Hazards of Medications 2022-2023 Final PDF

Hazards of Medications 4th year Pharmacy students By Dr. Mariam Ashraf Amin Pharmacology and Toxicology department Faculty of Pharmacy 2022-2023 A) Hazards of Medications: 1- Adverse Drug Reactions (ADRs) 2- Allergic & Photoallergic Reactions 3- D...

Hazards of Medications 4th year Pharmacy students By Dr. Mariam Ashraf Amin Pharmacology and Toxicology department Faculty of Pharmacy 2022-2023 A) Hazards of Medications: 1- Adverse Drug Reactions (ADRs) 2- Allergic & Photoallergic Reactions 3- Drug-Induced Diseases (Organ toxicity) 4- Drug interactions 5- Drug/ Substance abuse, dependence and addiction B) Selective Toxicity  I- Adverse drug reactions (ADRs) — A broad term referring to an injury or harmful effects associated with the use of a given medications under normal conditions. —WHO Define ADRs as: “Any noxious, unintended, undesired response to a drug which occurs at doses used for prophylaxis, diagnosis, or therapy of disease”. —These undesired effects may occur as a part of the pharmacological action of the drug or may be unpredictable in its occurrence. —They may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. — The study of ADRs is the concern of the field known as pharmacovigilance.  Comparison of various terminologies used to describe the untoward effects of drugs: — Adverse drug event (ADE): refers to any injury occurring at the time a drug is used, whether or not it is identified as a cause of the injury. An ADR is a special type of ADE in which a causative relationship can be shown. — Side effect: Unintended effect occurring at normal dose related to the pharmacological properties. This effect, whether therapeutic or adverse, is secondary to the one intended. Although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.  ADRs are common in: — Women — Extreme ages — Polytherapy — Multiple diseases  Types of ADRs 1. Type A reactions 2. Type B Reactions 3. Type C reactions 4. Type D reactions  Type A (Augmented Reactions) Dose dependent and predictable — Due to extension of pharmacologic effect. — Can be due to the primary (e.g. β-blocker-induced bradycardia) or secondary (e.g. β-blocker-induced bronchospasm) pharmacological characteristics of the drug. — Predictable (anticipated). — Dose – dependent & reversible. — Higher incidence than others. — Responsible for at least two-thirds of ADRs (Common). — Usually avoidable by adjusting the dose. — Usually mild, although they may be serious or even fatal (e.g. intracranial bleeding from warfarin). e.g., Heart block caused by propranolol. e.g., Hypoglycemia caused by insulin. e.g., Bleeding caused by excessive warfarin.  Mechanisms of Type A Reactions i) Overdosage toxicity: ADRs caused by excessive dosing. ◦ e.g., hypoglycemia with high doses of sulfonylurea or insulin. ii) Side Effects: Undesirable effect produced by therapeutic doses. ◦ e.g., sedation with antihistamines. iii) Secondary Effects: due to secondary pharmacological effect. ◦ e.g., Orthostatic hypotension with a phenothiazine. iv) Drug Interactions: When two drugs taken together & they affect each other’s response pharmacodynamically or pharmacokinetically: e.g., Theophylline toxicity increased in presence of ERYHTROMYCIN (ENZYME INHIBITOR)  Type B (Bizarre reactions) (Non-dose related ADRs) Ø Not related to known drug’s actions, not obviously due to an increase in drug concentration (pharmacokinetic) or drug effect (pharmacodynamic). Ø Caused by immunological response (allergy) or pharmacogenetic (idiosyncrasy) mechanisms. Ø Non-predictable. Ø Dose-independent & irreversible. Ø Rare incidence. Ø Non-avoidable. Ø Sometimes results in drug withdrawal. Ø Serious organ damage. Øe.g., Aplastic anemia with chloramphenicol Øe.g., Respiratory apnea with succinylcholine Øe.g., Anaphylaxis with penicillins  Mechanisms of Type B Reactions a) Idiosyncratic Reactions: Abnormal harmful or fatal response to drug due to genetic abnormality; appear in low doses ◦ e.g., Succinylcholine apnea due to enzyme deficiency. b) Immunological: Immune-mediated response (Ag-Ab reactions) ◦ e.g., Anaphylaxis with penicillin. c) Drug intolerance: Opposite of tolerance i.e., ­sensitivity to low doses – e.g., Severe bronchospasm and wheezing with small dose of aspirin. d) Abnormalities in rate of drug metabolism: as slow acetylators ◦ e.g., Isoniazid peripheral neuropathy in patients deficient in the enzyme N-acetyl transferase (in slow acetylators).  