Pharmacological properties of the drug Cialis
Tadalafil is a reversible, selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5). When sexual arousal causes local release of nitric oxide, inhibition of PDE5 by tadalafil results in increased levels of cGMP in the corpus cavernosum of the penis. The consequence of this is relaxation of the smooth muscles of the arteries and blood flow to the tissues of the penis, which causes an erection. Tadalafil has no effect in the absence of sexual stimulation. In vitro studies have shown that tadalafil is a selective PDE5 inhibitor. PDE-5 is an enzyme identified in the smooth muscles of the corpus cavernosum and vessels of internal organs, in skeletal muscles, platelets, kidneys, lungs and cerebellum. The effect of tadalafil on PDE-5 is 10,000 times greater than its effect on other types of phosphodiesterase (PDE-1, PDE-2, PDE-4 and PDE-7). Tadalafil is 10,000 times more active in blocking PDE-5 than PDE-3, an enzyme that is detected in the heart and blood vessels. This selectivity for PDE-5 over PDE-3 is important because PDE-3 is an enzyme involved in cardiac muscle contraction. In addition, tadalafil is approximately 700 times more active against PDE5 than against PDE6, an enzyme found in the retina that is responsible for phototransduction. Tadalafil is also 9000 times more potent against PDE5 than it is against PDE8, PDE9 and PDE10, and 14 times more potent than PDE11. The tissue distribution and physiological effects of PDE-8 and PDE-11 have not been determined. Tadalafil does not affect color perception (blue/green), which is explained by its low affinity for PDE-6 compared to PDE-5. In addition, there was no effect of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size. Tadalafil in healthy individuals does not cause significant changes in systolic and diastolic blood pressure compared to placebo in the supine position (average maximum decrease is 1.6/0.8 mm Hg) and in the standing position (average maximum decrease is 0.2/ 4.6 mmHg). Tadalafil does not cause a significant change in heart rate. A placebo-controlled study of the effect of taking tadalafil on spermatogenesis for 6 months did not reveal a clinically significant effect of the drug on sperm characteristics (number, motility and structure of sperm). Taking tadalafil had no effect on the levels of testosterone, LH and FSH in the blood. The drug is effective for 36 hours. The effect appears within 16 minutes after taking the drug in the presence of sexual arousal. Pharmacokinetics. Suction . After oral administration, tadalafil is rapidly absorbed. The average maximum concentration in blood plasma is achieved on average 2 hours after oral administration. The rate and extent of absorption of tadalafil do not depend on food intake, so the drug can be taken regardless of food. Time of administration (morning or evening) does not have a significant effect on the rate and extent of absorption. Distribution . The average volume of distribution is approximately 63 l. At therapeutic concentrations, 94% of tadalafil binds to plasma proteins. In healthy individuals, less than 0.0005% of the administered dose is detected in semen. Metabolism . Tadalafil is mainly metabolized with the participation of the CYP3A4 isoenzyme of cytochrome P450. The main circulating metabolite is methylcatechol glucuronide. This metabolite is 13,000 times less active against PDE-5 than tadalafil. Therefore, it can be assumed that this metabolite is not clinically significant at detectable concentrations. Removal . In healthy individuals, the average half-life is 17.5 hours. Tadalafil is excreted primarily in the form of inactive metabolites, mainly in feces (about 61% of the dose) and to a lesser extent in urine (about 36% of the dose). Selected groups of patients . In healthy elderly individuals (65 years and older), a lower clearance of tadalafil was observed when taking the drug orally, which was reflected in an increase in AUC by 25% compared with that in healthy individuals aged 19–45 years. This difference is not clinically significant and does not require dose adjustment. Kidney failure . In individuals with renal impairment (including patients on hemodialysis), tadalafil exposure (based on AUC value) was greater than in healthy individuals. Liver failure . The exposure of tadalafil (based on AUC value) in patients with mild to moderate hepatic impairment is comparable to that in healthy individuals. There are no data on the pharmacokinetics of tadalafil in severe hepatic impairment. In patients with diabetes mellitus , while using tadalafil, its exposure (AUC) was approximately 19% less than the AUC value in healthy individuals. This difference in exposure does not require dose adjustment.
What place do erection pills occupy among ED treatment methods?
