Phosphodiesterase Inhibitors

Phosphodiesterase (PDE) inhibitors are a group of drugs that act by inhibiting PDE enzymes. Phosphodiesterase inhibitors have various mechanisms of action depending on the subtype of PDE targeted, but their main action is increasing the amount of intracellular cAMP or cGMP, which in turn results in physiologic effects such as reducing inflammation, promoting smooth muscle relaxation, and vasodilation. Phosphodiesterase inhibitors are indicated in a wide variety of medical conditions, such as intermittent claudication, decompensated heart failure, chronic obstructive pulmonary disease, psoriasis, atopic dermatitis, erectile dysfunction, pulmonary artery hypertension, and benign prostatic hypertrophy. Contraindications, adverse effects, and warnings are category- and drug-dependent.

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Overview

Phosphodiesterase enzymes

  • Phosphodiesterase: 
    • Breaks phosphodiester bonds
    • Degrades secondary messengers, cAMP, and cGMP 
    • Regulates signal transduction pathways
  • Common functions:
    • Vasoconstriction
    • Contraction of smooth muscle 
    • Inflammatory effects

General mechanism of action

The common mechanisms of phosphodiesterase (PDE) inhibitors are:

  • Inhibition of phosphodiesterase → ↑ levels of cAMP and cGMP 
  • Effect: vasodilation and relaxation of smooth muscle in:
    • Heart
    • Vasculature
    • Lungs
    • Genitals 

Classification

The PDE inhibitors are classified based on the subtype(s) affected:

  • PDE3 selective inhibitors
    • Cilostazol
    • Dipyridamole 
    • Milrinone
  • PDE4 selective inhibitors
    • Roflumilast
    • Apremilast
    • Crisaborole
  • PDE5 selective inhibitors
    • Sildenafil
    • Tadalafil
    • Avanafil
    • Vardenafil
  • Nonselective phosphodiesterase inhibitors
    • Theophylline 
    • Pentoxifylline

Phosphodiesterase-3 Inhibitors

Medications in this class

  • Cilostazol
  • Dipyridamole 
  • Milrinone

Mechanism of action

  • Inhibition of PDE3 enzyme can cause the following effects:
    • Heart: ↑ cAMP → Ca influx → ↑ cardiac chronotropy, isotropy, and dromotropy
    • Vasculature: 
      • ↑ cAMP → myosin light-chain kinase (MLCK) inhibition → vasodilation
      • Also ↓ vascular smooth muscle cell proliferation
    • Platelets: ↑ cAMP → ↓ platelet aggregation
  • Drug targets:
    • Cilostazol and dipyridamole: vessels and platelets
    • Milrinone: vascular and cardiac cells
The mechanism of action of milrinone, a phosphodiesterase-3 (PDE3) inhibitor

Mechanism of action of milrinone, a phosphodiesterase-3 (PDE3) inhibitor:
By blocking the effect of PDE3, milrinone increases the concentration of cAMP in cardiac cells. This results in increased strength of contraction (inotropy).

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Pharmacokinetics

The following table summarizes the pharmacokinetics of the PDE3 inhibitors:

Table: Pharmacokinetics of the PDE3 inhibitors
MedicationFormulationDistributionMetabolismExcretion
CilostazolOralHighly protein-bound
  • Hepatic
  • Cytochrome P450
Mostly in urine
Dipyridamole
  • Oral
  • IV
  • Hepatic
  • Glucuronidation
Feces
MilrinoneIV (continuous infusion)Majority not metabolizedUrine

Indications

  • Cilostazol:
    • Intermittent claudication (reduces symptoms)
    • Secondary prevention of stroke:
      • Transient ischemic attack (TIA)
      • Noncardioembolic ischemic stroke
    • Alternative agent in percutaneous coronary intervention (if allergy to either aspirin or clopidogrel)
  • Dipyridamole:
    • Adjunct to warfarin in individuals with heart valve replacements
    • Adjunct to aspirin in individuals for secondary prevention of stroke. If someone has a stroke while taking aspirin, they can add dipyridamole.
    • Pharmacologic stress testing (diagnostic agent)
  • Milrinone: cardiac support for heart failure with reduced ejection fraction and ↓ cardiac output
    • ↓ Incidence of dysrhythmia as compared with dobutamine
    • Use may be limited by hypotension (due to vasodilation effect)

