Adverse Drug Reactions

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Adverse Drug Reactions Types: I. Predictable (Type A / Augmented) Reactions II. Unpredictable (Type B) Reactions

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Predictable (Type A / Augmented) Reactions: a. Due to excessive pharmacological activity. Exp: Bleeding with Anticoagulants, Hypoglycemic coma with Insulin b. Withdrawal symptoms or rebound responses after discontinuation of treatment: Example : Clonidine withdrawal--- hypertensive crisis. c. A/E unrelated to the main pharmacological action- -- Drug toxicity Nephrotoxicity by aminoglycosides.

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Unpredictable (Type B) Reactions: Drug Allergy Idiosyncracy Genetically determined effects:

Idiosyncracy: 

Idiosyncracy It is defined as qualitatively abnormal response to a drug , can be seen even after the first dose . It is highly unpredictable It has genetic basis. Seen only in small percentage in a population . May be fatal. Example: Idiosyncratic Aplastic Anemia with Chloramphenicol Chloramphenicol is an antibiotic given for treatment of infections. In 1 in 32, 000 patients can produce irreversible bone marrow suppression leading to inhibition of maturation & decrease in number of RBCs, even on first administration .It may be fatal.

Nervous system: 

Nervous system Extrapyramidal symptoms: Chloropromazine Metoclopramide Reserpine Phenothiazine

Nervous system: 

Nervous system Ototoxicity : Aminoglycosides Ethacrynic acid Frusemide Salicylates

Nervous system: 

Nervous system Peripheral neuropathy: Isoniazid (slow ) Amiodarone

Nervous system: 

Nervous system Hallucination: Digitalis Convulsions: Isoniazid chloroquine

Nervous system: 

Nervous system Ataxia: Streptomycin Phenytoin Metronidazole Lithium

Nervous system: 

Nervous system Nystagmus : Phenytoin

Cardiovascular system: 

Cardiovascular system Cardiac arrhythmias: Halogenated general anaesthtics Amitriptyline Levodopa Digitalis

Cardiovascular system: 

Cardiovascular system Hypertensive crisis: Clonidine (sudden stoppage) Tyramine containing foods. Myocardial depression: Emetine Chloroform

Lungs : 

Lungs Bronchospasm : Betablockers (non-selective) Allergic form of asthma: Penicillin Iron- dextran infusion Aspirin

Lungs : 

Lungs Pulmonary fibrosis: Methysergide Busulphan Nitrofurantoin

Lungs : 

Lungs Pulmonary Eosinophilia : Sulphonamide Tetracyclines Pulmonary alveolitis : Amiodarone

Eyes : 

Eyes Optic neuritis: Ethambutol Quinine Retinal damage: Chloroquine ( prolonged ↑ dosage)

Eyes : 

Eyes ↑ I.O.P: Atropine Succinylcholine

Gynaecomastia : 

Gynaecomastia Digoxin Reserpine Methyldopa Spironolactone Estrogens

Teratogenicity : 

Teratogenicity Diethylstilbestrol Thalidamide Angiotension converting enzyme inhibitor (ACE) HMG Co- reductase inhibitors

Carcinogenicity : 

Carcinogenicity Procarbazine – alkylating agent used for Hodgkin’s lymhoma is leukemogenic . Vinyl chloride – hepatoma Cigarette smoke………

Skin : 

Skin Acne-form: oral contraceptives, anticonvulsants, corticosteroids Eczematous: allopurinol , warfarin Pigmentation: griseofulvin Exfoliative dermatitis: carbamezipine , gold salts. Psoriasis: chloroquine , lithium Stevens-Johnson syndrome: sulphonamides

Skin : 

Skin Systemic lupus erythematosus : griseofulvin , hydralazine , sulphonamides Urticaria : cephalosporins , penicillin, aspirin Photosensitivity: antihistamines (1 st gen), tetracyclines , sulphonamides , sulphonylureas . Alopecia: cytotoxic drugs, heparin, warfarin .

