Transcript The drug.

Medical University of Sofia, Faculty of Medicine
Department of Pharmacology and Toxicology
Adverse Drug Reactions
(Summary)
Assoc. Prof. Iv. Lambev
E-mail: [email protected]
Adverse reactions (ARs) is any undesirable or unintended
consequence of drug administration. ARs include all kinds
of noxious effects – trivial, serious or even fatal.
All drugs are capable of producing ARs. Whenever a drug
is given a risk is taken. The magnitude of risk has to be
considered along with other therapeutic advantages
in deciding whether to use or not one drug.
ARs may develop promptly or only after prolonged medication or
even after stoppage of the drug. An incidence of 10–25% ARs has
been documented in different clinical studies. So drug ARs are
not rare. They are more common with multiple drug therapy and
in the elderly patients.
ARs have been classified in many ways. It is convenient
to classify drug ARs under the following headings
(by Bennett and Brown, 2003):
Type A (Augmented) reactions will occur in
everyone if enough of the drug is given because
they are due to excess of normal, predictable,
dose-related, pharmacodynamic effects. They are
common and skilled management reduces their
incidence, e.g. postural hypotension, hypoglycemia,
hypokalemia. Type A reactions also include
side, secondary and toxic effects of drugs.
Type B (Bizarre) reactions will occur only in
some people. They are not part of the normal
pharmacology of the drug, are not dose-related and
are due to unusual attributes of the patient interacting with the drug. These effects are predictable
where the mechanism is known (though predictive
tests may be expensive or impracticable), otherwise
they are unpredictable for the individual, although
the incidence may be known. The class includes
unwanted effects due to inherited abnormalities
(idiosyncrasy) and immunological processes
(drug allergy). These account for most drug fatalities.
Type C (Chronic) reactions due to long-term
exposure, e.g. analgesic nephropathy, dyskinesias
with levodopa.
Type D (Delayed) reactions following prolonged
exposure, e.g. carcinogenesis or short-term exposure
at 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 adrenocortical
insufficiency, of opioid causing the withdrawal
syndrome.
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 and
small increments of dose are more likely to induce augmented
(type A) reactions. Other drugs, e.g. antimicrobials, have a tendency to cause allergy and may lead to bizarre (type B) reactions.
Ingredients of a formulation, e.g. coloring, flavoring, sodium content, rather than the active drug may also cause ARs.
(3) The prescriber. ARs may occur because a drug is used
for an inappropriately long time (type C), at a critical phase
in pregnancy (type D), is abruptly discontinued (type E) or given
with other drugs (unwanted interactions).
Severity of adverse drug reactions
has been graded as:
Minor: No therapy or antidote required.
Moderate: Requires change in drug therapy, specific
treatment or prolongs hospital stay by at least one day.
Severe: Potentially life threatening, causes permanent
damage or requires intensive medical treatment.
Lethal: Directly or indirectly contributes to death
of the patient.
Drug ARs can be minimized (but not altogether
eliminated) 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 effects
that occur at therapeutic doses. They can be predicted
from pharmacological profile of a drug. Very often reduction of
dose relieves the symptoms. In many cases a side effect may
be based on the same action as the therapeutic effect, e.g.
M-cholinolytics atropine is used in
preanaesthetic medication for its
antisecretory action – produces
Atropine
xerostomia (dryness of
mouth) as a side effect.
Side effect may also be based on a different peculiarity of
drug action, e.g. estrogens cause nausea which is
unrelated to their main antiovulatory action.
(2) Secondary effects are indirect consequences of
a primary action of the drug, e.g. suppression of bacterial
flora by aminopenicillins, cephalosporines, tetracyclines,
chloramphenicol, fluoroquinolones or co-trimoxazole
results in the development of endogenous superinfections.
