Adverse Drug Reactions PDF

ADVERSE DRUG REACTIONS Prof. Kamal Matar Pharmacology 1140-113 Learning Objectives of ADRs By end of this lecture, you should be able to:  define and classify adverse drug reactions  assess the characteristics of each type of adverse drug reaction  describ...

ADVERSE DRUG REACTIONS Prof. Kamal Matar Pharmacology 1140-113 Learning Objectives of ADRs By end of this lecture, you should be able to:  define and classify adverse drug reactions  assess the characteristics of each type of adverse drug reaction  describe examples of adverse drug reactions  appraise the stages of drug evaluation pre- and post-marketing. Adverse Drug Reaction vs. Side Effect: How Are They Differ? Adverse drug reactions (ADRs) and side effects are both unintended responses to a medication. But ADRs are harmful and more unexpected than side effects. Side effects are more predictable than ADRs. Plus, side effects can be beneficial or harmful. Common causes of ADRS Failing to take the correct dosage at the correct times. Overdosing. Allergies to chemical components of the medicine. Combining medicine with alcohol. Taking other drugs or preparations that interact with the medicine. Taking a medicine that was prescribed for someone else. Factors affecting ADRs 1/ Patient-related factors: Age Sex Genetic influences Concurrent diseases (renal, liver, cardiac) Previous ADRs Compliance with the dosing regimen Total number of medications Miscellaneous (diet, smoking, environmental exposure) Age: Children are often at risk because their capacity to metabolize drugs is usually not fully developed. Children may be at risk of developing Reye’s syndrome (Rare but serious condition causes confusion, swelling of brain, liver damage) if given aspirin while infected with chickenpox or influenza. Elderly: 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 Pregnancy: Sulfonamides Jaundice and brain damage in the fetus. Warfarin Birth defects, & risk of bleeding problems in newborns & mothers. Lithium Defects of the heart (Ebstein’s Anomaly), lethargy, reduced muscle tone, & underactivity of the thyroid gland. Factors affecting ADRs (Cond.) 2/ Drug-related factors: Dose Duration Inherent toxicity of the agent PD properties PK properties FDA defines ADR as which: Results in death Life-threatening Requires hospitalization Causes disability Causes congenital anomalies Requires intervention to prevent permanent injury What is an ADR? ADR is a response to a medicinal product which is noxious & unintended. ADR is suspected to be due to a drug, occurs at doses normally used in man, requires ttt or decrease in dose or indicates caution for in future use of the same drug. Some Serious Adverse Drug Reactions Adverse Drug Reaction Types of Drugs Examples Certain antibiotics Chloramphenicol Anemia (resulting from decreased Drugs used to treat malaria or Chloroquine production or increased destruction of red blood cells) tuberculosis in people with G6PD Isoniazid enzyme deficiency Primaquine Angioedema (swelling of the lips, Captopril tongue, and throat causing difficulty in ACE inhibitors Enalapril breathing) Lisinopril Esomeprazole Bone fractures Proton pump inhibitors Lansoprazole Omeprazole Birth control drugs (all forms Drospirenone/ethinyl estradiol Blood clots including patches and pills) Norelgestromin/ethinyl estradiol Sedatives, including many Confusion and drowsiness Diphenhydramine antihistamines Metronidazole with Mebendazole (Vermox) adverse rxs Stevens-Johnson Syndrome (SJS) & Toxic epidermal necrolysis. Classifications of ADRs: Type A (Augmented) Type B (Bizarre) Type C (Chemical) Type D (Delayed) Type E (Exit/End of ttt) Type F (Familial) Type A (Augmented) Features: Type A reactions result from an exaggeration of a drug’s normal pharmacological actions when given at the usual therapeutic dose. Type A reactions are normally dose-dependent. Predictable. Low mortality Examples: Respiratory depression with Opioids Bleeding with Warfarin Dry mouth with Tricyclic Antidepressants Bradycardia with beta blockers Headache with nitrates. Management: Reduce dose or withhold drug Consider effects of concomitant therapy Type B (Bizarre); (Non-Dose Related) Features: Less common Not related to the pharmacological action of the drug Unpredictable. High mortality Examples: Immunological reactions: Anaphylaxis with penicillin Idiosyncratic reactions: malignant hyperthermia with general anesthetics Skin rashes with Antibiotics Management: