Vinca alkaloids adverse effects

The contractile proteins of the spindle apparatus must draw apart the replicated chromosomes before the cell can divide. This process is prevented by the so-called spindle poisons (see also colchicine, p. 316) that arrest mitosis at metaphase by disrupting the assembly of microtubules into spindle threads. The vinca alkaloids, vincristine and vinblastine (from the periwinkle plant. Vinca rosea) exert such a cell-cycle-specific effect. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms. 

Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea. Its mechanism of action involves inhibition of tubulin polymerization, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the biliary system. As such, dose modification is required in the setting of liver dysfunction. The main adverse effects are outlined in Table 54-4, and they include nausea and vomiting, bone marrow suppression, and alopecia. This agent is also a potent vesicant, and care must be taken in its administration. It has clinical activity in the treatment of Hodgkin s... 

A rare but well-known adverse effect of vinca alkaloids, including vinorelbine, is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (1195-1197). The diagnosis is usually based on clinical and laboratory... 

Vincristine, a vinca-alkaloid, prevents proliferation of tumor cells through the inhibition of tubulin polymerization. Vincristine is used as an anticancer agent for leukemia and lymphoma (Himes etal, 1976 Owellen etal., 1976). Clinical use of vincristine is often limited by its adverse effects, which include painful peripheral neuropathy (i.e., neuropathic pain) (Casey et al., 1973 Sandler et al., 1969). Elucidation of the detailed mechanism of neuropathic pain caused by vincristine is needed to improve quality-of-life for patients, and to make vincristine more tolerable for cancer treatment. 

The vinca alkaloids, vincristine and vinblastine (from the periwinkle plant, Vinca rosea), inhibit the polymerization of tubulin subunits into microtubuli. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms. 

IMATINIB VINCA ALKALOIDS t adverse effects of vinblastine and vincristine Inhibition of CYP3A4-mediated metabolism. Also inhibition of P-gp efflux of vinblastine Monitor FBCs and watch for early features of toxicity (pain, numbness, tingling in the fingers and toes, jaw pain, abdominal pain, constipation, ileus). Consider selecting an alternative drug... 

VINCA ALKALOIDS EFAVIRENZ T efficacy and t adverse effects of vinca alkaloids with efavirenz Likely i CYP3A4-mediated metabolism of vinca alkaloids Use with caution. Monitor U Es and FBC closely... 

VINCA ALKALOIDS ZIDOVUDINE t adverse effects when vincristine and possibly vinblastine are co administered with zidovudine Additive toxicity Use with caution. Monitor FBC and renal function closely. 1 doses as necessary... 

The most important adverse effects of vinca alkaloids include nervous system disorders, hematological effects, and gastrointestinal discomfort. Respiratory and cardiovascular adverse effects have to be particularly considered during combination chemotherapy. All the vinca alkaloids are tissue irritants, and extravasation without any adequate supportive management can result in severe local ulceration (1,2,5,8,20). 

Vinca alkaloid-associated myocardial infarction, angina pectoris, and transient electrocardiographic changes related to coronary ischemia are limited to case reports (22-24). In addition, patients with these adverse effects... 

Seizures associated with intravenous use of vinca alkaloids are very rare (60-62). Some cases may have been due to SIADH-associated hyponatremia. Other forms include tumor-related effects, nervous system infections, or cerebral hemorrhage, which often make direct causal relations between drug exposure and nervous system adverse effects very difficult. 

The authors concluded that vinblastine may have been responsible, because the other agents have not yet been associated with ototoxicity and because vincristine can cause ototoxicity too. The mechanism of this adverse effect is unclear but it may involve vinca alkaloid-associated damage to the eighth cranial nerve. This means that care should be taken when... 

Cersosimo RJ, Bromer R, Licciardello JT, Hong WK. Pharmacology, clinical efficacy and adverse effects of vin-desine sulfate, a new vinca alkaloid. Pharmacotherapy 1983 3(5) 259-74. 

Commercial formulations obtained from the alkaloids in Vinca minor may not be free from adverse effects. Ventricular dysrhythmias have been observed, but only after intramuscular or intravenous administration, and they seem to reflect a direct effect on myocardial cells. Hypokalemia and a prolonged QT interval seem to be predisposing factors. Vincamine should therefore be avoided in patients with a prolonged QT interval (SEDA-2, 183) (SEDA-5, 206) (SEDA-5, 207) (SEDA-7, 228). 

There has been very little experimental work conducted with natural products from the phylum Bryozoa. The family of bryostatins, macrolide polyketides isolated by Pettit from the bryozoan Bugula neritina, is certainly of greatest significance in terms of biomedical potential [92]. Bryostatin 1 (57) exhibits selective activity against B-cell lymphomas and leukemias, [93] and directly stimulates bone marrow progenitor cells to form colonies that functionally activate neutrophils [94]. Additionally, bryostatin 1 activates protein kinase C [95] and has immunomodulatory activity both in vitro and in vivo [96]. In combination with the vinca alkaloid vincristine, bryostatin 1 inhibits the growth of lymphoma cells without adverse effects on bone marrow cells [97]. 

What adverse effects may be mediated by vinca alkaloids ... 

Vinorelbine tartrate (Fig. 42.35) is used alone or in combination with cispiatin for first-line treatment of nonsmall cell lung cancer. This semisynthetic alkaloid is unique in having oral bioavailability (85), but it currently is available only for IV injection. The initial phase elimination half-life is on par with that observed for vincristine and vinblastine, and the terminal phase half-life is between 28 and 44 hours. Although dose-limiting granulocytopenia is the major adverse effect, potentially fatal interstitial pulmonary changes have been noted, and patients with symptoms of respiratory distress should be promptly evaluated. As with all vinca alkaloids, elimination is primarily hepatobiliary, and dosage reduction should be considered in patients with liver dysfunction. 

Information seems to be limited to this report. On the basis of their findings the authors suggest that erythromycin should be avoided at the time of vinblastine infusion. Use with clarithromycin may be safe. The UK manufacturers of vincristine and vindesine have warned that caution should be exercised in patients taking any drugs known to inhibit the CYP3A subfamily because of the risk of an earlier onset and/or increased severity of adverse effects. One manufacturer of vinblastine states that erythromycin may increase vinblastine toxicity. Note that itraconazole, another CYP3A4 inhibitor, is known to increase the toxicity of vincristine, see Vinca alkaloids -i- Azoles , p.668. 

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