Continuing Education Activity

Pentoxifylline is a xanthine derivative used in the management of peripheral vascular disease. As a phosphodiesterase inhibitor (PDEi), the drug improves blood flow by reducing viscosity and enhancing red blood cell flexibility. This activity outlines the mechanism of action, administration, indications, off-label uses, adverse drug reactions, and contraindications. Additionally, this activity reviews the pharmacokinetics, monitoring strategies, and clinical toxicology of pentoxifylline. Given the complexity of its pharmacological actions and potential interactions with other medications, clinicians must be well-versed in prescribing pentoxifylline appropriately and monitoring patients for adverse effects.

Clinicians should weigh the risks and benefits before prescribing pentoxifylline, with pharmacists playing a pivotal role in dose optimization to minimize adverse reactions. Empowering prescribing clinicians is essential for optimizing patient care and preventing adverse outcomes in associated cardiovascular conditions. Through interprofessional collaboration, teams can leverage collective expertise to optimize pentoxifylline therapy outcomes, improving patient well-being and healthcare delivery as a result.

Objectives:

• Identify appropriate indications for pentoxifylline in the management of peripheral vascular disease.

• Differentiate between common adverse reactions associated with pentoxifylline and other medications used for similar conditions.

• Assess patient response to pentoxifylline therapy and adjust the regimen as necessary for optimal outcomes.

• Implement effective collaboration among interprofessional team members to improve treatment efficacy for patients who might benefit from pentoxifylline.

Indications

Pentoxifylline is a vasoactive agent that improves blood flow by reducing viscosity.

FDA-Approved Indications

Pentoxifylline is FDA-approved for the symptomatic treatment of claudication. The drug is inferior to cilostazol or a supervised exercise program. Claudication is associated with chronic occlusive peripheral vascular disorders of the lower extremities.[1][2] The drug may improve tissue perfusion in such patients by enhancing blood flow and alleviating ischemic pain signs and symptoms.[3] Although this medication can alleviate symptoms, it is not meant to substitute standard treatments for peripheral vascular disease. Moreover, the American College of Chest Physicians and American Heart Association/American College of Cardiology (AHA/ACC) guidelines do not endorse pentoxifylline as a definitive treatment of peripheral arterial disease.[4] However, a network meta-analysis concluded that pentoxifylline is effective for the symptomatic treatment of intermittent claudication.[5][6]

Off-Label Uses

• Venous ulcers: A Cochrane review found pentoxifylline effective in treating venous ulcers with or without compression therapy compared to placebo or no treatment.[7] 

• 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 was superior to placebo in preventing fatal hepatorenal syndrome without any survival benefit in 1 month. Pentoxifylline is a suitable treatment for severe alcoholic hepatitis when contraindications to corticosteroids exist.[8]

• Osteoradionecrosis: Liquid pentoxifylline and vitamin E are promising as alternative formulations for patients with dysphagia or enteric feeding, offering clinical benefits for established osteoradionecrosis and prophylaxis before dental procedures. Retrospective data reveal favorable outcomes, with a high proportion of surgical sites healing completely and minimal reported adverse effects. More research is needed as the metanalysis findings provided insufficient evidence.[9][10][11]

Mechanism of Action

Pentoxifylline and the metabolites decrease blood viscosity and improve blood flow and peripheral tissue oxygenation. The precise mechanism of action that 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. This reduces blood viscosity by decreasing erythrocyte aggregation and stimulating fibrinolysis to reduce plasma fibrinogen concentrations. All these effects enhance the ability of blood to flow through peripheral vessels (hemorheological action).

• Pentoxifylline is a PDEi. By blocking the membrane-bound phosphodiesterase, pentoxifylline increases the concentration of cyclic AMP. The drug 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.[12]

• Pentoxifylline exerts vasodilation in the skeletal muscle vascular bed by inhibiting PDE and increasing the cAMP.[13]

• Pentoxifylline inhibits the leukocyte-derived free radicals generated during peripheral ischemia in patients with peripheral vascular disease. This has been shown to reduce the impairment of the filterability rate of unfractionated leucocytes, limiting ischemia-related tissue damage.[14]

• Pentoxifylline has immunomodulatory effects. The drug improves leukocyte deformability and chemotaxis, leading to depressed neutrophil degranulation, decreased endothelial leukocyte adhesion, and lowered sensitivity of leukocytes to cytokines. Pentoxifylline can inhibit the production of inflammatory cytokines.[15] 

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.[16] 

• 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.[17]