(3) Toxic effects are the result of excessive pharmacological action of the drug due to overdosage or prolonged
use. Overdosage may be absolute (accidental, homicidal,
suicidal) or relative (e.g. usual dose of aminoglycoside
antibiotics in presence of renal failure). Toxic effects are
predictable and dose related. They result from functional
alteration (in high dose atropine causes delirium) or drug
induced tissue damage (hepatic paracetamol necrosis).
Acute paracetamol poisoning occurs specially in
small children who have low hepatic glucoronide conjugating 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 highly
reactive arylating metbolite of paracetamol which detoxified by conjugation with glutathione. When a very large doses paracetamol are taken, glucuroconjugation capacity is
saturated, more NABQI is formed, hepatic glutathione is
depleted and NABQI binds covalently to proteins in liver
cells (and renal tubules) causing necrosis. In chronic alcoholic even 5–6 g/d taken for a few days can result in hepatotoxicity because ethanol induces CYP 2E2, that metabolizes paracetamol, to NABQI. Treatment needs activated
charcoal, given orally or through the tube to prevent GI absorption, and acetylcysteine (150 mg/g by i.v. infusion).
Metabolism of
Basic & Clinical Pharmacology – 10th Ed. (2007):
paracetamol
to hepatotoxic
metabolites
(NABQI etc.)
(GSH – glutathione;
SG – glutathione moiety)
Daily dose > 7.5 g:
hepatotoxicity
and
nephrotoxicity
NB: Acetylcysteine and GSH
contain –SH groups.
NABQI
Poisoning may result from dosages of drugs. Specific
antidotes (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 toxic
effects of a drug in a patient at therapeutic doses, e.g.
only a few doses of carbamazepine may cause ataxia in
some 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 the
population exposed to the drug. Prior sensitization is
needed and a latent period of at least 1–2 weeks is required
after the first exposure. The drug or its metabolite acts as
antigen (AG) or more commonly hapten (incomplete AG –
drugs with small molecules which become antigenic only
after binding with an endogenous protein) and induce
production 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 it
without a reaction. There are several types of allergic reactions: humoral (type I–III) and cell mediated (type IV).
Type I (anaphylactic) reactions – immediate hypersensitivity. Reaging antibodies (IgE) fix to the mast cells.
On exposure to the drug, AG/AB reaction takes place on
the 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. The
manifestations occur quickly after challenge.
ACE inhibitors – swelling of lips
Type II (cytolytic) reactions. Drug + component of
specific tissue cell act as AG. The resulting antibodies
(IgG, IgM) bind to the target cells. On reexposure AG/AB
reaction takes place on the surface of these cells, complement is activated and cytolysis occurs, e.g. thrombocytopenia, agranulocytosis, aplastic anaemia, haemolysis,
organ damage (liver, kidney, muscle), systemic lupus
erythematosus.
Type III (retarded, Arthus) reactions are mediated by
circulating antibodies (predominantly IgG). AG/AB complex
binds complement and precipitates on vascular endothelium
giving 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 symptoms
usually 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 are
mediated through production of sensitized T-lymphocytes
carrying receptors for the AG. On contact with AG T-lymphocytes produce lymphokines which attract granulocytes
and generate an inflammatory response, e.g. contact dermatatitis, some rashes, fever, photosensitization. These
type allergic reactions generally take > 12 h to develop.
Treatment of drug allergy
The 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. methylprednisolone or betamethasone. It acts slowly but is specially
valuable for prolonged reactions and in asthmatics.
(Tripathi, 2008)
Skin test (intradermal, patch) or intranasal test may
forewarn in case Type I hypersensitivity
but not in other types.
(6) Idiosyncrasy is genetically determined abnormal
reactivity to a drug and other xenobiotics. Certain ARs
of some drugs are largely restricted to individuals with
a particular genotype.
Acetylation is an important route of metabolism
for many drugs that possess an amine (-NH2) group.
