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Home , Enzyme inducer, Norethisterone enanthate, Rifampicin, Valproate

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A potential refers to the possibility that one drug may alter the pharmacological effects of another drug given concomitantly. The net result may be enhanced or diminished effects of one or both drugs, or the appearance of a new effect that is not seen with either drug alone.1,2

The most important adverse drug-drug interactions occur with drugs that have seri- ous toxicity and a low therapeutic index, where relatively small changes in drug level can have significant adverse consequences. Additionally, drug-drug interac- tions can be clinically important if the disease being controlled with the drug is serious or potentially fatal if undertreated. Not all drug interactions are clinically significant. Some patients experience severe reactions while taking interacting drugs, while other patients appear to be unaffected.1-3

Interactions may be either pharmacokinetic or pharmacodynamic. ANNOESJKA SWART BSc PHARMACOKINETIC DRUG-DRUG INTERACTIONS

Manager Pharmacokinetic interactions are divided into those that affect: Information Centre Division of • drug absorption University of Cape Town • drug binding • drug Annoesjka Swart is a pharmacist and currently • the manager of the Medicines Information 1,2 Centre, a unit situated in the Division of • transport systems. Pharmacology, Department of at the University of Cape Town’s Faculty of Health The result of pharmacokinetic drug-drug interactions may be an increase or Sciences. Her special interest is the provision decrease in the concentration of the drug at the site of action.1,2 The mechanism of drug information to all health care profes- sionals in South . most relevant to tuberculosis drug interactions is , which is explained in more detail below.

Drug metabolism interactions

Drugs are metabolised by two types of reactions: phase I reactions that involve oxi- dation, reduction or hydrolysis in which drugs are turned into more polar com- pounds, and phase II reactions that involve coupling drugs with some other sub- stance (e.g. glucuronic ) to make (usually) inactive compounds. These reactions make drugs more easily excretable. Drug metabolism interactions can increase or decrease the amount of drug available by inhibition or induction of metabolism.1,2

Enzyme induction

VANESSA HARRIS induction frequently affects phase I oxidation, which requires the presence B Pharm of the reduced form of dinucleotide phosphate (NADPH) and the haem-containing protein . Enzyme inducers increase the activ- Information Pharmacist ity of the microsomal (cytochrome P450 isoenzymes), increasing the rate Medicines Information Centre Division of Pharmacology of metabolism and excretion. As a result, larger doses of drugs metabolised by 1,2 University of Cape Town these enzymes are needed.

Vanessa Harris is an information pharmacist Enzyme induction interactions are delayed in both starting and stopping, taking working part-time at the Medicines Information from days to up to 3 weeks to develop fully, and may persist for a similar length of Centre. She assists with information research, article writing and project work carried out by time after the inducing drug is stopped. It is possible to accommodate the interac- the Medicines Information Centre. tion by simply raising the dosage of the drug affected, but this requires good moni-

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Table I. Important drug interactions with

Rifampicin Management interaction ANTIHYPERTENSIVES Diuretics No interactions found Safe option channel Rifampicin markedly reduces the Monitor response closely and increase blockers levels of blockers by dose of calcium increasing the metabolism of these if needed2 drugs in the gastrointestinal wall2 β-Blockers Rifampicin reduces levels β-blockers that undergo extensive of β-blockers by enzyme induction. metabolism (e.g. propranolol) would be (↓AUC of carvedilol by about 70%)3 expected to be affected by the enzyme- inducing effects of rifampicin Those β-blockers mainly lost unchanged in the (e.g. atenolol) would not be expected to be affected2,3 Monitor patient response (blood pressure, signs/symptoms of hepatic dysfunction) and adjust β-blocker dosage as needed3 ACE inhibitors Two isolated reports of interaction Monitor for continuing blood pressure control Captopril with enalapril, with minor clinical after the addition or withdrawal of rifampicin, Enalapril relevance2 adjusting the ACE inhibitor dose if needed Lisinopril to regain control 3

