Phosphodiesterase inhibitors

Phosphodiesterase inhibitors (PDE inhibitors) are a class of drugs that inhibit phosphodiesterase enzymes (PDEs). PDEs 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.

	Active ingredient	Indications	Mechanism of Action	Desired effect
Nonspecific phosphodiesterase inhibitors (inhibitors of PDE3, -4 and -5)	Theophylline	COPD Asthma	Nonspecific PDE inhibition → ↓ hydrolysis of cAMP → ↑ cAMP levels	Inhibition of proinflammatory mediators Deceleration of fibrotic changes in the lung Relaxation of the bronchial musculature
Phosphodiesterase type 5 inhibitor (PDE5 inhibitor)	Sildenafil (Viagra®) Tadalafil Vardenafil	Erectile dysfunction	PDE5 inhibition → ↓ breakdown of cGMP → ↑ cGMP → ↑ smooth muscle relaxation in reaction to NO activation: → Pulmonary vasodilation → Penile smooth muscle relaxation	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 neutrophils, granulocytes, and bronchial epithelium
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 (e.g., ↑ contractility) In peripheral vessels: ↑ cAMP → smooth muscle relaxation → vasodilation with reduced cardiovascular preload and afterload In platelets: ↑ cAMP → inhibition of platelet aggregation	Increase cardiac inotropy 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
	Cilostazol Dipyridamole	Intermittent vascular claudication Antiplatelet (anti-angina, TIA/stroke prevention) Prevention of coronary stent restenosis

References:^{[1][1][1][1][2][3][4]}

• Nonspecific phosphodiesterase inhibitors
  • Cardiotoxicity: arrhythmias, tachycardia
  • Neurotoxicity: dizziness; , headache; , insomnia, irritability, lightheadedness; at high levels, seizures
  • Gastrointestinal (GI) upset: nausea, diarrhea Toxicity can be treated with beta blockers.
• Phosphodiesterase type 5 inhibitors.
  • Headaches, cutaneous flushing
  • Lightheadedness
  • Visual deficits: blue-tinted vision, or cyanopia
  • 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! )
  • Headaches
  • Hypotension
  • Cutaneous flushing
  • GI upset: nausea, abdominal pain

References:^{[1][2][5][6][7][8]}

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:

• Phosphodiesterase type 5 inhibitors
  • Nitrates: Use of PDE5 inhibitors with nitrates can result in life-threatening hypotension.
    • Both nitrates (e.g., sublingual nitroglycerin) and PDE-5-inhibitors (e.g., vardenafil) function by increasing cGMP concentration → cGMP leads to activation of myosin-light-chain phosphatase (MLCP) → dephosphorylates 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
• 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, and myocardial infarction because of the risk of a life-threatening decrease in blood pressure!
References:^{[1][2][5][9][10]}

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