Phosphodiesterase inhibitors Flashcards
How do methylxanthines (theophylline, aminophylline) work?
They inhibit phosphodiesterase (PDE), increasing cAMP levels and causing bronchodilation. They also block adenosine receptors, reducing bronchoconstriction.
What are the clinical indications for theophylline?
Previously used for COPD and asthma as a bronchodilator, but now rarely first-line due to toxicity.
What is the primary indication for caffeine (a methylxanthine)?
Used in neonatal apnea to stimulate respiratory drive via CNS stimulation.
Why are methylxanthines not commonly used today?
They have a narrow therapeutic index, significant side effects, and many drug interactions.
What are the major side effects of theophylline?
CNS effects (seizures, tremors, insomnia), cardiovascular effects (tachycardia, arrhythmias), and GI effects (nausea, vomiting, diarrhea).
What is the most dangerous complication of theophylline toxicity?
Seizures and tachyarrhythmias (e.g., atrial fibrillation, ventricular arrhythmias).
Which drugs can increase theophylline toxicity?
CYP450 inhibitors like macrolides (erythromycin) and fluoroquinolones (ciprofloxacin).
Which drugs can decrease theophylline levels?
CYP450 inducers like rifampin and phenytoin.
How is theophylline toxicity managed?
Beta-blockers for arrhythmias, benzodiazepines for seizures, and activated charcoal if recently ingested.
Why is theophylline no longer first-line for asthma and COPD?
Safer and more effective alternatives like beta-agonists and inhaled corticosteroids are preferred.
What is the role of adenosine in methylxanthine action?
Methylxanthines block adenosine receptors, reducing bronchoconstriction and leading to mild inotropic and chronotropic effects.
Which methylxanthine is still widely used today?
Caffeine is used for neonatal apnea, unlike theophylline which has fallen out of favor.
What is the mechanism of action of phosphodiesterase (PDE) inhibitors?
PDE inhibitors prevent the breakdown of cyclic AMP (cAMP) or cyclic GMP (cGMP), leading to increased intracellular signaling and enhanced physiological responses.
What are the clinical uses of PDE-5 inhibitors (sildenafil, tadalafil, vardenafil)?
Used for erectile dysfunction, pulmonary hypertension, and benign prostatic hyperplasia (tadalafil).
How do PDE-5 inhibitors improve erectile function?
They increase cGMP levels, causing relaxation of vascular smooth muscle in the corpus cavernosum and enhancing blood flow.
Why are PDE-5 inhibitors contraindicated with nitrates?
Both increase cGMP, leading to excessive vasodilation and severe hypotension.
What are the common side effects of PDE-5 inhibitors?
Headache, flushing, dyspepsia, nasal congestion, and blue-tinted vision (cyanopsia, seen with sildenafil).
Which PDE-5 inhibitor has the longest half-life?
Tadalafil has a half-life of 17.5 hours, allowing for once-daily dosing.
What are the clinical uses of PDE-4 inhibitors (roflumilast, apremilast)?
Roflumilast is used for COPD to reduce exacerbations, and apremilast is used for psoriasis and psoriatic arthritis.
How do PDE-4 inhibitors work in COPD?
They increase cAMP in inflammatory cells, reducing cytokine release and decreasing inflammation.
What are the side effects of PDE-4 inhibitors?
Nausea, diarrhea, weight loss, and psychiatric symptoms (depression, anxiety).
What are the clinical uses of PDE-3 inhibitors (milrinone, cilostazol)?
Milrinone is used for acute heart failure, and cilostazol is used for intermittent claudication in peripheral artery disease (PAD).
How does milrinone work in heart failure?
Increases cAMP in cardiac myocytes, leading to increased contractility (positive inotropy) and vasodilation.
How does cilostazol help in PAD?
Inhibits platelet aggregation and causes vasodilation by increasing cAMP in vascular smooth muscle.
What are the contraindications of cilostazol?
Contraindicated in heart failure due to risk of worsening mortality.
Which PDE inhibitor is used in erectile dysfunction?
Sildenafil, tadalafil, vardenafil (PDE-5 inhibitors).
Which PDE inhibitor is used in COPD?
Roflumilast (PDE-4 inhibitor).
Which PDE inhibitor is used in heart failure?
Milrinone (PDE-3 inhibitor).
Which PDE inhibitor is used for peripheral artery disease?
Cilostazol (PDE-3 inhibitor).
Which PDE inhibitor is associated with blue-tinted vision?
Sildenafil (PDE-5 inhibitor).
Why should PDE-5 inhibitors not be combined with alpha-blockers?
Can cause severe hypotension due to excessive vasodilation.
