Clinical pharmacology

How Cialis works ?
The penis gets erect during sexual stimulation when increased blood flows to the penis resulting from relaxation of penile arteries and corpus cavernosal smooth muscle. This is due to the release of nitric oxide ( NO) from nerve terminals and endothelial cells which in turn leads to the synthesis of cGMP in smooth muscle cells.

Cyclic GMP (cGMP) causes muscle in the penis to relax so that more blood can flow in. Cialis is a selective inhibitor of PDE5. It inhibits the action of phosphodiesterase type 5 (PDE5) found in Corpus cavernosum smooth muscles in the penis. It is more effective, almost > 10,000-fold more potent for PDE5 than for other phosphodiesterases. Inhibition of PDE5 leads to an increases in the amount of cGMP.

Cialis Drug Interaction
•  Absorption :
Tadalafil, the active ingredient in Cialis, is rapidly absorbed after oral administration . After single oral-dose administration, Tadalafil achieves the maximum observed plasma concentration (C max ) between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of Tadalafil following oral dosing has not been determined . It can be taken without food and alcohol constraints as the rate and extent of absorption of Tadalafil are unaffected.

•  Distribution
Tadalafil easily gets distributed into tissues to the extent of 63 Litres. At therapeutic concentrations, 94% of Tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function. Samples collected from healthy human subjects approximately 5 hours after dosing indicated that <0.0005% of the total dose of Tadalafil is distributed to semen.

•  Metabolism
Tadalafil gets metabolised by the cytochrome P450 (CYP) 3A4 to a catechol metabolite. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than Tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.

•  Elimination
Tadalafil gets eliminated from the body mainly in the form of faeces ( 61%) and urine ( 36%). The mean oral clearance for Tadalafil is 2.5 L/hour and the mean half-life is 17.5 hours in healthy subjects.

•  Linearity/Non-Linearity
Tadalafil pharmacokinetics in healthy subjects is linear with respect to time and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are attained within 5 days of once-daily dosing. Pharmacokinetics determined with a population approach in patients with erectile dysfunction is similar to pharmacokinetics in subjects without erectile dysfunction.

Pharmacodynamics

• I. Effects on Blood Pressure :
A dose of 20 mg of Tadalafil when administered to healthy male subjects does not produce any significant difference compared to placebo on blood pressure. In addition, there is also no significant effect on the heart rate.

• II. Effects on Blood Pressure when CIALIS is Administered with Nitrates :
In clinical studies, Cialis (tadalafil) 10 mg augmented the hypotensive effects of nitrates due to the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. This can lead to lowering of blood presure to life-threating level.Therefore, administration of Cialis to patients who are using any form of organic nitrate is contraindicated. Cialis should not be used in patients with a known hypersensitivity to tadalafil or to any of the ingredients.

• III. Effects on Exercise Stress Testing
The effects of Tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled.

The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (Tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that Tadalafil was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received Tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by Tadalafil of the blood-pressure-lowering effects of nitrates.

• IV. Effects on Vision :
Tadalafil can lead to blurred vision, changes in colour vision, inability to discriminate between green and blue colour, conjunctivitis, eye pain, lacrimation increase and swelling of eyelids.

• V. Effects on Cardiac Electrophysiology : The effect of a single 100-mg dose of Tadalafil on the QT interval was evaluated at the time of peak Tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide)-controlled crossover study in 90 healthy males aged 18 to 53 years. A 100-mg dose of Tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of Tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100-mg dose of Tadalafil compared to placebo was 3.1 beats per minute.

• VI. Effects on Sperm Characteristics :
Cialis has no relevant effects on sperm concentration, sperm count, motility, or morphology. It also has no effect on serum levels of testosterone, luteinizing hormone, or follicle stimulating hormone.

Cialis dosage and administration

Cialis tablets are taken orally once a day.

•  Dosage for adult men
Healthy adult men can take a dose of 20 mg half an hour before sexual activity. The maximum recommended Cialis dosing frequency is once per day. It may be taken without food and alcohol constraints.

•  Dosage for eldery men
No dose adjustments are required for healthy elderly males (65 years or over). They can take the dose recommended for adult men.

•  Dosage for men with renal insufficiency
No dose adjustment is required for patients with mild renal insufficiency. For patients with moderate renal insufficiency , the starting recommended dose is 5mg not more than once a day and maximum dose of 10 mg not more than once in 48 hours. The dose of Cialis should be limited to 5 mg not more than once daily in patients with severe renal insufficiency.

•  Dosage for men with Diabetes
No dose adjustment is required for men with Diabetes.

•  Dosage for children
Cialis should not be used by individuals less than 18 yrs of age .