ADRs (VK)
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ADRs (VK)

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  • igen <br />
  • Make comment about diphenhydramine and sedation (positive outcome) <br /> Also about retonovir and ropenivir (retonovir increases concentrations of ropenivir, resulting in higher drug concentrations = lower doses) <br />
  • Thalidomide example for risk in pregnancy (resulted in severe birth defects). Now used in the treatment of multiple myeloma, although efficacy not fully established <br />

ADRs (VK) ADRs (VK) Presentation Transcript

  • ADVERSE DRUG REACTIONS
  • DEFINATIONS Adverse drug reactions (WHO): Any response to a drug that is noxious and unintended and that occurs at doses used in man for prophylaxis, diagnosis or therapy of disease or modification of physiological states.
  • No Drugs are Dangerous if used properly All Drugs are Dangerous Some drugs have a low therapeutic ratio Some drugs have a low incidence of horrendous effects Some drugs are dangerous in acute poisoning but not when used therapeutically The most dangerous drugs have the greatest potential for benefit Some adverse effects occur after a delay or after stopping BAD GOOD How dangerous a drug is depends on the skill of the prescriber Some adverse effects can be predicted if you know the pharmacology (Type A); some are not (Type B)
  • The Risk to Benefit Ratio When prescribing drugs a doctor must assess risk to benefit ratio in the individual patient by •Choosing an appropriate class of drug then an appropriate individual agent RISK BENEFIT •Is it effective ? •What are the chances of adverse effect ? •Are there features in this patient which affect choice eg other drugs, organ failure, aged •Tailoring the dose •Considering duration of treatment
  • Epidemiology 4% of hospital admissions 1 in 1000 deaths in medical wards 10 to 20 % of in-patients 5% of patients in general practice
  • More frequent in elderly: erratic drug taking multiple pathology altered pharmacokinetics increased sensitivity of CNS and CVS
  • Drugs - anti-coagulants, NSAIDs,corticosteroids, antihypertensives, anti-biotics, diuretics and insulin.
  • Occur in circumstances related to drug’s pharmacology, predisposing factors in the patient and care taken in choosing the drug and the dose.
  • SIDE EFFECTS Pharmacological effects produced with therapeutic dose of drug.  Troublesome in one condition but useful in others.  Ex. atropine UNTOWARD EFFECTS Undesirable effects with therapeutic dose of the drug ,if severe requires caessation of treatment.  Ex.tetracyclines,aspirin TOXIC EFFECTS Effects produced by large & / repeated doses  Ex. morphine
  • ADR TYPES QUANTITATIVE QUALITATIVE (Type A) (Type B) IDIOSYNCRASY Genetic ALLERGY Unknown I II III (HYPERSENSITIVITY) IV
  • Comparison –type A &B Type A Type B 1.Nature augmented/ attenuated normal Totally abnormal, bizarre response 2.Mechanism Hyper/ hypo response Genetic, immunological,UK 3. Predictable Yes No 4.Incidence high Low 5.Mortality Low High 6. Treatment Adjust dose Stop the drug 7.Dose dependent Yes No
  • IDIOSYNCRASY GENETIC • G6PD DEFECIENCY • ATYPICAL PSEUDOCHOLINESTRASES UNKNOWN Chloramphenicol –Aplastic anaemia
  • ALLERGIC REACTION FEATURES 1. Ranges from mild- severe (anaphylaxis) 2. Prior sensitization requried 3. Immunologically mediated 4. Low incidence , unpredictable, dose independent.
  • Hypersensitivity Hypersensitivity is an immune reaction to innocuous antigens that results in tissue injury and/or disease An antigen that causes allergy is an allergen
  • TYPES OF ALLERGIC REACTIONS I.IgE MEDIATED REACTION AND ANAPHYLAXIS-(immediate hypersensitivity) • Systemic anaphylaxis- ex.penicillin. Antigen + IgE antibodies—influx of ca++ ----degranulation of mast cells ,basophiles—release of histamine---anaphylaxis • Local anaphylaxis -Hay fever -Asthma -Diarrhea, gi.Pain. -Skin rash
  • Allergy (type I hypersensitivity mediated by IgE on mast cells)
  • Mast cell degranulation by antigen (allergen) cross-linking of FceR-bound IgE
  • Mast cell activation has many effects
