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.

Nonspecific phosphodiesterase inhibitors (inhibitors of PDE3, 4, and 5)

Indications

General considerations
- Close drug monitoring due to narrow therapeutic index (high risk of overdose).
- Metabolized in the liver by the cytochrome P450 oxidase system.
  - ↑ Risk of drug interactions (e.g., ciprofloxacin can increase theophylline serum levels).
Cardiotoxicity
- Tachycardia, arrhythmias
Neurotoxicity (dosage-dependent)
- At low levels of overdose: dizziness, lightheadedness, headache
- At high levels of overdose: seizures
Gastrointestinal (GI) toxicity
- Severe refractory nausea and vomiting
- Diarrhea
- Abdominal pain

Agents
- Cilostazol
- Dipyridamole
Indications
- Intermittent vascular claudication
- Antiplatelet (antianginal, TIA/stroke prevention)
- Coronary stent restenosis prophylaxis

Agent: Milrinone
Indications
- Acute treatment of decompensated cardiac failure with cardiogenic shock
Mechanisms
- Inhibition of smooth muscle proliferation
- 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

Tip

Vasodilators, see cGMP

Headache
Lightheadedness
Exanthema, flushing
Visual changes: photophobia, optic neuropathy, visual deficits (cyanopsia)
- Due to concomitant PDE 6 (photoreceptor) inhibition by PDE5 inhibitor in the retina.
GI symptoms (e.g., dyspepsia)
Runny nose, nasal congestion