TRENTOXIMAL

Indications

• Peripheral arterial disease (intermittent claudication)
• Chronic venous insufficiency (adjunctive treatment)
• Unlicensed use for venous leg ulcers

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: Initially 400 mg 2-3 times a day, adjusted based on clinical response. For intermittent claudication, 100 mg 3 times a day is also recommended.

Mechanism of action

Pentoxifylline lowers blood viscosity by increasing erythrocyte flexibility, reducing plasma fibrinogen levels, inhibiting neutrophil activation, and suppressing erythrocyte/platelet aggregation. It is proposed to act as a non-specific phosphodiesterase (PDE) inhibitor, particularly affecting PDE type III and IV, which increases intracellular cyclic adenosine monophosphate (cAMP) levels, leading to various downstream effects that improve microcirculatory flow.

Pharmacodynamics

Pentoxifylline demonstrates hemorheological, anti-oxidative, and anti-inflammatory effects, which are particularly pertinent in patients with PAD. Its use has been linked to potential side effects such as angina and arrhythmia in those with concurrent coronary artery disease. Careful monitoring is advised when used with anticoagulants like warfarin due to its effects on coagulation parameters.

Pharmacokinetics

Pentoxifylline is well absorbed after oral administration and undergoes extensive hepatic metabolism. Its elimination half-life ranges from 0.5 to 1.5 hours, and it is primarily excreted in the urine as metabolites. The drug's pharmacokinetics can be significantly influenced by hepatic function, necessitating caution in patients with liver impairment.

Contra-indications

• Acute myocardial infarction
• Severe cardiac arrhythmias
• Cerebral haemorrhage
• Extensive retinal haemorrhage
• Acute porphyrias

Adverse effects

• Dizziness
• Flushing
• Headache
• Nausea
• Diarrhoea
• Epigastric pain
• Rash
• Vomiting
• Myalgia
• Fatigue
• Gastrointestinal discomfort
• Photosensitivity
• Skin reactions
• Alopecia
• Arthralgia

Interactions

• Pentoxifylline + aminophylline: Moderate (increases concentration)
• Pentoxifylline + theophylline: Moderate (increases concentration)
• SSRIs + pentoxifylline: Unknown (increases exposure)
• Ciprofloxacin + pentoxifylline: Unknown (increases exposure)
• Fluvoxamine + pentoxifylline: Unknown (increases exposure)
• Warfarin: Requires more frequent monitoring of prothrombin times

Precautions

• Use caution in patients with coronary artery disease
• Monitor patients with risk factors for hemorrhage, such as retinal bleeding and peptic ulceration
• Avoid in patients with hepatic impairment presenting with oedema, paraesthesia, and postural hypotension

Pregnancy

Manufacturer advises to avoid unless potential benefit outweighs risk.

Breast-feeding

No information available.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Capsule 100 mg
• Capsule 250 mg
• Oral suspension

Mechanism of action

Patients with peripheral arterial disease (PAD) may suffer from intermittent claudication, exertional leg pain that resolves upon rest, which is underscored by a complex etiology including vascular dysfunction (reduced limb perfusion, angiogenesis, and microcirculatory flow), systemic inflammation, and skeletal muscle dysfunction. Pentoxifylline (PTX), (3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione) or 1-(5-oxohexyl)-3,7-­dimethylxanthine, is a methyl-xanthine derivative that acts to lower blood viscosity by increasing erythrocyte flexibility, reducing plasma fibrinogen, inhibiting neutrophil activation, and suppressing erythrocyte/platelet aggregation; it also has antioxidant and anti-inflammatory effects. Although the precise mechanism of action has yet to be elucidated, numerous studies have suggested several effects of PTX. The classical interpretation of PTX's broad effects is due to its ability to act, _in vitro_, as a non-specific cyclic-3',5'-phosphodiesterase (PDE) inhibitor at millimolar concentrations; specifically, it has been proposed that inhibition of PDE type III and IV isozymes leads to elevated cyclic adenosine monophosphate (cAMP) levels, which mediate diverse downstream effects. This view has been challenged, specifically by observing those plasma concentrations of PTX in routine clinical use are typically only around 1μM, far lower than those used to inhibit PDEs _in vitro_. Instead, several studies have suggested that PTX can modulate adenosine receptor function, specifically the Gα-coupled A2A receptor (A2AR). Whether PTX acts directly as an A2AR agonist is unclear, although it can clearly increase the response of A2AR to adenosine. A2AR activation activates adenylyl cyclase, which increases intracellular cAMP levels; this observation may explain PTX's ability to increase intracellular cAMP in a PDE-independent fashion. Elevated cAMP levels have numerous downstream effects. cAMP-mediated activation of protein kinase A (PKA) suppresses nuclear translocation of NF-κB, which suppresses transcription of pro-inflammatory cytokines such as tumour necrosis factor (TNF-α), interleukin-1 (IL-1), and IL-6 as well as TNF-induced molecules such as adhesion molecules (ICAM1 and VCAM1) and the C-reactive protein (CRP). PTX has also been shown to prevent the downstream phosphorylation of p38 MAPK and ERK, which are responsible for assembling the NADPH oxidase involved in the neutrophil oxidative burst. This effect is due to a PKA-independent decrease in Akt phosphorylation and a PKA-dependent decrease in phosphorylation of p38 MAPK and ERK. This transcriptional regulation at least partially explains the anti-inflammatory and anti-oxidative properties of PTX. Also, activated PKA can activate the cAMP response element-binding protein (CREB), which itself blocks SMAD-driven gene transcription, effectively disrupting transforming growth factor (TGF-β1) signalling. This results in lower levels of fibrinogenic molecules such as collagens, fibronectin, connective tissue growth factor, and alpha-smooth muscle actin. Hence, disruption of TGF-β1 signalling may explain the anti-fibrotic effects of PTX, including at least some of the decrease in blood viscosity. The picture is complicated by the observation that PTX metabolites M1, M4, and M5 have been shown to inhibit C5 Des Arg- and formyl-methionylleucylphenylalanine-induced superoxide production in neutrophils and M1 and M5 significantly contribute to PTX's observed hemorheological effects. Overall, PTX administration is associated with decreased pro-inflammatory molecules, an increase in anti-inflammatory molecules such as IL-10, and decreased production of fibrinogenic and cellular adhesion molecules.

Pharmacodynamics

Pentoxifylline, a synthetic dimethylxanthine derivative structurally related to [theophylline] and [caffeine], exhibits hemorheological, anti-oxidative, and anti-inflammatory properties and is traditionally indicated in the treatment of peripheral arterial disease (PAD). In PAD patients with concurrent cerebrovascular and coronary artery diseases, pentoxifylline treatment has occasionally been associated with angina, arrhythmia, and hypotension. Concurrent use with [warfarin] should be associated with more frequent monitoring of prothrombin times. Also, patients with risk factors complicated by hemorrhages, such as retinal bleeding, peptic ulceration, and recent surgery, should be monitored periodically for bleeding signs.