Evaluating Verapamil in the Control of Hypertension Daily IV verapamil infusions lower BP in resistant essential or renovascular hypertension

In an open study, 11 patients w1th severe essential (n = 1 0) or renovascular (n = 1) hypertension resistant to conventional medication received daily infusions of verapamil 25mg in 5% glucose solution at a rate of 2.5 mgjmin. The infusions were continued until diastolic BP was < 100mm Hg for> 24 hours All patients continued taking their conventional medication of thiazide diuretics, propranolol or a-methyldopa dunng and after the infusions. 30 days after the last infusion, mean BP was reduced from 201/129 to 159/101mm Hg and after 4 months was still Significantly reduced (172/109mm Hg).

In a subsequent study of 5 similar patients receiving the same therapy, baroreceptor sensitivity, as measured by the angiotensin II test, was increased after the verapamil infusions. The authors concluded that the verapamil programme has long term antihypertensive effects as a result of increased baroreceptor sensitivity and ' ... should be introduced as a new alternative in the treatment of resistant hypertension with

the possibility of being repeated every 4 months it pressure rises'.

Lur.J FlL Carrascv Rlvl Ameflcan Journal of Cardiology 57 640-680 Feb 1986

Verapamil compares well with atenolol in essential hypertension ... In a double-blind crossover trial, 24 patients with essential hypertension (WHO stage I or II) received

verapamil 120mg bid and atenolol 50mg bid for 4 weeks each. A 2-week placebo washout preceded each treatment period.

A significant decrease in supine BP occurred during both treatments, from 154/103 to 140j88mm Hg with verapamil and 142j90mm Hg with atenolol. Stabilisation of BP was achieved in 80 and 71% of verapamil and atenolol recipients, respectively. One patient on atenolol experienced nausea, asthenia and weakness of the lower limbs, and sinus bradycardia was observed in 3 verapamil and 4 atenolol recipients. There were no other adverse effects on cardiac function and no episodes of atrioventricular block. Verapamil and atenolol, therefore, appear to be effective and well-tolerated antihypertensive drugs. Escudero J. Hernandez H. Martmez F Ameflcan Journal of CardiOlogy 57 540·580 Feb 1986

... and with propranolol. .. In a randomised crossover trial, 19 patients with essential hypertension (BP > 160/95mm Hg) received

either verapamil 120-240mg (mean 185mg) bid or propranolol 40-240mg (mean 126mg) bid. Verapamil and propranolol significantly reduced mean daytime BP (1200-1800 hours) from 174/101mm Hg

to 148/85mm Hg and 139/80mm Hg (p < 0.001), respectively, with significant (p < 0.001) reductions being maintained for 24 and 21 hours, respectively, without changing the shape of the circadian curve. Both drugs significantly reduced BP during isometric handgrip and bicycle ergometer testing. Mean heart rate was reduced by both drugs over the 24-hour period but by propranolol significantly more than verapamil between 0600 and 2200 hours.

Side effects including constipation, ankle oedema and facial flushing (verapamil) and lethargy and vivid dreams (propranolol) did not require treatment withdrawal. Hornung RS. Jones Rl. Gould BA Sonecha T. Raftery EB Amencan Journal of Card1ology 57. 930-980, 26 Feb 1986

... in mild to moderate hypertension . .. In a double-blind trial, 17 male patients, (35-74 years old) with mild to moderate hypertension (diastolic

BP 95-114mm Hg) were randomised to treatment with verapamil80mg tid increased over 4 weeks to 160mg tid (n = 10) or propranolol 40mg tid increased over 4 weeks to 120mg tid (n = 7). A 4-week placebo period preceded the trial and after 4 weeks' active treatment the dosages were gradually decreased.

Mean sitting BP was reduced to 145/91mm Hg (p < 0.01) with verapamil, and from 154/103 to 147/ 96mm Hg (p = NS/ p < 0.01) with propranolol. Both drugs similarly reduced standing BP. Mean heart rate was reduced from 78 to 70 beats/min by verapamil (p = 0.03) and from 77 to 66 beats/min by propranolol (p < 0.01 ). The authors concluded that 'the results have indicated that as a single agent verapamillsat least as effective as propranolol in this setting'.

Smgh BN. Rebanal P. P1ontek M Nademanee K Amencan Journal of Card1ology 57. 990-1050, 26 Feb 1986

... in patients with concomitant chronic angina pectoris ... In 2 double-blind crossover trials, patients with hypertension and concomitant chronic stable angina

pectoris received either propranolol 60-320 mgjday or verapamil 240-480 mgjday (n = 12), or either diltiazem 90-360 mgjday or nifedipine 30-120 mgjday for 3 weeks each. Patients entered placebo washout periods before, between and after the active treatment phases.

Supine BP was significantly reduced by all 4 treatments. Verapamil was more effective than propranolol in reducing standing diastolic BP. Mean heart rate was decreased further by propranolol at rest and during exercise than by verapamil. Similarly, diltiazem reduced mean supine and standing heart rates. However, nifedipine increased both supine and standing heart rates. All 4 drugs lowered the number of weekly anginal

10 INPHARMA'"' 19 Apr 1986 0156-2703/86/1005-0010/0$0100/0 © ADIS Press

episodes and verapam1l. n1fed1p1ne and d1lt1azem mcreased the exerc1se tolerance. One pat1ent was With­

drawn from diltiazem because of Mob1tz type 1 arrhythmia. ' Fr >hman WH Cllanap s t(1~mel8 Goldberger J P~ pptOes G e1 a Amerrcan Journat of CaraiOiogy 57 220290 26 Feb 1986

