Thursday , November 23 2017
Home / Resources / Clinical Gems / ADA/PDR: Medications for the Treatment of Diabetes, Ch. 18, Pt. 3

ADA/PDR: Medications for the Treatment of Diabetes, Ch. 18, Pt. 3

Diabetic Neuropathic Disorders, Part 3

ADA/PDR_Medications_for_the_Treatment_of_Diabetes

John R. White, Jr., PharmD, PA
R. Keith Campbell, PharmB, MBA, CDE
Travis E. Sonnett, PharmD

Adaptation by Matthew Szabo, PharmD (candidate)

This week we conclude our three-part excerpt of the ADA/PDR text chapter on Neuropathic Disorders…. 

Erectile Dysfunction
 
Sildenafil
  • First approved for ED in 1998, and later approved for pulmonary hypertension in 2005
  • First drug of its class to be developed and approved
  • Over 4,000 patients have been tested in clinical trials
Pharmacology
  • A phosphodiesterase inhibitor, it exerts its action via blockade of cGMP-specific phosphodiesterase-5
  • Action on this enzyme raises levels of cGMP which improves smooth muscle relaxation in the corpus cavernosum, thereby improving erectile dysfunction
  • Also has a minor affinity for phosphodiesterase-6 enzyme
Kinetics
  • Administered orally and is 40% bioavailability
  • Onset in 30 minutes, reaches peak concentrations in 30-120 minutes
  • High fat meals can reduce absorption and delay onset of action
  • Protein binding is around 96%
  • Metabolism is via CYP3A4 and excretion occurs via the feces and a small amount in the urine
  • Active metabolites account for 20% of pharmacologic activity
  • Half-life is about four hours
  • Dose adjustment in both hepatic and renal impairment may be necessary
Clinical Advantages
  • One of the most studied medications for the use in ED
  • Fast onset and moderate duration of action allows for a minimization of side effects while also allowing for adequate time to engage in sexual activity
  • A wide range of dosing options are available, allowing for use in disease states affecting the drugs metabolism, such as hepatic disease
Therapeutic Considerations
  • Not recommended for use in patient taking nitrates, as the combination increases the overall risk of hypotensive crisis
  • Use in the elderly, hepatically impaired, or renally impaired warrant caution as plasma levels are increased when compared to younger healthier individuals
  • Combined use with CYP3A4 inhibitors may result in increased plasma concentrations of sildenafil via metabolic inhibition
  • Caution in use with patients with past history of cardiovascular events such as MI or stroke
  • Due to additional inhibition of the PDE-6 enzyme, visual disturbances or changes in color perception should be reported
  • Common side effects include: headache, flushing, dizziness, and rash
  • Continued exposure is recommended as repeated dosing has shown to improve response
  • Initial recommended dose in patients >65 is 25mg/dose, with escalation based on tolerance and results
 
Vardenafil
  • Second PDE inhibitor approved for the treatment of ED with PDE-5 selectivity
  • Has not been approved for pulmonary hypertension
Pharmacology
  • A phosphodiesterase inhibitor, it exerts its action via selective blockade of cGMP-specific phosphodiesterase-5
  • Results in smooth muscle relaxation in the corpus cavernosum, improving erectile function
  • Due to its selective PDE-5 inhibition, it does not affect PDE-6 in the retina
Kinetics
  • Onset of action occurs within 60 minutes, with peak concentrations reached in 30-120 minutes
  • Bioavailability is 15%
  • High fat meals reduced maximum concentration by as much as 50%
  • Protein binding is 95%
  • Primary metabolism is via CYP450 3A4 and excretion is mainly via the feces
  • Vardenafil metabolites account for 7% of activity
  • Lower dosing should be considered in the elderly and hepatically impaired
Clinical Advantages
  • Extensively studied, though in less populations than sildenafil
  • Fast onset and moderate duration of action allows for a minimization of side effects while also allowing for adequate time to engage in sexual activity
  • A wide range of dosing options are available, allowing for use in disease states affecting the drugs metabolism, such as hepatic disease
  • Due to PDE-5 selectivity, no visual disturbances have been recorded in contrast with sildenafil
Therapeutic Considerations
  • Not recommended for patients taking nitrates due to increased risk of hypotensive crisis
  • Use in the elderly, hepatically impaired, or renally impaired warrant caution as plasma levels are increased when compared to younger healthier individuals
  • Caution in use with patients with past history of cardiovascular events such as MI or stroke, and patients with a previous incidence of QT interval prolongation should not use the medication
  • Combined use with CYP3A4 inhibitors may lead to increased vardenafil concentrations and patients should be monitored for increase risk of side effects
  • Common side effects include: headache, flushing, rhinitis, dyspepsia, dizziness, and rash
  • Initial recommended dose in patients >65 is 5mg/dose, with escalation based on tolerance and results
 