ANALGESICS Paracetamol Increased clearance of paracetamol Clinical importance awaits further study2 in 2 patients NSAIDS Small study showed decreased May need ↑ dosage of diclofenac, more study Diclofenac levels of diclofenac 2 needed2 No interaction found with , Ibuprofen and aspirin are safer options Aspirin ibuprofen Tramadol No interactions found Rifampicin reduces levels2,3 Monitor for adequate pain control Morphine Doses of opioids may need to be increased and re-evaluated when rifampicin is discontinued3

ANTIFUNGALS Itraconazole Serum concentrations This can reduce or abolish the markedly reduced effects, depending on the infection being treated Serum rifampicin levels can also be reduced by the concurrent use of ketoconazole, and the drugs should be administered 12 hours apart to minimise this interaction CONTRACEPTIVES Oral contraceptives (OC) Rifampicin reduces effectiveness by Very unreliable contraceptive choice when given enzyme induction and by intestinal with rifampicin flora alteration, which in turn, alters Breakthrough bleeding and spotting commonly the enterohepatic circulation of the occur and conception and may drug3 not be prevented2 Should NOT be administered concomitantly -only Rifampicin reduces effectiveness by Safer alternative — injectable form injectable contraceptives enzyme induction 3 Interaction may be overcome by shortening acetate the interval between injections to 8 weeks enanthate for medroxyprogesterone acetate and to 6 weeks for norethisterone enanthate4

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Table I. Important drug interactions with rifampicin (continued)

Rifampicin Management interaction ARV AGENTS Didanosine (ddI) No interactions found (EFV) Rifampicin reduces EFV Rifampicin can be used with EFV without levels by enzyme induction 3 dosage modification5 No interactions found Lopinavir- Rifampicin reduces levels by Monitoring of liver function advised ritonavir enzyme induction3 Adults: add ritonavir 300 mg every 12 hours to (Kaletra) ↑ ALT/AST 2 usual Kaletra dose, while patient is on rifampicin and for 1 month after completion of TB therapy6 Children: swap from Kaletra to ritonavir only (NVP) Rifampicin reduces NVP levels by Alternative: If over 3 years old and over 10 kg, enzyme induction3 switch to efavirenz If under 3 years old or under 10 kg, switch to ritonavir if appropriate Stavudine No interactions found Rifampicin increases the clearance Dosage alterations may NOT be necessary with of AZT2,3,7 concurrent use, but be alert for any evidence of a reduced response to AZT2,3,7 ANTI-EPILEPTICS One case report of increased level Monitor the patient for signs of carbamazepine and toxicity of carbamazepine when toxicity, including ataxia, nystagmus, diplopia, and rifampicin are given , vomiting, apnoea, seizures and together, probably by inhibition of coma3 carbamazepine metabolism2,3 Rifampicin markedly reduces Monitor phenytoin levels and increase the phenytoin serum levels by enzyme dosage appropriately if rifampicin is induction2 started ALONE Decrease the dosage if rifampicin is stopped When rifampicin is used in If rifampicin and isoniazid are given combination with isoniazid the CONCOMITANTLY, the outcome may depend on phenytoin clearance is not the isoniazid acetylator status of the patient increased as much as when Fast acetylators will probably also need an rifampicin is given alone with increased phenytoin dosage phenytoin3 Slow acetylators may need a smaller phenytoin dosage if toxicity is to be avoided All patients should be monitored very closely as the outcome is unpredictable2 Valproic acid Rifampicin may decrease Monitor valproate levels and the patient for levels by increasing clearance3 seizure control. An adjustment in the dosage may be necessary 3 AUC = area under the curve.

