs actively secreted by tubular transport mechanisms, e.g. probenecid inhibits tubular secretion of penicillins and cephalosporins and prolongs their plasma t½. This is particularly utilized in the single dose treatment of gonorrhoea . Aspirin blocks the uricosuric action of probenecid and decreases tubular secretion of methotrexate .

76. Change in the pH of urine can also affect excretion of weakly acidic or weakly basic drugs. This has been utilized in the treatment of poisonings . Diuretics and to some extent tetracyclines , ACE inhibitors and certain I SAIDs have been found to raise steady-state blood levels of lithium by promoting its tubular reabsorption .

77. C ONCLUSION Every drug which has an effect has an adverse effect every time a drug is given risk is involved. What is there that is not a poison ? all things are poison & nothing is with out poison, solely dose determines that a thing is not a poison. For rational use of drug not only its clinical indications are important to be remembered equally important is remembering adverse effects. Early detection of adverse effects and its proper management can be life saving in many situations.

78. R EF E R E N C ES Goodman and Gilman's -12 th The Pharmacological basis of therapeutics Parthasaradhi clinical pharmacy, 2 nd edition Essentials of pharmacotherapeutics 5 th edition – F.S.K. Barar Essentials of Medical Pharmacology 7 th - K. D. Tripathi

79. Reports from Par t icipating Hospitals Reports from Private Practitioners Report from Drug Mfr. T rader s / Outlets Reports on Clinical Inve s tig a - tions Reports from Regulatory Aut h orities Reports from Int’l ADR Centers BFAD ADR UNIT NADRAC WHO Collaborating Center Director - BFAD Secretary of Health - DOH ADR Monitoring System

80. ADR S : 4 TH L EADING C AUSE OF D EATH Study: Drug reactions kill an estimated 100,000 a year April 14, 1998

81. K EY POINTS TO REMEMBER ADRs