Pharmacy Blog – Dr Vibore

Acute alcohol intake may possibly increase serum phenytoin levels,but moderate social drinking appears to have little clinical effect. However,chronic heavy drinking reduces serum phenytoinlevels so that above-average doses of phenytoin may be needed tomaintain adequate levels.

In a study designed to test effects of acute alcohol intoxication in epileptics, 25 patients were given a 12 oz (about 340 mL) drink of alcohol 25%. Blood-alcohol levels ranged from 39 to 284 mg%. All patients had signs of alcohol intoxication without any effect on seizure frequency (See reference number 1). The metabolism of a single dose of phenytoin was not affected in one study in healthy subjects by acute ingestion of alcohol (See reference number 2). However, manufacturers say that acute alcoholic intake may increase phenytoin serum levels (See reference number 3,4).

In a group of 15 drinkers (consuming a minimum of 200 g of ethanol daily for at least 3 months) phenytoin levels measured 24 hrs after last dose of phenytoin were approximately half those of 76 non-drinkers

Another study confirmed that alcoholics without liver disease have lower than usual plasma levels of phenytoin after taking standard doses while drinking (See reference number 6). Two reports describes a chronic alcoholic who was resistant to large doses of phenytoin,(See reference number 7) and seizures,which developed in a man when an increase in his alcohol consumption appeared to cause a reduction in his serum phenytoin levels (See reference number 8).

A study in non-drinking epileptics (17 in experimental group, 14 in control group) found that serum levels of phenytoin were unchanged by moderate drinking, and there was no influence on tonic-clonic convulsions or partial complex seizures. The experimental group drank 1 to 3 glasses of an alcoholic beverage (equivalent to a glass of beer containing

9.85 g of ethanol) over a 2-hour period,twice a week, for 16 weeks, and their maximum blood alcohol levels ranged from 5 to 33 mg% (See reference number 9).

Supported by animal data,(See reference number 10) evidence suggests that repeated exposure to large amounts of alcohol induces liver microsomal enzymes so that rate of metabolism and clearance of phenytoin is increased. Conversely,acute alcohol intake may decrease hepatic metabolism (See reference number 11).

An established and clinically important interaction, although documentation is limited. Heavy drinkers may need above-average doses of phenytoin to maintain adequate serum levels. However, be aware that patients with liver impairment usually need lower doses of phenytoin, so picture may be more complicated. Moderate drinking appears to be safe in those taking phenytoin (See reference number 1,9). Consider also Alcohol + Antiepileptics interaction.

Rodin EA,Frohman CE, Gottlieb JS. Effect of acute alcohol intoxication on epileptic patients. Arch Neurol (1961) 4, 115–18.

Schmidt D. Effect of ethanol intake on phenytoin metabolism in volunteers. Experientia (1975) 31,1313–14.

Epanutin Capsules (Phenytoin sodium). Pfizer Ltd. UK Summary of product characteristics,February 2007.

Dilantin Kapseals (Phenytoin sodium). Pfizer Inc. US Prescribing information,September2006.

Kater RMH,Roggin G, Tobon F, Zieve P, Iber FL. Increased rate of clearance of drugs fromthe circulation of alcoholics. Am J Med Sci (1969) 258, 35–9.

Sandor P,Sellers EM, Dumbrell M, Khouw V. Effect of short- and long-term alcohol use onphenytoin kinetics in chronic alcoholics. Clin Pharmacol Ther (1981) 30, 390–7.

Birkett DJ,Graham GG, Chinwah PM, Wade DN, Hickie JB. Multiple drug interactions withphenytoin. Med J Aust (1977) 2, 467–8.

Bellibas SE,Tuglular I. A case of phenytoin-alcohol interaction. Therapie (1995) 50, 487–8.

Höppener RJ,Kuyer A, van der Lugt PJM. Epilepsy and alcohol: the influence of social alcohol intake on seizures and treatment in epilepsy. Epilepsia (1983) 24, 459–71.

Rubin E,Lieber CS. Hepatic microsomal enzymes in man and rat: induction and inhibitionby ethanol. Science (1968) 162, 690–1.

Tanaka E. Toxicological interactions involving psychiatric drugs and alcohol: an update. J Clin Pharm Ther (2003) 28,81–95.

Some antihistamines cause drowsiness,which can be increased byalcohol. The detrimental effects of alcohol on driving skills areconsiderably increased by use of older more sedative antihistamines and appear to be minimal or absent with newernon-sedating antihistamines.