toring and there are risks when the Enzyme inhibition significance of the enzyme inhibition inducing drug is stopped without interactions depends on the extent to Enzyme inhibitors inhibit the microso- remembering to reduce the dosage of which serum levels rise. Examples of mal enzymes (cytochrome P450 isoen- the previously affected drug. Examples enzyme-inhibiting drugs are allopuri- zymes), decreasing the rate of metabo- of enzyme-inducing drugs are barbitu- nol, chloramphenicol, , lism and excretion of other drugs that rates, carbamazepine, nevirapine, , , flucona- are metabolised by these same phenytoin, rifampicin and tobacco zole, , isoniazid, ketocona- enzymes. These drugs begin to accu- smoke.1,2 zole, , protease mulate in the body and toxicity may inhibitors and verapamil.1,2 develop within 2 - 3 days. The clinical

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Table II. Isoniazid (INH) drug interactions

INH interaction Management

Antacids Absorption of INH is reduced by Give INH at least 1 hour before the antacid. concurrent use of Although didanosine tablets contain antacids in hydroxide 2,4 the formulation it has been shown that it is too little to affect the of INH if given concurrently Carbamazepine Serum levels of carbamazepine are Toxicity of carbamazepine can occur if dosage markedly and rapidly increased 2,4 is not reduced appropriately. Concurrent use should not be undertaken unless the effects can be closely monitored and suitable downward dosage adjustments made Oral contraceptives One or two cases of failure have The risk of failure appears to be low been reported 2 Paracetamol Potential toxicity of paracetamol 2 Normal daily analgesic dosages of 4 g may not be safe. It is prudent to warn patients to limit their use of paracetamol because it seems that some individuals risk possible paracetamol- induced liver toxicity, even with normal doses. More study is needed to clarify the situation2 Phenytoin ↑ levels of phenytoin with INH alone 2 Slow metabolisers of INH may develop phenytoin toxicity if the dosage of phenytoin is not reduced appropriately. If both rifampicin and INH are given, serum phenytoin levels may fall in patients who are fast acetylators of INH, but may occasionally rise in slow acetylators Theophylline Plasma level of theophylline may be Monitor levels increased 4

The most important adverse Cytochrome P450 isoenzymes PHARMACODYNAMIC and predicting drug interactions INTERACTIONS drug-drug interactions occur with drugs that have Cytochrome P450 is a large family of Pharmacodynamic interactions are serious toxicity and a low related isoenzymes of which about 30 those where the effects of one drug have been identified. The most fre- therapeutic index, where are changed by the presence of anoth- quently involved in drug interactions er drug at its site of action, without relatively small changes in are CYP3A4 and CYP2D6. There are alterations in the concentrations of drug level can have signifi- many drugs that are metabolised by either drug. Sometimes one drug com- cant adverse consequences. these cytochrome P450 isoenzymes. petes directly with another for particu- Drugs may be metabolised by more lar receptors, but often the reaction is 1,2 than one cytochrome isoenzyme. more indirect and involves the interfer- Drug metabolism interac- ence with physiological mechanisms, tions can increase or It is of value to know which particular making pharmacodynamic interactions decrease the amount of isoenzyme is responsible for the more difficult to classify than pharma- drug available by inhibi- metabolism of a specific drug as this cokinetic interactions. There are 4 makes it possible to predict with which tion or induction of metab- basic subdivisions: other drugs it may possibly interact. • additive or synergistic interactions olism.1,2 For example, cyclosporin is and combined toxicity metabolised by CYP3A4 and we know • antagonistic or opposing interac- that rifampicin is a potent inducer of Examples of enzyme-induc- tions this enzyme. The result, predictably, is • interactions due to changes in ing drugs are , that rifampicin reduces the effects of drug transport mechanisms carbamazepine, nevirap- cyclosporin. Knowing which liver • interactions due to disturbances in ine, phenytoin, rifampicin isoenzymes are concerned with metab- fluid and electrolyte balance.1,2 and tobacco smoke.1,2 olism of a drug is a good starting point in predicting drug interactions, but it is not definitive.1,2

