Br Heart J 1985; 54: 448-51

Management of a case of refractory variant anginawith benzhexol hydrochloride (trihexyphenidylhydrochloride)M JOY, G A HAYWOOD, M M WEBB-PEPLOE

From St Peter's Hospital, Chertsey, Surrey; and St Thomas's Hospital, London

SUMMARY A patient with severe variant angina that was refractory to conventional treatmentbecame symptom free when she was treated with benzhexol (trihexyphenidyl hydrochloride), a

cholinergic blocking agent used in the management of Parkinson's disease. There was a briefpsychotic reaction when a large dose was taken and some memory impairment on the maintenancedose. Benzhexol should be used with caution but may prove io be an additional therapeutic agentin the management of severe variant angina.

The syndrome of variant angina, first described byPrinzmetal et al in 1959,1 is characterised by sponta-neous angina pectoris associated with transient STsegment elevation in the electrocardiogram. Typi-cally episodes occur at the same time each day andare often associated with conduction disturbances.There are periods of spontaneous remission. Prinz-metal's hypothesis that the underlying mechanismwas coronary artery spasm resulting in transmuralischaemia has now received angiographic support.2It has also become evident that coronary arteryspasm is more widely involved in the pathogenesis ofangina pectoris34 than was formerly believed. Treat-ment with nitrates and calcium antagonists is usuallyeffective but some patients are refractory to treat-ment or unable to tolerate these drugs; alternativessuch as alpha, blocking agents have recently beenevaluated.5 Our patient had severe variant anginawhich was refractory to conventional treatment andproceeded to myocardial infarction.

Case report

This Lebanese woman aged 37 presented in 1982with a three month history of central chest pain radi-ating to the arms and neck which regularly woke herin the early morning and lasted for about 30 minutes.Subsequently the episodes increased in frequencyand occurred at rest up to three times in 24 hours andhad a repetitive diurnal pattern. The past medicalhistory included mild hypertension, anxiety, and

Requests for reprints to Dr M Joy, St Peter's Hospital, GuildfordRoad, Chertsey, Surrey KT16 OPZ.

palpitation treated with beta blocking agents, andRaynaud's phenomenon. The patient's mother andbrother had died aged 52 years and 51 yearsrespectively of myocardial infarction. She smokedoccasionally and consumed up to five measures ofspirits per day. She denied self medication, inparticular with ergot alkaloids.At initial examination she had a heart rate of 90

beats per minute in sinus rhythm and a blood pres-sure of 200/100 mm Hg. An apical fourth heartsound and multiple mid-systolic clicks were alsonoted. The electrocardiogram showed incompleteright bundle branch block and counterclockwiserotation of the heart about its longitudinal axis. Aradiograph of the chest was unremarkable apart fromsome old right basal lung scarring. M mode echo-cardiography showed no abnormality and Holtermonitoring showed asymptomatic periods ofT waveinversion associated with sinus tachycardia. Tread-mill exercise electrocardiography was terminated byfaintness at five minutes of the Bruce protocol. Non-specific repolarisation changes only were seen. Rou-tine haematology and biochemical assessmentshowed no abnormality. The atenolol that she hadbeen receiving was replaced by nifedepine which at> 30 mg/day seemed to worsen symptoms whereas 5mg three times a day was beneficial. Beta blockingagents with both high and low intrinsic sym-pathomimetic activity were not beneficial. Nitratesadministered sublingually or as a spray consistentlyaborted the attacks of angina but neither dinitratesnor mononitrates could be tolerated because theyproduced headache, and topical nitrates causedrashes.

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Management of a case of refractory variant angina wit,In August 1982, six months after presentation the

patient was admitted to hospital after a prolongedepisode of pain. Serum aspartate transaminase andlactate dehydrogenase -concentrations were slightlyincreased but technetium-99m pyrophosphatescanning did not show evidence of a myocardialinfarction. Subsequent coronary angiographyshowed only a 40% stenosis. of the right coronaryartery at the catheter tip, which persisted despitesublingual glyceryl trinitrate, and 30% stenosis ofthe coronary artery at the origin of the right ven&ric-ular branch. There was also a 30% stenosis at theorigin of the left anterior descending coronaryartery. Despite modification of treatment, includinga trial of verapamil, the symptoms became worse andangina on exercise developed- and resulted in -furtherhospital admissions (in April 1983 and July 1983).During the admission in July acute anterior myo-cardial infarction was diagnosed on the basis of elec-trocardiography (Fig. 1) and a concomitant increaseof concentrations of the serum enzymes. Sub-sequently a technetium-99m multiple gated acquisi-tion study of the left ventricle showed an ejectionfraction of 0-68 with good and uniform contraction.Myocardial scintigraphy with thallium-201 showed

I

II

aVR

aVL

hbenzhexol hydrochloride 449

evidence of anterior myocardial infarction with exer-cise induced ischaemia in the high lateral and lowerseptal walls. Recording of a simultaneous 12 leadexercise electrocardiogram was limited by pain, andST segment elevation and widening of the QRScomplexes were seen (Fig. 2).. Similar changes wereseen on one occasion during an episode of earlymorning pain on 24 hour ambulatory monitoring. Inview of continuing uncontrolled pain at rest and onexercise, a second coronary angiogram was per-formed in September 1983 but no appreciable.change was seen in the arterial lesions.

