sildenafil (Viagra, Revatio, Caverta)

Introduction

Sildenafil citrate. Tradename: Viagra.

Indications

• impotence/andropause
  • NOT useful in postmenopausal women
  • may help some women with sexual dysfunction
    • SSRI-induced sexual dysfunction
• less likely to help individuals with diabetes or benign prostatic hypertrophy (BPH)
• pulmonary hypertension* (Revatio)
• may be of benefit post prostate surgery (NOT FDA-approved use)
• Raynaud's phenomenon ?, individualized effect
• sildenafil may reduce risk of Alzheimer's disease (RR=0.31)

* NYHA functional pulmonary hypertension class & acute vasoreactivity study needed for Veteran's administration non formulary drug request

Contraindications

• concurrent administration of nitrates (amyl nitrite)
• concurrent administration of Viagra & Revatio
• intermediate-high risk of cardiovascular disease
• retinitis pigmentosa
• history of non-arteric ischemic optic neuropathy
• not for use in treating pulmonary hypertension in children
• use with caution in patients with
  • Peyronie's disease
  • conditions predisposing to priapism
    • multiple myeloma
    • sickle cell disease
  • pulmonary veno-occlusive disease

Dosage

• 50 mg PO 1 hour prior to sexual intercourse
• titrate to effect, 25-100 mg (oral, sublingual)
• start with 25 mg in patients with hepatic or renal insufficiency (creatinine clearance < 10 mL/min)
• start with 25 mg in the elderly
• daily for 12 months post prostate surgery
• 20 mg PO TID for pulmonary hypertension (Revatio)
• 50 mg BID for Raynaud's phenomenon
• maximum recommended daily use is once a day
• VA formulary maximum: 4 doses/month

Tabs: 25, 50, 100 mg

Dosage adjustment in renal failure

• none

Pharmacokinetics

• radidly absorbed after oral administration
• maximum plasma concentrations are reached 30-120 minutes after oral dosing; sublingual form may be faster
• absorption is delayed with a high-fat meal
• 96% is bound to plasma proteins
• volume of distribution is 105 L, indicating distribution into tissues
• eliminated predominantly by hepatic metabolism
  • cyt P450 3A4 (major route); cyt P450 2C9 (minor route)
  • N-desmethyl metabolite is active with properties similar to sildenafil
• elimination 1/2 life is 4 hours & 1/2 life of its active N-desmethyl metabolite is also 4 hours
• reduced clearance in the elderly

elimination via liver

protein binding = 96 %

1/2life = 4 hours

Adverse effects

• headaches (12%)
• GI upset (nausea, diarrhea, dyspepsia) (5-7%)
• flushing (9%)
• visual disturbances
  • "blue vision" (3%, due to PDE6* inhibition)
  • non-arteric ischemic optic neuropathy
• nasal congestion (2%)
• dizziness (1%)
• rash (1%)
• epistaxis
• insomnia
• back pain, mylagias
• increased risk of melanoma (HR=1.84)
  • no cause-effect relationship demonstrated
• NOT associated with hypertension, stress-induced ischemia, dyspnea, decrease in exercise tolerance, angina, exercise- induced cardiac wall motion abnormalities
• toxicity or overdose
  • dose-related increase in adverse effects
    • myalgia without evidence of muscle damage most common

* phosphodiesterase 6 present in retina, see below

• drug adverse effects of phosphodiesterase-5-inhibitors
• drug adverse effects of antihypertensive agents

Drug interactions

• sildenafil potentiates the hypotensive effects of nitrates
• inhibitors of cyt P450 3A4 inhibitors increase activity of sildenafil
  • ketoconazole, itraconazole, erythromycin, saquinavir
• ritonavir increases activity of sildenafil
• any drug that induces cyt P450 3A4 may diminish levels of sildenafil
• may increase risk of postural hypotension when administered concurrently with alpha blockers, Cardura, Hytrin, MiniPress, Flomax
• concurrent use of sildenafil is contraindicated with:
  • atazanavir, nelfinavir, cobicistat
  • elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil fumarate
  • isosorbide dinitrate, isosorbide mononitrate, nitroglycerin
  • riociguat, vericiguat
  • avanafil, sildenafil, tadalafil, vardenafil

• drug interaction(s) of nitrates with phosphodiesterase-5-inhibitors
• drug interaction(s) of phosphodiesterase-5-inhibitor with testosterone
• drug interaction(s) of phosphodiesterase-5-inhibitor with nitrates
• drug interaction(s) of phosphodiesterase-5-inhibitors with alpha-1-adrenergic receptor antagonists
• drug interaction(s) of NSAIDs & antihypertensives

Laboratory

• sildenafil citrate in serum/plasma

Mechanism of action

• sildenafil inhibits phosphodiesterase 5 (PDE5), increasing cGMP levels in the corpus cavernosum by inhibiting its degradation
• cGMP induces relaxation of smooth muscle allowing inflow of blood into the corpus cavernosum
• release of nitric oxide into the corpus cavernosum during sexual stimulation induces guanylate cyclase increasing cGMP
• thus sildenafil enhances vasodilation effects of nitric oxide
• sildenafil has no effect in the absence of sexual stimulation
• sildenafil inhibition is selective for PDE5 > 10-fold PDE6, 80-fold PDE1, > 1000-fold PDE2, PDE3, PDE4
• reduces pulmonary vascular resistance
  • vasodilates pulmonary vessels
• improves insulin sensitivity in prediabetes
• dose-dependent reduction of tau hyperphosphorylation (pTau181 & pTau205) in neurons derived from pleuripotent stem cells
• overall patient satisfaction is about 50%

- prevents & treats heart failure (diastolic dysfunction) in mice

Notes

• Pfizer to sell Viagra Online
• generic available Dec 11, 2017

More general terms

• phosphodiesterase-5 inhibitor

Additional terms

• cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)
• phosphodiesterase 5; cGMP-specific phosphodiesterase

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5281023
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5212
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=62853
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5282482