. .. but a combination of verapamil + propranolol is more effective than either treatment alone

In a double-blind crossover study 14 hypertensive pat1ents (diastolic BP 95-11 Omm Hg on smgle drug therapy) were given verapam1l 120mg lid and propranolol 80mg lid, alone and 1n combmatlon, and placebo for 4 weeks each

After treatment. supine diastoliC BP was 107mm Hg with placebo, 94 with propranolol, 90 w1th verapam11 and 84mm Hg w1th the comb1nat1on The reduction m BP and 1n heart rate was s1gmficantly greater w1th the drug combinat1on than w1th e1ther drug alone . The PR mterval was prolonged by the 3 active treatment reg1mens, and th1s was most marked w1th the combmallon The end-systolic and d1astolic d1mens1ons of the left ventricle were s1gmf1cantly mcreased by verapamd + propranolol compared w1th placebo. The auth­ors concluded that a comb1nat1on of verapam1l and propranolol IS very effect1ve 1n reducmg BP but treatment should be carefully mon1tored because of the possible adverse effects on cardiac function.

;ug•a H Cleland J f.f'dia) • ~ ·.,,a, G V.:lttres G Amerrcan Jourral ot Cawolog) 57 R00 82D Feo 1986

A bid regimen is as effective as tid during long term treatment ...

In an open study 43 pat1ents w1th m1ld to moderate hypertenSIOn rece1ved verapam1l 120.ug tid for 3 months then e1ther b1d (n = 13) or lid (n = 13) for 1 year. If sup1ne diastolic BP was not reduced to < 95mm Hg after 1 month, altizide 15mg + spironolactone 25 mg/ day (n = 14) was added to the treatment regimen

Verapam1l reduced mean sup1ne BP from 183,'105 to 165/ 94mm Hg (p < 0 001) after 1 month and to 157 j88mm Hg after 3 months (p < 0 001 compared w1th 1 month). The mean sup1ne BP of pat1ents rece1v1ng verapam1l b1d was 149/83mm Hg after 1 year and of pat1ents receiv1ng verapam1l lid was 154/87mm Hg w1th no sigmflcant difference between the 2 groups Mean sup1ne heart rate fell from 75 to 69 beatsjmm after 1 month (p < 0 001 ).

N1ne patients reported m1ld , generally transient s1de effects Including gastro1ntest1nal upsets (n = 5), t~redness ( 1) flushmg (2) and headaches ( 1)

The authors concluded that the study data' ... confirm the efficacy and tolerability of verapamil in treating mild to moderate hypertensive patients on both a short- and long-term basis'. Further the long term study showed b1d therapy was as effective as t1d therapy hus, 1ncreas1ng compliance

" • e• c• P Rooo.Ju' R Gosse P Da occn10 ·~ Amer~C<~n Journa' ol Cara:Oiog) 57 830 660 26 r:eb 1986

... and sustained release verapamil compares well with the conventional formulation

In an open study, 22 pat1ents w1th m1ld to moderate hypertension were g1ven verapamil 80·120mg lid for 6-7 months Ten of these pat1ents continued tak1ng d1uret1cs S1t11ng BP was reduced from 148/98 t o 130/80 mm Hg after 1 month of treatment and the reduct1on was ma1nta1ned for at least 4 months However. after 7 months mean BP was mcreased again to 143/93mm Hg Heart rate was unchanged

In a subsequent double-blind phase, the patients were random1sed to treatment w1th regular verapamil lid (n = 11) or sustained release verapamil once daily (n = 11) for 4 weeks The 2 formulations were s1m1lar in their effect on BP and th1s was conf~rmed dur·ng 24-hour ambulatory BP mon1tonng Side effects were mostly trans1ent and 1ncluded const1pat10n n = 6) and fat1gue (n = 2). Changes in ECG Included first­degree heart block (n = 3) and nonspec1hc ST-T changes (n = 5) The authors concluded that BP is effectively controlled by verapam1l m a sustamed release preparation .

' 7.•JchMan PK Sheps SG Sen rger A Sp•ei<errr.an RE 0 8nen PC e l al AmeriCan Journal o l CardiOlogy 51 740-790 Feb 1986

Plasma verapamil concentrations are dose-dependent and correlate significantly with BP reductions

In a single-blind study, 21 pat1ents (5 Blacks and 16 Wh1tes) w1th mild to moderate essential hypertension (s1tling diastolic BP 95· 114mm Hg) rece1ved verapam1l 80-160mg (mean 154mg) tablets bid for 4 weeks

Mean sitting BP fell from 152/ 104 to 143j94mm Hg (p < 0 01) w1thout affect1ng mean heart rate . Plasma verapam1l levels mcreased dose-dependently and a s1gn1hcant correlat1on between plasma verapam1l and BP reduction was recorded . A plasma verapam1l trough level (10·12 hours postdose) of 60-80 ,ug/ml generally 1nd1cated a therapeutic response

S1de effects were generally mild mclud1ng const1pat1on (n = 4), d1zz1ness (2). ep1sod1c palpitations (1) and un1focal premature ventricular contractions (1). One pat1ent w1th headaches w1thdrew from treatment and, in another palient, elevated serum transaminase levels returned to baseline after drug withdrawal

• tiSilman W Cl>artap S K·mmel 8 Sallzbcrg S. Stroll J. el al Arct11ves of Internal Med,cme 146 561·565. Mar 1986

0156-2703t 86! 1005.001lj OSOl.OO! O Cl ADIS Press INPHARMA F> 19 Apr 1986 11