Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

Invertebrate nervous systems in helminths and arthropods differ from those of vertebrates in important ways. The motoneurons in invertebrates, for example, are unmyelinated and are thus more susceptible to disturbances of nerve membranes than are the myelinated somatic motor fibers of vertebrates. Muscle fibers in arthropods are innervated by excitatory synapses, in which L- glutamic acid is the neurotransmitter, and by inhibitory nerves, which have -aminobutyric acid (GABA) as transmitter. Cholinergic nerves are concentrated in the central nervous system of arthropods. In nematodes, free-living species, eg, Caenorhabditis elegans, and gastrointestinal parasitic species, eg, A lumbricoides, appear to have identical neuronal systems and synaptic transmission. Cholinergic excitatory and glutamate inhibitory synapses are found in the ventral central cords, and GABAergic inhibitory synapses are identified at the neuromuscular junctions of the worms. The mammalian hosts, on the other hand, have mainly nicotinic receptors at the neuromuscular junctions (see Chapter 6: Introduction to Autonomic Pharmacology), and the GABA synapses and GABAA receptors are primarily confined within the central nervous system protected by the blood-brain barrier (Chapter 21: Introduction to the Pharmacology of CNS Drugs).

Neurotoxicant anthelmintics must be administered systemically to mammalian hosts to reach the parasitic nematodes. Therefore, if absorbed, they must be nontoxic to the nervous system of the host. Furthermore, they must penetrate the thick cuticle of the nematodes in order to be effective. It is therefore difficult to find a useful anthelmintic that acts on the nervous system of these parasites. Nevertheless, the majority of presently available anthelmintics do act on the nerves of nematodes. They can be classified into three groups: (1) those acting as ganglionic nicotinic acetylcholine agonists; (2) those acting directly or indirectly as GABA agonists; and (3) those acting on the chloride ion channel. The first category includes levamisole, pyrantel pamoate, oxantel pamoate, and bephenium. The acetylcholine receptors at the neuromuscular junctions of nematodes are of the ganglionic nicotinic type; these agonists are quite effective in causing muscular contraction of the worms. Experimentally, the ganglionic nicotinic antagonist mecamylamine can reverse the action of these anthelmintics.

The second category consists of only one drug, piperazine, an older agent that apparently acts as a GABA agonist at the neuromuscular junction and causes flaccid paralysis of the nematode.

The third category consists of a family of natural compounds, the milbemycins and avermectins. They act on the ventral cord interneuron and on the motoneuron junction of arthropods to cause paralysis by facilitating the opening of the chloride ion channel. Therefore, both the milbemycins and the avermectins are potent anthelmintics, insecticides, and antiectoparasitic agents with no cross-resistance problems with agents acting on the cholinergic systems. Picrotoxin, a specific blocker of the chloride ion channel, can reverse all of the physiologic effects of these drugs (see Chapter 21: Introduction to the Pharmacology of CNS Drugs).

Ivermectin, a simple derivative of the mixture of avermectin B1a and avermectin B1b, is highly effective as an anthelmintic in domestic animals. It is also effective in controlling onchocerciasis by eliminating the microfilariae. It is currently in wide clinical use in West Africa. Avermectins have little effect on the mammalian central nervous system because they do not cross the blood-brain barrier readily. However, when isolated mammalian brain synaptosomes and synaptic membranes are used as models for investigation, specific high-affinity binding sites for the avermectins can be identified in GABAergic nerves. This drug binding stimulates GABA release from the presynaptic end of the GABA nerve and enhances the postsynaptic GABA binding. Avermectins also stimulate benzodiazepine binding to its receptor and enhance diazepam muscle relaxant activity in vivo. There is little doubt that milbemycins and avermectins act on chloride channels associated with GABA receptors and amplify GABA functions in the mammalian central nervous system. In the free-living nematode, C elegans, however, avermectin was found to interact with glutamate-gated

chloride ion channels. The complementary DNA encoding an avermectin-sensitive, glutamate-gated chloride channel was recently identified and isolated. This channel may be an attractive target for future studies of antinematode chemotherapy.

