Adverse drug effects

Defintion , types and categories of ADR .
Reference; pharmacology by K.D.tripathi.

1. ADVERSE DRUG EFFECTS AND IT’S CLASSIFICATION Presented By :- Sharon Vijayanand Bachelor of Pharmacy C.L.Baid Metha College of Pharmacy

2. CONTENTS DEFINITION TYPES SEVERITY CATEGORIES PREVENTION

3. DEFINITION An adverse drug reaction is defined as, “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 in the future use of the same drug”

4. TYPES Predictable-(‘Type A’ or ‘Augmented Reaction ’) R elated to the main pharmacological action of the drug . Dose dependant and predictable . Example ; - postural hypotension with α 1 adrenergic adrenoreceptor antagonist ( α -Blockers). - bleeding with anticoagulants like warfarin - sedation with anxiolytics .

5. TYPES Unpredictable-(‘Type B’ or ‘Bizarre Reaction’) Idiosyncratic reaction – an abnormal physical reaction by an individual to a food or drug . Different from the pharmacological action of the drug . Example :- - aplastic anaemia from chloramphenicol. - anaphylaxis in response to penicillin . Based on peculiarities of the patient and not on the drug’s known action. (genetic history) Induces an immune response (immune-mediated toxicity).

6. TYPES Type C – Chronic Reaction Results from chronic use of the drug . Well known and accepted Eg ; tardive dyskinesia with prolonged use of antipsychotics. Eg ; analgesic nephropathy with analgesics.

7. TYPES TYPE D – Delayed reactions Delayed adr of drugs Refers to teratogenicity and carcinogenicity . Carcinogenic ; drugs which may cause cancer (diethylstilboestrol - reduce the risk of pregnancy complications but found to cause clear cell carcinoma , a rare vaginal tumour) Teratogenic ; drug induced birth defects (thalidomide – phocomelia ; phenytoin – foetal hydantoin syndrome)

8. TYPES TYPE E – End of treatment Withdrawal symptoms/ effect Eg ; β blockers used in the treatment of hypertension and slows down the HR , abrupt discontinuation of drug will cause rebound hypertension and tachycardia respectively . Withdrawal of drug should be slow .

9. SEVERITY MINOR :- no therapy, antidote or prolongation of hospitalization is required. MODERATE :- requires changes in drug therapy, specific treatment or prolongs hospital stay by at least one day . SEVERE :- potentially life threatening, causes permanent damage or requires intensive medical treatment. LETHAL :- directly or indirectly contributes to death of the patient.

10. CATEGORIES adverse drug reactions may be categorised into ; Side effects Secondary effects Toxic effects and poisoning Intolerance Idiosyncrasy Drug allergy Photosensitivity Drug dependence Drug withdrawal reactions Teratogenicity Mutagenicity and carcinogenicity Drug induced diseases

11. SIDE EFFECTS Unwanted but often unavoidable pharmacodynamics effect at therapeutic doses. Not serious. Reduction in dose reduces the symptoms. Further classified as follows ,

12. Side effect based on same action as therapeutic effect Ex : Atropine – anticholinergic drug used as preanaesthetic for its anti secretory effect – produces dryness of mouth as side effect. Ex : Glyceryl trinitrate –dilates the peripheral vasculature and relieves angina –produces postural hypotension and throbbing headache as side effect.

13. Side effect based on different facet of action Ex : Promethazine – antiallergic drug –produces sedation as a side effect which is unrelated to the therapeutic action of the drug . Ex : Estrogens – antiovulatory action –cause nausea as a side effect .

14. An effect may be therapeutic in one context but side effect in another context Ex : Codeine –drug used in the treatment of cough –produces constipation as side effect , the later being used as therapeutic effect in traveller's diarrhoea

15. Many drugs have been developed from observation of side effects Ex : Sulphonamides –antibacterial drug –produces hypoglycaemia and acidosis as side effect –directed research resulting in the development of hypoglycaemic sulfonylureas and carbonic anhydrase inhibitor –acetazolamide

16. 2. SECONDARY EFFECTS Indirect consequence of a primary action of the drug. Ex : Tetracycline –antibiotic –causes suppression of bacterial flora and paves the way for super infection.

