Pharmacology - An Illustrated Review

31. Antifungal and Antiparasitic Drugs

A human fungal infection, termed a mycosis, is related to either true fungal agents that possess virulence factors capable of avoiding the host defense or opportunistic fungi that thrive in a compromised immune system. Fungi are eukaryotic, but their cell membrane contains ergosterol instead of cholesterol that is present in the mammalian cell membrane. It is this unique cell membrane that allows for the selective toxicity of antifungal agents. The cell wall of fungi contains chitin and complex polysaccharides.

Pathogenic fungal forms

Pathogenic fungi are able to grow in two forms: filamentous and yeasts, depending on the growth conditions. Filamentous, or mold, forms grow as branching, threadlike filaments called hyphae. Several hyphae are collectively referred to as a mycelium. The hyphae may be septate, that is, divided by partitions, or coenocytic, with no partitions but a multinucleate hyphal structure. Yeasts grow as single cells that are ovoid or spherical and divide by budding or, rarely, by binary fission like bacteria. The ability to switch from one form to another is termed dimorphism and, with some fungi, correlates to a switch from free living to infectious organism.

 

Fungal reproduction

Fungi generally are capable of reproduction by asexual or sexual means. Asexual reproduction usually refers to the formation of spores, which show resistance to environmental conditions. Spores may be thallospores, which are produced from cells of the body of the fungus, or conidia, which are produced from specialized structures. Sexual reproduction occurs when two haploid nuclei come together in a single cell. The nuclei are combined to become diploid. Meiosis occurs and results in genetic exchange. Division then results in four haploid progeny nuclei.

 

31.1 Drugs Used in the Treatment of Fungal Infections

Polyene Antifungals

Mechanism of action. Polyene antifungals are named for large numbers of unsaturated bonds in their chemical structures. These drugs permeate into ergosterol-rich membranes (characteristic of fungi), where they produce a detergent-like effect (Fig. 31.1).

Nystatin

Pharmacokinetics

– Nystatin is available in tablets and suspensions for topical application. It is not absorbed after oral administration.

– It is highly toxic and is not used parenterally.

Uses

– Candida infections of the mouth or the gastrointestinal (GI) tract

Amphotericin B

Pharmacokinetics. This agent is ineffective after oral administration; therefore, it is given intravenously (IV).

Spectrum. Amphotericin B has a broad antifungal spectrum and is useful for most systemic fungal infections.

Uses

– Serious systemic fungal infections (use limited by toxicity)

Side effects

– Renal toxicity

Imidazole Antifungal Agents

Mechanism of action. Imidazole antifungal agents interfere with cytochrome P-450−dependent biosynthesis of ergosterol, causing disorganization of the fungal cell membrane (Fig. 31.1). These agents have a broad spectrum of activity against pathogenic fungi. They may also inhibit several cytochrome P-450−dependent drug oxidations in patients, leading to drug interactions.

Miconazole and Clotrimazole

Pharmacokinetics

– Topical use only

Uses

– Superficial tinea (ringworm) infections and vulvovaginal candidiasis

– Treatment of oral and esophageal candidiasis; prophylaxis against oral candidiasis in immunosuppressed patients (clotrimazole lozenges)

Fig. 31.1 image Antifungal drugs.

Imidazole derivatives inhibit the synthesis of ergosterol, an integral component of fungal cell membranes. Polyene antibiotics insert themselves into fungal cell membranes and cause the formation of hydrophilic channels. Flucytosine is an antimetabolite that is converted to 5-fluorouracil in candidal fungi by fungal cytosine deaminase. It is then incorporated into fungal DNA, causing disruption of DNA and RNA synthesis. Caspofungin inhibits fungal cell wall synthesis. Griseofulvin is active only against dermatophytes. It seems to inhibit fungal mitosis by acting as a spindle poison.

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Side effects. Vaginal preparations may cause vaginal or stomach discomfort.

Ketoconazole

Pharmacokinetics. Ketoconazole has erratic oral absorption. It is dependent on GI pH.

Uses. Use has declined due to erratic absorption, toxicity, and availability of other agents.

Side effects

– Fatal hepatic toxicity; adverse cardiac events when taken with terfenadine, astemizole, or cisapride

Tetrazole Antifungal Agents

Mechanism of action. The tetrazole drugs are chemically related to imidazoles and also act by inhibiting ergosterol biosynthesis by fungal cytochrome P-450 enzymes.

