Antiprotozoal drugs I: antimalarial agents

Antiprotozoal drugs I: antimalarial agents

Malaria is a parasitic disease caused by protozoa of the genus Plasmodium. With the exception of tuberculosis, malaria kills more people than any other infectious disease. According to the World Health Organization, between 350 and 500 million people are afflicted each year, and over 1 million die. About 90% of deaths occur in sub-Saharan Africa, almost entirely among young children. In the United States, of the 1300 cases reported annually, almost all were acquired outside the country.

Large-scale attempts to eradicate the disease have achieved only partial success. Eradication programs have been directed at the malarial parasite as well as the Anopheles mosquito, the insect that transmits malaria to humans. Failure to produce complete control has resulted largely from development of drug resistance by both the parasite and the mosquito. The incidence of malaria is rising in regions where it had once been suppressed. There remains a great need for safe, effective, and affordable agents capable of killing the malaria parasite and its mosquito carrier. Vaccines against malaria, which are in development, would be the ideal way to manage the disease.

In approaching the antimalarial drugs, we begin by reviewing the life cycle of the malaria parasite. After that we discuss the two major subtypes of malaria: falciparum malaria and vivax malaria. Next, we consider basic principles of treatment, focusing on therapeutic objectives and drug selection. Lastly, we discuss the pharmacology of the antimalarial drugs.

Life cycle of the malaria parasite

In order to understand the actions and specific applications of antimalarial drugs, we must first understand the life cycle of the malaria parasite. As indicated in Figure 98–1, the cycle takes place in two hosts: humans and the female Anopheles mosquito. Asexual reproduction occurs in humans. Sexual reproduction occurs in the mosquito.

Figure 98–1 Life cycle of the malaria parasite.
(RBC = red blood cell.)

Figure 98–1 Life cycle of the malaria parasite.
(RBC = red blood cell.)

The human phase begins when sporozoites are injected into the bloodstream by a feeding Anopheles mosquito. The sporozoites invade hepatocytes (liver cells), where they either (1) multiply and transform into merozoites or (2) transform into hypnozoites and lie dormant. The process of merozoite production, which takes 12 to 26 days (depending upon the species of parasite), is referred to as the pre-erythrocytic or exoerythrocytic phase of the life cycle. Following their release from hepatocytes, merozoites infect erythrocytes. Within the erythrocyte, each parasite differentiates and divides, becoming first a trophozoite and then a multinucleated schizont. The schizont then evolves into new merozoites. This asexual reproductive process takes 2 to 3 days, after which red blood cells burst, releasing new merozoites into the blood. The new merozoites then infect fresh erythrocytes, thereby establishing an escalating cycle of red cell invasion and lysis. Each time the erythrocytes rupture, they release pyrogenic (fever-inducing) agents, which cause the repeating episodes of fever that characterize malaria.

Sexual reproduction begins with the formation of gametocytes, which differentiate from some of the merozoites in red blood cells (see Figure 98–1). Following their release from red cells, gametocytes enter a female Anopheles mosquito when she ingests blood while feeding. Within the mosquito, the gametocytes differentiate into mature forms, after which fertilization takes place. The resulting zygote then produces sporozoites, thus completing sexual reproduction.

Types of malaria

Malaria is caused by four different species of Plasmodium. In this chapter, we limit discussion to the two species encountered most: Plasmodium vivax and Plasmodium falciparum. Malaria caused by either species is characterized by high fever, chills, and profuse sweating. However, despite similarity of symptoms, these forms of malaria are very different—especially with regard to severity of symptoms, relapse, and drug resistance. These and other differences are summarized in Table 98–1.

TABLE 98–1

Comparison of Vivax Malaria and Falciparum Malaria

	Type of Malaria
Characteristics	Vivax Malaria	Falciparum Malaria
Causative organism	Plasmodium vivax	Plasmodium falciparum
Frequency of infection	More common	Less common
Latency of symptoms	26 days	12 days
Intensity of symptoms	Mild	Severe
Timing of febrile paroxysms	Every 2 days	Irregular
Probability of relapse	High	None
Drug resistance	Uncommon	Common

Vivax malaria

Vivax malaria, caused by P. vivax, is the most common form of malaria. Fortunately, the disease is relatively mild and usually self-limiting. Because drug resistance by P. vivax is relatively uncommon, symptoms can be readily suppressed with medication.

Infection begins when the host is inoculated with P. vivax sporozoites. After 26 days, merozoites emerge from hepatocytes and begin their attack on erythrocytes. Symptoms of malaria (eg, chills, fever, sweating) commence as infected erythrocytes rupture, releasing pyrogens and other substances into the blood. Symptoms peak, decline, and peak again every 48 hours in response to cyclic reinfection and red cell lysis. This cycle continues until terminated by drugs or by acquired immunity. Unfortunately, relapse is likely following termination of the acute attack. Why? Because with P. vivax infection, dormant parasites (hypnozoites) remain in the liver. Periodically, these hypnozoites evolve into merozoites, undergo release into the blood, and start the erythrocytic cycle anew. Relapse becomes less frequent with the passage of time, and, after 2 or more years, ceases entirely. Relapse can be stopped with drugs that kill hypnozoites.

