Adverse Drug ReactionsAdverse Drug Reactions(Summary)(Summary)

Assoc. Prof. Iv. LambevE-mail: itlambev@mail.bgwww.medpharm-sofia.eu

Adverse reactions (ARs) is any undesirable or unintendedconsequence of drug administration. They include all kindsof noxious effects – trivial, serious or even fatal.

All drugs are capable of producing ARs.All drugs are capable of producing ARs. Whenever a drugWhenever a drugis given a risk is takenis given a risk is taken.. The magnitude of risk has to be considered along with other therapeutic advantagesin deciding whether or not to use a drug.

ARs may develop promptly or only after prolonged medication oreven after stoppage of the drug. An incidence of 10–25% ARshas been documented in different clinical studies. They are more common with multiple drug therapy and in elderly patients.

It is convenient to classify drug ARs under thefollowing headings:

Type A (Augmented) reactions will occur ineveryone if enough of the drug is given becausethey are due to excess of normal, predictable,dose-related, pharmacodynamic effects. Their common and skilled management reduces theirincidence, e.g. postural hypotension, hypoglycemia,hypokalemia. Type A reactions also includeside, secondary, and toxic effects of drugs.

Type B (Bizarre) reactions will occur only insome people. They are not part of the normalpharmacology of the drug and are not dose-related.These effects may be predictable when themechanism is known (though predictive tests maybe expensive or impracticable), otherwise they canbe unpredictable for the individual. The classincludes unwanted effects due to inheritedabnormalities (idiosyncrasy) andimmunological processes (drug allergy).

Type C (Chronic) reactions due to long-termexposure, e.g. analgesic nephropathy, dyskinesiaswith levodopa.Type D (Delayed) reactions following prolongedexposure, e.g. carcinogenesis or short-term exposureat a critical time, e.g. teratogenesis.Type E (Ending of use) reactions, where dicontinuation of chronic therapy is too abrupt, e.g.adrenal steroid causing rebound adrenocorticalinsufficiency, opioid causing the withdrawalsyndrome.F (Failures) – unwanted drug interactions.

Causes of drug ARs(1) The patient may be predisposed by age, genetic constitution,tendency to allergy, disease, personality, habits.(2) The drug. Anticancer agents are cytotoxic by nature. Some drugs, e.g. digoxin, have steep dose-response curves andsmall increments of a dose are more likely to induce augmented (type A) reactions. Other drugs, e.g. antimicrobials, have a ten-dency to cause allergy and may lead to bizarre (type B) reactions.Ingredients of a formulation, e.g. coloring, flavoring, sodiumcontent, rather than the active drug may also cause ARs.(3) The prescriber. ARs may occur because a drug is usedfor an inappropriately long time (type C), at a critical phasein pregnancy (type D), is abruptly discontinued (type E) or givenwith other drugs (type F – unwanted drug interactions).

Severity of adverse drug reactionshas been graded as:

Minor: No therapy or antidote required.

Moderate: Requires change in drug therapy, specifictreatment or prolongs hospital stay by at least one day.

Severe: Potentially life threatening, causes permanentdamage or requires intensive medical treatment.

Lethal: Directly or indirectly contributes to deathof the patient.

Drug ARs can be minimizedDrug ARs can be minimized (but not altogethereliminated) by observing the following practices(by Tripathi, 2008):• Avoid all inappropriate use of drugs.• Use appropriate dose, route and frequency of drug administration.• Elicit and take into consideration previous history of drug ARs.• Elicit history of allergic diseases and exercise caution (drug allergy is more common in patients with allergic diseases).• Rule out possibility of unwanted drug interactions.• Use correct drug administration technique (e.g. i.v. injection of aminophylline must be slow).• Carry out appropriate laboratory monitoring (e.g. prothrombin time and INR with acenocoumarol and warfarin; serum drug levels with lithium – 0.4–1 mmol/L).

(1) Side effects are unwanted pharmacodynamic effectsthat occur at therapeutic doses. They can be predictedfrom the pharmacological profile of a drug. Very often reductionof the dose relieves the symptoms. In many cases a sideeffect may be based on the same action as the therapeuticeffect, e.g. M-cholinolytics atropineis used in preanaesthetic medicationfor its antisecretory action producesxerostomia (dryness ofmouth) as a side effect.Side effect may also be based on a different peculiarity ofdrug action, e.g. estrogens cause nausea which isunrelated to their main antiovulatory action.