Fluconazole

Pharmacokinetics

– Eliminated in the urine; dosage modifications are necessary in cases of renal insufficiency

– Can penetrate into cerebrospinal fluid (CSF)

Uses. Useful for a variety of systemic fungal infections, including

– Candidiasis

– Cryptococcosis

– Especially useful for cryptococcal meningitis (due to CSF penetration)

Itraconazole

Pharmacokinetics

– Unlike fluconazole, itraconazole is cleared by hepatic metabolism.

Uses

– Similar to fluconazole in its properties and indications

Other Antifungals

Flucytosine

Mechanism of action. Fungi metabolize the drug to its active form, 5-fluorouracil (Fig. 31.1), which inhibits fungal DNA and RNA synthesis.

Pharmacokinetics

– Orally effective

Uses

– Systemic Candida or Cryptococcus infections, often in combination with amphotericin B

Side effects. Patients must be monitored carefully for hematologic, renal, and hepatic function.

Griseofulvin

Mechanism of action. Griseofulvin inhibits fungal cell mitosis.

Pharmacokinetics

– Given orally

Uses

– Used when itraconazole and terbinafine are contraindicated (e.g., hypersensitivity or liver disease)

– Persistent ringworm (tinea) infections, but prolonged administration is required

Side effects

– May include GI disturbances, central nervous system (CNS) abnormalities, and skin rashes

Terbinafine

Mechanism of action. This agent inhibits squalene epoxidase, a key enzyme in sterol biosynthesis.

Pharmacokinetics

– Given orally or topically

Uses

– Onychomycosis (nail infections) that are difficult to treat with other agents

Side effects

– After oral administration: hypersensitivity rash; increased liver enzymes; rare cases of liver failure

Echinocandins

Caspofungin, Micafungin, and Anidulafungin

Mechanism of action. These agents block the synthesis of β (1,3)-D-glucan, a polysaccharide component of the cell wall in many pathogenic fungi.

Spectrum

– Fungicidal against Candida and Aspergillus species

Uses

– Fluconazole-resistant candidiasis, aspergillosis

Side effects. These agents are generally well tolerated, but side effects may include

– Fever

– Elevated liver enzymes

– Anemia

– Occasional maculopapular rash

31.2 Drugs Used in the Treatment of Protozoan Infections

Amebicidal Drugs (Entamoeba histolytica)

Entamoeba histolytica is an intestinal protozoan. Most infections are asymptomatic but may lead to clinical syndromes ranging from dysentery to abscesses of the liver or other organs.

Metronidazole

Mechanism of action. Metronidazole has a direct amebicidal effect and acts by inhibiting a unique electron transfer system of a variety of anaerobic organisms.

Pharmacokinetics

– Orally effective

Uses

– Systemic and intestinal forms of amebiasis except for asymptomatic cyst carriers

– Useful for trichomoniasis and giardiasis

Side effects

– Nausea, vomiting, and headache

– Seizures

— Ataxia

– Leucopenia

– Alcohol intolerance (disulfiram-like reaction [see page 121]) has been reported.

Contraindications

– Pregnancy

Iodoquinol (Diiodohydroxyquinoline)

Spectrum. Iodoquinol is directly amebicidal to trophozoites and cysts.

Uses

– Used only for intestinal amebiasis

Side effects

– GI disturbances

– Neurotoxic effects: headache in the short term; peripheral neuropathy with higher doses in the longer term

– Thyroid enlargement

Paromomycin

Paromomycin is a poorly absorbed aminoglycoside antibiotic.

Spectrum. In addition to eliminating intestinal bacteria, paromomycin directly kills trophozoites and intestinal cestodes.

Uses

– Mild intestinal disease

The occurrence of protozoan infections in the United States is relatively rare, but it can be seen in immigrants or those returning from travel overseas. Protozoan organisms, the diseases they cause, and the drugs of choice are included in Table 31.1.

  Table 31.1 image Treatment of Protozoan Infections

Organism

Disease

Drug(s) of Choice

Entamoeba histolytica

Amebiasis

Metronidazole (pages 304 and 326)

Cryptosporidium parvum

Cryptosporidiosis

Nitazoxanide

Giardia lamblia (Giardia duodenalis)

Giardiasis

Metronidazole (1), quinacrine (2)

Leishmania braziliensis, Leishmania mexicana, and other species

Leishmaniasis

Sodium stibogluconate

Pneumocystis jiroveci

Pneumocystosis

Trimethoprim + sulfamethoxazole (1) (pages 302304310, and 330)

Trichomonas vaginalis

Trichomoniasis (a sexually transmitted protozoan infection)

Metronidazole (pages 304 and 326)

Toxoplasma gondii

Toxoplasmosis

Pyrimethamine + sulfadiazine (pages 303 and 331332)

Trypanosoma

South American trypanosomiasis (Chagas disease)

Nifurtimox

 

African sleeping sickness

Early stage: pentamidine (1), suramin (2)

Late stage: melarsoprol (an organic arsenical)

1, first-line agent; 2, second-line agent.