Most individuals are either rapid or slow acetylators
but the proportion of each varies greatly between
races. Some 90% of Japanese are rapid acetylators
whereas in Western populations the proportion is
50% or less. Isoniazid may cause peripheral
neuropathy in slow acetylators on standard doses
and pyridoxine is added to the antituberculosis
regimen where there is special risk, e.g. in diabetes,
alcoholism, renal failure. Acute hepatocellular
necrosis with isoniazid is more common in rapid
acetylators, perhaps because they more readily
form an hepatotoxic metabolite. Sulphasalazine
(used for rheumatoid arthritis) causes ARs
more frequently in slow acetylators, probably
because of the sulphapyridine, component which is
inactivated by acetylation.
Bacterial resistance to drugs is genetically
determined and is of great clinical importance.
Individuals who are Glucose-6-phosphate
dehydrogenase (G6PD) deficient may suffer
from acute haemolysis if they are exposed to certain
oxidant substances, including drugs (dapsone,
methylene blue, nitrofurantoin, primaquine,
fluoroquinolone, some sulphonamides). Characteristically there is an acute haemolytic episode
2–3 days after starting the drug. The haemolysis is
self-limiting, only older cells with least enzyme
being affected. The condition is common in African,
Mediterranean, Middle East and South East Asian.
The porphyrias comprise a number of rare, genetically
determined 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 attacks
of neurovisceral dysfunction precipitated principally by
a wide variety of drugs (and by alcohol and infection too).
Certain peculiarities of an individual (for which no definite
genotype has been described) are included among
idiosyncratic reactions, e.g. phenobarbital causes
excitement 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, that
results 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 abruptly 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 only
through the action of drugs. It may start as liking for the
drug effects and may progress to compulsive drug use
in some individuals. The intensity of psychological
dependence may vary from desire to craving.
Reinforcement is the ability of drug to produce effects
that 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 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 depressants
of CNS: opioids (morphinomimetics), barbiturates,
benzodiazepines, alcohol.
Central nervous stimulants such as amphetamines and
cocaine produce little or no physical dependence.
Drug abuse means the use of psychotropic substances
in a way that would “constitute a public health and social
problem”. For regulatory agency “drug abuse” refers to
any use of an illicit drug.
Drug addiction is a pattern of compulsive drug use
characterized by overwhelming involvement with the
use of a drug. Amphetamines, cocaine, cannabis, LSD
are drugs which produce addiction but little or no physical
dependence.
Drug habituation is less intensive involvement with the
drug, so that its withdrawal produces only mild discomphort
without 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 mixtures
induce a characteristic alteration of mood that does
not occur with either drug alone
— psychological dependence strong
— physical dependence occurs
— tolerance occurs.
Heroin-cocaine mixtures: similar characteristics.
(8) Drug withdrawal syndrome – sudden interruption
of therapy with certain drugs (glucocorticoids, antiepileptic
drugs, CV drugs etc.) usually results in ARs, mostly in
form of worsening of the clinical condition for which the
drug 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’s
compliance 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 chloroquine
and related drugs, adrenal steroids (topical and
systemic), phenothiazines and alkylating agents.
Corneal opacities occur with phenothiazines and
chloroquine. Retinal injury occurs with thioridazine
(particularly of the antipsychotics), chloroquine and
indomethacin.
Nervous system. Tardive dyskinesias occur with
neuroleptics; 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 abnormalities
of a drug, administered to the pregnant mother (by Tripathi, 2008).
The placenta does not strictly constitute a barrier and any
drug can cross to a greater or lesser extent. The embryo is
one of the most dynamic biological systems and in contrast
to adults, drug effects are
very often are irreversible.
The thalidomide disaster
(1958–1962) resulting in
10 000 of babies born with
phocomelia and other defects
focused attention to these
type of drug adverse effects.
Тhe biggest medical tragedy of modern times
The Australian obstetrician
William McBridge and the German
pediatrician Widukind Lenz suspected
a link between birth defects and
the drug, and this was proved
by Lenz in 1961. McBride was later
awarded a number of honours
including a medal and prize money by
the 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: 456
babies
USA: 17
babies
In 1962,
the Unated States Congress
enacted laws requiring tests
for safety during pregnancy
before a drug can receive
approval for sale in the U.S.