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Interactions with tuberculosis Other interactions to be aware of with we have access to the latest updated drugs quinolones are: information databases as well as to • reduced clearance of theophylline, clinical consultants from the University First-line agents for the treatment of leading to increased serum levels of Cape Town’s Faculty of Health tuberculosis include rifampicin, isoni- • increased anticoagulant effect of Sciences, Groote Schuur and Red azid, , and (prothombin time should Cross War Memorial Children’s .3,4 This article focuses on be monitored) Hospitals and other national and inter- the pharmacokinetic drug interactions • concurrent use of sucralfate, national experts. with these first-line agents. antacids containing aluminium, cal- cium or , or oral iron, Need help? Call the Medicines It is impossible to remember all clini- or magnesium supplements Information Centre, tel (021) 406- cally important drug interactions, but may reduce absorption of the 6829 or 086 110 0531, for any when one considers the drugs used for quinolones information relating to medicines, the treatment of tuberculosis, the • although the mechanism is not fully including drug interactions. important interactions are almost understood, the serum levels of exclusively caused by rifampicin. ciprofloxacin are markedly ACKNOWLEDGEMENT Rifampicin is a potent liver enzyme reduced if given at the same time inducer that increases the activity of as didanosine, probably because The authors would like to thank Maria the microsomal enzymes so that the of the interaction with the antacid Nunez, a pharmacy student at the pace of metabolism and excretion of buffers in the didanosine formula- University of Granada, Spain, for her other drugs metabolised by the same tion.2-4 help with the article. enzyme system is increased.3 References available on request. Table I lists the important drug interac- CONCLUSION tions with rifampicin and Table II the Drug-drug interactions are only one of interactions involving isoniazid, an the many factors that can alter a . patient’s response to therapy, but IN A NUTSHELL when unexpected effects are seen, a Ethambutol and pyrazinamide have drug interaction should be suspected. few significant drug interactions. There are many facets to drug-drug Taking careful drug histories is impor- Ethambutol together with pyrazi- interactions. tant, because patients may be taking namide and diuretics has the over-the-counter drugs or herbal prepa- Although there are numerous poten- potential to elevate serum urate levels. rations. Care must be exercised when tial drug interactions not all are clin- Pyrazinamide may interact with allop- major changes are made in a drug ically relevant. urinol and probenecid as pyrazi- regimen and drugs that are not neces- Interactions may either be pharma- namide inhibits the urate clearance. sary must be discontinued. When an cokinetic or pharmacodynamic. Dosage adjustments of these agents interaction is discovered, it is possible may be necessary.2-4 that the interacting drugs may be used Pharmacokinetic drug-drug interac- effectively with adjustment of dosage tions may occur at any point during When using streptomycin one should or other therapeutic modifications.1 absorption, distribution, metabolism be aware of the potential for or excretion. increased risk of oto- or MEDICINES INFORMATION Pharmacodynamic interactions may with other ototoxic or nephrotoxic CENTRE be caused by a large variety of drugs. Streptomycin (and other amino- mechanisms making them difficult to glycosides) possess neuromuscular The MIC is a unit situated within the study and classify. blocking activity. Appropriate meas- Division of Pharmacology, Department ures should be taken to accommodate of Medicine, at the University of Cape Rifampicin, a first-line agent for the the increased neuromuscular blockade Town’s Faculty of Health Sciences. The treatment of tuberculosis, is a potent and the prolonged and potentially Centre was established in 1980 and liver enzyme inducer. fatal respiratory that can forms part of a World Health Organi- Most of the drug-drug interactions occur with anaesthetics and conven- zation collaborating centre. that occur in patients on TB drug tional neuromuscular blocking drugs of therapy will be due to the enzyme- any kind.2,4 The MIC is dedicated to providing inducing effect of rifampicin. unbiased, up-to-date and well- Quinolone antibacterials (second-line researched drug information, in con- Isoniazid is an enzyme inhibitor. tuberculosis agent) should generally sultation with a multidisciplinary health When unexpected effects are seen be avoided in patients with care team, to all health care profes- in patients taking many drugs, sus- as quinolone antibacterials very occa- sionals in . To ensure this, pect a drug interaction. sionally cause convulsions.2,4

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