What You Don’t know About the “Little Blue Pill”

Few medications compare in popularity to the “little blue pill.” Sildenafil, brand name Viagra, was initially designed to treat pulmonary hypertension. As doctors prescribed Sildenafil for high blood pressure, patients began reporting one not-so-adverse side effect… stronger erections. Realizing the immeasurable potential to tap into a new market, manufacturers rebranded Sildenafil as the premier treatment for erectile dysfunction. (1)  

Quickly shifting trajectory after release, Sildenafil is now synonymous with male sexual health optimization. New research suggests Sildenafil and its successor Tadalafil (Cialis), offer substantial benefits across a broad spectrum of health vectors (2, 3) Some have even gone as far as saying they may replace the tried and true once-daily aspirin for heart disease prevention. To understand the promising future of these medications, let’s first consider how they work. 

Sildenafil and Tadalafil belong to a class of medications known as phosphodiesterase-5 inhibitors (PDE5i). Simply put, they dilate blood vessels by blunting the ability of PDE5 enzymes to degrade a molecule called cyclic-guanosine-monophosphate (cGMP). The accumulation of cGMP is essential for arterial relaxation and allows for optimized circulation. 

Contrary to popular belief, these medications don’t directly induce erections. Increased penile blood flow is a byproduct of improved endothelial function and occurs only after a threshold of sexual arousal is reached. However, assuming underlying conditions have been ruled out, these medications can significantly enhance sexual satisfaction. 

PDE5-inhibitors support health optimization across multiple body systems:

Sildenafil’s history sheds light on the importance of drug repositioning/repurposing in moving medicine forward. Many of the biggest leaps in pharmacology were made through “happy accidents.” For example, the leading hair loss medication Minoxidil was also designed as a treatment for high blood pressure. Patients reported significant improvements in hair growth and the medication was rebranded. (4) The repurposing of Sildenafil and Tadalafil as PDE5 inhibitors for treating erectile dysfunction has led to their recognition as potential therapeutic agents for improving overall health.  

“Recently accumulated data on chronic usage of low-dose PDE-5 inhibitors indicate that low-dose therapy can provide additional potential benefits in diverse medical conditions, apart from their well-established erectogenic action.” (5) 

Many chronic health conditions share the same etiology. Endothelial dysfunction is often at the root of erectile dysfunction, cardiovascular disease, insulin resistance, neurodegenerative disease, and hypertension. Seeing as cGMP activity drastically declines as we age, PDE5-inhibitors show potential to therapeutically restore this essential pathway. Research shows these medicines reduce arterial stiffness and inhibit platelet aggregation, directly reducing cardiovascular risk. (6,7,8)

Tadalafil interacts with sex hormone cascades, optimizing the testosterone-to-estrogen ratio via a simultaneous reduction in aromatase expression and upregulation of androgen receptor activity. Observing these effects led to the discovery that the PDE5 enzyme interacts with the androgen receptor. Tadalafil is now a staple ancillary as a complement to testosterone replacement therapy. (9, 10)

Tadalafil administration is associated with improvements in lean body mass due to its effect on sex hormones, insulin sensitivity, and endothelial function.(11, 12)

 Multiple studies have concluded Tadalafil additionally improves glucose metabolism by way of enhanced pancreatic β-cell function and anti-inflammatory capacity. As a result, PDE5 inhibitors may become first-line medications for managing metabolic syndrome. (13) 

PDE5-inhibitors are rightfully at the forefront of research into neurological disease prevention. Neurodegeneration from aging and brain injury is often characterized by reduced blood flow (hypoperfusion) and elevated levels of inflammation (14,15,16,17). A review of the existing literature and ongoing clinical trials report: 

“The current literature strongly supports the potential efficacy of sildenafil for the treatment of brain injury in adults and neonates, and also suggests that sildenafil could be both neuroprotective and neurorestorative by improving function, reducing infarct size, protecting neurons, regulating neuroinflammation, promoting myelination, and balancing vascular function” (14) 

In our pursuit of innovation, we often overlook the potential for existing technologies to be reimagined for new applications. PDE5-inhibitors are effective, well tolerated, and remarkably safe, which makes them a perfect candidate for repositioning. When we consider a “happy accident” paved the way for an obscure blood pressure medication to become a household-name male sexual health treatment, the untapped potential of drug repurposing becomes clear.  

Marek Health is committed to being at the forefront of the current paradigm shift in care. Our providers and coaches stay up to date on advancements being made in the world of medicine, nutrition, disease prevention, pharmacology, and biochemistry. We guide our patients through optimized health, performance, and longevity. To learn more about how we can support you, book an intake consultation here.

Disclaimer: This blog post/article is for informational purposes only and does not constitute medical advice. This is not a substitute for professional medical advice and should not be relied upon. If you are considering a treatment, always consult your primary care physician to discuss the risks and benefits.

Sources/References 

1. The Serendipitous Story of Sildenafil: An Unexpected Oral Therapy for Erectile Dysfunction

2. PDE5 inhibitors and their applications

3. PDE5 inhibitors beyond erectile dysfunction

4. Minoxidil and its use in hair disorders: a review

5. Effect of low-dose tadalafil once daily on glycemic control in patients with type 2 diabetes and erectile dysfunction: a randomized, double-blind, placebo-controlled pilot study 

6. Sildenafil potentiates nitric oxide mediated inhibition of human platelet aggregation

7. Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data 

8. Administration of daily 5 mg tadalafil improves endothelial function in patients with benign prostatic hyperplasia

9. Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model

10. Efficacy of testosterone replacement therapy plus alternate-day tadalafil for patients with late-onset hypogonadism: An open-label, randomized, crossover study

11. Tadalafil improves lean mass and endothelial function in nonobese men with mild ED/LUTS: in vivo and in vitro characterization

12. Correcting imbalance of sex hormones by a phosphodiesterase 5 inhibitor improves copulatory dysfunction in male rats with type 2 diabetes 

13. Phosphodiesterase 5 inhibition improves beta-cell function in metabolic syndrome

14. The Role of Sildenafil in Treating Brain Injuries in Adults and Neonates.

15. Nitric oxide and geriatrics: Implications in diagnostics and treatment of the elderly

16. Cerebral blood flow in Alzheimer’s disease

17. The role of neuroinflammation in dementias

Repurposing PDE5 inhibitor tadalafil and sildenafil as anticancer agent against hepatocellular carcinoma via targeting key events of glucose metabolism and multidrug resistance