Antihypertensive drugs(Alpha adrenoceptor antagonists)

            Alpha adrenoceptor antagonists

Mechanism of action:-

The sympathetic nervous system plays a major role in the pathogenesis of essential hypertension and is mediated by the alpha and beta receptors. The alpha receptor is divided into two types, alpha 1 and alpha 2, based on response to epinephrine and norepinephrine. alpha 1-Adrenergic receptors have a high affinity for drugs such as prazosin, doxazosin, and terazosin, which act to reduce blood pressure by selective blockade of the receptor. These agents provide a rational approach to the treatment of hypertension by correcting elevated total peripheral resistance, the fundamental hemodynamic abnormality in essential hypertension. In contrast, early alpha-adrenergic receptor blockers nonselectively blocked both alpha 1 and alpha 2 receptors and were unsuitable as antihypertensive agents because they induced tachycardia and patients developed a tolerance to them rapidly. alpha 1-Adrenergic blockers also have beneficial effects on plasma lipoproteins, tending to decrease levels of triglycerides and cholesterol and increase levels of high-density lipoprotein (HDL) cholesterol and the HDL cholesterol/total cholesterol ratio. beta-Adrenergic blockers, such as propranolol and atenolol, have been shown to have an adverse effect on the lipid profile by tending to increase levels of triglycerides and decrease HDL cholesterol. A number of mechanisms contribute to these effects, in particular, adrenergic modulation of lipoprotein lipase and the triglyceride secretion rate. Doxazosin has been shown to increase the activity of LDL receptors, which may be partly responsible for its beneficial effect on plasma lipids and lipoproteins.

Competitive alpha1-adrenoceptor antagonists are effective in the treatment of both hypertension and cardiac failure. Prazosin has both a short half-life and a short duration of action, but other related quinazoline derivatives, such as doxazosin and terazosin, have pharmacokinetic and pharmacodynamic profiles which make them potentially suitable for once-daily administration. Acute reductions in blood pressure have been correlated with plasma concentrations of prazosin but in most instances, particularly during long term therapy, there is no simple, direct relationship between drug concentration and the fall in blood pressure. Using integrated pharmacokinetic-pharmacodynamic analysis, correlations have been described not only for reductions in blood pressure during short and long term treatment but also for alpha1-adrenoceptor antagonist activity. Furthermore, this integrated approach defines the drug concentration-effect relationship in individual subjects and provides a mathematical description of response that is potentially useful for investigating the factors (both kinetic and dynamic) which influence the inter- and intrasubject variability in antihypertensive effect of alpha-adrenergic blockers. Preliminary data suggest that the long term response to treatment with prazosin and doxazosin is mainly dependent upon the height of the pretreatment blood pressure and the response to the first dose

Alpha-adrenoceptor antagonists in the treatment of benign prostatic hyperplasia.

Lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH) have a significant impact on the lifestyle of older men. Transurethral resection of the prostate (TURP) is the most effective surgical therapy for this condition but an increasing number of patients are electing conservative medical therapy. Alpha-Adrenoceptor antagonists and 5alpha-reductase inhibitors are the 2 categories of drug therapy currently available for BPH. Use of alpha-adrenoceptor antagonists in the treatment of BPH is based on their ability to prevent the neural stimulation which induces prostate smooth muscle contraction, producing lower urinary tract symptoms. Several studies have demonstrated that alpha-receptors predominate in the prostatic stroma, capsule and bladder neck. Initial work focused on the use of phenoxybenzamine, a nonspecific alpha-blocker, in the treatment of BPH. While results were promising, significant adverse effects and concern over potential mutagenicity have resulted in a lack of use of this medication for this indication. Subsequent attention was directed towards the short-acting alpha-specific antagonist prazosin. Results conflicted regarding whether an actual sustained improvement in lower urinary tract symptoms could be achieved with this medication, and because of twice daily dosing compliance issues were a drawback. Thus, the mainstay in pharmacological treatment of BPH over the past decade has been 2 once-a-day alpha-specific antagonists, doxazosin and terazosin. Over 75% of all prescriptions written for BPH are for one of these 2 medications. Despite their tremendous success in both decreasing urinary symptoms and increasing urinary flow rates, systemic adverse effects can be bothersome. Recently, efforts have focused on use of alpha1A-urospecific antagonists such as tamsulosin and alfuzosin in an attempt to achieve similar clinical results as doxazosin and terazosin without systemic adverse effects. Thus far, results are promising, but long term studies must be done to determine whether pharmacological uroselectivity is actually clinically relevant.

Adverse effects:-

Palpitation

Headache

Dizziness

Salt and water retention

First dose can cause severe postural hypotension

Doses

Prazosin:3-30mg daily

Terazosin:5-20mg daily once

Doxazosin:1-4mg once