INTRODUCTION
DEFINITION OF A.D.R AND DRUG INTERACTIONS
CLASSIFICATION OF ADVERSE DRUG REACTIONS
ADR DUE TO DRUG INTERACTIONS
CRITERIA FOR DRUG REACTIONS
INTRODUCTION
:
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 na�ve 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.
DEFINITION OF A.D.R AND DRUG INTERACTIONS
:
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.
CLASSIFICATION OF ADVERSE DRUG REACTIONS
:
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.
ADR DUE TO DRUG INTERACTIONS
:
Drugs can
interfere with immunization procedures: 6MP, Methotrexate and steroids are
dangerous after small pox 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:
Hinderance with intestinal absorption:
Antacids �
tetracycline
Digoxin �
Resins
Azole antifungals �
Antiacids, H2 blockers
Oral anticoagulants and lateration 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.
CRITERIA FOR DRUG REACTIONS
:
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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