• 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 nitric oxide synthase (NOS) activity, local action of the nitric oxide, and attenuation of oxidative metabolism and proinflammatory cytokines.[18]

• In a murine macrophage cell line model, pentoxifylline reduced TNF protein levels by inhibiting TNF mRNA transcription in response to bacterial infection.[19]

• Pentoxifylline minimized liver damage induced by ischemia-reperfusion in albino rats.[20]

Multiple clinical studies have demonstrated the role of pentoxifylline's anti-inflammatory, anti-fibrotic, and hemorheological properties 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.[21]

• 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 3 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.[22]

• In patients with type-2 diabetic nephropathy on ACEi or angiotensin receptor blockers (ARBs) for more than 6 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.[23]

• Oral administration of pentoxifylline can improve cerebral blood flow in patients with cerebrovascular disease.[24]

• In a double-blind placebo-controlled trial, administering pentoxifylline to patients with multi-infarct dementia showed intellectual and cognitive function improvements.[25]

Pharmacokinetics

Absorption: Pentoxifylline is rapidly and completely absorbed in the gastrointestinal (GI) tract after oral administration. The drug is usually recommended with meals (food or milk) to minimize GI irritation. It is usually a sustained-release tablet with an early peak plasma pentoxifylline concentration 2 to 3 hours postadministration.

Bioavailability: 20% to 30%, because of a high first-pass clearance.[26][27]

Metabolism: Erythrocytes and the liver extensively metabolize pentoxifylline to its active metabolites (M1).[28]

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 to 0.8 hours, and the metabolites are about 1 to 1.5 hours.

Administration

Available Dosage Forms and Strengths

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: Pentoxifylline is available as a 400 mg extended-release oral tablet.

Adult Dosing

Intermittent claudication: 400 mg orally 3 times per day with meals. Reduce the dose to 400 mg twice daily if GI intolerance is observed.[2][28]

Off-Label Indications

• Severe alcoholic hepatitis: 400 mg orally 3 times daily for 4 weeks.[29]

• Venous leg ulcer: 400 mg orally 3 times daily.[30][7]

• Treatment of neuropathic pain secondary to diabetic neuropathy: 400 mg orally 3 times daily after meal.[31]

• Treatment of Kawasaki disease: The recommended dosage is 20 mg/kg/day to reduce the prevalence of coronary artery lesions.[32][33]

• Pentoxifylline has been used in isolated case reports for specific indications. In Behcet syndrome-related ocular disease, a 2-week regimen of 600 mg per oral has been used. For prophylaxis against acute claudication in sickle cell disease, a dosage of 400 mg per oral 3 times daily after meals has been suggested. Further research is needed to validate its efficacy and safety in these contexts.[34][35]

Specific Patient Population

Hepatic impairment: Pentoxifylline should be used with caution in mild to moderate liver impairment as it may cause an increase in the exposure of pentoxifylline and its active metabolite. The use of pentoxifylline should be avoided in severe hepatic impairment.

Renal impairment: In patients with renal impairment and creatinine clearance (CrCl) below 30 mL/min, the dose of pentoxifylline should be reduced to 400 mg/day.

Pregnancy 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.

Breastfeeding considerations: Caution is advised when administering pentoxifylline to breastfeeding mothers, as pentoxifylline and its metabolites can be secreted in milk. Although evidence indicates that the drug is generally safe for breastfed infants, particularly those older than 2 months, it is advised to carefully consider whether to continue nursing or cease the medication, weighing the drug's significance for the mother.[36]

Pediatric patients: Pentoxifylline in patients aged below 18 is not advised because its safety profile and efficacy have not yet been established.

Older patients: The older patients exhibit higher peak plasma levels of the metabolites of pentoxifylline, leading to potential toxicity. Starting the pentoxifylline dosage at a lower level is recommended, considering polypharmacy and impaired renal/hepatic/cardiac function.

Adverse Effects

The most common adverse effect of pentoxifylline is nausea and vomiting. Other common adverse drug reactions are listed below.

• GI system: Abdominal discomfort, bloating, and diarrhea

• Cardiovascular system: Flushing; other infrequent side-effects are chest pain, arrhythmias, hypertension, dyspnea, tachycardia, and hypotension.

• Central nervous system: Dizziness, headache[5]

Drug-Drug Interactions

• Antihypertensive agents: Pentoxifylline has been used with antihypertensive drugs, including beta blockers and diuretics. Some patients treated with pentoxifylline and nifedipine or captopril have shown slight reductions in blood pressure.[37][38] Periodic monitoring of systemic blood pressure in patients receiving concurrent antihypertensive therapy with pentoxifylline is recommended. If necessary, consider adjusting the dosage of the antihypertensive agents.