Note: Page references in parentheses indicate sites of fuller discussions of these agents.

Antimalarial Drugs

Malaria is one of the most common protozoan infections. It is caused by Plasmodium species that are transferred into the bloodstream via the bite of infected mosquitoes. Symptoms include interspersed bouts of fever and chills. The disease is most commonly found in tropical and subtropical climates.

The Plasmodium species involved include

— P. vivax, P. ovale, and P. malariae, which have erythrocytic and tissue (exoerythrocytic) cycles

— P. falciparum, which has no tissue cycle

Chloroquine

Mechanisms of action. Growth of malarial parasites in host erythrocytes requires digestion of hemoglobin in their acidic food vacuoles. This produces heme, which is normally crystallized to a nontoxic form. Free heme is highly reactive and toxic to the parasite. Chloroquine accumulates in the digestive vacuoles and prevents detoxification of heme, leading to increased free heme and parasite death. Chloroquine also has an antiinflammatory effect (Fig. 31.2).

Spectrum. Chloroquine kills erythrocytic forms of P. falciparum but is not effective on liver forms.

Pharmacokinetics

– It is rapidly and almost completely absorbed after oral administration.

– It accumulates in the liver (which suggested its use for hepatic amebiasis) and is slowly excreted.

Uses

– Malaria prophylaxis and treatment

– Rheumatoid arthritis (see p. 356)

Side effects

– Toxicity is dose related, ranging from GI distress, rashes, and headache to ocular toxicity (retinopathy and corneal deposits, which suggest a “bull's-eye”) and CNS hyperexcitability.

– Methemoglobinemia and hemolytic anemia can occur in individuals with a genetic deficiency of glucose-6-phosphate dehydrogenase (G6PD) deficiency (see page 27).

Primaquine

Mechanism of action. The mechanism of action of primaquine is unclear.

Spectrum. Primaquine can destroy exoerythrocytic, liver-lurking forms and is gametocidal.

Pharmacokinetics

– Rapidly absorbed after oral administration and metabolized to active forms by the liver

Side effects

– Mild toxicity includes anorexia, nausea, vomiting, and cramps.

– In individuals with G6PD deficiency, methemoglobinemia and hemolytic anemia can occur.

Methemoglobinemia

Methemoglobinemia is a condition in which there are higher levels of methemoglobin in the blood than normal. It occurs when the ferrous ion (Fe2+) is oxidized to the ferric state (Fe3+) in red blood cells when they are exposed to exogenous oxidizing drugs and their metabolites. Methemoglobin does not bind oxygen, so people with this condition will show signs of hypoxia, including dyspnea (shortness of breath), dizziness, cyanosis, fatigue, and mental changes. It is treated by giving oxygen therapy and methylene blue, which is a substance that is able to reduce iron in hemoglobin to its normal, oxygen-carrying state.

 

Quinine

Mechanism of action. Quinine is thought to act similarly to chloroquine (Fig. 31.2).

Spectrum

– Effective against erythrocytic forms and not on liver forms

Uses. Quinine is a traditional agent now largely replaced by newer drugs, but it is still useful in drug-resistant strains of P. falciparum.

Fig. 31.2 image Malaria: stages of the plasmodial life cycle in the human, therapeutic options.

A mosquito carrying malaria feeds on human blood and injects a parasite in the form of sporozoites into the bloodstream. The sporozoites travel to the liver and invade liver cells. Sporozoites mature into forms known as schzionts, which divide to form haploid twins called merozoites. Merozoites exit the liver and enter the bloodstream, where they invade erythrocytes and undergo asexual replication. Some merozoites develop into sexual forms of the parasite, called male and female gametocytes, that circulate in the bloodstream. When a mosquito bites an infected human, it ingests the gametocytes, which eventually form sporozoites. Different antimalarials selectively kill different developmental forms of parasites. Chloroquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit the polymerization of heme released from digested hemoglobin. Free heme is toxic to schizonts. Pyrimethamine and proguanil inhibit dihydrofolate reductase, and sulfadoxine inhibits the synthesis of dihydrofolic acid. Atoraquone suppresses the synthesis of pyrimidine bases, probably by interfering with mitochondrial electron transport.

image

Side effects

– Cinchonism (headache, tinnitus, and diplopia)

– Allergic skin rashes

– Hypotension

– Skeletal muscle weakness

– Renal damage

– It can cause intravascular hemolysis in sensitized individuals and also methemoglobinemia and hemolytic anemia in individuals with G6PD deficiency.

