Vardenafil & Dapoxetine
Vardenafil & Dapoxetine
Dapoxetine, marketed as Priligy, among others, is a medication used for the treatment of premature ejaculation (PE) in men 18–64 years old. Dapoxetine works by inhibiting the serotonin transporter, increasing serotonin’s action at the postsynaptic cleft, and as a consequence promoting ejaculatory delay.
Vardenafil is used to treat erectile dysfunction (impotence; inability to get or keep an erection) in men. Vardenafil is in a class of medications called phosphodiesterase (PDE) inhibitors. It works by increasing blood flow to the penis during sexual stimulation. This increased blood flow can cause an erection.
Mechanism of action:
- Vardenafil inhibits cGMP specific phosphodiesterase 5 (PDE5) which is responsible for the degradation of cGMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is due to increased penile blood flow as a result of relaxation of the penile arteries and the corpus covarnosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle dysfunction and increases in the blood vessel. Inhibition of phosphodiesterase type 5 (PDE5) by vardenafil enhances erectile function by increasing the amount of cGMP.
- 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 preoptic 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.
- Absorption: In vardenafil tablets, vardenafil is rapidly absorbed with maximum observed plasma concentrations, reaching 15 minutes of oral administration in some men. However, 90% of the time, maximum plasma concentrations reach 30 to 120 minutes (mid-60 minutes) of the oral dose in the fasting state. Mean complete oral bioavailability is 15%. The oral dosage of vardenafil is increased proportionally to approximately the recommended dose range (5 – 20 mg) of AUC and Cmax.
- When vardenafil tablets are taken with a high-fat diet (containing 57% fat), the rate of absorption decreases, an increase in the median of 1 hour and an average decrease in Cmax of 20%. Vardenafil AUC is not affected. After a 30% fat meal, the rate and extent of absorption of vardenafil (Tmax, Cimax and AUC) are unchanged compared to administration under fasting conditions.
- Distribution: The average stable volume of distribution of Vandenfil is 208 L, indicating distribution in tissues. Vardenafil and its major circulating metabolite (M1) are highly bound to plasma proteins (approximately 95% of vardenafil or M1). For vardenafil as well as M1, protein ligation is independent of total drug concentrations.
- Depending on the measurement of vardenafil in the semen of healthy subjects 90 minutes after the dose, no more than 0.00012% of the administered dose may appear in the semen of the patients.
- Biotransformation: Vardenafil is metabolized primarily by liver metabolism in tablets via the cytochrome P450 (CYP) isoform 3A4 with some contributions to CYP3A5 and CYP2C isoforms.
- A major circulating metabolite (M1) in humans results from abrogation of valdnafil and is subject to a subsequent half-life metabolism with plasma elimination of approximately 4 hours. Some parts of M1 occur as glucuronide in the systemic circulation. The metabolite M1 exhibits a phosphodiesterase selectivity similar to vardenafil and in vitro potency for approximately 28% of phosphodiesterase type 5 compared to vodafil, resulting in an efficacy contribution of approximately 7%.
- Elimination: The total body clearance of vardenafil is 56 L / h resulting in a half-life of approximately 4–5 hours. After oral administration, vardenafil is excreted primarily in the form of metabolites administered in feces (approximately 91–95% of the administered dose) and to a lesser extent in the urine (approximately 2–6% of the administered dose).
- Dapoxetine is a selective serotonin reuptake inhibitor. Dapoxetine is a short-acting SSRI drug currently being considered for approval by the Food and Drug Administration (FDA) for the treatment of premature ejaculation in men, which would be the first drug approved for such treatment. Despite two clinical trials ending in 2006, experts suspect it will soon be approved by the FDA as SSRIs come with undesirable side effects after prolonged use, such as psychiatric problems, skin reactions, body Increase in weight, reduced sex-drive. Nausea is troubled by headaches, stomach and weakness, thus the risk versus premature ejaculation does not outweigh the benefits of the drug. Unlike SSRIs approved for depression, which take 2 weeks or longer to reach steady state, dapoxetine has a unique pharmacokinetic profile, with a short serum maximum serum concentration (approximately 1 hour) and rapid elimination ( Initial half-life) 1-2 h).
- Vardenafil can cause a condition that affects the heart rhythm (prolonged QT). Prolonged QT can rarely cause severe (rarely fatal) rapid / irregular heartbeats and other symptoms (such as severe dizziness, fainting) that require immediate therapy.