A double-blind study found that terfenadine 60 to 240mg alone did not affect psychomotor skills, nor did it affect adverse effects of alcohol (See reference number 1). Another study had similar findings (See reference number 2). However, a later study found that terfenadine 240mg slowed brake reaction times in laboratory when given either alone or with alcohol (See reference number 3). Acrivastine 4 and 8 mg,given with and without alcohol, was found in a study to behave like terfenadine (which interacts minimally or not at all) (See reference number 4). Other studies have shown that astemizole 10 to 30mg daily,(See reference number 5-7)desloratadine,(See reference number 8)ebastine 20 mg,(See reference number 9)fexofenadine 120 to 240 mg,(See reference number 10,11)levocabastine 2 nasal puffs of 0.5 mg/mL,(See reference number 12)loratadine 10 to 20 mg(See reference number 2,13) and mizolastine 10 mg(See reference number 14)do not interact with alcohol. Cetirizine 10mg did not appear to interact with alcohol in two studies(See reference number 14,15)but some slight additive effects were detected in other studies (See reference number 13,16). Similarly,a single oral dose of rupatadine 10 mg did not interact with alcohol, but a 20mg dose given with alcohol produced more cognitive and psycho-motor impairment than alcohol alone (See reference number 16).

The effects of alcohol (blood levels about 50 mg%) and antihistamines, alone or together, on performance of tests designed to assess mental and motor performance were examined in 16 subjects. Clemizole 40mg or tripelennamine 50mg alone did not significantly affect performance under stress of delayed auditory feedback, neither did they potentiate effect of alcohol (See reference number 17). Clemastine in 3mg doses had some additive detrimental effects with alcohol on co-ordination,whereas clemastine

1.5 mg and 1mg did not (See reference number 18,19). A study in 5 subjects showed that detrimental effects of 100 mL of whiskey on performance of driving tests on a racing car simulator (blood alcohol estimated as less than 80 mg% were not increased by cyclizine 50mg (See reference number 20). However 3 of subjects experienced drowsiness after cyclizine, and other studies have shown that cyclizine alone causes drowsiness in majority of subjects (See reference number 21). Significant impairment of psychomotor performance was seen in healthy subjects given chlorphenamine 12mg with alcohol 0.5 g/kg (See reference number 5). A further study similarly found significant impairment in driving skills when chlorphenamine was given with alcohol,see (c) below. In 13 healthy subjects alcohol

0.75 g/kg given with dexchlorpheniramine 4 mg/70 kg significantly impaired performance of a number of tests (standing steadiness, reaction time, manual dexterity, perception, etc.) (See reference number 22). A study in 17 subjects found that mebhydrolin 0.71 mg/kg enhanced alcohol-induced deficits in performance of a number of tests on perceptual, cognitive and motor functions (See reference number 23). No interaction was detected in one study of combined effects of pheniramine aminosalicylate 50mg or cyproheptadine hydrochloride 4mg and alcohol 0.95 mL/kg (See reference number 24). Triprolidine 10mg alone can significantly affect driving performance,(See reference number 2) and marked deterioration in driving skills has been demonstrated with 10 mL of Actifed Syrup (triprolidine with pseudoephedrine) alone and with a double whiskey (See reference number 25).

Diphenhydramine in doses of 25 or 50mg was shown to increase detrimental effects of alcohol on performance of choice reaction and coordination tests in subjects who had taken 0.5 g/kg of alcohol (See reference number 18). The interaction between diphenhydramine in doses of 50,75 or 100mg and alcohol in doses of 0.5 to 0.75 g/kg has been confirmed in other reports (See reference number 1,17,26-28). Emedastine in oral doses of 2 or 4mg twice daily was found to be sedating and impair driving ability in 19 healthy subjects. The addition of alcohol increased this impairment (See reference number 29). A marked interaction can also occur with hydroxyzine(See reference number 11,16) or promethazine (See reference number 30). A very marked deterioration in driving skills was clearly demonstrated in a test of car drivers given 20 mL of Beechams Night Nurse (promethazine with dextromethorphan),10 mL of Benylin (diphenhydramine with dextromethorphan), or 30 mL of Lemsip Night time flu medicine (chlorphenamine with dextromethorphan). Very poor scores were seen when they were also given a double Scotch whiskey about 1.5 hrs later (See reference number 25).

When an interaction occurs it appears to be due to combined or additive central nervous depressant effects of both alcohol and antihistamine. The highly-sedating antihistamines are highly lipophilic and readily cross blood-brain barrier; consequently they have considerable sedative effects that may persist into next day. The sedating antihistamines do not cross blood-brain barrier so readily, and are therefore less sedating. Most of non-sedating antihistamines, such as fexofenadine, do not appear to cross blood-brain barrier (See reference number 11). The authors of one study found that sedating effects of cetirizine and emedastine were more marked in women than in men, and they noted that they had also previously seen this with acrivastine, clemastine and mizolastine (See reference number 29). The reason for this is not established although it has been suggested that a smaller volume of distribution in women may result in higher plasma antihistamine levels.

