The Broad Scope of Antihypertensive Therapy Choosing an antihypertensive agent in patients with diabetes and hypertension

Depending on the population, it is estimated that between lO and 80% of diabetic patients have hypertension. Elevated BP among diabetics is as-sociated with an increase in mortality rate. As BP reduction can decrease the secondary complica-tions of diabetes mellitus, treatment of hyperten-sion in such patients is of particular importance.

Therapeutic modalities The risk profile of the hypertensive diabetic

patient may be influenced by a programme of weight reduction, smoking cessation, sodium and fat restriction and alcohol moderation used in con-junction with antihypertensive drug therapy.

Although the Working Group on Hypertension in Diabetes recommends a small dose of a thiazide diuretic, beta blocker, prazosin, ACE inhibitor or calcium antagonist as initial antihypertensive therapy, the differences in metabolic effects for each pfthese agents make some more appropriate to use in hypertensive patients with diabetes than others.

Thiazide diuretics have an unfavourable effect on lipoproteins and may reduce glycaemic control. They are not very effective in diabetics with nephropathy, and loop diuretics may be more ap-propriate. Sodium restriction, alone or with a cal-cium antagonist possessing some intrinsic diuretic effects, is a better choice than a thiazide in non-insulin-dependent diabetes without nephropathy or overt fluid retention.

Beta blockers may reduce glycaemic control and have an unfavourable effect on lipoproteins, al-though beta blockers with intrinsic sympathomim-etic effects have lesser effects on lipoproteins. Non-selective beta blockers have a greater negative effect on glucose homeostasis, may exacerbate hypogly-caemic problems and may further reduce peri-pheral blood flow and thus should be avoided in patients with diabetes.

Cardioselective beta blockers, however, have a lesser effect on glucose homeostasis than nonselec-tive beta blockers, have a potential preventive ef-fect on coronary disease, and are highly beneficial.

Prazosin has positive metabolic effects and may be used, although a low initial dose may be nec-essary to avoid orthostatic hypotension.

ACE inhibitors effectively reduce BP without af-fecting lipoprotein levels or impairing glucose con-trol. Secondary complications of diabetes are re-duced without serious adverse effects, proteinuria is reduced and progression of renal disease slowed

0I56-170J/ 90/ 02l0-00SI/ O$OI.OO/ O ® ADIS Pm.>

in those with nephropathy, with positive effects on quality of life.

Calcium antagonists favourably affect the lipo-protein profiles, but have the potential to alter glu-cose homeostasis because many of the processes in-volved in glycaemic control are calcium-dependent. Verapamil can be neutral or improve glucose con-trol, although an overdose can produce hypergly-caemia. Glucose homeostasis may be impaired with nifedipine, although nifedipine is apparently neu-tral in the majority of patients. Diltiazem has no apparent effect on glucose homeostasis and is ef-fective in the prevention of early reinfarction and severe angina pectoris following a non Q-wave myocardial infarction. In non insulin-dependent diabetes coronary artery disease is common, and calcium antagonists, in particular diltiazem, may be suitable alternatives to cardioselective beta blockers. Future drug therapy

In the future, the role of nonselective beta block-ers and thiazide diuretics in the management ofhy-pertensive diabetics will probably decline, and th~ use of agents with more favourable metabolic ef-fects, such as calcium antagonists and ACE inhib-itors, will probably increase. Andren L. General considerations in selecting antihypertensive agents in pati en ts wi th type II diabetes mellitus and hype rtension . A merican Journal of Medicine 87 (Suppl. 6A): 39-41. 8 Dec 1989 [72 references]

Treatment of hypertension in pregnancy Approximately 10% of all pregnant women have

hypertension at some stage during their pregnancy, with associated risks to the health and survival of the mother and baby. If hypertension is severe (~ 170/llOmm Hg), there is a risk of cerebral haem-orrhage, eclampsia and maternal death. Less severe hypertension is associated with the development of 'superimposed pre-eclampsia', reduced placental function , retarded fetal growth and increased peri-natal morbidity and mortality. Appropriate therapy and care may be sufficient to prevent many of the consequences of hypertension in pregnancy. Recognition of indicators

Hypertension of pregnancy is generally defined as an increase in BP of 30/15mm Hg from earlier stable values, or an absolute level of ~ 1301 85mm Hg, whichever is lower. In general, during pregnancy, systolic and diastolic BP will drop by about I 0-15mm Hg from nonpregnant levels, and failure to exhibit this change by the end of the first trimester is apparent in a large proportion of women who later develop frank hypertension. Other fac-

INPIIARMA® 10 F~h 1990

SJ

S2

tors increasing the risk of hypertension later in the pregnancy include first pregnancy, family history of pre-eclampsia, diabetes mellitus, multiple preg-nancy and extremes of age.

