Practolol (Eraldint), a recently developed beta-adrenergic blocking agent, has been found useful in conjunction with digitalis and diuretics in 6 patients with thyrocardiac disease who had been refractory to therapy. In all cases cardiac failure improved dramatically, suggesting better myocardial efficiency and a return of digitalis responsiveness after practolol. This drug might be a useful therapeutic adjunct in thyrocardiac disease

Epstein, S.

Pimstone, B

English

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812 S.A. MEDICAL JOURNAL 24 July 1971Practolol in Hyperthyroid Cardiac Failure *S. EPSTEIN, M.R.C.P. AND B. PIMSTONE, M.D., M.R.C.P., Thyroid Clinic, Groote Schuur Hospital, Cape TownSUMMARYPractolol (Eraldint), a recently developed beta-adrenergicblocking agent, has been found useful in conjunctionwith digitalis and diuretics in 6 patients with thyrocardiacdisease who had been refractory to therapy. In all casescardiac failure improved dramatically, suggesting bettermyocardial efficiency and a return of digitalis responsive-ness after practolol. This drug might be a useful thera-peutic adjunct in thyrocardiac disease.s. Air. Med. J., 45, 812 (I971).Blockade of beta-adrenergic receptor sites produ;:es dra-matic improvement in many of the catecholamine-mediatedfeatures of hyperthyroidism, notably the pulse rate,'tremor,' nervousness, agitation3 and sweating.' As a con-sequence, beta-adrenergic blockade with propranolol hasbeen successfully used in a number of clinical situationsin hyperthyroidism, namely with "'I therapy; pre-operatively with Lugol's iodine: and in thyroid crisis.'While some workers have claimed this drug to be effectivein thyrocardiac disease; its known depressive action onmyocardial function" has been implicated in the precipi-tation of cardiac failure. Most clinicians, therefore, arehesitant in using propranolol in thyrocardiac patients,many of whom have an ischaemic "element to their disease.Practolol is a new beta-adrenergic blocking agent withcertain advantages over propranolol. Apart from a longerhalf-life," necessitating only bi-daily administration, andcardio-selectivity leading to a lower incidence of broncho-spasm, it produces less myocardial depression, probablydue to its intrinsic sympathomimetic activity." This articlerecords our experience with this therapy in 6 patients withsevere refractory congestive cardiac failure associated withhyperthyroidism.CASE REPORTSCaselThe patient, a 60-year-old female, complained of swelling ofthe ankles and dyspnoea for one year, which did not respondto digitalis and diuretic therapy. Other features were 28 kgweight loss, and a decided preference for cold weather.Examination showed a diffuse thyroid enlargement with acontinuous bruit, hyperactivity, tremor, lid-lag, warm sweatypalms, and a proximal myopathy. In addition, signs of cardiacfailure were found. notably ankle oedema, a raised jugularvenous pressure. hepatomegaly and atrial fibrillation. Protein-bound iodine concentration was 12 .ug /100 ml and neck "'Iuptake 73% and 69% at 6 and 24 hours respectively. X-ray'Date received: 7 April 1971.. ICI (SA) (Pharmaceuticals) Ltd, Johannesburg.of the chest showed cardiomegaly with congestion of thelung fields.The patient was diagnosed as having thyrotoxicosis andcardiac failure. Previous therapy (digoxin, Lasix and potassium)was continued and practolol was started with an initial doseof 50 mg. This was gradually increased over 2 days to 200 mgb.d. Within 4 days, dramatic improvement was evident. Thepulse rate slowed from 150 to llO/minute with a decrease injugular venous pressure, and improvement ·in her tremor,hyperkinesis, sweating and general well-being. A therapeuticdose of "'I was subsequently given, followed later by neo-mercazole.Case 2The patient was a known diabetic woman of 60 years,maintained on oral hypoglycaemic agents for the past 10 years.Six months before admission, proximal muscle weakness de-developed and progressed markedly, followed a few months laterby paroxysmal nocturnal dyspnoea, dyspnoea on effort andorthopnoea. The thyroid was enlarged. The eyes had a staringappearance with minimal proptosis. A fine tremor of the out-stretched hands and a tachycardia of over lOO/minute wasnoted. Blood pressure was ISO/lOO rnmHg, with elevation ofjugular venous pressure, hepatomegaly and ankle oedema. Thefundi showed diabetic retinopathy. Marked proximal muscleweakness was present in both upper and lower limbs