An adverse interaction between alcohol and highly-sedating antihistamines (see table 1 below,) is well established and clinically important. Marked drowsiness can occur with these antihistamines taken alone,which makes driving or handling other potentially dangerous machinery much more hazardous. This can be further worsened by alcohol. Patients should be strongly warned. Remember that some of these antihistamines are present in non-prescription products licensed as antiemetics and sedatives,and as components of cough, cold and influenza remedies

(e.g. some preparations of Benylin,Lemsip or Night Nurse). Emedastine may also cause marked sedation when used orally,but it is usually given as eye drops.

The situation with some of sedating antihistamines is less clear cut, and tests with some of them failed to detect an interaction with normal doses and moderate amounts of alcohol; however, it has been clearly seen with Actifed Syrup (containing triprolidine). It would therefore be prudent to issue some cautionary warning, particularly if patient is likely to drive.

The non-sedating antihistamines seem to cause little or no drowsiness in most patients and risks if taken alone or with alcohol appear to be minimal or absent. However, incidence of sedation varies with non-sedating antihistamine (e.g. sedation appears to be lower with fexofenadine and loratadine than with acrivastine or cetirizine)(See reference number 31) and with individual (e.g. women may be more affected than men) (See reference number 29). Therefore, patients should be advised to be alert to possibility of drowsiness if they have not taken drug before. Any drowsiness would be apparent after first few doses. The patient information leaflets for acrivastine and cetirizine suggest avoidance of alcohol or excessive amounts of alcohol,(See reference number 32-34)

The possible interactions of alcohol with other antihistamines not cited here do not seem to have been formally studied,but increased drowsiness and increased driving risks would be expected with any that cause some sedation. Patients should be warned about drinking alcohol when taking sedative antihistamines. The risks with antihistamines given as eye drops or nasal spray (e.g. azelastine,epinastine) are probably minimal, but this needs confirmation.

Moser L,Hüther KJ, Koch-Weser J, Lundt PV. Effects of terfenadine and diphenhydraminealone or in combination with diazepam or alcohol on psychomotor performance and subjective feelings. Eur J Clin Pharmacol (1978) 14, 417–23.

O’Hanlon JF. Antihistamines and driving performance: The Netherlands. J Respir Dis (1988) (Suppl),S12–S17.

Bhatti JZ,Hindmarch I. The effects of terfenadine with and without alcohol on an aspect ofcar driving performance. Clin Exp Allergy (1989) 19, 609–11.

Cohen AF,Hamilton MJ, Peck AW. The effects of acrivastine (BW825C), diphenhydramineand terfenadine in combination with alcohol on human CNS performance. Eur J Clin Pharmacol (1987) 32, 279–88.

Hindmarch I,Bhatti JZ. Psychomotor effects of astemizole and chlorpheniramine, alone andin combination with alcohol. Int Clin Psychopharmacol (1987) 2, 117–19.

Bateman DN,Chapman PH, Rawlins MD. Lack of effect of astemizole on ethanol dynamicsor kinetics. Eur J Clin Pharmacol (1983) 25, 567–8.

Moser L,Plum H, Bückmann M. Interaktionen eines neuen Antihistaminikums mit Diazepamund Alkohol. Med Welt (1984) 35, 296–9.

Rikken G,Scharf M, Danzig M, Staudinger H. Desloratadine and alcohol coadministration:no increase in impairment of performance over that induced by alcohol alone. Poster at EAACI (European Academy of Allergy and Clinical Immunology) Conference, Lisbon, Portugal.2-4 July 2000.

Mattila MJ,Kuitunen T, Plétan Y. Lack of pharmacodynamic and pharmacokinetic interactions of the antihistamine ebastine with ethanol in healthy subjects. Eur J Clin Pharmacol (1992) 43, 179–84.

Vermeeren A,O’Hanlon JF. Fexofenadine’s effects, alone and with alcohol, on actual drivingand psychomotor performance. J Allergy Clin Immunol (1998) 101, 306–11.

Ridout F,Shamsi Z, Meadows R, Johnson S, Hindmarch I. A single-center, randomized, double-blind, placebo-controlled, crossover investigation of the effects of fexofenadine hydrochloride 180mg alone and with alcohol, with hydroxyzine hydrochloride 50mg as a positiveinternal control, on aspects of cognitive and psychomotor function related to driving a car.Clin Ther (2003) 25, 1518–38.

Nicholls A,Janssens M, James R. The effects of levocabastine and ethanol on psychomotorperformance in healthy volunteers. Allergy (1993) 48 (Suppl 16), 34.

Ramaekers JG,Uiterwijk MMC, O’Hanlon JF. Effects of loratadine and cetirizine on actualdriving and psychometric test performance, and EEG during driving. Eur J Clin Pharmacol (1992) 42, 363–9.

Patat A,Stubbs D, Dunmore C, Ulliac N, Sexton B, Zieleniuk I, Irving A, Jones W. Lack ofinteraction between two antihistamines, mizolastine and cetirizine, and ethanol in psychomotor and driving performance in healthy subjects. Eur J Clin Pharmacol (1995) 48, 143–50.

