DOSING INTERVALS IN BETA-BLOCKER THERAPY

800 ENDOSCOPY IN THE POSTCHOLECYSTECTOMY SYNDROME

SIR,-Ruddell et al.l have clearly demonstrated the problems of diagnosing the postcholecystectomy syndrome. Recognition of the underlying morphological abnormality has increased in importance since the introduction of endoscopic retrograde cholepancreatography (ERCP). In our series of 3142 ERCP studies, 811 patients (26%) had the postcholecystectomy syndrome. Our obsorvations have led to two conclusions which supplement the data of Ruddell et al. Of the

patients investigated by ERCP

because of

postcholecy-

stectomy syndrome 402 had extrahepatic biliary flow obstruction; 173 (42%) had had biochemical indications of cholestasis. Almost half the patients with radiological evidence of biliary obstruction had normal laboratory findings, so there seems to be no close relation between the morphological and the biochemical changes, and bile flow obstruction is not necessarily associated with the laboratory features of cholestasis. Our ERCP findings (see table) suggest that the clinical symptoms were a direct consequence of surgery in only 6% of patients (i.e., the

only

target organ damage (e.g., grade nthv retinopathy, and left ventricular hypertrophy) despite mild hypertension. In 16 of the 65 patients who fulfilled our criterion for mild hypertension a 131I-hippuran scan was done for the above reasons. In 3 (19%) cases the renogram appeared abnormal: Case 1. —A 43-year-old man was referred to the clinic by his family doctor because of mild hypertension. He was on 320 mg propranolol, 150 mg hydralazine, and 50 mg chlorthalidone daily, but his blood pressure remained at 180/110 mm Hg. A 131-hippuran renogram showed a delayed and decreased uptake in the left kidney. Renal arteriography revealed a subtotal stenosis of the left renal artery. After arterial reconstruction this patient’s blood pressure returned to normal and has not been on treatment since. Case 2.-A 63-year-old man presented with a blood pressure of 170/105 mm Hg. Despite this mild degree of hypertension he had grade m fundal changes. A 131I-hippuran scan was compatible with right renal artery stenosis and renal arteriography revealed a 6007o stenosis. Selective renal vein renin sampling yielded a 2’ 3/2 - 0 ratio. Because of this he was not referred to a vascular surgeon but treated with metroprolol, chlorthalidone, and prazosin. He became normotensive within a month and his fundal changes have since

regressed. ERCP DIAGNOSES IN PATIENTS WITH POST-CHOLECYSTECTOMY

SYNDROME

I

49 with evidence of postoperative stricture of the bileduct). On the other hand, 41 % of patients had morphological abnormalities which could have been detected at surgery-e.g., retained stones, stenosis of the papilla of Vater, and juxtapapillary diverticulum. All these abnormalities, including at least some of those revealed in the pancreas, could have been diagnosed before and during the operation and could probably have been corrected surgically. Upper panendoscopy is thus strongly recommended in patients presenting with symptoms of the postcholecystectomy syndrome, since most if not all diverticula and papillary anomalies will be revealed before surgery. Further, if anterograde cholangiography is not reliable,.ERCP should be included in the diagnostic work-up of such patients. The risks of these procedures is insignificant compared with those of a second laparotomy. Gastroenterological Endoscopic Centre, Semmelweis University, 1083 Budapest, Hungary

Z. TULASSAY

J. PAPP

INTRAVENOUS PYELOGRAPHY OR 131I-HIPPURAN RENOGRAPHY TO SCREEN FOR RENOVASCULAR

HYPERTENSION

SIR,-Dr Russell and his colleagues (Sept. 6, p. 529) report a poor yield of intravenous pyelography (IVP) in their series of hypertensive patients. At the hypertension clinic at this hospital we are investigating several treatments for mild hypertension (diastolic pressure 95-110 mm Hg). To screen for possible renovascular hypertension we use 13 ’I-hippuran renography instead of IVP for patients under 40 years of age, for patients who remain hypertensive despite prolonged treatment, and for patients with signs of severe 1. Ruddell

WSJ, Lintott DJ, Ashton MG, Axon ATR. Endoscopic retrograde cholangiography and pancreatography in investigation of post-cholecystectomy patients Lancet 1980;

i:

444-47.

