Blood Pressure Lowering Drugs

Blood pressure lowering drugs reduce risk of stroke (and myocardial infarction and death) in middle aged patients and even better in the elderly (NNT 86 vs 29 over 5 years) (Pearce 1998). However in the elderly the dysfunction in the autoregulation of brain blood flow, salt and fluids, and increased sensitivity to adverse effects and symptoms may change the picture. 

Scheme 13 depicts an interesting application of this methodology in the synthesis of a crucial intermediate for the blood pressure-lowering drug Aliskiren with the less-encumbered ligand 16c. In the presence of excess amounts of triethylamine, 58b was produced in 96% yield and 98% ee. Catalyst loadings were optimized at 0.016 mol% or S/C ratio of 6,000. At S/C ratio of 10,000, a slight loss of enantios-electivity and yield was noticed. 

Nowadays a broad spectrum of quite specific blood pressure lowering drugs is available which restricts the use of ganglion blockade. There are only a few situations in which the pharmacological blockade autonomous ganglia is clinically useful hypertensive emergencies, controlled hypotension in neurosurgery and in the treatment of pulmonary edema. 

B. Weidmann, Renin inhibitors, from transition state analogs and peptide mimetics to blood pressure lowering drugs, Chimia 1991, 45, 367-376. 

Cardiac work furthermore depends strongly on the state of the circulation system physical rest or work demand appropriate cardiac performance the level of mean blood pressure is an additional decisive factor. Chronic elevation of afterload leads to myocardial insuf ciency. Therefore, all blood pressure-lowering drugs can have an important therapeutic influence on the myocardium. Vasodilator substances (e.g., nitrates) lower the venous return and/or peripheral resistance and, hence, exert a favorable effect in angina pectoris or heart failure. 

Even people who have been taking blood pressure-lowering drugs will benefit from this natural choice. And individuals who are determined to get their blood pressure down without drugs will benefit enormously. Tomato extract, which is rich in the antioxidant polyphenols lycopene, phytoene, and phytofluene, has been shown to reduce blood pressure for treated but not completely controlled hypertensive individuals, as well as for never-treated men and women in the category of prehypertension. Two studies have been done at the University of the Negev in Beer Sheva, Israel, by Dr. Esther Paran and her colleagues. 

Three trials compared an angiotensin blocker with other blood pressure lowering drugs, and found a 20% reduction in the proportion of patients in whom proteinuria worsened or serum creatinine doubled during follow-up ... 

Webb DJ, Freestone S, Allen MJ, Muirhead GJ. Sildenafil citrate and blood-pressure-lowering drugs results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol 1999 83(5A) C21-8. 

ANG II is also known to induce release of catecholamines from the adrenal medulla and to suppress the reflex inhibition of the heart rate, with the latter probably the inhibiting vagal (cholinergic) neurons to the heart. This has a specific clinical effect that is useful in the use of ACE inhibitors as antihypertensives (see later) namely, the absence of reflex tachycardia seen with other types of blood pressure-lowering drugs such as a-blockers, diazoxide, hydralazine, and ganglionic blockers. 

The first successful drug treatments for hypertension were introduced after World War II. By that time, researchers had learnt that blocking the sympathetic nervous system could lower blood pressure. In 1946, tetraethyl-ammonium, a drug known for 30 years to block nerve impulses, was introduced as a treatment for hypertension. Hexamethonium, an improved version of tetraethylammo-nium, was available for use by 1951. Another effective blood pressure-lowering drug, hydralazine, resulting from the search for antimalarial compounds, was diverted to the treatment of hypertension when it was found to have no antimalarial activity, but to lower blood pressure and increase kidney blood flow. 

C. Ganglion-Blocking Drugs Nicotinic blockers that act in the ganglia (eg, trimethaphan) are very efficacious but because of their severe adverse effects (Table 11-2) are now considered obsolete. Hexamethonium and trimethaphan are extremely powerful blood pressure-lowering drugs. The major compensatory response is salt retention. Toxicities reflect parasympathetic blockade (blurred vision, constipation, urinary hesitancy, sexual dysfunction) and sympathetic blockade (sexual dysfunction, orthostatic hypotension). 

The same inheritance controls the acetylation (deactivation) of the antibacterial sulfonamides, the anti-arrhythmic cardiac drug, procainamide (7.56) (Woosley et aL, 1978), the blood-pressure-lowering drug, hydralazine 11.47), and the amine derived by metabolism of the sedative, nitrazepam (12.98). In each case, rapid acetylation reduces the effect of the drug, but slow acetylators of hydralazine are unfortunate for they are prone to develop systemic lupus erythematosis, with arthritis-like symptoms (Batchelor a/., 1980). 

An example of a steric hindrance necessary to achieve the desired pharmacological response is afforded by bretylium (13.4), which has been used as a blood-pressure lowering drug. The bromine in this substance can be... 

---