G.I.T: 

G.I.T Nausea & vomiting: cardiac glycosides, dopamine agonist ( levodopa ), morphine, cisplatin (most notorius ….anticipatory vomiting, Rx with ondansetron ). Bisphosphonates ( aldrenonate )…. aggrevate oesophageal ulcer.

Acute hepatic injury : 

Acute hepatic injury By direct action: halothane & CCl 4 Cholestatic jaundice: anabolic steroids, rifampin .

Chronic hepatic injury: 

Chronic active hepatitis: isoniazid , methyldopa, acetaminophen. Hepatic cirrhosis: ethanol & inorganic arsensic . Chronic hepatic injury

Kidney : 

Kidney Acute tubular necrosis: aminoglycosides , 1 st gen. cephalosporins , amphotericin B.

Drug Allergy/ hypersensitivity : 

Drug Allergy/ hypersensitivity Definition Drug allergy is an acquired qualitatively altered response of the body to a drug having immunological basis-- due to antigen-antibody reactions ,in a previously sensitized individual.

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How drugs act as allergens Antigens High MW drug – Proteins ,peptide. Hepetens: Low MW drug + Endogenous Protein ---- conjugate acts as antigen .

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Types of Allergic Reactions a. Acute Allergic Reactions: occur Immediately i. Mild: Urticaria , skin rashes ii. Severe/Fatal :-Anaphylactic shock (anaphylaxis) b. Sub acute Reactions: occur after 1-24 hrs or a few days. c. Delayed Allergic Reactions: called Serum Sickness. occur after 1-3 wks.

Mechanism of Allergy / Hypersensitivity : 

Mechanism of Allergy / Hypersensitivity Humoral Type-I Anaphylactic reactions, skin rashes. Type-II Auto & iso antibodies to the blood cells e.g. Haematological drug reactions Agranulocytosis. Aplastic anemia , Haemolytic anemia. , Erythroblastosis fetalis , Tranfusion reaction Type-III. A & A local mediated hypersensitivity e.g. Haematological reactions LE type reactions. Cell mediated Type-IV delayed hypersensitivity e.g. skin rashes, haematological reactions.

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Distinctive Features of Allergic Reactions These are abnormal, unexpected and qualitatively different responses , not related to known pharmacological properties of the drug Not dose dependent. Very small dose may cause very severe effects. They occur in previously exposed / sensitized individuals . It recurs upon repeated exposure even to traces of the drug. They occur in a small number of patients

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They disappear on stopping the drug and reappear on exposure to a small dose. The same drug produces different effects in different patients. Patients with allergic disease e.g. eczema, are more prone to allergy to drugs. Some drugs e.g. penicillin , are more likely to cause allergy than other drugs. It is possible to achieve desensitization .

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a. Acute Allergic Reactions: occur Immediately i. Mild: Urticaria , skin rashes ii. Severe/Fatal :-Anaphylactic shock (anaphylaxis)

Anaphylaxis: 

Anaphylaxis Definition Anaphylaxis may be defined as a rapidly developing immunologic reaction due to reaction of antigen with antibody bound to mast cells in previously sensitized individuals. The main features are marked hypotension, bronchoconstriction & laryngeal edema. Death may occur due to loss of intravascular fluid.

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Mechanism: Type -1 Hypersensitivity Reaction. Chemical Mediators Of Anaphylaxis Histamine. Prostaglandins. Leukotrienes Platelet activating factor. Cytokines. Features of mediators Vasoactive , Chemotactic Spasmogenic

Drugs That May Cause Anaphylaxis: 

Drugs That May Cause Anaphylaxis Penicillins. Cephalosporins. Vaccines. Plasma expanders e.g dextran. Streptokinase. Heparin. Radiological contrast media. L-Asparaginase Others.

