Phosphodiesterase-Type 5 Inhibitors Mechanism:

During sexual arousal, nitric oxide (NO) is released from nerve terminals and endothelial cells in the corpus cavernosum. NO activates guanylate cyclase to convert guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP), triggering a cGMP-dependent cascade of events. The accumulation of cGMP leads to smooth-muscle relaxation in the corpus cavernosum and increased blood flow to the penis.

PDE5 is an enzyme found primarily in the smooth muscle of the corpus cavernosum that selectively cleaves and degrades cGMP to 5′-GMP. PDE5 inhibitors are similar in structure to cGMP; they competitively bind to PDE5 and inhibit cGMP hydrolysis, thus enhancing the effects of NO. This increase in cGMP in the smooth muscle cells is responsible for prolonging an erection.

PDE5 inhibitors lack a direct effect on corpus cavernosum smooth-muscle relaxation. Therefore, after administration, adequate sexual stimulation is necessary for an erection to occur.

 

PDE-5 Inhibitor Products:

Sildenafil was the first PDE5 inhibitor to arrive on the market, in 1998. The usual dose of sildenafil is 50 mg (25 to 100 mg) taken one hour before sexual activity. The effects of sildenafil last for approximately four hours, and patients should be instructed to use no more than one dose within 24 hours. Fatty meals reduce the absorption of sildenafil; therefore, the drug should be taken on an empty stomach.

Vardenafil (Levitra), the first second-generation PDE5 inhibitor to be developed, is given at a usual dose of 10 mg (2.5 to 20 mg) one hour before sexual activity. Elderly patients and those with moderate liver dysfunction should receive a lower initial dose of 5 mg. Vardenafil begins working within 30 to 45 minutes after administration and lasts for about four hours. As with sildenafil, patients taking vardenafil should not use more than one dose within a 24-hour period. Patients should not take vardenafil within three hours of fatty meals, due to a reduction in absorption.

The newest PDE5 inhibitor is tadalafil (Cialis), which has a longer duration of action--approximately 36 hours--than sildenafil or vardenafil. In addition, the usual dose of 10 mg (5 to 20 mg) should be taken about 30 minutes before sexual activity--possibly allowing patients more opportunity for spontaneity. Food intake does not appear to affect the absorption of tadalafil; thus, the drug may be taken without regard to meals.

Though considered generally safe for most patients, including those taking multiple antihypertensives, PDE5 inhibitors are not a viable treatment option for every man with ED. Patients with a cardiovascular history that includes a recent myocardial infarction or stroke (within the past two weeks), cerebral vascular accident, life-threatening arrhythmia, hypertension (blood pressure >170/100 mmHg), hypotension (blood pressure <90/50 mmHg), unstable angina, and/or moderate to severe heart failure (New York Heart Association class III or IV) should not receive therapy with these agents. The risks and benefits associated with PDE5 inhibitor therapy and the patient's medical history must be assessed.

Because PDE5 is inhibited in penile tissue as well as extragenital tissue, patients treated with PDE5 inhibitors may experience headache, facial flushing, nasal congestion, dyspepsia, and dizziness. Sildenafil also inhibits PDE type 6 in the retina. Therefore, patients treated with sildenafil may experience sensitivity to light, blurred vision, and loss of blue-green color discrimination, all of which are generally considered reversible. Tadalafil also inhibits PDE type 11 in skeletal tissue, possibly leading to back and muscle pain. Priapism, or painful, prolonged erections, is an extremely rare adverse effect, especially with shorter-acting agents, such as sildenafil and vardenafil. However, patients should be counseled to seek immediate medical attention if they experience erections lasting longer than four hours. PDE5 inhibitors may also cause various cardiovascular effects, including ventricular arrhythmias, cerebrovascular hemorrhages, myocardial infarctions, transient ischemic attacks, hypertension, and even sudden cardiac death. These adverse cardiac effects confirm the importance of a thorough cardiology evaluation in patients with a significant cardiovascular history.