Withhold & avoid in the future Type C (Chemical); (Dose related & Time related) Features Uncommon Persists for a relatively long time Related to the cumulative dose Examples Osteoporosis of jaw with bisphosphonates Nephrotoxicity by NSAIDs Hepatotoxicity by paracetamol Hypothalamic-pituitary-adrenal axis suppression by corticosteroids. Osteonecrosis of the jaw with bisphosphonates Management Reduce dose or use an alternate day therapy Withdrawal may have to be prolonged Type D (Delayed); (Time Related) Features Uncommon Usually dose-related Occurs or becomes apparent sometime after use of the drug Examples Carcinogenesis Teratogenesis Tardive dyskinesia Leucopenia with lomustine (after 6 weeks on medication) Management Tardive dyskinesia Often intractable Type E (Exit/End of ttt) Features Uncommon Occurs soon after the withdrawal of the medicine Examples Withdrawal syndrome with opiates or Benzodiazepines (e.g., insomnia, anxiety) Management Reintroduce drug and withdraw slowly Type F (Failure): (Unexpected Failure of Therapy) Features Common Dose related Often caused by drug interactions Examples Inadequate dosage of an oral contraceptive when used with an enzyme inducer. Resistance to antimicrobial agents Management Increase dosage Consider effects of concomitant therapy Classification of ADRs…. Depending on Severity Minor ADRs: No therapy, antidote or prolongation of hospitalization is required. Moderate ADRs: Requires change in drug therapy, specific treatment or prolongs hospital stay by at least 1 day. Severe ADRs: Potentially life-threatening, causes permanent damage or requires intensive medical treatment. Lethal: Directly or indirectly contributes to death of the patient. ADEs may be categorized into:  Side effects  Secondary effects  Toxic effects  Intolerance  Idiosyncrasy  Drug allergy  Photosensitivity  Drug dependence  Drug withdrawal reactions  Teratogenicity  Mutagenicity and Carcinogenicity  Drug-induced diseases (Iatrogenic disorders or Iatrogenicity)  SIDE EFFECTS Unwanted often unavoidable PD effects. Occur at therapeutic doses. Predictable Examples Benzodiazepines Drowsiness, dizziness, confusion H1 Anti-histaminics Sedation An effect may be therapeutic in one context but side effect in another context  e.g., Constipation by codeine is a side effect but can be used as therapeutic effect in patients with diarrhea.  SECONDARY EFFECTS Indirect consequences of a primary action of the drug. Examples: Corticosteroids weaken host defence: Activation of latent tuberculosis. Tetracyclines Bacterial flora Superinfection.  TOXIC EFFECTS Over-dose or prolonged use. The effects are predictable and dose-related. Examples: High dose heparin Bleeding. High dose of paracetamol Hepatic necrosis. Prolonged use of gentamicin Ototoxicity, nephrotoxicity.  INTOLERANCE It is the appearance of characteristic toxic effects of a drug in an individual at therapeutic doses. It indicates a low threshold of the individual to the action of a drug. Sensitivity to low doses. Examples carbamazepine (few doses) cause ataxia in some individuals. Chloroquine (single tablet) Vomiting & abdominal pain in some individuals. Un-Predictable  IDIOSYNCRASY It is genetically determined abnormal reactivity to a chemical. The drug interacts with some unique feature of the individual, not found in majority of subjects, and produces the uncharacteristic reaction. Examples Chloramphenicol Aplastic anaemia (non-dose-related) in rare patients. Barbiturates Excitement and mental confusion in some patients. Un-Predictable  DRUG ALLERGY It is also called drug hypersensitivity. It is an immunologically mediated allergic reaction producing stereotype symptoms which are unrelated to the PD profile of the drug. It generally occurs even with much smaller doses and has a different time course of onset and duration. Un-Predictable  Allergic reactions occur only in a small proportion of the population exposed to the drug. History of prior sensitization may or may not be evident. The drug or its metabolite acts as antigen (AG) or more commonly hapten (incomplete antigen) and induces production of antibody (AB)/sensitized lymphocytes.  TYPES OF ALLERGIC REACTIONS A) HUMORAL 1. Type I/ Anaphylactic reactions. It is due to IgE antibodies, min: 2 -3 h. Examples: urticaria, angioedema, anaphylactic shock (Penicillins). 