Assoc. Prof. Iv. LambevE-mail: itlambev@mail.bg

Adverse Drug Reactions(Summary)

Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology

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

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

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

ARs have been classified in many ways. It is convenientto classify drug ARs under the following headings(by Bennett and Brown, 2003):

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. They arecommon 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, are not dose-related andare due to unusual attributes of the patient interact-ing with the drug. These effects are predictablewhere the mechanism is known (though predictivetests may be expensive or impracticable), otherwisethey are unpredictable for the individual, althoughthe incidence may be known. The class includesunwanted effects due to inherited abnormalities(idiosyncrasy) and immunological processes (drug allergy). These account for most drug fatalities.

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.of adrenal steroid causing rebound adrenocorticalinsufficiency, of 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 by their nature cytotoxic. Some drugs, e.g. digoxin, have steep dose-response curves andsmall increments of 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, sodium con-tent, 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 (unwanted 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 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 aminophyllne 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 pharmacological profile of a drug. Very often reduction ofdose relieves the symptoms. In many cases a side effect maybe based on the same action as the therapeutic effect, e.g.M-cholinolytics atropine is used inpreanaesthetic medication for itsantisecretory 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.

Atropine

(2) Secondary effects are indirect consequences of a primary action of the drug, e.g. suppression of bacterialflora by aminopenicillins, cephalosporines, 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 presence of renal failure). Toxic effects arepredictable and dose related. They result from functionalalteration (in high dose atropine causes delirium) or druginduced tissue damage (hepatic paracetamol necrosis).

Acute paracetamol poisoning occurs specially insmall children who have low hepatic glucoronide conjuga-ting ability. If a large dose (> 150 mg/kg or > 10 g in adult)is taken, serious toxicity can occur. Letal dose is 250 mg/kg.N-acetyl-p-benzoquinoneimine (NABQI) is a highlyreactive arylating metbolite of paracetamol which detoxi-fied by conjugation with glutathione. When a very large do-ses paracetamol are taken, glucuroconjugation capacity issaturated, more NABQI is formed, hepatic glutathione isdepleted and NABQI binds covalently to proteins in livercells (and renal tubules) causing necrosis. In chronic alco-holic even 5–6 g/d taken for a few days can result in hepa-totoxicity because ethanol induces CYP 2E2, that metabo-lizes paracetamol, to NABQI. Treatment needs activatedcharcoal, given orally or through the tube to prevent GI ab-sorption, and acetylcysteine (150 mg/g by i.v. infusion).

Metabolism of

paracetamol to hepatotoxicmetabolites (NABQI etc.)(GSH – glutathione; SG – glutathione moiety)

Daily dose > 7.5 g:hepatotoxicity

and nephrotoxicity

NABQI

NB: 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 include:•Termination of exposure•Prevention of GI absorbtion 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 individual to 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 metabolite acts asantigen (AG) or more commonly hapten (incomplete AG – drugs 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 are several types of allergic re-actions: humoral (type I–III) and cell mediated (type IV).

Type I (anaphylactic) reactions – immediate hyper-sensitivity. Reaging antibodies (IgE) fix to the 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.) resulting in urticaria, itching,angioedema, asthma, rhinitis or anaphylactic shock. Themanifestations occur quickly after challenge.

ACE inhibitors – swelling of lips

Type II (cytolytic) reactions. Drug + component ofspecific tissue cell act as AG. The resulting antibodies (IgG, IgM) bind to the target cells. On reexposure AG/ABreaction takes place on the surface of these cells, comple-ment is activated and cytolysis occurs, e.g. thrombocyto-penia, agranulocytosis, aplastic anaemia, haemolysis,organ damage (liver, kidney, muscle), systemic lupuserythematosus.

Type III (retarded, Arthus) reactions are mediated bycirculating antibodies (predominantly IgG). AG/AB complexbinds complement and precipitates on vascular endotheliumgiving rise to a destructive 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–Johnsonsyndrome after oralintake of Co-trimoxazole(Color Atlas and Synopsisof 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 type allergic reactions generally take > 12 h to develop.

Treatment of drug allergyThe offending drug must be immediately stopped. Most mild ARs (some skin 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 of anaphylactic shock or angioedema of larynx:a) Put the patients 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 only life saving measure.c) Administer a H1-blocker (e.g. chlorpheniramine 10–20 mg i.m. or slow i.v.). It may adjuvant value.d) In severe/recurrent cases inject slow i.v. methylpredni- solone or betamethasone. It acts slowly but is specially valuable for prolonged reactions and in asthmatics.

