1. ADVERSE DRUG EFFECTS SIVA NAGESWARARAO MEKALA SIVA NAGESWARARAO MEKALA ASSISTANT PROFESSOR ASSISTANT PROFESSOR DEPT OF CLINICAL PHARMACOLOGY DEPT OF CLINICAL PHARMACOLOGY

2. Adverse Drug Reaction (ADR) is defined as any undesirable or unwanted effect due to drug administration.  Severity of adverse drug reactions has been graded as  Minor: No therapy, antidote or prolongation of hospitalization is required required  Moderate: Requires change in drug therapy, specific treatment or prolongs hospital stay by at least one day prolongs hospital stay by at least one day  Severe: Potentially life threatening, causes permanent damage or requires intensive medical treatment requires intensive medical treatment  Lethal: Directly or indirectly contributes to death of the patient

3.  Pharmacovigilance (Adverse drug reaction monitoring)  Has been defined by the WHO as the  ‘ Science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problems ’  The information generated by pharmacovigilance is useful in educating doctors about adverse drug reactions and in the official regulation of drug use  It has an important role in rational use of medicines, as it provides the basis for assessing safety of medicines

4. ADRs could be either dose related or non dose related. Dose related ADRs : ( Predictable) These are the most common of all types of adverse reactions.these reactions are often predictable. are often predictable. 1) Side effects : These are unwanted effects of a drug which are seen with therapeutic doses therapeutic doses Atropine used in the treatment of heart block also produces dryness of Atropine used in the treatment of heart block also produces dryness of mouth, blurring of vision, urinary retention etc which are unwanted side mouth, blurring of vision, urinary retention etc which are unwanted side effects. effects.

5. 2) Toxic effects : These are the effects of a drug, which are either due to over dosage or These are the effects of a drug, which are either due to over dosage or chronic use. chronic use. Eg: Bleeding due to chronic use/ over dosage of anticoagulants and Eg: Bleeding due to chronic use/ over dosage of anticoagulants and nephrotoxicity with aminoglycosides especially in elderly patients. nephrotoxicity with aminoglycosides especially in elderly patients.  They are more common, dose related and mostly preventable and reversible reversible  Adverse effects may develop promptly or only after prolonged medication or even after stoppage of the drug or even after stoppage of the drug  Adverse effects are not rare; an incidence of 10-25 % has been documented in different clinical settings in different clinical settings

6. Non dose related ADRs: (Unpredictable ) Hypersensitivity reactions (Drug Allergy): It is an abnormal response to a drug due to Ag:Ab reaction resulting in the release of various mediators. They are less common, often non dose related, generally more serious and require withdrawal of the drug

7. Mechanism and types of allergic reactions A. Humoral A. Humoral Type I (anaphylactic) reactions Type I (anaphylactic) reactions Type II (cytolytic) reactions Type II (cytolytic) reactions Type III (retarded, Arthus) reactions Type III (retarded, Arthus) reactions B. Cell mediated B. Cell mediated Type IV (delayed hypersensitivity) reactions Type IV (delayed hypersensitivity) reactions

8. Type I (anaphylactic) reactions: It is rapidly occurring reaction, hence called immediate hypersensitivity. The manifestations are itching, Utricaria,Hay fever,asthma or even anaphylactic shock. It is derived from ana means without phylaxis means protection phylaxis means protection IgE mediated acute allergic reaction to certain drugs IgE mediated acute allergic reaction to certain drugs ( Penicillin,aspirin,lignocaine ) ( Penicillin,aspirin,lignocaine ) On re exposure to the same drug On re exposure to the same drug AG:AB reaction occurs on the mast cell surface AG:AB reaction occurs on the mast cell surface Release of mediators (Histamine,5HT,PGs,LTs,PAF) Release of mediators (Histamine,5HT,PGs,LTs,PAF) Hypotension,bronchospasm,angioedema, utricaria and rhinitis Hypotension,bronchospasm,angioedema, utricaria and rhinitis

9. It is medical emergency and should be treated promptly with : 1.Inj.adrinaline (1:1000)0.3-0.5 ml i.m Repeat every 5-10 minutes in case patient does not improve or Repeat every 5-10 minutes in case patient does not improve or improvement is transient improvement is transient This is the only life saving measure This is the only life saving measure 2.Inj.hydrocortisone 100-200 mg i.v 3.inj.diphenhydramine 25-50 mg i.m or i.v 4. Intravenous fluids.

