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

Chemistry. Ivermectin exists as an odorless off-white powder with
high lipid solubility but poor solubility in water. It is a mixture of at
least 80% 22,23-dihydroavermectin B 1a
and no more than 20%
22,23-dihydroavermectin B 1b
. B 1a
and B 1b
have nearly identical
antiparasitic activities. The hydrogenation of avermectin B 1
at the
C22-23 linkage confers increased activity against Haemonchus contortus,
an important veterinary parasite, and against the cattle parasite
Onchocerca cervicalis.
Antiparasitic Activity and Resistance. Ivermectin
immobilizes affected organisms by inducing a tonic
paralysis of the musculature. Studies of Caenorhabditis
elegans indicate that avermectins induce paralysis by
activating a family of ligand-gated Cl – channels, particularly
glutamate-gated Cl – channels that are found
only in invertebrates. There is close correlation among
activation and potentiation by avermectins and milbemycin
D of glutamate-sensitive Cl – current, nematicidal
activity, and membrane binding affinity (Arena et al.,
1995; Cully et al., 1996). Moreover, glutamate-gated
Cl – channels are expressed in the pharyngeal muscle
cells of these worms, consistent with the marked and
potent inhibitory effect of avermectins on the feeding
behavior of the organisms (Sangster and Gill, 1999).
Therefore, ivermectin probably binds to glutamateactivated
Cl – channels found in nematode nerve or muscle
cells, and causes hyperpolarization by increasing
intracellular chloride concentration. This results in
paralysis of the parasite. Resistance or relative unresponsiveness
to avermectin action has been observed in
different nematodes, especially those species parasitizing
livestock.
Several different avermectin-“resistant” developmental and
physiological phenotypes have been described, but definitive relationships
among these phenotypes and native avermectin receptor
subtypes, locations, numbers, and binding affinities require clarification
(Hejmadi et al., 2000; Sangster and Gill, 1999). Alterations in
genes encoding ATP-dependent P-glycoprotein transporters that bind
avermectins and in those encoding putative components of the glutamate-gated
Cl – channel have been associated with the development
of resistance in Haemonchus contortus (Xu et al., 1998). A significant
increase in low-affinity glutamate binding has been detected in
ivermectin-resistant nematodes, but how this relates to drug resistance
is unclear (Hejmadi et al., 2000).
Glutamate-gated Cl – channels probably are one of several sites
of ivermectin action among invertebrates (Zufall et al., 1989).
Avermectins also bind with high affinity to γ-aminobutyric acid
(GABA)-gated and other ligand-gated Cl – channels in nematodes such
as Ascaris and in insects, but the physiological consequences are less
well defined. Lack of high-affinity avermectin receptors in cestodes
and trematodes may explain why these helminths are not sensitive to
ivermectin (Shoop et al., 1995). Avermectins also interact with GABA
receptors in mammalian brain, but their affinity for invertebrate receptors
is ~100-fold higher (Schaeffer and Haines, 1989).
In humans infected with O. volvulus, ivermectin causes a
rapid, marked decrease in microfilarial counts in the skin and ocular
tissues that lasts for 6-12 months (Newland et al., 1988). The drug
has little discernible effect on adult parasites, even at doses as high
as 800 μg/kg (Molyneux et al., 2003) but affects developing larvae
and blocks egress of microfilariae from the uterus of adult female
worms (Court et al., 1985). By reducing microfilariae in the skin,
ivermectin decreases transmission to the Simulium black fly vector
(Cupp et al., 1989). Regular treatment with ivermectin also has been
conjectured to act prophylactically against the development of
Onchocerca infection (Molyneux et al., 2003).
Ivermectin also is effective against microfilaria but not
against adult worms of W. bancrofti, B. malayi, L. loa, and M. ozzardi.
The drug exhibits excellent efficacy in humans against Ascaris lumbricoides,
Strongyloides stercoralis, and cutaneous larva migrans.
Other GI nematodes are either variably affected (Trichuris trichura
and Enterobius vermicularis), or unresponsive (Necator americanus
and Ancylostoma duodenale).
Absorption, Fate, and Excretion. In humans, peak levels of ivermectin
in plasma are achieved within 4-5 hours after oral administration.
The long terminal t 1/2
(~57 hours in adults) primarily reflects a low
systemic clearance (~1-2 L/hour) and a large apparent volume of
distribution. Ivermectin is ~93% bound to plasma proteins. The
drug is extensively converted by hepatic CYP3A4 to at least 10
metabolites, mostly hydroxylated and demethylated derivatives
(Zeng et al., 1998). Virtually no ivermectin appears in human urine
in either unchanged or conjugated form (Krishna and Klotz, 1993).
Studies in transgenic mice lacking a P-glycoprotein efflux pump
showed neurotoxicity, indicating that this drug transporter, located in
the endothelium of brain microvasculature, reduces ivermectin penetration
to the CNS (Schinkel et al., 1994). This, and the relatively
lower affinity of ivermectin for mammalian CNS receptors, may
explain the paucity of CNS side effects and the relative safety of this
drug in humans.
Therapeutic Uses
Onchocerciasis. Ivermectin administered as a single oral dose (150 to
200 μg/kg) given every 6-12 months is the drug of choice for treatment
of onchocerciasis, in adults and children ≥5 years of age (Goa
et al., 1991). Ivermectin given in mass drug administration programs
has become a critical component of onchocerciasis control programs
in the Americas and in sub-Saharan Africa. Equally important, such
therapy results in reversal of inflammatory changes in ocular tissues
and arrests the development of further ocular pathology due to microfilariae.
Marked reduction of microfilariae in the skin results in major
relief of the intense pruritus that is a feature of onchocerciasis.
Clearance of microfilariae from skin and ocular tissues occurs within
a few days and lasts for 6-12 months; the dose then should be
repeated. The drug is not curative, however, because ivermectin has
little effect on adult O. volvulus. Ivermectin has been used since 1987
as the mainstay for onchocerciasis control programs in all of Africa
and in the Middle East and Latin America, where the disease is
endemic. Nearly 20 million people have received at least one dose of
the drug, and many have received six to nine doses (Dull and
Meredith, 1998). The Onchocerciasis Elimination Programme in the
Americas (OEPA) has effectively reduced transmission in the
endemic nations of the Americas, Brazil, Colombia, Ecuador,
Guatemala, Mexico, and Venezuela through biannual treatment with
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CHAPTER 51
CHEMOTHERAPY OF HELMINTH INFECTIONS