Nondrug therapy Patients with pre-existing or pregnancy-associ-

ated hypertension should be managed in consul-tation with a specialist obstetric unit, and trans-ferred to such a unit if maternal indications such as refractory high BP, increasing proteinuria, cere-bral irritability, abnormal renal or hepatic func-tion, abnormal coagulation status, or fetal indica-tions prior to 35 weeks' gestation (such as cessation of growth or unreactive cardiotocography) are found. Of primary importance is stabilisation of the patient's medical condition prior to transfer.

Initial assessment should include BP measure-ment, testing of the reflexes, inspection of the optic fundi, assessment of fetal growth, and checking of laboratory values such as urinary protein, serum uric acid and creatinine, haematocrit and platelet count.

Ongoing nondrug management should include serial uterine ultrasound examinations for the de-tection of fetal growth retardation, intermittent un-stfessed monitoring of fetal heart rate from about 30 weeks' gestation onwards and maternal rest. Dietary sodium restriction or diuretic therapy is not recommended unless there is evidence of intravas-cular volume overload, because of the contraction in plasma volume which occurs in most hyperten-sive women.

Drug therapy With the advent of effective antihypertensive

therapies, perinatal mortality has been reduced from > 30% in the 1940s to < 2% in specialist centres in the 1980s. Improved fetal monitoring, control of maternal hypertension, scheduled delivery and improved neonatal care have contributed to this improvement.

I

Centrally acting, beta blocking and vasodilating drugs have been used successfully. However, ACE inhibitors are not recommended because of a high incidence of stillbirths found in treated animals. Some of the more recent calcium channel blockers may be teratogenic and should not be used in the first half of the pregnancy.

Termination of the pregnancy should be consid-ered if continuation poses a significant threat to the welfare of the mother or the fetus. Eclampsia is a medical emergency and delivery should be rapid once the convulsions and hypertension have been controlled.

Although the hypertension will improve within 24 hours of delivery in most patients, some patients exhibit a transient worsening for some days. There-fore, monitoring is required until improvement is

JO Feb 1990 INPIIARMA@

confirmed. The underlying causes for the hyper-tension should be investigated.

Conclusion 'Because of the risks to hoth mother and hahy of hyper-

tension in pregnancy, this high-risk group of patients should he supervised closely throughout pregnancy in con-sultation with a Specialist Ohstetric Unit.' Gallery EDM. Child AG. Management of hypertension in pregnancy. Bulletin of the Postgraduate Committee in Medicine, University of Sydney 45: 11-16, Fcb 1989 [9 references] '1'.1

Drug therapy improves the prognosis of elderly hypertensive patients

Although it is well established that drug treat-ment of hypertension in young and middle-aged patients will decrease the associated morbidity and mortality, the prognosis resulting from drug treat-ment of hypertension in elderly patients remains uncertain.

Information from 6 recently published con-trolled studies with a lower age limit at randomi-sation of 60 years and which examined the hy-pothesis that antihypertensive treatment would improve the prognosis in elderly patients, was col-lated, along with data from other similar trials.

Ol'erall findings Intervention with antihypertensive therapy

clearly improved the prognosis of elderly hyperten-sive patients; however, to what degreee this finding can be extrapolated to the general population, is uncertain. Whether certain subgroups of elderly patients with complicated or uncomplicated hyper-tension derive more benefit from antihypertensive therapy than others has not yet been established. However, from subgroup analyses, it was found that the benefits of therapy are largely independent of BP upon trial entry and the presence or absence of cardiovascular complications. The treatment bene-fits gained tended to lessen with advancing age, and little or no benefit was apparent in treating patients > 80 years of age; whether the reduced benefit was merely associated with or causally related to ad-vancing age could not be established. This effect was also evident in the incidence of stroke events in both sexes, the benefits gained being greater in the 60-69 year subgroup than in the 70-79 year subgroup.

As many intervention trials did not include patients aged ~ 80 years, it was not established whether drug intervention improved the prognosis of patients in this age group. Many elderly subjects may have isolated or predominantly systolic hyper-tension, however, the effect of antihypertensive therapy in this group of patients has not been es-tablished. Studies are now in progress which may

0J56-270J/90/02JO-00S2/0S01.00/0 © ADIS Press

help to decide whether or not isolated systolic hypertension should be treated. Choice of drug therapy

In the trials studied, the agents used as first-line antihypertensives were either a diuretic, a centrally acting agent, or a beta blocker. Although diuretics are generally considered first-line agents, an in-creasing number of clinicians in Europe and Aus-tralia tend to initiate antihypertensive therapy with a beta blocker. Beta blockers have the advantages of causing fewer biochemical changes than diuret-ics and also possess a cardioprotective action in postinfarction patients, although the latter has not been confirmed in elderly patients.

