Tadalafil in the Treatment of Erectile Dysfunction: TREATMENT

In: Drug

25 May 2010

Treatment should begin with the least invasive therapies. Any drugs that might be contributing to ED should be discontinued. In the case of antihyperten-sive agents, other drugs with a different mechanism of action should be considered. Next, psychotherapy and behavior modifications might be considered, followed by oral drugs; locally injected drugs; vacuum devices; and, finally, implanted devices.

PHARMACOLOGY

During sexual stimulation, an erection is caused by increased blood flow in the penile area. The increased blood flow is the result of relaxation of penile arteries and the smooth muscle of the corpus cavernosum. The release of nitric oxide (NO) arbitrates this response, which stimulates the synthesis of cyclic guano-sine monophosphate (cGMP) in smooth muscle cells. cGMP causes smooth muscle relaxation and increases blood flow into the corpus cavernosum. The inhibition of PDE5 enhances erectile function by increasing the amount of cGMP. Although tadalafil inhibits PDE5, this inhibition has no effect in the absence of sexual stimulation because sexual stimulation is required to initiate the local release of NO.

PHARMACOKINETICS

An increased dose of tadalafil (2.5-20 mg) corresponds to a proportional elevation in serum concentrations in healthy subjects. Steady-state plasma concentrations are reached within five days of once-daily dosing. Exposure is approximately 1.6-fold higher than after a single dose. After a single oral dose, the maximum observed plasma concentration of tadalafil is achieved between 30 minutes and six hours, with an average time of two hours. Because the rate and extent of absorption of tadalafil canadian are not influenced by food, this agent may be taken with or without food.

The mean apparent volume of distribution following oral administration is approximately 63 liters, indicating dissemination into the tissues. At therapeutic concentrations, 94% of tadalafil is bound to proteins in plasma. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.

Tadalafil medication is eliminated primarily by hepatic metabolism via the cytochrome P450 3A4 (CYP3A4) pathway. The average terminal half-life of tadalafil is 17.5 hours in healthy subjects. It is excreted mainly as metabolites in the feces (61% of the dose) and, to a lesser extent, in the urine (30% of the dose).

PHARMACODYNAMICS

Kloner et al. conducted a randomized, placebo-controlled, double-blind, crossover, multicenter study to determine the enhancing effect of a 20-mg dose of tadalafil on the subsequent hypotensive response of a sublingual dose of nitroglycerine that was given 2 to 96 hours later. A total of 150 men who were at least 40 years of age received either placebo for seven consecutive days. On the seventh day, after a final dose of either tadalafil or placebo, 0.4 mg of sublingual nitroglycerine was administered at 2, 4, 8, 24, 48, 72, and 96 hours.

A significant interaction between tadalafil and nitroglycerine was observed at each time point, up to and including 24 hours. At 48 hours, the interaction was not observed; however, a few more tadalafil subjects than placebo subjects experienced a greater hypotensive effect. After 48 hours, the interaction was not detectable.


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