Type C (Chronic effects) — Associated with long-term use of drugs. — Involves dose accumulation. — Well known and can be anticipated. e.g., Analgesic nephropathy. e.g., Cushing’s syndrome with prolonged prednisolone. e.g. Benzodiazepine or opioid dependence.  Type D (Delayed) Reactions — Delayed in onset & very rare — e.g., Carcinogenic & teratogenic effects: 1. Carcinogenic Effect (delayed effects following prolonged exposure): ◦ Carcinogenic means chemicals inducing cancer, usually after several months or years of chemical exposure. ◦ e.g., Exposure to CCL4, high dose of progesterone, Phocomelia benzene. 2. Teratogenic effect (short-term exposure at critical time): ◦ Teratogens are chemicals that cause congenital Cleft Lip malformation if given during pregnancy. ◦ e.g., thalidomide-induced phocomelia after months, Phenytoin-induced cleft-lip/cleft-palate. Type E: End-of-treatment effects: these may also include: — Withdrawal reactions Opiates, benzodiazepines, corticosteroids — Rebound reactions Clonidine, beta-blockers, corticosteroids There is also a new proposed type F for (Failure of therapy) as Resistance to antimicrobials  Drugs Withdrawn by FDA or Restricted as a Result of ADRs Drugs Year ADRs. Outcome Thalidomide 1961 Congenital malformation; Withdrawn phocomelia Aspirin 1986 Reye’s syndrome Uses restricted Rofecoxib 2004 Cardiac sudden death Withdrawn Troglitazone 2000 Hepatotoxicity Withdrawn Grepafloxacin 1999 Torsade de pointes Withdrawn  Effects of Chemical Combinations on ADRs: — Combinations of chemicals may result in antagonism, synergism or potentiation. — e.g., Hepatotoxicity is enhanced as a result of exposure to both ethanol and carbon tetrachloride (synergism). — e.g., Isopropanol, is not hepatotoxic in itself but its combination with carbon tetrachloride increases the toxic response to the carbon tetrachloride (potentiation). — e.g., Phosphate reduces lead absorption in the GIT by forming insoluble lead phosphate (antagonism).  2- Allergic or Hypersensitivity Reactions — Hypersensitivity refers to undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system. — Result from previous sensitization. — Immune- based reactions i.e., depend on antigen-antibody reactions. ◦ Drugs may act as an antigen (Ag) per se or as a hapten (small molecules that elicit an immune response only when attached to a large carrier such as a protein) to form an antigenic complex. ◦ Antigen sensitizes the cells to produce antibody (Ab). ◦ Re-exposure to the antigen ® Ag-Ab reactions ® allergic manifestations. — Allergic reactions are dose-independent.  Clinical manifestations of hypersensitivity reactions — Fever — Rashes: as urticaria, eczema, erythema and dermatitis. — Blood disorders: thrombocytopenia, hemolytic anemia and neutropenia. — Respiratory disorders: as asthma and rhinitis — Anaphylaxis: angioneurotic edema, severe bronchospasm and laryngospasm as well as severe hypotension.  Phototoxic vs photoallergic reactions — Phototoxic: Drug accumulates in skin à absorbs light à photochemical reaction (photobiological reaction) à tissue damage [e.g., erythema, edema, blistering etc] e.g., tetracyclines. ◦ Ö Dose-dependent, not-based on immune reactions and occurs in all individuals after single exposure. — Photoallergic drug à cell mediated immune response à contact dermatitis on exposure to light. e.g., sulfonamides, griseofulvin etc. ◦ Ö Dose-independent, immune-based reactions, occurs in some individuals after repeated exposures.  B) Selective toxicity Definition: — Chemicals produce injury to one kind of living matter (undesirable) without harming another (desirable); even though they exist together in close contact. ◦ e.g., parasite (undesirable) and the host (desirable).  Mechanims of selective toxicity 1. Differences in toxicokinetics “ADME” ◦ e.g., Malathion: non toxic to human but lethal to insects why?? – In mammals (as human beings): malathion is biotransformed by hydrolysis to relatively safe metabolites. – In insects: malathion is oxidized to malaoxon, which is lethal to insects. – In addition, insects have larger surface area per unit weight compared to humans and so insects absorb more malathion than human. ◦ Therefore, malathion selective toxicity may be due to differences in toxicokinetics.  