Case 3.-A 36-year-old male was first seen because of chest pain. Extensive work-up showed no abnormalities, apart from a blood pressure of 170/110 mm Hg. A 131-hippuran scan showed a small left kidney with a decreased and delayed perfusion. On renal arteriography two patient renal arteries were found.The left kidney was very small; the picture was compatible with a chronic nephritis probably caused by reflux in his youth. The right kidney was enlarged due to compensatory hypertrophy and showed abnormal arterioles. A left nephrectomy was considered but rejected because of the abnormal findings in the right kidney. At present he is being treated according to the protocol of our hypertension intervention trial. 131 I-hippuran renography is safer than IVP which has a morbidity of 02%. It is much less taxing to the patient, and the radiation exposure is 1/20th of that for an IVP. The yield of 131I-hippuran renography is comparable with if not superior to that of IVP. Even in mild hypertension 13’I-hippuran renography should be used for screening if renovascular hypertension is suspected. Department of Medicine, University of Amsterdam, Wilhelmina Gasthuis, Amsterdam, Netherlands

TH. M. ERWTEMAN

J. ROOS

DOSING INTERVALS IN BETA-BLOCKER THERAPY

SIR,—All drugs should be prescribed according to their pharmacokinetic properties. However, in the light of recent prescription rules for the use of beta-blocking agents in the treatment of, for example, hypertension, 1-3 we would like to re-emphasise the view of Dr Frick and Dr Kala (Sept. 13, p. 588) who concluded that "while the antihypertensive effect of once daily and twice daily administrations are similar, beta blockers with short plasma halflives should preferably be given twice daily in the treatment of hypertension if the presumed cardioprotective effect is to be sustained for 24 h". Our comparative study of the effects of atenolol (A), pindolol (P), and metoprolol (M) on exercise test performance, amplify this aspect of beta blocker therapy. In ten healthy young males undergoing repeated maximal bicycle exercise tests, 100 mg A x 1,7 - 5 mg P x 2, and 150 mg M x 2 were given. On each drug regimen exercise tests were done at time zero and 2y h and 12 h after the first dose and at exactly 24 h (i.e., 12 h after the second dose in the afternoon) as 1 Wilson M, Morgan G, Morgan T. The effect on blood pressure of betaadrenoceptor blocking drugs administered once daily and their duration of action when therapy is ceased. Br JClin Pharmacol 1976; 3: 857-61. 2. Wilcox RG. Randomized study of six beta-blockers and a thiazide diuretic in essential hypertension. Br Med J 1978, ii: 383-85. 3. Cruickshank JM. The clinical importance of cardio-selectivity and lipophilicity in beta blockers. Am Heart J 1980, 100: 160-78.

801

well as at a steady state-i.e., after 5-6 days on the beta blockers (24 h after the last A and 12 h after the last P and M dose). In addition 2-,L Z h, 12 h, and 24 h data were obtained on 15 mg P x 1 and 300 mg M x 1. The degree of beta blockade was assessed by measuring heart rate, blood pressure, and ECG response during maximal exercise. (The exercise tests were continued up to complete exhaustion, and a maximal effort was obtained in all subjects, as judged by blood lactate levels obtained 5 min post-exercise. 4) Our data for A and M (table I) confirm the suggestions of Frick and Kala which imply a twice daily dosage for M and once daily for A for

what might have expected from the plasma halflife.Hence, despite the short plasma halflife, pindolol may be given at a dosage of 15 mg once daily for the treatment of hypertension (and, by extrapolation, angina pectoris and arrhythmias related to adrenergic mechanisms). Data from our exercise tests (not shown) also emphasise the wellknown fact3that beta-blockers with a significant first-pass effect have a more variable dose-effect response than beta-blockers in which the first-pass effect is negligible. This fact should also be taken into consideration in the first choice of beta blocker and in

suggesting dosage schedules.3 J. ERIKSSEN

Medical Department B and Cardiovascular Laboratory,

TABLE I-PEAK HEART RATE AND BLOOD PRESSURE DURING MAXIMAL BICYCLE EXERCISE

R. MUNDAL E. THAULOW S. NITTER-HAUGE

Rikshospitalet, Oslo 1, Norway

AMNIOTIC-ADHESION MALFORMATIONS IN ITALY

SIR,-Dr Herva and colleagues’ reported of

severe

a possible cluster amniotic-adhesion malformations in Finland. The

problem is puzzling. The highest incidence of the "severe" form is reported by Ossipoff and Ha1l2: 1/3700 (8 cases of a series of 24). Miller and Smith3 reported a minimum incidence of the severe form of 1/25 000.