PDE5 inhibitors should never be used in patients who are receiving scheduled or intermittent nitrates, due to a risk for severe hypotension. Organic nitrates supply additional NO, which increases cGMP levels and can lead to hypotension. Interestingly, dietary sources of nitrates and nitrites do not interact with the PDE5 inhibitors, as they do not increase circulating levels of NO. The PDE5 inhibitors are metabolized through the cytochrome P-450 isoenzyme 3A4 (CYP3A4). Therefore, inhibitors of CYP3A4 (e.g., cimetidine, ketoconazole, ritonavir) may prolong the effects of PDE5 inhibitors. Patients receiving such agents may need a lower dose of the PDE5 inhibitor. Alpha-adrenergic antagonists (e.g., terazosin, doxazosin, prazosin) commonly used in the management of benign prostatic hyperplasia (BPH)can cause hypotension, especially when given in combination with PDE5 inhibitors. For patients receiving more than 25 mg of sildenafil, the dose of the alpha-antagonist and sildenafil should be separated by at least four hours. Both tadalafil and vardenafil are labeled for precautious use with alpha-antagonists. However, tadalafil may be given concomitantly with tamsulosin 0.4 mg.

References:

  1. Brown, Dana. The Management of Erectile Dysfunction and Identification of Barriers to Treatment. US Pharm. 2006;8:53-64.
  2. Huang et al. Phosphodiesterase-5 (PDE5) Inhibitors In the Management of Erectile Pharmacy and Therapeutics. 013 Jul; 38(7): 407, 414-419.

 


Comparison of Currently FDA Approved PDE-5 Inhibitors

PDE 5 Inhibitors small 

Source: Smith et al. The devil is in the details: an analysis of the subtleties between phosphodiesterase inhibitors for erectile dysfunction. Transl Androl Urol. 2016 Apr; 5(2): 181–186.

 

PDE-5 Indications:

Sildenafil, vardenafil, tadalafil, and avanafil are approved for as-needed use in the treatment of ED. In 2008, tadalafil was granted FDA approval for once-daily use in the treatment of ED and in 2011, it was given an indication for BPH with or without ED. Sildenafil and tadalafil are also approved for PAH under the trade names of Revatio and Adcirca, respectively.

 

PDE-5 Contraindications:

PDE5 inhibitors are contraindicated in patients who are taking any form of organic nitrates, regularly or intermittently. Because these agents modify the cGMP and NO pathways, PDE5 inhibitors, if used with nitrates, may synergistically contribute to hypotensive effects. Rare but serious hypersensitivity reactions, such as Stevens–Johnson syndrome and exfoliative dermatitis, have been reported with sildenafil and tadalafil. Cases of pruritus and eyelid swelling have been reported with avanafil. All PDE5 inhibitors are contraindicated in patients with a known hypersensitivity to any component of the agents.

References

  1. Viagra (sildenafil), prescribing information. New York: Pfizer; Jan,
  2. Levitra (vardenafil), prescribing information. Wayne, N.J.: Bayer Healthcare/GlaxoSmithKline; revised November
  3. Cialis (tadalafil), prescribing Indianapolis, Ind.: Eli Lilly; Oct, 2011.
  4. Stendra (avanafil), prescribing information. Mountainview, Calif.: Vivus, Inc.; Apr,

 

Drug to Drug Interactions:

CYP3A4 Isoenzymes - Because of their extensive CYP3A4 metabolism, PDE5 inhibitors carry a risk of interacting with potent CYP3A4 inhibitors and inducers.

Alpha Blockers - Co-administration of PDE5 inhibitors with alpha-adrenergic blocking agents can result in additive vasodilatory effects, causing potentially significant reductions in blood pressure (BP)

Reference: Kloner RA. Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: Focus on alpha-blocker interactions. Am J Cardiol. 2005;96(12B):42M–46M.

Nitrates- Nitrates such as nitroglycerin increase the production of cGMP. PDE5 inhibitors decrease cGMP degradation. The concomitant use of these agents can cause a significant increase in cGMP accumulation, resulting in a synergistic reduction in BP. Therefore, the use of PDE5 inhibitors with any form of organic nitrates is contraindicated.

Reference: Rosen RC, Jackson G, Kostis JB. Erectile dysfunction and cardiac disease: Recommendations of the Second Princeton Conference. Curr Urol Rep. 2006;7:490–496.

 

Benefits of Using a Compounded PDE-5 Inhibitor

Affordability: The cost of a compounded PDE5 inhibitor is often significantly lower that commercial brand name products (roughly 10% of the retail price). Insurances often do not cover PDE5 medications, therefore patients must self-pay.

Customization: Compounded PDE5 medication can be made into a variety of strengths, combinations, and alternate dosage forms.

 

PDE-5 Inhibitor Potentiators:

How to improve PDE-5 inhibitor efficacy in patients with low to moderate response.

