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Year : 1993  |  Volume : 39  |  Issue : 2  |  Page : 85-8

Newer concepts in drug therapy of hypertension.

Dept of Cardiology, KEM Hospital, Bombay, Maharashtra.

Correspondence Address:
B Dalvi
Dept of Cardiology, KEM Hospital, Bombay, Maharashtra.

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Source of Support: None, Conflict of Interest: None

PMID: 0007909564

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Keywords: Adrenergic alpha-Antagonists, therapeutic use,Angiotensin-Converting Enzyme Inhibitors, therapeutic use,Antihypertensive Agents, therapeutic use,Calcium Channel Blockers, therapeutic use,Diuretics, therapeutic use,Human, Hypertension, drug therapy,etiology,metabolism,Risk Factors,

How to cite this article:
Dalvi B, Vora A. Newer concepts in drug therapy of hypertension. J Postgrad Med 1993;39:85

How to cite this URL:
Dalvi B, Vora A. Newer concepts in drug therapy of hypertension. J Postgrad Med [serial online] 1993 [cited 2023 May 31];39:85. Available from:

The most common reason for patient visits to doctors and for prescription of drugs, is hypertension[1]. The past decade has seen more than two dozen trials on antihypertensive therapy trying to provide answers to basic questions like: Why? When? How? and finally, how far to treat? Over the last few years, our understanding of the pathophysiology of hypertension has undergone a radical change necessitating modifications in our approach to the medical therapy of hypertension. Hypertension is no more believed to be a sign comprising of an elevated reading of blood pressure measurement. It is considered a syndrome characterized by numerous metabolic and structural abnormalities[2]. Thus the aim of treatment of hypertension in the 90's is not merely bringing down the blood pressure to within the normal range but to try to correct the underlying metabolic and structural derangements.

No controversy exists about the role of drug therapy for moderate or severe hypertension. It has been adequately shown that drug therapy improves morbidity and mortality associated with these grades of hypertension[3],[4]. A physician is however, confronted with the dilemma of therapy for mild hypertension. Active drug therapy for mild hypertension has been advocated in the past few years based on the findings from various trials viz: Hypertension Detection and Follow-up Program - HDFP[5], European Working Party on Hypertension in the Elderly - EWHPE[6], Medical Research Council - MRC[7] and Australian[8]. These studies have shown that even minimally elevated pressures increase the overall risk for premature cardiovascular disease and that the progression of hypertension, strokes, renal damage and heart failure can be reduced by adequate therapy of mild hypertension[7],[8]. In contrast, most of the trials have failed to show a reduced incidence of fatal or non-fatal myocardial infarction in the treated groups (except EWHPE). The reason for the difference in the impact of therapy on cerebrovascular and cardiovascular morbidity and mortality is unknown but may be related to hypertension being the most important risk factor for strokes but only one of several risk factors for coronary artery disease[9].

Aggressive drug treatment of mild hypertension is now being seriously questioned since it has failed to show improvement in coronary mortality[3]-[7],[10],[11],[12],[13],[14]. Moreover, there have been growing concerns about the adverse effects of therapy, not only on biochemical markers of the syndrome of hypertension, but also upon the quality of life[15]. Finally, in the current era of resource crunch, there has been increasing recognition that the financial cost of protecting the relatively few who benefit is much larger than anticipated[16],[17].

The failure to show protection against coronary artery disease by drug treatment of hypertension may not reflect a fault in the reduction of blood pressure, but could mean that there is a fallacy in the manner in which it is being lowered. The majority of the trials which doubted the reduction in coronary events were conducted with beta blockers and diuretics[18],[19],[20] as anti-hypertensive agents. Both groups of drugs are known to alter the metabolic milieu by lowering potassium, raising lipid levels and altering glucose tolerance. This could result in a worsening of atherosclerosis and promoting arrhythmias, which could be life-threatening. With a change in the first line anti hypertensive drugs viz. a choice from angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers and alpha blockers it may be possible to increase coronary protection.

