Download Mechanism of Action

In the name of God
Vinca alkaloids
By: Dr Malek
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 •
.The Vinca alkaloids are naturally occurring or
semisynthetic nitrogenous bases extracted
from the pink periwinkle plant Catharanthus
roseus
Many Vinca alkaloids have been . •
extensively evaluated, but only vincristine
(VCR), vinblastine (VBL), and vinorelbine
(VRL) are approved for use in the United
States.
•
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
.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
. 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
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
Clinical Pharmacology
Vincristine •
VCR is rapidly distributed to the peripheral •
compartment following intravenous
administration
VCR is metabolized and excreted primarily by •
the hepatobiliary system
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.
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
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
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 sensorymotor, and autonomic polyneuropathy
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.
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
•
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.
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
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
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.
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
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
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.
Mild and reversible alopecia occurs in •
approximately 10% and 20% of patients
treated with VRL and VCR, respectively
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.
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
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.