Doms M,Vanhulle G, Baelde Y, Coulie P, Dupont P, Rihoux J-P. Lack of potentiation bycetirizine of alcohol-induced psychomotor disturbances. Eur J Clin Pharmacol (1988) 34, 619–23.

Barbanoj MJ,García-Gea C, Antonijoan R, Izquierdo I, Donado E, Pérez I, Solans A, Jané F.Evaluation of the cognitive, psychomotor and pharmacokinetic profiles of rupatadine, hydroxyzine and cetirizine, in combination with alcohol, in healthy volunteers. Hum Psychopharmacol (2006) 21, 13–26.

Hughes FW,Forney RB. Comparative effect of three antihistaminics and ethanol on mentaland motor performance. Clin Pharmacol Ther (1964) 5, 414–21.

Linnoila M. Effects of antihistamines,chlormezanone and alcohol on psychomotor skills related to driving. Eur J Clin Pharmacol (1973) 5, 247–54.

Franks HM,Hensley VR, Hensley WJ, Starmer GA, Teo RKC. The interaction between ethanol and antihistamines. 2. Clemastine. Med J Aust (1979) 1, 185–6.

Hughes DTD,Cramer F, Knight GJ. Use of a racing car simulator for medical research. Theeffects of marzine and alcohol on driving performance. Med Sci Law (1967) 7, 200–4.

Brand JJ,Colquhoun WP, Gould AH, Perry WLM. (–)-Hyoscine and cyclizine as motionsickness remedies. Br J Pharmacol Chemother (1967) 30, 463–9.

Franks HM,Hensley VR, Hensley WJ, Starmer GA, Teo RKC. The interaction between ethanol and antihistamines. 1: Dexchlorpheniramine. Med J Aust (1978) 1, 449–52.

Franks HM,Lawrie M, Schabinsky VV, Starmer GA, Teo RKC. Interaction between ethanoland antihistamines. 3. mebhydrolin. Med J Aust (1981) 2, 477–9.

Landauer AA,Milner G. Antihistamines, alone and together with alcohol, in relation to driving safety. J Forensic Med (1971) 18, 127–39.

Carter N. Cold cures drug alert. Auto Express (1992) November Issue 218,15–16.

Baugh R,Calvert RT. The effect of diphenhydramine alone and in combination with ethanolon histamine skin response and mental performance. Eur J Clin Pharmacol (1977) 12, 201–4.

Burns M,Moskowitz H. Effects of diphenhydramine and alcohol on skills performance. Eur J Clin Pharmacol (1980) 17, 259–66.

Burns M. Alcohol and antihistamine in combination: effects on performance. Alcohol Clin Exp Res (1989) 13,341.

Vermeeren A,Ramaekers JG, O’Hanlon JF. Effects of emedastine and cetirizine, alone and with alcohol, on actual driving of males and females. J Psychopharmacol (2002) 16, 57–64.

Hedges A,Hills M, Maclay WP, Newman-Taylor AJ, Turner P. Some central and peripheraleffects of meclastine, a new antihistaminic drug, in man. J Clin Pharmacol (1971) 11, 112–

19.

Mann RD,Pearce GL, Dunn N, Shakir S. Sedation with “non-sedating” antihistamines: fourprescription-event monitoring studies in general practice. BMJ (2000) 320, 1184–6.

Semprex (Acrivastine). Glaxo Wellcome. UK Patient information leaflet,February 2002.

Cetirizine. Actavis UK Ltd. UK Patient information leaflet,January 2004.

Zirtek Allergy (Cetirizine). UCB Pharma Ltd. UK Patient information leaflet,December2005.

Xyzal (Levocetirizine). UCB Pharma Ltd. Patient information leaflet,February 2006.

Table 1 Systemic antihistamines (classified by sedative potential) and topical antihistamines
Sedative potential	Antihistamine
Non-sedative	Acrivastine, Astemizole,* Cetirizine, Desloratadine, Ebastine,* Fexofenadine, Levocetirizine, Loratadine, Mizolastine,* Rupatadine, Terfenadine*
Sedating	Azatadine, Brompheniramine, Buclizine, Chlorphenamine, Cinnarizine, Clemastine, Cyclizine, Cyproheptadine, Dexchlorpheniramine, Flunarizine, Meclozine, Mepyramine, Mequitazine, Pheniramine, Tripelennamine, Triprolidine
Significantly sedating	Alimemazine, Bromazine, Carbinoxamine, Dimenhydrinate, Diphenhydramine, Doxylamine, Hydroxyzine, Promethazine, Trimeprazine
Topical use (mainly)	Antazoline, Azelastine, Emedastine, Epinastine, Levocabastine, Olopatadine