Some of the more recent drugs, such as ACE in-hibitors, alpha blockers and calcium antagonists may also be considered as first-line agents in the elderly. In particular, calcium antagonists have few contraindications and evidence suggests that the ef-ficacy of this class of drugs increases with age. Fur-ther studies are required to establish whether newer agents can increase longevity and improve well being to a similar or greater extent than the cur-rently used agents. Lijnen P. Pharmacological intervention trials in elderly hypertensives. Drugs of Today 25: 787·797, No. 12 1989 [26 references] ""

Pinacidil: an antihypertensive agent with a novel mechanism of action

Pinacidil is a peripheral vasodilator, which ap-pears to cause relaxation of arterial smooth muscle by opening potassium channels, resulting in a shift in membrane potential towards the potassium equilibrium potential. As vasoconstriction is a ma-jor contributing factor to BP elevation, the use of agents which act as peripheral vasodilators has in-creased. Pharmacokinetics and pharmacology

Following oral administration, pinacidil is rap-idly and almost completely absorbed from the gas-trointestinal tract. The absorption of pinacidil is not affected by food intake. Calculated oral bio-availability is 80-100%; peak plasma levels are achieved within 0.5-1 hour and the plasma half-life is about 4 hours. An extended release formulation, 'Pindac', yields peak plasma levels at 1-3 and 5-7 hours, with a duration of activity of approximately 12 hours. The antihypertensive effect is propor-tional to drug plasma level which is also dose-re-lated. Pinacidil is 60-65% protein bound but is not ~fsplaced by such drugs as salicylates and warfarin. ~v olume of distribution is relatively high.

Elimination is primarily by renal excretion of the major metabolite (N-oxide). This metabolite is produced by hepatic oxidation and possesses one

0I56-2703/90/01J0-00S3/0$01.00/O (!) ADIS Press

third to one fifth of the vasodilator activity of the parent compound, but does not contribute to the antihypertensive activity of pinacidil under normal conditions. However, in the presence of impaired renal function the levels of the N-oxide metabolite may be increased several-fold, and in the presence of impaired liver function, levels of pinacidil are also increased.

The BP lowering effect of pinacidil is propor-tional to the BP at baseline, with a greater anti-hypertensive effect in those with higher baseline BP. Antihypertensive activity is dose-dependent in the range of 0.5-2.5 mg/kg. Pinacidil produces a marked reduction in peripheral vascular resistance both with single dose and chronic therapy. The decrease in arterial BP is accompanied by a reflex increase in HR, stroke volume, cardiac output and myo-cardial oxygen consumption, which can be com-pletely abolished by beta blockade. Evidence sug-gests that, compared with placebo, acute treatment with pinacidil can significantly improve supine BP and HR, cardiac and stroke volume indices, total peripheral resistance and forearm blood flow; compared with placebo, chronic therapy can significantly improve mean supine arterial pres-sure, cardiac index and systemic vascular resist: ance. Evidence suggests that long term pinacidil therapy does not affect renal function.

Therapeutic efficacy . Extensive clinical studies conducted in Europe

and the USA involving 4000 patients, over 2000 of whom received pinacidil, have evaluated the ef-ficacy and safety of pinacidil in the treatment of hypertension and over 400 patients have partici-pated in long term studies (~1 year). Evidence from an 8-week study of patients with mild to moderate hypertension, suggests that a mean daily dose of pindacidil 68mg can produce a response (supine diastolic BP ~ 90mm Hg and/or a reduction of ~ lOmm Hg) rate of 67% , significantly higher than placebo (24%). Further data show that combined pinacidiljhydrochlorothiazide therapy can yield a greater response rate than either drug alone.

In 2 studies, patients received pinacidil, prazo-sin or hydralazine monotherapy for initial control of hypertension; concomitant hydrochlorothiazide and/or propranolol were allowed for further BP control or to control adverse effects. In comparison with the prazosin group, the response rate to pin-acidil monotherapy plus allowed concurrent treat-ment with thiazide diuretic and/or beta blocker was higher (83 vs 75%); in comparison with the hy-dralazine group, the response rate was slightly higher in the pinacidil group, but not significantly so. The primary reason for concomitant thiazide therapy in pinacidil recipients was control of fluid retention, while prazosin and hydralazine recipi-

INPHARMA@ 10 Feb 1990

e~t.s received concomitant thiazide therapy for ad-dltlOnal control of hypertension. Approximately 50% of pinacidil recipients were found to respond to a dosage of ~ 25mg bid.

. Adverse effects which were found to occur sig-nIfica.ntly more frequently with pinacidil than pla-cebo 10cluded oedema, headache, palpitations and tachycardia. The frequency of fluid retention was found to be markedly reduced with concomitant thiazide therapy with a dosage regimen of pinacidil of < 25 mg bid.

