PDE-5 Inhibitors

N.O. activates guanylyl --> forms cGMP from guanosine triphosphate. cGMP causes smooth muscle relaxation through a reduction in intracellular calcium concentration. The duration of action of cGMP is controlled by phosphodiesterase (PDE). Sildenafil, Vardenafil, Tadalafil, and Avanafil inhibit PDE-5 (isozyme responsible for degradation of cGMP in the corpus cavernosum). Inhibition of PDE-5 prevents degradation of cGMP thereby increasing blood flow during sexual stimulation.

Should be taken 1 hr prior to sex and last for up to 4 hrs, and absorption is delayed by high fat meal.

This drug(s) is available as a ODT which is not affected by a high fat meal, and should be placed under the tongue without water

_____ has a higher bioavailability than _____ so the products are not interchangeable

Has a slower half onset of action and half-life than others in its class (18 hrs), so it is daily dosing with results lasting 36 hours. Absorption not impacted by food. Timing less of an issue due to its long duration.

Quickest onset of action (30-45 mins)

Metabolized by CYP3A4

Contraindicated in severe renal impaiment?

Contraindicated with with organic nitrates (NO or isosorbide)

Should be used with caution with alpha-adrenergic antagonists

Contraindicated with Dronedarone and Fluconazole (risk of QT prolongation)

Adverse Drug Effects – (most common) headache, flushing, dyspepsia, and nasal congestion; color vision changes that are dose dependent (disruption of PDE-6), sudden hearing loss (changes in sinus pressure during vasodilation); cardiac risk associated with sexual activity; priapism.

Adverse effects - does not cause changes in color vision like other drugs in its class; associated with back pain and myalgias (inhibition of PDE-11);

Exacerbate hypotensive activity of NO and alpha-adrenergic antagonists, interact with inhibitors of CYP3A4, and some can exacerbate the effects of drugs knowns to prolong QT interval

Dosage adjustments of these PDE-5 Inhibitors are recommended in patients with mild to moderate hepatic dysfunction.

These PDE-5 Inhibitor doses should be reduced in severe renal dysfunction

Use caution in patients with a history of or risk factors for CV disease

Do not use more than once per day for ED treatment

Exacerbate hypotensive activity of alpha-adrenergic antagonists and should be used with caution. Patients should be placed on a stable dose of alpha-adrenergic antagonists prior to being placed on this drug, and should be started at the lowest dose

Use caution when prescribing this drug with other drugs that prolong QT interval

May need to adjust doses of ________ when combining with drugs that are known inhibitors of CYP3A4 (Clarithromycin and Ritonavir)

Prostaglandin E1 (PGE1) Drug Examples

Allows for relaxation of smooth muscle in the corpus cavernosum by an unknown mechanism, but it is believed that increases concentrations of cAMP within the cavernosal tissue resulting in protein kinase activation allowing trabecular smooth muscle relaxation and dilation of cavernosal arteries, increased blood flow to the erection chamber compresses venous blood outflow so that blood is entrapped and erection may occur

Systemic absorption is minimal, but if it is absorbed it is quickly metabolized. Onset is 2-25 minutes by injection causing an erection lasing for approximately 30-60 minutes.

They are rare since it is not systemically absorbed. However, hypotension and headache are possible since PGE-1 is a vasodilator. Bleeding from injection site is rare. Hematoma, ecchymosis, and rash from injection site is possible but rare. Priapism may occur.

Terazosin, Doxazosin, Tamsulosin, Alfuzosin, and Silodosin

Selective competitive blockers of the alpha receptors (1A and 1B) causing prostatic smooth muscle relaxation, which improves urine flow. Doxazosin, Terazosin, and Alfuzosin block alpha (1A and 1B) receptors and decrease PVR and arterial BP, whereas Tamsulosin and Silodosin block alpha-1A receptors only and have less effect on BP because they are more selective.

Pharmacokinetics for Alpha-adrenergic antagonists

Contraindications for Silodosin

Adverse Drug Effects of Alpha-adrenergic antagonists

Drugs that inhibit CYP3A4 and CYP2D6 (Verapamil and Dilitazem) may increase plasma concentrations of _______.

Drugs that induce the CYP450 system (Carbamazepin, Phenytoin, and St. John’s Wart) may _____.

