day of complete cessation of the drug, 2 days and 7 days later showed gradual ... ney function or concomitant drug administration data are available on patients ...
Clin. Cardiol. 11, 53-54 (1987)
Sinus Arrest Associated with Clonidine Therapy E. SCHWARTZ, M.D.,* E. FRIEDMAN, M.D.,* M. MOUALLEM, M.D.,*
z. FARFEL, M.D.*,t
Department of *Medicineand ?Clinical Pharmacology Unit, Sheba Medical Center, Tel Aviv University School of Medicine, Tel Hashomer, Israel
Summary: A 65-year-old male with diabetes, hypertension, and mild renal failure developed dizziness and syncope one week after starting clonidine 0.45 mg/day. A continuous ECG recording revealed sinus bradycardia, nodal rhythm, and multiple episodes of sinus arrest lasting up to 4.5 seconds. Upon discontinuationof clonidine, serial continuous ECG recordings revealed gradual decrease in the number and duration of the sinus arrest episodes, until their complete disappearance shortly after the third day off clonidine. This report shows that clonidine may cause a concentration-dependent sinus node dysfunction in addition to the atrioventricular (AV) node abnormalities previously ascribed to it. Key words: clonidine, sinus arrest
Introduction Clonidine hydrochloride is an antihypertensive agent which is a partial agonist of presynaptic alpha2-receptors. In the central nervous system this agonism d e c m e s sympathetic outflow and enhances vagal tone. * Stimulation of peripheral alpha2-receptors inhibits norepinephrine release from nerve terminals. Cardiac conduction abnormalities associated with clonidine have been infrequently ~ p o r t e d . Recently, ~-~ we treated a patient who developed transient symptomatic sinus arrest in the course of clonidine treatment.
Case Report
A 65-year-old mildly diabetic man was admittedbecause of recurrent syncope. Excessive hypertension (260/ 120 d g ) was diagnosed two months earlier and treatment with nifedipine and chlorothiazide was started. After 6 weeks nifedipine was replaced by clonidine 0.45 mg/day because of ankle edema. This regimen achieved adequate blood pressure control (170/80 d g ) . However, on the first week of clonidine therapy the patient began to experience dizzy spells and two episodes of syncope occurred a week later. A 24-h ambulatory ECG recording demonstrated many episodes of sinus arrest, a few lasting up to 4.5 s each, and nodal bradycardia (30-40beatdmin) (Table I). Blood pressure was 150/80 without orthostasis, heart rate 58 beatslmin regular. Physical examination was normal. Admission ECG showed sinus bradycardia with a left ventricular strain pattern. Routine laboratory evaluation was normal except for mild hyperglycemia (170190 mg/dl) , and mild renal insufficiency (urea 60 mg/dl, cmtinine 2 mgldl, cmtinine clearance 40 ml/min). Clonidine was tapered off, and within 48 hours completely discontinued. Symptomatic improvement was concomitantly noted: no syncope recurred and dizziness disappeared. Serial continuous 24-h ECG recording performed on the day of complete cessation of the drug, 2 days and 7 days later showed gradual decrease in the number and duration of the sinus arrest episodes until their complete disappearance on the last of these recordings. An additional continuous ECG recording 24 days later, while the patient was asymptomatic, was normal except for rare ventricular premature beats (Table I).
Discussion Address for reprints: Zvi Farfel, M.D. Department of Medicine Sheba Medical Center Tel Hashomer, Israel Received: June 4, 1987 Accepted: August 1 1, 1987
The patient described had symptomatic sinus arrest which appeared a week after starting clonidine treatment and gradually resolved until complete disappearanceshortly after the third day off clonidine. No other medications were concomitantly administered that could account for this phenomenon, and there was no evidence of active cardiac disease. Even though rechallenge with clonidine
54
Clin. Cardiol. Vol. 1 1 , January 1988
TABLEI Continuous 24-h ECG recording
Clonidine use
2 weeks on clonidine 0.45 mglday Day after clonidine cessation lb 3
Sinus arrest episodes per 24 h Heartrate range > 4 s a > 3 s > 2 s 24-98
8
21-98 54-1 10 44-1 12
25
42-118
14
>20
1
2
6
0 0 0
0 0 0
2 0 0
5
aDuration of episode. bThe patient received 0.075 mg clonidine in the morning.
or were receiving concomitant digoxin. It is noteworthy that in patients where kidney function data are available, some degree of renal insufficiency was present. No kidney function or concomitant drug administration data are available on patients reported by Yeh ef al. and Abiuso and Abelow.2 The patient described by us also had mild renal failure. The definite mechanism responsible for clonidine-associated-cardiac conduction disturbances is not known. Only one patient underwent electrophysiological studies which failed to demonstrate any pathology.2 However, considering the effect of clonidine on the autonomic nervous system,' the apparent dose-response association between clonidine and cardiac conduction abnormalities4 and the common feature of mild renal failure, one can hypothesize that clonidine affects the AV node and the SA node in a concentration-dependent mechanism. It is not clear yet whether this adverse effect may occur only in patients with a diseased conduction system, or also in supersensitive patients with normal conduction. In patients with renal failure, diseased conduction system, those receiving high doses of the drug, or concomitant digoxin, clonidine should be administered with caution.
was not performed for ethical reasons, it seems most likely that this agent caused the sinus arrest. The time course of appearance and disappearance of the toxic effect in our patient corresponds to the half-life elimination of clonidine which is 25 hours in normal subjects,6 and is prolonged in the presence of renal failure, since about 50% of the drug is cleared unchanged by the kidney.' This time References course also supports a concentration-dependentmechanism of clonidine-induced sinus arrest. 1. Lowenstein J: Clonidine. Ann Intern Med 92, 74 (1980) In all previously reported cases of clonidine-associated 2. Abiuso P, Abelow G : Atrioventricular dissociation in a patient receiving clonidine. J Am Med Assoc 240, 108 (1973) conduction abnormalities, conduction was distuhed at the atrioventricularnode level: Wenckebach type AV b l ~ k , ~ . ~3. Kibler LE, Gazes PC: Effect of clonidine on atrioventricular conduction. J Am Med Assoc 238, 1930 (1977) atrial flutter with high-grade (20: 1) block,3 AV dissocia4. Williams PL, Krafcik JM, Potter BB, Hooper JH, Heame MJ: tioq2 and complete heart block.4Thus the present patient Cardiac toxicity of clonidine. Chest 72, 784 (1977) demonstrates that clonidine may also cause severe dys5. Yeh BK, Nantel A, Goldberg LI: Antihypertensive effect of function of the sinoatrial (SA) node in addition to its clonidine. Arch Intern Med 127, 233 (1971) known effect of sinus bradycardia. 6. Arndts D, Doevendans J , Kirsten R , Heintz B: New aspects Most previous cases were encountered in patients who of the pharmacokinetics and pharmacodynamicsof clonidine were o~erdosed,~ had evidence of pre-existing diseased in man. Eur J Clin Pharmacol24, 21 (1983) myocardium and conduction systems: cardiomegaly, right 7. Lowenthal DT: Pharmacokineticsof clonidine. J Cardiovusc Pharmacol 2 (suppl I), S29 (1980) bundle-branch block (RBBB),and first-degree AV block,g
