madman
Super Moderator
Abstract
Tadalafil is a phosphodiesterase inhibitor currently approved for use in erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension (PAH). While tadalafil’s benefits in ED and BPH have been well-established for years, its benefits in PAH were identified only recently in major clinical trials, resulting in the recent approval of a single tablet, combination therapy of tadalafil with an endothelin receptor antagonist for PAH. With Tadalafil’s cardiovascular benefits in ED, BPH, and PAH, clinical researchers have begun investigating whether tadalafil’s use extends to other cardiovascular diseases, especially heart failure (HF), an emerging epidemic in medicine. Recent research in animal models has demonstrated a potential benefit of tadalafil use in ischemic cardiomyopathy and HF, as numerous studies in mice and sheep demonstrated improved left ventricular function and contractility, with reduced adverse remodeling and hypertrophy. A retrospective cohort study identified that tadalafil use in patients with ED and coronary artery disease was associated with a significant decrease in the incidence of HF, acute myocardial infarction, and mortality compared with sildenafil or no treatment. However, a randomized controlled trial in patients with comorbid PAH and HF with preserved ejection fraction demonstrated no significant benefit with the use of tadalafil. Unfortunately, there is limited evidence from clinical trials investigating the impact of tadalafil in patients with HF with reduced or preserved ejection fraction without comorbid PAH. Further studies are needed on this topic to better identify whether tadalafil has a role in the prevention or treatment of HF.
TADALAFIL MECHANISM OF ACTION
Tadalafil is a selective inhibitor of PDE5, an enzyme found in the smooth muscle cells of the corpus cavernosum of the penis, prostatic tissue, and pulmonary vasculature, in addition to other locations. PDE5 is responsible for breaking down cyclic guanosine monophosphate (cGMP), a second-messenger molecule produced via an intracellular cascade. This cascade begins when nitric oxide is released and activates the enzyme guanylate cyclase, which converts guanosine triphosphate to cGMP, which acts as a second messenger with multiple downstream actions. Relevant to our discussion, cGMP is responsible for the relaxation of smooth muscle cells and, therefore, causes vasodilation of blood vessels. PDE5 breaks down cGMPto help regulate vascular tone and balance between vasodilation and vasoconstriction.2 Therefore, inhibition of PDE5 prevents the degradation of cGMP and prolongs and enhances its effects.
In its treatment of ED, tadalafil effectively increases cGMP levels, causing relaxation of the smooth muscle cells in the corpus cavernosum, vasodilation of the arteries, and increased blood flow into the penile tissue to achieve erection. In addition, nitric oxide release is increased drastically during sexual stimulation, promoting downstream production of cGMP and increasing tadalafil’s effectiveness in ED.2
Due to PDE5’s presence in prostatic tissue as well, tadalafil is an effective treatment for BPH by increasing cGMP levels and inducing relaxation of the smooth muscle cells in the periprostatic tissue and detrusor muscle of the bladder. This alleviates BPH symptoms by improving urinary flow.3
PDE5 is also present in the pulmonary vasculature, allowing for tadalafil’s use in PAH. By selective inhibition of PDE5, tadalafil increases cGMP levels in the pulmonary vasculature, causing vasodilation and reducing pulmonary arterial pressure.1
TADALAFIL USE IN ED
TADALAFIL USE IN BPH
TADALAFIL IN PAH
TADALAFIL USE IN HF
TADALAFIL SIDE EFFECT PROFILE
Tadalafil is generally a well-tolerated medication, but it doe shave some very common side effects that patients should be notified about. The most reported side effect of tadalafil is a headache, most likely due to its vasodilatory effect on the cerebral vasculature. These headaches are generally transient but can range anywhere from mild to severe. Another common side effect of tadalafil is dyspepsia, characterized by indigestion and abdominal discomfort, most likely due to tadalafil’s relaxation of the gastrointestinal smooth muscle. In patients with existing gastroesophageal reflux disease, tadalafil can cause worsening of acid reflux symptoms. Tadalafil can also cause muscle and back pain/discomfort, with an unclear mechanism potentially related to the relaxation of smooth muscle tissue in these parts of the body.1
Other side effects of tadalafil include hypotension, nasal congestion, flushing, nausea, and dizziness. An uncommon side effect of tadalafil can be blurry vision or alteration in color vision. In rare cases, tadalafil can cause nonarteritis anterior ischemic optic neuropathy that leads to sudden vision loss and permanent blindness in one or both eyes. Another uncommon side effect includes a sudden decrease or loss of hearing, with the potential for permanent hearing loss. One of the most severe side effects of tadalafil is priapism, a prolonged, painful erection lasting >4 hours, which occurs via the same mechanism by which tadalafil treats ED in this patient population. Priapism is a side effect that must be warned against and requires immediate medical attention to prevent permanent injury to the penile tissue. Other uncommon side effects of tadalafil include the development of a rash, urticaria, or swelling of the lips, tongue,or throat after the use of the medication.1
CONCLUSIONS
Tadalafil is approved for use in ED, BPH, and PAH based on proven efficacy in large randomized controlled trials. However, its cardiovascular benefits may potentially extend beyond these conditions. Research in HF animal models has demonstrated that tadalafil use results in improved LV function and contractility with reduced negative remodeling and hypertrophy. A retrospective cohort study identified that tadalafil use in patients with ED and CAD was associated with a significant reduction in the incidence of HF, acute MI, and mortality compared with sildenafil and no treatment. Unfortunately, because there are limited clinical trial data on tadalafil’s impact on HF, further studies are needed on this topic to better identify whether tadalafil has a role in the prevention or treatment of HF.
