Indian J Pediatr 53 : 19-23, 1986

Clinically important drug interactions in pediatric practice ~l. Baird-Lambert and D . MacKintosh

Pediatric Pharmacology Unit, Department of Pediatrics, Westmead Hospital, Westmead N S W 2145, Australia. Although the potential for drug interactions is enormous, only a limited number of interactions predicted on theoretical grounds or shown to occur in the test-tube are of significance to the patient. A clinically significant interaction can be said to occur when the coadministration of two or more drugs results in altered effects on the patient, necessitates a change in drug dosage or produces toxicity. For an interaction between two drugs to be of clinical significance, the drugs must have a steep dose-response curve, that is a large change in effect is seen with small changes in dose or blood levels (e.g. anticoagulants antidepressants), or show significant dose-dependent toxicity (e.g. phenyton, theophylline). Alternatively, the interaction will be significant if a drug with potent and necessary effect has its effect diminished because of the interaction (e.g. dexamethasone with phenobarbitone). Clearly, the drugs must be given concurrently to the patient. Thus, patients receiving chronic treatment for a long-term illness (e.g. epilepsy or asthma) may experience problems when a second drug is added to treat an intercurrent acute illness (e.g. erythromycin for infection). Patients with altered ability to Reprint requests : J. Baird Lambert.

metabolise or eliminante drugs (e.g. in hepatic or renal impairment or immaturity) and those in whom acid-base equilibrium is disturbed, such that distribution and renal excretion of some drugs may be altered, will have an increased susceptibility to drug interactions. Drug interactions may occur through any of three general mechanisms. (1) Pharmacokinetic interactions, arise where one drug alters the absorption, distribution (including protein binding), metabolism (especially by hepatic microsomal enzymes) or excretion of another, thereby changing total circulating levels. Displacement of a drug from its protein binding sites results in an increase in free, and therefore active, fraction of the drug while total levels remain unchanged. Protein binding interactions are usually only clinically significant if the drug is greater than 90 per cent protein bound. (2) Pharmacodynamic interactions, where the two drugs may act on the same physiological or biochemical system to produce additive, synergistic or antiagonistic effects. Such interactions are generrally predictable and therefore avoidable, from consideration of the pharmacology of each of the drugs separately. (3) In vitro, physical or pharmaceutical interactions occur outside the body.

20 THE INDIAN JOURNAL OF PEDIATRICS W h e r e two d r u g s which are physicaUy i n c o m p a t i b l e are m i x e d e i t h e r p r i o r to o r a t t h e site o f injection, o n e o r b o t h d r u g s will be i n a c t i v a t e d a n d a p r e c i p i t a t e m a y be f o r m e d . I n general, d r u g s s h o u l d n o t be m i x e d in a n i n t r a v e n o u s s o l u t i o n o r v i a the j u n c t i o n o f a n i n t r a v e n o u s line. O f p a r t i c u l a r i m p o r t a n c e here are interact i o n s with h e p a r i n , which i n a c t i v a t e s such d r u g s as e r y t h r o m y c i n , h y d r o c o r t i s o n e a n d v a r i o u s o t h e r antibiotics.

Vol. 53, No. 1 P e d i a t r i c patients are less likely then a d u l t s to be a t risk f r o m p o s s i b l e d r u g i n t e r a c t i o n s due to the s m a l l e r n u m b e r o f d r u g s to which they are e x p o s e d . H o w ever, a few d r u g s in r e l a t i v e l y c o m m o n use in p e d i a t r i c s show a m a r k e d p r e d i s p o s i t i o n to intereact. O f p a r t i c u l a r i m p o r tance are some antibiotics, a n t i c o n v u l sants a n d t h e o p h y l l i n e . I n the f o l l o w i n g table ( T a b l e I) only the m o r e likely a n d clinically signiticant i n t e r a c t i o n s are noted

Table. Drugs most likely to produce significant interactions in pediafric patients. Primary drug

Interacting drugs

Type of interaction

Outcome and prevention

Antibiotics

Aminoglycosides (e.g. gentamicin)