Mechanisms of selective toxicity cont. 2. Differences in comparative cytology: e.g., Bacteria contain cell wall, while human beings do not. So, Beta lactam antibiotics which acts as cell wall synthesis inhibitors are selectively toxic to bacteria but not to human. 3. Differences in biochemistry: e.g., Bacteria can’t absorb folic acid but synthesize it from p- aminobenzoic acid. However, mammalians can’t synthesize folic acid but have to absorb it from GIT. This give the selectivity of sulfonamides in treating bacterial infections.  DRUG-INDUCED DISEASES “DRUGS- AND TOXICANTS-INDUCED ORGAN TOXICITY”  Iatrogenic disease — An iatrogenic disorder occurs when the deleterious effects of the therapeutic or diagnostic regimen causes pathology independent of the condition for which the regimen is advised. — Diagnostic procedures (mechanical and radiological or by drugs), therapeutic regimen (drugs, surgery, other invasive procedures), hospitalization and treating doctor himself can bring about iatrogenic disorders.  DRUG-INDUCED DISEASES — A drug-induced disease is the unintended effect of a drug, which results in mortality or morbidity with symptoms sufficient to prompt a patient to seek medical attention and/or require hospitalization. — Can result from unanticipated or anticipated drug effects. — Can also occur from product impurities, as was the case with deaths attributed to the use of contaminated heparin in 2008. Vigilance on regulatory authorities, drug manufacturers, clinicians, and patients is necessary to minimize the potential harm resulting from drug use.  Drug-induced auditory diseases — “Ototoxicity” means drug-induced damage to the auditory or vestibular parts of the inner ear. Ototoxic drugs are those medications that can cause ototoxic (ear damaging) side effects, such as hearing loss, tinnitus and others. Examples: — Analgesics: - Aspirin — Antibiotics: - Aminoglycosides e.g. gentamicin - Chloramphenicol - Erythromycin - Tetracycline - Vancomycin — Chemotherapy drugs: - Cisplatin - Vincristine - Methotrexate  Drug-induced auditory diseases (cont.) — Loop diuretics: - Bumetanide - Ethacrynic acid - Furosemide — Loop diuretics have reversible effects on the auditory system, mostly as potentiating agents when given together with aminoglycoside antibiotics (this combination has devastating effects on the auditory system). — Also, potentially ototoxic agents are organometals such as organic mercury preparations & the solvents toluene. — The formation of reactive oxygen species and a resulting oxidative stress may be part of the mechanism of ototoxicity of cisplatin & aminoglycosides.  Drug-induced cutaneous manifestations Some of the cutaneous manifestations are: 1. Alopaecia: Cytotoxic agents, valproic acid 2. Erythema multiforme and Steven Johnson syndrome: Sulphonamides, ampicillin. 3. Exfoliative dermatitis: streptomycin 5. Fixed drug eruption: Barbiturates, Tetracyclines 6. Photosensitivity: Tetracycline, Griseofulvin  Drug-induced hematological disorders Megaloblastic Anaemia (MA) Phenytoin, phenobarbitone and primidone cause MA due to folic acid deficiency. Colchicine cause MA due to vitamin B12 deficiency. 6-Mercaptopurine, 5-flurouracil, acyclovir and zidovudine cause MA by interfering with DNA metabolism Hemolytic anemia Drugs causing haemolysis by direct action: phenacetin, sulphonamides (toxicity) by immune mechanism: chlorpromazine, quinine and tetracycline (allergy) in G-6-PD deficient patients, antimalarials (primaquine) and antibiotics (nitrofurantoin) (idiosyncrasy) Aplastic anemia Drugs that regularly produce bone marrow depression: busulphan, cyclophosphamide, chlorambucil, vinblastine, and 6- mercaptopurine. Drugs which rarely produce bone marrow depression: chloramphenicol, sulphonamides, isoniazid, NSAIDs, anticonvulsants. Drugs producing Neutropenia: Analgesics and NSAIDs :Indomethcin Anticonvulsants :Phenytoin, Carbamazepine Antithyroid drugs :Thiouracil, Methimazole Phenothiazines :Chlorpromazine Antiarrhythmic :Quinidine Drugs that cause thrombocytopenia: Alpha-methyldopa, carbimazole, chloramphenicol, cyclosporins, phenylbutazone, quinine, quinidine, rifampicin, sulphonamides and heparin. There are two types of drug-induced thrombocytopenia: Immune: the drug causes the body to produce antibodies, which seek and destroy platelets, e.g., heparin. Nonimmune: the drug prevents the bone marrow from making enough platelets, e.g., chemotherapy drugs (e.g., Methotrexate, cisplatin, chlorambucil, cyclophosphamide) and valproic acid.  