Vinca Alkaloids: Vincristine and Vinblastine

Mechanism

Pharmacological Class and Group

Antineoplastic agents that inhibit microtubules of natural origin (derived from the plant Catharanthus roseus), phase-specific of the cell cycle (G2/M phase).

Mechanism of Action

Unlike taxanes, vinca alkaloids inhibit microtubule assembly and induce cytoskeletal depolymerization.

Inhibition of Tubulin Polymerization and Mitotic Disintegration

1. Vinca Domain Binding: The molecules bind specifically to the vinca-binding domain of soluble dimeric tubulin (αβ), interfering with the lateral self-association of the dimers.

2. Blocking Microtubule Growth: This binding disrupts the addition of dimers to the growing ends ("plus ends") of microtubules, inhibiting polymerization at low therapeutic concentrations:

Vinca Alkaloid + Dimeric Tubulin Assembly Blocking Spindle Depolymerization

3. Spindle Dissolution and Mitotic Arrest: At high concentrations, they induce the depolymerization of the preexisting microtubules of the mitotic spindle, breaking up its structure. The mitotic apparatus is destroyed, the chromosomes are scattered throughout the cytoplasm incapable of dividing in metaphase, which activates cycle arrest and apoptosis.

Pharmacokinetics

High Resolution Pharmacokinetics

• Distribution: They have an extremely rapid plasma distribution half-life with high cellular and platelet fixation. They do not cross the intact blood-brain barrier, although they penetrate deeply into peripheral nerves.
• Metabolism: They undergo selective phase I hepatic biotransformation mediated almost exclusively by the cytochrome P450 isoenzyme CYP3A4, generating deaminated and deacetylated metabolites of primary biliary clearance.
• Elimination: Predominant hepatobiliary clearance, with more than 80% of the unchanged drug or metabolites being excreted through the bile into the feces. Less than 10% is recovered in the urine.
• Half-life (t_1/2): It presents a very long triphasic elimination kinetics, with a terminal elimination half-life of 19 to 155 hours for vincristine.

Indicators and dose

Clinical Indications and Frequent Regimens

• Vincristine (CHOP Scheme): Diffuse large B-cell non-Hodgkin lymphoma, Acute Lymphoblastic Leukemia (ALL) in induction and systemic consolidation protocols.
• Vinblastine (ABVD Scheme): Classic Hodgkin lymphoma, combined with Doxorubicin, Bleomycin and Dacarbazine every 14 days.
• Vinorelbine (3rd Generation Vinca): Advanced or metastatic non-small cell lung cancer and refractory breast cancer.

Dosage and Clinical Adjustment

• Vincristine IV: 1.4 mg/m² as a short IV infusion of 5-10 minutes every 14 or 21 days. Maximum single dose strictly limited to 2.0 mg per cycle in adults to limit the development of neuropathy and refractory constipation.
• Adjustments in Liver Failure: Both compounds require strict reduction if transaminases or bilirubin are elevated:
  • Bilirubin between 1.5 - 3.0 mg/dL: Reduce the dose of vincristine by 50%. Discontinue if it is greater than 3 mg/dL.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• INTRATHECAL ADMINISTRATION: It is 100% fatal due to ascending cerebral and bulbar chemical demyelination.
• Hypersensitivity to the active ingredient or alkaloids of vinca.
• Active hereditary demyelinating neuropathy (Charcot-Marie-Tooth disease).
• Severe liver failure (total bilirubin > 3 mg/dL).

Relative Contraindications

• Previous grade 2 sensory-motor peripheral neuropathy.
• Severe chronic constipation or history of functional paralytic ileus.

Adverse Effects (ADR) and Specific Toxicity

• Hematological: Vinblastine causes profound dose-dependent myelosuppression (nadis after 7-10 days). On the contrary, vincristine has a practically zero myelotoxic profile, which facilitates its combination with immunosuppressive chemotherapy drugs.
• Neurological (Vincristine): Peripheral sensory-motor and autonomic neuropathy dose-limiting. It is associated with microbular axonal damage with loss of deep tendon reflexes, paresthesias, peripheral motor weakness (foot drop) and severe dysautonomia manifested clinically by persistent constipation or functional paralytic ileus.
• Tissue: Powerful vesicant. Accidental extravasation causes deep painful chemical cellulitis and tissue necrosis. It is treated locally with heat and hyaluronidase (do not apply cold, which enhances the toxicity of vincas).

Absolute Critical Toxicity: The Risk of Death by Intrathecal Route

The vinca alkaloids are extremely neurotoxic to the direct central nervous system. Accidental intrathecal injection of vincristine causes fulminant ascending chemical demyelination of the brainstem and medulla oblongata:

Vincristine Intrathecal Myelitis and Ascending Encephalopathy Chemical Respiratory Failure and Death in 100% of cases

It is one of the most documented medical error emergencies in oncology. Prevention should be ensured by strict labeling of syringes containing vincristine ("INTRATHECAL ROUTE PROHIBITED - FOR IV USE ONLY") and administered exclusively in small volume infusion bags (50 mL of 0.9% SS) rather than direct bolus syringes to eliminate confusion with intrathecal methotrexate or cytarabine.