AGRANULOCYTOSIS ASSOCIATED WITH AJMALIN THERAPY

Acta med. scand. Vol. 190, pp. 35-39, 1971

AGRANULOCYTOSJS ASSOCIATED WITH AJMALIN THERAPY

J . H. P. Wilson, Trijn Cazemier and H. 0. Nieweg

Froin the Division of Haematology, Department of Internal Medicine, University Hospital, Groningen, The Netherlands

Abstract. The case reports of five patients who developed agranulocytosis while taking the antiarrhythmic drug ajmalin are presented. All five responded rapidly to withdrawal of the drug and, in four of the five, antileucocyte ajmalin-dependent activity was demonstrated in the serum by means of a leucocytotoxicity test.

Laboratory and clinical trials with the rauwolfia alkaloid ajmalin have shown it to be a valuable antiarrhythmic agent, comparable to quinidine in its actions and indications, but with apparently fewer toxic effects (1, 5). Given intravenously it is effective in the treatment of paroxysmal supraventricular and ventricular tachycardias. Although the absorption is irregular and the oral route is not as reliable as parenteral injection, we have been giving this drug to :elected patients orally since 1967 for the long term suppression of ectopic beats and tachycardias.

During a relatively short period we saw 3 patients who developed an agranulocytosis while receiving ajmalin, and we were given the oppor- tunity to perform serological studies on 2 further patients admitted to another hospital. Cytotoxic, ajmalin-dependent antileucocyte activity was detected in sera from 4 of the 5 patients.

CASE REPORTS Patient I A 61-year-old retired administrator was admitted in Aug. 1968 with an acute myocardial infarction. At the time he was taking para-aminosalicylic acid and isoniazid for suspected reactivation of an old pulmonary tuberculous lesion. On admission he was started on ajmalin orally, 300 mg daily, because of multiple ventricular extrasystoles. He was also started on acenocoumarin (Sintromm,), the thrombotest being maintained between 5 and 15%. After 3 weeks he was discharged, and shortly thereafter the tuberculostatic drugs were discontinued. On the 14th Dec.

1968 he was readmitted with a 2-week history of sore throat, malaise and fever, which had failed to respond to oral penicillin therapy. The patient denied having taken any drugs apart from the ajmalin, acenocoumarin and penicillin. On examination he was found to have a temperature of 39.4"C and his pharynx was inflamed with a small area of white exudation. The following laboratory results were obtained: Hb 14.8 g/100 ml, haematocrit 43 %, leucocyte count 2 200/mm3 and in the smear atypi- cal lymphocytes and monocytes without recognisable granulocytes, and platelet count 220 OOO/mmY. Urine examination was normal, ECG and chest X-ray unchanged in comparison with those taken 4 months pteviously at discharge. The ajmalin was stopped and the acenocoumarin continued. He received antibiotics (initially penicillin and streptomycin, later ampicillin). Five days after admission his temperature had fallen to normal levels, his complaints had markedly diminished and the leucocyte count had risen to 4 100/mms with reappearance of the granulocytes. The Hb and platelet count remained normal. He was discharged on the eighth day with a leucocyte count of 7 100/mms and a normal differential count. Throughout this period and subrequently he continued to receive the acenocoumarin and there has been no subsequent recurrence of the leucopenia.

Patient 2

A 73-year-old retired salesman was admitted in Feb. 1969 complaining of chest pain and shortness of breath. His ECG showed a supraventricular tachycardia of 180 beats/ min. Two years previously he had been treated at home for a myocardial infarction and had been seen regularly at the outpatient department in the intervening period because of angina pectoris, for which he took pentaerythritol tetranitrate (Peritratem). As eyeball presure and carotid massage failed to have any effect, he was given ajmalin (50 mg i.v. followed by a drip infusion at a rate of 1.5 mg ajmalin/min). When this failed to work, a single injection of 250 mg diphenylhydantoin i.v. was given, also without effect. He was then started on digoxin intravenously. Shortly afterwards a flutter with two to one block appeared, followed on the second day by a sinus rhythm. O n the eleventh day he developed multiple ventricular ectopic beats, and was started on ajmalin orally in a dosage of 600 mg daily. During the following 2 weeks