Drug-induced GIT diseases 1-Acid peptic disease: NSAIDs, corticosteroids, methylxanthins, reserpine, cholinomimetics, alcohol and others. 2-Pancreatitis: azathioprine, glucocorticoids and oral contraceptives. 3-Malabsorption: broad-spectrum antibiotics, cholestyramine. 4-GIT paralysis: opioids, atropine and direct smooth muscle relaxants. 5-Pseudomembranous colitis: clindamycin and other broad- spectrum antibiotics  Drug-induced Hepatic damage Drug induced liver injury is a potential complication of nearly every medication because liver metabolizes virtually most drugs. Types of hepatic injury 1- Fatty Liver: is an abnormal accumulation of fat in hepatocytes. 2- Necrosis: is an acute degenerative injury of hepatic cells leading to cell death and occasional hepatic failure. 3- Cholestasis: is the suppression or stoppage of bile flow. Inflammation or blockage of the bile ducts results in retention of bile salts as well as bilirubin accumulation, leading to jaundice.  Types of hepatic injury (cont.) 4- Cirrhosis: degeneration of cells, inflammation, and fibrous thickening of tissue, results from chronic chemical injury as that caused by chronic use of ethanol or HCV. 5- Hepatitis: is an inflammation of the liver and is usually viral in origin; however, certain chemicals, usually drugs, can induce a hepatitis that closely resembles that produced by viral infections. 6- Carcinogenesis: The most common type of liver tumor is hepatocellular carcinoma that happens on top of liver cirrhosis.  Examples of hepatotoxic agents and associated liver injury Acute (acetaminophen, halothane) and chronic (nitrofurantoin, methyldopa) hepatocellular injury. 1- Necrosis and fatty liver: - Carbon tetrachloride - Chloroform -Acetaminophen 2- Cholestasis (drug-induced): - Chlorpromazine - Imipramine - Diazepam - Methimazole - Estradiol - Tolbutamide 3- Hepatitis (drug-induced): - Halothane - Isoniazid - Indomethacin - 6-Mercaptopurine - Colchicine - Methyldopa 4- Hepatocellular carcinoma: -Sex and anabolic steroids - Nitrosamines -Urethane  Mechanism of some Hepatotoxicants 1- Ethanol: acts as hepatotoxic by: A. Interfering with hepatic lipid metabolism. B. Induction of both inflammation and necrosis in the liver. C. Oxidative stress. 2- Bromobenzene: - Toxic industrial solvent producing hepatic necrosis through formation of reactive epoxides metabolites.  Cont. 3- Carbon tetrachloride: It is a classic example of a chemical activated by cytochrome P450 to form a highly reactive free radical that cause hepatic necrosis. 4- Acetaminophen: therapeutic dose is very safe but overdoses may cause an acute fatal hepatic necrosis due to formation of a reactive intermediate benzoquinoneimine metabolite. This reactive metabolite is usually inactivated by conjugation with reduced glutathione and excreted. But, higher doses of acetaminophen will progressively deplete hepatic glutathione causing hepatic necrosis. Mechanism of hepatic injury by paracetamol  Respiratory disorders due to drugs Type of reaction & examples: 1.Airway obstruction (Bronchospasm): β-Blockers, NSAIDs and parasympathomimetics. 2.Cough: ACE inhibitors. 3.Nasal congestion: Oral contraceptives, Reserpine, Guanithidine 4.Pulmonary edema: Methadone 5.Pulmonary hypertension: Fenfluramine 6.Pulmonary thrombo- embolism: Oral contraceptives 7- Respiratory depression: Opioids, Barbiturates, General anesthetics 8- Pulmonary fibrosis: Busulfan, Bleomycin, Methotrexate 9- Infective complications: –immunosuppressants Some Important Industrial Lung Toxicants and Associated Injury  Drug-induced cardiovascular diseases Exacerbation of angina (alpha blockers) Arrhythmias (digitals, beta-adrenergic agents, tricyclic anti- depressants and quinine) and Torsades de pointes (quinidine) Cardiomyopathy (daunorubicin and lithium) Hypotension (ACE inhibitors, alpha blockers, vasodilators) or hypertension (glucocorticoids and sympathomimetics)  NEPHROTOXICITY The kidney is the main excretory organ of the body and hence affected by most drugs. Renal disorders caused by drugs 1. Pre-renal failure: NSAIDs, ACE inhibitors, Diuretics, Amphotericin B. Noradrenaline and dopamine in high doses. *NSAIDs indirectly affect renal blood flow by inhibiting production of prostaglandins. 