_______ may prolong QT interval so use caution with other drugs that prolong QT interval (class III anti-arrhythmics).

Drugs that inhibit _____may increase Silodosin concentrations

______should be administered with food. _______should be taken without food.

______ requires dosage adjustment in renal impairment

5 alpha-reductase inhibitors

Mechanism of Action for 5 alpha-reductase inhibitors

Pharmacokinetis of 5 alpha-reductase inhibitors

Decreased ejaculate and libido, ED, gynecomastia, and oligospermia. Both drugs are teratogenic can should not be handled by women of childbearing age or who are pregnant. Although they are metabolized by the CYP450 system, drug interactions are rare. Not recommended to use these drugs with testosterone since they inhibit conversion of testosterone to DHT.

Should be taken with alpha-blockers to relieve symptoms, and both drugs are available in a combo with an alpha-blocker

What produces the greatest reduction in BPH symptoms?

A 68-year old man presents to his physician with complaints of inability to maintain an erection during sexual intercourse. He is diagnosed with ED and started on PDE-5 inhibitor. What is the mechanism of action in the treatment of ED?

A patient who is taking a PDE-5 inhibitor for ED is diagnosed with angina. Which of the following antianginal medications would be of particular concern in this patient?

Which of the following statements most accurately describes Alprostadil in the treatement of ED?

Which of the following enzymes or receptors does Tamsulosin block to aid in the treatment of BPH?

A patient is worried about starting a new medication to treat BPH beause he is very sensitive to side effects of medications. Which of the following alpha-1-adrenergic antagonists could be recommended because of a lower incidence of systemic side effects?

A 74-year old patient presents to his PCP to discuss treatment for ED. His current medications include furosemide, isosorbide dinitrate, lisinopril, metformin, and metoprolol succinate. Which of the following would be the safest option for his ED?

A patient with BPH has been taking Finasteride for 6 weeks. He reports no improvement in symptoms of urinary frequency, hesitancy, and urgency. On physical exam, it is deterimined that his prostate is significantly enlarged. Which of the following is the best recommendation for this patient?

A 70-year old man with BPH and has enlarged prostate continues to have urinary symptoms after an adequate trial of Tamsulosin. He is diagnosed with ED. Which medication can be used to treat both BPH and ED in this patient?

A patient who is currently being treated for ED with Tadalafil tells the physician that the medication takes too long to work. As such, he would like an alternative that has a faster onset of action. Which of the following PDE-5 inhibitors would be the most appropriate alternative of this patient?

Which of the following is the CORRECT mechanism of action for Finasteride?

Which agent [s] has/have a low likelihood of causing CV adverse effects in a patient with BPH who is also taken meds for HTN? 1. Alfuzosin [Uroxatrol] 2. Tamulosin [Flomax] 3. Finasteride [Proscar]

Stimulation of muscarinic cholinergic receptors in the bladder muscle may be responsible for:

Which of the following drugs in most appropriate for managing incontinence related to bladder overactivity?

Which of the following distinguishes the phosphodiesterase type 5 [PDE-5] inhibitor Tadalafil [Cialis] from the other inhibitors Sildenafil [Viagra] and Vardenafil [Levitra]?

Which of the following is NOT a desired characteristic of a therapy for ED?

What is the MOA of the PDE-5 inhibitors?

Your patient is taking a PGE-5 inhibitor for ED—he is diagnosed with angina. Which of the following medications would be of particular concern in this man?

Which of the following is TRUE regarding Finasteride [Proscar]?

Your patient is concerned about starting Terazosin because he is very sensitive to side effects of medications. Which of the following adverse effects would be most expected in this patient?

Your patient is a 62 y/o female with UI, 6 weeks ago she began estrogen vaginal cream at bedtime and Kegel exercises—she says she is no better. She states she leaks whenever she is doing any activity—none when seated or recumbent. She has a history of HTN and she takes HCTZ to control her BP. What kind of UI are you treating?What is the most appropriate next step? What is the most important third step?

Doses of _____may need to be reduces in the presence of potent inhibitors of CYP34A (clarithromycin and ritonavir)

It is not ideal to use 5-Alpha Reductase Inhibitors with _____?

Should be avoided in severe hepatic impairment

Verapamil and Dilitazem may increase plasma concentrations of _______.

Carbamazepin, Phenytoin, and St. John’s Wart may _____.