INTERACTIONS BETWEEN ANTIHYPERTENSIVE …

1 IntroductionThe vast majority of hypertensive patients is treatedwith ANTIHYPERTENSIVE drugs for many years. Othertherapeutic agents are frequently used simultaneously,thus giving rise to the possibility of drug-drug interac-tions. The potential for drug-drug INTERACTIONS increas-es with rising age, since elderly patients receive largernumber of drugs, but also because the renal excretionof several therapeutic agents is impaired in the elderly,as a result of diminishing kidney function (1, 2). Theinteractions BETWEEN ANTIHYPERTENSIVE drugs and othertherapeutic agents will be discussed and summarizedin the present issue, after a brief general explanationof the various mechanisms underlying drug-drug inter-actions. The combination and mutual interactionsbetween various categories of ANTIHYPERTENSIVE agentswill be dealt with by us in a separate issue of thisnewsletter. MechanismsThere are several mechanisms by which drugs mayinteract (3-5), and most of these mechanisms can becategorized as pharmacokinetic (involving intestinalabsorption, distribution, metabolism, and elimination)or as pharmacodynamic, or as additive toxicity, INTERACTIONS : the interaction in intes-tinal absorptionis best illustrated by an example: tetra-cylines and other broad-spectrum antibiotics mayimpair the absorption of oral contraceptives (in particu-lar those with low-dose progestogens and/or estro-gens) and hence render contraception unsafe.

2 Severaldrugs are subject to inactivation via metabolic degra-dationit the liver, catalysed by various liver formation of these enzymes can be induced orenhanced by drugs such as rifampicine, griseofulvine,and several anti-epileptics (carbamazepin, phenytoine,phenobarbital), but also by regular alcohol consump-tion. This process, which requires several weeks oftreatment and which is indicated as enzyme induction,enhances the metabolic degradation of several practice, enzyme induction may play a relevant rolefor oral anticoagulants (coumarin type), corticosteroids(glucocorticoids), oral contraceptives, or , these categories of drugs are metabo-lized/inactivated more rapidly and their doses shouldtherefore be increased. A comparable but oppositeproblem is the inhibition of liver enzymesinvolved inthe biotransformation by a variety of drugs, such ascimetidine, erythromycin, metronidazole, tricyclic anti-depressants, phenothiazine-neuroleptics, andsulphonamides (also in co-trimoxazole).

3 Enzymeinhibitors of this type impair the biodegradation of cer-tain drugs and hence increase their effects. A well-known problem is the enhanced effect of anticoagu-lants (as reflected by bleeding) induced by additionaltreatment with co-trimoxazole. Certain drugs mayimpair the renal excretion(3-5) of other agents, usuallyat the renal tubular level. A well-known relevantexample is the rise in the plasma level and toxicity ofdigoxin, provoked by verapamil, amiodarone, or quini-dine. Similarly, thiazide diuretics may decelerate therenal elimination of lithium salts and hence reinforcetheir toxicity. A beneficial effect of such an interactionis the impaired excretion of penicillin antibioticsinduced by simultaneously administered INTERACTIONS and additive toxicity(3-5: Pharmacodynamic INTERACTIONS BETWEEN similarlyacting drugs may lead to additive or even over-additiveeffects (potentiation). A well-known example is thecombination of verapamil and a -blocker, whichmay cause additive impairment of cardiac A-V conduc-tion and the risk of A-V block.)

4 Another possibility is theinhibition of the therapeutic effect of a drug by an addi-tional agent. Over-additive adverse reactions are illus-trated by the following example: a most importantinteraction, probably caused by non-specific mecha-nisms, is the mutual enhancement of the central nerv-ous depressant effects of all drugs that are known todampen the activity of the central nervous interaction holds for hypnotics, anxiolytics (minortranquillizers), antipsychotics (neuroleptics, major tran-quillizers), anti-epileptics, and opioids, but also fordrugs with central nervous depressant adverse reac-tions, such as antihistamines, centrally acting antitus-sives (codeine, etc.), and scopolamine (3-5, 9).Furthermore, alcohol enhances the central nervousdepressant effects of all of the aforementioned thera-peutics. Accordingly, enhanced sedation, impairedpsychomotor skills (driving), but also respiratorydepression may agents and other drugsThe most relevant INTERACTIONS BETWEEN antihyperten-sive and other drugs have been listed in the Table 1,and the effect of these INTERACTIONS on blood pressurein the Table few comments may be made: it goeswithout saying that a combination of two or more anti-hypertensive agents may be expected to cause anadditive blood-pressure lowering effect, to be dis-2003; 4: No.

5 17 INTERACTIONS BETWEEN ANTIHYPERTENSIVE AGENTS AND OTHER DRUGSP eter A. van Zwieten, Departments of Pharmacotherapy, Cardiology and Cardio-Thoracic Surgery, AcademicMedical Centre, The Netherlands, and Csaba Farsang, 1st Department of Internal Medicine, St. Imre Hospital,Budapest, HungaryNewsletter 10:47 Page 1cussed in more detail in a forthcoming issue of thisnewsletter. Central nervous depressant effects of alldrugs suppressing the activity of the central nervoussystem enhance the side effects of centrally actingantihypertensives (reserpine, alpha-methyldopa, guan-facine, clonidine) (3-5, 9). More recently, a great dealof attention has been paid to the interaction betweenantihypertensive drugs and NSAID's. Example:indomethacin and other nonsteroidal antiinflammatorydrugs (NSAID's) may counteract the antihypertensiveeffects of thiazide diuretics, -blockers, ACE-inhibitorsand AT1-receptor antagonists, as a result of sodiumand fluid retention as well as of decreased formationof vasodilatory prostaglandins (6,7).