10. Type II (cytolytic) reactions: The antibodies react with cell bound antigen and cause activation of complement which destroys the cells. IgG and IgM mediated IgG and IgM mediated The antibody reacts with cell bound antigens The antibody reacts with cell bound antigens binding of antibody with antigen binding of antibody with antigen Activation of compliment Activation of compliment Destruction of cells Destruction of cells Eg: Blood transfusion reactions Hemolytic anemia's produced by qunine, cephalosporins. cephalosporins.

11. Type III (retarded, Arthus) reactions: In this type of reaction antibodies involved are mainly IgG. Ag:Ab complex is formed Ag:Ab complex is formed Fix compliment Fix compliment Complexes are deposited on vascular endothelium Complexes are deposited on vascular endothelium Destructive inflammatory response Destructive inflammatory response Eg: Serum sickness (Fever,utricaria, joint pain ) with penicillins and sulphonamides sulphonamides

12. Type IV (delayed hypersensitivity) reactions: It is mediated by sensitized T lymphocytes. Re exposure to the antigen leads to a local inflammatory response. The manifestations usually occur 2-3 days after exposure to the sensitizing antigen. Eg: contact dermatitis due to local anesthetic creams, topical antibiotics and antifungal agents. antifungal agents. Type II, Type III and Type IV reactions are treated with I.V glucocorticoids.

13.  DRUGS FREQUENTLY CAUSING ALLERGIC REACTIONS  Penicillins Salicylates  Cephalosporins Carbamazepine  Sulfonamides Allopurinol  Tetracyclines ACE inhibitors  Quinolones Methyldopa  Antitubercular drugs Hydralazine  Phenothiazines Local anaesthetics

14. Idiosyncrasy: Idiosyncrasy:  It is genetically determined abnormal reactivity to a chemical or drug  The drug interacts with some unique feature of the individual, not found in majority of subjects, and produces the uncharacteristic reaction. Examples are Examples are  Barbiturates cause excitement and mental confusion in some individuals  Succinylcholine apnoea  Chloramphenicol produces nondose related serious aplastic anaemia in rare individuals

15.  Drug Dependence :   Drug dependence is a state in which use of drugs for personal satisfaction is accorded a higher priority than other basic needs, often in the face of known risks to health. Psychological dependence : There is an intense desire to continue taking the drug as the patient feels his well being depends up on the drug. Physical dependence : Repeated drug use produces physiological changes in the body, which makes continuous presence of the drug in the body necessary to maintain normal function. Abrupt stoppage of the drug results in an imbalance wherein the body has to readjust to the absence of the drug resulting in the development of signs and symptoms known as withdrawal syndrome. The withdrawal signs and symptoms are generally opposite to the effects produced by the drug.

16. Drug withdrawal reactions:   Severe hypertension, restlessness and sympathetic over activity may occur shortly after discontinuing clonidine   Worsening of angina pectoris, precipitation of myocardial infarction may result from stoppage of β blockers   Frequency of seizures may increase on sudden withdrawal of an antiepileptic – can be minimized by gradual withdrawal

17. Treatment for drug dependence :   Hospitalization   Substitution therapy : methadone/buprinorphine substitution for morphine addiction   Aversion therapy : disulphiram for alcohol addiction   Blockade therapy : naltrexone blockade therapy for opioid dependence   General measures: maintain nutrition,family support etc  DRUG HABITUATION: It denotes less intensive involvement with drug, so that its withdrawal produces only mild discomfort  Consumption of tea, coffee, tobacco, social drinking are regarded habituating, physical dependence is absent

18. Latrogenic disease : Latros (Greek word) That means “physician” Physician induced disease due to drug therapy. Eg: parkinsonism due to metoclopramide Acute gastrities and peptic ulcer due to NSAIDs Acute gastrities and peptic ulcer due to NSAIDs Carcinogenicity and mutagenicity: The ability of a drug to cause cancer is carcinogenicity The agent is known as carcinogen.the abnormalities of genetic material in a cell produced by a drug are known as mutagenicity. Eg: anti cancer drugs, radioisotopes, estrogens, tobacco