• Oral hypoglycemic drugs: In animal studies, pentoxifylline enhances the anti-glycemic action of antidiabetic agents such as glibenclamide or metformin. Pentoxifylline has been demonstrated to inhibit ATP-sensitive K channels similar to glyburide in diabetic rats.[39] A dose reduction of anti-glycemic agents and glucose monitoring is recommended.

• Antiplatelet drugs: Pentoxifylline can increase the risk of bleeding in patients taking warfarin or antiplatelet agents. Monitoring PT/INR is recommended. The study has demonstrated that in patients with chronic kidney disease, the administration of pentoxifylline, particularly at daily doses exceeding 800 mg, requires monitoring for bleeding risk, especially in patients with a history of ischaemic stroke and regular aspirin use.[40]

• Theophylline: Pentoxifylline increases the plasma levels of theophylline by decreasing the clearance of theophylline, necessitating therapeutic drug monitoring.[41]

• Ketolorac: Administering ketorolac concurrently with pentoxifylline should be avoided due to increased bleeding risk.[42]

Contraindications

The following are contraindications to pentoxifylline:

• Patients with recent retinal or cerebral hemorrhage
• Allergy to xanthine derivatives, eg, caffeine, theophylline, theobromine[43]

Precautions

• Acute myocardial infarction or severe coronary disease due to increased risk of myocardial demand
• Severe liver disease (Child-Pugh class C) or cirrhosis
• Anaphylaxis due to pentoxifylline has been reported. Do not administer pentoxifylline in patients with a history of anaphylaxis.[44]
• Patients receiving pentoxifylline, particularly those with a history of peptic ulceration, recent surgery, or at risk of bleeding, especially in individuals with chronic kidney disease, should undergo regular assessments for signs of bleeding, including monitoring hematocrit and hemoglobin levels.[40]

Monitoring

Older patients are at higher risk of adverse effects from pentoxifylline. Careful monitoring of blood pressure and glucose levels is recommended when administering pentoxifylline to patients on antihypertensive and antidiabetic medications. They are at high risk for hypotension, falls, and hypoglycemia. Patients with liver disease should also undergo 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 cardiac arrhythmias and low blood pressure patients. Ankle-brachial index (ABI), pain-free walking distance, and maximum walking distance should be monitored for patients with peripheral arterial disease.[5][45]

Toxicity

Signs and Symptoms of Overdose 

Reports of adverse effects of pentoxifylline are apparent in patients on chronic hemodialysis.[46] Metabolic acidosis, hypokalemia, and arrhythmias are the primary symptoms of pentoxifylline overdose. Additionally, oliguria, cardiovascular collapse, and altered consciousness, including delirium, agitation, and coma, have been reported.

Management of Overdose

No reported antidote is available for this medication. The prescriber should discontinue the drug in suspected cases of toxicity. The symptomatic treatment includes administering IV fluids, NaHCO₃ supplementation, and norepinephrine infusion. In cases of significant overdose, consideration should be given to gastric lavage. Extracorporeal elimination is not currently recommended; however, it may be a viable option for patients with severe metabolic acidosis or impaired kidney function.[47][48]

Enhancing Healthcare Team Outcomes

Clinicians should prescribe pentoxifylline after considering the risk-benefit analysis. Pharmacists play a crucial role in determining the proper dose of medication to minimize adverse drug reactions. A retrospective cohort study analyzed the association between a specialist clinical pharmacist collaborating with medical staff and prescribing practices in peripheral arterial disease. The study compared 2 patient groups admitted to a vascular surgery unit in 2007 (control group) before the introduction of a comprehensive clinical pharmacy service and in 2009 (comparison group) after its implementation. Data was collected from electronic reports and medical records, revealing significant improvements in medication initiation and risk factor management with the inclusion of a clinical pharmacist in the collaborative healthcare team.[49] 

The contributions of both nurses and dieticians are essential to educating patients, ensuring medication adherence, and making necessary adjustments to mitigate risk factors associated with atherosclerotic disease. Complex cases of peripheral vascular disease should be managed in consultation with vascular surgeons. In overdose, emergency medicine clinicians should rapidly stabilize patients. Significant overdose may require MICU admission under the supervision of critical care. If the overdose is intentional, close consultation with a psychiatrist is needed. An interprofessional team approach between clinicians (MDs, DOs, NPs, PAs), pharmacists, nurses, and specialists is required to optimize patient outcomes related to pentoxifylline pharmacotherapy.