Why PDE5 inhibitors Boomed the Global Pharmaceutical Market

» Men probably are not aware of the fact that their robust sexual function entirely depends upon the presence of PDE5 (cGMP-specific phosphodiesterase type 5) in a body – an enzyme distributed in all human tissues but prevalently in the cavernous bodies (erectile tissues), retina, lungs, and CNS. This enzyme suppresses the action of cGMP (Cyclic guanosine monophosphate) – the nucleotide that is responsible for the signal translation and relaxation of plain muscles located in the penile veins.

Under sexual excitement, the penile tissues start the production of nitric oxide (NO), which binds to the synaptic sites of guanylate cyclase. This mixture raises the blood level of cGMP what leads to vasodilation (expansion) of helicine arteries inside the penile shaft. Relaxed and expanded arteries let more blood into the organ what results in the stiffness of the phallus (erection). The higher concentration of cGMP is means the better rigidness is reached.

The sadly-remembered PDE5 causes the breakdown of cGMP. Typically, this happens when a sexual performance is over and a man does not need the erection anymore. But under many health- or psychology-related reasons, the activation of RDE5 starts much earlier, preventing a male from reaching or/and maintaining a good erection. Why does this Phosphodiesterase type 5 break the cyclic nucleotides? Just to keep the organism chemically balanced.

 PDE5 inhibitors are the pharmaceutical agents blocking (inhibiting) the function of the PDE5 enzyme. These selective inhibitors are actively used in the modern medicine to treat different health conditions. Contrary to the common belief, PDE5 blockers are indicated not only for erectile dysfunction sufferers.

PDE5 inhibitors are memory enhancers

The heightened interest in PDE 5 blockers emerged after they have been found out to be effective against neuroinflammatory diseases, neurodegenerative impairments, and cognitive disorder. The matter is that PDE5 inhibitors regulate cell signaling by boosting the concentration of cGMP in the brain what leads to an enhanced cerebral blood flow.

These inhibitors also have an anti-inflammatory and neuroprotection action as they intensify the NOS (nitric oxide synthases) expression and cGMP formation. PDE 5 inhibitors activate PKG – the cGMP-dependent protein kinase G – a signal pathway of which is crucially important in the development of multiple neuro affections like multilocular sclerosis (MS), Alzheimer’s dementia (AD), and Parkinson’s disease (PD).

Aging and accumulation of amyloid peptides are the two factors that can provoke the development of mental debility. It is known: a deficiency of the cGMP concentration occurs in the brain with the increase of years. Owing to the fact that PDE5 inhibitors regulate the NO/cGMP/PKG pathways by enhancing the levels of cGMP throughout the body and brain, in particular, they turn out to be right candidates to treat mental impairment.

PDE5 inhibitors like Sildenafil citrate (the active agent of Viagra and its generics) influence the retention of long-term memory by controlling the mechanisms participating in memory storage. More than that, the neutralization of PDE5 has a positive effect on object recognition memory, stops spatial learning difficulties driven by the inhibition of NOS, and improves synaptic plasticity (synapses are a part of a nerve cell able to weaken or strengthen to transmit signals between neurons).

Vardenafil, Tadalafil, and Sildenafil (the most popular PDE5 inhibitors) have the molecular architecture akin to cGMP. The potent use of these medications in the central nervous system is associated with their ability to reach the BBB (blood-brain barrier) in sufficient concentrations where they induce the cleavage of PDE5.

A number of clinical studies have approved that inhibitors with selectivity for PDE5 have a neuroprotective action. For instance, Sildenafil (Viagra) reduces the neurological abnormalities, promotes neurogenesis (generation of new neurons in the brain) and memory, and contributes to the recovery of brain functions after focal cerebral ischemia and a cerebrovascular incident in rodents. Tadalafil is found out to have the same neurogenetic effect along with an ability to minimize the deleterious action of a heart attack, which usually affects motor coordination and memory.

» Sildenafil is confirmed to be beneficial for cognition function. In a study conducted by My Canadian Pharmacy Pro, 100 men over 45 with erectile dysfunction demonstrated brighter cognitive abilities and reduced proclivity for mood disorders and depression after two months of Sildenafil therapy. This effect was achieved by a boost in the NO/cGMP signal pathway, improved delivery of glucose and oxygen to the cells of a brain, and raised self-esteem in tested people.

PDE5 inhibitors are diabetes fighters

pde5 and diabetesIf taken chronically (for three months or more), Sildenafil reduces levels of endothelin, C-reactive protein, and nitrite in people with type II diabetes and has a positive action on glycometabolic control.

