9-Nitrominocycline

Uses

9-Nitrominocycline is a 9-substituted Minocycline (M344800) derivative used as antibacterial agent.

Uses

9-Nitrominocycline is used as a reagent in the preparation of tigecycline from minocycline hydrochloride.

Indications

Minoxidil, an antihypertensive agent, produces arteriolar vasodilation by an unknown mechanism. In limited clinical studies, minoxidil increases penile rigidity and has been used in the long-term treatment of organic impotence.

Biological Functions

Minoxidil (Loniten) is an orally effective vasodilator. It is more potent and longer acting than hydralazine and does not accumulate significantly in patients with renal insufficiency. It depends on in vivo metabolism by hepatic enzymes to produce an active metabolite, minoxidil sulfate. Minoxidil sulfate activates potassium channels, resulting in hyperpolarization of vascular smooth muscle and relaxation of the blood vessel.

Pharmacology

The hemodynamic effects of minoxidil are generally similar to those of hydralazine, with the noteworthy exception that a greater decrease in peripheral vascular resistance and consequently a larger reduction in blood pressure can be achieved with minoxidil. Minoxidil produces no important changes in either renal blood flow or glomerular filtration rate. It has little or no effect on venous capacitance and does not inhibit the reflex activation of the sympathetic nervous system. Orthostasis and other side effects of sympathetic blockade are therefore not a problem. As with hydralazine, there is a significant increase in cardiac output that is secondary to reflex increases in sympathetic activity, hyperreninemia, and salt and water retention.These effects can substantially reduce the effectiveness of minoxidil when it is used alone.The addition of a -blocker and a diuretic to the therapeutic regimen will preserve minoxidil’s antihypertensive action while attenuating some of the undesirable side effects.

Clinical Use

The major indications for the use of minoxidil are (1) severe hypertension that may be life threatening and (2) hypertension that is resistant to milder forms of therapy. Compromises in renal function do not prolong either the plasma or the therapeutic half-life of minoxidil, and therefore, it seems to be particularly important for hypertensive patients with chronic renal failure.

Side effects

Signs of toxicity common to vasodilator therapy in general also occur with minoxidil; they are attributable to vasodilation and reflex increases in sympathetic nerve activity. These include headache, nasal congestion, tachycardia, and palpitations. These effects do not have great clinical importance, since minoxidil is almost always administered in combination with a -blocker, which antagonizes the indirect cardiac effects. A more troublesome side effect, particularly in women, is the growth of body hair, possibly due to a direct stimulation of the growth and maturation of cells that form hair shafts. Apparently, minoxidil activates a specific gene that regulates hair shaft protein. In any case, this particular side effect has been capitalized upon, and minoxidil is now marketed as Rogaine for the treatment of male pattern baldness.

Metabolism

Peak concentrations of minoxidil in the blood occur 1 hour after oral administration, although the therapeutic effect may take 2 or more hours to manifest. This is probably related to the time it takes to convert minoxidil to minoxidil sulfate. The antihypertensive action after an oral dose of minoxidil lasts 12 to 24 hours. The long duration of action allows the drug to be administered only once or twice a day, a regimen that may be beneficial for compliance. Interestingly, the therapeutic half-life is considerably longer than the plasma half-life. This may be, as has been suggested for hydralazine, a result either of accumulation of the drug and its active metabolite in arterial walls or a longer plasma half-life of the sulfated metabolite, or both.
The ultimate disposition of minoxidil depends primarily on hepatic metabolism and only slightly on renal excretion of unchanged drug. Because of this, pharmacological activity is not cumulative in patients with renal failure.