For social and historical reasons alcohol is usually bought from a store or in a bar or restaurant,rather than from a pharmacy, because it is considered to be a drink and not a drug. However, pharmacologically it has much in common with medicinal drugs that depress central nervous system. Objective tests show that as blood-alcohol levels rise, ability to perform a number of skills gradually deteriorates as brain becomes progressively disorganised. The myth that alcohol is a stimulant has arisen because at parties and social occasions it helps people to lose some of their inhibitions and it allows them to relax and unwind. Professor JH Gaddum put it amusingly and succinctly when, describing early effects of moderate amounts of alcohol, he wrote that “logical thought is difficult but after dinner speeches easy.” The expansiveness and loquaciousness that are socially acceptable can lead on,with increasing amounts of alcohol, to unrestrained behaviour in normally well-controlled individuals, through to drunkenness, unconsciousness, and finally death from respiratory failure. These effects are all a reflection of progressive and deepening depression of CNS.

table 1 below, gives an indication in very broad terms of reactions of men and women to different amounts and concentrations of alcohol.

On whole women have a higher proportion of fat in which alcohol is not very soluble, their body fluids represent a smaller proportion of their total body mass, and their first-pass metabolism of alcohol is less than men because they have less alcohol dehydrogenase in their stomach walls. Consequently if a man and woman of same weight matched each other, drink for drink, woman would finish up with a blood alcohol level about 50 % higher than man. The values shown assume that drinkers regularly drink, have had a meal and weigh between 9 and 11 stones (55 to 70 kg). Higher blood-alcohol levels would occur if alcohol was drunk on an empty stomach and lower values in much heavier individuals. The liver metabolises about one unit per hour so values will fall with time.

Since alcohol impairs skills needed to drive safely, almost all national and state authorities have imposed maximum legal blood alcohol limits (see table 2 below,). In a number of countries this has been set at 80 mg/100 mL (35 micrograms per 100 mL in breath) but impairment is clearly detectable at lower concentrations, for which reason some countries have imposed much lower legal limits.

Alcohol can interact with many drugs both by pharmacokinetic and/or pharmacodynamic mechanisms. The quantity and frequency of alcohol consumption can affect bioavailability of alcohol and other drugs. Several hepatic enzymes are important in metabolism of alcohol; primarily alcohol dehydrogenases convert alcohol into acetaldehyde, but other enzymes, in particular cytochrome P450 isoenzyme CYP2E1, are also involved, especially in moderate to heavy alcohol consumption. Enzyme induction of CYP2E1 (and possibly other isoenzymes) occurs after prolonged heavy alcohol intake,and this can result in an increased metabolic rate and lower blood levels of drugs metabolised via this system. Conversely, short term binge drinking is likely to cause inhibition of this enzyme group by direct competition for binding sites and therefore decrease metabolism of other drugs.

Probably most common drug interaction of all occurs if alcohol is drunk by those taking other drugs that have CNS depressant activity, result being even further CNS depression. Blood-alcohol levels well within legal driving limit may, in presence of other CNS depressants, be equivalent to blood-alcohol levels at or above legal limit in terms of worsened driving and other skills. This can occur with some antihistamines,antidepressants, anxiolytics, hypnotics, opioid analgesics, and others. This section contains a number of monographs that describe results of formal studies of alcohol combined with a number of recognised CNS depressants, but there are still many other drugs that await study of this kind, and which undoubtedly represent a real hazard.

A less common interaction that can occur between alcohol and some drugs, chemical agents, and fungi, is flushing (Antabuse) reaction. This is exploited in case of disulfiram (Antabuse) as a drink deterrent (see Alcohol + Disulfiram interaction), but it can occur unexpectedly with some other drugs, such as some antifungals and cephalosporins, chlorpropamide and metronidazole, and can be both unpleasant and possibly frightening, but it is not usually dangerous.

After Which? October 1984,page 447 and others.

Belize,Canada,* Cape Verde, Central African Republic, Ghana, Guatemala, Ireland, Kenya, Luxembourg, Malaysia, Malta, Mexico, New Zealand,* Nicaragua, Niger, Paraguay, Seychelles, Singapore, Suriname, Switzerland, Uganda, United Kingdom, United States of America,* Uruguay, Zambia

Bolivia,Ecuador, Honduras

Brazil,Sri Lanka

Argentina,Australia,* Austria, Belarus, Benin, Bosnia & Herzegovina, Bulgaria, Cambodia, Croatia, Denmark, El Salvador, Finland, France, French Polynesia, Germany, Greece, Guinea-Bissau, Iceland, Israel, Italy, Kyrgyzstan, Mauritius, Micronesia (Federated States of), Namibia, Netherlands, Peru, Philippines, Portugal, Slovenia, South Africa, Spain, Thailand, The former Yugoslav Republic of Macedonia, Turkey, United Republic of Tanzania, Venezuela