Adverse effects

Cilostazol:

  • CNS: 
    • Headache
    • Dizziness
  • GI: 
    • Nausea
    • Diarrhea and abnormal stools
  • Cardiovascular:
    • Palpitations
    • Tachycardia
    • Peripheral edema
    • Hypotension

Dipyridamole:

  • Bleeding risk
  • Angina
  • Dizziness
  • Headache
  • Hepatic insufficiency

Milrinone:

  • Ventricular arrhythmias
  • Supraventricular arrhythmia
  • Hypotension
  • Headache

Contraindications

  • Cilostazol: heart failure
  • Milrinone:
    • Severe pulmonary hypertension → can worsen ventilation/perfusion mismatch
    • Severe renal impairment

Drug interactions

Cilostazol and dipyridamole are associated with ↑ bleeding risk when used with:

  • Antiplatelet agents
  • Anticoagulants
  • Thrombolytic agents

Phosphodiesterase-4 Inhibitors

Medications in this class

  • Roflumilast
  • Apremilast
  • Crisaborole

Mechanism of action

Inhibition of PDE4 enzymes leads to ↑ intracellular cAMP in immune and/or lung cells:

  • Antiinflammatory effect:
    • Suppression of cytokine release
    • Regulates inflammatory mediators (e.g., nitric oxide, interleukins, tumor necrosis factor alpha)
  • ↓ Smooth muscle cell proliferation and pulmonary remodeling

Pharmacokinetics

The following table summarizes the pharmacokinetics for the PDE4 inhibitors:

Table: Pharmacokinetics of the PDE4 inhibitors
MedicationFormulationDistributionMetabolismExcretion
RoflumilastOralHighly protein-bound
  • Hepatic
  • Cytochrome P450 system
Urine
ApremilastOral68% protein-bound
  • Hepatic
  • Cytochrome P450 system
Urine and feces
CrisaboroleTopicalHighly protein-boundHepaticUrine

Indications

  • Roflumilast: 
    • Prevention of chronic obstructive pulmonary disease (COPD) exacerbation
    • Not used for acute bronchospasm
  • Apremilast:
    • Oral ulcers from Behçet disease
    • Moderate to severe psoriasis
    • Psoriatic arthritis
  • Crisaborole: topical treatment for atopic dermatitis

Adverse effects

Roflumilast and apremilast:

  • Neuropsychiatric:
    • Depression
    • Headache
    • Dizziness
    • Insomnia
    • Suicidal ideation
  • Metabolic: weight loss
  • GI: 
    • Diarrhea
    • Nausea
  • Respiratory: upper respiratory tract infection

Crisaborole:

  • Urticaria
  • Allergic contact dermatitis

Contraindications

Roflumilast:

  • Acute bronchospasm 
  • Hepatic impairment (moderate to severe)
  • Use with caution in individuals with depression

Apremilast:

  • Lack of data on use in pregnancy and breastfeeding
  • Use with caution in individuals with depression

Phosphodiesterase-5 Inhibitors

Medications in this class

  • Sildenafil
  • Tadalafil
  • Avanafil
  • Vardenafil

Mechanism of action

Erectile dysfunction:

  • Erection in men:
    • Initiated by NO release in the corpus cavernosum during sexual stimulation
    • NO activates guanylate cyclase → ↑ cGMP → relaxes smooth muscle 
    • ↑  Blood flow into the corpus cavernosum → erection
  • PDE5 inhibitors:
    • ↑ NO effect: inhibits PDE5
    • Prevents degradation of cGMP in the corpus cavernosum → ↑ cGMP

Pulmonary arterial hypertension (PAH):