It is important to know the level of blood pressure, which should prompt introduction of drug therapy. Pooled data from various studies reveals that the benefit of treating patients with diastolic blood pressure above 100 mm Hg is certain, above 95 mm Hg is less certain but reasonably strong and those with diastolic blood pressure between 90 and 95 mm Hg, who constitute 40% of the entire hypertensive population, have not been found to benefit from drug therapy[5],[6],[7],[10],[11],[12],[13],[14]. Part of this failure to demonstrate the benefit may be due to the fact that many of the patients in these trials were not actually hypertensive. One third to one half of patients with diastolic blood pressure above 95 mm Hg will be persistently below 90 mm Hg after 4-6 months on no therapy[1]. On the basis of available data, the position adopted by WHO and the International Society of Hypertension[21], seems to be an appropriate compromise. They advocate that after 3-6 months of non-drug therapy, 95 mm Hg should be used as the level for institution of active drug therapy. However, patients who are at a high overall risk of developing coronary artery disease should probably be treated even if they have lower levels of diastolic blood pressure[22]. Included in this group are patients with known coronary artery disease, patients with a history of hypercholesterolemia, cigarette smoking, family history of premature coronary artery disease and diabetes. Due to a relatively lower degree of risk for developing cardiovascular events at every level of pressure, women are relatively less in need of drug therapy than men i.e. the level of instituting pharmacological therapy in most women may appropriately be a diastolic blood pressure of 100 mm Hg, rather than the level of 95 for most men. It Is important to understand that most of the studies which have compared clinic and ambulatory blood pressure values in hypertensive patients have shown poor agreement between the two and that there are substantial number of patients in whom clinic blood pressure overestimates the pressure at other times. This has led to the concept of "white coat" hypertension, which may be defined as a persistently elevated clinic pressure together with normal ambulatory pressure[23]. The main reasons for such a difference in observations are observer bias, error due to within subject variability of blood pressure and error arising from the alerting response or "white coat" effect. With ambulatory monitoring, the measurements become objective, greater in number and are outside the clinic thus eliminating the major sources of error. However, there are no criteria laid down on the basis of ambulatory blood pressure recording for the purpose of inclusion of patients in anti hypertensive drug trials. Moreover, of late the very existence of such white coat hypertension has been challenged[24]. Till such time that the issue is resolved, one will have to continue to depend on clinic blood pressure recordings.

The following broad principles should guide treatment of hypertension in any given individual.

1. It is advisable to decrease the blood pressure gradually to diastolic of less than 90 mm Hg without increasing the other cardiovascular risk factors[25].

2. It is mandatory to use non-drug therapy as effectively as possible, so that minimum drug therapy

is needed[25].

3. Stepwise therapy is the thing of the past[26]. The step care approach for treatment of hypertension consisted of using diuretics, beta blockers, vasodilators and sympathetic blockers in a stepwise manner. Although it helped in making the drug therapy for hypertension uniform, it did not give a free hand to the prescribing physician to choose what he considered best for that patient. This approach was modified in 1988 when even a calcium channel blocker or ACE inhibitor was recommended as the first step[27]. Presently, the emphasis is on individualizing therapy[27] i.e. choosing a particular drug according to the individual's level of blood pressure, his metabolic status, left ventricular function and a presence of associated diseases or risk factors eg. ACE inhibitors in diabetic patients, beta blockers or calcium channel blockers for hypertensives with associated ischaemic heart disease, calcium channel blockers for associated bronchial asthma, diuretics and ACE inhibitors for those with left ventricular dysfunction.

4. The logical approach is to start treatment preferably with one drug to be taken once or twice a day. After optimizing the dose and giving an adequate trial, if the response is unsatisfactory it is prudent to add another drug of a different class. Sometimes, one may have to consider combining two drugs before reaching the maximum dosage of any one if the patient complains of untoward effects. Since the treatment for hypertension is almost always long-term, the best compliance is known with fewer drugs prescribed with least frequency[27].