17. 3. TOXIC EFFECT Result of excessive pharmacological action of drug due to over dosage or prolonged use. over dosage –absolute (accidental, homicidal, suicidal) –relative (relating to some other cause .Ex : usual dose of gentamicin in presence of renal failure.) Manifestations are often predictable and dose related . Organs commonly involved in drug toxicity are, CNS CVS Kidney Liver Lungs Skin Blood forming organs

18. 3. TOXIC EFFECT Result from , Functional alteration. Ex : high dose of atropine –delirium Drug induced tissue damage. Ex: hepatic necrosis from paracetamol over dosage. Extension of the therapeutic effect itself. Ex: coma by barbiturates, bleeding due to heparin. A different action of the drug. Ex: morphine –respiratory failure.

19. 4. INTOLERANCE Inability of an individual to tolerate the adverse effect of a medication, generally at therapeutic doses . Converse of tolerance and indicative of a low threshold of an individual to the action of the drug. Ex : Triflupromazine (antipsychotic) -single dose induces muscular dystonia. Ex : few doses of Carbamazepine (antiepileptic) may cause ataxia.

20. 5. IDIOSYNCRCY Genetically determined abnormal reaction to a chemical. Drug interacts with some unique feature of the individual (not found in majority of the subjects) and produces uncharacteristic reaction. The type of reaction is restricted to individuals with a particular genotype. Ex : Barbiturates cause excitement and mental confusion in certain individuals Ex : Chloramphenicol causes non dose related aplastic anaemia in rare individuals.

21. 6. DRUG ALLERGY / HYPERSENSITIVITY Abnormal reaction of the immune system to a drug . Occur with much smaller doses. Organs affected: skin, airways, blood vessel, blood and GIT . Drug/metabolite -act as antigen(AG)/ 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.

22. MECHANISM AND TYPES OF DRUG ALLERGY A. HUMORAL Mediated by macromolecules found in the extracellular fluid (secreted AB, complement proteins and certain antimicrobial peptides. Types , Type 1 (anaphylactic reaction) Type 2 ( cytolytic ) Type 3 (retarded arthus reactions )

23. MECHANISM AND TYPES OF DRUG ALLERGY A. HUMORAL TYPE 1 (anaphylactic reactions ) On exposure to drug, AG:AB reaction on mast cell surface occurs. Causing the release of mediators (histamines, 5-HT, LT, PG, PAF). Result in ; urticaria , itching, angioedema, bronchospasm, rhinitis and anaphylactic shock. Treatment : antihistamines are beneficial.

24. MECHANISM AND TYPES OF DRUG ALLERGY A. HUMORAL TYPE 2 ( Cytolytic reactions) Drug + component of a specific tissue cell act as AG. Result in release of AB (IgG, IgM) B inds to target cells and AG:AB reaction occurs on the surface of these cells. Complement is activated and cytolysis occurs. Ex: thrombocytopenia, agranulocytosis, aplastic anaemia, haemolysis, organ damage (liver, kidney, muscle.),

25. MECHANISM AND TYPES OF DRUG ALLERGY A. HUMORAL TYPE 3 (Retarded Arthus Reaction) Local vasculitis associated with deposition of immune complex and activation of complement system. Mediated by circulating AB (IgG). AG:AB complex bind, complement and precipitate on vascular endothelium –destructive inflammatory response. Manifestations –rashes, serum sickness/fever, arthralgia, lymphadenopathy, poly arteritis nodosa , S teven-Johnson syndrome etc.

26. MECHANISM AND TYPES OF DRUG ALLERGY B. CELL MEDIATED TYPE 4 (Delayed Hypersensitivity Reactions) Mediated through the production of T-lymphocytes. The T-cells carry receptors for AG AG-binds to receptor –production of lymphokines –attract granulocytes-inflammatory response (such as contact dermatitis, rashes, fever, photosensitivity).

27. TREATMENT FOR DRUG ALLERGY Drug causing allergy must be withdrawn. Antihistamine administered for Type 1 reactions. For anaphylactic shock and angioedema , - put patient in reclining position –administer oxygen –perform CPR if required. - inject adrenaline, H1 antihistamines , IV glucocorticoids For type 2, type 3, and type 4 reactions administer glucocorticoids.