Chile,Costa Rica, Latvia

Georgia,India, Japan, Republic of Moldova

Estonia,Mongolia, Norway, Poland, Sweden

Guyana,Palau

Armenia,Azerbaijan, Colombia, Czech Republic, Equatorial Guinea, Eritrea, Gambia, Guinea, Hungary, Islamic Republic of Iran, Jordan, Kazakhstan, Malawi, Nepal, Nigeria, Panama, Romania, Russian Federation, Slovakia

China,Comoros, Congo (Brazzaville), Dominican Republic, Ethiopia, Lao People’s Democratic Republic, Togo, Ukraine

Note: For easy comparison legally allowable blood alcohol limits have all been expressed as mg%

(See reference number *)Variations occur within these countries e.g. in Australia no alcohol is allowed for drivers of heavy,dangerous goods, public transport vehicles; learners and drivers under 25

Adapted from WHO Global Status Report: Alcohol policy, Geneva, 2004.

Table 2 Maximum legally allowable blood alcohol limits when driving in various countries
80 mg%	Belize, Canada,* Cape Verde, Central African Republic, Ghana, Guatemala, Ireland, Kenya, Luxembourg, Malaysia, Malta, Mexico, New Zealand,* Nicaragua, Niger, Paraguay, Seychelles, Singapore, Suriname, Switzerland, Uganda, United Kingdom, United States of America,* Uruguay, Zambia
70 mg%	Bolivia, Ecuador, Honduras
60 mg%	Brazil, Sri Lanka
52 mg%	Republic of Korea
50 mg%	Argentina, Australia,* Austria, Belarus, Benin, Bosnia & Herzegovina, Bulgaria, Cambodia, Croatia, Denmark, El Salvador, Finland, France, French Polynesia, Germany, Greece, Guinea-Bissau, Iceland, Israel, Italy, Kyrgyzstan, Mauritius, Micronesia (Federated States of), Namibia, Netherlands, Peru, Philippines, Portugal, Slovenia, South Africa, Spain, Thailand, The former Yugoslav Republic of Macedonia, Turkey, United Republic of Tanzania, Venezuela
49 mg%	Chile, Costa Rica, Latvia
40 mg%	Lithuania
35 mg%	Jamaica
33 mg%	Turkmenistan
30 mg%	Georgia, India, Japan, Republic of Moldova
20 mg%	Estonia, Mongolia, Norway, Poland, Sweden
10 mg%	Guyana, Palau
0 mg%	Armenia, Azerbaijan, Colombia, Czech Republic, Equatorial Guinea, Eritrea, Gambia, Guinea, Hungary, Islamic Republic of Iran, Jordan, Kazakhstan, Malawi, Nepal, Nigeria, Panama, Romania, Russian Federation, Slovakia
No legislation	China, Comoros, Congo (Brazzaville), Dominican Republic, Ethiopia, Lao People’s Democratic Republic, Togo, Ukraine

An isolated report describes a rise in blood pressure in one hypertensive patient,which was attributed to an interaction between enalapril and rifampicin. Rifampicin may reduce theplasma levels of active metabolites of imidapril and spirapril.

A man taking enalapril and a variety of other drugs (warfarin,acebutolol, bendroflumethiazide, dipyridamole, metoclopramide and Gaviscon) developed a fever. He was given streptomycin, oxytetracycline and rifampicin, because of a probable Brucella abortus infection, whereupon his blood pressure rose from 164/104 to 180/115 mmHg over next 5 to 6 days. It was suspected that an interaction with rifampicin was possibly responsible. Subsequent studies in same patient showed that rifampicin, reduced AUC0-7 of enalaprilat, active metabolite of enalapril, by 31%, although AUC of enalapril was unchanged (See reference number 1). There is also hint of this interaction in another report, where enalapril failed to control blood pressure in a patient taking rifampicin (See reference number 2).

The manufacturer of spirapril briefly noted in a review that use of rifampicin with spirapril modestly decreased plasma levels of spirapril

and its active metabolite,spiraprilat (See reference number 3). The manufacturer of imidapril notes that rifampicin reduced plasma levels of imidaprilat, active metabolite of imidapril (See reference number 4).

The mechanism of this interaction is not clear, because rifampicin is a potent liver enzyme inducer, which might have been expected to cause production of more, rather than less, of active metabolites of these ACE inhibitors. However, authors of one of reports postulated that rifampicin might have increased loss of enalaprilat in urine,(See reference number 1) and others suggested that rifampicin stimulates elimination of spiraprilat non-specifically (See reference number 3).

The general importance of these interactions is uncertain. The isolated reports with enalapril suggest minor clinical relevance. The manufacturers of spirapril did not consider modest pharmacokinetic changes to be clinically relevant (See reference number 3). However, manufacturers of imidapril state that rifampicin might reduce antihypertensive efficacy of imidapril,(See reference number 4) but this awaits clinical assessment.

Kandiah D,Penny WJ, Fraser AG, Lewis MJ. A possible drug interaction between rifampicinand enalapril. Eur J Clin Pharmacol (1988) 35, 431–2.

