Chief Editor
DR T. R .RAMANUJAM M.D., C.MI.Biol (Lond)
INTRODUCTION
DEFINITION OF A.D.R AND DRUG INTERACTIONS
CLASSIFICATION OF ADVERSE DRUG REACTIONS
ADR DUE TO DRUG INTERACTIONS
CRITERIA FOR DRUG REACTIONS
Every
effort has been made to cover most of
the aspects of Adverse Drug Reactions
(A.D.R) in this article. Various types
of ADR, few examples of drugs commonly
encountered and the possible
mechanisms have been included. No drug can be completely safe
and only those who are
pharmacologically naïve can reassure
themselves or their patients that a
drug is harmless as water. Even the most scrupulous work
in animals will not always predict
human toxicity because of species
difference or because it may rarely
occur in animals or because of the
presence in the clinic or hospital
population of diseases that
predisposes patients to drug toxicity.
Many drugs that are in wide use cause
catastrophic damage only rarely, so
that physicians are lulled into false
sense of security e.g.. Aspirin. Drugs can cause toxicity, which
is tantalising regard to time effect
relationship. It is a pity that drug toxicity
does not turn “On and Off” like an
electric bulb, with untoward effects
appearing promptly upon reinstitution
of drug therapy and disappearing
promptly on cessation. E.g.. Gold salts &
Chloramphenicol leading to aplastic
anemia becomes manifest long after
cessation of therapy. Similarly cholestatic hepatitis
with phenothiazines (Largactil). It is too difficult to prove
the cause of effect
relationship because of multiple drugs
being taken simultaneously and because
of scientific ethical and legal
problems involved in challenging the
patients with a dose of a drug in the
absence of reliable “Invitro” test
which would render such challenge
unnecessary.
Any potent drug therapy carries an
inherent risk of A.D.R. which may be
minor or major and the use of drug
should not be with-held if the benefit
to risk ratio favors therapy.
Introduction:
“DID
MY PATIENT REALLY SUSTAIN AN ADVERSE
DRUG REACTION (A.D.R)? IF SO WHO IS AT
FAULT?”
An enormous range of potent and
valuable drugs produced by
pharmaceutical industries during the
last six decades have served to
transform the face of therapeutics and
has conferred undoubted benefits on
patients suffering from a variety of
diseases. The problem of unwanted and
adverse effects possessed by many of
these agents whilst ensuring that
patients receives maximum benefits and
therapeutic advantages from them is
one which increasingly demands
attention as drugs become ever more
widely used. Indeed it is probably one of
the most intellectually stimulating
problems that face medicine. The
occurrence of adverse drug reaction is
a price that we or rather our patients
have to pay for the great benefits
that have been produced by modern
medicine and which we anticipate will
continue to be produced in the future.
“PROGRESS IS A DOUBLE EDGED
SWORD AND PROGRESS IS OFTEN
PAINFUL”.
a). When a drug is administered to a
patient two types of drug effects can
be anticipated.
i) Desired
drug actions: which result is preventive,
diagnostic, prognostic and therapeutic
effects primarily sought.
ii) Drug
reaction:
Manifested by additional effects not
primarily sought.
No drug is absolutely free from some
capacity to produce unsought reactions
which may be harmful or innocuous.
The judgment of the physician is
continuously needed as he evaluates
his patient on one hand and drug
reactions on the other. Optimum medication of human
patients requires every physician to
balance his therapeutics effect
against possible undesirable
reactions.
The word A D R coined by FDA –
meaning all reactions associated with
any given drug therapy i.e., occurring
during or subsequent to the
administrations.
What is Adverse Drug Reaction?
“IT
IS SIMPLY ANY EVENT THAT FOLLOWS THE ADMINISTRATION
OF A DRUG IN THE RECOMMENDED DOSE AND
IS ATTRIBUTABLE TO THE ADMINISTRATION
OF THAT DRUG WHICH IS HARMFUL TO THE
RECIPIENT, THE FETUS SHE CARRIES OR BY
AN EFFECT ON THE GONADS TO THE
RECIPIENT’ S
DESCENDENTS”
Therefore adverse drug reaction is
differentiated from poisoning in which
harmful effects are produced by dose
beyond permissible limits.