Prevention Of Anaphylaxis: 

Prevention Of Anaphylaxis 1. Previous history of allergy to a drug . 2. Skin tests for detection of allergy e.g Penicillin: Scratch test (Scratch the skin through a drop of sol -containing 10,000 units of penicillin G/ml). Central wheal after 10 min. Intradermal Test : 0.05 ml Penicilloyl Polylysine. OR 0.02 ml of 100 units/ml sol. of Penicillin. G IgE titer in plasma

Treatment Of Anaphylaxis: 

Treatment Of Anaphylaxis I. First Line Drug: Epinephrine 1:1000 sol 0.3-0.5 ml I/M. May be repeated after 3 minutes . Acts immediately by physiological antagonism. Avoid I/V because fatal ventricular fibrillation may occur.

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II. Second Line Drugs: a. Corticosteroids Inj. Hydrocortisone 100mg I/V b. Antihistamines (H 1 – Antagonists) Chlorpheniramine 10 mg I/V c. Miscellaneous Drugs Aminophylline 6mg/kg BW I/V slowly over 10-20 min. Isoprenaline or Metaraminol : I/V Infusion.

Supportive Treatment I/V Fluids Oxygen Tracheostomy Endotracheal Intubation: 

Supportive Treatment I/V Fluids Oxygen Tracheostomy Endotracheal Intubation

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b. Sub acute Reactions: occur after 1-24 hrs or a few days. 1. Urticarial skin rashes , Angioneurotic edema , Treatment : Epinephrine , Glucocorticoids & H1 antagonists Tracheostomy: 2. Exfoliative dermatitis , conjunctivitis , Arthralgia , Lupus erythmatosis like generalized autoimmune disease e.g. Hydralazine, procainamide produce Syndrome like SLE. Treatment : Withdrawal of drug. Glucocorticoids & H1 antagonists.

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Drug-induced haematological reactions : Due to type II, III or IV hypersensitivity. Haemolytic Anaemia by Sulfonamides, Methyldopa. Aranulocytosis by carbimazole, clozapine. Thrombocytopenia by quinine, heparin. Reversible Aplastic Anaemia by Chloramphenicol.

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Allergic Liver Damage: (Type II, III) Halothane → reactive metabolite Enflurane Treatment : Withdrawal of drug. Glucocorticoids

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Delayed Allergic Reactions: (Type III, IV) called Serum Sickness syndrome occur after 1-3 wks----Urticaria , fever , arthralgia & lymphadenopathy. Drug-induced haematological reactions may also occur

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Prevention of adverse effects to drugs A/E can be minimized by the following : Select drugs according to patient’s clinical condition. Dose, route and frequency of drug admin. should be based on patient’s specific variables. Elicit and take into consideration previous history of drug reactions. Elicit history of allergic disease and exercise caution.

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Rule out possibility of drug interactions Administration technique should be correct e.g. I/V inj. of Aminophylline over 10-20 min. Carry out appropriate laboratory monitoring when indicated. e.g. Prothrombin time with Warfarin, serum drug levels with Lithium

Hypersusceptibility Exaggerated response in some patients than normal expected response of drug. e.g. 10 mg of morphine produces sleep for 4 – 6 hrs. In Hypersusceptibility ------ up to 10 – 12 hrs. : 

Hypersusceptibility Exaggerated response in some patients than normal expected response of drug. e.g. 10 mg of morphine produces sleep for 4 – 6 hrs. In Hypersusceptibility ------ up to 10 – 12 hrs.

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Effect of Climate. In hot humid climate metabolism is depressed so less dose is required as compared to winter. Purgatives act better during summer. Diuretics act better during winter. Effect of Altitude. Higher we go lesser oxygen we get. This leads to ↓ metabolic destruction of drugs, so less dose should be given. Reverse at sea level.

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Racial Differences . Castor oil --- purgative to other but not to Chinese Ephedrine --- dilatation . of pupil in fair skinned people but not in Negroes Species differences. A type of rabbit have atropinase in its liver & can tolerate large doses of Belladonna as opposed to humans. Strychnine cause convulsions in vertebrates but no effect in invertebrates.

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Dosage forms of drugs Solid forms of drug need disintegration & dissolution so OOA is slow as compared to liquid preparation of drug. Age of drug . Certain drugs used beyond shelf life or improperly stored during shelf life may be toxic . e.g. chloroform, paraldehyde, tetracycline → fanconi like syndrome.