Little is known about the nervous systems of cestodes and trematodes except that they probably differ from those of nematodes, since milbemycins and avermectins have no effect on them. However, a highly effective antischistosomal and antitapeworm agent, praziquantel (see Chapter 54: Clinical Pharmacology of the Anthelmintic Drugs), is known to enhance Ca2+ influx and induce muscular contraction in those parasites, though it exerts no action on nematodes or insects. Some benzodiazepine derivatives have activities similar to those of praziquantel; these activities are unrelated to the anxiolytic activities in the mammalian central nervous system. The nerves and muscles in schistosomes and tapeworms are thus interesting subjects for future chemotherapeutic studies.

Drugs Whose Mechanisms Have Not Yet Been Conclusively Identified

In spite of considerable progress in defining the mechanisms of action of the drugs described above, there are still wide gaps in our understanding of a number of other important antiparasitic agents. These include the compounds presented in Table 52–2. From the biochemical activities that have been identified for them, it appears that many are capable of binding DNA, and some can uncouple oxidative phosphorylation in mammals. These types of activity, which are toxic to the host but could also be involved in the antiparasitic action, may have been preferentially detectable in random screens routinely used for antiparasitic agents in the past.

Table 52–2. Some Major Antiparasitic Agents with Undefined Mechanisms of Action.

Chapter 53. Antiprotozoal Drugs

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Treatment of Malaria

Four species of plasmodium cause human malaria: Plasmodium falciparum, P vivax, P malariae, and P ovale. Although all may cause significant illness, P falciparum is responsible for nearly all serious complications and deaths. Drug resistance is an important therapeutic problem, most notably with P falciparum.

Parasite Life Cycle

An anopheline mosquito inoculates plasmodium sporozoites to initiate human infection. Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage tissue schizonts mature in the liver. Merozoites are subsequently released from the liver and invade erythrocytes. Only erythrocytic parasites cause clinical illness. Repeated cycles of infection can lead to the infection of many erythrocytes and serious disease. Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites.

In P falciparum and P malariae infection, only one cycle of liver cell invasion and multiplication occurs, and liver infection ceases spontaneously in less than 4 weeks. Thus, treatment that eliminates erythrocytic parasites will cure these infections. In P vivax and P ovale infections, a dormant hepatic stage, the hypnozoite, is not eradicated by most drugs, and subsequent relapses can therefore occur after therapy directed against erythrocytic parasites. Eradication of both erythrocytic and hepatic parasites is required to cure these infections.

Drug Classification

Several classes of antimalarial drugs are available (Table 53–1; Figure 53–1). Drugs that eliminate developing or dormant liver forms are called tissue schizonticides; those that act on erythrocytic parasites are blood schizonticides; and those that kill sexual stages and prevent transmission to mosquitoes are gametocides. No one available agent can reliably effect a radical cure, ie, eliminate both hepatic and erythrocytic stages. Few available agents are causal prophylactic drugs, ie, capable of preventing erythrocytic infection. However, all effective chemoprophylactic agents kill erythrocytic parasites before they grow sufficiently in number to cause clinical disease.

Table 53–1. Major Antimalarial Drugs.

1Not available in the USA.

Figure 53–1.

Katzung PHARMACOLOGY, 9e > Section VIII. Chemotherapeutic Drugs > Chapter 53. Antiprotozoal Drugs >

Treatment of Amebiasis

Amebiasis is infection with Entamoeba histolytica. This agent can cause asymptomatic intestinal infection, mild to moderate colitis, severe intestinal infection (dysentery), ameboma, liver abscess, and other extraintestinal infections. The choice of drugs for amebiasis depends on the clinical presentation (Figure 53–2; Table 53–4).

Figure 53–2.

Structural formulas of other antiprotozoal drugs.

Table 53–4. Treatment of Amebiasis.1

1Route is oral unless otherwise indicated. See text for additional details and cautions.

2Not available in the USA.

3Available in the USA only from the Drug Service, CDC, Atlanta (404-639-3670).

Treatment of Specific Forms of Amebiasis

Asymptomatic Intestinal Infection

Asymptomatic carriers generally are not treated in endemic areas but in nonendemic areas they are treated with a luminal amebicide. A tissue amebicidal drug is unnecessary. Standard luminal amebicides are diloxanide furoate, iodoquinol, and paromomycin. Each drug eradicates carriage in about 80–90% of patients with a single course of treatment. Therapy with a luminal amebicide is also required in the treatment of all other forms of amebiasis.