Frusemide Penicillins

Ch ioramphenicot

Tet racyclhles

Anti-epileptic drugs Carbamazepine (see note 1)

Physical

Ahzyme-inducing agents Anti-epileptic drugs Pharmacokinetic Rifampicin lncreasad metabolism of chloramphenicol Anti-epileptic drugs Pharmacokinetic Decreased metabolism eg. of doxycycline I ron Pharmacokh~etic Milk and Antacids Decreased absorption of tetracyclines

Phenytoin Phenobarbitone

Erythromycin

Pharmacokhtetic Increased metabolism (variable) of carbamazepine Pharmacokhtetic Decreased metabolism of carbamazepine

Increased ototoxicity. Avoid combination or reduce aminoglycoside dose. Inactivation of aminoglycosid when mixed in solution. Do not mix. Reduced efficacy. Monitor drug levels and adjust doses. Reduced efficacy e.g. doxycycline.

of

Reduced efficacy of tetracyclines. Avoid concurrent administration. Decreased efficacy. Monitor levels and adjust dosage where changes occur. Increased levels -->toxicity. Monitor levels and adjust dosage or use alternative antibiotic.

Note : Drugs appearing in this table are listed as primary drug where this is the drug whose effect will be changed by the interacfion. Reference to each of the drugs being given concurrently should be made to ensure that no interaction is lil
BAIRD-LAMBERT AND MACKINTOSH : DRUG ]NTERACTIONS IN PEDIATRICS

21

"fable (contd.) Primary drug

Phenobarbitone tsee note 1)

PhenytoJn ~see note 1)

Valproic acid

Interacting drugs

Type of interaction

Outcome and prevention

Phenytoin

Pharmacokinetic Increased OR decreased metabolism of phenobartbitone

Variable efl$cacy. Monitor serum levds and adjust dosage where changes occur.

Valproic acid

Pharmacokinetic Decreased metabolism of phenobarbitone.

Increased phenobarb levels -~toxicity. Monitor serum levels and adjust dosage where changes occur.

Carbamazepine

Pharmacokinetic Increased metabolism of phenyloin.

Decreased ettlcacy. Monitor serum levels and adjust dosage where changes occur.

Phenobarbitone

Pharmacokinetie Variable efficacy. Monitor Increased OR decreas- serum levels and adjust ed metabolism of dosage where changes occur. Phenotoin.

Valproic acid

Pharmacok inetic Variable efficacy. Monitor Initially decreased serum levels and adjust dometabolism of pheny- sage where changes occur. toin. Later decreased protein-binding of phenytoin --->increased elimination

Carbamazepine Phenytoin Phenobarbitone Salicylates

Pharmacokinetic Increased metabolism of valproic acid. Pharmacokinetic Complex. Decreased proteinbinding of valproate-increased free drug, but decreased elimination.

Decreased efficacy. Monitor serum levels and adjust dosage where changes occur. Avoid use together, substitute paracetamol.

Note 1 : Drugs causing hepatic microsomal enzyme induction e.g. anti-epileptic drugs or rifampicin will decrease the efficacy of each of the above AEDs whilst drugs causing inhibition of metabolism e.g. chloramphenicol., cimetidine, erythromycin, metronidazole and sulphonamides will increase the toxicity of each of the above AFDs.

22 THE INDIAN JOURNAL OF PEDIATRICS

Vol. 53, No. 1

Table (Contd.) Primary drug

Interacting drugs

Cortieosteroids, systemic e.g. Dexamethasone Phenobarbitone Hydrocortisone Phenytoin MethylpredniRifampicin solone Prednisolone etc. Oral contraceptives

Heparin

Aspirin

Methotrexate

Basic drugs Antihistamines Phenothiazines Tetracyclines etc. Salieylates

Oral contraceptives

Rifampicin

Salicylates

Theophylline

Type of interaction

Outcome and prevention

Pharmaeokinetic Increased metabolism of corticosteroid

Decreased efficacy. Steroid dosage may need to be increased.