  • PDE5 degrades cGMP in the smooth muscle of the pulmonary vasculature.
  • PDE5 inhibitors prevent the degradation of cGMP → ↑ cGMP → ↑ relaxation and vasodilation in the pulmonary vasculature

Benign prostatic hyperplasia (BPH): 

  • PDE5 inhibition → ↓ endothelial and smooth muscle cell proliferation
  • Additional effects:
    • ↑ NO effect → ↑ smooth muscle relaxation
    • ↓ Afferent nerve activity

Pharmacokinetics

  • Formulation:
    • Oral: 
      • Should be taken on an empty stomach
      • Fatty meals can delay absorption.
    • Sildenafil can be given IV.
  • Distribution: highly protein-bound
  • Metabolism:
    • Hepatic
    • Cytochrome P450 system (CYP3A4, CYP2C9)
    • Most have active metabolites.
  • Excretion: primarily fecal

Indications

  • Erectile dysfunction:
    • Can be used as initial therapy
    • ↑ Number and duration of erections
    • PDE5 inhibitors function only in the presence of sexual stimulation.
  • PAH:
    • May be indicated for:
      • Nonvasoreactive PAH
      • Vasoreactive PAH and failed calcium channel blocker therapy
    • Often used in combination with another drug class, such as an endothelin receptor antagonist
  • BPH:
    • Good choice for men with concurrent erectile dysfunction
    • Can improve symptoms
  • Other indications:
    • High-altitude pulmonary edema
    • Raynaud’s phenomenon

Adverse effects

  • CNS:
    • Headache
    • Paresthesia
    • Dizziness
    • Insomnia
    • Visual disturbances (sildenafil: blue-tinted vision)
  • Respiratory:
    • Nasal congestion
    • Rhinitis
  • Cardiovascular: 
    • Flushing
    • Hypotension
    • Syncope
    • Tachycardia
  • GI: 
    • Nausea
    • Dyspepsia
  • Musculoskeletal: 
    • Myalgia
    • Back pain
  • Genitourinary: priapism

Precautions

Be cautious with individuals who may be predisposed to priapism:

  • Sickle cell anemia
  • Multiple myeloma
  • Leukemia

Drug interactions

Increased risk of hypotension associated with:

  • Ethyl alcohol
  • Alpha-1 blockers
  • Nitrates (contraindication)
  • Nitroprusside

Nonselective Phosphodiesterase Inhibitors

Medications in this class

  • Theophylline 
  • Pentoxifylline

Mechanism of action

Theophylline:

  • PDE3 and PDE4 inhibition: ↑ cAMP → pulmonary smooth muscle relaxation → bronchodilation
  • Additionally: 
    • Suppresses airway response to stimuli
    • ↑ Calcium uptake through adenosine-mediated channels → ↑ diaphragmatic muscle contraction

Pentoxifylline:

  • ↑ cAMP → vasodilation
  • ↑ RBC ATP and cAMP → ↑ RBC flexibility
  • ↑ Fibrinolysis
  • ↓ Thromboxane synthesis
  • Effect:
    • ↓ RBC aggregation 
    • ↓ Blood viscosity
    • ↑ Blood flow

Pharmacokinetics

The following table summarizes the pharmacokinetics for the nonselective PDE inhibitors:

Table: Pharmacokinetics of the nonselective PDE inhibitors
MedicationFormulationMetabolismExcretion
Theophylline
  • Oral
  • IV
  • Hepatic
  • Cytochrome P450 system
  • Active metabolites
Urine
PentoxifyllineOral
  • Hepatic
  • Extensive 1st-pass
  • Active metabolites
Primarily in urine

Indications

Theophylline:

  • COPD and asthma
  • Has been used for acute and chronic therapy
  • Use is now controversial; not a preferred medication
  • Reversal of dipyridamole-induced reactions (e.g., during cardiac stress testing) 

Pentoxifylline:

  • Intermittent claudication
  • Improves symptoms
  • Not definitive therapy
  • Severe alcoholic hepatitis (when corticosteroids are contraindicated)

Adverse effects

Theophylline:

  • Cardiac: arrhythmia
  • CNS:
    • Headache 
    • Hyperactivity in children
    • Restlessness and insomnia
    • Seizures and status epilepticus 
    • Tremors
  • GI:
    • Gastroesophageal reflux
    • Nausea and vomiting

Pentoxifylline:

  • Nausea 
  • Vomiting

Contraindications and precautions

The following are contraindications and precautions for theophylline.

