Clinical trial with intravenous clonidine in treatment of severe hypertensionUG Gadgil, JD Sunavalla, IJ Pinto, UK Sheth
Department of Cardiology, K.E.M, Hospital Bombay, and Clinical Pharmacology Unit of Department of Pharmacology, Seth G. S. Medical College and K.E.M. Hospital, Parel, Bombay-400 012., India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 615261
Source of Support: None, Conflict of Interest: None
Thirty six patients with severe hypertension were treated with intravenous clonidine. In 67% of cases maximum response was obtained within 11 hours of administration of the drug. Average reduction in mean arterial pressure was 29%. Paradoxical rise in blood pressure was observed in some patients, immediately after clonidine administration. This could be prevented with prior administration of phentolamine intravenously. Clonidine (I.V.) supplied by two drug firms gave identical results.
Clonidine is a well established drug for management of hypertension. It is an imidazoline derivative synthesized by Stahle and associates  in 1962. Chemically, it is 2- (2, 6-dichlorophenyl amino) -2 imidazoline hydrochloride. This drug is effective when given in microgram doses. The mode of action of clonidine in lowering blood pressure is the central stimulation of alpha adrenergic receptors at hypothalamic level, which reduces the peripheral sympathetic tone,  and a peripheral mechanism, characterised by a reduction in the response of vascular smooth muscle to stimuli.  Acute intravenous administration of clonidine produces an initial rise in blood pressure, owing to a direct peripheral alpha adrenergic action,  and this is followed by a prolonged period of hypotension. This paradoxical rise in blood pressure can be prevented by administration of phentolamine or tolazoline, or use of intravenous sodium nitroprusside.
Effect of clonidine on parenteral administration (i.v.) and its value in treating severe hypertension are presented in this article.
Thirty six patients with moderate to severe hypertension were selected for this study. All the patients except one, had mean arterial pressure (Diastolic blood pressure + 1/3 pulse pressure) of 130 mm. Hg. or more. Patients were divided into four grades according to the severity of blood pressure.
The patients were admitted to the Intensive Cardiac Care Unit. The ECG, pulse rate and blood pressure were continuously monitored during the trial. Blood pressure and pulse rate were recorded in lying down, sitting and standing positions, just before the trial. Patients with either systolic blood pressure of 230 mm. Hg., or diastolic blood pressure of 140 mm. Hg., or more were administered 5 mgm. of phentolamine intravenously 10 minutes before the trial. Then clonidine 150 micrograms diluted in 5 ml. of 5% glucose was administered intravenously in bolus form.
Blood pressure and pulse rate were recorded in all the three positions at following intervals.
A. Every 1 minute for first 5 minutes.
B. Every 5 minutes upto 15 minutes.
C. Every 15 minutes upto 30 minutes.
D. Every J hour upto 2 hours.
E. Every 1 hour upto 6 hours.
F. Every 6 hours upto 24 hours.
In some cases, where fall in blood pressure was not significant, a second dose of clonidine (150 micrograms in 5 ml. of 5% glucose intravenously, in bolus form) was given.
Each trial lasted for 24 hours at the end of which the results were analysed.
Analysis of results was done under following headings.
A. Maximum response as regards fall in blood pressure and grading of the response.
B. Time taken to obtain maximum response after clonidine administration.
C. Relationship of pulse rate and fall in blood pressure following administration of the drug.
D. Paradoxical rise of blood pressure.
E. Time taken to return to pre-trial blood pressure level.
F. Presence of side effects.
Maximum response was graded according to fall in mean arterial pressure (MAP) after administration of the drug. Since this drug is used parenterally and is likely to be used during acute hypertensive emergencies in clinical practice, supine blood pressure was considered in evaluating the response.
Criteria for grading the response
A. Poor response: (i) Mean arterial pressure does not fall by any of the above mentioned grades [Table 1].
(ii) If mean arterial pressure falls by less than 10 mm. Hg. inspite of a fall in grade.
(iii) Presence of severe side effects or severe postural hypotension.
B. Fair Response:
If mean arterial pressure falls by one grade only.
C. Good Response:
If mean arterial pressure falls by two grades.
D. Excellent Response:
If mean arterial pressure falls by three grades or comes to normal.
The average age was 45.3 years. The youngest patient was a 10 year old girl while the eldest one was a 74 year old male.
There were 29 males and 7 females taken for the trial.