2. Acute tubular necrosis (direct toxicity to the tubular cells): paracetamol, amphotericin B, aminoglycosides, NSAIDs. 3. Acute interstitial nephritis (the drug functions as an antigen or as a hapten and the resulting antigen antibody reaction damages renal interstitium): penicillins, cephalosporins, NSAIDs, captopril, thiazides, sulfonamides. N.B. Analgesic nephropathy: heavy and prolonged consumption of compound analgesic preparations can cause chronic renal failure. This analgesic nephropathy is part of a broader analgesic syndrome, which includes hypertension, peptic ulcer, anemia and recurrent headache.  Mechanisms of some nephrotoxic drugs 1- Nephrotoxic Aminoglycosides — e.g., Streptomycin, neomycin, kanamycin, and gentamycin. — Aminoglycosides, are nephrotoxic in humans, especially in high doses or after prolonged therapy. — Aminoglycosides are polar cations that are filtered by the glomerulus and excreted unchanged into the urine. — In the proximal tubule, a fraction is reabsorbed by binding to anionic membrane phospholipids, followed by endocytosis and sequestration in lysosomes. When a threshold concentration is reached, the lysosomes rupture, releasing hydrolytic enzymes that cause tissue necrosis.  2- Amphotericin B — With some drugs, renal damage may be related to the drugs’ biochemical mechanism of action. — Amphotericin B is a polymycin systemic antifungal agent. — The nephrotoxicity is the result of: a) Direct action of the drug on the renal tubules: Mediated by changes in membrane permeability, i.e. the same mechanism responsible for its antifungal activity. It is a surface-active agent that binds to membrane phospholipids, disrupting the integrity of the membrane and resulting in leaky cells. The particular structure of amphotericin B (having both a hydrophilic and a lipophilic portion) makes it suitable for incorporation in the cell membranes, where it induces oxidative-type (lipid peroxidation) and ionophoric damage. This latter type of damage is caused by the creation of pores or channels in the membrane with leakage of the cell content and increased intracellular uptake of small solutes b) a vasoconstricting action (mainly preglomerular, but also postglomerular) due to direct action of the molecule or indirect action mediated by thromboxanes, with consequent reduction of blood flow and glomerular filtration.  Examples of nephrotoxicants 1- Metals: - Many heavy metals are potent nephrotoxicants, and relatively low doses can produce toxicity characterized by glucosuria, aminoaciduria, and polyuria. As the dose increases, renal necrosis, anuria, and death will occur. - After low dose exposure and often before detectable signs of developing nephrotoxicity, significant concentrations of metal are found bound to renal lysosomes resulting in tissue damage. A- Cadmium: — In humans, exposure to cadmium is primarily through food or industrial exposure to cadmium dust. — In Japan, a disease called Itai-itai Byo is known to occur among women who eat rice grown in soils with very high cadmium content. The disease is characterized by anemia, damage to proximal tubules, and severe bone and mineral loss.  Examples of nephrotoxicants B- Mercury: — Mercury exerts its principle nephrotoxic effect on the membrane of the proximal tubule cell. In low concentrations, mercury binds to the sulfhydryl groups of membrane proteins and acts as a diuretic by inhibiting sodium reabsorption. — Organomercurial diuretics were introduced into clinical practice in the 1920s and were used clinically into the 1960s. Despite their widespread acceptance as effective therapeutic diuretics, it was well known that problems related to severe kidney toxicity were possible. — More recently organomercurial chemicals have been implicated as environmental pollutants, responsible for renal damage in humans and animals.  