Pentoxifylline (PTXF) is a vasoactive agent that improves the flow of blood by reducing its viscosity.

It is FDA approved for the symptomatic treatment of:

• Claudication associated with chronic occlusive peripheral vascular disorders of lower extremities.[1][2] In such patients, it may improve tissue perfusion by enhancing the blood flow and can alleviate the signs and symptoms of ischemic pain.[3] 

Pentoxifylline is also used off-label for the treatment of:

• Venous ulcers. A Cochrane review found pentoxifylline to be effective in treating venous ulcers with or without compression therapy when compared to placebo or no treatment.[4]
• Severe alcoholic hepatitis. Pentoxifylline is a tumor necrosis factor-α (TNF-α) inhibitor, a major cytokine in the pathogenesis of alcoholic hepatitis. In a meta-analysis, researchers noted pentoxifylline to be superior to placebo in the prevention of fatal hepatorenal syndrome without any survival benefit in one month. It may be an effective treatment of severe alcoholic hepatitis when there are contraindications to corticosteroids.[5]

Pentoxifylline and its metabolites decrease blood viscosity and improve the blood flow and peripheral tissue oxygenation. The precise mechanism of action by which it leads to symptom improvement remains yet to be determined. However, several pathways are likely involved.

• Pentoxifylline increases red blood cell flexibility by increasing erythrocyte ATP and cyclic nucleotide levels.[6] It reduces the viscosity of blood by decreasing erythrocyte aggregation and stimulating fibrinolysis to reduce plasma fibrinogen concentrations.[7] All these effects enhance the ability of blood to flow through peripheral vessels (hemorheological action).
• Pentoxifylline is a phosphodiesterase (PDE) inhibitor. By blocking the membrane-bound phosphodiesterase, it increases the concentration of cyclic AMP. It also inhibits thromboxane synthesis and increases prostacyclin synthesis. These actions result in reduced platelet aggregation. Further, in patients with circulatory disorders, pentoxifylline has demonstrated decreased adhesion of platelets to the vessel wall.[6]
• Pentoxifylline exerts vasodilation in the skeletal muscle vascular bed by inhibition of PDE and increasing the cAMP.[8]
• Pentoxifylline inhibits the leukocyte-derived free radicals generated during peripheral ischemia in patients with peripheral vascular disease. It has shown to reduce the impairment of the filterability rate of unfractionated leucocytes, limiting the ischemia related tissue damage.[9]
• Pentoxifylline has immunomodulatory effects. The drug improves leukocyte deformability and chemotaxis. It depresses neutrophil degranulation, decreases endothelial leukocyte adhesion, and lowers the sensitivity of leukocytes to cytokines. Besides, pentoxifylline can inhibit the production of inflammatory cytokines.[7] 

Several animal studies have demonstrated the role of pentoxifylline in attenuating ischemia-reperfusion injury, drug-induced nephrotoxicity, infection, and inflammation.

• Pentoxifylline minimized the ischemia related tissue damage to the intestinal mucosa during reperfusion in Wistar rats.[10] 
• Treatment with pentoxifylline attenuated methotrexate-induced renal tissue injury, cell death, and suppressed the elevation of blood urea nitrogen and creatinine levels in Wistar rats.[11]
• Pentoxifylline exerts beneficial, gastroprotective effect against stress-induced gastric lesions by improving gastric microcirculation in Wistar rats. This effect is likely due to the enhanced NOS (nitric oxide synthase) activity, local action of the nitric oxide, and by the attenuation of oxidative metabolism and proinflammatory cytokines.[12]
• Pentoxifylline reduced TNF protein levels by inhibiting TNF mRNA transcription in response to bacterial infection in a murine macrophage cell line model.[13]
• Pentoxifylline minimized liver damage induced by ischemia-reperfusion in albino rats.[14]

Multiple clinical studies have demonstrated the role of anti-inflammatory, anti-fibrotic, and hemorheological properties of pentoxifylline in various disease states.