AtropineAtropine

(2) Secondary effects are indirect consequences of a primary action of the drug, e.g. suppression of bacterialflora by aminopenicillins, cephalosporins, tetracyclines,chloramphenicol, fluoroquinolones, or co-trimoxazole results in the development of endogenous superinfections.(3) Toxic effects are the result of excessive pharmaco-logical action of the drug due to overdosage or prolongeduse. Overdosage may be absolute (accidental, homicidal,suicidal) or relative (e.g. usual dose of aminoglycosideantibiotics in the presence of renal failure). Toxic effects arepredictable and dose related. They result from functionalalteration (in high dose atropine causes delirium) or drug-induced tissue damage (hepatic paracetamol necrosis).

Acute paracetamol poisoning occurs especially insmall children who have low hepatic glucuronide conjugating ability.If a large dose (> 150 mg/kg or > 10 g in adult) is taken, serious toxicity can occur. The letal dose is 250 mg/kg. N-acetyl-p-benzoquinoneimine (NABQI)N-acetyl-p-benzoquinoneimine (NABQI) is a highlyreactive metabolite of paracetamol which is detoxified byconjugation with glutathione. When a very large doses ofparacetamol are taken, the glucuroconjugation capacity issaturated, more NABQINABQI is formed, hepatic glutathione isdepleted and NABQINABQI binds covalently to proteins in livercells and renal tubules causing necrosis. In chronic alcoholicseven 5 g/d paracetamol taken for a few days can result in hepatotoxicity(because ethanol induces CYP2E1&1A2 that metabolize paracetamol,to NABQI). Treatment needs activated charcoal, given orally or throughthe tube to prevent GI absorption, and for an exogenious donor of–SH groups – acetylcysteine is used (150 mg/g by i.v. infusion).

Metabolism of

Paracetamol(Acetaminophen) to hepatotoxicmetabolites: NABQI…,… etc.(GSH – glutathione)

Daily dose > 7.5 g:hepatotoxicity

and nephrotoxicity

NABQI

Acetylcysteine and GSHcontain –SH groups.

Basic & Clinical Pharmacology – 10th Ed. (2007):

Poisoning may result from dosages of drugs. Specificantidotes (receptor antagonists, chelating agents, or specific antibodies) are available only for few poisons.General supportive and symptomatic treatment includes:•Termination of exposure.•Prevention of GI absorption of ingested poisons with suspension of 20–40 g of activated charcoal in 200 ml water.•Maintenance of patient airway (artificial respiration, if needed).•Maintenance of blood pressure and heart beat by fluid infusion, pressor agents, cardiac stimulants, if needed.•Hastening elimination of poison by inducing diuresis (furosemide, mannitol), altering urinary pH (alkalinisation for acidic drugs, acidification for basic drugs), haemodialysis and haemoperfusion (passage of blood through a column of charcoal or absorbent resin)

(4) Intolerance is the appearance of characteristic toxiceffects of a drug in a patient at therapeutic doses, e.g. only a few doses of carbamazepine may cause ataxia insome people; one tablet of chloroquine (250 mg) may cause vomiting and abdominal pain in some individuals.Intolerance indicates a low threshold of the individualto the action of drugs.(5) Allergic reactions occur only in a small part of thepopulation exposed to the drug. Prior sensitization isneeded and a latent period of at least 1–2 weeks is requiredafter the first exposure. The drug or its metabolites act asantigen (AG) or more commonly hapten (incomplete AG – drug with small molecules which become antigenic only

after binding with an endogenous protein) and induceproduction of antibody (AB)/sensitized lymphocytes. Chemically related drugs often show cross sensitivity.One drug can produce different types of allergic reactions.The course of drug allergy is variable. An individual previously sensitive to a drug may subsequently tolerate itwithout a reaction. There areThere are several types of allergic reactions: several types of allergic reactions:

• humoral (type I–III)humoral (type I–III)• cell mediated (type IV)cell mediated (type IV)..

Type I (anaphylactic) reactions – immediate hypersensitivity.

Drug-specific antibodies of the IgE type combine viatheir Fc moiety with receptors on the surface of mast cells.On exposure to the drug, AG/AB reaction takes place onthe mast cell surface releasing mediators (histamine, 5-HT, LT-C4, LT-D4, PGs, PAF, etc.) resultingin urticaria, itching, angioedema, asthma, rhinitis,or anaphylactic shock. The manifestations occur quickly after challenge.

