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Sildenafil, Uses, Dosage, Side Effects, Interactions, Pregnancy

Sildenafil functions as a selective and competitive inhibitor of type 5 phosphodiesterases (PDE5) on smooth muscle cells in the penis and pulmonary vasculature, and is used extensively for erectile dysfunction and less commonly for pulmonary hypertension. Sildenafil has been associated with rare instances of clinically apparent liver injury.

Sildenafil is a vasoactive agent used to treat erectile dysfunction and reduce symptoms in patients with pulmonary arterial hypertension (PAH). Sildenafil elevates levels of the second messenger, cGMP, by inhibiting its breakdown via phosphodiesterase type 5 (PDE5). PDE5 is found in particularly high concentrations in the corpus cavernosum, erectile tissue of the penis. Sildenafil acts by inhibiting cGMP-specific phosphodiesterase type 5 (phosphodiesterase 5, PDE₅), an enzyme that promotes degradation of cGMP, which regulates blood flow in the penis.

Mechanism of Action of Sildenafil

Sildenafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal 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 relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by sildenafil enhances erectile function by increasing the amount of cGMP.

It has been extensively demonstrated that hydrogen sulfide (H2S) is implicated is several physiological and pathological conditions. In particular, it has been shown that H2S causes relaxation in human penile tissues and inhibits phosphodiesterase (PDE) activity in vessels. Beside sildenafil increases H2S generation in human bladder and tadalafil in myocardial tissues. Therefore, the aim of the study was to demonstrate the link between H2S and PDE-5 in mice corpus cavernosum tissues. The effects of sildenafil (10 uM, 0.5 hr); PDE-5 inhibitor, on H2S production as well as the H2S -induced relaxations in mice penile tissues /was investigated/. Penile tissues from CD1 mouse corpus cavernosum (MCC) were used. Functional studies were performed by myograph in Krebs solution. Western blot analysis was performed in order to evaluate CBS and CSE expression and methylene blue assay for measurement of H2S levels. In order to investigate the functional significance of H2S on sildenafil-induced augmentation of endothelial relaxation in MCC the sildenafil effect was evaluated on acetylcholine (ACh), L-cysteine and NaHS-induced relaxations in the presence or not of CSE enzyme inhibitor PPG (10 uM, 0.5 hr). In order to achieve this issue the H2S production in MCC tissues was also evaluated by incubating the penile tissue with sildenafil in presence or absence of the CSE inhibitor PPG (10 uM, 0.5 hr) Both CBS and CSE were expressed in MCC and the enzymes efficiently converted L-cysteine into H2S. Further, it was shown that sildenafil caused a significant increase in H2S production and this augmentation was reversed by CSE inhibition. It was found that sildenafil-induced an increase in both ACh and L-cysteine-induced relaxations and these augmentations reversed by CSE inhibitor PPG in MCC pre-contracted with phenylephrine. Beside sildenafil did not significantly increase the NHS -induced relaxations. Therefore it was suggested that both gaseous transmitters NO and H2S affect sildenafil action. In particular, results demonstrate that sildenafil effect is partially mediated by the H2S pathway. Thus, H2S signaling may represent a new mechanism involved in the effect of sildenafil on erectile dysfunction.

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Indications of Sildenafil

For the treatment of erectile dysfunction and to relieve symptoms of pulmonary arterial hypertension .
Erectile Dysfunction
Sexual Dysfunction
Pulmonary Hypertension
Poor sexual desire
Poor control over intercourse
Sexual Dysfunction
Persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the patient wishes; and
Marked personal distress or interpersonal difficulty as a consequence of PE; and
Poor control over ejaculation; and
A history of premature ejaculation in the majority of intercourse attempts over the prior 6 months.
Very short sexual intercourse
Inability to sustain a satisfactory erection to complete intercourse

Therapeutic Indications [FDA Leveling]

Replacement treatment in acute attacks of angioedema in patients with congenital
Treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity.
Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.
Treatment of pediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary hemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease.
Treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.
Treatment of pediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary hemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease.
Phosphodiesterase 5 Inhibitors; Urological Agents; Vasodilator Agents

Viagra is indicated for the treatment of erectile dysfunction

Revatio is indicated for the treatment of pulmonary arterial hypertension in adults to improve exercise ability and delay clinical worsening

The role, if any, of sildenafil in the management of sexual dysfunction in women, remains to be established. The U.S. Food and Drug Administration (FDA) is clarifying its previous recommendation related to prescribing Revatio (sildenafil) for children with pulmonary arterial hypertension (PAH).

