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.

SildenaFIL, tadalaFIL, avanaFIL, and vardenaFIL: FIrst-Line therapy for FILling the corpus cavernosum

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

• Nonspecific phosphodiesterase inhibitors
  • General considerations
    • Close drug monitoring due to narrow therapeutic index (high risk of overdose).
    • Metabolized in the liver by the cytochrome P450 oxidase system.
      • Elimination time varies.
      • Serum concentrations are prone to fluctuations.
      • ↑ Risk of drug interactions (e.g., ciprofloxacin can increase theophylline serum levels).
    • Concomitant adenosine receptor block: associated with severe cardiac and neurological adverse effects
  • Cardiotoxicity
    • Tachycardia, arrhythmias
    • Hypotension (in severe overdose)
  • Neurotoxicity (dosage-dependent)
    • At low levels of overdose: dizziness, lightheadedness, headache, tremor, agitation, irritability, insomnia, psychotic symptoms
    • At high levels of overdose: seizures
  • Gastrointestinal (GI) toxicity
    • Severe refractory nausea and vomiting
    • Diarrhea
    • Abdominal pain
• Phosphodiesterase type 5 inhibitors ^[4][5]
  • Headache
  • Lightheadedness
  • Exanthema, flushing
  • Visual changes: photophobia, optic neuropathy, visual deficits (cyanopsia) ^[6]
  • GI symptoms (e.g., dyspepsia)
  • Runny nose, nasal congestion
  • Rare: myocardial infarction, stroke, hearing loss
• Phosphodiesterase type 4 inhibitors ^[7]
  • Weight loss
  • GI symptoms (e.g., nausea, abdominal pain)
  • Psychiatric symptoms: sleep disturbances, anxiety, depression
• Phosphodiesterase type 3 inhibitors ^[4]
  • Most common and severe adverse effects: tachycardia, ventricular arrhythmias (PDE 3 inhibitors are not recommended for long-term use or patients with acute heart failure due to the high risk of adverse effects.)
  • Headaches
  • Flushing
  • Hypotension
  • GI symptoms (e.g., nausea)

References:^[1]

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 activating guanylate cyclase in the cytosol of vascular smooth muscle cells → 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][8][9]

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