ACE inhibitors – swelling of lipsACE inhibitors – swelling of lips

Type II (cytolytic) reactions

Complexes drug / antibody (IgG) bind to receptorslocated on the surface of blood cells. In reexposureof drug on the surface of these cells develops AG/ABreaction, complement system (representing circulatingin an inactive form of protein) is activated and thiscauses cytolysis:thrombocytopenia, agranulocytosis, aplasticanaemia, haemolysishaemolysis, organ damage (liver,kidney, muscle), systemic lupus erythematosus.

Type III (immune complex vasculitis) reactions

are mediated by circulating antibodies (predominantly IgG).AG/AB complex binds complement and precipitates on vascular endothelium giving rise to adestructive inflammatory response. Manifestations are rashes, serum sickness (fever,arthralgia, lymphadenopathy), polyarteriitis nodosa, Stevens–Johnson syndrome (erythema muliforme, arthritis,nephritis, myocarditis, mental symptoms). These symptomsusually subsides in 1–2 weeks.

Stevens–Johnson syndrome after oral intake of Co-trimoxazole(Color Atlas and Synopsis of Clinical Dermatology, 1999)

Type IV (delayed hypersensitivity) reactions. They aremediated through production of sensitized T-lymphocytescarrying receptors for the AG. On contact with AG T-lym-phocytes produce lymphokines which attract granulocytesand generate an inflammatory response, e.g. contact der-matatitis, some rashes, fever, photosensitization. These types of allergic reactions generally take > 12 h to develop.

Treatment of drug allergyThe offending drug must be immediately stopped. Most mild ARs (some skin rashesskin rashes) subside without treatment.Antihistamine (H1-blockers desloratadine, levocetirizine)are beneficial in type I reactions (urticaria, rhinitis,

swelling of lips) and some skin rashes. In case ofanaphylactic shock or angioedema of the larynx:a) Put the patient in reclining position, administer oxygen and perform cardiopulmonary resuscitation if required.b) Inject adrenaline 0.5 mg/1 ml i.m. (not i.v.); repeat every 5 to 10 min if the patient does not improve. This is the only life-saving measure.c) Administer an H1-blocker (e.g. chlorpheniramine 10–20 mg i.m. or slow i.v.). It may have an adjuvant value.d) In severe/recurrent cases inject slow i.v. methylpredni- solone or betamethasone. It acts slowly but is especially valuable for prolonged reactions and in asthmatics.

Instructional Video for ANAPENInstructional Video for ANAPEN®®::http://www.youtube.com/watch?v=ZR5c5VP2rOs

I.M.

Pre-filled syringes: Anapen® and EpiPen®: I.M.

(Tripathi, 2008)

Skin testSkin test (intradermal, patch) or intranasal test mayusually forewarn in about 10%10% of cases with Type I Type I hypersensitivity hypersensitivity but not in other types.but not in other types.

(6) Idiosyncrasy is genetically determined abnormalreactivity to a drug and other xenobiotics. Certain ARsCertain ARsof some drugs are largely restricted to individuals with of some drugs are largely restricted to individuals with a particular genotypea particular genotype. . AcetylationAcetylation is an important route of metabolismfor many drugs that possess an amine (– (– NHNH22) group.Most individuals are either rapid or slow acetylatorsbut the proportion of each varies greatly betweenraces. Some 90% of Japanese are rapidSome 90% of Japanese are rapidacetylators whereas in Western acetylators whereas in Western populations the proportion is 50%populations the proportion is 50% orless. IsoniazidIsoniazid may cause peripheralperipheralneuropathyneuropathy in slow acetylators on standard doses

and pyridoxine is added to the antituberculosisregimen where there is a special risk, e.g. in diabetes,alcoholism, renal failure. Acute hepatocellularAcute hepatocellularnecrosis with isoniazid is more common in rapidnecrosis with isoniazid is more common in rapidacetylatorsacetylators, perhaps because they more readilyform a hepatotoxic metabolite. Sulphasalazine(used for rheumatoid arthritis) causes ARsmore frequently in slow acetylators, probablybecause it forms sulphapyridine, a component whichis inactivated by acetylation.Bacterial resistance to drugs is geneticallyBacterial resistance to drugs is geneticallydetermineddetermined and is of great clinical importance.