withabsent knee and ankle jerks and impaired distal sensation.Urine analysis showed albumin 3+ and glucose 3 +.Myopathy in the deltoid, triceps and vastus medialis muscleswas confirmed by electromyography. Her random bloodglucose concentration was 260 mg/lOO m!. The ECG showedleft ventricular hypertrophy and sinus tachycardia of 120/minute. "'I uptakes at 6 and 24 hours were 75'% and 85%respectively. Creatine phosphokinase and nerve conductiontime were norma!.The patient's diabetes was controlled on oral hypoglycaemicagents and diet. Her congestive cardiac failure responded onlypartially to digoxin and diuretics, leaving her with tachycardia,dyspnoea and oedema. Practolol 50 mg was then given, thedose being increased over 36 hours to 200 mg h.d. The patient'scardiac failure improved rapidly within 2 - 3 days. The pulserate dropped to 80/minute. diuresis followed and dyspnoealessened. No improvement in the myopathy was observed. 1311therapy was given, followed 6 days later by the administrationor neomercazole.Case 3A 50-year-old woman had had proven thyrotoxicosis atano~her hospital 4 years before the present admission, but hadreceived no de.finitive therapy. Angina pectoris had subsequentlydeveloped, With severe dyspnoea and fluid retention. Thepatient had taken her medication irregularly and was admittedto hospital in severe congestive cardiac failure after stoppingher treatment altogether.Examination revt;aled a thin female, severely dyspnoeic,with blsal crepltahons, oedema and atrial fibrillation. Thepulse rate was approximately l20/minute and the bloodpressure !50/l00 mmHg. Tremor. lid-Iag and enlargement ofthe thyroid gland were found. Urine analysis showed a heavyproteinuria. Haemoglobin concentration was 9·5 g/IOO ml and24 Ju1ie 1971 S.-A. MEDIESE TYDSKRIF 813blood urea 200 mg/ lOO ml on repeated occasions. Creatinineclearance varied between 1·5 - 2 ml/minute. Chest X-ray showedcardIOmegaly wIth congested lung fields. Thyroid functionstudies o~howed that 1311 uptakes at 6 and 24 hours were 24 ~oand 46/~ respectJ~ely,. and proteIn-bound iodine was 8·0 p.g/lOO m!. Charcoat reslll test was, however, III the hyperthyroidrange.The patient was treated cautiously with digitalis and intra-venous diuretics with deterioration in the cardiac status.Because of the past history of thyrotoxicosis and the con-firmatory clinical signs, treatment with practolol and neomer-cazole was started, despite equivocal function studies. Practolol50 mg was given as a single dose and increased gradually to200 mg b.d. Within 2 days her extreme dyspnoea had markedlyImproved, and the neck vews had become less distended. Thepulse rate.(though still fibrillating) had decreased to lOO/minuteand sweatlllg was less. Her renal function remained unchanged,however, and in spite of a maintained response of her cardiacand thyroid status, she died in terminal renal failure 2 monthslater.Case 4In February 1969 a 68-year-old woman was investigated foratrial fibrillation and congestive cardiac failure. No cause wasestablished and the patient was treated with digoxin, diureticsand potassium with good initial improvement. However, a fewmonths later, cardiac failure recurred in spite of continuedtherapy. Careful interrogation at this stage revealed a loss ofweight over the previous 2 years. A nodular enlarged thyroidwas found on examination.She was ad;nitted to hospital distressed and dyspnoeic withevidence of loss of weight and muscle bulk. Cardiomegaly wasevident with aortic systolic and diastolic murmurs and anapical soft systolic murmur. Atrial fibrillation 140 - 150/minute, basal crepitations, hepatomegaly and ankle oedemawere also found. Generalized weakness of both upper andlower proximal muscle groups was .elicited. Cardiomegaly andcongested lung fields were evident on chest X-ray. An ECGshowed a ventricular rate of 140/minute, atrial fibrillation andprobably an old anterior infarct. A patchy myopathy wassuggested by electromyography. Thyroid function tests showed1a11 uptakes of 48 % and 76 % at 6 and 24 hours and protein-bound iodine of 10·2 p.gjlOO m!.Digitalis and diuretics were maintained in spite of previousrefractoriness, and in view of the thyrotoxicosis, 50 mg practo-101 was given. As no adverse effects were observed, the dosewas increased 12 hours later to lOO mg b.d. Improvement wasdramatic over 3 days with diminution of pulmonary con-gestion, dyspnoea and pulse rate (from 140 to between 90 andlOO/minute). A therapeutic dose of 