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Safety and drug interactions

Published in Pharmacology

drug interactionsAs with every PDE5 inhibitor, tadalafil is absolutely contraindicated with nitrate medications for angina pectoris secondary to the potentiated hypotensive effect the drugs can have together. Because of the longer half-life, treatment with nitrate medications must be deferred for at least 48 hours after ingestion of tadalafil, compared with 24 hours for sildenafil (Viagra) and vardenafil (Levitra).

The cardiac effects of PDE5 inhibitors have received considerable attention because the drugs were originally studied as a treatment for angina pectoris secondary to their action of smooth muscle relaxation. All of the PDE5 inhibitor trials have tediously monitored study participants’ vital signs, particularly heart rate and blood pressure, monitored drug effects on cardiac electrophysiology, and tabulated the numbers of cardiovascular adverse events.

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Adverse events

Published in Pharmacology
Tags: tadalafil

Adverse eventsA large study of 2102 men from 11 different multicentered, randomized, double-blind, placebo controlled trials of tadalafil reported the drug is well tolerated overall. Fifty-one percent of men using tadalafil 20 mg had at least one adverse event (AE), but only 3.2% discontinued treatment. The most common AEs reported with the 20 mg dose were headache (15%), dyspepsia (8%), and back pain (5%) (Table 1). Most AEs are a result of vasodilation of vascular beds other than in the penis.

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Metabolism and excretion

Published in Pharmacology
Tags: tadalafil

MetabolismThe metabolism of generic tadalafil is via the hepatic enzyme cytochrome P450 34A (CYP34A) to a catechol metabolite, which undergoes further metabolism to its primary circulating metabolite, methylcatechol glucuronide, a 10,000-fold less potent molecule than tadalafil. The CYP34A metabolism pathway of tadalafil was verified with studies using a CYP34A inhibitor ketoconazole and a CYP34A inducer rifampin. Tadalafil is excreted largely as metabolites, approximately two-thirds into the feces and one-third into the urine.

Duration of action

Published in Pharmacology
Tags: ED, PDE5, tadalafil

Duration of action

Among the three PDE5 inhibitors, the half-life and thus duration of action is the pharmacologic parameter that is the most strikingly dissimilar. The half-life of tadalafil is 17.5 hours in normal healthy men and 21.6 hours in elderly men, while the half-lives of sildenafil and vardenafil are similar at 4 hours. This longer half-life provides a therapeutic window of 36 hours for generic tadalafil.

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Dosing and absorption Tadalafil (Cialis)

Published in Pharmacology

doseRecommended starting doses of tadalafil are 10 mg for on-demand dosing and 2.5 mg for once-daily dosing, and these doses can then be titrated up or down according to the efficacy and tolerability. It is absorbed as a low-solubility and high-permeability, or Class 2, drug within the FDA Biopharmaceuticals Classification System. With oral ingestion, after first-pass metabolism, tadalafil is approximately 80% bioavailable, compared to 40% and 15% with sildenafil professional and vardenafil professional, respectively. Tadalafil Professional has the slowest absorption of the available PDE5 inhibitors with a mean of 2 hours to reach its maximum concentration, compared with about 50 minutes for sildenafil and vardenafil. The onset of action of tadalafil may occur in as early as 15 minutes of dosing, although successful erections occur in fewer than 40% of men at this time point. It is not advisable to counsel patients that the drug effect may be seen in as early as 15 minutes because it may take up to 2 hours for a response in the majority of men. This may only create performance anxiety or loss of confidence in the treatment, leading to treatment failure.

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Phosphodiesterase selectivity

Published in Pharmacology

Phosphodiesterase selectivityTadalafil is at least 9000 times more selective for PDE5 than most of the other families of PDEs, with the exception of PDE11. PDE11 is found in the testes and prostate; however, despite partial inhibition of PDE11 by tadalafil at therapeutic doses, clinical significance of this observation has yet to be fully understood. A study by Hellstrom and colleagues concluded that there are no harmful effects of tadalafil on spermatogenesis or testicular function.

The PDE enzyme responsible for phototransduction in the retina, PDE6, is inhibited to some degree by canadian sildenafil and canadian vardenafil, but not canadian tadalafil. The inhibition of PDE6 explains the side effect of blue vision experienced by some patients with these two drugs, as PDE6 inhibition in the retina causes impairment of blue-green color discrimination. Slightly less common with vardenafil, altered vision is a reported side effect for 11% of men taking sildenafil 100 mg. Compared with sildenafil and vardenafil, tadalafil is much less inhibitory for PDE6, and it is over 700 times more potent for PDE5 than PDE6. For this reason, generic tadalafil has less than 0.1% occurrence of vision abnormalities.

Tadalafil pharmacology

Published in Pharmacology
Tags: tadalafil

The three available PDE5 inhibitors share a similar mechanism of action, but they have structural, pharmacologic, and clinical differences. The molecular structure of tadalafil is available in Figure 1. Tadalafil’s molecular structure is different than the similar structures of generic sildenafil and generic vardenafil. All three have a heterocyclic nitrogen-containing doublering system, with a central ring that is analogous to that of cGMP and allows for competitive binding of the drug with PDE5 at the catalytic site. Tadalafil is different in that it is a β-carboline-type PDE5 inhibitor with a piperazinedione ring formed from a modification of the hydantoin ring of sildenafil (Viagra).

Molecular structure of tadalafilFigure 1
Molecular structure of tadalafil.