The most commonly used medication for initial blood pressure reduction is a thiazide diuretic. The mechanism of action is to reduce plasma and extracellular ﬂuid volume. This lowering of volume is thought to decrease peripheral resistance. Cardiac output initially decreases and then normalizes (25). The important long-term effect is a slight decrease in extracellular ﬂuid volume. The maximum therapeutic dose of thiazides should be lowered to 25 mg, rather than the commonly used 50 mg. The benefit of higher doses is eliminated by the corresponding increase in side effects. Potassium-sparing diuretics (spironolactone, triamterene, or amiloride) are available in fixed doses and should be prescribed to prevent the development of hypokalemia. Potassium supplementation is less effective than the use of potassium-sparing agents. Thiazide diuretics are best used in patients with creatinine levels less than 2.5 g/L. Loop diuretics (furosemide) work better than thiazide diuretics at lower glomerular filtration rates and higher serum creatinine levels. Control of hypertension with concurrent renal insufficiency is difficult and is probably best handled by an internist or nephrologist. Thiazides and loop diuretics should not be used concurrently because profound diuresis may occur and lead to renal impairment. Concurrent use of nonsteroidal anti-inﬂammatory drugs (NSAIDs) limits the effectiveness of this class of drugs. Other side effects that further limit the usefulness of thiazide diuretics include hyperuricemia, which may contribute to acute gout attacks, glucose intolerance, and hyperlipidemias (26). The metabolic side effects of these drugs limit their popularity.
Beta-blockers were used extensively for years as antihypertensive agents. The mechanism of action is decreasing cardiac output and plasma renin activity, with some increase in total peripheral resistance. As a class, they are an excellent source of first-line therapy, especially for migraine sufferers. The original formulation, propranolol, is highly lipid soluble and contributed to bothersome side effects such as depression, sleep disturbances (nightmares in the elderly), and constipation in higher doses. Propranolol has a relative lack of beta selectivity, which promotes other undesirable phenomena. Formulations such as atenolol are water soluble, are beta1 selective, and have fewer side effects than propranolol. At higher doses, beta2 effects emerge. There is no evidence to support speculation that beta1 selective agents may be safe for use in individuals who have asthma. An advantage of water-soluble agents is a longer half-life. Reduced dosing schedules improve compliance. Side effects of beta-blockers include an increase in triglyceride levels and a decrease in high-density lipoprotein (HDL) cholesterol and blunting of adrenergic release in response to hypoglycemia. NSAIDs may decrease the effectiveness of beta-blockers. Contraindications to beta-blockers are asthma, sick sinus syndrome, or bradyarrhythmia. Beta-blockers are often used for the treatment of angina and after myocardial infarctions. However, if these drugs are acutely withdrawn, a rebound phenomenon of ischemia may occur, leading to acute myocardial infarction. Despite these potential problems, beta-blockers continue to be useful in counteracting reﬂex tachycardia, which often occurs with the use of smooth muscle relaxing drugs.