Falciparum malaria

Malaria caused by P. falciparum is less common than malaria caused by P. vivax, but is much more severe. In the absence of treatment, the disease kills about 10% of its victims. Making matters worse, many strains of P. falciparum are now drug resistant. Unlike the symptoms of vivax malaria, which peak every 48 hours, symptoms of falciparum malaria occur at irregular intervals. The erythrocytic cycle of P. falciparum can destroy up to 60% of circulating red blood cells, resulting in profound anemia and weakness. The hemoglobin released from these cells causes the urine to darken, giving rise to the term black-water fever. Falciparum malaria can produce serious complications, including pulmonary edema, hypoglycemia, and toxic encephalopathy, characterized by confusion, coma, and convulsions. When treated immediately, falciparum malaria usually responds well. However, if treatment is delayed (by as little as 1 or 2 days), the disease may progress rapidly to irreversible shock and death. In contrast to infection with P. vivax, infection with P. falciparum does not relapse. Why? Because P. falciparum does not form hypnozoites. As a result, once the erythrocytic forms have been eliminated, the patient is parasite free.

Principles of antimalarial therapy

Therapeutic objectives

Drug responsiveness of the malaria parasite changes as the parasite goes through its life cycle. The erythrocytic forms are killed with relative ease, whereas the exoerythrocytic (hepatic) forms are much harder to kill—and sporozoites do not respond to drugs at all. Because of these differences, antimalarial therapy has three separate objectives: (1) treatment of an acute attack (clinical cure), (2) prevention of relapse (radical cure), and (3) prophylaxis (suppressive therapy). Because sporozoites are insensitive to available drugs, drugs cannot prevent primary infection of the liver.

Treatment of an acute attack.

Clinical cure is accomplished with drugs that are active against erythrocytic forms of the malaria parasite. By eliminating parasites from red blood cells, the erythrocytic cycle is stopped and symptoms cease. For patients with vivax malaria, clinical cure will not prevent relapse, because hypnozoites remain in the liver. However, for patients with falciparum malaria, successful treatment of the acute attack prevents further episodes (until reinfection occurs).

Prevention of relapse.

People infected with P. vivax harbor dormant parasites in the liver. In order to prevent relapse, a drug that can kill these hepatic forms must be taken. The use of drugs to eradicate hepatic P. vivax is referred to as radical cure. Since reinfection by a mosquito bite is a virtual certainty as long as one remains in a malaria-endemic region, radical cure is often postponed until departure from the area.

Prophylaxis.

Persons anticipating travel to an area where malaria is endemic should take antimalarial medication for prophylaxis. Although drugs cannot prevent primary infection of the liver, they can prevent infection of erythrocytes. Hence, although the parasite may be present, symptoms are avoided. Because prophylactic treatment prevents only symptoms but not invasion of the liver, such treatment is often referred to as suppressive therapy.

Nondrug measures can help greatly to prevent infection. Since Anopheles mosquitoes only bite between dusk and dawn, clothing that covers as much skin as possible should be worn during this time. A diethyltoluamide (DEET)–containing insect repellent should be applied to skin that remains exposed. Sleeping under mosquito netting that has been impregnated with an insecticide (eg, permethrin) further reduces the risk of a bite.

Drug selection

Selection of antimalarial drugs is based largely on two factors: (1) the goal of treatment and (2) drug resistance of the causative strain of Plasmodium. Drugs of choice for treatment and prophylaxis are discussed below and summarized in Table 98–2.

TABLE 98–2

Drugs of Choice for Malaria *

Therapeutic Objective	Plasmodium falciparum	Plasmodium vivax
Therapeutic Objective	Chloroquine Sensitive	Chloroquine Resistant	Chloroquine Sensitive	Chloroquine Resistant
Treatment of a moderate attack	Chloroquine	Atovaquone/proguanil OR Artemether/lumefantrine OR Quinine plus either doxycycline, tetracycline, or clindamycin	Chloroquine	Atovaquone/proguanil plus primaquine OR Artemether/lumefantrine plus primaquine OR Quinine plus either doxycycline, tetracycline, or clindamycin plus primaquine OR Mefloquine plus primaquine
Treatment of a severe attack by P. vivax or P. falciparum	Intravenous quinidine gluconate plus either doxycycline, tetracycline, or clindamycin OR Intravenous artesunate^† followed by either atovaquone/proguanil, doxycycline, or mefloquine
Relapse prevention	NA^‡	NA^‡	Primaquine	Primaquine
Prophylaxis	Chloroquine	Atovaquone/proguanil, doxycycline, or mefloquine	Chloroquine	Atovaquone/proguanil, doxycycline, or mefloquine

^*All drugs are given orally except where noted otherwise.

^†Artesunate is available from the Centers for Disease Control and Prevention.

^‡Not applicable. Malaria caused by P. falciparum does not relapse following successful treatment of the acute attack.

Treatment of acute attacks.

For mild to moderate malaria, oral therapy is employed. Chloroquine is the drug of choice for an acute attack caused by chloroquine-sensitive strains of P. falciparum or P. vivax. As a rule, a 3-day course of treatment produces clinical cure. For strains of P. falciparum or P. vivax that are chloroquine resistant, quinine is a drug of first choice, combined with either doxycycline, tetracycline, or clindamycin. Malarone, a fixed-dose combination of atovaquone plus proguanil, is an effective alternative. Mefloquine may also be used, but is considered less desirable owing to concerns about neuropsychiatric effects.

For severe malaria caused by P. falciparum or P. vivax, parenteral therapy is required. In the United States, only one drug—quinidine gluconate—is approved by the Food and Drug Administration (FDA) for parenteral use in malaria. When used for severe malaria, IV quinidine should be combined with doxycycline, tetracycline, or clindamycin. An alternative to quinidine, known as artesunate, is recommended by the World Health Organization. Unfortunately, artesunate is not commercially available here, although it can be obtained by special request from the Centers for Disease Control and Prevention (CDC).

Prevention of relapse.

The agent of choice for preventing relapse of vivax malaria is primaquine, a drug that is highly active against the hepatic forms of P. vivax. For falciparum malaria, no treatment is needed, since relapse does not occur following clinical cure.

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Jul 24, 2016 | Posted by admin in NURSING | Comments Off

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