Antihypertensive treatment

Diuretics, such as those of the thiazide type, have been the cornerstone of first-line antihypertensive treatments for decades. However, popularity and use have eroded as a result of increases in sudden death in patients on diuretic therapy, and unfavorable effects on blood Hpids profile, ie, increasing cholesterol and triglyceride. These effects have been impHcated as possible causes for the lack of decrease in the mortaUty rate resulting from acute MI in patients treated with a diuretic (187,240,241). However, diuretics do protect against stroke and CHF. 

Finally, drug treatment in the elderly is of great importance and warrants special attention with regard to safety and tolerability, since systolic blood pressure is recognized as an important target for treatment, particularly in older persons. The benefits of antihypertensive treatment in the elderly and in patients with isolated systolic hypertension are greater than in younger persons. 

Because of their relative - selectivity, low doses of metoprolol, acebutolol, bisoprolol, and atenolol may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Bradycardia Metoprolol produces a decrease in sinus heart rate in most patients this decrease is greatest among patients with high initial heart rates and least among patients with low initial heart rates. 

For initial therapy, start with the 0.1 mg system. If, after 1 or 2 weeks, desired blood pressure reduction is not achieved, add another 0.1 mg system or use a larger system. Dosage greater than two 0.3 mg systems usually does not improve efficacy. Note that the antihypertensive effect of the system may not commence until 2 to 3 days after application. Therefore, when substituting the transdermal system in patients on prior antihypertensive therapy, a gradual reduction of prior drug dosage is advised. Previous antihypertensive treatment may have to be continued, particularly in patients with severe hypertension. 

Diltiazem, a benzothiazepine, has a pharmacodynamic and side-effect profile that is intermediary between those of nifedipine and verapamil. Diltiazem is mostly used in the treatment of stable angina. It also displays antihypertensive activity, although it is not widely used in antihypertensive treatment. In certain countries diltiazem is used as an antiarrhyth-mic agent with the same type of applications as verapamil. 

Diuretic-induced effects on lipid metabolism are dose-related (344,345) at low dosages of thiazides, changes are very slight while antihypertensive efficacy is well maintained. Diuretic-induced lipid changes have not been prominent in studies lasting one year or longer (364,365,359,362,366). An association between thiazide use or antihypertensive treatment and changes in serum lipids has been shown in some population surveys (367,368) but not in others (369). 

Aksnes TA, Reims HM, Kjeldsen SE, Mancia G. Antihypertensive treatment and new-onset diabetes mellitus. Curr Hypertens Rep. 2005 7 298-303. 

Table 1 Single Nucleotide Polymorphisms Associated to Reduction in Systolic Blood Pressure Upon Antihypertensive Treatment...

Kurland L, Liljedahl U, Karlsson J, Kahan T, Malmqvist K, Melhus H, Syvanen AC, Lind L. Angiotensinogen gene polymorphisms relationship to blood pressure response to antihypertensive treatment. Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) trial. Am J Hypertens 2004 17 8-13. 

Liljedahl U, Lind L, Kurland L, Berglund L, Kahan T, Syvanen A-C. Single nucleotide polymorphisms in the apolipoprotein B and low density lipoprotein receptor genes affect response to antihypertensive treatment. BMC Cardiovasc Disord 2004 4 16. 

Tabacova S, Little R, Tsong Y, Vega A, Kimmel CA (2003) Adverse pregnancy outcomes associated with maternal enalapril antihypertensive treatment. Pharmaco-epidemiol Drug Saf, 12 633-646. 

Gil-Nunez AC, Vivancos-Mora J (2005). Blood pressure as a risk factor for stroke and the impact of antihypertensive treatment. Cerebrovascular Diseases 20 40-52 GISSI-Prevenzione Investigators (1999). Dietary supplementation with -3 polyunsaturated fatty acids and vitamin E after myocardial infarction results of the GISSI-Prevenzione trial. Lancet 354 447-455 Glader CA, Stegmayr B, Boman J et al. (1999). Chlamydia pneumoniae antibodies and high lipoprotein (a) levels do not predict ischemic cerebral infarctions results from a nested case-control study in northern Sweden. Stroke 30 2013-2018... 

Figure 10.19. False transmitters that are used for antihypertensive treatment, a a-Methyldopa passes the blood brain barrier and is decarboxylated to a-methyldopamine, which upon synaptic release stimulates presynaptic 02-receptors. b Guanethidine acts on catecholaminergic synapses in the peripheral autonomous nervous system.