Currently, there are 5 groups of methods for treating erectile dysfunction:
- Psychotherapy and sex therapy, which is used only for so-called psychologically caused or psychogenic ED, less often as an auxiliary method for somatic or organic ED.
- Taking tablets or Viagra tablets for an erection: Cialis, Levitra. It is used as a first choice (first line of therapy) for all forms of organic ED, regardless of its cause.
- Injection pharmacotherapy or “erection on demand”. It is used as a second-line treatment for all forms of ED in cases where erection pills do not provide the desired effect or their use is contraindicated. Erection pills and injections of vasodilators into the penis can be used together as a combination treatment option for ED.
- Vacuum erection therapy or the use of vacuum erectors of various models and modifications to obtain or maintain an erection. It is a type of second-line treatment for organic and, less commonly, psychogenic forms of ED. — 90% efficiency; — There is no need to use medications that have side effects; — Non-aggressive method of treatment; - Helps create an erection while maintaining all precautions.
- Surgical methods of treatment: operations on the vessels of the penis and penile prosthesis. The first group of interventions is divided into operations on the veins (limiting venous outflow) and arteries (increasing arterial inflow) of the penis. Vein surgery can be used effectively in selected cases of ED, especially in combination with erection pills. Surgeries on arteries are ineffective and are used less and less. Penile prosthesis is the most effective and radical of all types of treatment for ED, the only method that provides a complete cure for organic ED. Surgical methods, as a rule, are used only in cases of organic ED when conservative therapy has failed.
So, erection pills are the first-line therapy, which most often begins in the treatment of any form of ED. Viagra, Cialis and Levitra are today the only tablet drugs available in the world that are truly effective in treating ED. The effectiveness of all other advertised tablets, as a rule, is invented (and absolutely not proven) by their manufacturers and is no different from a pacifier. All these domestic “impazs”, “golden skates”, foreign “veromaxes”, “superyochimbe extracts” and many others. other drugs are nothing more than means of making money based on people who trust primitive advertising.
How do erection pills work? How harmful are they? Is it possible to become addicted to erection pills? What are the side effects and contraindications? What are the known drug interactions?
Viagra, Cialis and Levitra have exactly the same mechanism of action and are selective (selective) inhibitors of the activity of the enzyme - phosphodiesterase type 5 (PDEס). This enzyme, in turn, inhibits the production of cyclic guanosine monophosphate (CGMP) in smooth muscle tissue, which is formed from guanosine monophosphate (GMP) under the influence of nitric oxide (NO). The main function of CGMP is to relax the smooth muscles of the cavernous (cavernous) bodies of the penis. When the action of PDE is inhibited, a significantly larger amount of CGMP accumulates in the corpora cavernosa, their smooth muscles relax much better and a significantly larger amount of blood rushes to the penis, which causes an erection.
Drugs in this group act selectively in the vascular tissue of the penis and are practically harmless. They do not cause lasting negative consequences with long-term and regular use. No addiction to erection pills develops. With the exception of purely psychological dependence. Having once tried an erection pill and felt its significantly better quality, feeling the lost voluptuousness, a man sometimes does not want to give up Viagra pills. This is similar to how a driver who has once driven a high-quality foreign car tends to never drive a Zhiguli again.
Side effects of Cialis
The most common symptom is headache (≥10% of cases). Other common side effects (with an incidence of ≥1% but ≤10%) are back pain, dyspepsia, dizziness, flushing, myalgia, nasal congestion. In isolated cases (with a frequency of ≥0.1%, but ≤1%), swelling of the eyelids, painful sensations in the eyes, and conjunctival hyperemia were noted. In post-marketing studies, the following side effects were very rarely identified: General reactions: hypersensitivity reactions - skin rash, urticaria and facial swelling, Stevens-Johnson syndrome, exfoliative dermatitis; from the cardiovascular system: cases of such severe reactions from the cardiovascular system as myocardial infarction, sudden cardiac death, stroke, angina pectoris, tachycardia have been described, however, most patients had a history of risk factors from the cardiovascular system . However, it is impossible to establish a reliable connection between the development of the above reactions and cardiac risk factors, taking tadalafil, sexual activity, or a combination of all of these factors. The development of arterial hypotension (usually in the case of simultaneous use of tadalafil with antihypertensive drugs), hypertension (arterial hypertension), fainting has also been reported; from the gastrointestinal tract : abdominal pain, gastroesophageal reflux; from the skin : hyperhidrosis; from the organ of vision: blurred vision, non-arterial anterior optical ischemic neuropathy, retinal vein occlusion, visual field impairment; from the genitourinary system: prolonged erection, priapism. from the central nervous system : migraine from the respiratory system : nosebleeds. Side effects reported that were not encountered during clinical trials and therefore their frequency is unknown: seizures, temporary memory loss, some disorders affecting ocular circulation, arrhythmia, skin rash, and sudden decrease or loss of hearing. Sometimes men experienced a decrease in sperm concentration.