Such events may vary from
trifling irritation to death or from
immediate nausea to the development of
cancer 50 yrs later or expression of
recessive mutation after several
generations.
The range of events is
therefore enormous and methods by
which detected are correspondingly
various.
What is Drug Interaction (DI)?
“DRUG
INTERACTION IS PHENOMENON WHICH OCCURS
WHEN THE EFFECTS OF A DRUG UPON
ADMINISTRATION TO A PATIENT ARE
MODIFIED BY ANOTHER (OR THE SAME)
DRUG, BY ENDO-GENOUS PHYSIOLOGICAL
AGENT OR BY A DISEASE (INFECTION) OR
BY A DIETARY COMPONENT”.
Although many drug interactions may be
clinically insignificant, the
potential hazard of unwanted
unexpected drug interaction can be so
significant that caution should be
exercised when patients are receiving
drugs that are known to result in
interactions or when the patients have
conditions that later pharmacokinetic
and pharmacodynamic characteristics of
the drugs.
a)
. Dose
related (dose dependent which are
augmented or extension effects) occurs
in all patients which may vary from
patient to patient and are specific
for the drug.
Some are exaggeration of
therapeutic (EX: myocardial conduction
defects with beta blockers in
hypertensive patients) or unrelated to
the pharmacological or therapeutic
effects viz., Ototoxicity of
aminoglycosidies.
Dose related ADR may occur because of
the variations in the pharmaceutical,
pharmacokinetic, pharmacogenetic or
pharmacodynamic properties of the drug
(s).
The reactions are more common
with drugs having low margin of safety
i.e., the ratio between effective dose
and toxic dose is very narrow.
Warfarin sodium, Quindine,
Digitalis, aminoglycosides, oral
contraceptives, antihypertensives,
cytotoxics and immunosuppressive
agents are classical examples with low
margin of safety.
i) Pharmaceutical
Variation:
Example Phenytoin toxicity was
enhanced in Australia in 1960 when the
expedient of phenytoin was changed
from calcium sulphate to lactose which
resulted the undue increase in the
bioavailability of the active drug.
Change in formulation characteristics
can alter drug influence in the body.
ii) Pharmacogenetic
Variation:
Acylation
process –
INH, hydralazine, procaineamide and
sulfas metabolism is influenced by
genetic type of the drug enzyme Viz,
rapid or slow acylators.
The drug toxicity is enhanced
in slow acylators.
Hydroxylation
– Debrisoquin, dilantin and
phenformin metabolism can be altered.
Red cell membrane enzyme (g 6 PD def)
may result in haemolytic anemia with
Dapsone, Furadantin, phenacetin,
sulfas, primaquin, phenylbutazone
etc.,
Malignant hyperthermia precipitated by
halothane, succinylcholine,
methoxyflourane (fatal reaction –
genetically mediated).
iii). Pharmacokinetic
Variation:
Hepatocellular
dysfunction as in hepatitis reduce the
clearance of dilantin, theophylline,
warfarin, opioids, proporanolol,
labetalol, largactil.
Renal dysfunction enhanced
toxicity of digitalis, aminoglycoside,
allopurinol, cephalosporins, Li and
amphoterecin B etc.
iv).
Pharmacodynamic
Variation:
Hepatic disease may influence
pharmaco dynamic response to drugs.
Drugs like oral anticoagulants,
NSAIDS, by inhibiting clotting may
cause bleeding and phenothazines,
opiates precipitate hepatic
encephalopathy.
Sodium and water retention can be
enhanced by carbenoxobne carbamazepine
phenylbutazone (NSAIDS), steroids
etc., similarly hypokalemia and
hypercalcemia produced by thiazines
can increase the digitalis toxicity
and also hypokalemia reduce the
effectiveness of lignocaine,
procaineamide, quinidine, and
disopyramide etc.
b). Non-dose related ( or dose independent) occurs only in small number of patients.
i).Immunological
reactions: (durg allergy /
hypersensitivity)
No relation to pharmacological
effects and there is always delay
between the first and subsequent
exposure to the drug and usually
reaction disappears on withdrawal of
the offending agents and reappears
when the offending agent is
administered.
