PDE5 inhibitors

Definitions & Key takeaways

PDE5 (phosphodiesterase type 5) inhibitors are a class of drugs that are used to treat erectile dysfunction and pulmonary hypertension. These drugs work by inhibiting the activity of the enzyme phosphodiesterase type 5 (PDE5), which is responsible for breaking down cyclic guanosine monophosphate (cGMP) in the body. By inhibiting PDE5, these drugs increase the levels of cGMP, which relaxes the smooth muscle tissue in the blood vessels of the penis and lungs, leading to an increase in blood flow. Examples of PDE5 inhibitors include drugs like sildenafil, vardenafil, and tadalafil.

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Introduction0:00–0:29

Phosphodiesterase type 5, or PDE5, inhibitors are a class of medications used to treat erectile dysfunction and pulmonary hypertension.
As their name implies, they inhibit the PDE5 enzyme in endothelial cells, which allows for smooth muscle relaxation and thus, promotes blood vessel dilation.
They include sildenafil, vardenafil, and tadalafil. Alright, first, let’s focus on the structure of blood vessels.

Physiology0:29–2:22

Blood vessels have three layers, also called “tunics,” or coverings, that surround the vessel lumen, the hollow part of the vessel that contains the blood.
The innermost tunic is the tunica intima, which includes the endothelial cells; the next one is the tunica media, or middle tunic, which is mostly made of smooth muscle cells and sheets of elastin protein; and finally, there’s the tunica externa, or outside tunic, which is made up of loosely woven fibers of collagen.
Moreover, the tunica media can contract, causing vasoconstriction, where the lumen gets a lot smaller; or it can relax, or vasodilate, causing the lumen’s diameter to increase, allowing for more blood flow.
Now, within endothelial cells of the tunica intima, there’s an enzyme called nitric oxide synthase, which uses the amino acid L-arginine and molecular oxygen to synthesize nitric oxide or NO for short.
Once synthesized, nitric oxide diffuses to adjacent smooth muscle cells in the tunica media, where it binds and activates an enzyme called guanylyl cyclase.
This enzyme converts guanosine triphosphate, GTP, into cyclic guanosine monophosphate, cGMP, which is a second messenger that induces relaxation of smooth muscle cells in vessel walls.
Alright, now the cGMP-specific phosphodiesterase type 5, or PDE5, is an enzyme found in various tissues, mainly in the corpus cavernosum of the penis and the retina.
It’s also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle.
Recently it’s been discovered to play a role in the cardiovascular system. PDE5 normally breaks down cGMP causing its inactivation.
Okay, now PDE5 inhibitors include sildenafil, vardenafil, and tadalafil. These medications inhibit the PDE5 enzyme in endothelial cells which normally breaks down cGMP.

Mechanism of action2:22–4:12

Increased cGMP increases the smooth muscle relaxation in response to nitric oxide. As a result there is an increase in blood flow in the corpus cavernosum of the penis, and a reduction in pulmonary vascular resistance.
Now, PDE5 inhibitors are used in the treatment of erectile dysfunction, which is the inability to develop or maintain an erection due to psychological or organic causes.
It does this by enhancing the erectile response to sexual stimulation. PDE5 inhibitors also treat pulmonary hypertension, which refers to increased blood pressure in the pulmonary circulation, more specifically, a mean pulmonary arterial pressure that is greater than 25 millimeters of mercury.
Peak plasma concentration of sildenafil occurs approximately 30 minutes to two hours after its given orally and can be delayed by eating.
Therefore, a single dose should be given at least an hour before sexual activity. Tadalafil lasts longer than sildenafil and that means it can be taken longer before sexual intercourse.
Tadalafil, in contrast to the other PDE5 inhibitors, can be used to treat urinary signs and symptoms of benign prostatic hyperplasia, or BPH, a non-cancerous growth of the prostate gland, like urinary hesitancy, dysuria, meaning pain during urination, dribbling, which is a weak and inconsistent stream of urine, feeling of bladder fullness, and nocturia which means increased frequency of urination at night.

Side effects4:12–4:49

Alright, now PDE5 inhibitors can cause hypotension, flushing, headache, and dyspepsia, which includes epigastric pain related to eating food, early satiety, postprandial belching, and nausea.
These side effects are caused by vasodilation in other vascular beds. PDE5 inhibitors can also impair vision and cause cyanopia, or blue-tinted vision.
Now, PDE5 inhibitors must not be used in patients receiving nitrates, as nitrates work through increasing cGMP, and severe life-threatening hypotension might occur due to the combination of such medications.
Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts about PDE5 inhibitors.

Memory palace4:49–6:01

Let’s go to a grandparents’ house and their most prized possession is an old reel of film which represents all the PDE5 inhibitors that end in “-afil.” For the main indications, let’s have the grandpa lying in bed since he can’t stand erect, and this represents erectile dysfunction.
The grandmother is over inflating a lung shaped balloon to represent pulmonary hypertension. Next to the grandfather, there’s his old unicycle with 5 pedals, which represents the main enzyme these drugs target: PDE5.
The gramps used to cycle a lot so you know these drugs work by increasing cGMP. Now for the side effects, the room is rather hot and the grandma is feeling lightheaded and her face is flushed red.
She’s wearing bandages on her head to represent headaches and she’s wearing a t-shirt with a flaming stomach for dyspepsia.
Finally, she’s also wearing a pair of cool, blue sunglasses for cyanopia. Now the last item we want to talk about is an old suit of knight’s armor representing nitrates and let’s put a “for sale” sign on it since they should not be used with PDE5 inhibitors due to the possibility of severe hypotension.
All right, as a quick recap…PDE5 inhibitors include sildenafil, vardenafil, and tadalafil. They are all used in the treatment of erectile dysfunction and pulmonary hypertension, while tadalafil can also be used to treat urinary signs and symptoms of benign prostatic hyperplasia, BPH.

Review6:01–6:38

Side effects attributed to vasodilation include hypotension, flushing, headache, and dyspepsia. Blue-tinted vision, or cyanopia may also present as a side effect.
Life-threatening hypotension may occur in patients taking nitrates in combination with PDE5 inhibitors. But wait, there’s more: Here’s a mind map with all of the mnemonics.

Review6:38–6:49

Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers after the credits.