6 It has been clearlydemonstrated, however, that low-dose acetylsalicylicacid (ASA; Aspirin , 75 mg daily) does not interferewith the ANTIHYPERTENSIVE activity of ACE-inhibitors andother types of ANTIHYPERTENSIVE drugs (8).References1. Popplewell PY, Henschke PJ. Acute admissions to a geriatric assessmentunit. Med J Aust 1982; 1: 343 - Williamson J, Chopin JM. Adverse reactions to prescribed drugs in the elderly: a multicenter investigation. Age Ageing 1980; 9: 73 - Hansten PhD. Important drug INTERACTIONS . In: Katzung BG (Ed). Basic andclinical pharmacology. Prentice-Hall Int, Englewood Cliffs NJ, USA, 5th Ed,1992; pp 931 - Stockley IH. Drug INTERACTIONS . Pharmaceutical Press, London, 5th Ed, Opie LH. Cardiovasscular drug INTERACTIONS . In: Messerli FH (Ed).Cardiovascular drug therapy. Saunders Company, Philadelphia, USA, 2nd Ed, 1996; pp 347 - Fogari R, Zoppi A, Carretta R, Veglio F, Salvetti A. Effect of indomethacin onthe ANTIHYPERTENSIVE efficacy of valsartan and lisinopril: a multicentre study.

7 J Hypertens 2002; 20: 1007 - Beilin LJ, Non-steroidal anti-inflammatory drugs and ANTIHYPERTENSIVE drugtherapy. J. Hypertens 2002; 20: 849 - Zanchetti A, Hansson L, Leonetti G, Rahn KH, Ruilope L, Warnolt I, WedelH. Low-dose aspirin does not interfere with the blood pressure-loweringeffects of ANTIHYPERTENSIVE therapy. J Hypertens 2002; 1015 - Van Zwieten PA, Eijsman L. Drug therapy in cardio-thoracic surgery. VanZuiden Communications, Alphen a/d Rijn, The Netherlands, 2nd Ed, 2001;pp 262 - 1. INTERACTIONS BETWEEN ANTIHYPERTENSIVE and other drugsDrugs (class)Interaction withMechanismEffect -Blockersverapamil diltiazemAdditive effectsA-V conduction impaired; risk of A-V blockoral antidiabetics 2-receptor blockadesymptoms of hypoglycaemia are suppressedbroncho-spasmolytic agents 2-receptor blockadesuppression of the bronchospasmolytic effectdobutamine 1-receptor antagonismthe inotropic action of dobutamine is inhibitedThiazid diureticsdigoxinHypokalaemiadigoxin becomes more toxic (arrhythmogenic)lithium ionsrenal excretion of lithium ions impairedaccumulation of lithium ions -Blockersnoradrenaline 1-receptor blockadenoradrenaline shows less vasoconstrictor activityCalcium antagonistsVerapamil, diltiazem -Blockeradditive effectA-V conduction impaired; risk of A-V blockdigoxinrenal excretion of digoxindigoxin may accumulate.

8 Arrhythmogenic effectprotease inhibitors (HIV-treatment)inhibition of hepatic degradationaccumulation of verapamil or -blocker -receptor blockadesuppression of reflex tachycardia (favourable)FelodipineGrapefruit JuiceEnzymic inhibition ( system) accumulation of felodipine ACE-inhibitorsdiuretics (thiazide)additive effectstrong hypotensive actionDiuretics (K+-sparing)reduced renal excretion of K+hyperkalemia NSAID -s including highdose ASAretention of Na+and H2 Oreduced ANTIHYPERTENSIVE effectslithium ionsReduced excretion of lithium ionslithium ions accumulateAT1-receptor antagonistsvirtually the same as ACE-inhibitors INTERACTIONS as ACEi-s (see above)described beforeCentrally acting antihypertensives -methyl-DOPAFe2+-ionsenteral absorption of -methyl-DOPA reduced ANTIHYPERTENSIVE action clonidine tricyclic antidepressantsantagonism of central 2-adrenoceptorsIbid. -blockersunknownthe clonidine rebound phenomenon is more frequentboth clonidine and -methyl-DOPA centrally acting depressant agents additive effect, non-specificsedation,fatigue(hypnotics, tranquillizers, neuroleptics, anti-epileptics, some anti-depressants, H1-anti-histaminic agents, alcohol)Table 2.

9 Effect of drug INTERACTIONS on blood pressureDrugsMechanism of actionIncrease in BPInterferes with antihy-pertensive effect SympathomimeticsNasal decongestants ( -rec.)YESNOE rgot alkaloidsAntimigraine drugs (5HT) Bronchodilators ( 2rec.)YESNONSAIDsSodium retention Inhibition of vasodil. PGsYESYESOral contraceptivesEstrogens and progesteroneYESNOC orticosteroidsSodium retentionYESYESP sychotropesChlorpromazine, Tricyclics, MAO-inhibitors in blood viscosityYESNOC yclosporineHypothetical (via NO)YESNOR esinInhibition of GI Absorption of anti-HT drugsYESYESA nabolic steroidsSodium retentionYESNON ewsletter 10:47 Page 2