Factors like macromolecular drug
proteins form hapten, atopic
conditions of the patient or the
presence of incidental disease like
infectious mononucleosis may
precipitate allergic type of ADR.
For example hydrallazine causes
systemic lupus erythema like syndrome
in patients with HLA Dr 4 tissue type
and ampicillin causes rashes in
patients with Infectious
mononucleosis.
Mechanisms
& types of Immunological
reactions:
Type
I Anaphylaxis (Urticaria &
angioedema) –involving IGE
with resulting mediators like
histamine, SRS – A etc., Penicillins,
sulfas, Amphoterecin B etc.
Type II
Cytotoxic (thrombcytopenia and
hemolytic anemia) involving
circulating Ab IGM, IGA resulting in
the activation of complement and cell
lysis.
Thrombopenia: Quinine,
Quindine, Rifadin, Chlorpropamide,
metronidazole.
Haemolytic anemia:
Penicillins, rifadin, furans,
quinidine.
Type III
Immunocomplex involving
IgG resulting in the activation of
complement and damage to capillary
endothelium – serum sickness. ATS,
penicillins, aminoglycosides, sulfas,
antithyroid drugs.
Type IV
Cell mediated or delayed
hypersensitivity –
contact dermatitis.
Local anesthetic ointments,
antihistamine creams topical
antimicrobials etc.
Few of
the allergic manifestations &
drugs implicated:
Drug Fever:
Penicillins, sulfas, dilantin,
hydraliazine, chloramphenicol,
aminoglycosides, quinidine.
Rashes:
Toxic
erythema –
penicillins, sulfas, phenylbutazone
urticaria – sulfas aspirin, codeine,
phenecetin.
Erythema
multiforme – (
Stevens Johnson's Syndrome);
penicillins, sulfas, barbiturates,
phenothiazines, NSAIDS dilantin.
Erythema
nodosum: sulfas, sulfones, oral contraceptives, Cutaneous
vasculities: sulfas,
phenylbutazone, dilantin purpura
Non-thrombopenic:
steroids, meprobamate, sulfas
Exfoliative
dermatitis: Gold,
Phenylbutazone
Photosensitivity:
Sulfas, demecolcycline, largactil, Quinolones Fixed drug
eruptions (FDE) sulfas, tetracyclines,
barbiturates phenolphthalein etc.
Toxic
epidermal necrolysis (TEN):
Dilantin, sulfas, Gold tetracycline,
allopurinol etc.
Connective
Tissue disease:
SLE – hydrallazine, sulfas,
procaineamide.
Pharmacogenetic
variations ( Include Idiosyncratic
Reactions):
Heinz body hemolytic anemia –
sulfas, sulfones, primaquine, INH,
phenylbutazone.
Acute
porphyria:
Barbiturates, meprobamate.
c).
Long term effects causing ADR:
1.
Due to
Adaptive changes –
physical
dependence by narcotic analgesics.
Tardive dyskinesia associated with
long term neuroleptic therapy for
schizophrenia.
2.
Due to
Rebound phenomenon: Narcotic
analgesics, alcohol, benzodiazepines
producing withdrawal syndrome.
More important ones are those
produced by clonidine withdrawal
rebound hypertension.
Withdrawal of beta blockers in
hypertension leading to rebound
cardiac ischemia and rebound
hypercoagulability is noted in
patients receiving portwine to counter
act heparin overdose.
3.
Other
Long terms effects:
Chloroquine induced corneal
deposits and pigmentary retinopathy
especially in patients receiving
concomitant pronbenecid therapy.
4.
Delayed
effects causing ADR:
(i) Carcinogenesis:
Uterine
endometrial carcinoma with post
menopausal estrogen replacement
therapy vaginal adenocarcinoma of the
female off spring whose mother
received estrogen for threatened
abortion.