Special instructions for the use of Cialis
Special security measures. Sexual activity has potential risks for patients with cardiovascular disease. Therefore, treatment of erectile dysfunction, including the use of Cialis, should not be carried out in men with heart diseases for which sexual activity is not recommended. The potential risk of complications during sexual activity should be taken into account in patients with cardiovascular diseases such as: - myocardial infarction within the last 90 days, - unstable angina or angina that occurs during sexual intercourse, - heart failure II class II above NYHA, developed in during the last 6 months, - uncontrolled heart rhythm disturbances, arterial hypotension (BP ≤90/50 mm Hg) or hypertension (arterial hypertension), - stroke suffered during the last 6 months. An assessment of erectile dysfunction includes determining its underlying cause and the advisability of a course of treatment. Before initiating any treatment for erectile dysfunction, the physician must evaluate the patient's cardiovascular condition, since there is a certain degree of risk associated with sexual activity. Non-arterial anterior ischemic optic neuropathy (NAION) can cause vision impairment, including vision loss. NAPION has been rarely reported with PDE5 inhibitors in post-marketing studies. It is unknown whether NAPI is associated with the use of PDE5 inhibitors or other factors. The patient should be informed that in case of sudden loss of vision, it is necessary to stop using tadalafil and consult a doctor. It is also necessary to warn the patient about a significant increase in the risk of NAPION if he has a history of NAPION. The safety and effectiveness of the combination of Cialis with other types of treatment for erectile dysfunction have not been studied, so the use of such combinations is not recommended. There have been reports of priapism occurring with the use of PDE5 inhibitors, including tadalafil. Patients should be warned to seek immediate medical attention if an erection occurs that persists for 4 hours or more. Untimely treatment of priapism leads to damage to the tissues of the penis with the onset of long-term impotence. Cialis should be used with caution in patients with a predisposition to priapism (eg, sickle cell disease, multiple myeloma, or leukemia) or in those with penile deformity (eg, angular curvature, cavernous fibrosis, or Peyronie's disease). Given the lack of data on the use of Cialis in patients with severe liver dysfunction (Child-Pugh class C), Cialis is prescribed to patients in this group with caution. Caution should be exercised when prescribing Cialis to patients taking α-1 adrenergic blockers (doxazosin), as in some cases, simultaneous use of these drugs can lead to symptomatic hypotension. Like other PDE5 inhibitors, tadalafil can have a systemic vasodilatory effect, which can lead to a transient decrease in blood pressure. Therefore, before starting treatment, the doctor should assess the likelihood of a similar effect in patients with diseases of the cardiovascular system. Use during pregnancy or breastfeeding. Cialis is not indicated for use in women, so studies on the use of the drug during this period have not been conducted. Children. The use of the drug is not recommended for persons under 18 years of age. The ability to influence reaction speed when driving vehicles or other mechanisms. Cialis does not have or has an insignificant effect on the ability to drive vehicles and operate machinery.
What is erectile dysfunction, what causes it and how common is it?
Erectile dysfunction (ED) can be defined as the inability of a man to achieve or maintain an erection sufficient to insert the penis into the vagina and perform satisfactory sexual intercourse.