5. Regular check of blood pressure in supine and standing position is mandatory while treating hypertension so that drug therapy can be optimized without significant side effects. Of late, it is believed that there is a role for reduction and even omission of treatment if the blood pressure remains persistently normal. Perhaps in one fourth of mild hypertensives, drug therapy could be omitted[28].

The syndrome of hypertension consists of lipid abnormalities characterized by an increase in triglycerides, VLDL and LDL cholesterol with decrease in HDL cholesterol[2]. This is accompanied by hyperglycemia and hyperinsulinemia, which results from increased peripheral insulin resistance. As a part or because of insulin resistance there is hyperglycemia. Hyperinsulinemia has been considered as a bigger culprit for morbidity and mortality associated with hypertension as it results in an unfavourable lipid profile which predisposes to atherosclerosis and hypertension and also causes trophic changes in the vessel wall and cardiac muscle resulting in left ventricular hypertorphy (LVH). This has resulted in the increasing use of ACE inhibitors, calcium channel blockers and alpha blockers as the drug of choice rather than a beta blocker or diuretic.

Van Hooft et al[29] showed that the glomerular efferent arterioles of hypertensive patients have an exaggerated response to the renin angiotensin system and these alterations in renal hemodynamics are the basis of hypertension. Moreover, local cardiac renin-angiotensin system has been found to be responsible for left ventricular hypertrophy associated with hypertension. These changes in our understanding of pathophysiology of hypertension have resulted in more frequent and the early use of ACE inhibitors.

Left ventricular hypertrophy has been shown to be an independent predictor of cardiovascular morbidity and mortality in patients with hypertension[30]. It has been shown that at least a part of LVH is primary and may be related to the trophic influences of catecholamines, renin or insulin. Drugs like ACE inhibitors, calcium channel blockers and beta blockers are known to decrease LVH significantly and therefore could offer more cardiovascular protection[30].

One question which has evoked a lot of controversy over the last 3-4 years has been "How far to treat hypertension"? Until recently, it was assumed that the effect of reduction of blood pressure on cardiovascular risk was linear[31], thus justifying the opinion "lower, the better". Cruickshenk et al[32] have called attention to the J curve phenomenon in the treatment of hypertension, reflecting a progressive fall in risk as pressure is lowered, but only to a certain level; below which, the risk of coronary ischaernia increases. The J point is usually between 85-90 mm Hg diastolic blood pressure. However, such a cut-off point could not be defined for prevention of stroke and renal damage. The probable reasons for the occurrence of J curve are as follows: i) hypertrophied myocardium requires more nutrients and hence a fall in pressure below a particular point decreases the nutrient supply; ii) oxygen delivery to myocardium is near maximal even in a non-hypertrophied heart so there is no further extraction of oxygen when perfusion pressure is lowered; iii) coronary arteries are poor autoregulators, unlike cerebral vesse1s[33]; and iv) Coronary vascular reserve is limited, so a fall in pressure is not tolerated[34]. In 1990, McMohan et al[35] challenged the existence of such J curve. They combined the results of 9 studies[35]-[36] to refute the existence of such a threshold and concluded that the apparent J shape of the curve was because a one time diastolic blood pressure reading was used rather than the usual diastolic blood pressure thus resulting in a significant regression dilution bias and underestimation of true association. Moreover, previous history of vascular disease could have vitiated such an association. The studies selected to stress the importance of J curve were small and selective, too.

Although, there is no consensus on the level to which hypertension needs to be treated, most believe that it is not worth pushing the blood pressure to below diastolic of 85 mmHg. The end point of treatment[37], however, is not merely controlling the blood pressure but to achieve overall metabolic improvement consisting of a favourable lipid profile, adequate glucose tolerance, improved insulin sensitivity, maintenance of serum potassium and magnesium levels and also to reduce vascular complications and regress LVH.

  ::   Acknowledgment Top

Authors wish to thank Dr PM Pai, Dean and Dr PA Kale, Honorary Professor of Cardiology, King Edward Memorial Hospital for their help and guidance.

