10/16/2020 Phosphodiesterase inhibitors - AMBOSS

Phosphodiesterase inhibitors
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Summary

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.

Pharmacodynamics

Active ingredient Indications Mechanism of Action Desired effect

Nonspecific Theophylline COPD Nonspecific PDE Inhibition of

phosphodiesterase Asthma inhibition → ↓ proinflammatory
inhibitors hydrolysis of cAMP → mediators
(inhibitors of ↑ cAMP levels Deceleration of
PDE3, -4 and -5) fibrotic changes
in the lung
Relaxation of
the bronchial
musculature

Phosphodiesterase Sildenafil Erectile PDE5 inhibition → ↓ Decrease in

type 5 inhibitor (Viagra®) dysfunction breakdown of cGMP pulmonary
Tadalafil → ↑ cGMP → ↑ vascular
(PDE5 inhibitor) smooth muscle resistance
relaxation in reaction ↑ Blood flow in
to NO activation the corpus
Pulmonary cavernosum →
→ Pulmonary increase in
hypertension
vasodilation penis size
→ Penile during an
smooth muscle erection
relaxation

Benign Inhibition of
prostatic proinflammatory
hyperplasia mediators
(tadalafil only) Deceleration of
fibrotic changes
in the lung
Phosphodiesterase Roflumilast Severe COPD PDE4 inhibition → ↑ Relaxation of
type 4 inhibitor cAMP in neutrophils, the bronchial
granulocytes, and musculature
(PDE4 inhibitor) bronchial epithelium

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10/16/2020 Phosphodiesterase inhibitors - AMBOSS

Active ingredient Indications Mechanism of Action Desired effect

Phosphodiesterase Milrinone Acute treatment PDE3 inhibition → ↑ Increase

type 3 inhibitor Amrinone of cAMP cardiac inotropy
decompensated acutely in
(PDE3 inhibitor) cardiac failure In the cardiac failure
with myocardium: ↑
cardiogenic cAMP → Vasodilation
shock activation of and antiplatelet
calcium action in
channels → intermittent
cardiostimulatory claudication
Cilostazol Intermittent effects (e.g., ↑
Dipyridamole vascular contractility) Inhibition of
claudication In peripheral platelet
Antiplatelet vessels: ↑ cAMP aggregation for
(anti-angina, → smooth angina
TIA/stroke muscle prophylaxis,
prevention) relaxation → TIA/stroke
Prevention of vasodilation with prevention, and
coronary stent reduced deceleration of
restenosis cardiovascular restenosis in
preload and coronary stents
afterload
In platelets: ↑
cAMP →
inhibition of
platelet
aggregation

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

Adverse effects

Nonspecific phosphodiesterase inhibitors

Cardiotoxicity: arrhythmias, tachycardia
Neurotoxicity: dizziness, headache, insomnia, irritability, lightheadedness; at high levels, seizures
Gastrointestinal (GI) upset: nausea, diarrhea
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

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10/16/2020 Phosphodiesterase inhibitors - AMBOSS

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.

Contraindications

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]

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