Phosphodiesterase Inhibitors

Phosphodiesterase inhibitors are a class of medications that interfere with certain types of chemical reactions in your blood. This helps blood vessels relax, reduces inflammation and more. They are best-known for their use in treating erectile dysfunction, but also have many other uses related to the heart and circulatory system.

Overview

What are phosphodiesterase inhibitors?

Phosphodiesterase inhibitors are medications that cause blood vessels to relax and widen, improving circulation and lowering blood pressure. That makes them useful for treating a wide range of medical conditions, including problems with your skin and joints, your heart and lungs, and even sexual dysfunction.

How do they work?

Phosphodiesterases (foss-fo-dy-ess-ter-aze-s) are enzymes, a type of molecule that helps chemical reactions happen much faster and easier than normal. PDEs come in several different types in humans, with numbers assigned to each type to tell them apart. These different types of PDEs usually occur in specific places in your body.

  • PDE-3: This type of PDE is specific to your heart and circulatory system. It also has a role in how your blood clots.
  • PDE-4: This type is specific to your lungs, causing muscles in your airway (especially your bronchial tubes) to constrict and tense up.
  • PDE-5: These are in the lungs, and in the penis (for those assigned male sex at birth).

Phosphodiesterase (PDE) inhibitors are medications that block those enzymes. Some PDE inhibitors are selective, meaning they target a specific type of PDE. Other PDE inhibitors are nonselective, meaning they can interfere with all PDEs to some extent.

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What conditions are treated by this class of medication?

PDE inhibitors have approval from the U.S. Food and Drug Administration to treat over a dozen different medical concerns, conditions and diseases. These include:

Heart and circulatory conditions

  • Decompensated heart failure. When a system in your body is struggling, your body tries to compensate to keep you going. Decompensation is when your heart fails because your body can’t keep up with the problem(s). Decompensated heart failure is when long-term problems cause your heart to become too weak to pump on its own.
  • Pulmonary hypertension. This is high blood pressure in the lungs. It’s usually related to heart problems.
  • Peripheral artery disease (PAD). This is when your body struggles to provide enough blood flow to your limbs, especially your legs.
  • Post-surgery thromboembolism (clotting) prevention. Clotting after surgery can be dangerous because of the risk of stroke, heart attack or pulmonary embolism (a clot that gets stuck and blocks blood flow in the lungs).
  • Thrombocythemia. This is when your body makes too many platelets, a type of blood cell that helps your blood clot.

Inflammatory diseases

  • Eczema. Also known as atopic dermatitis, this is a condition that makes skin inflamed, irritated and itchy.
  • Psoriasis. This is a condition where the immune system inflames areas of the skin.
  • Psoriatic arthritis. This condition is an inflammation of the joints, which starts immune-related inflammation with psoriasis.

Reproductive (male) disorders

Respiratory conditions

  • Chronic obstructive pulmonary disorder. Also known as COPD, this is a condition that includes several specific diseases that cause breathing problems.
  • Neonatal apnea. This is trouble breathing in premature newborns, especially those born at least seven weeks early.

Are phosphodiesterase inhibitors commonly prescribed?

PDE inhibitors prescriptions are very common, especially PDE-5 inhibitors for the treatment of treat erectile dysfunction. In 2019, there were more than 4 million prescriptions for just the top two PDE inhibitor medications, sildenafil and tadalafil. Both rank in the top 300 among most commonly prescribed medications in the United States.

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How many phosphodiesterase inhibitors are there?

As of Sept. 2021, there are 14 PDE inhibitors with FDA approval. U.S. Food and Drug Administration.

PDE inhibitors by type

PDE-3
Amrinone/Inamrinone
PDE-4
Apremilast
PDE-5
Avanafil
Non-selective
Caffeine*
Anagrelide
PDE-4
Crisaborole
PDE-5
Sildenafil
Non-selective
Pentoxifylline
Cilostazol
PDE-4
Roflumilast
PDE-5
Tadalafil
Non-selective
Theophylline
Dipyridamole
PDE-4
PDE-5
Vardenafil
Non-selective
Milrinone
PDE-4
PDE-5
Non-selective

*Caffeine does act as a PDE inhibitor and comes in medicinal forms. One of those forms, caffeine citrate, comes in specific dosages for medical use.