 :: References Top

1. Kaplan N. Systemic hypertension: therapy. In: Braunwald E, editor. Heart Disease, A Textbook of Cardiovascular Medicine. vol 1, 4th ed. Philadelphia: W B Saunders Co; 1992, pp 852-874.  Back to cited text no. 1    
2.Weber MA, Smith DHG, Neutel JM, Graettinger WF. Cardiovascular and metabolic characteristics of hypertension. Am J Med 1991; 91(Suppl. 1A):45-105.  Back to cited text no. 2    
3.Verterans Administration Cooperative Study Group on Antihypertensive agents. Effects of treatment on morbidity in hypertension II. Results in patients with diastolic blood pressure averaging 90 through 114 mmHg. JAMA 1970; 213:1143-1152.  Back to cited text no. 3    
4.Verterans Administration Cooperative Study Group on Anti hypertensive agents: Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressure averaging 115 through 129 mmHg. JAMA 1967; 202:1028-1034.  Back to cited text no. 4    
5.Hypertension Detection and Follow up Program Cooperative Research Group: The effect of anti hypertensive drug treatment on mortality in the presence of resting electrocardiographic abnormalities at base line; The HDFP experience. Circulation 1984; 70:996-1002.  Back to cited text no. 5    
6.Amery A, Birkenhager W, Brixko P. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985; 1:1349-1354.  Back to cited text no. 6    
7.Medical Research Council Working Party: MRC trial of treatment of mild hypertension: Principal results. Br Med J 1985; 291:97-104.  Back to cited text no. 7    
8.Reader R, Bauer GE, Doyle AE. The Australian therapeutic trial in mild hypertension: report by the management committee. Lancet. 1980; 1:1261-1267.  Back to cited text no. 8    
9.British Hypertension Society Working Party. Treating mild hypertension. Agreement from the large trials: Report of the British Hypertension Society Working Party. Br Med J 1989; 298:674-698.  Back to cited text no. 9    
10.Cutler JA, MacMohan SW, Furberg CD. Controlled clinical trials of drug treatment for hypertension. A review. Hypertension 1989; 13:1-36.  Back to cited text no. 10    
11.US Public Health Service Hospitals Cooperative Study Group, Smith WM. Treatment of mild hypertension. Results of a ten year intervention trial. Circ Res 1977; 40(Suppl 1):1-98.  Back to cited text no. 11    
12.Perry HM, Goldman AI, Lavin MA. Evaluation of drug treatment in mild hypertension: VA-NHILBI feasibility trial. Ann NY Acad Sci 1978; 304:267-288.  Back to cited text no. 12    
13.Helgeland A. Treatment of mild hypertension: A five year controlled drug trial. The Oslo study. Am J Med 1980: 69:725-732.  Back to cited text no. 13    
14.Multiple Risk Factor Intervention Trial Research Group,: Baseline rest electrocardiograph ic abnormalities, antihypertensive treatment and mortality in the Multiple Risk Factor Intervention Trial. Am J Cardiol 1985; 55:1-15.  Back to cited text no. 14    
15.Bulpitt CJ Fletcher AE, Importance of well being to hypertensive patients. Am J Med 1988; 84(Suppl 1 B): 40-6.  Back to cited text no. 15    
16.Littenberg B, Garber AM, Sox HC Jr. Screening for hypertension. Ann Intern Med 1990; 112:192-202.  Back to cited text no. 16    
17.Menard J. Hypertension costs: source, evolution and impact of cost-containment measures in various health-care systems. Clin Exp Hypertens (A) 1989; 11(5-6):1149-1169.  Back to cited text no. 17    
18.IPPPSH. Collaborative Group. Cardiovascular risks and risk factors in a randomized trial of treatment based on the beta blocker oxprenolol: The International Prospective Primary Prevention Study in Hypertension (IPPPSH). J Hypertens 1985; 3:379-392.  Back to cited text no. 18    
19.Wilhelmsen L, Berglund G, Eimfeldt D. Beta-blocker versus diuretic in hypertensive men: main results from the HAPPHY trial. J Hypertens 1987; 5:561-572.  Back to cited text no. 19    
