Continuing Education Activity

Pentoxifylline is a drug used in the management of the peripheral vascular disease. It is a xanthine derivative. This activity outlines the mechanism of action, administration, indications, and other off-label uses, side effects, and toxicity of this medication.

Objectives:

• Outline the approved and off-label uses of pentoxifylline.
• Explain the therapeutic mechanism of action of pentoxifylline.
• Summarize the importance of monitoring pentoxifylline therapy when treating intermittent claudication.
• Review the importance of collaboration and coordination among the interprofessional team to enhance patient care when dosing and monitoring pentoxifylline to improve patient outcomes.

Indications

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. It has been found to be inferior to cilostazol or a supervised exercise program.

• Claudication is associated with chronic occlusive peripheral vascular disorders of the 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 and severe alcoholic hepatitis.

• Venous ulcers:  A Cochrane review found pentoxifylline to be effective in treating venous ulcers with or without compression therapy 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]

Mechanism of Action

Pentoxifylline and its metabolites decrease blood viscosity and improve 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, pentoxifylline has demonstrated decreased adhesion of platelets to the vessel wall in patients with circulatory disorders.[6]
• Pentoxifylline exerts vasodilation in the skeletal muscle vascular bed by inhibiting 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 been shown to reduce the impairment of the filterability rate of unfractionated leucocytes, limiting 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 a 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 attenuation of oxidative metabolism and proinflammatory cytokines.[12]
• In a murine macrophage cell line model, pentoxifylline reduced TNF protein levels by inhibiting TNF mRNA transcription in response to bacterial infection.[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 more than six months and on conventional treatment, the addition of pentoxifylline therapy reduced proteinuria and 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 multi-infarct dementia showed intellectual and cognitive function improvements.[19]

Administration

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.

Dosage form: It is available as a 400 mg extended-release oral tablet.

Dosing 

• Intermittent claudication: 400 mg per oral three times per day with meals.
  • Reduce the dose to 400 mg twice a day if gastrointestinal intolerance is observed.[2][20]
• Severe alcoholic hepatitis: 400 mg per oral three times per day for four 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 the 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-release tablet with an early peak plasma pentoxifylline concentration two to three hours postadministration.

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

Metabolism: Erythrocytes and the 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 also secreted in breast milk. The half-life of pentoxifylline is about 0.4 hours to 0.8 hours, and its metabolites are about 1 to 1.5 hours.

Adverse Effects

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

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

Medication Interactions Associated with Pentoxifylline

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

Pentoxifylline is shown to enhance the anti glycemic action of antidiabetic agents such as glibenclamide or metformin in animal studies. Pentoxifylline has been 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. Monitor prothrombin time frequently when pentoxifylline is concomitantly used with warfarin.

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

Contraindications

Contraindications

• Patients with bleeding or those who are at increased risk of retinal bleeding, peptic ulcer, or preoperative patients
• Patients with creatinine clearance less than 30 mL/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) or cirrhosis 

Precautions

Pediatric Patients: The use of pentoxifylline in patients below 18 years of age is not advised because its safety profile and efficacy have not been established.

Geriatric Patients: The elderly population exhibits higher peak plasma levels of the metabolites of pentoxifylline.

Pregnancy and Breastfeeding Considerations: Pentoxifylline crosses the placenta in mice; evidence in humans is lacking. Therefore, it is not recommended for pregnant women unless the benefits outweigh the risks. Pentoxifylline and its metabolites are secreted in milk; hence, nursing women should avoid it. It is classified as FDA risk category C.

Patients with Renal Impairment: There is an increased risk of side effects in patients with diminished renal function when CrCl is less than 80mL/min.

Monitoring

Older patients are at higher risk of side effects from pentoxifylline. Careful monitoring of blood pressure and glucose level is recommended when administering pentoxifylline in patients on antihypertensive and antidiabetic medications. They are at high risk for hypotension, falls, and hypoglycemia. Patients with liver disease should also receive close follow-up with periodic laboratory monitoring. Patients at increased risk of bleeding should be advised of potential signs and symptoms of bleeding and monitored with periodic laboratory data, including hematocrit and hemoglobin. Clinicians should exercise caution with patients who have cardiac arrhythmias and low blood pressure.

Toxicity

There is no reported antidote for this medication. The drug prescriber should discontinue the drug in suspected cases of toxicity. There are reports of adverse effects of pentoxifylline in patients on chronic hemodialysis.[31]

Enhancing Healthcare Team Outcomes

Appropriate patient selection for pentoxifylline therapy requires the attention of an interprofessional team composed of clinicians (including mid-level practitioners), nursing staff, and pharmacists. A pharmacist plays a crucial role in determining the proper dose of medication to minimize side effects. Both nurses' and dieticians' roles are vital in patient education to ensure medication compliance and modification of risk factors related to atherosclerotic disease. The interprofessional team approach and care coordination are crucial for the best patient outcomes with the fewest adverse events. [Level 5]