Previous

data

limited to limb deformities incidence in different surveys is statistics include aborted fetuses, and some are

(1/10 000).4 Comparing the

* Zero values were: heart rate 188±5/min, blood pressure 205--t mm Hg. For each regimen the heart rate in beats/min is given first with blood pressure in mm Hg printed in italic type. Data given as mean SD.

adequate 24 h beta blockade, according to serum/blood half lives.3,5,6 Thus 300 mg Mx 1 was clearly inadequate in controlling heart

rate

and blood pressure response to exercise at 24 h. our findings for P (table i) suggest that one should be

However,

cautious in basing dosage schedules solely on pharmacokinetic studies. Our data suggest that the bloodlbeta-receptor equilibrium is

TABLE II-PLASMA LEVELS OF PINDOLOL

Dosage pmdolol 7’ 5

mg x 2;

samples for assay taken immediately before exercise tests.

.

Zero in 3. t Zero 5. m

≠Zero in 5.

always simple. Thus at a time when six of the ten subjects repeatedly had a zero plasma level of P (table II), more than 50% of the maximal beta-blocking effect (i.e., 22 h effect) was still present. Thus P (in contrast to A and M) has a biological effect which exceeds

difficult because some do not. In a multicentre prospective study (on behalf of the Italian Multicentre Survey Study Group) on selected congenital malformations in Italy, in which all malformed cases are reported with a written detailed description and/or with photographs, we found 11 infants with amniotic-adhesion malformations (5 with limbs and body-wall deficiency and 6 with limb deficiency only) among 160 000 births (1/14 500). 3 infants with the severe form were born in the same county (Perugia) between October, 1977, and June, 1980 (an incidence of at least 1/5300 births). 2 of these infants were born in April, 1980. Of the 11 subjects (6 female, 5 male), 7 were live-born and 4 stillborn. The gestational age ranged from 30 to 42 weeks (35 weeks average). 3 were small for gestational age. The average birth weight was 2338 g. 5 were first-born, 5 were secondborn, and 1 was third-born. The mean maternal and paternal ages were 25 and 28 years respectively. No consanguinity was recorded among parents. Karyotypes (when obtained) were normal. Enhanced recognition of this pattern of malformations and greater attention to the nature of abortuses and causes of stillbirths may explain the apparent clusters. A problem which remains unsolved is the definition of cluster. However, because amniotic-adhesion malformations consist of a wide spectrum of structural defects, the specific diagnostic criteria for inclusion of all infants with mild or severe defects should be improved, and more surveys should be undertaken to determine the setiology, which is probably environmental. University Department of Paediatrics, Rome, Italy

PIERPAOLO MASTROIACOVO

University Department of Pædiatrics, Perugia

ANNA CALABRO

not

7. 4. Astrand PO. Quantification of exercise capability and evaluation of man. Progr Cardiovasc Dis 1976; 19: 51-67

5. von Bahr

physical capacity

in

C, Collste P, Frisk-Holmberg M, Haglund K, Jorfelt L, Orme M, Østman J, levels and effects of metoprolol on blood pressure, adrenergic beta blockade and plasma renin activity in essential hypertension. Clin Pharmacol Ther 1976; 20: 130. 6. McDevitt DG, Johnston GD, Kelly JG, Shanks RG. Investigation of chronic dosing regimens of atenolol. Postgrad Med J 1977; 53: 79-82.

Sjoquist F. Plasma

Herold W, Dengler HJ. Pharmacokinetics of Pharmacol 1974; 7: 17-24.

Gugler R,

pindolol in man. Europ J Clin

Rapola J, Rosti J, Carlson H. Cluster of severe amniotic adhesion malformations in Finland. Lancet 1980; i: 818-19. 2. Ossipoff V, Hall BD. Etiologic factors in the amniotic band syndrome: A study of patients. Birth Defects Orig Article Ser 1977; 13: 117-32. 3. Miller M, Smith DW. Severe amniotic adhesion malformations. Lancet 1980; i: 1298-99. 4. Baker CJ, Rudolf AJ. Congenital ring constrictions and intra uterine amputations. Am J Dis Child 1971; 121: 393-400. 1. Herva R,