Imhof P. The significance of betal-beta2-selectivity and intrinsic sympathomimetic activity in beta-blockers, with particular reference to antihypertensive treatment. Adv Clin Pharmacol 1976 11 26-32. 

Wikstrand J, Berglund G. Antihypertensive treatment with beta-blockers in patients aged over 65. BMJ (Clin Res Ed) 1982 285(6345) 850. 

Feleke E, Lyngstam O, Rastam L, Ryden L. Complaints of cold extremities among patients on antihypertensive treatment. Acta Med Scand 1983 213(5) 381-5. 

In the UK Medical Research Council (MRC) trial, the outcome of antihypertensive treatment based on diuretics was compared with placebo in a very large number of hypertensive subjects (11). Treatment based on a thiazide did not increase the incidence of coronary events or sudden death indeed, thiazide-based treatment reduced the incidence of strokes by 67% and of all cardiovascular complications by 20%. It should be noted that the dose of bendroflumethiazide used in the MRC trial (lOmg/day) is now known to be unnecessarily high and that it was used without prophylaxis against hypokalemia. Even so, a subgroup analysis of data from the MRC Trial provided no evidence that the association between major electrocardiographic abnormalities and an increased likelihood of a clinical event was strengthened by bendroflumethiazide treatment (12). 

There is no vahd evidence that diuretics contribute to myocardial infarction, sudden death, or a failure of antihypertensive treatment or other risk factor interventions to prevent coronary deaths (50). An association between diuretics and sudden death has been suggested only in selected subset analyses, which allow no vahd conclusions. Even in subjects with electrocardiographic abnormalities before treatment, there is no sound or consistent evidence to support the suggestion that diuretics predispose to sudden death. 

Philipp T, Anlauf M, Distler A, Holzgreve H, Michaelis J, Wellek S. Randomised, double bhnd, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment results of the HANE study. HANE Trial Research Group. BMJ 1997 315(7101) 154-9. 

Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie G, Oberman A, Rutan GH, Stamler J. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA 1996 276(23) 1886-92. 

A 63-year-old hjrpertensive woman, who had a carcinoma of the distal esophagus resected 19 months earlier, developed chronic diarrhea. Clostridium difficile toxin was identified in her stools and the diarrhea resolved after treatment with metronidazole. Enalapril was added to her antihypertensive treatment, and 3 months later the diarrhea recurred. Stool examination was negative and there was no Clostridium difficile toxin. Her condition worsened and she lost 5 kg in weight She had marked eosinophiha (2.4 x 10 /1), and a small bowel biopsy showed mild chronic inflammation and edema, partial villous atrophy, and large clusters of eosinophils in the lamina propria with some focal infiltration of the epithelium. She stopped taking enalapril and her diarrhea promptly abated and the eosinophil count fell to 0.5 X 10 /1 at 3 weeks and 0.1 x 10 /1 at 2 months. 

In a retrospective chart review in 103 transplanted patients from January to November 1994, hypertension requiring perioperative treatment was observed in 51 cases (8). Treatment for hyperkalemia was necessary in 13 of the 38 patients who were treated with labetalol, compared with 11 of the 65 who were treated with another antihypertensive treatment. 

A particular feature of minoxidil is excessive hair growth (7), which occurs in about 70% of patients who take oral minoxidil, usually within 2 months of the start of therapy. Severe hypertrichosis, unacceptable even to men, has comphcated the otherwise successful antihypertensive treatment of six patients after renal transplantation, for which ciclosporin was also used. Since hypertrichosis has also been described with ciclosporin, there may be an additive pharmacodynamic interaction (8). 

A 68-year-old woman had a bullous eruption of pemphigus vulgaris after antihypertensive treatment with nifedipine. She was given high-dose systemic glucocorticoids. However, she was unresponsive and nifedipine was finally withdrawn. Although new lesions did not appear, she died a few days later with uncontrollable sepsis. 

Even if the increase in mean blood pressure is probably modest (less than 5.0 mmHg) the clinical relevance of such an increase can be large, especially in elderly people. In fact, an overview of randomized clinical trials of antihypertensive treatment has shown that a 5-6 mmHg increase in diastolic blood pressure over a few years can be associated with a 67% increase in the incidence of strokes and a 15% increase in coronary heart disease (30). These effects are apparent in both normotensive and hypertensive patients. 

Gurwitz JH, Avorn J, Bohn RL, Glynn RJ, Monane M, Mogun H. Initiation of antihypertensive treatment during nonsteroidal anti-inflammatory drug therapy. JAMA 1994 272(10) 781-6. 

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