• Clinical science

Phosphodiesterase inhibitors

Abstract

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.

Effects

Active ingredient Indications Mechanism of Action Desired effect

Nonspecific phosphodiesterase inhibitors

(inhibitors of PDE3, -4 and -5)

  • Nonspecific PDE inhibition → ↓ hydrolysis of cAMPcAMP levels
  • Inhibition of proinflammatory mediators
  • Deceleration of fibrotic changes in the lung
  • Relaxation of the bronchial musculature

Phosphodiesterase type 5 inhibitor

(PDE5 inhibitor)

  • PDE5 inhibition → ↓ breakdown of cGMPcGMP → ↑ smooth muscle relaxation in reaction to NO activation:
    • → Pulmonary vasodilation
    • → Penile smooth muscle relaxation
  • Inhibition of proinflammatory mediators
  • Deceleration of fibrotic changes in the lung
  • Relaxation of the bronchial musculature

Phosphodiesterase type 4 inhibitor

(PDE4 inhibitor)

Phosphodiesterase type 3 inhibitor

(PDE3 inhibitor)

  • PDE3 inhibition → cAMP
    • In the myocardium: cAMP → activation of calcium channels → cardiostimulatory effects (e.g., ↑ contractility)
    • In peripheral vessels: cAMPsmooth 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

References:[1][1][1][1][2][3][4]

Side effects

References:[1][2][5][6][7][8]

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

Contraindications

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

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.