Hypotensive Effect of Clonidine
Average reduction in mean arterial pressure for all 36 patients was 29% [Table 2].
According to our criteria, out of 36 patients 4 showed excellent response, 11 good, 12 fair and 9 showed poor response.
Fall in Systolic and Diastolic Blood Pressure
Average systolic pressure before trial was 210.5 mm. Hg. which came down to 155.2 mm. Hg., at which time maximum fall in blood pressure was obtained, showing a 26.3% fall [Table 2].
Average diastolic blood pressure was 136.7 mm. Hg. before trial which fell to an average of 106.7 mm. Hg, with clonidine administration showing a fall of 21.9%.
Time taken for obtaining Maximum Response
When an antihypertensive agent is administered parenterally, time taken to obtain its maximum effect is very important. Analysing our cases, we found that, in 670 of patients, maximum response was obtained within 12 hours of administering the drug [Table 3].
Paradoxical Rise in Blood Pressure after Intravenous Administration of Clonidine
In 11 out of first 24 cases, blood pressure increased instead of decreasing after administration of Clonidine, in the first few minutes. This rise was especially frequent in grade IV cases. Therefore, 5mg. of phentolamine was administered intravenously, 10 minutes before Clonidine administration, to all cases with systolic blood pressure of 230 mm. Hg., or more and/or with diastolic pressure of 140 mm. Hg., or more. After that, only 2 cases showed paradoxical rise in blood pressure.
None of the patients went into left ventricular failure in spite of this sudden rise in blood pressure immediately after Clonidine administration.
Return of Blood Pressure to Pre-trial Level
Except in 5 cases, blood pressure did not return to pre-trial level within 24 hours after drug administration. Out of 5 cases, 1 took 24 hours, 1 took 5 hours, two took 4 hours and one came to pretrial level in 2 hours time.
Fall in pulse Rate
There was an average fall of 9 beats/ min. when maximum fall in blood pressure was obtained. No severe bradycardia was observed in any of these cases.
Comparison of Two Brands of Clonidine
Clonidine supplied by M/s. C. H. Boehringer, Ingelham was used for first 18 cases and that supplied by M/s. Unichem Laboratories was used for next 18 cases. On comparing the results by students t-test, no statistically significant difference was found between these two brands of I.V. Clonidine, both in patient response and side effects.
Almost half the patients (17) suffered from side effects, which might be attributed to the therapy. Drowsiness was the commonest side effect followed by giddiness and headache. One patient developed a syncopal attack and one got rigors following administration of the drug [Table 4].
The hypotension following intravenous Clonidine is due to reduction in cardiac output and heart rate without a corresponding rise in peripheral resistance. , These facts are also observed in haemo-dynamic studies in normotensive and in uncomplicated hypertensive patients after intravenous Clonidine administration. , Onesti et al  have noted that greatest decrease in blood pressure is within 1-2 hours after drug administration.
At present no ideal drug for treatment of hypertensive crisis exists. Therefore many workers have compared antihypertensive effect after intravenous Clonidine administration with effectiveness of other currently available antihypertensive agents. Considering the potency, speed of action, contra-indications, and side effects of currently available antihypertensive drugs, Clonidine appeared to be superior to reserpine, methyl dopa, hydralazine and guanethidine. When compared with trimetaphan, sodium nitroprusside and diazoxide, clonidine appeared to be inferior in speed of action and potency, but has less serious side effects. 
In our patients, clonidine was very effective in reducing both systolic and diastolic blood pressure in cases of severe hypertension and hypertensive emergencies. Most of the patients showed their response in first 90 minutes. Except drowsiness, a few minor side effects were observed in a small number of cases. Our results are comparable to those of Niar chos et al  and Mroczek et al .
Parenteral Clonidine is a safe and effective alternative drug for the treatment of severe hypertension and hypertensive emergencies. Clonidine I.V. as supplied by both the firms showed identical results.
Our thanks are due to the Dean, Seth G. S. Medical College and K. E. M. Hospital, Parel, Bombay-40-0012, for his kind permission to publish this article.
Joint financial support for this study from, C. H. Boehringer and Unichem Laboratories through Research Society, Seth G. S. Medical College and K. E. M. Hospital, Bombay, is gratefully acknowledged.
Thanks are also due to C. H. Boehringer and Unichem Laboratories for the generous supply of clonidine IN. as Catapress and Arkamine respectively.
[Table 1], [Table 2], [Table 3], [Table 4]