Treatment of erectile dysfunction

AdultsTreatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. Pediatric population treatment of pediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary hemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease.
Revatio solution for injection is for the treatment of adult patients (≥ 18 years) with pulmonary arterial hypertension who are currently prescribed oral Revatio and who are temporarily unable to take oral therapy, but are otherwise clinically and hemodynamically stable.
Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance. In order for Sildenafil Actavis to be effective, sexual stimulation is required.
Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance
Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance.
indicated in adult men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance. In order for VIAGRA to be effective, sexual stimulation is required.
Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance. In order for Vizarsin to be effective, sexual stimulation is required.
Treatment of congenital diaphragmatic hernia

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Contra-Indications of Sildenafil

Concomitant use of nitric oxide donors
Organic nitrites and nitrates
Nitroglycerin
Isosorbide mononitrate
Isosorbide dinitrate
Sodium nitroprusside
Alkyl nitrites (commonly known as “poppers”)
Concomitant use of soluble guanylyl cyclase stimulators, such as riociguat
Known hypersensitivity to sildenafil

Dosage of Sildenafil

Strengths : 20 mg, 25mg , 50mg, 100mg

Erectile Dysfunction

The usual recommended dose is 25 to 100 mg 1 hour before sexual activity.
The maximum dose is 100 mg daily.
The elderly (over 65 years of age) should start at 25 mg before sexual activity.
Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state.

Erectile Dysfunction

Initial dose: 25 mg orally once a day 1 hour prior to sexual activity

Pulmonary Hypertension

Initial dose: 5 or 20 mg orally three times a day, 4 to 6 hours apart
Maximum dose: 20 mg orally three times a day

Injection

Initial dose: 2.5 or 10 mg IV bolus three times a day

Side Effects of Sildenafil

The most common

Facial flushing (reddening),
Headaches,
Constipation
Sleepiness or unusual drowsiness
Clumsiness or unsteadiness
Dizziness
Drowsiness
dry mouth
False sense of well-being
increased watering of mouth
lightheadedness
constipation;
vision changes;
breast swelling (in men or women); or
decreased sex drive, impotence, or difficulty having an orgasm.
blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
restless muscle movements in your eyes, tongue, jaw, or neck;

Common

Drowsiness and lightheadedness the day after taking the medicine.
Confusion.
Numbed emotions.
Visual disturbances such as blurred vision or double vision.
Shaky movements and unsteady walk (ataxia).
Loss of memory (amnesia).
Muscle weakness.
Dizziness.
A headache.
Skin rashes.
Disturbances of the gut such as diarrhea, c onstipation, nausea, vomiting or abdominal pain.
Difficulty in passing urine (urinary retention).
Changes in sex drive.
Low blood pressure (hypotension).
Blood disorders.
Jaundice.
Unexpected aggression, restlessness or irritability (tell your doctor if you experience this).
Nightmares or hallucinations (tell your doctor if you experience this).

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Rare

agitation
anxiety
behavioral changes, including aggressiveness, angry outbursts, bizarre behavior, or decreased inhibitions
confusion
increased trouble sleeping
memory problems
muscle spasms
shortness of breath
signs of depression (e.g., poor concentration, changes in weight, changes in sleep, decreased interest in activities, thoughts of suicide)
sleepwalking

Drug Interactions of Sildenafil

Sildenafil may interact with following drugs, supplements, & may change the efficacy of drugs

alpha agonists (e.g., clonidine, methyldopa)
alpha-blockers (e.g., doxazosin, terazosin)
angiotensin-converting enzyme inhibitors (ACEIs; e.g., captopril, enalapril, ramipril)
angiotensin receptor blockers (ARBs; e.g., candesartan, irbesartan, losartan)
aripiprazole
“azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
beta-adrenergic blockers (e.g., atenolol, propranolol, sotalol)
calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
carbamazepine
dexamethasone
diuretics (water pills; e.g., furosemide, hydrochlorothiazide, )
fusidic acid
macrolide antibiotics (e.g., clarithromycin, erythromycin)
methyldopa
metronidazole
phenytoin
sertraline
“statins” (e.g., lovastatin, simvastatin, atorvastatin)
tocilizumab
tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)

Pregnancy & Lactation of Sildenafil

Pregnancy

There are no adequate or well-controlled studies of sildenafil in pregnant women to inform of any drug-associated risks for adverse developmental outcomes during pregnancy. Animal studies did not show adverse developmental outcomes when administered during organogenesis at doses higher than the maximum recommended human dose.