Phosphodiesterase inhibitors

Phosphodiesterase inhibitors (PDE inhibitors) are a class of drugs that inhibit phosphodiesterase enzymes (PDE enzymes). PDE enzymes normally break off phosphate groups and decrease cAMP or cGMP in target cells. PDE inhibitors are classified according to which enzyme(s) they act upon as nonspecific, PDE5, PDE4, and PDE3 inhibitors. PDE5 inhibitors cause pulmonary vasodilation and penile smooth muscle relaxation, and are used for pulmonary hypertension and erectile dysfunction. PDE4 inhibitors enable bronchial dilation in severe COPD. PDE3 inhibitors have positive inotropic, vasodilator, and antiplatelet effects, which are used in acute heart failure and in peripheral vascular disease. PDE3 inhibitors are not recommended for long-term use in patients with heart failure because of their strong cardiostimulatory effects. Nitrates or alpha-blockers are strongly contraindicated in patients taking PDE5 inhibitors because of the risk of life-threatening hypotension.

Phosphodiesterase (PDE) inhibitors are a heterogenic class of drugs that target various isoforms of PDE enzymes. Normally, the PDE decreases cAMP or cGMP in target cells by catalyzing the hydrolysis of these second messengers. By inhibiting this step, PDE inhibitors actually increase cAMP and/or cGMP concentrations. They are classified according to their target isoforms as nonspecific, PDE5, PDE4, and PDE3 inhibitors, each of which has a different clinical use.

Phosphodiesterase inhibitors
Types	Active ingredient	Indications	Mechanism of Action	Desired effect
Nonspecific phosphodiesterase inhibitors (inhibitors of PDE3, 4, and 5)	Theophylline (methylxanthines)	COPD (severe and refractory cases) Asthma	Nonspecific PDE inhibition → ↓ hydrolysis of cAMP → ↑ cAMP levels Adenosine receptor blockade	Inhibition of proinflammatory mediators Deceleration of fibrotic changes in the lung Relaxation of the bronchial musculature → bronchodilation
Phosphodiesterase type 5 inhibitor (PDE5 inhibitor)	Sildenafil Tadalafil Avanafil Vardenafil	Erectile dysfunction	PDE5 inhibition → ↓ breakdown of cGMP → ↑ cGMP → ↑ smooth muscle relaxation in reaction to nitrous oxide activation → pulmonary vasodilation, penile smooth muscle relaxation, and increased blood flow	Decrease in pulmonary vascular resistance ↑ Blood flow in the corpus cavernosum → increase in penis size during an erection
		Pulmonary hypertension
		Benign prostatic hyperplasia (tadalafil only)		Inhibition of proinflammatory mediators Deceleration of fibrotic changes in the lung Relaxation of the bronchial musculature
Phosphodiesterase type 4 inhibitor (PDE4 inhibitor)	Roflumilast	Severe COPD	PDE4 inhibition → ↑ cAMP in bronchial epithelium, granulocytes, and neutrophils
Phosphodiesterase type 3 inhibitor (PDE3 inhibitor)	Milrinone Amrinone Enoximone	Acute treatment of decompensated cardiac failure with cardiogenic shock	PDE3 inhibition → ↑ cAMP In the myocardium: ↑ cAMP → activation of calcium channels → cardiostimulatory effects → ↑ inotropy and ↑ chronotropy In peripheral vessels: ↑ cAMP → inhibition of myosin light chain kinase → smooth muscle relaxation → vasodilation with reduced cardiovascular preload and afterload In platelets: ↑ cAMP → inhibited platelet aggregation ↓ Adenosine reuptake → ↑ extracellular adenosine concentration → vasodilation (dipyridamole)	Increase cardiac contractility acutely in cardiac failure Vasodilation and antiplatelet action in intermittent claudication Inhibition of platelet aggregation for angina prophylaxis, TIA/stroke prevention, and deceleration of restenosis in coronary stents Dipyridamole dilates the coronary arteries and can therefore be used in cardiac stress testing
	Cilostazol Dipyridamole	Intermittent vascular claudication Antiplatelet (antianginal, TIA/stroke prevention) Coronary stent restenosis prophylaxis

Sildenafil, tadalafil, avanafil, and vadenafil are the first-line therapy for filling the corpus cavernosum.

References:^[1][2][3]

• Nonspecific phosphodiesterase inhibitors
  • Cardiotoxicity: tachycardia that may degenerate into arrhythmias and hypotension in severe cases
  • Neurotoxicity: dosage-dependent
    • At low levels: dizziness, lightheadedness, headache, tremor, agitation, irritability, insomnia, psychotic symptoms
    • At high levels: seizures
  • Gastrointestinal (GI) upset: severe, refractory nausea and vomiting, diarrhea, abdominal pain
  • Theophylline
    • Narrow therapeutic index → ↑ risk of toxicities → need for drug monitoring
    • Metabolism by the liver cytochrome P450 oxidase system
      • Elimination time varies between individuals.
      • Serum concentrations prone to fluctuations
      • ↑ Risk of drug interactions
    • Adenosine receptor block: seems to be mainly responsible for severe cardiac and neurological side effects
• Phosphodiesterase type 5 inhibitors ^[4][5]
  • Headaches, cutaneous flushing
  • Lightheadedness
  • Sildenafil: visual deficits (blue-tinted vision, or cyanopia) due to PDE-6 inhibition in the retina ^[6]
  • Runny nose, nasal congestion
  • Exanthema
  • Dyspepsia
  • Rarely: myocardial infarction, stroke, hearing loss, optic neuropathy
• Phosphodiesterase type 4 inhibitors
  • GI upset (nausea, abdominal pain)
  • Weight loss
  • Mental disorders: sleep disturbances, anxiety, depression
• Phosphodiesterase type 3 inhibitors
  • Tachycardia, ventricular arrhythmias; (most common and severe side effect, so not recommended for chronic use)
  • Headaches
  • Hypotension

References:^[1][4][5][7]

We list the most important adverse effects. The selection is not exhaustive.

Because of their vasodilatory and arrhythmogenic effects, PDE inhibitors have a number of contraindications:

• Theophylline
  • Damaged cardiac muscle (e.g., following myocardial infarction)
  • Significant risk of drug interactions (e.g., ciprofloxacin, cimetidine)
• Phosphodiesterase type 5 inhibitors
  • Nitrates: Use of PDE5 inhibitors with nitrates (e.g., nitroglycerin) can result in life-threatening hypotension.
    • Both nitrates (e.g., sublingual nitroglycerin) and PDE-5 inhibitors (e.g., vardenafil) function by increasing cGMP concentration → activation of myosin light chain phosphatase (MLCP) → dephosphorylation of light chains of myosin → smooth muscle cell relaxation in blood vessels → vasodilation
  • Alpha blockers: Use of PDE5 inhibitors with alpha blockers can also result in hypotension. ^[8]
• Phosphodiesterase type 3 inhibitors
  • Severe obstructive cardiomyopathy or ventricular aneurysm
  • Hypovolemia
  • Tachycardia

Patients being treated with PDE5s should not receive nitrates in unstable angina pectoris, acute coronary syndrome, or myocardial infarction because this could result in a life-threatening decrease in blood pressure!

References:^[1][4][9][8]

We list the most important contraindications. The selection is not exhaustive.