Amebic Colitis

Metronidazole plus a luminal amebicide is the treatment of choice for colitis and dysentery. Tetracyclines and erythromycin are alternative drugs for moderate colitis but are not effective against extraintestinal disease. Dehydroemetine or emetine can also be used, but these agents are best avoided (when possible) because of their toxicity.

Extraintestinal Infections

The treatment of choice is metronidazole plus a luminal amebicide. A 10-day course of metronidazole cures over 95% of uncomplicated liver abscesses. For unusual cases where initial therapy with metronidazole has failed, aspiration of the abscess and the addition of chloroquine to a repeat course of metronidazole should be considered. Dehydroemetine and emetine are toxic alternative drugs.

Metronidazole

Metronidazole, a nitroimidazole (Figure 53–2), is the drug of choice for the treatment of extraluminal amebiasis. It kills trophozoites but not cysts of E histolytica and effectively eradicates intestinal and extraintestinal tissue infections.

Chemistry & Pharmacokinetics

Oral metronidazole is readily absorbed and permeates all tissues by simple diffusion. Intracellular concentrations rapidly approach extracellular levels. Peak plasma concentrations are reached in 1–3 hours. Protein binding is low (< 20%), and the half-life of the unchanged drug is 7.5 hours. The drug and its metabolites are excreted mainly in the urine. Plasma clearance of metronidazole is decreased in patients with impaired liver function.

Mechanism of Action

The nitro group of metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoans. Reactive reduction products appear to be responsible for antimicrobial activity.

Clinical Uses

Amebiasis

Metronidazole is the drug of choice for the treatment of all tissue infections with E histolytica. It is not reliably effective against luminal parasites and so must be used with a luminal amebicide to ensure eradication of the infection. Tinidazole, a related nitroimidazole, appears to have similar activity and a better toxicity profile than metronidazole, but it is not available in the USA.

Giardiasis

Metronidazole is the treatment of choice for giardiasis. The dosage for giardiasis is much lower— and the drug thus better tolerated—than that for amebiasis. Efficacy after a single treatment is about 90%. Tinidazole is equally effective.

Trichomoniasis

Metronidazole is the treatment of choice. A single dose of 2 g is effective. Metronidazole-resistant organisms may lead to treatment failures. Tinidazole may be effective against some of these infections, but it is not available in the USA. Such cases may require repeat courses of metronidazole at higher doses than normally recommended—or topical therapy.

Adverse Effects & Cautions

Nausea, headache, dry mouth, or a metallic taste in the mouth occurs commonly. Infrequent adverse effects include vomiting, diarrhea, insomnia, weakness, dizziness, thrush, rash, dysuria, dark urine, vertigo, paresthesias, and neutropenia. Taking the drug with meals lessens gastrointestinal irritation. Pancreatitis and severe central nervous system toxicity (ataxia, encephalopathy, seizures) are rare.

Metronidazole has a disulfiram-like effect, so that nausea and vomiting can occur if alcohol is ingested during therapy. The drug should be used with caution in patients with central nervous system disease. Intravenous infusions have rarely caused seizures or peripheral neuropathy. The dosage should be adjusted for patients with severe liver or renal disease.

Metronidazole has been reported to potentiate the anticoagulant effect of coumarin-type anticoagulants. Phenytoin and phenobarbital may accelerate elimination of the drug, while cimetidine may decrease plasma clearance. Lithium toxicity may occur when the drug is used with metronidazole.

Metronidazole and its metabolites are mutagenic in bacteria. Chronic administration of large doses led to tumorigenicity in mice. Data on teratogenicity are inconsistent. Metronidazole is thus best avoided in pregnant or nursing women, though congenital abnormalities have not clearly been associated with use in humans.

Iodoquinol

Iodoquinol (diiodohydroxyquin) is a halogenated hydroxyquinoline. It is an effective luminal amebicide that is commonly used with metronidazole to treat amebic infections. Its pharmacokinetic properties are poorly understood. Ninety percent of the drug is retained in the intestine and excreted in the feces. The remainder enters the circulation, has a half-life of 11–14 hours, and is excreted in the urine as glucuronides.