Tadalafil
  • PDE inhibitor approved for the treatment of ED with PDE-5 selectivity
  • Approved in 2003 for male ED, but gained a broader time distinction due to its longer half-life and duration of action
Pharmacology
  • A phosphodiesterase inhibitor, it exerts its action via selective blockade of cGMP-specific phosphodiesterase-5
  • Results in smooth muscle relaxation in the corpus cavernosum, improving erectile function
  • Due to its selective PDE-5 inhibition, it does not affect PDE-6 in the retina
Kinetics
  • Administered orally with an onset of 30-45 minutes, with peak concentration at 30-360 minutes, and a duration of action of up to 36 hours
  • Administration with food does not seem to affect absorption or serum levels
  • Protein binding is 94%
  • Metabolized primarily by CYP450 3A4, and is primarily excreted via the feces and secondarily the urine
  • Lower dosing should be considered for the elderly and hepatically impaired, as well as patients with moderate to several renal impairment
Clinical Advantages
  • Due to its 36 hour duration of action, it allows for the largest window for patients to engage in sexual activity
  • A wide range of dosing is available, allowing for use in patients with disease states affecting drug metabolism
  • Due to PDE-5 selectivity, no visual disturbances have been recorded in contrast with sildenafil
Therapeutic Considerations
  • Not recommended for patients taking nitrates due to increased risk of hypotensive crisis
  • Use in the renally impaired warrant caution as plasma levels are increased when compared to younger healthier individuals
  • Dose adjustments based on age or hepatic impairment are not necessary, although doses higher than 10mg daily are not recommended in the hepatically impaired
  • Combined use with CYP3A4 inhibitors may result in increased plasma concentrations of tadalafil via metabolic inhibition
  • Use with grapefruit juice is not recommended as it could lead to increased drug serum levels
  • Common side effects include: headache, flushing, rhinitis, dyspepsia, dizziness, and rash
  • Due to tadalafil’s extended half-life and duration of action, initiation with a low starting dose (5 mg) and titration based on results is recommended to minimize adverse events as they occur
  • Repeated dosing is recommended as continued exposure has been shown to improve response
  • Initial recommended dose in patients >65 is 10mg/dose, with escalation based on tolerance and results
Vardenafil
  • Naturally occurring prostaglandin E found in the seminal vesicles and cavernous tissues of the penis
  • Approved by the FDA for ED in 1995
Pharmacology
  • Mechanism involves acting upon the smooth muscle of the corpus cavernosum, stimulating the activity of adenylate cyclase, leading to an increase in camp which decreases adenylate cyclase, resulting in muscle relaxation
  • It also causes a decrease in norepinephrine, which leads to increased arterial blood flow
Kinetics
  • Administration occurs via intracavernosal injection or intraurethral tablet application
  • Onset of action is 5-10 minutes and lasts for 30-60 minutes
  • Successful erection occurs within 2-25 minutes and may last up to several hours
  • Majority of drug is absorbed locally with little systemic absorption, with no reported tolerance
  • Alprostadil is broken down into inactive metabolites and mainly excreted in the urine
Clinical Advantages
  • Usable in patients who are unable to take PDE-5 inhibitors (sildenafil, etc.) due to nitrate use or other reasons
  • Systemic absorption is minimal with little to no adverse effects associated with the medications
  • No dose adjustments are necessary for age, hepatic impairment, or renal impairment
Therapeutic Considerations
  • Not recommended for patients who have experienced or are at risk for experiencing priapism (erection lasting >6 hours)
  • The intraurethral tablet is not recommended for patients with penile deformities or structural abnormalities
  • If injection site reactions occur, discontinuation is recommended
  • Some noted, but not common, side effects include hypotension and syncope
  • No reported drug interactions have been reported, however they could theoretically occur if coadministered with other antihypertensive agents
  • No official dosing recommendations exist, but recommendations include starting at 1.25 mcg for injection and 125 mcg per intraurethral tablet, with titration based on response.
  • Injections should not be given more than 3 times per week, with 24-hours between doses
 
If you are interested in purchasing this text, just follow this link to the Amazon website: ADA/PDR Medications for the Treatment of Diabetesalt.

Copyright © 2008 and published by the Healthcare business of Thomson Reuters at Montvale, NJ, 07645