Subsequent management

During the next two months her symptoms becameworse and, since parasympathetic activation may beone mechanism in variant angina,6 we decided totreat her with the anticholinergic drug benzhexol(trihexyphenidyl hydrochloride) which is commonlyused in the management of Parkinson's disease. Theinitial dose of 2 mg three times a day was increasedslowly to 4 mg four times a day. In the three monthsthat the patient was on benzhexol she had only oneepisode of angina. With her agreement we then

VI

V2

k'I I

V5

.-..-.-.. ...

III a~~~VF

Fig. I Twelve lead electrocardiogram recorded when the patient was admitted to hospital in July 1983. The Pardee T

wave inversion subsequently resolved.

V3. V6

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,. A .!. A., -.1

.,: "-- "-: a Z' I

I iI.I

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reduced the dose of benzhexol by 2 mg every twodays. When benzhexol was stopped completely thepatient reported attacks of angina both at rest and onexercise which were associated with vomiting. Sheasked to restart the drug and was instructed toincrease the dose by 2 mg every two days but shemisunderstood these instructions and took the fulldose of 4 mg four times a day. This precipitated abrief psychotic reaction with excitability and para-noia which resolved when the dose was reduced.Apart from the attacks of pain that she experiencedduring the period of withdrawal, the patient has hadonly four episodes of angina in the nine months sincetreatment with benzhexol was started, and two ofthese were associated with emotional upsets. Shereports increased feelings of wellbeing andimpairment of memory on the full dose-both areknown side effects of benzhexol. She continues totake 4 mg of benzhexol three times a day.

Joy, Haywood, Webb-Peploe

Discussion

The use of benzhexol is a novel approach to treatingvariant angina. Yasue reported that atropine (a para-sympathetic blocking agent) at a dose of 1 -2 to 2-0 mgat night suppressed attacks of pain in about 80% ofcases.7 He nevertheless commented that atropinewas not likely to have any advantages over the newlydeveloped calcium antagonists. Our patientresponded well to benzhexol, after treatment with acalcium antagonist had been unsuccessful. Themechanisms involved in variant angina when thecoronary arteries appear to be nearly normal byangiography and the condition is refractory to cal-cium channel blocking agents are unknown. In vitrothe contractile response of human coronary arteriesto various physiological agents, including acetyl-choline, is biphasic.8 The response to acetylcholineis dependent on a fast phase of contraction mediated

A ~ ~ ~ A

Fig. 2 The recording of this computer synthesised exercise electrocardiogram was limited by pain. The leads are from tOpto bottom VI, V5, aVF. The single QRS specimen complexes were recorded at rest, after hyperventilation (EX-O), aftereach three minutes of exercise, at maximum exercise, and for each minute for ten minutes of recovery. Note the ST segmentelevation in V5.

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Management of a case of refractory variant angina with benzhexol hydrochloride

by intracellular calcium release and a slow phaserelated to calcium influx via cell membrane channels.Calcium antagonists block only the cell membranechannels, thus in patients with refractory variantangina the fast phase of contraction may be domi-nant. This could explain the apparent success ofparasympathetic blockade in the management of thispatient when treatment with slow channel calciumantagonists was unsuccessful. It also emphasises theinvolvement of the parasympathetic nervous systemin variant angina.

References

1 Prinzmetal M, Kennamer R, Merliss R, Wada T, BorN. Angina pectoris. I. A variant form ofangina pectoris:preliminary report. Am Med 1959; 27: 375-88.

2 Oliva PB, Potts DE, Pluss RG. Coronary arterial spasmin Prinzmetal angina. Documentation by coronary arte-riography. N Engl Med 1973; 288: 745-51.

3 Braunwald E. Coronary artery spasm. JtAMA 1981;246: 1957-9.

4 Maseri A, Severi S, De Nes M, et al. "Variant" angina:one aspect ofa continuous spectrum ofvasospastic myo-cardial ischemia. Am Cardiol 1978; 42: 1019-35.

5 Tzivoni D, Keren A, Benhorin J, Gottlieb S, Atlas D,Stern S. Prazosin therapy for refractory variant angina.Am Heart 1983; 105: 262-6.

6 Yasue H, Touyama M, Shimamoto M, Kato H, TanakaS, Akiyama F. Role of autonomic nervous system in thepathogenesis of Prinzmetal's variant form of angina.Circulation 1974; 50: 534-9.

7 Yasue H. Pathophysiology and treatment of coronary

arterial spasm. Chest 1980; 78: 216-23.8 Ginsberg R, Bristow MR, Harrison DC, Stinson EB.

Studies with isolated human coronary arteries. Chest1980; 78: 180-6.

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