When muscles of arteries and sinusoids relax (erectile tissue fills with blood at arterial pressure); compression of plexus of subtunical arteries reduces venous outflow

Demutescence occurs with reversal of this process

Degrades cGMP 

Partially accounts for detumescence (although norepinephrine released by sympathetic nerves plays a larger role)

Also involved in smooth muscle relaxation 

Agents like papaverine and PGE1 work through cAMP

Opening of potassium channels -- hyperpolarization

Sequestration of intracellular calcium by ER

Inhibition of voltage dependent calcium channels blocking influx

Activation of myosin phosphatase 

Try lifestyle modification or termination of drugs that may cause ED

If options are unsuccessful, treatment may include drugs, psychotherapy, vacuum devices, or surgery

Injected in base of penis (minimal pain fibers), take 5-10 min, greater rigidity of erection

PGE1 (alprosadil)

Trimix (phentolamine, papverine, PGE1)

Most common AE: pain at injection site

Fibrotic episodes are rare

An intraurethral form is available, however is less effective and can cause burning and itching

Phentolamine blocks a1 -- less constriction

papaverine causes vasorelaxation directly or indirectly inhibiting phosphodiesterase 5

PGE1 - increases cAMP

**pharmacologic synergy**

each agent is used at a lower concentration so less fibrosis 

Over 50 in the body, but 5 in the penile tissues (most prominent is PDE-5 in corpus cavernosum(

Side effects from PDE-5 inhibitors are because of presence in other tissues

Potentiates relaxant effect necessary for erection initiated by NO release from autonomic nerves of parasympathetic system and vascular endothelium 

Inhibition of PDE-5 prevents the degradation of cAMP - thereby potentiates relaxation of corporeal arterial and sinusoidal smooth muscle 

Oral

Onset usually an hour but some people less than 30 hour; half life is 4-6 hours;duration of effect is 4-5 hours

High fat meals decrease rate of absorption 

Degraded by P450 3A4 and 2C9 -- therefore patients with hepatic dysfunction, over 65 years old, or taking CYT P450 inhibitors would have elevated levels (grapefruit juice, cimetidine, erythromycin) 

Over 70% of patients will get an erection even with comorbidities 

Response might be lower in diabetics

Some patients may switch to injectables because rigidity of erection is greater; however oral form is more convenient 

Headache

Flushing

Dyspepsia

Nasal Congestion

Altered Vision - usually blue aura 

Diarrhea 

Priapism will only occur if sildenafil was used in combination with other therapies for ED 

Can potentiate effects of NO donors -- life threatening hypotension; therefore should be used in caution with people on alpha blockers 

Also in caution in patients with coronary related problems

Nonarteritic anterior ischemia optic neuropathy (NAION) has been thought to be associated with PDE inhibitors 

Half life is 18 hours and duration of effect is 36 hours

Onset of action may be slightly longer

Plasma concentration usually unaffected by food

Degraded in liver by cytochrome P450 3A4 and 2C9, therefore patients with hepatic dysfunction, older than 65, or taking cytochrome p450 inhibitors could elevate drug concentration (i.e. grapefruit juice, cimetidine, erythromycin)

Greatest selectivitiy of PDE5 vs PDE3A therefore less cardiac effects

Greater selectivity for PDE5 vs PDE6 therefore less visual effects 

Centrally acting agent

Sublingual formation that works within 20 minutes

Dopamine D1/D2 agonist

Works at level of hypothalamus