DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

CLINICAL PHARMACOLOGY
Nitrogen Mustards
The chemistry and the pharmacological actions of the
alkylating agents as a group, and of the nitrogen mustards,
have been presented in the preceding sections. Only the
unique pharmacological characteristics of the individual
agents are considered in this section.
Mechlorethamine. Mechlorethamine was the first clinically used nitrogen
mustard and is the most reactive of the drugs in this class. It rarely
is used in current practice.
Absorption and Fate. Severe local reactions of exposed tissues necessitate
rapid intravenous injection of mechlorethamine for most clinical
uses. In either water or body fluids, at rates affected markedly
by pH, mechlorethamine rapidly undergoes chemical degradation as
it combines with either water or cellular nucleophiles, and the parent
compound disappears from the bloodstream within minutes.
Therapeutic Uses. Mechlorethamine HCl (MUSTARGEN) formerly
was used in the combination chemotherapy regimen MOPP
(mechlorethamine, vincristine, procarbazine, and prednisone) in
patients with Hodgkin’s disease. It is given by intravenous bolus administration
in doses of 6 mg/m 2 on days 1 and 8 of the 28-day cycles of
each course of treatment. It has been largely replaced by cyclophosphamide,
melphalan, and other, more stable alkylating agents.
It also is used topically for treatment of cutaneous T-cell lymphoma
(CTCL) as a solution that is rapidly mixed and applied to
affected areas of the skin.
Clinical Toxicity. The major acute toxic manifestations of
mechlorethamine are nausea and vomiting, lacrimation, and myelosuppression.
Leukopenia and thrombocytopenia limit the amount of
drug that can be given in a single course.
Cyclophosphamide
Absorption, Fate, and Excretion. Cyclophosphamide is well absorbed
orally and is activated to the 4-hydroxy intermediate (Xie et al.,
2003) (Figure 61–3). 4-Hydroxycyclophosphamide exists in equilibrium
with the acyclic tautomer aldophosphamide. The rate of
metabolic activation of cyclophosphamide exhibits significant interpatient
variability and increases with successive doses in high-dose
regimens but appears to be saturable at infusion rates of >4 g/90 min
and concentrations of the parent compound >150 μM (Chen et al.,
1995). 4-Hydroxycyclophosphamide may be oxidized further by
aldehyde oxidase, either in liver or in tumor tissue, to inactive
metabolites. The hydroxyl metabolite of ifosfamide similarly is inactivated
by aldehyde dehydrogenase. 4-Hydroxycyclophosphamide
and its tautomer, aldophosphamide, travel in the circulation to tumor
cells where aldophosphamide cleaves spontaneously, generating stoichiometric
amounts of phosphoramide mustard and acrolein.
Phosphoramide mustard is responsible for antitumor effects, while
acrolein causes hemorrhagic cystitis often seen during therapy with
cyclophosphamide. Cystitis can be reduced in intensity or prevented
by the parenteral co-administration of mesna. Mesna does not negate
the systemic antitumor activity of the drug.
Patients should receive vigorous intravenous hydration during
high-dose treatment. Brisk hematuria in a patient receiving daily
oral therapy should lead to immediate drug discontinuation.
Refractory bladder hemorrhage can become life-threatening, and
cystectomy may be necessary for control of bleeding.
Inappropriate secretion of antidiuretic hormone has been
observed in patients receiving cyclophosphamide, usually at doses
>50 mg/kg (see Chapter 25). It is important to be aware of the
possibility of water intoxication, because these patients usually are
vigorously hydrated to prevent bladder toxicity.
Pretreatment with CYP inducers such as phenobarbital
enhances the rate of activation of the azoxyphosphorenes but does
not alter total exposure to active metabolites over time and does not
affect toxicity or therapeutic activity in humans. Cyclophosphamide
can be used in full doses in patients with renal dysfunction, because
it is eliminated by hepatic metabolism. Patients with mild hepatic
dysfunction (bilirubin <3 mg/dL) can be treated with full doses of
this drug, but those with more significant hepatic dysfunction should
receive reduced doses.
Urinary and fecal excretion of unchanged cyclophosphamide
is minimal after intravenous administration. Maximal concentrations
in plasma are achieved 1 hour after oral administration, and the t 1/2
of parent drug in plasma is ~7 hours.
Therapeutic Uses. Cyclophosphamide (LYOPHILIZED CYTOXAN, others)
is administered orally or intravenously. Recommended doses
vary widely, and standard protocols for determining the schedule
and dose of cyclophosphamide in combination with other
chemotherapeutic agents should be consulted.
As a single agent, a daily oral dose of 100 mg/m 2 for 14 days
has been recommended for patients with lymphomas and CLL.
Higher doses of 500 mg/m 2 intravenously every 2-4 weeks are used
in combination with other drugs in the treatment of breast cancer
and lymphomas. The neutrophil nadir of 500-1000 cells/mm 3 generally
serves as a lower limit for dosage adjustments in prolonged therapy.
In regimens associated with bone marrow or peripheral stem cell
rescue, cyclophosphamide may be given in total doses of 5-7 g/m 2
over a 3- to 5-day period. GI ulceration, cystitis (counteracted by
mesna and diuresis), and, less commonly, pulmonary, renal, hepatic,
and cardiac toxicities (a hemorrhagic myocardial necrosis) may
occur after high-dose therapy with total doses >200 mg/kg.
The clinical spectrum of activity for cyclophosphamide is
very broad. It is an essential component of many effective drug combinations
for non-Hodgkin’s lymphomas, other lymphoid malignancies,
breast and ovarian cancers, and solid tumors in children.
Complete remissions and presumed cures have been reported when
cyclophosphamide was given as a single agent for Burkitt’s lymphoma.
It frequently is used in combination with doxorubicin and a
taxane as adjuvant therapy after surgery for carcinoma of the breast.
Because of its potent immunosuppressive properties,
cyclophosphamide has been used to treat auto-immune disorders,
including Wegener’s granulomatosis, rheumatoid arthritis, and the
nephrotic syndrome. Caution is advised when the drug is considered
for non-neoplastic conditions, not only because of its acute toxic
effects but also because of its potential for inducing sterility, teratogenic
effects, and leukemia.
Ifosfamide. Ifosfamide (IFEX, others) is an analog of
cyclophosphamide. Severe urinary tract and central
nervous system (CNS) toxicity limited the use of ifosfamide
when it first was introduced in the early 1970s.
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CHAPTER 61
CYTOTOXIC AGENTS