RAZAGIN

Indications

• Parkinson's disease
• Management of motor fluctuations in Parkinson's disease

Dosage

Adults: Initially 1 mg/24 hours, increased as necessary in steps of 1 mg/24 hours weekly, maximum dose 3 mg/24 hours.

Mechanism of action

Rasagiline acts as an irreversible inhibitor of monoamine oxidase B (MAO-B), leading to increased extracellular levels of dopamine in the striatum. This increase in dopamine enhances dopaminergic activity, which is beneficial for managing symptoms of Parkinson's disease. Additionally, rasagiline has been shown to activate multiple neuroprotective pathways, including up-regulation of protein kinase C (PKC) and induction of neurotrophic factors such as brain-derived neurotrophic factor (BDNF).

Pharmacodynamics

As a propargylamine, rasagiline selectively inhibits the MAO-B enzyme, which is primarily responsible for the metabolic degradation of dopamine in the brain. This inhibition leads to increased dopamine availability, thereby alleviating symptoms of Parkinson's disease. Rasagiline's selectivity for MAO-B over MAO-A minimizes the risk of hypertensive reactions commonly associated with non-selective MAO inhibitors. The drug also exhibits neuroprotective effects by promoting survival pathways that may enhance neuronal resilience.

Pharmacokinetics

Rasagiline is absorbed following oral administration, with peak plasma concentrations typically achieved within 0.5 to 1 hour. It undergoes hepatic metabolism primarily via cytochrome P450 enzymes, particularly CYP1A2. The elimination half-life is approximately 3 hours, and it is predominantly excreted in urine as metabolites. Renal impairment may affect its clearance, thus caution is advised in cases of severe renal dysfunction.

Adverse effects

• Asthenia
• Behaviour abnormality
• Syncope
• Oedema
• Sleep disorders
• Psychiatric disorders
• Skin reactions
• Hypotensive reactions
• Impulse control disorders
• Weight changes
• Vomiting
• Vertigo

Interactions

• rasagiline+methylphenidate: Severe (increases risk of hypertensive crisis)
• givosiran+rasagiline: Moderate (increases exposure)
• axitinib+rasagiline: Unknown (increases exposure)
• mexiletine+rasagiline: Unknown (increases exposure)
• rasagiline+opioids: Unknown (increases risk of adverse effects)
• rasagiline+pethidine: Unknown (increases risk of adverse effects)
• osilodrostat+rasagiline: Unknown (increases exposure)
• rucaparib+rasagiline: Unknown (increases exposure)
• vemurafenib+rasagiline: Unknown (increases exposure)

Precautions

• Avoid exposure of the patch to heat
• Caution in hepatic impairment
• Patients should be counselled on the risk of impulse control disorders

Pregnancy

Avoid-no information available.

Breast-feeding

May suppress lactation; avoid-present in milk in animal studies.

Storage

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

Formulations

• Transdermal patches: 1 mg/24 hours, 3 mg/24 hours

Mechanism of action

The precise mechanisms of action of rasagiline is unknown. One mechanism is believed to be related to its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline's beneficial effects seen in models of dopaminergic motor dysfunction. The anti-Parkinson drug rasagiline (Azilect), an irreversible and selective monoamine oxidase (MAO)-B inhibitor, was shown to possess neuroprotective activities, involving multiple survival pathways among them the up-regulation of protein kinase C (PKC)alpha, PKCepsilon, the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w and the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). More recently, employing conventional neurochemical techniques, as well as transcriptomic and proteomic screening tools, combined with a biology-based clustering method, it was shown that rasagiline also possesses neurorescue/neurogenesis activity in mice midbrain dopaminergic neurons when given chronically, post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This action was attributed to the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway, including ShcC, SOS, AF6, Rin1, and Ras and the increase in the Trk-downstream effecter phosphatidylinositol 3 kinase (PI3K) protein and its substrate, Akt/PKB. ... The anti-Parkinson's disease drug rasagiline, the anti-Alzheimer's disease drug ladostigil, and their propargyl moiety, propargylamine, enhanced the expression levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, endogenous neurotrophic factors associated with activation of phosphatidylinositol 3-kinase, protein kinase, and mitogen-activated protein kinase cell signaling/survival pathways. ... Rasagiline mesylate, a propargylamine, is an irreversible monoamine oxidase-B (MAO-B) inhibitor. MAO is a mitochondrial enzyme that regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. There appear to be at least 2 isoforms of MAO, MAO-A and MAO-B, which differ in localization and substrate specificity. MAO-A, predominantly found in the GI tract and liver, regulates the metabolic degradation of circulating catecholamines and dietary amines (e.g., tyramine). MAO-B, predominantly found in the brain, regulates the metabolic degradation of dopamine and phenylethylamine. Inhibition of MAO-A in the periphery results in systemic absorption of dietary amines (e.g., tyramine), which, in substantial amounts, can cause release of norepinephrine and subsequent substantial increases in blood pressure. Inhibition of MAO-B results in increased extracellular concentrations of dopamine and, therefore, enhanced dopaminergic activity in the striatum. While the precise mechanisms of activity of rasagiline have not been fully characterized, data from ex vivo animal studies indicate that the drug potently and irreversibly inhibits MAO-B in brain, liver, and intestinal tissues; the selectivity of rasagiline in inhibiting MAO-B (and not MAO-A) in humans has not been fully elucidated to avoid restriction of dietary tyramine and sympathomimetic amines.

Pharmacodynamics

Rasagiline is a propargylamine and an irreversible inhibitor of monoamine oxidase (MAO). MAO, a flavin-containing enzyme, regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. It is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO-A is found predominantly in the GI tract and liver, and regulates the metabolic degradation of circulating catecholamines and dietary amines. MAO-B is the major form in the human brain and is responsible for the regulation of the metabolic degradation of dopamine and phenylethylamine. In ex vivo animal studies in brain, liver and intestinal tissues rasagiline was shown to be a potent,selective, and irreversible monoamine oxidase type B (MAO-B) inhibitor. At the recommended therapeutic doses, Rasagiline was also shown to be a potent and irreversible inhibitor of MAO-B in platelets. The selectivity of rasagiline for inhibiting only MAO-B (and not MAO-A) in humans and the sensitivity to tyramine during rasagiline treatment at any dose has not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications.