• Sign Up

Pentoxifylline


Pentoxifylline

Article Author:
Pavan Annamaraju
Article Editor:
Krishna Baradhi
Updated:
6/25/2020 12:06:25 PM
For CME on this topic:
Pentoxifylline CME
PubMed Link:
Pentoxifylline

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 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]

Mechanism of Action

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]

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.

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.

Adverse Effects

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

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.

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. There is an increased risk of side effects in patients with diminished renal function, CrCl < 80mL/min. The patients who are at increased risk of bleeding should be advised of potential signs and symptoms of bleeding and monitored with periodic laboratory data. 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 may require consultation with a physician or a surgeon.  A pharmacist plays a crucial role in determining the proper dose of medication to minimize side effects. Both nurse's and dietician's roles are vital in patient education to ensure medication compliance and modification of risk factors related to atherosclerotic disease. An interprofessional team approach and care coordination are crucial for the best patient outcomes.


References

[1] Girolami B,Bernardi E,Prins MH,Ten Cate JW,Hettiarachchi R,Prandoni P,Girolami A,Büller HR, Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyl: a meta-analysis. Archives of internal medicine. 1999 Feb 22;     [PubMed PMID: 10030306]
[2] Aviado DM,Porter JM, Pentoxifylline: a new drug for the treatment of intermittent claudication. Mechanism of action, pharmacokinetics, clinical efficacy and adverse effects. Pharmacotherapy. 1984 Nov-Dec;     [PubMed PMID: 6393073]
[3] Dawson DL,Cutler BS,Hiatt WR,Hobson RW 2nd,Martin JD,Bortey EB,Forbes WP,Strandness DE Jr, A comparison of cilostazol and pentoxifylline for treating intermittent claudication. The American journal of medicine. 2000 Nov;     [PubMed PMID: 11063952]
[4] Jull AB,Arroll B,Parag V,Waters J, Pentoxifylline for treating venous leg ulcers. The Cochrane database of systematic reviews. 2012 Dec 12;     [PubMed PMID: 23235582]
[5] Parker R,Armstrong MJ,Corbett C,Rowe IA,Houlihan DD, Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis. Alimentary pharmacology     [PubMed PMID: 23489011]
[6] Ward A,Clissold SP, Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs. 1987 Jul;     [PubMed PMID: 3308412]
[7] Zhang M,Xu YJ,Mengi SA,Arneja AS,Dhalla NS, Therapeutic potentials of pentoxifylline for treatment of cardiovascular diseases. Experimental and clinical cardiology. 2004 Summer;     [PubMed PMID: 19641695]
[8] Kamphuis J,Smits P,Thien T, Vascular effects of pentoxifylline in humans. Journal of cardiovascular pharmacology. 1994 Oct;     [PubMed PMID: 7528848]
[9] Ciuffetti G,Mercuri M,Ott C,Lombardini R,Paltriccia R,Lupattelli G,Santambrogio L,Mannarino E, Use of pentoxifylline as an inhibitor of free radical generation in peripheral vascular disease. Results of a double-blind placebo-controlled study. European journal of clinical pharmacology. 1991;     [PubMed PMID: 1667754]
[10] Brasileiro JL,Inoye CM,Aydos RD,Silva IS,Falcão GR,Marks G,Pereira DM, Ischemia and reperfusion of rat small intestine using pentoxyfilline and prostaglandin E1. Acta cirurgica brasileira. 2013 Nov;     [PubMed PMID: 24316743]
[11] Asvadi I,Hajipour B,Asvadi A,Asl NA,Roshangar L,Khodadadi A, Protective effect of pentoxyfilline in renal toxicity after methotrexate administration. European review for medical and pharmacological sciences. 2011 Sep;     [PubMed PMID: 22013722]
[12] Kwiecień S,Brzozowski T,Konturek PC,Pawlik MW,Pawlik WW,Kwiecień N,Konturek SJ, Gastroprotection by pentoxyfilline against stress-induced gastric damage. Role of lipid peroxidation, antioxidizing enzymes and proinflammatory cytokines. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 2004 Jun;     [PubMed PMID: 15213357]