  • TYPE II ALLRGIC REACTION Cytotoxic type reactionAntibodies binds to antigen present on the cell surface promotes phagocytosis of cell or cell destruction by polymorphs, macrophages or by lymphoid killer cells. ExamplesTransfusion reactions Rh incompatibility • drugs-antigenic complex with blood cells----increase humoral antibodies----cytotoxic – haemolysis / agranulocytosis / thrombocytopenia
  • Type II hypersensitivity (IgG-mediated anticell-associated antigen response) is rare Immune response to certain drugs (e.g., penicillin) where drug binds to cell surface and antibody cause removal of the cells (usually by macrophages).
  • TYPE III IMMUNE COMPLEX MEDIATED REACTIONS ANTIGEN+HUMORAL ANTIBODIES IMMUNE COMPLEXES Ab EXCESS Ppt.NEAR SITE OF ENTRY SKIN-ERYTHEMA,EDEMA, ETC. ARTHUS REACTION Ag EXCESS DEPOSIT IN SKIN, JOINTS KIDNEY SERUM SICKNESS
  • Arthus Reaction: acute antibodymediated hypersensitivity to soluble antigens
  • TYPE IV CELL MEDIATED REACTION-(Delayed hypersensitivity)  Inflammatory reaction initiated by T cells.  Delayed-secondary cellular response occurs after 48 hrs of antigen exposure.  Examples1.montoux reaction-i.d. tuberculin inj. 2.Sulphonamides
  • Four Types of Hypersensitivities
  • MANIFESTATION OF ADR 1. Haemopoetic toxicity 2. Hepatotoxicity –direct / immunological 3. Nephrotoxicity 4. Abnormality in taste & smell 5. Occular toxicity 6. Ototoxicity 7. Behavioural toxicity 8. Iatrogenic diseases 9.Teratogenicity
  • Risk Factors for Adverse Drug Reactions Simultaneous use of several different drugs – Drug-drug interactions Very young, or very old in age Pregnancy Breast Feeding Hereditary Factors Disease states which may effect drug absorption, metabolism, and/or elimination 32
  • Risk Factors Examples: Simultaneous Drug Use or Drug-Drug Interactions Cerivastatin-Gemfibrozil interactions in hypercholesterolemia patients (rhabdomyolysis) Coumadin-NSAID interactions (increased inhibition of platelet aggregation) Venlafaxine-indinavir interactions in depressed HIVinfected patients (decreased indinavir concentrations) 33
  • Risk Factors Examples: Age Related Issues Children are often at risk because their capacity to metabolize drugs is usually not fully developed – Newborns cannot metabolize or eliminate chloramphenicol, an antibiotic – Children younger than 18 may be at risk of developing Reye’s syndrome if given acetylsalicylic acid (aspirin) while infected with chickenpox or influenza – Central nervous system effects of topiramate in children (seizures, tremor, and dizziness) 34
  • Risk Factors Examples: Age Related Issues  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 – Disease states leading to drug ADME changes – Decreased drug ADME activity due to age  These conditions are exacerbated by malnutrition and dehydration, common in the elderly 35
  • Risk Factors Examples: Pregnancy  Use of sulfonamides (antibiotic) can lead to jaundice and brain damage in the fetus  Warfarin use for anticoagulation can lead to birth defects, and increased risk of bleeding problems in newborns and mothers  Lithium, for bipolar disorder, can lead to defects of the heart, lethargy, reduced muscle tone, and underactivity of the thyroid gland 36
  • Risk Factors Examples: Breastfeeding  Similar concerns, as for other children with underdeveloped capability to metabolize or excrete xenobiotics  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) 37
  • Risk Factors Examples: Hereditary Factors  Genetic polymorphisms may play a role – Evident in CYP2C9 and 2C19, especially in the Asian population (phenytoin) – May lead to impaired metabolism in mutation of enzymes  Higher risk of hemolysis in some populations, such as African, Middle Eastern, and South East Asian races – Quinolones – Antimalarials 38
  • Risk Factors Examples: Disease States  Metabolism (Phase I or II) may be impaired with hepatic disease – Cirrhosis – Hepatic Carcinoma  Renal Insufficiency – Acute or Chronic Renal Failure – Decreased glomerular filtration rate (GFR)  Drug levels may become toxic if too high, so dosing modifications may be indicated 39