28. 7. PHOTOSENSITIVITY Cutaneous reaction resulting from drug induced sensitization of the skin to UV radiation. Types Phototoxic P hoto allergic

29. 7. PHOTOSENSITIVITY a). Phototoxic Drug /metabolite accumulates in skin , absorbs light and undergoes photochemical reaction followed by photo biological reaction , resulting in local tissue damage (sun burn like) i.e. erythema(redness of skin), oedema, blistering Fast onset and short duration. Followed by hyperpigmentation and desquamation. Shorter wavelengths are responsible (290 - 320 nm , UV-B ). Drugs involved in acute reactions- tetracycline ( demeclocycline ) and tar products. Drugs causing chronic reactions – halidixic acid , fluoroquinolones, dapsone etc. Phototoxic reactions are more common than photoallergic recations .

30. 7. PHOTOSENSITIVITY b). Photoallergic Drug/ metabolite induces a cell mediated immune response. Light of longer wavelength is responsible (320- 400 nm UV-A) Produces papular , eczematous contact dermatitis. May persist long after exposure and withdrawal of light source. Rarely antibodies mediate causing flare, itching, wheal on exposure to sun. Small doses trigger reactions. Drugs involved are sulphonamides, griseofulvin , chloroquine, carbamazepine.

31. 8. DRUG DEPENDANCE Physical condition in which the body has adapted to the presence of a drug. If an individual with drug dependence stops taking that drug suddenly that person will experience predictable and measurable symptoms known as ‘withdrawal syndrome’. Different aspects of drug dependence includes Psychological dependence Physical dependence Drug abuse Drug addiction Drug habituation

32. 8. DRUG DEPENDANCE Psychological dependence ; individual believes that the optimal state of well being is achieved only through the action of the drug. (Ex; opioid, cocaine). Physical dependence ; altered physiological state produced by repeated action of drug causing continuous use of drug to maintain physiological equilibrium. (Ex: opioids, barbiturates and other CNS depressants). Drug abuse : use of drug by self medication in a manner not approved medically (continuous/ occasional).(Ex: opioids , cocaine, amphetamine.) Drug addiction : uncontrollable overwhelming need to use a drug, this compulsion is long lasting – relapse unexpectedly after period of improvement.(Ex: amphetamine, cannabis) Drug habituation : denotes less intense involvement with drug, withdrawal produces only mild discomfort. (Ex: tea, coffee , tobacco, social drinking.)

33. 9. DRUG WITHDRAWAL Sudden interruption in drug therapy/use result in adverse consequences mostly in form of worsening of clinical condition for which the drug was used. Ex : frequency of seizures may increase on sudden withdrawal of antiepileptic drugs. Ex : severe hypertension, restlessness and sympathetic over activity may occur shortly after discontinuing clonidine (antihypertensive drug).

34. 10. TERATOGENICITY Capacity of a drug to cause foetal abnormality when administered to the pregnant women . The placenta does not constitute an effective barrier and drugs are capable of crossing it. Ex : thalidomide causes phocomelia (seal like limbs) and other defects . Ex : androgens, progestin cause masculization of female foetus .

35. 10. TERATOGENICITY Drugs can affect foetus in 3 stages Fertilization and implantation (unto 17 days)-failure of pregnancy Organogenesis (18-55 days)-increased deformities Growth and development (56 th day onward)-developmental and functional abnormalities. It is wise to avoid all drugs during pregnancy unless strong reasons exist for their use .

36. 11. MUTAGENICITY AND CARCINOGENICITY Capacity of a drug to genetic defects and cancer respectively. Mutagenicity :- oxidation of drug results in production of reactive intermediates-affects genes- structural changes in chromosome –modified to induce mutation- inherited. Carcinogenicity :- if the modified DNA sequences code for factors that regulate cell growth/ proliferation (proto oncogenes) – it causes tumour. Anticancer drugs, radio isotopes , oestrogens, tobacco are carcinogenic.

37. 12. DRUG INDUCED DISEASES Iatrogenic (Physician induced) diseases. Functional disturbances caused by drugs which persist even after the offending drug has been withdrawn. Ex:- peptic ulcer by salicylates and corticosteroids. Ex;- parkinsonism by phenothiazine and other antipsychotic drugs. Ex:- hepatitis by isoniazid.

38. PREVENTION Avoid inappropriate drug use. Use appropriate dose, route and frequency. Consider previous history of drug reactions. Elicit history of allergic reactions. Rule out the possibilities of drug interactions(when more than one drug is given). Adopt correct drug administration technique(Ex;- IV for vancomycin must be slow). Carry out appropriate lab monitoring (Ex;- prothrombin time with warfarin, serum level of lithium).

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