  1. Check testosterone free and total levels using blood analysis to determine if the patient has low testosterone. There is an emerging body of evidence to show that combination therapy is safe and could be beneficial. The most widely accepted cut-off below which hypogonadism is diagnosed is a serum testosterone level <300 ng/dL (10.4 nmol/L). Furthermore, adding testosterone for a short time in cases of low-normal testosterone levels (300 to 400 ng/dL) seems helpful in some men who did not respond to initial treatment with PDE5 inhibitors alone and in whom testosterone therapy is not contraindicated. The lower the baseline testosterone level, the more likely combination therapy will have a superior improvement in sexual function over PDE5 inhibitor monotherapy.

Reference: Alhathal, et al. Synergetic effect of testosterone and phosphodiesterase-5 inhibitors in hypogonadal men with erectile dysfunction: A systematic review. Can Urol Assoc J 2012;6(4):269-74.

  1. Supplement L-Citrulline daily at 5g-6g (3g BID). Citrulline is an amino acid that improves nitric oxide (NO), which is an important gas that widens blood vessels and improves blood flow. Combining L-Citrulline with PDE5 inhibitors appears to provide good results in men who do not respond adequately to either treatment alone. Since Citrulline increases NO, and the role of PDE5 inhibitors is to help retain NO in the penile tissue, taking both together can be an effective strategy for improving blood flow and erectile hardness.

References:

  1. Sáenz de et al. Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to International Journal of Impotence Research (2004) 16, S40–S42.
  2. Cormio et Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction. Urology. 2011 Jan; 77(1):119-22.

 

 

Compounded PDE-5 Inhibitor Formulations by Dosage Form:

 

I.       Buccal Troche

Definition: Troches are small lozenges that dissolve between the cheek and gum over a period of about 10-20 minutes. As the troche dissolves, the medication is gradually absorbed into the blood stream so that it can be absorbed more efficiently and in some cases more rapidly than if it was taken orally.

Anecdotal Benefits: Reported by some patients to have a faster onset than orally administered tablets.

Reported Negative: Some medications can leave a bitter aftertaste despite flavoring. Sometimes the troche does not completely dissolve and needs to be swallowed.

Route of Administration: Buccal administration refers to a topical route of administration by which drugs held or applied in the buccal area (in the cheek) diffuse through the oral mucosa (tissues which line the mouth) and enter directly into the bloodstream. If the troche is swallowed prior to dissolving, it will still absorb PO.

Storage: To prevent melting, troches should be stored at 70 degrees or lower. We suggest storing them in the refrigerator in warmer climates.

1.    Sildenafil

Dosage form: Buccal troche Available strength: 100 mg Commercial version: Viagra; Revatio

Dose: Dissolve ½-1 troche between the gum and cheek (buccally) 60 min prior to sexual activity. Troches are small lozenges that dissolve between the cheek and gum over a period of about 10-20 minutes. As it dissolves, the medication is gradually absorbed into the bloodstream so that it can be absorbed more efficiently and in some cases faster than if the same medication was taken orally.

2.    Tadalafil

Dosage form: Buccal troche Available strength: 25 mg Commercial version: Cialis

Dose: Dissolve one troche between the gum and cheek (buccally) 60 min prior to sexual activity. Do not take more than 25 mg every 36 hours. Tadalafil troches are scored and can be broken into smaller doses, this allows for a cost-effective method of administering smaller daily dosages.

3.    Avanafil

Dosage form: Buccal troche Available strength: 200 mg Commercial version: Stendra

Dose: Dissolve one troche between the gum and cheek (buccally) 15-30 min prior to sexual activity. Based on individual efficacy and tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity, or decreased to 50 mg (1/4 troche) taken approximately 30 minutes before sexual activity. The lowest dose that provides benefit should be used. The maximum recommended dosing frequency is once per day.

4.    Vardenafil

Dosage form: Buccal troche Available strength: 10 mg; 20 mg Commercial version: Levitra

Dose: Dissolve one troche between the gum and cheek (buccally) 60 min prior to sexual activity. Recommended starting dose is 10 mg and can be increased to 20 mg depending on the patient’s tolerance.

5.    Sildenafil/Testosterone

Dosage form: Buccal troche combination of sildenafil and micronized testosterone

Available strength: 20 mg/20 mg (Women) and 100 mg/100 mg (Men)

Commercial version: Available as a compounded medication only. No commercial equivalent.