• In a prospective randomized study, pentoxifylline demonstrated a statistically significant reduction in hemolysis during cardiopulmonary bypass compared to the control sample of patients.[15]
• In a prospective, placebo-controlled, randomized clinical trial, of coronary artery bypass graft candidates with an ejection fraction lower or equal to 30%, pretreatment with pentoxifylline for three days before the procedure, was associated with reduced tumor necrosis factor-α level, interleukin-6 level, improved left ventricular ejection fraction, decreased intensive care unit stay, ventilation time, and need for inotropic agents and blood transfusion.[16]
• In patients with type-2 diabetic nephropathy on ACE inhibitors or angiotensin receptor blockers (ARBs) for greater than six months and on conventional treatment, the addition of pentoxifylline therapy reduced proteinuria, improved glucose control and insulin resistance without a significant change of serum TNF-α in patients.[17]
• Oral administration of pentoxifylline can improve cerebral blood flow in patients with cerebrovascular disease.[18]
• In a double-blind placebo-controlled trial, the administration of pentoxifylline to patients with multiinfarct dementia showed improvements in intellectual and cognitive function.[19]

Generic name: Pentoxifylline

Chemical name: 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione.

Solubility: Pentoxifylline is soluble in chloroform, methanol, and water.

Dosing: 

• Intermittent claudication - 400 mg per oral three times per day with meals
  • Reduce dose to 400 mg twice a day if gastrointestinal intolerance observed.[2][20]
• Severe alcoholic hepatitis - 400 mg per oral three times per day x 4 weeks in a randomized clinical trial[21]
• Venous leg ulcer - 400 mg per oral three times per day observed in a randomized clinical trial.[22][4]
• Treatment of neuropathic pain secondary to diabetic neuropathy 400 mg per oral three times daily after meal. A randomized clinical trial.[23]
• Treatment of Kawasaki disease patients with pentoxifylline to reduce the prevalence of coronary artery lesions (pentoxifylline 20 mg/kg/day per oral).[24][25]
• Pentoxifylline has been tried in isolated case reports for following indications:
  • Treatment of ocular disease in Behcet syndrome - pentoxifylline 600 mg per oral for two weeks.[26]
  • Prophylaxis for acute claudication due to sickle cell disease - 400 mg per oral three times daily after meal.[27]

Pharmacokinetics

Oral administration and absorption: Pentoxifylline is rapidly and completely absorbed in the gastrointestinal tract after oral administration. It is usually recommended with meals (food or milk) to minimize gastrointestinal irritation. It is usually a sustained releasing tablets that have an early peak plasma pentoxifylline concentration two to three hours of post-administration.

Bioavailability: 20% to 30%, because of a high first-pass clearance.[28][29]

Metabolism: Erythrocytes and liver extensively metabolize pentoxifylline to its active metabolites (M1).[20]

Excretion: Pentoxifylline and its metabolites are primarily eliminated by the kidneys and less than 5% by feces. On the other hand, its key metabolites are secreted in breast milk also. The half-life of pentoxifylline is about 0.4 hours to 0.8 hours, and its metabolites are about 1 to 1.5 hours.

The most common adverse effect of pentoxifylline is nausea and vomiting. Other common side effects are:

• Gastrointestinal system - Abdominal discomfort, bloating, diarrhea
• Central nervous system - Dizziness, headache
• Cardiovascular system - Flushing; other infrequent side-effects are chest pain, arrhythmias, and hypotension.

Medication interactions associated with pentoxifylline:

Pentoxifylline may potentiate the effect of antihypertensive agents. A dose reduction of antihypertensives should merit consideration with careful monitoring of blood pressure.

Pentoxifylline can enhance the anti glycemic action of antidiabetic agents. Pentoxifylline has demonstrated to inhibit  ATP-sensitive K channels similar to glyburide in diabetic rats.[30] A dose reduction of anti glycemic agents and glucose monitoring is recommended.

Pentoxifylline can increase the risk of bleeding in patients taking warfarin or antiplatelet agents.

Pentoxifylline increases the plasma levels of theophylline. It may cause excess central nervous stimulation when administered with other xanthine derivatives.

Contraindications

• Patients with bleeding or those who are at increased risk - retinal bleeding, peptic ulcer, preoperative patients
• Creatinine clearance <30mL/min
• Allergy to xanthine derivatives, e.g., caffeine, theophylline, theobromine
• Acute myocardial infarction or severe coronary disease, due to increased risk of myocardial demand
• Severe liver disease(Child pugh class C), Cirrhosis 

Precautions

The use of pentoxifylline in patients below 18 years of age is not advised because its safety profile and efficacy have not been established. The older population have a higher peak plasma levels of the metabolites of pentoxifylline. Pentoxifylline crosses the placenta in mice; evidence in humans is lacking. Therefore, it is not recommended in pregnant women unless the benefits outweigh the risks. Pentoxifylline and its metabolites are secreted in milk; hence it should be avoided in nursing women. It is classified as FDA risk category C.