Pharmacokinetic Monitor for in,'eased side Decreased metabolism effects of steroids. Decrease and decreased volume steroid dose if clinically inof distribution of dicated. corticosteroid. Increased risk of bleeding. Pharmaeodynamic inhibition of platelet Avoid use together, substitute aggregation paracetamol. Avoid mixing of these prePhysical paration if necessary to use Pracipitate forms at one time. on mixing

Activity of methotrexate increased Carbamazepine Pharmacokinetic. Phenobartbitone Increased metabolism Phenytoin, rifampicin of oral contraceptives Phenobarbitone Pharmacokinetie. (May be other hepatic Increased metabo • ism microsomal enzyme or rifampicin inducer) Corticosteroids Pharmacokinetic. Increasad renal clearance of salicylates Chloramphcnicol Pharmacokinetic. Erythromycin Decreased metabolism Oral Contraceptives of theophylline.

Phenobarbitone Phenytoin Rifampicin Other hepatic microsomal enzyme inducers.

Pharmacokinetic. Increased metabolism of theophylline.

Avoid use together, substitute paracetamol. Decreased efficacy--, risk o f pregnancy. Use other birth control. Decreased efficacy. Avoid combination where possible; or adjust rifampicin dosage. Decreased efficacy. Possible toxicity on steroid withdrawal. Monitor serum levels and adjust dosage. Increased serum levels--~ possible toxicity. Avoid combination, or monitor serum theophylline levels. Decreased efficacy. Monitor serum levels and adjust dosage.

Note 2 : Drugs causing hepatic rnicrosomal enzyme ir~dt:cticn rill dercrease l~e efficacy of systemic corticosteroids. Many of the interactions discussed here are well recognised and the original literature has not been cited. For more detailed or extensive discussion, a number of recent reviews of this complex area are referenced.l-6

BAIRD-LAMBERTAND MACKINTOSH : DRUG INTERACTIONSIN PEDIATRICS References 1. Avery GS. Drug interactions that really maUer : A guide to major importance drug interactions. Drugs 14 (1977) 132. 2- Baciewicz AM. Oral contraceptive drug interactions. Therap Drug Monit 7 (1985) 26. 3. Birkett D.I, Drug interactions that matter in general practice. Current Therap 26 (1985)

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4. Bochner F, Carruthers G, Kampmann J, Steiner J : Handbook o] clinical pharmacology Little Brown & Co, Boston, 1978 5. Brodie MJ : Adverse drug interactions. Medicine [nternat 2 (1984) 295 6. Cupit GC, Bryan CK : Drug Interactions. In, Pediatric pharmacology. Yaffe SJ (r Grune & Stratton, New York, 1980, p 439.

17.

WANTED : A NEW BREED OF DOCTORS A thoughtful observer stated that he was troubled by the extent to which medical schools were isolated from health service system. In many countries these schools were ivory towers, concerned with obscure yet supposedly high international academic standards and with the preparation of students for dimly perceived requirements of the twenty-first century, while largely forgetting or even ignoring the pressing health needs of today and tomorrow. Developing countries, even though their health stakes are greater and gravel-, mostly pursue similar policies to those of their industrialized cousins. What is needed is the promotion of proper balance between primary heahh care and secondary and tertiary medical care, in both education and research. If a new doctor is to be in place by the year 2000, now is the time for change. You might wish to consider whether present medical education is appropriate for the needs of your country by asking yourself and others whether medical graduates think and behave in terms of : - h e a l t h rather than disease, applying techniques of prevention and heahh promotion as well as cure and rehabilitation; --family and community, and not the sick patient alone; ---membership of a health team; --making the most effective use of the financial and material resources available; --their country's patterns of health and disease, and the relevant priorities. If the answer to the foregoing questions is "yes" in each case, then the essential has been achieved. Otherwise, you might consider it advisable to look into the possibility of influencing the orientation and training programmes of medical schools in your country. A bsiracted from World Health Forum 6 : 291, 1985