1311 was administeredfollowed 14 days later by neomercazoJe.CaseSA 42-year-old female was first seen in 1967 when thyrotoxi-cosis was diagnosed and treatment with neomercazole andpropranolol commenced. In spite of a good response, shefailed to return for long-term continuation of therapy. Twomonths before admission, a 'flu-like' illness occurred, associatedwith vomiting and an upper respiratory tract infection. On theday of admission in August 1970, the patient developed a left-sided hemiplegia. Definite symptoms of thyrotoxicosis werenot evident. The patient was distressed and extremely dyspnoeicwith thyroid enlargement, a coarse tremor of the outstretchedhands and gross proptosis. Her pulse was 140/minute andfibrillating. Cardiomegaly, a gallop rhythm, pulmonary con-gestion and oedema were marked. Chest X-ray confirmedpulmonary oedema and cardiomegaly with an enlarged pul-monary conus. The ECG showed a ventricular rate of 140/minute with atrial fibrillation and ventricular ectopic beats.Thyroid function tests showed that 131 1 uptakes at 6 and 24hours were 72% and 66% respectively, with 'charcoal' resin testin the hyperthyroid range. Pulmonary function tests werenormal.The patient was immediately started on digoxin. diureticsand antIcoagulants, the provisional diagnosis beIng an embolusfollowing atrial fibrillation. In view of the past history andobvious physical signs of thyrotoxicosis, practolol was addedto the therapy shortly thereafter. A test dose of 50 mg wasgiven, followed 12 hours later by 50 mg b.d. for I day andthen lOO mg b.d., on which the patient was maintained. Theresponse to this regimen was rapid. Ventricular rate slowedto lOO/minute after the initial 50 mg dose of practolol. Twodays after the s!art of therapy pulmonary congestion hadImproved both clInically and radiologically. Her general con-dItIOn was also markedly improved at this stage. Two weeksafter admiSSIOn a therapeutic dose of 1311 was given followed5 days later by the commencement of neomercazole.Case 6Eighteen months after a thyroidectomy performed for thyro-tOXICOSIS III 1930, a 77-year-old woman developed pretibialmyxoedema and aggravation of exophthalmos which had beenpresent before the operation. Thyroid sicca 4 gr. daily wasstarted, and contmued unttl 1964 when the patient was admittedto hospItal in left ventricular failure. thouaht to be on anischaemic basis because of associated angina pectoris. Sheresponded well to digitalis and diuretic treatment. Thyroidslcca was changed to thyroxine 0·1 mg I.d.s. This therapy wasmallltaIned until her present admission. In 1969, she developedasthma and thereafter was seen on numerous occasions in con-gestive cardiac failure exacerbated by respiratory infections.In. September 1970 she was admitted to hospital with in-creasIng dyspnoea, frequent palpitations, and a 'constant pres-sure on the chest' which she distinguished from her long-standing angina pectoris. For the previous 14 months her doseof thyroxine had been 0·2 mg/ day. Otherwise she had beenon digitalis and diuretics as previouslv.The patient was plethoric, dyspn'oeic and sweatina withwarm hands. Pretibial myxoedema and endocrine exophthalmoswere marked. No thyroid remnant was palpable in the neck.The pulse rate was l20/minute at rest and the blood pressurewas 180/100 mmHg/minute. A triple rhythm was audible atthe cardiac apex. Bilateral basal crepitations and a tenderhepatomegaly confirmed her cardiac failure. The ECG showeda sinus rhythm with atrial premature systoles and non-specificleft ventricular changes. Blood urea and electrolytes werenormal. Lasix, digoxin, Aminophyllin and thyroxine werecontinued, but improvement on the regimen and bed rest waslimited. Dyspnoea, sweating and palpitations persisted and thediagnosis of 'thyrotoxicosis artefacta' was entertained. Thyroid"'I uptakes (on thyroxine therapy) were 2% and 7~~ at 6 and24 hours respectively, and serum cholesterol was 233 mg/!OO ml.Thyroxine was stopped and 50 mg practolol was given. andincreased 12 hours later to lOO mg b.d., on which dose shewas maintained. Within 24 hours, marked improvement wasnoted. The pulse rate decreased to 88/minute, dyspnoea easedand the lung bases cleared. The patient commented 'that itwas as if the load had been lifted off my chest'. Practolol wascontinued for 3 weeks. One month after stopping the thyroxine.thyroid function studies were repeated and 1311 uptakes were3·7°b and 1·5% at 6 and 24 hours respectively, and serumthyroxine 