Note: All quinine antimalarials (“quines”) possess this genetically determined toxicity.

Mefloquine

Mechanisms of action

– Similar to chloroquine

Spectrum

– Effective against erythrocytic forms and not on liver forms

Pharmacokinetics

– Mefloquine has a long half-life (10–14 days) and is taken as a single dose to treat mild to moderate malaria and once per week as prophylaxis.

Uses

– Used when chloroquine resistance is likely

– Mild to moderate malaria (not for severe cases)

– Malaria prophylaxis

Side effects

– GI distress is the most common.

Atovaquone/Proguanil

Mechanisms of action

– Atovaquone inhibits mitochondrial electron transport of Plasmodium.

– Proguanil inhibits dihydrofolate reductase of Plasmodium.

Spectrum

– Effective against erythrocytic and exoerythrocytic forms

Pharmacokinetics

– Effective orally

– Three doses daily to treat malaria

– Daily as prophylaxis

Uses

– Used for chloroquine-resistant malaria

– Malaria prophylaxis

Side effects

– GI distress is the most common.

– Serum liver enzyme levels increased

Dihydrofolate Reductase Inhibitors

Pyrimethamine, Chloroguanide, and Trimethoprim

Mechanism of action. These agents act slowly by inhibiting dihydrofolic acid reductase and preventing the production of tetrahydrofolic acid (Fig. 31.2).

Spectrum. Erythrocytic and exoerythrocytic forms are inhibited.

Pharmacokinetics

– Pyrimethamine is the most potent and has the longest duration of action.

– Chloroguanide is a prodrug (the active metabolite is cycloguanil) and has the shortest action.

Uses. Use of these agents is limited primarily to treatment of chloroquine-resistant P. falciparum, but many strains are now resistant to dihydrofolate reductase inhibitors as well.

Side effects. These agents can cause weak inhibition of human dihydrofolic acid reductase, which results in megaloblastic anemia. Folinic acid will remedy the anemia without interfering with the chemotherapy.

Resistance. Resistance to one drug usually confers resistance to the others.

31.3 Drugs Used in the Treatment of Metazoan Infections

Treatment of Nematode Infections (Roundworm)

Mebendazole

Mechanism of action. Mebendazole binds to and inhibits tubulin synthesis; it also inhibits glucose uptake and larval development.

Pharmacokinetics

– Largely unabsorbed

Side effects. Side effects are uncommon and include occasional abdominal distress and diarrhea.

Contraindications

– Pregnancy and allergy

Pyrantel

Mechanism of action. Pyrantel is a noncompetitive, depolarizing neuromuscular blocking agent that causes worm paralysis.

Side effects. Some mild and transient GI, CNS, skin, and hepatic reactions may occur.

Thiabendazole

Mechanism of action. Thiabendazole inhibits the mitochondrial fumarate reductase of helminths.

Pharmacokinetics

– Rapidly absorbed

Uses

– Cutaneous larvae migrans (a common tropical skin disease caused by the larvae of various nematode parasites)

Side effects. Side effects are mild and transient and include

– Vomiting, nausea, lethargy, and dizziness. These symptoms are reduced by giving thiabendazole after meals.

– Hepatotoxic higher doses diminish mental alertness.

Piperazine

Mechanism of action. Piperazine produces competitive block of acetylcholine on worm muscle. Worms are paralyzed and eliminated alive.

Side effects

– Mild, transient GI effects and rash

Ivermectin

Mechanism of action. Ivermectin paralyzes worms by actions on gamma-aminobutyric acid (GABA) synapses in the periphery.

Treatment of Cestode Infections (Flatworm)

Praziquantel

Mechanism of action. Praziquantel increases the permeability of cell membranes to Ca2+, causing spastic paralysis of worm muscle followed by disintegration of its tegument.

Spectrum

– Broad

Pharmacokinetics

– Well absorbed and well tolerated

Uses

– Effective for a variety of cestode and trematode infections

Side effects. No major adverse effects have been reported.