A clinical pharmacological approach to the effective and safe use of tadalafil
The mechanism of action leading to penile erection involves inhibition of PDE5, the major cyclic guanosine monophospate (cGMP) hydrolyzing enzyme located in the vascular smooth muscle cells of corpus cavernosum. Sexual stimulation triggers the release of the endothelium dependent relaxing factor nitric oxide (NO), stimulating through the protein kinase G the release of guanylyl cyclase with an increase of intracellular cGMP, thus causing a decrease in intracellular calcium and, ultimately, the relaxation of trabecular erectile tissues and the dilatation of the helicine artery of the penis. The increase in blood flow causes the engorgement of the sinusoidal spaces of the corpora cavernosa, the tunica albuginea compresses the subtunical venules that drain the corpora and reduces the venous outflow increasing penile blood pressure and causing erection. This mechanism acts primarily to maintain the tumescence phase, whereas neuronal-derived NO is mainly active in the induction of erectile function. Inhibiting PDE5 prolongs the effects of nerve stimulation. Tadalafil, like the PDE5 inhibitors sildenafil and vardenafil, competitively blocks the cGMP hydrolysis by PDE5, thereby fostering cGMP accumulation and the relaxation of vascular smooth muscle. Increased concentrations of cGMP produce higher PDE5 promoter activities. cGMP accumulation stimulates cGMP degradation, but the pharmacological PDE5 inhibition blocks this negative feedback process. Thus, with PDE5 inhibitors, erection develops in a physiologic manner and only with sexual stimulation.
Chronic PDE inhibition, via the persistent activation of PDE5 promoters, may up-regulate PDE expression and, therefore, be associated with the development of drug tachyphylaxis. It has been shown that in the trabecular smooth muscle of the rat penis, sildenafil moderately down-regulated PDE5. The clinical long–term consequences of chronic PDE5 inhibition are still unknown. It has been reported that 20% of long-term sildenafil responders required increased dosages, while 17% discontinued because of loss of efficacy. It is also possible that the positive erectile response obtained with chronic administration may be related to functional tissue modifications involving up-regulation of either muscarinic receptors, or the transduction mechanism leading to the activation of endothelial NO synthase. As PDEs are expressed in different tissues, selectivity is a prerequisite for therapeutic application of PDE inhibitors. Canadian Tadalafil is selective for PDE5 and minimally inhibits PDE6, which works for visual transduction in the retina. With respect to PDE5, a 780-fold greater concentration of canadian tadalafil is needed to inhibit PDE6, and a 14-fold greater concentration to inhibit PDE11, an enzyme with unknown physiological function. Cheap Tadalafil’s nonselectivity with respect to PDE1 (expressed in the brain, myocardium, and vascular smooth muscle cells), may result in vasodilatation and tachycardia.
Generic Tadalafil is rapidly absorbed with the maximum plasma concentration occurring at 2.0 h, the extended terminal half life being 17.5 h. The rate and extent of absorption of tadalafil is not altered by food ingestion, age, diabetes, or mild to moderate hepatic insufficiency. The earliest significant time from dosing to erectogenic effect, objectively determined by a stopwatch in a placebo-controlled design, is 16 minutes with tadalafil 20 mg, and 30 minutes with the dose of 10 mg. This demonstrates that effective plasma level is achieved before reaching the maximum plasma concentration. Nevertheless, most men would require more time for generic tadalafil to be optimally effective; in particular, patients with severe ED or older patients should be encouraged to optimize the period of sexual stimulation.
In healthy subjects, over a range of 2.5–20 mg, tadalafil’s systemic exposure increases proportionally with the dose. Steady state plasma concentrations are attained within 5 days of once-daily dosing, with an exposure that is approximately 1.6-fold greater than after a single dose.