  • Contraindication: allergy to corn-related products (IV route)
  • Use with caution:
    • Coronary artery disease 
    • Renal impairment 
    • Hepatic impairment
    • Hyperthyroidism
    • Epilepsy 
    • Elderly

Drug interactions

  • Theophylline:
    • ↓ Serum concentration of theophylline derivatives:
      • Carbamazepine
      • Macrolides
    • ↑ Serum concentration of theophylline derivatives:
      • Fluconazole
      • Isoniazid
      • Quinolones 
      • Verapamil
      • Allopurinol
      • Antithyroid agents
    • ↓ Bronchodilation effect: beta blockers
  • Pentoxifylline: ↑ risk of bleeding:
    • Anticoagulants
    • NSAIDs
    • Antiplatelet agents

References

  1. Khera, M. (2021). Treatment of male sexual dysfunction. UpToDate. Retrieved October 4, 2021, from Treatment of male sexual dysfunction – UpToDate
  2. Hopkins, W., Rubin, L. (2021). Treatment of pulmonary arterial hypertension (group 1) in adults: pulmonary hypertension-specific therapy. UpToDate. Retrieved October 10, 2021, from https://www.uptodate.com/contents/treatment-of-pulmonary-arterial-hypertension-group-1-in-adults-pulmonary-hypertension-specific-therapy
  3. Cilostazol: drug information. UpToDate. Retrieved September 22, 2021, from Cilostazol: Drug information – UpToDate
  4. Milrinone: drug information. UpToDate. Retrieved September 22, 2021, from Milrinone: Drug information – UpToDate
  5. Manaker, A. (2021). Use of vasopressors and inotropes. UpToDate. Retrieved September 22, 2021, from Use of vasopressors and inotropes – UpToDate
  6. Roflumilast: drug information. UpToDate. Retrieved September 23, 2021, from Roflumilast: Drug information – UpToDate
  7. Apremilast: drug information. UpToDate. Retrieved September 23, 2021, from Apremilast: Drug information – UpToDate
  8. Crisaborole: drug information. UpToDate. Retrieved September 23, 2021, from Crisaborole: Drug information – UpToDate
  9. Sildenafil: drug information. UpToDate. Retrieved September 24, 2021, from Sildenafil: Drug information – UpToDate
  10. Tadalafil: drug information. UpToDate. Retrieved September 25, 2021, from Tadalafil: Drug information – UpToDate
  11. Vardenafil: Drug information. UpToDate. Retrieved September 25, 2021, from Vardenafil: Drug information – UpToDate
  12. Avanafil: drug information. UpToDate. Retrieved September 25, 2021, from Avanafil: Drug information – UpToDate
  13. Theophylline: drug information. UpToDate. Retrieved September 30, 2021, from Theophylline: Drug information – UpToDate
  14. Aminophylline: drug information. UpToDate. Retrieved September 30, 2021, from Aminophylline: Drug information – UpToDate
  15. Padda, I. S., Tripp, J. (2020). Phosphodiesterase inhibitors. StatPearls. Retrieved September 30, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK559276/
  16. Boswell-Smith, V., Spina, D., Page, C. P. (2006). Phosphodiesterase inhibitors. British Journal of Pharmacology 147(Suppl 1):252–257. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760738/
  17. Giuliano, F., et al. (2012). The mechanism of action of phosphodiesterase type 5 inhibitors in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. European Urology 63:506–516. https://pubmed.ncbi.nlm.nih.gov/23018163/

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