Tadalafil is a phosphodiesterase inhibitor currently approved for use in erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension (PAH). While tadalafil’s benefits in ED and BPH have been well-established for years, its benefits in PAH were identified only recently in major clinical trials, resulting in the recent approval of a single tablet, combination therapy of tadalafil with an endothelin receptor antagonist for PAH. With Tadalafil’s cardiovascular benefits in ED, BPH, and PAH, clinical researchers have begun investigating whether tadalafil’s use extends to other cardiovascular diseases, especially heart failure (HF), an emerging epidemic in medicine. Recent research in animal models has demonstrated a potential benefit of tadalafil use in ischemic cardiomyopathy and HF, as numerous studies in mice and sheep demonstrated improved left ventricular function and contractility, with reduced adverse remodeling and hypertrophy. A retrospective cohort study identified that tadalafil use in patients with ED and coronary artery disease was associated with a significant decrease in the incidence of HF, acute myocardial infarction, and mortality compared with sildenafil or no treatment. However, a randomized controlled trial in patients with comorbid PAH and HF with preserved ejection fraction demonstrated no significant benefit with the use of tadalafil. Unfortunately, there is limited evidence from clinical trials investigating the impact of tadalafil in patients with HF with reduced or preserved ejection fraction without comorbid PAH. Further studies are needed on this topic to better identify whether tadalafil has a role in the prevention or treatment of HF.
TADALAFIL MECHANISM OF ACTION
Tadalafil is a selective inhibitor of PDE5, an enzyme found in the smooth muscle cells of the corpus cavernosum of the penis, prostatic tissue, and pulmonary vasculature, in addition to other locations. PDE5 is responsible for breaking down cyclic guanosine monophosphate (cGMP), a second-messenger molecule produced via an intracellular cascade. This cascade begins when nitric oxide is released and activates the enzyme guanylate cyclase, which converts guanosine triphosphate to cGMP, which acts as a second messenger with multiple downstream actions. Relevant to our discussion, cGMP is responsible for the relaxation of smooth muscle cells and, therefore, causes vasodilation of blood vessels. PDE5 breaks down cGMPto help regulate vascular tone and balance between vasodilation and vasoconstriction.2 Therefore, inhibition of PDE5 prevents the degradation of cGMP and prolongs and enhances its effects.
In its treatment of ED, tadalafil effectively increases cGMP levels, causing relaxation of the smooth muscle cells in the corpus cavernosum, vasodilation of the arteries, and increased blood flow into the penile tissue to achieve erection. In addition, nitric oxide release is increased drastically during sexual stimulation, promoting downstream production of cGMP and increasing tadalafil’s effectiveness in ED.2
Due to PDE5’s presence in prostatic tissue as well, tadalafil is an effective treatment for BPH by increasing cGMP levels and inducing relaxation of the smooth muscle cells in the periprostatic tissue and detrusor muscle of the bladder. This alleviates BPH symptoms by improving urinary flow.3
PDE5 is also present in the pulmonary vasculature, allowing for tadalafil’s use in PAH. By selective inhibition of PDE5, tadalafil increases cGMP levels in the pulmonary vasculature, causing vasodilation and reducing pulmonary arterial pressure.1
TADALAFIL USE IN ED
TADALAFIL USE IN BPH
TADALAFIL IN PAH
TADALAFIL USE IN HF
TADALAFIL SIDE EFFECT PROFILE
Tadalafil is generally a well-tolerated medication, but it doe shave some very common side effects that patients should be notified about. The most reported side effect of tadalafil is a headache, most likely due to its vasodilatory effect on the cerebral vasculature. These headaches are generally transient but can range anywhere from mild to severe. Another common side effect of tadalafil is dyspepsia, characterized by indigestion and abdominal discomfort, most likely due to tadalafil’s relaxation of the gastrointestinal smooth muscle. In patients with existing gastroesophageal reflux disease, tadalafil can cause worsening of acid reflux symptoms. Tadalafil can also cause muscle and back pain/discomfort, with an unclear mechanism potentially related to the relaxation of smooth muscle tissue in these parts of the body.1
Other side effects of tadalafil include hypotension, nasal congestion, flushing, nausea, and dizziness. An uncommon side effect of tadalafil can be blurry vision or alteration in color vision. In rare cases, tadalafil can cause nonarteritis anterior ischemic optic neuropathy that leads to sudden vision loss and permanent blindness in one or both eyes. Another uncommon side effect includes a sudden decrease or loss of hearing, with the potential for permanent hearing loss. One of the most severe side effects of tadalafil is priapism, a prolonged, painful erection lasting >4 hours, which occurs via the same mechanism by which tadalafil treats ED in this patient population. Priapism is a side effect that must be warned against and requires immediate medical attention to prevent permanent injury to the penile tissue. Other uncommon side effects of tadalafil include the development of a rash, urticaria, or swelling of the lips, tongue,or throat after the use of the medication.1
CONCLUSIONS
Tadalafil is approved for use in ED, BPH, and PAH based on proven efficacy in large randomized controlled trials. However, its cardiovascular benefits may potentially extend beyond these conditions. Research in HF animal models has demonstrated that tadalafil use results in improved LV function and contractility with reduced negative remodeling and hypertrophy. A retrospective cohort study identified that tadalafil use in patients with ED and CAD was associated with a significant reduction in the incidence of HF, acute MI, and mortality compared with sildenafil and no treatment. Unfortunately, because there are limited clinical trial data on tadalafil’s impact on HF, further studies are needed on this topic to better identify whether tadalafil has a role in the prevention or treatment of HF.