[13] Lin HI,Chu SJ,Wang D,Feng NH, Pharmacological modulation of TNF production in macrophages. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi. 2004 Feb;     [PubMed PMID: 15060681]
[14] Vardareli E,Saricam T,Koken T,Degirmenci I,Aral E,Erenoglu E, The effect of alpha-tocopherol and pentoxyfilline on ischemia-reperfusion induced liver injury in rats. Hepato-gastroenterology. 1998 Sep-Oct;     [PubMed PMID: 9840094]
[15] Golbasi I,Akbas H,Ozdem S,Ukan S,Ozdem SS,Kabukçu H,Turkay C,Bayezid O, The effect of pentoxifylline on haemolysis during cardiopulmonary bypass in open-heart surgery. Acta cardiologica. 2006 Feb;     [PubMed PMID: 16485727]
[16] Mansourian S,Bina P,Fehri A,Karimi AA,Boroumand MA,Abbasi K, Preoperative oral pentoxifylline in case of coronary artery bypass grafting with left ventricular dysfunction (ejection fraction equal to/less than 30%). Anatolian journal of cardiology. 2015;     [PubMed PMID: 25880052]
[17] Han SJ,Kim HJ,Kim DJ,Sheen SS,Chung CH,Ahn CW,Kim SH,Cho YW,Park SW,Kim SK,Kim CS,Kim KW,Lee KW, Effects of pentoxifylline on proteinuria and glucose control in patients with type 2 diabetes: a prospective randomized double-blind multicenter study. Diabetology     [PubMed PMID: 26300986]
[18] Vaizova OE,Vengerovsky AI,Alifirova VM, [Endothelium-protective effects of vinpocetine, pentoxifylline and enalapril in patients with chronic brain ischemia]. Eksperimental'naia i klinicheskaia farmakologiia. 2011;     [PubMed PMID: 21678652]
[19] European Pentoxifylline Multi-Infarct Dementia Study. European neurology. 1996;     [PubMed PMID: 8864715]
[20] Aviado DM,Dettelbach HR, Pharmacology of pentoxifylline, a hemorheologic agent for the treatment of intermittent claudication. Angiology. 1984 Jul;     [PubMed PMID: 6380349]
[21] De BK,Gangopadhyay S,Dutta D,Baksi SD,Pani A,Ghosh P, Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial. World journal of gastroenterology. 2009 Apr 7;     [PubMed PMID: 19340904]
[22] Stana J,Stergar J,Gradišnik L,Flis V,Kargl R,Fröhlich E,Stana Kleinschek K,Mohan T,Maver U, Multilayered Polysaccharide Nanofilms for Controlled Delivery of Pentoxifylline and Possible Treatment of Chronic Venous Ulceration. Biomacromolecules. 2017 Sep 11;     [PubMed PMID: 28776978]
[23] Hosseini F,Mohammadbeigi A,Aghaali M,Borujerdi R,Parham M, Effect of pentoxifylline on diabetic distal polyneuropathy in type 2 diabetic patients: A randomized trial. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences. 2019;     [PubMed PMID: 31741661]
[24] Furukawa S,Matsubara T,Umezawa Y,Motohashi T,Ino T,Yabuta K, Pentoxifylline and intravenous gamma globulin combination therapy for acute Kawasaki disease. European journal of pediatrics. 1994 Sep;     [PubMed PMID: 7957426]
[25] Best BM,Burns JC,DeVincenzo J,Phelps SJ,Blumer JL,Wilson JT,Capparelli EV,Connor JD, Pharmacokinetic and tolerability assessment of a pediatric oral formulation of pentoxifylline in kawasaki disease. Current therapeutic research, clinical and experimental. 2003 Feb;     [PubMed PMID: 24944359]
[26] Yasui K,Ohta K,Kobayashi M,Aizawa T,Komiyama A, Successful treatment of Behçet disease with pentoxifylline. Annals of internal medicine. 1996 May 15;     [PubMed PMID: 8610918]
[27] Sacerdote A, Treatment of homozygous sickle cell disease with pentoxifylline. Journal of the National Medical Association. 1999 Aug;     [PubMed PMID: 12656436]
[28] Beermann B,Ings R,Månsby J,Chamberlain J,McDonald A, Kinetics of intravenous and oral pentoxifylline in healthy subjects. Clinical pharmacology and therapeutics. 1985 Jan;     [PubMed PMID: 3965236]
[29] Poondru S,Devaraj R,Boinpally RR,Yamsani MR, Time-dependent influence of pentoxifylline on the pharmacokinetics of orally administered carbamazepine in human subjects. Pharmacological research. 2001 Mar;     [PubMed PMID: 11401423]
[30] Garcia FA,Pinto SF,Cavalcante AF,Lucetti LT,Menezes SM,Felipe CF,Alves AP,Brito GA,Cerqueira GS,Viana GS, Pentoxifylline decreases glycemia levels and TNF-alpha, iNOS and COX-2 expressions in diabetic rat pancreas. SpringerPlus. 2014;     [PubMed PMID: 24991532]
[31] Silver MR,Kroboth PD, Pentoxifylline in end-stage renal disease. Drug intelligence     [PubMed PMID: 3428162]