Acta med. scand. I90

36 J . H. P . Wilson et al.

12000-

PATIENT No 2

OlGOXlN 0 , 5 m Q ORALLV - 1 I @ipxJiq 3 m m p I V

0 AJYALIN AJMALIN 10DmP ORALLV I 200 m i I v

FEB MARCH

a gradual decline in the total leucocyte count and granulocyte count was seen (Fig. 1). The H b and platelet count remained normal. He had no complaints at this time. Sternal puncture showed a relative increase in lymphoid cells. Abnormalities in the liver function tests were seen in the form of a temporarily raised alkaline phosphatase, to a maximum of 5.6 Bessey units, and an aspartate transaminase to a maximum of 76 Wroblewski units. The ajmalin was stopped, after which the leucocyte count returned to normal levels. Apart from the digoxin, which he continued to take, the single dose of diphenylhydantoin, heparin during the first few days and ajmalin, he received no other drugs during his admission. The digoxin has been continued, and at subsequent follow-up exarnina- tions his blood picture has remained normal.

Putient 3 A 72-year-old man was admitted in Jan. 1969 because of complaints of palpitations and retrosternal pain with signs of mild congestive cardiac failure. The ECG demonstrated a supraventricular tachycardia with a ventricular rate of 200/min. The following laboratory results were obtained on admission: Hb 14.3 g/100 ml, haematocrit 42%, leucocyte count 7 400/mm3, platelet count 180 OOO/ mm’, blood urea 74 mg/100 ml, serum creatinine 1.4 mg/100 ml, urine albumin positive with, in the sediment, one to two pus cells, five to eight red cells and a few cellular casts per high power field. The aspartate transaminase was S8 Wroblewski units and the lactic dehydro- genase 880 units with a markedly raised first fraction. The chest X-ray showed a slightly enlarged heart. A diagnosis of myocardial infarction with supraventricular tachycardia, and disturbed renal function possibly due to preexistent renal disease, was made.

He was given 20 mg of ajmalin i.v., after which he con- verted to atrial fibrillation. He was then started on ajmalin orally, 300 mg daily, heparin i.v., 300 mg daily, acenocoumarin and digoxin by mouth. On the following

Acta med. scand. 190

APRIL

Fig . 1 . Patient 2. Relation of drug therapy to total leucocyte count and granulocyte count.

day he reverted to sinus rhythm, and the ECG then showed signs of an anteroseptal myocardial infarction. Because of a bronchial infection he was given a short course of prednisolone and tetracyline. He remained anx- ious about his condition and was also started on diazepam (Valium@) orally, 15 mg daily. On the tenth day he developed macroscopic haematuria, the thrombotest at the time being 7%, and the acenocoumarin was stopped. A microscopic haematuria, however, persisted.

On the 34th day after admission he developed a fever and complained of tiredness and weakness, It then appeared that he had developed agranulocytosis. All drugs were stopped-diazepam, digoxin and ajmalin. Within the following few days there was a rapid return to normal levels, the smear showing a marked “shift to the left” (Fig. 2). During this period the Hb decreased to a minimum of 8.1 g/lOO ml, the platelet count remained normal. The sternal bone marrow showed a relative lack of cells except for lymphocytes. During the following week he developed an oliguria and his urea and creatinine rose from the admission levels to a maximum of 336 mg/100 ml and 12 mg/100 ml respectively. Two weeks later, after a polyuric phase, these fell to 85 mg/100 ml and 2.1 mg/100 ml respectively.

While oliguric he again developed a supraventricular tachycardia, for which he was given quinidine orally. Af- ter a further 14 days he presented with a maculopapular rash, which disappeared o n cessation of ihe quinidine therapy.

Renal biopsy, performed during the oliguric phase, showed the following changes. Of the six glomeruli, one was hyaline and one ischaemic. The remaining four showed the presence of granulocytes, there was no endo- thelial o r mesangial cell proliferation. The interstitium contained lymphocytic and plasmacytic infiltrates, and some tubular atrophy was seen. Immunofluorescence in- vestigations showed a granular anti-IgA fluorescence lo- calised in the axial areas with sporadic membranous de-

A jmalin agranulocytosis 37

I PATIENT No 3

A . H l i l h 300 ma 0441.Y I 0 . 42 E P I H I $_mp >OA &V.- I 0 COX h 0 6 rnp ORA..Y J

PREONISO~ON I IF.HA’3ANllh LOO mp] ORALLY 16000

1L000-

12000-

10000-

1

JAN. FEB.

Fig. 2. Patient 3. Relation of drug therapy to total leucocyte count and granulocyte count.

posits. Anti-IgM and anti-IgG fluorescence was present axially in one glomerulus. Fibrin and albumin were present diffusely throughout the interstitiurn. The findings of the renal biopsy suggested a glomerulonephritis with, in addition, tubular and interstitial changes which were possibly unrelated to the glomerular process.

