Avanafil & Dapoxetine

Mechanism of action:

• The mechanism of penis erection involves the release of nitric oxide (NO) into the corpus cavernosum during sexual stimulation, which then activates the enzyme guanylate cyclase leading to increased cGMP levels, leading to spontaneous muscle relaxation in the corpus cavernosum and blood flow Is produced for a construction.
• Avanafil is more powerful than other known phosphodiesterases (over 100-fold for PDE6), over 1,000-fold for PDE4, PDE8 and PDE10, over 5,000-fold for PDE2 and PDE7, over 10,000-fold for PDE1, on PDE5. , PDE3, PDE9, and PDE11). Avanafil is 100 times more potent for PDE5 than PDE6, which is found in the retina and is responsible for phototransfection. Dapoxetine is a potent selective serotonin reuptake inhibitor (SSRI) with IC50 at 1.12 nm, while its major human metabolites, desmethyldapoxetine (IC50 <1.0 nM) and didesmethyldapoxetine (IC50 = 2.0 nM) are equivalent or low-potency (POPE). (IC50 = 282 nM)).
• Human ejaculation is primarily mediated by the sympathetic nervous system. The ejaculation pathway arises from a spinal reflex center, mediated by the stem of the brain, which is initially affected by multiple nuclei in the brain (medial prophylactic and paraventricular nuclei).
• The mechanism of action of dapoxinate in premature ejaculation is thought to be associated with the inhibition of neuronal burst of serotonin and subsequent potentiation of neurotransmitters at pre- and postsynaptic receptors.

Pharmacokinetics:

• Avanafil is rapidly absorbed after oral administration, a median of 30 to 45 minutes. Its pharmacokinetics are dose-proportional over the recommended dose range. It is mainly abolished by liver metabolism (mainly CYP3A4). Is associated with concomitant use of potent CYP3A4 inhibitors (such as ketoconazole and ritonavir) with increased plasma exposure to avanafil.
• Absorption: Avanafil is rapidly absorbed. The maximum observed plasma concentrations are reached within 0.5 to 0.75 hours of oral dose in the fasting state. When avanafil is taken with a high-fat diet, the rate of absorption decreases with an average delay in Tmax of 1.25 hours and a mean decrease in Cmax of 39% (200 mg). There was no effect on the extent of exposure (AUC). Small changes in avanafil Cmax are considered to be of minimal clinical importance.
• Distribution: Avanafil is approximately 99% bound to plasma proteins. Protein binding is independent of total active substance concentrations, age, renal and liver function. Avanafil was not found to be deposited in plasma when 200 mg was applied twice daily over 7 days. Depending on the measurement of avanafil in the semen of healthy volunteers 45–90 minutes after the dose, less than 0.0002% of the administered dose may appear in the semen of the patients.
• Biotransforming: Avanafil is mainly cleared by CYP3A4 (major pathway) and CYP2C9 (minor pathway) liver microsomal isoenzymes. Plasma concentrations of the major circulating metabolites, M4 and M16, are approximately 23% and 29% of the parent compound. The M4 metabolite shows a phosphodiesterase selectivity similar to avanafil and has an in vitro inhibitory capacity for PDE5 18% of avanafil. Therefore, M4 accounts for about 4% of the total pharmacologic activity. The M16 metabolite was inactive against PDE5.
• Elimination: Avanafil is extensively metabolized in humans. After oral administration, avanafil is excreted primarily in the form of metabolites administered in feces (about 63% of the administered oral dose) and to some extent in the urine (about 21% of the administered oral dose).
• Absorption: Dapoxetine is a white powdered substance and water-insoluble. Taken 1-3 hours before sexual activity, it is rapidly absorbed into the body. Its maximum plasma concentration (Cmax) is reached within 1-2 hours after oral administration. Cmax and AUC (plasma vs. area under time curve) is dose dependent. Cmax and TM (time required to achieve maximum plasma concentration) are 297 and 498 ng / ml 1.01 and 1.27 hours after single doses of demaxitine 30 mg and 60 mg. A high-fat diet slightly reduces Cmax, but is negligible. In fact, food does not alter dapoxetine pharmacokinetics. It can be taken with or without food.
• Distribution: Dapoxetine is absorbed and rapidly distributed throughout the body. More than 99% of daphoxin is bound to plasma proteins. The average steady-state volume is 162 L. Its initial half-lives are 1.31 hours (30 mg dose) and 1.42 hours (60 mg dose), and its terminal half-life is 18.7 hours (30 mg dose) and 21.9 hours (60 mg dose).
• Metabolism: Dapoxetine is extensively metabolized in liver and kidney by several enzymes in the form of CYP2D6, CYP3A4, and flavin monoxide. The major product at the end of the metabolic tract is the proliferation of dapoxetine N-oxide, which is a weak SSRI and produces no clinical effect. Other products presented less than 3% in plasma are desmethyldapoxitin and daemmethidapoxetine. Desmethyldapoxetine is almost identical to dapoxetine.
• Excretion: Metabolites of dapoxetine are rapidly eliminated in the urine with a terminal half-life of 18.7 and 21.9 hours for a single dose of 30.7 mg and 60 mg, respectively.

