Silenafil Citrate. Sildenafil, 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-phenylsulfonyl]-4-methylpiperazine citrate (Viagra), is a potent inhibitor of PDE5. It was initially studied for use in hypertension and angina pectoris because of its ability to increase intracellular levels of cyclic nucleotides. However, during phase I clinical trials, it was noted that the drug had little effect on angina and was unpredictable in managing hypertension. However, patients noted that there were improved effects in their sexual dysfunction. Therefore, the manufacturer decided to develop the investigational compound for treating erectile dysfunction, rather than for angina or hypertension. In March 1998, the FDA approved the drug for use in erectile dysfunction, becoming the first oral agent approved to treat erectile dysfunction in the United States. Within a year, it soon had annual sales exceeding $1 billion per year. The chemical structure of sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5.
Sildenafil is also effective in the rare disease, PAH (presented earlier in this chapter under "Endothelin Receptor Antagonist"). By increasing cycli nucleotide levels, it relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. As a result of the selective distribution of PDE-5 within the arterial smooth muscle of the lungs and penis, sildenafil acts selectively in these areas. In June 2005, the FDA approved sildenafil (Revatio) for the management of PAH. To avoid confusion with its use in either PAH or erectile dysfunction, the product used for erectile dysfunction is a blue oval tablet, whereas the product used for management of PAH is a round white tablet.63
Vardenafil Hydrochloride. Vardenafil, 4-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonyl-phenyl]-9-methyl-7-propyl-3,5,6,8-tetrazabicyclo[4.3.0]nona-3,7,9-trien-2-one (Levitra), was the second PDE5 introduced in the U.S. market. The metabolism of vardenafil is primarily by CYP3A4. As such, concomitant use of CYP3A4 inhibitors such as ri-tonavir, indinavir, ketoconazole, as well as moderate CYP3A inhibitors such as erythromycin typically results in significant increases of plasma levels of vardenafil.
Tadalafil. Tadalafil, (6^-trans)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino[1', 2':1,6] pyrido[3,4-b]indole-1,4-dione (Cialis), is a potent PDE5 inhibitor. It received FDA approval for the treatment of erectile dysfunction in December 2003. Because of its half-life of 17.5 hours, it is marketed as a 36-hour treatment. Tadalafil is predominantly metabolized by hepatic enzymes, including CYP3A4. The concomitant use of CYP3A4 inhibitors such as ritonavir, indinavir, ketoconazole, as well as moderate CYP3A inhibitors such as erythromycin have been shown to result in significant increases in tadalafil plasma levels. Much like sildenafil, tadalafil is under clinical investigation for managing PAH.64
Tadalafil POTASSIUM CHANNEL AGONISTS
The two agents that can be classified in this category are di-azoxide and minoxidil. These drugs are also called potassium channel openers. These agents activate ATP-sensitive potassium channels, which leads to a decrease of intracellular Ca2+ and reduces the excitability of smooth muscle. The primary action of these drugs is to open potassium channels in the plasma membrane of vascular smooth muscle. An efflux of potassium from the cell follows, resulting in hyperpolar-ization of the membrane, which produces an inhibitory influence on membrane excitation and subsequent vasodilation.
Diazoxide, USP. Diazoxide is used as the sodium salt of 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1, 1 -dioxide (Hyperstat IV). Diazoxide lowers peripheral vascular resistance, increases cardiac output, and does not compromise renal blood flow.
This is a des-sulfamoyl analog of the benzothiazine diuretics and has a close structural similarity to chlorothiazide. It was developed intentionally to increase the antihypertensive action of the thiazides and to minimize the diuretic effect.
It is used by intravenous injection as a rapidly acting antihypertensive agent for emergency reduction of blood pressure in hospitalized patients with accelerated or malignant hypertension. More than 90% is bound to serum protein, and caution is needed when it is used in conjunction with other protein-bound drugs that may be displaced by diazoxide. The injection is given rapidly by the intravenous route to ensure maximal effect. The initial dose is usually 1 mg/kg of body weight, with a second dose given if the first injection does not lower blood pressure satisfactorily within 30 minutes. Further doses may be given at 4- to 24-hour intervals if needed. Oral antihypertensive therapy is begun as soon as possible.
The injection has a pH of about 11.5, which is necessary to convert the drug to its soluble sodium salt. There is no significant chemical decomposition after storage at room temperature for 2 years. When the solution is exposed to light, it darkens.
Minoxidil, USP. Minoxidil, 2,4-diamino-6-piperidinopy-rimidine-3-oxide (Loniten), was developed as a result of isosteric replacement of a triaminotriazine moiety by tri-aminopyrimidine. The triaminotriazines were initially observed to be potent vasodilators in cats and dogs, following their formation of n-oxides in these animals. The triazines were inactive in humans because of their inability to form n-oxide metabolites; this led to the discovery of minoxidil. Minoxidil is the only direct-acting vasodilator that requires metabolic activation to produce its antihypertensive effect (Fig. 19.16). It is converted to minoxidil sulfate in the liver by a sulfotransferase enzyme.65
The antihypertensive properties of minoxidil are similar to those of hydralazine hydrochloride, in that minoxidil can decrease arteriolar vascular resistance. Minoxidil exerts its vasodilatory action by a direct effect on arteriolar smooth muscle and appears to have no effect on the CNS or on the adrenergic nervous system in animals.66 The serum half-life is 4.5 hours, and the antihypertensive effect may last up to 24 hours.
Minoxidil is used for severe hypertension that is difficult to control with other antihypertensive agents. The drug has
Minoxidil Minoxidil Sulfate
Figure 19.16 • Activation of minoxidil.
Minoxidil Minoxidil Sulfate
Figure 19.16 • Activation of minoxidil.
some of the characteristic side effects of direct vasodilatory drugs. It causes sodium and water retention and may require coadministration of a diuretic. Minoxidil also causes reflex tachycardia, which can be controlled by use of a ^-adrenergic blocking agent.
Minoxidil topical solution is used to treat alopecia andro-genitica (male-pattern baldness). Although the mechanism is not clearly understood, topical minoxidil is believed to increase cutaneous blood flow, which may stimulate hair growth. The stimulation of hair growth is attributed to va-sodilation in the vicinity of application of the drug, resulting in better nourishment of the local hair follicles.
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