The patient was eventually mobilised and discharged on a low protein diet as his only therapy. He has since been seen as an outpatient with a recurrence of the supraventricular tachycardia. This was again treated with acenocoumarin and digoxin, without further complications in the form of haematuria, leucopenia or rashes. There has been no progression in the renal insufficiency.

Patient 4

A 76-year-old diabetic man was admitted in Dec. 1968 because of an acute anterolateral myocardial infarction. He was treated with anticoagulants (heparin and acenocoumarin); the tolbutamide and diabetic diet on which he had been prior to admission were continued. While being monitored multiple ventricular extrasystoles were seen, and he was started on 300 mg ajmalin daily. The anticoagulants were stopped shortly afterwards due to rectal bleed- ing from haemorrhoids. An attempt was made to stop the ajmalin when the patient was mobilized, but it had to be restarted due to the reappearance of the arrhythmia. Six weeks after the infarction he was readmitted with pyrexia and signs of pulmonary congestion. His leucocyte count was 1 700/mm3 with 18% segmented granulocytes and 6% band forms in the smear. Renal and liver function tests were normal. The patient was treated with

HARCH

aminophylline, digoxin and frusemide, the tolbutamide was continued and only the ajmalin was stopped. Within 2 days the temperature had returned to normal followed by an equally rapid increase in the leucocyte count and normalisation of the smear.

Patient 5

A 54-year-old man was first seen with complaints sug- gestive of angina pectoris in Feb. 1968. Telemetric electro- cardiographic examination revealed ST segment depres- sions after walking approximately 350 metres, associated with many ventricular extrasystoles. He was started on acenocoumarin, 300 mg ajmalin daily and trinitroglycerine tablets during an attack. A month later he was readmitted with epilepsy, for which he was treated with phenobarbitone from the fifth day. On the eighth day after this admission he developed a fever with malaise, and the blood counts revealed an agranulocytosis. Only the a& malin was stopped, and this resulted in a rapid improve- ment in the leucocyte count and a normal temperature on the second day. The phenobarbitone was continued, as was the acenocoumarin. The patient has subsequently taken trinitroglycerine without ill-effect.

SEROLOGICAL STUDIES

A leucocytotoxicity test was performed in each case; in addition a complement fixation test was carried out with sera from patients 1, 2 and 3.

The leucocytotoxicity test was performed according to


38 J . H . P . Wilson et al.

10-

8-

6 -

LEUCOCYIOlOXICI lY TEST - PATIENT No, 1

c_ P A l I E N l SERUM. AJMALIN

c-+ PAlIENT SERUM. S A L I N E A f----. CONlROL SERUM. AJMALIN . - + CONlROL SERUM * SALINE

= 2 -

- -_ -_ - _ c - - --.-

an adaptation of the dye exclusion technique of Engel- friet et al. ( 3 , 4). Donor leucocyte suspension was obtained from I healthy group 0, rhesus negative male, and was incubated with patient serum and varying concentrations of ajmnlin. The complement necessary for this test is present in the donor plasma. Each patient was tested on two occasions against a total of four or five different control sera (Fig. 3). Preparations were examined after 15, 30 and 60 min incubation and addition of trypan blue, and tht: percentage of cells taking u p the dye was plotted graphically to facilitate comparison. More than 6% coloured cells in the preparation at 15 and 30 min, if reproducible, was regarded as a positive result. Using this technique, cytotoxic activity dependent on the presence of ajmalin was detected in serum from patients 1 , 3, 4 and 5 taken during the acute episode. Serum from patient 2, as well as sera from patients 1 and 3 taken 12 and 6 weeks respectively after the acute episode, gave negative results.

The complement fixation test in the presence of leuco- cyles and ajmalin and a simple precipitation test using ajmalin solution were negative in all cases in which these tests were performed.

DISCUSSION

Agranulocytosis has been reported as a complica- tion of the administration of a large number of drugs. The mechanisms responsible for the

AJMALIN OUINlOlNE

Fig. 4. Chemical structure of ajmalin and quinidine.

Acta med. scatid. 190

neutropenia vary. Some drugs, e.g. the cytotoxic agents, regularly cause neutropenia if given in suf- ficient dosage, the neutropenia often being part of a pancytopenia. On the other hand many drugs are only sporadically associated with agranulocytosis, the appearance of the agranulocytosis pre- sumably being dependent on idiosyncracy or the development of hypersensitivity to the drug. Since the demonstration of leucoagglutinins in a patient with amidopyrine agranulocytosis by Moeschlin and Wagner (9), drug-dependent antileucocyte antibodies have been described in cases of “allergic” agranulocytosis caused by several other drugs.