Risks / Benefits

What are the advantages of phosphodiesterase inhibitors?

PDE inhibitors have several advantages that make them beneficial — if not ideal — for treating certain conditions. These advantages include:

  • Convenient forms. PDE inhibitors come in various forms, including those you take by mouth, creams you apply to your skin, and medications in the form of intravenous (IV) injections. Depending on the medication, you can take some daily, while others you will take as-needed or when the situation calls for it.
  • Targeted treatment. Selectively targeting certain PDEs allows treatment of a condition without affecting other parts of the body (which can cause undesired side effects).
  • Multiple beneficial effects. There are some conditions that PDE inhibitors can treat that commonly happen at the same time. Examples of this are benign prostatic hyperplasia and erectile dysfunction. Tadalafil, a PDE-5 inhibitor, has FDA approval to treat both. Another example is apremilast, which can treat both psoriasis and psoriatic arthritis.
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What are the possible side effects and complication risks of these medications?

The major side effects and complications for PDE inhibitors strongly depend on the type in question.

PDE-3 inhibitor side effects and complications

  • Amrinone / Inamrinone: Mild and moderate side effects include thrombocytopenia (low platelet count), gastrointestinal effects (nausea, vomiting and abdominal pain) and liver damage. Severe side effects include irregular heart rhythm (arrhythmia) and immune system hypersensitivity (overreaction).
  • Anagrelide: Mild and moderate side effects include headache, weakness, swelling and gastrointestinal effects (nausea, vomiting, indigestion, diarrhea). Severe side effects include heart palpitations and low blood pressure.
  • Cilostazol: Mild and moderate side effects include headache and gastrointestinal effects (nausea, diarrhea or bloody/tarry poop). Severe side effects include fast heartbeat (tachycardia) or heart palpitations.
  • Dipyridamole: Mild and moderate side effects include feeling dizzy or lightheaded, upset stomach or other gastrointestinal effects, rash, headache and liver enzyme test results that are higher than normal. Severe side effects include unusual bleeding or bruising, jaundice and chest pain.
  • Milrinone: Mild and moderate side effects include headache, low potassium levels and shaking or tremor. Severe side effects include irregular heart rhythm (arrhythmia).

PDE-4 inhibitor side effects and complications

  • Apremilast: Mild and moderate side effects include gastrointestinal problems (weight loss, nausea, vomiting, diarrhea), upper respiratory illnesses and infections, and headache. Severe side effects include depression that gets worse and suicidal thoughts.
  • Crisaborole: Mild to moderate side effects include a burning sensation where it’s applied to your skin. Severe side effects include hypersensitivity (itching, swelling, rash).
  • Rofumilast: Mild to moderate side effects include gastrointestinal problems (loss or decrease in appetite, nausea, vomiting, diarrhea), anxiety, nervousness or insomnia (trouble sleeping), headache and dizziness. Severe complications include depression that gets worse.

PDE-5 inhibitor side effects and complications

If you take nitroglycerin under your tongue for chest pain, you should immediately go to the emergency room if you have chest pain within 24 hours after taking any PDE-5 inhibitor.

A severe side effect of PDE-5 inhibitors is priapism. This is an erection you don't want or that happens without sexual arousal; these last at least four hours but can happen on and off for several hours. Other side effects include:

  • Avanafil: Mild to moderate side effects include headache, flushed skin, back pain, nasal congestion. Severe side effects include hearing loss (partial or total), or ringing in your ears; changes in your vision; and itching, rash or swelling around your eyes.
  • Sildenafil: Mild to moderate side effects include headache, flushed skin, gastrointestinal problems (nausea, indigestion), dizziness or feeling lightheaded, low blood pressure, back pain and rash. At high doses, this can cause a blue tint to lights or cause lights to appear brighter than normal (this is temporary). Severe side effects include changes to vision, hearing loss (partial or total) and liver damage.
  • Tadalafil: Mild to moderate side effects include headache, low blood pressure, nasal congestion or irritation, and muscle aches. Severe side effects include changes to vision and hearing loss (partial or total).
  • Vardenafil: Mild to moderate side effects include headache, flushed skin, flu-like symptoms, sinus congestion and gastrointestinal problems (nausea, indigestion). Severe side effects include hearing loss.