20.Collins R, Peto R, MacMohan S. Blood pressure, stroke and coronary heart disease. Part 11, short term reduction in blood pressure: overview of randomized drug trials in their epidemiological context. Lancet 1990; 335:827-838.  Back to cited text no. 20    
21.World Health Organ izationll nte rnational Society of Hypertension, Mild hypertension liaison Committee. 1989 guidelines for the management of mild hypertension. Memorandum from a WHO/ISH meeting. J Hypertens 1989; 7:689-699.  Back to cited text no. 21    
22.Samueisson O. Experiences from Hypertension trials. Impact of other risk factors. Drugs 1988; 36(Suppl 3):9-20.  Back to cited text no. 22    
23.Pickering TG. Differing perspectives on white coat hypertension. Arch Int Med 1992; 152:691-692.  Back to cited text no. 23    
24.Pearce KA, Grimm RH, Rao S, Svendsen K, Liebson PR, Neaton JD, Ensrud K, et al. Population derived comparisons of ambulatory and office blood pressures: implications for the detection of usual blood pressure and the concept of white coat hypertension. Arch Int Med 1992; 152:50-56.  Back to cited text no. 24    
25.Kaplan N. Cost Benefit of anti hypertension therapy. Cardiology Guide, 1991: 2:3-5.  Back to cited text no. 25    
26.Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. The 1984 report of Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Int Med 1984; 114:1045-1057.  Back to cited text no. 26    
27.Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure.The 1988 report of Joint National Committee on Detection, Evaluation and Treatment of High blood pressure. Arch Int Med 1988; 148: 1023-1037.  Back to cited text no. 27    
28.Alderman MH, Lamport B. Withdrawal of drug therapy in the treatment of hypertension. In: Kaplan NM, Brenner BM, Laragh JH, editors. New Therapeutic Strategies in Hypertension. New York: Raven Press; 1989, pp 171.  Back to cited text no. 28    
29.Van Hooft IMS, Grobbe DE, Derekx FHM, DeLeew PW, Schalekamp MADH, Hofman A. Renal hemodynamics and the renin-angiotensin aidosterone system in normotensive subjects with hypertensive and normotensive patents. N Eng J Med 1991; 324:1305-1311.  Back to cited text no. 29    
30.Frohlich ED. Cardiac Hypertrophy in hypertension. New Eng J Med 1987; 317:831-833.  Back to cited text no. 30    
31.Epstein FH. Proceedings of the XVth International Congress of Therapeutics, Sept. 5-9, 1979, Brussels: Excerpta Medica; 1980.  Back to cited text no. 31    
32.Cruickshenk JM. Coronary flow reserve and the J curve infarction. Br Med J 1988: 297:1227-1230.  Back to cited text no. 32    
33.Berglund G. Goals of anti hypertensive therapy. Is there a point beyond which pressure reduction is dangerous? Am J Hyperlens 1989; 2:586-593.  Back to cited text no. 33    
34.Pepi M, Alimento M, Maltagliata A, Guazzia MD. Cardiac hypertrophy in hypertension. Repolarisation abnornalities elicited by rapid lowering of pressure. Hypertension 1988; 11:84-91.  Back to cited text no. 34    
35.Alderman MH, Ooi WL, Madhavan S, Cohen H. Treatment induced blood pressure reduction and the risk of myocardial infarction. JAMA 1989; 262:920-924.  Back to cited text no. 35    
36.MacMohan S, Peto R, Cutler J. Collins R. Blood Pressure, stroke, and coronary heart disease, part 1. Prolonged difference in blood pressure: prospective observational studies corrected for the regressional dilution bias. Lancet 1990; 335:765-74.  Back to cited text no. 36    
37.Schmieder RE, Messereli FH. Is the decrease in arterial pressure the sole factor for reduction of left ventricular hypertrophy? Am J Med 1992; 92(suppl 4B):285-385.   Back to cited text no. 37    


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Online since 12th February '04
2004 - Journal of Postgraduate Medicine
Official Publication of the Staff Society of the Seth GS Medical College and KEM Hospital, Mumbai, India
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