19.  Teratogenicity  It refers to capacity of a drug to cause foetal abnormalities when administered to the pregnant mother administered to the pregnant mother  The placenta does not strictly constitute a barrier and any drug can cross it to a greater or lesser extent to a greater or lesser extent  The embryo is one of the most dynamic biological systems and in contrast to adults, drug effects are often reversible to adults, drug effects are often reversible  The thalidomide disaster (1958-61) resulting in thousands of babies born with phocomelia (seal like limbs) and other defects focused attention to with phocomelia (seal like limbs) and other defects focused attention to this type of adverse effect this type of adverse effect

20. Drugs can affect the foetus at 3 stages Drugs can affect the foetus at 3 stages  (i) Fertilization and implantation – conception to 17 days – failure of pregnancy which often goes unnoticed  (ii) Organogenesis – 18 to 55 days of gestation – most vulnerable period, deformities are produced  (iii) Growth and development – 56 days onwards – developmental and functional abnormalities can occur, e.g. ACE inhibitors can cause hypoplasia of organs, specially lungs and kidneys;  It is, therefore, wise to avoid all drugs during pregnancy unless compelling reasons exist for their use regardless of the assigned category, or presumed safety

23.  Photosensitivity  It is a cutaneous reaction resulting from drug induced sensitization of the skin to UV radiation. The reactions are of two types skin to UV radiation. The reactions are of two types  (A) PHOTOTOXIC: Drug or its metabolite accumulates in the skin, absorbs light and undergoes a photochemical reaction light and undergoes a photochemical reaction  Followed by a photobiological reaction resulting in local tissue damage (sunburn like), i.e. erythema, edema, blistering followed by hyperpigmentation and desquamation  The shorter wave length (290-320 nm, UV-B) are responsible  Drugs involved in acute phototoxic reactions are tetracyclines (especially demeclocycline)

24.  (B) PHOTOALLERGIC: Drug or its metabolite induces a cell mediated immune response which on exposure to light of longer wave length immune response which on exposure to light of longer wave length (320-400 nm, UV-A) produces a papular or eczematous contact (320-400 nm, UV-A) produces a papular or eczematous contact dermatitis like picture dermatitis like picture  Drugs involved are sulfonamides, sulfonylureas, griseofulvin, chloroquine, chlorpromazine chlorpromazine  Hepatotoxicity : Isoniazide,rifampicin,pyrazinamide,paracetamol  Nephrotoxicity : Aminoglycosides,cyclosporine,heavy metals  Ototoxicity : Aminoglycosides,loop diuretics  Ocular toxicity : chloroquine,glucocorticoids

25.  Poisoning :  Many drugs in high doses may cause poisoning Eg: barbiturates poisoning – The manifestations are hypotension, Eg: barbiturates poisoning – The manifestations are hypotension, respiratory depression, circulatory failure,coma and death respiratory depression, circulatory failure,coma and death General principals in the treatment of drug poisoning are :  Hospitalization  Airway should be cleared : in comatose patients, there is a danger of respiratory obstruction by the tongue, secretions and aspiration of vomitus.hence a cuffed endotracheal tube should be inserted and secretions should be aspirated regularly.  Breathing should be assessed: if there is respiratory insufficiency, patient should be mechanically ventilated  Circulation should be assessed (pulse rate and BP) and an i.v line should be maintained.

26.  Gastric lavage : to remove the unabsorbed portion of the drug in case of ingested poison. After lavage,activated charcoal is added to the stomach  Diuretics : are used to produce the elimination of absorbed portion of the drug.  Dialysis is used in case of severe poisoning. It is suitable only for the drugs that are not highly protein bound and for the drugs with low volume of distribution eg: aspirin  Symptomatic treatment : i.v diazepam 5-10mg if there is convulsions and external cooling for hyperpyrexia  Maintenance of fluid and electrolyte balance  Administer antidote, if any eg: atropine for organophosphorous poisoning,naloxone for morphine poisoning

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