- If you have some medical conditions or may have prolonged QT, taking other medications may increase the risk of prolonged QT. Before using vardenafil, tell your doctor or pharmacist about all the medications you take and if you have any of the following conditions: definite heart problems (heart failure, slow heart rate, EKG Prolonged QT), family history of some heart problems (QT), prolonged age in EKG, sudden cardiac death).
- Low levels of potassium or magnesium in the blood may also increase your risk of prolonged QT. This risk may increase if you use certain medications (such as diuretics / “water pills”) or if you have conditions such as severe sweating, diarrhea, or vomiting. Talk to your doctor about using vardenafil safely.
- Rarely, a sudden loss or loss of hearing can sometimes occur with ringing and dizziness in the ears. If these effects occur, stop taking wardenfil immediately and seek medical help. In the rare event that you have painful or prolonged pain lasting 4 or more hours, stop using this medicine and seek medical attention immediately, or permanent problems may occur. If you have any very serious side effects, seek medical attention immediately: rapid / irregular heartbeat, seizures, temporary memory loss. A very severe allergic reaction to this drug is rare. However, if you notice symptoms of a severe allergic reaction, seek medical attention, including: rash, itching / swelling (especially of the face / tongue / throat), severe dizziness, shortness of breath.
- Usual adult dose for erectile dysfunction:
- Initial dose: 10 mg once a day, as needed, about 60 minutes before sexual activity. Increase to 20 mg or decrease to 5 mg depending on efficacy and tolerability.
- Maximum: 20 mg once a day
- Patients on stable alpha blocker therapy:
- Initial dose: 5 mg orally once a day
- In a single-dose volunteer study, doses including 80 mg and wardenafil per day were tolerated without demonstrating serious adverse reactions.
- There have been cases of severe back pain when vardenafil was administered in high doses and more than the recommended dose regimen (40 mg tablets twice daily). It was not associated with any muscle or neurological toxicity.
- In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance, as vardenafil is highly bound to plasma proteins and is not significantly depleted in urine.
- Some medicines may cause unwanted or dangerous effects when used with valdanafil. Tell your doctor about all your medications, especially Riociguat (adempas).
- Do not take vardenafil if you are using nitrate medication for chest pain or heart problems, including nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, and some recreational drugs such as “poppers”. Taking wardenfil with a nitrate medication can cause a sudden and severe decrease in blood pressure.
Drug- drug interactions:
- Vardenafil with all PDE5 inhibitors should not be used by people taking nitrate medications, as combining them with vardenafil can lead to potentially life-threatening hypotension (low blood pressure). In addition, vardenafil causes the QT interval to be prolonged. Therefore, it should not be taken by people taking other drugs that affect the QT interval (such as amiodarone).
- Common, adverse drug reactions are similar to other PDE5 inhibitors. Repeated vardenafil-specific side effects are nausea; contagious side effects are abdominal pain, back pain, sensitivity, abnormal vision, eye pain, facial edema, hypotension, palpitation, tachycardia, arthralgia, myalgia, rash, itching, and retardation. Possibly severe, but rare, side effects with vardenfill are heart attacks. Also, in rare cases, vardenafil use can cause priapism, a very painful emergency that can lead to impotence when impotent. On 18 October 2007, the US Food and Drug Administration (FDA) announced that a warning about possible deafness would be added to the drug label of vardenafil and other PDE5 inhibitors.
- There are no studies on the use of this medicine in pregnant women.
- Vardenafil is not indicated for use by women. There are no studies of vardenafil in pregnant women. There are no reproduction data available.
- Hypersensitivity to any of the active substances or excipients.
- Co-administration of vardenafil with nitrates or nitric oxide donors in any form is contraindicated.
- Vardenafil is contraindicated in patients who have vision loss in one eye because of non-arterial anterior ischemic optic neuropathy (NAION), regardless of whether this episode preceded exposure to phosphodiesterase 5 (PDE5) inhibitor.
- Medicinal products for the treatment of erectile dysfunction should generally not be used in men for whom sexual activity is unknown (such as in patients with cardiac disorders such as unstable angina or severe heart failure).
- Store this medicine in original packaging at room temperature away from light and moisture. Do not store in the bathroom.
- After a single oral dose of 3 mg / kg, 3.3% of the administered dose was excreted in milk within 24 hours.
- This medicine is not indicated for use in female patients.
- Excreted in human milk: unknown
- Excreted in animal milk: yes