2. Type-II / Cytolytic reactions. (IgG, IgM). It is due to antigen antibody complex, within 72 h. Examples: Hemolytic anemia (Methyldopa), SLE. 3. Type-Ill / Retarded or Arthus reactions. (IgG, IgM). Immune complex mediated rxs, 72 h 1 – 2 weeks. Examples: Serum sickness (fever, arthralgia, lymphadenopathy), Steven Johnson syndrome, procainamide induces SLE.  TYPES OF ALLERGIC REACTIONS (Cond.) B) CELL MEDIATED: Type-IV (delayed hypersensitivity) reactions. (T cell). Examples: Contact dermatitis by topically applied drugs.  PHOTOSENSITIVITY It is a cutaneous reaction resulting from drug-induced sensitization of the skin to UV radiation. The reactions are of two types: a) Phototoxicity: 1. Drug or its metabolite Accumulates in the skin, 2. absorbs light and undergoes a Photochemical reaction followed by 3. Photobiological reaction resulting in: 4. Tissue damage (sunburn-like): i.e. erythema, edema, blistering , hyperpigmentation, desquamation. The shorter wavelengths (290-320 nm, UVB) are responsible. More common: e.g., Tetracyclines (esp. Demeclocycline), Nalidixic acid, Fluoroquinolones. (b) Photoallergicity: Drug or its metabolite induces a cell mediated immune response which on exposure to Light of longer wavelengths (320 - 400 nm) produces a papular or eczematous contact dermatitis. Less common e.g., Drugs involved are sulfonamides, sulfonylureas, griseofulvin, chloroquine, chlorpromazine.  DRUG DEPENDENCE 1. Psychological dependence: Individuals believe that optimal state of well being is achieved only through the actions of the drug. Examples: Opioids, cocaine 2. Physical dependence: It is an altered physiological state produced by repeated administration of a drug which necessitates the continued presence of the drug to maintain physiological equilibrium. Discontinuation of the drug results in a characteristic withdrawal (abstinence) syndrome. Drugs producing physical dependence are: opioids, barbiturates, alcohol and benzodiazepines.  DRUG DEPENDENCE (Cond.) Drug abuse : Refers to use of a drug by self medication in a manner and amount that deviates from the approved medical and social patterns in a given culture at a given time. Drug addiction: It is a pattern of compulsive drug use characterized by overwhelming involvement with the use of a drug. Procuring the drug and using it takes precedence over other activities  DRUG DEPENDENCE (Cond.) Drug habituation (Psychological dependence) It denotes less intensive involvement with the drug, so that its withdrawal produces only mild discomfort. Consumption of tea, coffee, tobacco, social drinking are regarded habituating, physical dependence is absent.  DRUG WITHDRAWAL REACTIONS Sudden interruption of therapy with certain drugs results in adverse consequences, mostly in the form of worsening of the clinical condition for which the drug was being used Examples: Corticosteroids in asthma precipitates acute attacks, myalgia, depression. ß-blockers worsening of angina, precipitates myocardial infarction. Opiates Insomnia, irritability, depression, anxiety, hallucinations.  TERATOGENICITY Capacity of a drug to cause fetal abnormalities when administered to the pregnant mother. Drugs can affect the fetus 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): developmental and functional abnormalities can occur. Examples: ACE inhibitors , Thalidomide (Phocomelia), Warfarin, Barbiturates.  MUTAGENICITY AND CARCINOGENICITY Capacity of a drug to cause genetic defects and cancer, respectively. Reactive intermediates which affect genes and may cause structural changes in the chromosomes Even without interacting directly with DNA, certain chemicals can promote malignant change in genetically damaged cells, resulting in carcinogenesis. Chemical carcinogenesis generally takes several (10 – 40) years to develop. Examples: anticancer drugs, radioisotopes, estrogens, tobacco.  DRUG INDUCED DISEASES These are also called iatrogenic (physician induced) diseases. They are functional disturbances (disease) caused by drugs which persist even after the offending drug has been withdrawn and largely eliminated. Examples: Isoniazid Hepatitis. Salicylates, corticosteroids Peptic ulcer. Chloroquine Retinal damage. PREVENTION OF ADVERSE EFFECTS TO DRUGS Avoid inappropriate use of drugs. Appropriate drug administration (Rational Therapeutics) Dose Dosage form Duration Route Frequency Technique Ask for previous history of drug reactions and allergies Always suspect ADR when new symptom arises after initiation of treatment. ( No new drug for new symptom). Ask for laboratory findings such as serum creatinine etc.