In a similar way, continuous usage of Tadalafil reduces the infarct size in a heart, diminishes the concentration of proinflammatory cytokines, and improves fasting glucose levels in type II diabetic sufferers. The chronic taking of Tadalafil reduces the formation of reactive oxygen species and free-radical lipid oxidation. Thus, PDE5 inhibitors can be a possible therapeutic strategy to treat ALS (Amyotrophic lateral sclerosis).

Pre-marketing clinical trials also acknowledged that the beneficial effect of Tadalafil therapy on the cardiovascular function occurs through the improvement of endothelial function indicators like endothelin-1 and C-reactive protein.

In 2015, the American Diabetes Association announced the results of two studies of men with type II diabetes (with 7860 and 857 participants respectively) confirming that the administration of PDE5 inhibitors reduces all-cause mortality even in those who had a history of acute myocardial infarction (AMI).

The second research established that in different populations of males diagnosed with type II diabetes who were receiving concomitant treatment with testosterone and PDE5 inhibitors demonstrated reduced mortality too. It is supposed, inhibitors with PDE5 selectivity are cardioprotective agents and able to relieve arrhythmias.

It is also believed that a man taking any PDE5 inhibitor has a lower risk of dying from diabetes even if he is of a senior age with a history of myocardial infarction, smoking, unstable blood pressure, or regularly uses metformin or beta-blockers.

PDE5 inhibitors are PAH curers

Pulmonary arterial hypertension is a disabling condition characterized by an increased blood pressure in lungs. In approximately 10-15% of cases, the disease has one-year mortality. This rise in pressure begins on the increased pulmonary arterial resistance what often results in right heart strain. The two main markers of PAH are an increased expression of the PDE5 enzyme, which has a vasoconstrictive property (it narrows the blood vessels), and a deficient production of NO, which acts as a vasodilator (it widens the veins) in the pulmonary vasculature.

Phosphodiesterase type 5 is prolifically expressed in the lungs and breakdowns cyclic guanosine monophosphate (cGMP), which is a transmitter of the nitric oxide pathway within the lung tissue. PDE5 inhibitors stop the breaking of cGMP, which has an antiproliferative action too (prevents the growth and spread of malignant cells) on the pulmonary vasculature. PAH patients taking PDE5 inhibitors as a part of a complex therapy have significant improvements in severity of pulmonary hypertension, pulmonary wedge pressure, right ventricular and lung functions, and quality of life overall.

Sildenafil and Tadalafil are those PDE5 inhibitors that are FDA-approved to treat PAH in the USA. These drugs are actively used for this purpose in Canada as well and are always available in the stock of My Canadian Pharmacy Pro.

Sildenafil is highly selective for PDE5.The medicine’s half-life is nearly 4 hours what means its 20 mg dose is required to be taken three times a day to cure PAH. Sildenafil is primarily metabolized by CYP3A4 (an enzyme in a liver) to inactive metabolites. It means that severe drug interactions are possible if Sildenafil is taken with any CYP3A4 inhibitors including Erythromycin and Ritonavir.

» Like Sildenafil, Tadalafil has high selectivity for PDE5. Thanks to its prolonged half-life (about 17 hours), 40 mg of Tadalafil is recommended to be dosed once per day. Tadalafil action does not depend on food or alcohol taking. CYP3A4 metabolizes the drug to metabolic products in a liver. Hence, inducers and inhibitors of CYP3A4 can influence plasma levels of Tadalafil.

PDE5 inhibitors are ED killers

ed killersThough PDE5 inhibitors have confirmed their effectiveness against pulmonary hypertension, diabetes, and dementia, they cracked the global pharmaceutical market due to their property of improving sexual function.

The loss of sexual power can have physiological, psychological or mixed etiology. ED is a phenomenon that can negatively affect a male’s sexual behavior, public conduct, self-conception, and even psychological state.

For too long, the stigma of impotence was increasing in the awkward society, which assumed ED as an integral part of aging, until Viagra, Cialis, and Levitra were invented on the cusp of the 20th and 21st centuries. These PDE5 inhibitors are the first verified methods of curing sexual frustration that revolutionized the male health medicine.

The improvement of sexual performance in the course of PDE5 inhibitors therapy is manifested in enhancing the erectile function, recovering the self-confidence, and refining the psychological adjustment.

The astonishing success of PDE5 inhibitors lies in their effectiveness (95-98%), good tolerability even in senior males, a minimum number of side-effects, which vary only from mild to moderate, few contraindications. These drugs are safe for patients with a history of myocardial infarction, cardiovascular diseases, prostate cancer, kidney, and liver impairment and are also used to prevent impotence after radical prostatectomy.

Despite their efficacy and clinically-supported safety, PDE5 inhibitors are not recommended to be consumed without a doctor’s consultation because erectile problems are always a symptom of some pathology developing in a body. By checking this issue with a medical specialist and taking the necessary laboratory tests, a patient is sure to get the most out of PDE5 inhibitors medications.