1·3 p.g/IOO ml (normal 5 - 13 p.gjlOO ml). Accordinglyshe was restarted on thyroxine 0·1 mg daily.DISCUSSIOSix patients with hyperthyroidism (in I instance thyroxine-induced) and severe cardiac failure, refractory in 5 cases tostandard digitalis and diuretic therapy, were additionallytreated with the new beta-adrenergic blocking agent practo-101, starting with a single trial dose of 50 mg. In all patientsthere was considerable improvement in the symptoms and814 S.A. MEDICAL JOURNAL 24 July 1971signs of cardiac failure within 2 - 4 days of starting thedrug. Many of the hyperthyroid manifestations-tremor,pulse rate, sweating-and general well-being improved. Wecannot exclude a concomitant effect of bed rest, but theprevious total refractoriness to standard treatment of allbut one of the patients even while in hospital, and theirrapid and dramatic improvement after the addition ofpractolol (a response which paralleled improvement ofhyperthyroid features), suggests a direct and specific bene-ficial effect of this drug.Beta-adrenergic blockade using propranolol is nowestablished as a!l important adjunct in the therapy of hyper-thyroidismY Apart from the lack of cardioselectivity andhence a tendency to bronchospasm" the main contra-indi-cat~n to the use of this drug has been the presence ofcardiac failure because of its known depressant effect onmyocardial function." There have been reports in whichpropranolol has been successfully used in thyrocardiacdisease' but because of the mixed nature of the cardiacdisorder (many patients have severe ischaemic heartdisease), most authorities tend to avoid the use of thisagent in these specialized circumstances.Practolol, by contrast, has less myocardial depressanteffect, largely because of its intrinsic sympathomimeticactivity." It has been postulated that this might be a contra-indication to its use in thyrotoxicosis because of the long-held view that enhanced sensitivity to catecholamines is afeature of this condition." On the other hand Levey et al. Hhave reported no increased sensitivity of cardiac adenyl-cyclase to catecholamines in the hyperthyroid animal, sug-gesting that at least in respect of the cardiac manifestationsof thyroid disease, practolol might not be contra-indicated.Indeed, our own experience with oral practolol in otherBoeke OntvangW issenschafdiche Zeitschri/t. Zur Pathogenese und Klinik derprogressiv ·chronischen Polyarthritis. Redaktionskollegium:H. Ambrosius, H. Drischel, G. Grau. H. D. Hass. J.Schulz und H. J. Troll. 193 seiten, 48 Abb. L 6, brosch.,16,-M (Vorzugspreis fUr die DDR 5,-M). Leipzig: Kar/-Marx-Universitat. 1970.Pathology of Tumours of the Nervous System. 3rd ed. By D. S.Russell, SeD.. M.A., M.D., F.R.C.P. and L. J. Rubinstein,M.D. Pp. 429. Illustrated. £10.00. London: EdwardArnold. 1971.VifGmin C and rhe Common Cold. By L. Pauling. Pp. 122.£1.90. Cloth; 80p paper. Reading: W. H. Fr~eman. 1971.The Psychiarric Disorders of Childhood. 2nd ed. By C. R.Shaw, M.D. and A. R. Lucas, M.D. Pp. x + 499. R9.00.London and Durban: Butterworth. 1971.cases of thyrotoxicosis suggests a satisfactory improve-ment in well-being, sweating, nervousness and pulse rate.The precise mechanism of the beneficial effect of prac-tolol should be considered. Weiner et al. 15 have shown thatbeta-adrenergic blockade improves the positive chrono-tropic and inotropic effects of thyroid hormone and pre-sumably reduces the increased myocardial oxygen require-ments of thyrotoxicosis with improvement in myocardialefficiency. This, in turn, could lead to increased digitalisresponsiveness, as has been described by Waldstein et al.,16with guanethidine.REFERENCESI. Howitt, G. and Rowlanils, D. J. (1966): Lancet, I, 628.2. Shanks, R. G., Hadden, D. R., Lowe, D. c., McDevitt, D. G. andMontgomery, D. A. D. (1969): Ibid., I, 993.3. Marsden, C. D., Gimlette, J. D., McAllister, R. G., Owen, D, A. L.and Miller, T. N. (1968): Acta endocr. (Kbh.), 57, 353.4. Krikler, D. M. (1966): Lancet, I, 268.5. Hadden. D. R., Montgomery. D. A. D., Shanks, R. G. and Weaver,J. A. (1968): Ibid., 2, 852.6. Vinik, A. I., Pimstone, B. L. and Hoffenberg, R, (1968): J. Clin,Endocr., 28, 725.7. Parsons, V. and Jewitt, D. (1967): Poslgrad. Med, J., 43, 756.8. 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Practolol in Hyperthyroid Cardiac Failure

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Practolol in Hyperthyroid Cardiac Failure

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