Tadalafil is the third drug used to treat MED after sildenafil and vardenafil

Tadalafil is the third drug used to treat MED after sildenafil and vardenafil

[Background and Overview]

Phosphodiesterase 5 (PDE 5) inhibitors are an important drug used primarily to treat male sexual dysfunction (MED). There are currently three main drugs on the market, namely sildenafil (trade name Viagra, Viagra), vardenafil (Vardenafil, trade name Levitra, Elida) and Tadalafil. , the trade name Cialis, Xia Li). Currently, more clinical uses of phosphodiesterase 5 (PDE 5) inhibitors are still being developed and studied, including the treatment of pulmonary hypertension. After PDE 5 inhibitors have been put on the market, their market sales are increasing year by year. The first PDE 5 inhibitor for the treatment of MED is sildenafil citrate, which was approved by the FDA in the United States in 1998. When it went on the market, it quickly became the best-selling drug on the market. Tanafin was developed by GSK and transferred to Lilly-ICOS. It was approved by the FDA in 2003 and is the third drug to treat MED after sildenafil and vardenafil. Compared with similar drugs, it has the advantages of high selectivity, long half-life, and greater autonomy of patients.

Tadalafil is a reversible, selective phosphodiesterase-5 inhibitor (PDE5), a potent, long-acting, reversible PDE-5 inhibitor with pulmonary vascular selectivity that significantly increases NO levels and Expanding pulmonary blood vessels, oral absorption is rapid, healthy adults take 10mg and 20mg each time are safe and tolerant, no serious negative events, the best use on an empty stomach, do not drink alcohol, drink strong tea, eat spicy before taking . Tadalafil seems to be linear with time and dose. The plasma concentration is basically proportional to the dose. The average onset time is 16~30min. The plasma concentration peaks at 2~8h after taking, and the half-life is up to 17.5h. It is only necessary to take it once a day for PAH treatment.

【structure】

【specification】

Film-coated tablets: 5 mg, 10 mg and 20 mg in 3 sizes.

【Dosage】

There are two ways of administration, one is once a day, and the other is on-demand. Mild and moderate patients take 50 mg once a day, morning medication, for 3 weeks; on-demand medication can take 10-25 mg 30-60 min before sexual intercourse, including diabetic patients; only take every 24 h 1 time, the longest treatment period is 12 weeks; for liver function or renal insufficiency, the manufacturer recommends a dose of 10 mg.

[indications]

Male erectile dysfunction.

【Mechanism】

This product works by selectively inhibiting phosphodiesterase-5 (PDE5). Preclinical studies have found that this product is highly selective for PDE5, while other PDE isozymes such as PDE1, PDE2, PDE3, PDE4 and PDE6 The impact is small, so the impact of this product on the visual is less than sildenafil. Patients over the age of 45 continue to take 10 or 20 mg / d of this product, and will not affect sperm production and hormone regeneration within 6 months.

【Pharmacokinetics】

Absorption and distribution: oral administration of 20 mg of this product is rapid, and it takes effect within 30 to 45 minutes. The peak plasma concentration is 2 h, the peak value is 378 ng/mL, the effect lasts for 24 to 36 h, the protein binding rate is 94%, and the Vd is 62.6. L, t1/2 was 17.5 h, which was about 4 times that of sildenafil, and the plasma clearance rate was 2.48 L/h.

Metabolism and excretion: This product is mainly metabolized by hepatic cytochrome P4503A4 (CYP3A4) isoenzyme. The main metabolite is guaiacol glucoside, whether it is excreted by the kidney, and the food has no effect on its pharmacokinetic parameters.

【Adverse reactions】

1. Central nervous system: Headache is the most common adverse reaction, which can occur when it exceeds 10 mg, and its incidence is dose-related. The study found that in the case of on-demand treatment, the proportion of headaches in patients taking 2.5, 10, and 25 mg was 5.7%, 2.7%, 16.7%, and 13.9%, respectively, and the incidence of one dose per day was higher. .

2. Gastrointestinal system: There are reports of dyspepsia during treatment, the incidence of dyspepsia is high in one dose per day, but another study shows dose-independent doses of 2.5, 10, and 25 mg. The incidence of dyspepsia was 0%, 8.1%, 2.8%, and 8.3%, respectively, and some patients discontinued treatment due to indigestion and nausea.

3. Effects on skeletal muscle: Some patients have back pain and myalgia. There was no clear dose-effect relationship during on-demand treatment. When taking 2.5, 10, and 25 mg of this product, the proportion of back pain was 2.9%, 0%, 8.3%, and 2.8%, respectively; receiving 10 or 25 mg dose At the time, the patient's myalgia accounted for 2.8%, and some patients discontinued the drug because of back pain; the incidence of back pain and myalgia was higher in the daily dose group.

4. Eyes: Due to its mechanism of action, it should be significantly less than sildenafil or not, but further confirmation is needed. Eyelid edema may be related to this product, but it is rarely reported.