Examples of nephrotoxicants C- Lead: — Lead, as Pb2+, is taken up readily by proximal tubule cells, where it damages mitochondria and inhibits mitochondrial function, altering the normal absorptive functions of the cell. D- Uranium: — About 50 % of plasma uranium is bound, as the uranyl ion to bicarbonate, which is filtered by the glomerulus. — As a result of acidification in the proximal tubule, the bicarbonate complex dissociates, followed by reabsorption of the bicarbonate ion; the released uranyl ion (UO22+) then becomes attached to the membrane of the proximal tubule cells. — The resultant loss of cell function is evidenced by increased concentrations of glucose, amino acids, and proteins in the urine  Examples of nephrotoxicants 2- Chloroform — Chloroform is a common industrial organic solvent that can be a hepatotoxicant or a nephrotoxicant in both humans and animals. — As a nephrotoxicant, it is both species and gender-dependent. For example, following chloroform administration male mice develop primarily kidney necrosis whereas female develop liver necrosis. — As a nephrotoxicant, chloroform most probably undergoes metabolic activation in the kidney itself. Chloroform is metabolized to phosgene by a cytochrome P450-dependent reaction. — Phosgene is capable of binding to cellular proteins to produce the cellular necrosis associated with chloroform toxicity to the kidney.  Examples of nephrotoxicants 3- Hexachlorobutadiene: — Hexachlorobutadiene is an industrial solvent and heat-transfer agent. It is a widespread environmental contaminant that is a potent and relatively specific nephrotoxicant. — Hexachlorobutadiene first forms a glutathione conjugate, which is further metabolized to a cysteine conjugate. In the kidney, the cysteine conjugate is cleaved to a reactive intermediate. 4- Tetrafluoroethylene: — The nephrotoxic mode of action of tetrafluoroethylene is similar to that of hexachlorobutadiene. — It is first metabolized to a cysteine conjugate, which is metabolized to a reactive product that can bind to cellular macromolecules.  Neurological manifestations 1. Extra pyramidal lesions (as Parkinsonism): -Haloperidol -Methyldopa -Phenothiazines -Reserpine -Metoclopramide 2. Peripheral neuropathy: -Isoniazid -Metronidazole 3.Convulsions: Amphetamine, Analeptics, Lithium, Phenothiazine, Methylxanthines, NSAIDs, Opioids (produce hypoxia-related seizures), Immunosuppressives (cyclosporine), Anesthetics, Antidepressants, Hypoglycemics (insulin, sulfonylureas) 4. Stroke: Oral contraceptives 5. Neuroleptic malignant syndrome: (Rigidity, hyperthermia, altered mental status resembling catatonia, labile blood pressure and autonomic dysfunction) characterize one of the serious complications of neuroleptic agents like Haloperidol. 6. Headache: -Vasodilators -Sex hormones -Chemotherapeutic drugs -Immunomodulating drugs 7- CNS depression (including respiratory depression and coma): - Opioids as morphine - Barbiturates - General anesthetics - H1-antagonists  Drug-induced psychiatric syndromes 1. Delirium or Confusion state : Anticholinergics, Glucocorticoids, Phenothiazines 2. Depression: Beta blockers, Glucocorticoids, Reserpine 3. Drowsiness: Antihistamines 4. Hallucinations: Beta blockers, Levodopa, Narcotics 5-Hypomania and Mania: Glucocorticoids, Sympathomimetics 6. Paranoid states: Amphetamines  Drug-induced musculoskeletal /rheumatic disorders 1.Arthralgia: growth hormone, Quinolones (in children). 2.Hyper-uricaemia and Gout: Cytotoxic drugs, Cyclosporine, Salicylates, Ethambutol, Levodopa, Nicotinic acid, Phenytoin, Diuretics. 3. Mylagia/Myositis: Amphotericin B, Chloroquine, Cimetidine, Clofibrate, Colchicine, Cyclosporines, Gemfibrozil, Lovastatin, Levodopa, Penicillamine, Phenytoin, Rifampicin, Vincristine, Zidovudine. 4. Osteoporosis: Anticonvulsants, Corticosteroids, Heparin, Methotrexate.  Ophthalmological complications 1. Cataract: Busulphan 2. Corneal opacities: Chloroquine 3. Colour vision alteration: Digitalis 4. Glaucoma: Sympathomimetics, corticosteroids and atropine- like agents 5. Optic neuritis: Quinine, ethambutol 6. Retinopathy: Chloroquine  Drugs producing malignant diseases 1. Leukemia: Anticancer agents, Chloramphenicol and Phenyl-butazone 2. Cancer of breast and endometrium: Estrogens 3. Cancer of vagina: Diethyl stilbesterol 4. Liver cancer: Anabolic steroids, Oral contraceptives Drug-induced fever Drug fever constitutes one percent of all fevers of unknown origin. Any drug can cause fever (barbiturates, iodides, penicillins, phenytoin, propylthiouracil, progesterone, beta- lactum antibiotics etc). A history of allergy, skin rash or eosinophilia is often absent in cases of drug fever