Various in vitro tests have been developed to detect such antibodies-such as leucoagglutina- tion, leucocytotoxicity, complement fixation or antiglobulin consumption techniques (7). These tests do not provide identical information and it has been suggested that more than one should be tried when investigating a drug-induced cytopenia. All these tests, however, are not very sensitive and, as antibody concentrations may be low, false negative results may occur (10).

At present there is unfortunately no way of telling whether a new therapeutic agent will be likely to give rise to allergic cytopenia or not. No direct correlation exists between the chemical structure and this capacity, although certain groups constantly recur. Ajmalin was immediately suspect as being the offending agent in our first patient, as its chemical formula is very similar to that of quinidine (Fig. 4) which often causes an allergic cytopenia, as may also occasionally be seen during treatment with the other rauwolfia alkaloid, reserpine (2) . The rapid response of the patient to cessation of the ajmalin only, and the demonstration of the cytotoxic antileucocyte antibodies, provided confirmatory evidence.

A similar course, with prompt recovery after the ajmalin had been discontinued, and a positive test, was seen in patients 4 and 5. Patient 2 dif- fered in that he had no symptoms and the leucocytotoxicity test was negative. His leucocyte count also fell and rose gradually. That this occurred on stopping only the ajmalin makes it likely that this drug was also the cause of the agranulocytosis in this patient, although possibly by a different type of immunological reaction or even a different non-immunological mechanism.

In the case of the third patient, who had a posi-

Ajmalin agranulocytosis 39

tive leucocytotoxicity test, the question arises whether the oliguric episode which coincided with the agranulocytosis might not also have been an allergic reaction. I t is of interest to note that drugs which have been reported to cause an acute, pre- sumed allergic, interstitial nephritis are often the same as may cause allergic cytopenia (6). Any conclusions which one may be tempted to draw in this case, however, remain purely speculative. Although nitrofurantoin cannot be excluded as the causative agent in this patient, the literature contains few references to agranulocytosis associated with this widely used drug (2 , 8).

The combination of the clinical response to withdrawal of the ajmalin medication in all of the five patients, and the positive leucocytotoxicity tests in four of them, strongly suggest that the ajmalin was the cause of the agranulocytosis. The agranulocytosis developed between 14 days and 16 weeks after commencing treatment with the ajmalin. As at present there is no way of dis- tinguishing beforehand the patients who are likely to develop allergic agranulocytosis, we feel that ajmalin should preferably not be given orally for any length of time but reserved for the acute treatment of arrhythmias by parenteral administration.

1.

2.

3.

4.

5 .

6.

7.

8.

9.

10.

REFERENCES Bazika, V., Lang, T-W., Pappelbaum, S. & Corday, E.: Ajmalin, a Rauwolfia alkaloid for the treatment of digitoxic arrhythmias. Amer. J. Cardiol. 17: 227, 1966. Bernard, J., Dausset, J. & Magis, C.: Les cytopdnies m6dicamenteuses. Masson, Paris 1965. Engelfriet, C. P. & Eijsvoogel, V. P.: Cytotoxic iso- antibodies against leucocytes. Vox Sang. (Basel) 10: 228, 1965. Engelfriet, C. P. & Britten, A,: Cytotoxic antibodies against leucocytes. Vox Sang. (Basel) 11: 334, 1966. Forster, G. & Holzmann, M.: Zur Ajmalintherapie von Herzrhythmusstorungen. Schweiz. med. Wschr. 97: 185, 216, 1967. Heptinstall, R. H.: Pathology of the kidney. 455. Little, Brown, Boston 1966. Magis, C. C., Barge, A. & Dausset, J.: Serological study of an allergic agranulocytosis due to horamido- pyrine. Clin. exp. Immunol. 3: 989, 1968. Meyler, L. & Herxheimer, A.: Side effects of drugs, Excerpta Medica. (Amst.) Vol. VI. 1968. Moeschlin, S. & Wagner, K.: Agranulocytosis due to the occurrence of leucocyte agglutinins. Acta haemat. (Basel) 8: 304, 1952. Young, R. C., Nachman, R. L. & Horowitz, H. I.: Thrombocytopenia due to digitoxin. Amer. J. Med. 41:605, 1966.


Documents

AGRANULOCYTOSIS ASSOCIATED WITH AJMALIN THERAPY