(Tripathi, 2008)

Skin test (intradermal, patch) or intranasal test mayforewarn in case Type I hypersensitivity

but not in other types.

(6) Idiosyncrasy is genetically determined abnormalreactivity to a drug and other xenobiotics. Certain ARsof some drugs are largely restricted to individuals with a particular genotype. Acetylation is an important route of metabolismfor many drugs that possess an amine (-NH2) group.Most individuals are either rapid or slow acetylatorsbut the proportion of each varies greatly betweenraces. Some 90% of Japanese are rapid acetylatorswhereas in Western populations the proportion is50% or less. Isoniazid may cause peripheralneuropathy in slow acetylators on standard doses

and pyridoxine is added to the antituberculosisregimen where there is special risk, e.g. in diabetes,alcoholism, renal failure. Acute hepatocellularnecrosis with isoniazid is more common in rapidacetylators, perhaps because they more readilyform an hepatotoxic metabolite. Sulphasalazine(used for rheumatoid arthritis) causes ARsmore frequently in slow acetylators, probablybecause of the sulphapyridine, component which isinactivated by acetylation.Bacterial resistance to drugs is geneticallydetermined and is of great clinical importance.

Individuals who are Glucose-6-phosphatedehydrogenase (G6PD) deficient may sufferfrom acute haemolysis if they are exposed to certainoxidant substances, including drugs (dapsone,methylene blue, nitrofurantoin, primaquine,fluoroquinolone, some sulphonamides). Charac-teristically there is an acute haemolytic episode2–3 days after starting the drug. The haemolysis isself-limiting, only older cells with least enzymebeing affected. The condition is common in African,Mediterranean, Middle East and South East Asian.The porphyrias comprise a number of rare, geneticallydetermined enzyme defects in haem biosynthesis.

Porphyrins represent precursors of haem. But in people with porphyria the various porphyrins accumulate.Acute porphyrias are characterized by severe attacksof neurovisceral dysfunction precipitated principally bya wide variety of drugs (and by alcohol and infection 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.

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

(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, needor 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 individual believe the optimal state of wellbeing is achieved onlythrough the action of drugs. It may start as liking for thedrug effects and may progress to compulsive drug usein some individuals. The intensity of psychologicaldependence may vary from desire to craving. Reinforcement is the ability of drug to produce effectsthat make the user whish to take it again. Opioids,cocaine and amphetamine are strong 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 thedrug results in a characteristic withdrawal (abstinence)syndrome.

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

Drug abuse means the use of psychotropic substancesin a way that would “constitute a public health and socialproblem”. For 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 discomphortwithout physical dependence (e.g. tea, coffee, tobacco).

Types of drug dependence (Bennett, Brown, 2003)

Morphine-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

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

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

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

Eye. Toxic cataract can be due to chloroquineand related drugs, adrenal steroids (topical andsystemic), phenothiazines and alkylating agents.Corneal opacities occur with phenothiazines andchloroquine. Retinal injury occurs with thioridazine(particularly of the antipsychotics), chloroquine andindomethacin.Nervous system. Tardive dyskinesias occur withneuroleptics; polyneuritis with metronidazole;optic neuritis with ethambutol.

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

(10) Teratogenisity represents 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 are very often are irreversible.The thalidomide disaster (1958–1962) resulting in10 000 of babies born withphocomelia and other defectsfocused attention to thesetype of drug adverse effects. Тhe biggest medical tragedy of modern times

The Australian obstetricianWilliam McBridge and the German

pediatrician Widukind Lenz suspecteda link between birth defects andthe drug, 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 limbs(W. Lenz, K. Knapp. Thalidomide embryopathy.Dtsch Med Wochenschr. 1962 Jun 15; 87:1232–42).

Germany: 2500 babies

UK: 456babies

In 1962, the Unated 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 DNA in G–C (guanine – cytosine) rich regions.