Dose: Dissolve one troche between the gum and cheek (buccally) 60 min prior to sexual activity.

 

II.      Capsules

Definition: Capsules have been used for administering medications to patients for more than a century and have an important role in drug delivery. When a primary care provider prescribes a tablet, the choice is usually, but not always, limited to commercially available products. A capsule, however, can be prepared extemporaneously, which provides dosing flexibility for the primary care provider and the pharmacist. Compounded capsules are usually gelatin based.

Benefits: Free of excipients and dyes. Can be made without fillers. Capable of sustained release, which alters the pharmacokinetics of the medication by slowing metabolism to lengthen duration of action.

Reported Negative: Cannot be broken into smaller dosages. The entire capsule must be administered at once.

Route of Administration: Taken by mouth (PO). Storage: Room temperature.

1.    Sildenafil SR

Dosage form: Sustained Release Capsule Available strengths: 36 mg; 75 mg; 110 mg Commercial version: Viagra; Revatio

Dose: Take 1 capsule 60min prior to sex. Allow only one dose within 24 hours. Do not combine with other PDE5 inhibitors or penile injections on the same day otherwise there is risk of priapism.

2.    Tadalafil SR

Dosage form: Sustained release capsule Available strengths: 3 mg; 7 mg; 12 mg; 25 mg Commercial version: Cialis

Dose: Take one capsule 60min prior to sex. Do not take more than 25 mg every 36 hours. Alternatively, tadalafil can be taken daily at common doses of 3 mg- 7 mg taken at approximately the same time every day, without regard to timing of sexual activity.

3.    Sildenafil/Tadalafil combination Dosage form: Capsule

Available strength: 55 mg/12.5 mg (Sildenafil/Tadalafil)

Commercial version: Available as a compounded medication only. No commercial equivalent

Dose: Take 1 capsule 60min prior to sex. Allow only one dose within 24 hours. Do not combine with other PDE5 inhibitors or penile injections on the same day otherwise there is risk of priapism.

 

III.    Oral Dissolvable Tablets (ODT)

Definition: An ODT is a solid dosage form that disintegrates and dissolves in the mouth (either on or beneath the tongue or in the buccal cavity) without water within 60 seconds or less. This dosage form is also helpful for patients who have difficulty swallowing.

Anecdotal Benefits: Faster onset of medication has been reported. Increased compliance in patients who have difficulty swallowing tablets. Can be taken without water.

Reported Negative: Some medications can leave a bitter aftertaste despite flavoring.

Route of Administration: Sublingual administration is when medication is placed under the tongue to be absorbed by the body. The word “sublingual” means “under the tongue.” Buccal administration involves placement of the drug between the gums and the cheek. If the troche is swallowed prior to dissolving, it will still absorb PO.

Storage: Room temperature.

1.    Sildenafil

Dosage form: ODT

Available strengths: 36 mg; 75 mg; 110 mg

Commercial version: Viagra; Revatio

Dose: Place 1 tablet under tongue and dissolve sublingually 60min prior to sex. Allow only one dose within 24 hours. Do not combine with other PDE5 inhibitors or penile injections on the same day otherwise there is risk of priapism.

2.    Tadalafil

Dosage form: ODT

Available strength: 3mg; 7mg; 12mg; 25 mg

Commercial version: Cialis

Dose: Place 1 tablet under tongue and dissolve sublingually 60 min prior to sexual activity. Do not take more than 25 mg every 36 hours.

3.    Avanafil

Dosage form: ODT

Available strength: 100mg; 200 mg

Commercial version: Stendra

 Dose: Place 1 tablet under tongue and dissolve sublingually 15min-30 min prior to sexual activity. Based on individual efficacy and tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity, or decreased to 50 mg (1/2 100mg tablet) taken approximately 30 minutes before sexual activity. The lowest dose that provides benefit should be used. The maximum recommended dosing frequency is once per day.

4.    Vardenafil

Dosage form: ODT

Available strength: 10 mg; 20 mg

Commercial version: Levitra

Dose: Place 1 tablet under tongue and dissolve sublingually 60 min prior to sexual activity. Recommended starting dose is 10 mg and can be increased to 20 mg depending on the patient’s tolerance.

This information is not a recommendation nor is it intended to provide direction regarding diagnoses, treatments, or potential outcomes. Any interpretation of this information is the opinion of Clinic Optimizers and should be used by the prescriber at his/her discretion.

Source:  www.clinicoptimizers.com

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