Pharmacodynamics:

• Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor. The physiology of ejaculation mainly depends on serotonin and dopamine receptors, including 5-HT1a and 5-HT2c. Dapoxetine hydrochloride prevents bursting of the serotonin transporter. The drug binds with reuptake transporters of norepinephrine and dopamine and inhibits reuptake.

Precautions:

• Dapoxetine should not be used:
• Patients are allergic to its contents.
• Patients suffering from kidney disease or dialysis.
• Patients suffering from liver diseases
• Patients with heart problems (heart failure, irregular heart rate, valvular heart disease)
• Patients with bleeding disorders
• History of syncope (syncope)
• History of severe depression
• Tour history
• Serious alcoholics

Side effects:

Some of the commonly observed side effects may include:

• head ache
• Dizziness
• Sleepiness
• Tremors of earthquake
• Difficulty sleeping
• Nausea
• Loss of libido
• Diarrhea
• Dry mouth

Dosage:

For premature ejaculation and erectile dysfunctions (Adults):

• For premature ejaculation and erectile dysfunction (adult):
• The recommended adult dose of dapoxetine hydrochloride is 30 – 60 mg / day. The maximum dose should not exceed 100 mg / day. Take dapoxetine hydrochloride at least two hours before sexual intercourse to get maximum treatment benefits.

Over dosage:

• There have been no reported cases of drug overdose during clinical trials.

Warning:

• Pcan make you faint. You may experience warning symptoms such as nausea, dizziness or mild sadness before you faint. Unless you feel nauseous, dizzy or light-headed, until the symptoms pass, lie on your head or sit between your knees. This will prevent falls and injury. Do not take more than one PRILIGY tablet once every 24 hours due to the risk of syncope.

Duration of action:

• Dapoxetine is a short acting SSRI and doses of 30 mg and 60 mg have been evaluated through our meta-analysis. Peak plasma concentrations of dapoxetine were observed within 1.01–2.27 hours after oral administration 24. The elimination half-life time is 1.3–1.4 hours and there appears to be very little accumulation.

Drug- drug interactions:

• With phosphodiesterase inhibitors (PDE5 inhibitors): Many men who have PE also suffer from erectile dysfunction (ED). Treatment for these patients should consider drug – drug interactions between dapoxetine and PDE5 inhibitors such as tadalafil (Cialis) or sildenafil (Viagra). In the Dresser study (2006), plasma concentrations of 24 subjects were obtained. Half of the sample pools were treated with dapoxetine 60 mg + tadalafil 20 mg; the other half were treated with dapoxetine 60 mg + sildenafil 100 mg. These plasma samples were analyzed using liquid chromatography – tandem mass spectrometry. The results showed that dapoxetine does not alter the pharmacokinetic of tadalafil or sildenafil.
• With ethanol: Ethanol does not affect the pharmacokinetics of dapoxetine when taken concurrently.

Adverse reactions:

• The most common effects on taking dapoxetine are nausea, dizziness, dry mouth, headache, diarrhea, and insomnia. Relapse due to adverse effects is related to dose. According to McMahon in a recent study in Asia, the rate of discontinuation is 0.3%, 1.7%, and 5.3% of 1067, respectively, with placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively. In contrast to other SSRIs used to treat depression, which have been associated with a higher incidence of sexual dysfunction, dapoxetine is associated with lower rates of sexual dysfunction. Taken as needed, dapoxetine has very mild adverse effects of decreased libido (<1%) and erectile dysfunction (<4%).

Pregnancy:

• May or may not be harmful to an unborn fetus. Consult a doctor if you are planning to conceive during dapoxetine hydrochloride treatment.

Fertility:

• There is no information related to sperm measures, pregnancy results or fetal / fetal development on fertility.

Contraindications:

• Dapoxetine should not be used in men with moderate to severe liver impairment and in receiving CYP3A4 inhibitors such as ketoconazole, ritonavir, and telithromycin. Dapoxetine may also not be used in patients with heart failure, permanent pacemakers, or other significant ischemic heart disease. Caution is advised in men receiving thioridazine, monoamine oxidase inhibitors, SSRIs, serotonin-norepinephrine reuptake inhibitors, or tricyclic antidepressants. If a patient stops taking one of these medicines, they should wait for 14 days before taking dapoxetine. If a patient stops taking dapoxetine, they should wait 7 days before receiving these drugs.

Breastfeeding:

• It is not known whether dapoxetine or its metabolites are excreted in human milk.