4. vinca alkaloids :)

Vinca alkaloids are derived from

• Part of the natural product cancer chemotherapy drugs

• Derived from the Madagascar periwinkle plant, Catharanthus roseus (formerly called Vinca rosea).

• Include:

i. Vincristine ii. Vinblastine iii. Vinorelbine

vinca alkaloids includes

Include:

i. Vincristine

ii. Vinblastine

iii. Vinorelbine

MOA

MITOTIC SPINDLE INHIBITORS

• Inhibit tubulin polymerization→ disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle.

• Results in mitotic arrest in metaphase→halts cell division, leading to cell death.

Microtubules are found in high concentrations in the brain - disruption causes neurotoxicity

Are vinca alkaloids cell cycle specific

specific to the M phase

inhibit mitotic spindle formation → preventing cell division

PK OF VINCA ALKALOIDS

• Aministration - IV

  • VINCA ALKALOIDS SHOULD NOT BE ADMINISTERED INTRATHECALLY → IN CAN RESULT IN DEATH.

• Extensively metabolized in the liver

• Metabolites are excreted in bile

• < 15% is going in the urine unchanged

• Dose adjustment required in patients with hepatic dysfunction

• Half lives:

Vincristine= 20 hrs

Vinblastine= 23 hrs

Vinorelbine=24 hrs

1. Vinblastine

Is given intravenously

• Avoid subcutaneous extravasation → painful irritation and ulceration.

Therapeutic uses of vinblastin

i. Testicular tumors (administered with bleomycin and cisplastin)

ii. Hodgkin's lymphoma

iii. Kaposi sarcoma

iv. Neuroblastoma

v. Langerhans cell histiocytosis

vi. Carcinoma of the breast

vii. Choriocarcinoma.

Clinical toxicities

• Leukopenia- nadir (lowest WBC count) within 7-10 days, with recovery in another 7 days.

• VBL IS A POTENT MYELOSUPPRESSANT.

• Mild neurological manifestations.

• Nausea, vomiting, anorexia & diarrhea.

• Alopecia, stomatitis & dermatitis.

• Extravasation → cellulitis.

2. Vincristine

ADMINISTRATION AND DOSAGE

Is given IV

dose - • Dose : 2mg/m2 in children : 1.4mg/m2 in adults

• Better tolerated by children than adults, who may experience severe, progressive neurological toxicity.

• Given at weekly intervals.

Therapeutic uses

• Childhood leukemia - ALL

• Pediatric solid tumors- Wilms tumor, neuroblastoma & rhabdomyosarcoma

Hodgkin’s lymphoma

• Non Hodgkin’s lymphoma

Clinical toxicities of vincristine

• Mostly neurological- sensory & motor disturbances → NEUROTOXIC - PERIPHERAL NEUROPATHY

• Severe constipation

• Alopecia in 20% (reversible without cessation of therapy)

• Thrombocytopenia, anemia.

• Myelosuppression is much less than that caused by Vinblastine. (VINOCRISTINE IS BONE MARROW SPARING)

• Extravasation → cellulitis and phlebitis

3. Vinorelbine administration and dosage

Administered in normal saline as an iv infusion over 10 minutes

• Dose: 25- 30 mg/m2 weekly

Indications of vinorelbine

Useful in:

i. Non-small cell lung cancer

ii. Breast cancer

Clinical toxicities of vinorelbine

Has an intermediate toxicity profile

• Primary toxicity is granulocytopenia

• Allergic reactions

• Mild changes in liver enzymes

Advantage of vinorelbine compared to other vinca alkaloids

Less neurotoxicity than other vinca alkaloids