Nonselective PDE inhibitor side effects and complications

  • Caffeine: Mild to moderate side effects include irritability or restlessness, trouble sleeping, shakiness and tremors, and gastrointestinal problems (nausea, vomiting and diarrhea). Severe side effects include fast heartbeat or heart palpitations.
  • Pentoxifylline: Mild to moderate side effects include gastrointestinal problems (nausea, vomiting and diarrhea), dizziness and headache. Severe side effects include chest pain and irregular heart rhythm (arrhythmias).
  • Theophylline: Mild to moderate side effects include low blood pressure, fast heartbeat and gastrointestinal problems (nausea, vomiting and diarrhea). Severe side effects include seizures and irregular heart rhythm (arrhythmias).

What are the reasons I should not take these medications?

There are several reasons, including personal circumstances and medical conditions, which mean you shouldn't take a PDE inhibitor. These are contraindications, and they come in two types: absolute (meaning you definitely shouldn’t take this medication) or relative (meaning providers should be cautious when prescribing these medications, and you should be cautious when taking them).

Absolute contraindications include:

  • All PDE inhibitors: If you’ve had hypersensitivity issues in the past, where your immune system overreacted strongly to something. This could be a type of allergy or where your immune system caused inflammation or damage in a part of your body.
  • Cilostazol: Heart failure of any kind means you should not take this medication.
  • PDE-5 inhibitors (avanafil, sildenafil, tadalafil, vardenafil): Heart (cardiovascular) disease and high-risk conditions like unstable angina, severe heart failure, recent heart attack or heart valve problems, and severe heart rhythm problems.

Other contraindications include:

  • PDE-5 inhibitors (avanafil, sildenafil, tadalafil, vardenafil): If you take nitrites or nitrates, be cautious when taking these medications. They can cause very low blood pressure, which might make you pass out. This can also happen with alpha-blockers (also known as alpha-receptor antagonists).
  • Amrinone and milrinone: People with aortic or pulmonic valvular disease shouldn’t take amrinone. People who are already taking disopyramide should talk at length with their healthcare provider before taking amrinone. Milrinone can cause problems if you have acute kidney injury and/or end-stage renal disease. This is because your kidneys are responsible for clearing it out of your body.
  • Cilostazol: If you have a condition that causes problems with bleeding, you shouldn’t take this medication.
  • Pentoxifylline: Avoid taking this if you have a recent history of bleeding in your eyes or brain.

Pregnancy

You may want to avoid taking certain PDE inhibitors if you are pregnant or trying to become pregnant. While there’s limited evidence to show a risk to a fetus in humans, there are studies in animals that show potential problems with these medications:

  • Anagrelide.
  • Avanafil.
  • Cilostazol.
  • Milrinone.
  • Roflumilast.
  • Sildenafil.
  • Theophylline.

Do phosphodiesterase inhibitors interact with any other medications?

PDE inhibitors can interact with a wide range of medications, especially those that affect your heart, lungs or circulatory systems. Your healthcare provider can provide more information and advise you on what to avoid when taking these medications.

Recovery and Outlook

How long can I stay on phosphodiesterase inhibitors?

How long you need to take a PDE inhibitor depends on the reason you take it. Some people may only need to take them temporarily. Others may need to take them indefinitely.

When to Call the Doctor

When should I call my healthcare provider?

Your healthcare provider can best explain the signs or symptoms that mean you need to call their office or go to the hospital right away. This is especially true if your symptoms start to change and affect your daily life or routine.

In general, you should go to the hospital immediately if you have any of the following:

  • Heart attack symptoms. These include chest pain, trouble breathing, sweating, dizziness, nausea, etc.
  • Priapism. This is an erection that lasts for at least four hours or that comes and goes over several hours. Priapism happens without sexual arousal, and it can be unpleasant or painful.
  • Loss of vision or hearing. Any sudden decrease in your eyesight or hearing needs immediate medical attention. If you delay getting help, these problems can be permanent.

A note from Cleveland Clinic

Phosphodiesterase inhibitors are medications that can help people with a wide range of medical conditions and needs. Though they are well-known because they can help with erectile dysfunction, their uses go far beyond sexual health. However, you should not take these medications unless you have a prescription. Taking any of these medications without a doctor’s prescription can cause dangerous or even deadly medical conditions.

Medically Reviewed

Last reviewed by a Cleveland Clinic medical professional on 06/08/2022.

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