Benign liver tumors with oral
contraceptives.
(ii) Adverse
effects with reproduction:
affecting fertility fetus and neonate.
Impaired fertility – reversible –
sulfasalazine, furans pargylin,
antimalarials.
Irreversible – chlorambucil,
cyclophosphamide
Teratogenesis: Drug interfering with
growth and development of the fetus
during I trimester.
Androgens, methotrezate, steroids,
tetracyclines, Warfarin, Dilantin,
alcohol, clofibrate etc.
During last trimester drugs causing
adverse effects include aspirin,
aminoglycosides, anti-thyroid,
oral-anticoagulants, etc.
Adverse effects due to drugs excreted
in breast milk: Antineoplastics,
antithyroids, INH, Quinolones, oral
contraceptives, sulfas beta blockers,
xanthine, Diazepam, Ergotamine etc.
Drugs can interfere with immunization procedures: 6MP, Methotrexate and steroids are dangerous after smallpox vaccination. Chloramphenicol with tentanus vaccine – interference with immunity. Oral contraceptives interferes with tuberculin testing.
Diagnostic test | Drug involved |
Positive coomb’s test | Cephalothin, Rifampin |
Increased 17 | Penicillins |
Ketosteroids | Aldomet |
Increased SGOT | Diaoxide |
Increased Uric acid | Thiazides |
Increased blood | Furosemide |
glucose | D thyroxine, Caffeine |
Seruk Alk | Salicylates, Clofibrate |
Phosphatases | Erythrocin, Dilantin, |
Allopnrinol |
Drug interaction outside of the body:
Physical incompatibility–sodium phenobarb
Codeine PO4
Pen G Pt x Vitamin
C Penicillins x
aminoglycosides
Pharmacokinetic
drug interaction:
Hindrance with intestinal
absorption:
Antacids ´
tetracycline
Digoxin ´
Resins
Azole antifungals ´
Antiacids, H2 blockers
Oral anticoagulants and alteration of
bacterial flors
Interference
with binding & storage:
Sulfas ´
Phenylbutazone – diaplacement from
binding leading to toxicity
Warfarin ´
salicylates
Drug
interaction at receptor sites:
Nasal decongestants ´
anti HT
Dopamine ´
Caffeine – antagonism
Imipramine ´
catecholamine – enhanced activity
Drug interaction with
biotransformation:
MAO I ´
tricyclics – potentiation
Barbiturate ´
dilantin – reduced dilantin effect
Barbiturate ´
Warfarin – reduced warfarin effect
Drug
interaction with Excretion:
Alkalisation increases
aminoglycoside excretion
Probenecid ´
penicillin haiazides reduce plasma K
and increase plasma Ca and Increase
the toxicity of digoxin.
Important determinants of ADR:
1. The
administrated drug:
Physicochemical
and pharmacokinetic characteristics
Formulation
characteristic
Dose of
drug administered
Frequency
& route of administration
2. Patient
and his conditions:
Age,
Sex pregnancy and nutrition
(Physiological)
Associated
diseases and inter current illness
(Pathological)
Allergic
states
Genetic
predisposition
3. Additional
extrinsic factors:
Other drugs administered
concurrently
Alcohol / tobacco consumption
Environmental
pollutants.
a)
Problems
of the physician:
Did the physician test
sensitivity to the drug?
Did the physician withdraw all
unsuitable medications?
Did the physician known about the
diet?
Did the physician was aware of the
physico chemical and therpeutic
characteristics of drugs?
Did the physician observe ADR
himself?
Does the ADR pose immediate
hazard or not?
b) Environmental
problems:
Presence of environmental
pollutant
Was the drug properly stored
/ date expired or not ?
c) Problem
of the patient:
Did the patient receive the
drug prescribed?
Did the patient take the drug
prescribed?
Did the patient take the drug
in proper dose?
Did the patient take any
other OTC remedies or old
prescription?
5.
Surveillance
methods of detecting A D R:
1. Anecdotal
reporting by individual doctors.
2. Voluntary
but organised reporting.
3. Post
marketing surveillance.
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