(S)-thalidomide (R)-thalidomide

Drugs can affect the fetus at follow 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, deformities are produced.•Fetogenesis (growth and development) – from 56 days of gestation to birth: developmental and functional abnormali- ties can occurs, e.g. aminosides 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 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 development

ABC

D

X

PregnancyRiskCategories(PRCs) – FDA

The FDA (USA) has established 5 categoriesto indicate the potential of systematically absorbed drug for causing birth defects. Thekey 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. The possibility offetal harm appears remote. 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, or animal-reproductionstudies have shown an ARs (other than a decrease infertility) that was not confirmed in controlled studies inwomen in the first trimester and there is no evidence of later trimesters. 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. 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 cannot be used are ineffective.).Examples: phenytoin, valproate, diazepam, lorazepam.

PRC X: Studies in animals or human beings have demonstrated fetal abnormalities or there is evidenceof fetal risk based on human experience, or both, 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,isotretionoin, ergometrine.

(Tripathi, 2008)

С

Phenytoin syndrome

(11) Lactation Risk Categories – LRCs (adapted by T. Hale, 2004; 2008 – Medications and Mothers’ Milk)

L1: Safest

Drug which has been taken by a large number of breastfeeding mothers without any observedincrease in adverse effects in the infant. Controlled studies in breastfeeding women fail to demonstrate a risk to the infant and the possibilityof harm to the breastfeeding infant is remote;or the product is not orally bioavailable in an infant. Examples: Paracetamol, Ibuprofen, Epinephrine.

L2: Safer

Drug which has been studied in a limited number of breastfeeding women without an increase in adverse effects in the infant. And/or, the evidence of a demonstrated risk which is likely to follow use of this medication ina breastfeeding woman is remote.Example: Diclofenac, Fentanyl, Omeparzole.

L3: Moderately Safe

There are no controlled studies inbreastfeeding women, however the risk of untoward effects toa breastfed infant is possible; or, controlled studies show only minimal non-threatening adverse effects.Drugs should be given only if the potential benefitjustifies the potential risk to the infant.Examples: Acarbose, Aspirin, Indometacin, Morphine

L4: Possibly Hazardous

There is positive evidence of risk to a breastfed infantor to breastmilk production, but the benefits from use in breastfeeding mothers may be acceptable despite the risk to the infant. (e.g. if the drug is needed in alife-threatening situation or for a serious disease forwhich safer drugs cannot be used or are ineffective). Examples: Colchicine, Diazepam (in chronic use),Lithium

L5: Contraindicated

Studies in breastfeeding mothershave demonstrated that there is significant and documented risk tothe infant based on human experience, or it is a medicationthat has a high risk of causing significant damage to aninfant. The risk of using the drug in breastfeeding womenclearly outweighs any possible benefit from breastfeeding.The drug is contraindicated in women who arebreastfeeding an infant.Examples: Cyclophosphamide, Mitoxantrone.

PRCs LRCsA: controlled studies

show no risk

B: no evidence of risk in

humans

C: risk cannot be ruled

out

D: positive evidence of

risk

X: contraindicated in

pregnancy

L1: safest

L2: safer

L3: moderately safe

L4: possibly hazardous

L5: contraindicated

(12) Cancerogenesity and mutagenesity refers to capacity of a drug to cause cancer and genetic defectsrespectively. Oxidation of the drug may result in theproduction of reactive intermediate compounds whichaffect genesis and can case structural changes in chromosomes. Chemically cancerogenesis usually takes10–40 years to develop. Chemical compounds implicatedin these ARs include some anticancer drugs, radioisotops,estrogens, nicotine (tobacco) etc.

(13) Drug induced diseases are also callediatrogenic (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.

Selected References

Bennett PN, Brown MJ. Clinical pharmacology. 9th Edition. London, Churchill Livingstone, 2003.

Color Atlas and Synopsis of Clinical Dermatology. 3rd Ed. ThomasB. Fitzpatrick (ed.). Mc Grow-Hill International, Ney York, 1999.

Katzung BG (Editor). Basic & Clinical Pharmacology. 10th Edition. The MaGraw-Hill Companies, Inc. (Lange Medical Books), New York, 2007.

Lacy CF et al. (eds). Drug Information Handbook. 6th Edition.Lexi-Comp Inc. Hudson (Cleveland), APhA,1998-99.

Rang HP et al. Pharmacology. 6th Edition. London, ChirchillLivingstone, 2007.

Tripathi KD. Essentials of Medical Pharmacology. 6st Edition. Jaypee Brothers. New Delhi, 2008.