Tada Y,Tsuda Y, Otsuka T, Nagasawa K, Kimura H, Kusaba T, Sakata T. Case report: nifedipine-rifampicin interaction attenuates the effect on blood pressure in a patient with essentialhypertension. Am J Med Sci (1992) 303, 25–7.

Grass P,Gerbeau C, Kutz K. Spirapril: pharmacokinetic properties and drug interactions.Blood Pressure (1994) 3 (Suppl 2), 7–13.

Tanatril (Imidapril). Trinity Pharmaceuticals Ltd. UK Summary of product characteristics,May 2003.

Clinical evidence,mechanism, importance and management

Twenty-six patients with ovarian or small-cell undifferentiated cancers were treated with chemotherapy followed by recombinant human interleukin-3. Three of 26 were taking ACE inhibitors (not named) and all three developed marked hypotension (WHO toxicity grade 2 or 3) within 1 to 4 hrs of first interleukin-3 injection. Their blood pressures returned to normal while continuing interleukin-3 when ACE inhibitors were stopped. When interleukin-3 was stopped, they once again needed ACE inhibitors to control their blood pressure. None of other 23 patients had hypotension, except one who did so during a period of neutropenic fever (See reference number 1). The authors of report suggest (and present some supporting evidence) that drugs act synergistically to generate large amounts of nitric oxide in blood vessel walls. This relaxes smooth muscle in blood vessel walls causing vasodilatation and consequent hypotension (See reference number 1). Information seems to be limited to this single report,but it would be prudent to monitor blood pressure even more closely in patients receiving interleukin-3 while taking ACE inhibitors.

1. Dercksen MW,Hoekman K, Visser JJ, ten Bokkel Huinink WW, Pinedo HM, Wagstaff J. Hypotension induced by interleukin-3 in patients on angiotensin-converting enzyme inhibitors.Lancet (1995) 345, 448.

Potentiation of antihypertensive effect of clonidine by ACE inhibitors can be clinically useful.(See reference number 1) However, limited evidence suggests that effects of captopril may be delayed when patientsare switched from clonidine.(See reference number 2) Note that sudden withdrawal of clonidine may cause rebound hypertension.

Catapres Tablets (Clonidine hydrochloride). Boehringer Ingelheim Ltd. UK Summary of product characteristics,May 2006.

Gröne H-J,Kirchertz EJ, Rieger J. Mögliche Komplikationen und Probleme der Captopriltherapie bei Hypertonikern mit ausgeprägten Gefäßschäden. Therapiewoche (1981) 31, 5280–7.

ACE inhibitors (angiotensin-converting enzyme inhibitors) prevent production of angiotensin II from angiotensin I. The angiotensin II receptor antagonists are more selective, and target angiotensin II type I (AT1) receptor, which is responsible for pressor actions of angiotensin

Angiotensin II is involved in renin-angiotensin-aldosterone system, which regulates blood pressure, sodium and water homoeostasis by kidneys, and cardiovascular function. Angiotensin II stimulates synthesis and secretion of aldosterone and raises blood pressure via a direct vasoconstrictor effect.

Angiotensin converting enzyme (ACE) is identical to bradykinase, so ACE inhibitors may additionally reduce degradation of bradykinin and affect enzymes involved in production of prostaglandins.

Many of interactions of ACE inhibitors and angiotensin II receptor antagonists involve drugs that affect blood pressure. Consequently in most cases result is either an increase in hypotensive effect (e.g. alcohol, ) or a decrease in hypotensive effect (e.g. indometacin,).

In addition, due to their effects on aldosterone, ACE inhibitors and angiotensin II antagonists may increase potassium concentrations and can therefore have additive hyperkalaemic effects with other drugs that cause elevated potassium levels. Furthermore, drugs that affect renal function may potentiate adverse effects of ACE inhibitors and angiotensin II antagonists on kidneys.

Most ACE inhibitor and angiotensin II receptor antagonist interactions are pharmacodynamic, that is, interactions that result in an alteration in drug effects rather than drug disposition, so in most cases interactions of individual drugs will be applicable to group. In vitro experiments suggest that role of cytochrome P450 isoenzymes in metabolism and interactions of angiotensin II receptor antagonists (candesartan, eprosartan, irbesartan, losartan and valsartan) is small, although losartan, irbesartan, and to a minor extent, candesartan, are metabolised by CYP2C9. Only losartan and irbesartan were considered to have a theoretical potential for pharmacokinetic drug interactions involving CYP2C9 enzyme.(See reference number 1)See Angiotensin II receptor antagonists + Azoles interaction. The ACE inhibitors do not appear to undergo interactions via cytochrome P450 isoenzymes.

table 1 below, (see below) lists ACE inhibitors and angiotensin II receptor antagonists. Although most of interactions of ACE inhibitors or angiotensin II receptor antagonists are covered in this section, if ACE inhibitor or angiotensin II receptor antagonist is affecting drug, interaction is dealt with elsewhere.

