Trental

• Approved Indications:
• Intermittent Claudication (Peripheral Artery Disease):
  To improve walking distance in patients with intermittent claudication caused by chronic occlusive arterial disease of the limbs (due to its hemorheologic effect).
• Clinically Accepted Off-Label Uses:
• Chronic Venous Ulcers
• Diabetic Neuropathy
• Vascular Dementia
• Alcoholic Hepatitis
• Idiopathic Male Infertility (with varicocele)
• Radiation-induced tissue injury (e.g., radiation-induced fibrosis)
• Sickle Cell Disease (as an adjunct to improve blood flow)
• Systemic Sclerosis–related digital ulcers

• Route: Oral
• Adults (Intermittent Claudication):
• Extended-release tablets: 400 mg orally three times daily, preferably with meals to minimize GI discomfort.
• Dose Adjustment:
• Renal impairment (CrCl <30 mL/min): Consider reducing to 400 mg twice daily.
• Hepatic impairment: Use cautiously; no formal adjustment guidelines, but monitor closely.
• Elderly:
• No specific adjustments, but initiate cautiously and monitor for adverse effects.
• Pediatrics:
• Not approved; safety and efficacy not established in children.
• Duration:
• A minimum of 8 weeks of therapy is usually required to evaluate efficacy; full effect may take up to 12 weeks.

Pentoxifylline is a methylxanthine derivative that acts primarily as a hemorheologic agent, improving erythrocyte flexibility and reducing blood viscosity. It also inhibits platelet aggregation and reduces fibrinogen concentration. At the molecular level, pentoxifylline inhibits phosphodiesterase, leading to increased intracellular cyclic AMP in blood cells and vascular smooth muscle. This promotes vasodilation and improved microcirculation, enhancing oxygen delivery to ischemic tissues, especially in the peripheral vasculature. It also exhibits anti-inflammatory effects by downregulating cytokine production such as TNF-α.

• Absorption:
  Rapidly absorbed after oral administration. Bioavailability is approximately 20% due to first-pass metabolism.
• Peak Plasma Time:
  2–4 hours (extended-release formulation)
• Distribution:
  Widely distributed, plasma protein binding approximately 28%.
• Metabolism:
  Extensively metabolized in the liver into active metabolites, including metabolite I (M-1), which contributes significantly to therapeutic effect.
• Half-life:
  Parent drug: ~0.4–0.8 hours;
  Active metabolites: ~1–1.6 hours
• Elimination:
  Excreted mainly via the urine (~95%, mostly as metabolites); small amount via feces.

• Pregnancy:
  Category C (FDA): Animal studies have shown adverse effects; no adequate studies in humans. Use only if the potential benefit justifies the risk to the fetus.
• Lactation:
  Excretion into human milk is unknown. Caution is advised; consider risk-benefit ratio before prescribing in lactating mothers.

• Primary Class:
  Hemorheologic agent
• Subclass:
  Xanthine derivative / Peripheral vasodilator

• Known hypersensitivity to pentoxifylline, methylxanthines (e.g., caffeine, theophylline), or any component of the formulation
• Recent cerebral or retinal hemorrhage
• Active bleeding (e.g., gastrointestinal or intracranial bleeding)
• History of severe arrhythmias or recent myocardial infarction (relative contraindication)

• Bleeding risk:
  Use with caution in patients at risk of bleeding or taking anticoagulants or antiplatelet agents.
• Hypotension:
  May cause blood pressure drop; monitor in patients with cardiovascular disease.
• Liver or kidney impairment:
  Use cautiously and adjust dosage as needed; monitor for accumulation or toxicity.
• Gastrointestinal symptoms:
  Common early in treatment; administer with food to reduce nausea and vomiting.
• Seizures:
  Use with caution in patients with seizure disorders, as xanthine derivatives may lower seizure threshold.

• Gastrointestinal:
  Nausea, vomiting, dyspepsia, bloating, diarrhea
• Neurological:
  Dizziness, headache, agitation, tremor
• Cardiovascular:
  Hypotension, palpitations, chest pain (rare)
• Dermatologic:
  Rash, flushing, pruritus
• Serious (rare):
  Anaphylactic reaction, angioedema, bleeding (GI or cerebral), thrombocytopenia, leukopenia
• Most side effects are mild, dose-dependent, and improve with continued use or dose reduction.

• Anticoagulants (e.g., warfarin):
  ↑ Risk of bleeding—monitor INR and signs of bleeding closely.
• Antiplatelet agents (e.g., aspirin, clopidogrel):
  Additive bleeding risk.
• Theophylline and other xanthines:
  Additive CNS stimulation, risk of toxicity.
• Antihypertensives:
  May potentiate hypotensive effects.
• Cimetidine:
  May increase pentoxifylline plasma levels.
• CYP Enzyme Interactions:
  Primarily metabolized via CYP1A2 and CYP2E1; use caution with inhibitors or inducers of these pathways.

• New Evidence in Liver Disease:
  Pentoxifylline is increasingly studied in alcoholic hepatitis, especially in patients with contraindications to corticosteroids, although recent trials show mixed efficacy.
• Ongoing Research in COVID-19 and Inflammation:
  Its anti-TNF-α and anti-fibrotic effects have prompted experimental use in COVID-19–related inflammatory syndromes, but not yet guideline-approved.
• No recent changes in regulatory-approved dosing or labeled indications by FDA or EMA.

• Temperature:
  Store at 20°C to 25°C (68°F to 77°F)
• Handling:
  Protect from moisture and direct light
• Container:
  Keep bottle tightly closed; do not use expired tablets
• Special Instructions:
  Do not crush or chew extended-release tablets