Individuals who are Glucose-6-phosphatedehydrogenase (G6PD) deficient may sufferfrom acute haemolysisacute haemolysis if they areexposed to certain oxidant substances,including drugs (dapsone, methyleneblue, nitrofurantoin, primaquine,fluoroquinolone, some sulphonamides).

Characteristically there is an acute haemolytic episode2–3 days after starting the drug. The haemolysis isself-limiting, only older cells with least enzymesonly older cells with least enzymesbeing affectedbeing affected. The condition is common in Africa, theMediterranean, the Middle East, and South East Asia.

Porphyrins represent precursors of haem. But in But in people with porphyria the various porphyrins accumulate.people with porphyria the various porphyrins accumulate.Acute porphyrias are characterized by severe attacksof neurovisceral dysfunction precipitated principally bya wide variety of drugs (barbiturates, sulphonamides,hormonal contraceptives), some mushrooms, infections, and alcohol too. Certain peculiarities of an individual (for which no definitegenotype has been described) are included amongidiosyncratic reactions, e.g. phenobarbital causesexcitement and mental confusion in some patients.

The porphyrias comprise a number of rare, geneticallydetermined enzyme defects in haem biosynthesis.

Porphyria cutanea tarda. Periorbital and molar violaceous coloration, hyperpigmentation,and hypertrichosis on the face; bullae, crusts, and scars on the dorsa of the hands.

Amanita phalloides can cause Amanita phalloides can cause porphyriaporphyria..

(7) Drug dependence is a state arising from repeated,periodic or continuous administration of a drug, thatresults in harm to the individual and sometimes to society(Bennett ad Brown, 2003).The subject feels a desire, need,or compulsion to continue using the drug and feels ill if ab-ruptly deprived of it (abstinence or withdrawal syndrome).Drug dependence is characterized by:• Psychological dependence: there is emotional distress if the drug is withdrawn.• Physical dependence: there is a physical illness if the drug is withdrawn.• Tolerance.

Psychological dependence develops when anindividual believes that the optimal state of wellbeing isachieved only through the action of drugs. It may start asliking for the drug effects and may progress tocompulsive drug use in some individuals. The intensityof psychological dependence may vary from desireto craving.

Reinforcement is the ability of a drug to produce effectsthat make the user wish to take it again. Opioids,Opioids,cocaine, and amphetamine are strong reinforcers,cocaine, and amphetamine are strong reinforcers,while benzodiazepines are week reinforcers.while benzodiazepines are week reinforcers.

Physical dependence is an altered physiological stateproduced by repeated administration of a drug which necessitates the continued presence of the drug tomaintain physiological equilibrium. Discontinuation of the drug results in a characteristicwithdrawal (abstinence) syndrome.

Drugs producing physical dependence are depressantsof CNS: opioids (morphinomimetics), barbiturates,benzodiazepines, alcohol.Central nervous stimulants such as amphetamines andCentral nervous stimulants such as amphetamines andcocaine produce little or no physical dependence.cocaine produce little or no physical dependence.

Physical dependencePhysical dependence

Drug abuse Drug abuse means the use of psychotropic substancesmeans the use of psychotropic substancesin a way that would “constitute a public health and socialin a way that would “constitute a public health and socialproblemproblem”.”. For a regulatory agency “drug abuse” refers toany use of an illicit drug. Drug addiction is a pattern of compulsive drug usecharacterized by overwhelming involvement with theuse of a drug. Amphetamines, cocaine, cannabis, LSDare drugs which produce addiction but little or no physicaldependence.Drug habituation is less intensive involvement with thedrug, so that its withdrawal produces only mild discomfortwithout physical dependence (e.g. tea, coffee, tobacco).

Types of drug dependence Types of drug dependence (Bennett, Brown, 2003)(Bennett, Brown, 2003)

Morphine or Heroin type:— psychological dependence severe— physical dependence severe; develops quickly— tolerance marked— cross-tolerance with related drugs— naloxone induces abstinence syndrome.

Barbiturate-type:— psychological dependence severe— physical dependence very severe; develops slowly at high doses— tolerance less marked than with morphine— cross-tolerance with alcohol and benzodiazepines

Cocaine

Amphetamine-type:— psychological dependence severe— physical dependence slight: psychoses occur during use— tolerance occurs.