The incidence of ED varies depending on age. If in the age group from 20 to 40 years it averages 3%, then in the age group from 40 to 60 years it occurs in 15 - 20% of men. Over the age of 70, erectile dysfunction can affect up to 30% of men. At any age, ED is not the norm, because... the ability to have a regular and satisfactory sex life is one of the essential functions of a man of any age. Erection disorders can be caused by two groups of reasons: psychological (psychogenic) and somatic (organic). Research over the past 20 years has shown that ED is quite rarely caused by purely psychological reasons (stress, depression, behavioral characteristics, etc.). At the same time, it became known that about 80% of all cases of erectile dysfunction are caused by some physical (somatic, organic) conditions. These include: diabetes mellitus, high blood pressure, high blood cholesterol and vascular atherosclerosis, renal and liver failure, thyroid diseases, hormonal disorders, consequences of operations on the prostate gland and rectum, trauma and diseases of the spinal cord and brain (stroke , Alzheimer's disease, etc.), consequences of pelvic injuries, Peyronie's disease. Erection disorders can also be caused by taking certain medications. Persistent erectile dysfunction can develop due to bad habits such as drinking alcohol, smoking and taking drugs.
Cialis drug interactions
Cialis does not have a clinically significant effect on the clearance of drugs whose metabolism occurs with the participation of the cytochrome P450 isoenzyme. The results of the study confirmed that tadalafil does not inhibit or induce the isoenzymes CYP 3A4, CYP 1A2, CYP 2D6, CYP 2C19, CYP 2E1 and CYP 2C9. Tadalafil is mainly metabolized by the CYP3A4 enzyme. The selective CYP3A4 inhibitor ketoconazole, when taken at a dose of 400 mg/day, increases the AUC of tadalafil after a single dose by 312%, increases the maximum concentration in blood plasma by 22%, and at a dose of 200 mg/day - by 107 and 15%, respectively. Ritonavir (inhibitor of CYP 3A4, 2C9, 2C19 and 2D6) at a dose of 200 mg 2 times a day increases the AUC of tadalafil after a single dose by 124%, without changing the maximum concentration in the blood. Although specific interactions have not been studied, it can be assumed that protease inhibitors such as saquinavir, as well as CYP3A4 inhibitors such as erythromycin and intraconazole, increase the plasma levels of tadalafil. The selective inducer of CYP 3A4 rifampicin at a dose of 600 mg/day reduces the AUC of tadalafil after a single dose by 88%, and increases its maximum plasma concentration by 46%. It can be expected that the simultaneous use of other CYP3A4 inducers will also reduce the concentration of tadalafil in the blood plasma. Antihypertensive drugs . Tadalafil has a systemic vasodilating effect, which may potentiate the hypotensive effect of antihypertensive drugs. In addition, patients with poorly controlled hypertension taking multiple antihypertensive drugs simultaneously may experience greater reductions in blood pressure. In the vast majority of patients, a decrease in blood pressure is not accompanied by symptoms of hypotension. Patients treated with antihypertensive drugs and taking tadalafil should be given appropriate clinical advice. α-adrenergic receptor blockers . There was no significant reduction in blood pressure in patients taking tadalafil and the selective α1-adrenergic receptor blocker tamsulosin simultaneously. When tadalafil was prescribed to healthy volunteers taking the α1-adrenergic receptor blocker doxazosin at a dose of 4–8 mg/day, an increase in the hypotensive effect was noted. Some patients experienced dizziness. Alcohol . Tadalafil had no effect on ethanol concentrations, and ethanol had no effect on tadalafil concentrations. When taking ethanol in high doses (0.7 g/kg), simultaneous administration of tadalafil did not lead to a statistically significant decrease in blood pressure. Some patients experienced postural dizziness and orthostatic hypotension. Taking tadalafil with lower doses of ethanol (0.6 g/kg) did not cause the development of arterial hypotension, and dizziness was detected with the same frequency as when taking alcohol alone. H2 antagonists . An increase in gastric pH as a result of taking the H2 receptor blocker nizatidine did not affect the pharmacokinetics of tadalafil. Antacids (magnesium hydroxide/aluminum hydroxide) . Concomitant use of antacids (magnesium hydroxide/aluminum hydroxide) with tadalafil reduces the rate of its absorption without changing the AUC exposure of tadalafil. Acetylsalicylic acid . Tadalafil does not increase the duration of bleeding while taking acetylsalicylic acid. Warfarin . Tadalafil has no clinically significant effect on the pharmacokinetics of S-warfarin or R-warfarin and does not affect the prothrombin time induced by warfarin. Theophylline . Tadalafil does not have a clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline.
