In the name of God

1. In the name of God Vinca alkaloids By: Dr Malek

2. References • Holland-Frei Cancer Medicine. 6th edition. • Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. • Sauerland C, Wickham R. Vesicant extravasation Part I: Mechanisms, pathogenesis, and nursing care to reduce risk. Oncology Nursing Forum. -41Hamilton (ON):BC Decker; 2007 • Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. • Benzie IFF, Wachtel-Galor S, editors. • Boca Raton (FL): CRC Press; 2011

3. .The Vinca alkaloids are naturally occurring or semisynthetic nitrogenous bases extracted from the pink periwinkle plant Catharanthusroseus • . Many Vinca alkaloids have been extensively evaluated, but only vincristine (VCR), vinblastine (VBL), and vinorelbine (VRL) are approved for use in the United States.

4. The Vinca alkaloids have dimeric chemical structures composed of two basic multiringed units an indole nucleus (catharanthine), and a dihydroindole nucleus (vindoline), joined together with other complex systems

5. .the principal mechanisms of cytotoxicity relate to their interactions with tubulin and disruption of microtubule function, particularly of microtubules comprising the mitotic spindle apparatus, leading to metaphase arrest

6. . Other activities such as : • including inhibiting synthesis of proteins and nucleic acids, elevating oxidized glutathione, altering lipid metabolism and membrane lipids, elevating cyclic adenosine monophosphate

7. Mechanism of Action • The Vinca alkaloids bind to their binding sites in intact microtubules with different affinities • This action suppresses dynamic instability, which increases the time that microtubules spend in a state of attenuated activity, neither growing nor shortening

8. Clinical Pharmacology • Vincristine • VCR is rapidly distributed to the peripheral compartment following intravenous administration • VCR is metabolized and excreted primarily by the hepatobiliary system

9. Vinblastine • The pharmacologic behavior of VBL is similar to that of VCR Terminal half-life values ranging from 20 to 24 h have been reported • VDS disposition is primarily by hepatic metabolism and biliary clearance, and the cytochrome P450 isoform CYP3A plays a major role in drug metabolism.

10. Drug Interactions • In cell culture, VCR or VBL enhances methotrexate accumulation in tumor cells, an effect mediated by a Vinca alkaloid-induced blockade of drug efflux • l-Asparaginase may reduce the hepatic clearance of the Vinca alkaloids, particularly VCR, which may result in increased toxicity. To minimize the possibility of this interaction, VCR should be given 12 to 24 h before l-asparaginase

11. Drug interactions • There are several reports of seizure activity following treatment with the Vinca alkaloids, which has also been associated with subtherapeutic plasma phenytoin concentrations

12. Toxicity • . All of the Vinca alkaloids induce a characteristic peripheral neurotoxicity, but VCR is most potent in this regard. • The neurotoxicity is principally characterized by a peripheral, symmetric mixed sensory-motor, and autonomic polyneuropathy

13. Toxicity • The primary pathologic effect is axonal degeneration and decreased axonal transport, most likely caused by a drug-induced perturbation of microtubule function. • At onset, only symmetric sensory impairment and paresthesia in a length-dependent manner (distal extremities first) is often encountered.

14. Toxicity • pain and loss of deep tendon reflexes may develop with continued treatment, which may be followed by foot drop, wrist drop, motor dysfunction, ataxia, and paralysis. • Cranial nerves may also be affected rarely, resulting in hoarseness, diplopia, jaw pain

15. Acute, severe autonomic neurotoxicity is uncommon, but may arise as a consequence of high-dose therapy (greater than 2 mg/m2) or in patients with diminished drug clearance because of altered hepatic function. Toxic manifestations include constipation, abdominal cramps, paralytic ileus, urinary retention, orthostatic hypotension, and hypertension and facial palsies.

16. Patients with antecedent neurologic disorders, such as Charcot-Marie-Tooth disease, hereditary and sensory neuropathy type I, Guillain-Barré syndrome, and childhood poliomyelitis, are highly predisposed to neurotoxicity. • VCR treatment in patients with hepatic dysfunction or obstructive liver disease is associated with an increased risk of developing neuropathy because of impaired drug metabolism and delayed biliary excretion

17. The only known effective intervention for Vinca alkaloid neurotoxicity is discontinuing treatment • . Although a number of antidotes, including thiamine, vitamin B12, folinic acid, pyridoxine, and neuroactive agents , have been used, these treatments have not been clearly shown to be effective

18. Neutropenia is the principal dose-limiting toxicity of VBL, VDS, and VRL. Thrombocytopenia and anemia are usually less common and less severe. • The onset of neutropenia is usually 7 to 11 days after treatment, and recovery is generally by days 14 to 21.

19. The Vinca alkaloids are potent vesicants and may cause significant tissue damage if extravasation occurs. • If extravasation occurs or is suspected, treatment should be discontinued immediately and aspiration of any residual drug remaining in the tissues should be attempted

20. The application of local heat and injection of hyaluronidase, 150 mg subcutaneously, in a circumferential manner around the needle site are thought to minimize both discomfort and latent cellulitis

21. Phlebitis may also occur along the course of an injected vein, with resultant acute inflammation followed by sclerosis. • The risk of phlebitis may increase if veins are not adequately flushed after treatment. The incidence of phlebitis can be reduced with shorter administration durations.

22. Mild and reversible alopecia occurs in approximately 10% and 20% of patients treated with VRL and VCR, respectively

23. Acute cardiac ischemia, chest pains without evidence of ischemia, fever without an obvious source, acute pulmonary effects (alone or in combination with mitomycin C), Raynaud phenomenon, hand-foot syndrome, and pulmonary and hepatic toxicity have also been reported with the Vinca alkaloids.

24. All of the Vinca alkaloids have been implicated as a cause of SIADH, and patients who are receiving intensive hydration are particularly prone to severe hyponatremia secondary to SIADH.1

25. the major role of the liver in the disposition of the Vinca alkaloids implies that dose modifications should be considered for patients with hepatic dysfunction • . A 50% dose reduction is often recommended for patients with total bilirubin levels between 1.5 and 3.0 mg/dL (50% dose reduction for bilirubin levels between 2.0 and 3.0 mg/dL is recommended for VRL), and at least a 75% dose reduction for plasma total bilirubin levels above 3.0 mg/dL.