(S)-thalidomide
(R)-thalidomide
Thalidomide is racemic – it contains both left- and right-handed
isomers. The (R) enantiomer is effective against morning sickness.
The (S) is teratogenic and causes birth defects. The enantiomers
can interconvert in vivo. The (S) enantiomer intercalates (inserts)
into DNA in G–C (guanine – cytosine) rich regions.
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 abnormalities 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.
Embryogenesis
Dorland’s Illustrated Medical Dictionary (2003, 2004)
Schematic diagram of critical periods of human development
(By Moore KL: The Developing Human: Clinically Oriented Embryology, 4th ed. Saunders, 1988.)
Pregnancy
Risk
Categories
(PRCs) – FDA
The FDA (USA) has established 5 categories
to indicate the potential of systematically
absorbed drug for causing birth defects. The
key differentiation among the categories
rests upon the reliability of documentation
and the risk:benefit ratio (Lacy et al., 1998).
A
B
C
D
X
PRC A: Controlled studies in pregnant women fail to
demonstrate a risk to the fetus in the first trimester with
no evidence of risk in later trimesters. The possibility of
fetal 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-reproduction
studies have shown an ARs (other than a decrease in
fertility) that was not confirmed in controlled studies in
women 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 studies
in women are not available. Drug should be given only
if 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 be
acceptable despite the risk (e.g. if the drug is needed in
a life-threatening situation or for a serious disease for
which 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 evidence
of fetal risk based on human experience, or both, and
the risk of the use of the drug in pregnant women clearly
outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
Examples: thalidomide, estrogens,
isotretionoin, ergometrine.
(Tripathi, 2008)
Phenytoin syndrome
С
(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 observed
increase in adverse effects in the infant.
Controlled studies in breastfeeding women fail to
demonstrate a risk to the infant and the possibility
of 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 in
a breastfeeding woman is remote.
Example: Diclofenac, Fentanyl, Omeparzole.
L3: Moderately Safe
There are no controlled studies in
breastfeeding women, however
the risk of untoward effects to
a breastfed infant is possible;
or, controlled studies show only
minimal non-threatening adverse effects.
Drugs should be given only if the potential benefit
justifies the potential risk to the infant.
Examples: Acarbose, Aspirin, Indometacin, Morphine
L4: Possibly Hazardous
There is positive evidence of risk to a breastfed infant
or 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 a
life-threatening situation or for a serious disease for
which safer drugs cannot be used or are ineffective).
Examples: Colchicine, Diazepam (in chronic use),
Lithium
L5: Contraindicated
Studies in breastfeeding mothers
have demonstrated that there is
significant and documented risk to
the infant based on human experience, or it is a medication
that has a high risk of causing significant damage to an
infant. The risk of using the drug in breastfeeding women
clearly outweighs any possible benefit from breastfeeding.
The drug is contraindicated in women who are
breastfeeding an infant.
Examples: Cyclophosphamide, Mitoxantrone.
PRCs
A: 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
LRCs
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 defects
respectively. Oxidation of the drug may result in the
production of reactive intermediate compounds which
affect genesis and can case structural changes in
chromosomes. Chemically cancerogenesis usually takes
10–40 years to develop. Chemical compounds implicated
in these ARs include some anticancer drugs, radioisotops,
estrogens, nicotine (tobacco) etc.
(13) Drug induced diseases are also called
iatrogenic (physician induced) diseases. They represent
functional disturbances (diseases) caused by drugs which
persist even after the offending remedy has been
withdrawn 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. Thomas
B. 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, Chirchill
Livingstone, 2007.
Tripathi KD. Essentials of Medical Pharmacology. 6st Edition.
Jaypee Brothers. New Delhi, 2008.