Cannabis-type:Cannabis-type:— psychological dependence— physical dependence dubious (no characteristic abstinence syndrome)— tolerance occurs.

Cocaine-type:— psychological dependence severe— physical dependence slight— tolerance slight (to some actions).

Alcohol-type:— psychological dependence severe— physical dependence with prolonged heavy use— cross-tolerance with other sedatives.

Tobacco-type:— psychological dependence— physical dependence.

Drug mixtures: Barbiturate-amphetamine mixturesinduce a characteristic alteration of mood that doesnot occur with either drug alone

— psychological dependence strong— physical dependence occurs— tolerance occurs.

Heroin-cocaine mixtures: similar characteristics.

Nicotine is anNicotine is anenzyme inducerenzyme inducer..

karoshi

ModernModernobsessionsobsessions

(8) Drug withdrawal syndrome – sudden interruptionof therapy with certain drugs (glucocorticoids, antiepilepticdrugs, CV drugs, etc.) usually results in ARs, mostly in theform of worsening of the clinical condition for which thedrug was being used. Examples:• Frequency of seizures may increase on sudden withdrawal of an antiepileptic drugantiepileptic drug.• Worsening of angina pectoris or acute myocardial infarction may result from stoppage of beta-blockers or nitrovasodilators.• Severe hypertension and sympathetic overactivity may occur shortly after discontinuing clonidine. In all these cases, it is very important to keep patient’scompliance and/or to stop the drug gradually.

(9) Effects of prolonged administration: Chronic organ toxicity (types C and D reactions)

Eye. Toxic cataractToxic cataract can be due to chloroquineand related drugs, adrenal steroids (topical andsystemic), phenothiazines and alkylating agents.Corneal opacities occur with phenothiazines,amiodarone, and chloroquine. Retinal injuryRetinal injuryoccurs with thioridazine (particularly of theantipsychotics), chloroquine, and indometacin.Nervous system. Tardive dyskinesiasTardive dyskinesias occur withneuroleptics; polyneuritispolyneuritis with isoniazid, metronidazole,or zalcitabine; optic neuritis with ethambutol.

PolyneuritisPolyneuritis

Tardive Tardive dyskinesiadyskinesia

Pulmotoxicity. Amiodarone may cause pulmonary fibrosis.Sulphasalazine is associated with fibrosing alveolitis.Nephrotoxicity: Aminoglycosides, polymyxines, gold salts.Hepatotoxicity: Methotrexate, paracetamol, halothane.Thyreotoxicity: Amiodarone

Carcinogenesis. The principal mechanisms are:•Alteration of DNA (genotoxicity, mutagenicity).•Immunosuppression. A wide range of cancers develop in immunosuppressed patients, e.g. after organ transplantation and cancer chemotherapy.•Hormonal. Long-term use of estrogen replacement in

postmenopausal women induces endometrial cancer.

Тhe biggest medical tragedy of modern times

(10) Teratogenisity represents the the fetal abnormalitiesof a drug, administered to the pregnant mother (by Tripathi, 2008).

The placenta does not strictly constitute a barrier and anydrug can cross to a greater or lesser extent. The embryo isone of the most dynamic biological systems and in contrastto adults, drug effects very often are irreversible.The thalidomide disasterthalidomide disaster (1958–1962) resulting in10 000 of babies born withphocomeliaphocomelia and other defectsfocused attention to thesetypes of drug adverse effects.

The Australian obstetricianWilliam McBride and the German

pediatrician Widukind Lenz suspecteda link between birth defects andbirth defects andthalidomidethalidomide, and this was proved

by Lenz in 1961. McBride was laterawarded a number of honours

including a medal and prize money bythe L'Institut de la Vie in Paris.

Phocomelia– seal-like limbsseal-like limbs(W. Lenz, K. Knapp. Thalidomide embryopathy.Dtsch Med Wochenschr. 1962 Jun 15; 87:1232–42).

Germany: 2500 babies

UK: 456babies

- Absence of the auricles with deafness.- Defects of the muscles of the eye and of the face.- Absence or hypoplasia of arms, preferentially affecting the radius and the thumb.- Thumbs with three joints.- Defects of the femur and of the tibia.- Malformations of the heart, the bowel, the uterus, and the gallbladder.

W. Lenz

In 1962, the United States Congressenacted laws requiring tests for safety during pregnancybefore a drug can receive approval for sale in the U.S.