1. Taavitsainen P,Kiukaanniemi K, Pelkonen O. In vitro inhibition screening of human hepaticP450 enzymes by five angiotensin-II receptor antagonists. Eur J Clin Pharmacol (2000) 56, 135–40.

Benazepril,Captopril, Cilazapril, Delapril, Enalapril, Fosinopril, Imidapril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, Spirapril, Temocapril, Trandolapril, Zofenopril

Candesartan,Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan

Table 1 ACE inhibitors and Angiotensin II receptor antagonists
Group	Drugs
ACE inhibitors	Benazepril, Captopril, Cilazapril, Delapril, Enalapril, Fosinopril, Imidapril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, Spirapril, Temocapril, Trandolapril, Zofenopril
Angiotensin II receptor antagonists	Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan

Nine out of 11 kidney transplant patients taking ACE inhibitors (enalapril or captopril) had a fall in their haematocrit from 34 % to 27%,and a fall in their haemoglobin from 11.6 g/dL to 9.5 g/dL when ciclosporin was replaced by azathioprine. Two patients were switched back to ciclosporin,and had a prompt rise in their haematocrit. Another 10 patients taking both drugs similarly developed a degree of anaemia,when compared with 10 others not taking an ACE inhibitor (haematocrit of 33 % compared with 41%, and a haemoglobin of 11.5 g/dL compared with 13.9 g/dL) (See reference number 1). A later study by same group of workers (again in patients taking enalapril or captopril) confirmed these findings: however, no pharmacokinetic interaction was found between enalapril and azathioprine (See reference number 2).

A patient whose white cell count fell sharply when taking both captopril 50 mg daily and azathioprine 150mg daily,did not develop leucopenia when each drug was given separately (See reference number 3). Another patient who was given captopril (increased to 475mg daily [sic] then reduced to 100mg daily) immediately after discontinuing azathioprine,developed leucopenia. She was later successfully treated with captopril 4 to 6mg daily [sic] (See reference number 4). Other patients have similarly shown leucopenia when given both drugs;(See reference number 5,6) in one case this did not recur when patient was rechallenged with captopril alone (at a lower dose) (See reference number 6).

The anaemia appears to be due to suppression of erythropoietin by ACE inhibitors, and azathioprine may cause patients to be more susceptible to this effect (See reference number 2). The cause of leucopenia is unknown. It may just be due to additive effects of both drugs.

Anaemia caused by captopril and enalapril has been seen in kidney transplant patients and in dialysis patients (see ACE inhibitors and Angiotensin II receptor antagonists + Epoetin interaction). The evidence that this effect can be potentiated by azathioprine is limited,but it would be prudent to monitor well if these drugs are used together.

The evidence that concurrent use of ACE inhibitors and azathioprine increases risk of leucopenia is also limited. However, UK manufacturer of captopril recommends that captopril should be used with extreme caution in patients receiving immunosuppressants, especially if there is renal impairment. They advise that in such patients differential white blood cell counts should be performed before starting captopril, then every 2 weeks in first 3 months of treatment, and periodically thereafter (See reference number 7). The UK manufacturers of a number of other ACE inhibitors also state in their prescribing information that use of ACE inhibitors with cytostatic or immunosuppressive drugs may lead to an increased risk of leucopenia. For other potential interactions with ACE inhibitors that might lead to an increased risk of leucopenia,see also ACE inhibitors + Allopurinol interaction, and ACE inhibitors + Procainamide.

Gossmann J,Kachel H-G, Schoeppe W, Scheuermann E-H. Anemia in renal transplant recipients caused by concomitant therapy with azathioprine and angiotensin-converting enzyme inhibitors. Transplantation (1993) 56, 585–9.

Gossmann J,Thürmann P, Bachmann T, Weller S, Kachel H-G, Schoeppe W, ScheuermannE-H. Mechanism of angiotensin converting enzyme inhibitor-related anemia in renal transplantrecipients. Kidney Int (1996) 50, 973–8.

Kirchertz EJ,Gröne HJ, Rieger J, Hölscher M, Scheler F. Successful low dose captopril rechallenge following drug-induced leucopenia. Lancet (1981) i, 1363.

Case DB,Whitman HH, Laragh JH, Spiera H. Successful low dose captopril rechallenge following drug-induced leucopenia. Lancet (1981) i, 1362–3.

Elijovisch F,Krakoff LR. Captopril associated granulocytopenia in hypertension after renaltransplantation. Lancet (1980), i, 927–8.

Edwards CRW,Drury P, Penketh A, Damluji SA. Successful reintroduction of captopril following neutropenia. Lancet (1981) i, 723.

Capoten (Captopril). E. R. Squibb & Sons Ltd. UK Summary of product characteristics,June2005.