ADVERSE DRUG REACTIONS

 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

Prologue

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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?

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“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 ( ADR ) Skip Chapter

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: Skip Chapter

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.

Criteria for drug reaction

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.