USA: 17babies

Thalidomide is racemic: it contains both left- and right-handedisomers. The (R) enantiomer is effective against morning sickness.The (S) is teratogenic and causes birth defects. The enantiomerscan interconvert in vivo. The (S) enantiomer intercalates (inserts)into the DNA in G–C (guanine – cytosine) rich regions.

(S)-thalidomide (R)-thalidomide

Drugs can affect the fetus at the following stages:•Fertilization and implantation – from conception to 14–17 days: failure of pregnancy (which often goes unnoticed).•Embryogenesis (organogenesis) – between 15–18 to 55 days of gestation: most vulnerable period, major morphologic deformities are produced.•Fetogenesis (growth and development) – from 56 days of gestation to birth: developmental and functional abnormali- ties can occur, e.g. aminoglycosides can cause ototoxicitiy, ACE inhibitors – hypoplasia of cranium, lungs, and kidneys; NSAIDs may induce premature closure of d. arteriosus. The type of malformation depends on the drug as well as the stage of exposure to the teratogen.

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Dorland’s Illustrated Medical Dictionary (2003, 2004)Dorland’s Illustrated Medical Dictionary (2003, 2004)

(By Moore KL: The Developing Human: Clinically Oriented Embryology, 4th ed. Saunders, 1988.) (By Moore KL: The Developing Human: Clinically Oriented Embryology, 4th ed. Saunders, 1988.)

Schematic diagram of critical periods of human developmentSchematic diagram of critical periods of human development

ABC

D

X

Pregnancy andLactation RiskCategories (PRCs and LRCs

The FDA (USA) has established 5 categoriesto indicate the potential of systematically absorbed drugs for causing birth defects. The key differentiation among the categoriesrests upon the reliability of documentationand the risk:benefit ratio (Lacy et al., 1998).

PRC A: Controlled studies in pregnant women fail todemonstrate a risk to the fetus in the first trimester withno evidence of risk in later trimesters. Examples: Folic acid, T4, Magnesium sulfate (inj.!)

PRC B: The animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women.Examples: penicillins, erythromycin, paracetamol,lidocaine.

PRC C: The studies in animals have revealed ARs on the fetus (teratogenic, embryocidal, or other effects)and there are no controlled studies in women, or studiesin women are not available. The drug should be given onlyif the potential benefits justify the potential risk to the fetus.Examples: atropine, adrenaline, thiopental, bisoprolol.

PRC D: There is positive evidence of human fetal risk,but the benefits from use in pregnant women may beacceptable despite the risk (e.g. if the drug is needed ina life-threatening situation or for a serious disease forwhich safer drugs that can be used are ineffective).Examples: phenytoin, valproate, diazepam, lorazepam.

СPhenytoin syndrome

PRC X: Studies in animals or human beings have demonstrated fetal abnormalities andthe risk of the use of the drug in pregnant women clearlyoutweighs any possible benefit. The drug is contraindi-cated in women who are or may become pregnant.Examples: thalidomide, estrogens, isotretinoin,ergometrine.

(Tripathi, 2008)

EythroxylonEythroxylon coca L.coca L.•CocaineCocaine

Lactation Risk Categories – LRC)Lactation Risk Categories – LRC)

PRCs LRCs

A: controlled studies

show no risk (Vit. B9)

B: no evidence of risk in

humans (Penicillins)

C: risk cannot be ruled

out (Bisoprolol)

D: positive evidence of

risk (Diazepam)

X: contraindicated in

pregnancy (Estrogens)

L1: safest (Ibuprofen,

Paracetamol)

L2: safer (Cephalosporins,

Omeprazole)

L3: moderately safe

(Acarbose, Aspirin)

L4: possibly hazardous

(Diazepam, Lithium)

L5: contraindicated

(ACE inhibitors)

(11) Drug-induced diseases(11) Drug-induced diseases are also called are also callediatrogeniciatrogenic (physician induced) diseases(physician induced) diseases.. They representfunctional disturbances (diseases) caused by drugs whichpersist even after the offending remedy has beenwithdrawn and largely eliminated. Examples:•Parkinsonism by phenothiazine and other neuroleptics.•Hepatitis by isoniazid.•Peptic ulcer by salicylates, glucocorticoids, or reserpine•Aplastic anaemia by chloramphenicol etc.

PolypragmasyPolypragmasy

ParkinsonismParkinsonism

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