5. Others: occasional skin flushing during treatment. There was no significant effect on blood pressure, heart rate and ECG parameters of normal people. Healthy subjects and patients with mild ED over 45 years of age did not have an effect on serum testosterone, LH and FSH hormone levels. No effect on kidney function. No liver toxicity has been reported in the current study.

【medicine interactions】

Because this product inhibits PDE5 enzyme and thus affects cGMP degradation, the combination of this product and organic nitrate preparation may cause extreme blood pressure drop and increase the risk of syncope.

CYP3A4 enzyme inducer will reduce the bioavailability of this product; combined with rifampicin, cimetidine, erythromycin, clarithromycin, itraconazole, ketoconazole, HIV protease preparations, etc. may increase the blood of this product. The concentration of the drug should be adjusted to adjust the dose.

So far, no reports have been made of food and ethanol affecting the pharmacokinetic parameters of this product. However, it should be avoided in combination with grapefruit juice because of its enzyme inhibition.

【Precautions】

1. Disabled for allergic to this product.

2. Patients taking heart disease with nitroglycerin or their foil, patients with low liver disease/hepatic blood flow, renal insufficiency, and abnormal penile erection (eg sickle cell disease, leukemia, multiple myeloma, polycythemia, penile erection) Abnormal history), penile malformations such as Peyronie disease (invasion of the penis cavernous, painful penile erection), cavernous fibrosis and anatomical deformity are used with caution.

3. Pay attention to monitoring blood pressure and heart rate during medication, especially those with cardiovascular disease, headache, back pain, gastrointestinal discomfort, mild headache and dizziness should pay attention.

【Clinical application】

1. Erectile Disorder: A total of 1112 patients with normotensive or hypertensive erectile dysfunction were randomized, double-blind, and placebo-controlled for a clinical m-stage trial at a dose of 2.5-20 mg. The results showed that the erectile function was significantly enhanced in the medication group compared with the placebo group, the erectile function was improved by 81%, and the sexual impulse was 75%. No effect of blood pressure on the efficacy was observed. The main adverse reactions were headache and dyspepsia, but they were generally mild. There was no significant difference between the drug-administered group and the placebo group. This product has a good effect on patients with severe ED and related complications. 216 male patients with diabetic ED received placebo or tadalafil with a maximum dose of 20 mg for 12 weeks. Regardless of age, duration, and severity of ED, the drug group significantly improved sexual function compared with the placebo group, with 64% of patients in the high-dose group having increased erectile function and only 25% in the placebo group. The subjects covered a variety of diabetic patients, despite the complications of diabetes, but there were fewer reports of adverse drug reactions, mainly headaches and indigestion, accounting for 5% of the subjects. The adverse reactions were mild and easy to adjust. As the treatment continued to decrease, no changes in ECG or blood pressure were observed in clinical trials, and this product was not associated with color vision damage. Two test tests showed that the product was still effective after 24 hours of taking the drug.

2. Pulmonary hypertension: PHIRST-1 is the first large-scale clinical trial of tadalafil completed by Galie et al., a 16-week multicenter, randomized, double-blind, placebo-controlled study involving special hair Sexual, familial, diet drug-related, connective tissue disease-related, HIV infection, and congenital heart disease (including atrial septal loss, resting arterial oxygen saturation > 88% or ventricular septal defect / patent ductus arteriosus repair Patients with relevant PAH at least 1 year after surgery were enrolled in the age of 12 years or older. In this trial, 405 patients with PAH who did not take targeted therapy or took bosentan basic therapy (about 53%) were randomized to receive oral tadalafil (2.5 mg, 10 mg, 20 mg or 40 mg daily) or placebo. week. The results showed that oral administration of 40 mg once a day in tadalafil increased the walking distance by 6 minutes, delayed the clinical deterioration time, reduced the incidence of clinical deterioration, and improved the exercise capacity and quality of life of the patients, but the WHO cardiac function classification did not significantly improve. However, in the untreated group, tadalafil 40 mg was administered once a day, 37.8% of heart function improved, and 10.8% of heart function deteriorated; there was no statistically significant change in cardiac function in the bosentan-based group. The above trials have investigated the use of tadalafil in patients with PAH in heart function class II and III lesions. It is not clear whether these drugs are beneficial for patients with grade I and grade IV PAH. The European Medicines Evaluation Agency only approved tadalafil for PAH patients with grade III lesions, and the FDA did not limit the scope of approved use according to the WHO cardiac function classification. Subsequently, the PHIRST-2 test was performed on the basis of PHIRST-1. The study showed that the treatment of tadalafil 20mg or 40mg for 16 weeks can increase the walking distance by 6min. If the treatment time is increased by 52 weeks, the previously increased 6min walking distance will remain. The same, further confirms the effectiveness and safety of tadalafil long-term treatment.

【synthesis】

Using D-tryptophan as a raw material, the methyl esterification reaction is first carried out, and the resulting D-tryptophan methyl ester hydrochloride is subjected to Pictet-spengler reaction with piperonal in isopropanol to obtain a cis-tetrahydroporphyrin compound. Then, it was reacted with chloroacetyl chloride and methylamine in turn, and the total yield was 56%. After screening, glacial acetic acid was further purified as a recrystallization solvent.

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