Pinacidil has been shown to reduce total serum cholesterol by 4-5% in patients with mild to mod-erate hypertension, with a reduction in serum tri-gl.ycer.id~s of 13% vs an increase of 5% with placebo. P1OaCld11 has also been shown to increase levels of HDL cholesterol and reduce LDL cholesterol. The ?egree of effect on blood lipids appears to be greater ~n . t.hose wit.h hi.gher initial lipid levels at therapy InItiatIOn. P10acldil can also to some extent reduce the adverse effects on blood lipids of the diuretics.

Conclusions . Pinacidil belo.ngs to a new class of antihyperten-

Sives, the potassIUm channel openers, with a novel mec.hanism of activity. It acts by elevating the po-tassIUm conductance in vascular smooth muscle resulting in hyperpolarisation and vasodilatation' p~e~erenti~lly i~ precapillary vessels. In large scal~ clImcal tnals, pmacidil has been shown to be a safe and effective antihypertensive. Fluid retention ap-pears to be the main adverse effcct however con-comitant thiazide therapy markedly reduc~s the fr.equ~n~y of oed~ma and improves the efficacy of p1Oacldll. In addition, pinacidil has favourable ef-fects on blood lipid profiles. Ahnfelt-R0nnc 1. Jllrgensen HJ. Pinaeidil (Pindac®): a new antihy pertensive agent. Drugs of Today 25: 65-74. Jan 1989 [23 relerenccs]

Urapidil: update Urapidil is a postsynaptic alpha I antagonist with

antihypertensive applications

Pharmacodynamics . ~he pharmacodynamic profile of urapidil is

slmtlar to that of prazosin, although urapidil also has so~e central activity and improved tolerability 1Oclud1Og the absence of first dose syncope. Animal studies have indicated that urapidil reduces total peripheral resistance without the development of tolerance. At high doses urapidil possesses antiar-rhythmic properties.

Both in vitro studies and clinical trials have in-dicated that urapidil is free of effects on lipid and glucose metabolism . In patients with chronic ob-structive pulmonary d -:-ase. urapidil significantly lowered systemic and vIimonary arterial pressures at rest and during exercise, and may improve gas

10 reI> 1990 INPIIARMA@

exchange dunng exercise 10 these patients.

Pharmacokinetics Oral administration of urapidil controlled re-

lease capsules produces peak plasma concentra-tions which increase linearly with dose, with an ab-solute bioavailability of 72%; absorption is not affected by food. The apparent volume of distri-bution of urapidil is 0.41 to 0.77 L/kg.

Urapidil is extensively metabolised in the liver and excreted in the urinc. The elimination half-lif~ following IV or oral administration of urapidil is 2.7-4.8 hours, increasing markedly in patients with liver impairment. Urapidil pharmacokinetics are relatively unaffected by renal impairment.

Therapeutic use In clinical trials urapidil has been shown to cause

significant reductions in BP in patients with mild to severe hypertension, without significant in-creases in HR. Urapidil is an effective antihyper-tensive when administered as monotherapy or in combination with beta blockers and thiazide di-uretics .

Urapidil has also been successfully used in the treatme~t of hypertensive emergencies, including eclampsia and pre-eclampsia, hypertensive crisis and hypertension occurring during general and cardiac surgery, rapidly lowering BP without alter-ing HR. In the few patients with cardiac dysfunc-tion who have been studied to date, urapidil has improved myocardial oxygen consumption, sys-temic vascular resistance, left ventricular function cardiac output and pulmonary capillary wedg~ pressure; however, further study is needed to assess the full therapeutic potential of urapidil in these patients. In addition, urapidil may be beneficial to patients with pulmonary hypertension.

Oral urapidil 30 to 90mg bid may be used to treat essential hypertension, with titration of the dosage to the BP response of the individual patient. In the treatment of severe or refractory hyperten-sion and hypertensive emergencies, IV urapidil 10 to 50mg may be administered, with a further dose 5 minutes later if the response is unsatisfactory. Al-ternatively, continuous IV infusion of 9 mg/h for a maximum of 48 hours may be givcn, depending on BP response. Lower dosages may be required when the drug is administered to elderly patients. At present there are no dosage guidelines for the lise of urapidil in children. Conclusion

Thus, urapidil offers a useful alternative to cur-rently available drugs for the treatment of mild to sever~ hyperte~sion, either as monotherapy or in combInatlOn With other antihypertensive drugs. Langtry HD. Mammen GJ. Sorkin EM. U rapidil. A review of its pharmacod ynamic unu pharmacokinetic properties. and therapeutic potential In the treatment of hypertension. Drugs 38: 900-940. Dec 19H9 [14~ re ferences]

0I56-270J/ 90/ 01l0-00S4/ 0S()J.(IO/ O 1D ..1/)[."1 Prw