Antimicrobial Agents III
ANTIPROTOZOAL DRUGS[edit | edit source]
ANTIMALARIAL DRUGS[edit | edit source]
Four species of Plasmodium are responsible for human malaria: P. vivax and P. ovale that cause three-days malaria; P. malariae (four-days malaria) and P. falciparum (tropical malaria). The transmitter of Plasmodium is mosquito. The sporozoites that develop in the mosquito are then inoculated into humans at its next feeding. In the first stage of development in humans, the exoerythrocytic stage, the sporozoites multiply in the liver to form tissue schizonts. Later, the parasites escape from the liver into the bloodstream as merozoites to initiate the erythrocytic stage. In this stage they invade red blood cells, multiply in them, and finally rupture the cells, releasing a new crop of merozoites. This cycle may be repeated many times. Meanwhile, partly merozoites are transformed in gametocytes (the sexual stage) and they may be taken in by another mosquito, which becomes infected, by taking human blood that contains gametes. In P. vivax and P. ovale infections, sporozoites also induce in hepatic cells the dormant stage (the hypnozoite) that causes subsequent recurrences (relapses) of the infection.
Drugs that eliminate developing tissue schizonts or latent hypnozoites in the liver are called tissue schizonticides (see diagram 3.2). Those that act on blood schizonts are blood schizonticides. Gametocides are drugs that prevent infection of mosquitoes by destroying gametocytes in the human blood. Sporonticidal agents are drugs that act on sporozoites noninfective in the mosquito. For causal malaria prophylactic are used sporonticides and tissue schizonticides (chloridine, bigumale, and primaquine). However, blood schizonticides are prescribed for abortion and prevention of malaria attacks. Gametocides are useful for social chemoprophylaxis of malaria spreading.
Classification of antimalarial drugs
1. Blood schizonticides: chloroquine, mefloquine, quinine, chloridine, bigumale, acriquine, and sulfanilamides.
2. Tissue schizonticides:
a. agents that acts on preerythrocytic forms (tissue schizonts) - chloridine, bigumale, primaquine;
b. agents that active against paraerythrocytic forms (hypnozoites) - primaquine, quinocide.
3. Gametotropic drugs:
a. gametocides drugs - chloroquine, primaquine, quinocide;
b. sporonticidal agents - chloridine, bigumale.
Chloroquine is a synthetic 4-aminoquinoline. Chloroquine is a highly effective blood schizonticide and is most widely used in chemoprophylaxis and in treatment of malaria attacks. It is also moderately effective against gametocytes. Chloroquine act by blocking the synthesis of DNA and RNA in both mammalian and protozoal cells. Within the parasite, the drug interferes with the parasite's ability to metabolize and utilize erythrocyte hemoglobin. Selective toxicity for malarial parasites depends on a chloroquine-concentrating mechanism in parasitized cells. Also chloroquine has anti-inflammatory activity. It has been useful in the treatment of autoimmune disorders and for amebic liver abscess.
It is rapidly and almost completely absorbed from the gastrointestinal tract, reaches maximum plasma concentrations (50-65% protein-bound) in about 3 hours, and is rapidly distributed to the tissues. From tissues it is slowly released and metabolized. It is excreted in the urine with a half-life of 3-5 days. Renal excretion is increased by acidification of the urine. Gastrointestinal symptoms, pruritus, blurring of vision are appear during prolonged treatment of autoimmune diseases. Chloroquine cumulation may contribute to the development of irreversible retinopathy, hepatoxicity, heart disorders.
Chloridine (pyrimethamine) and bigumale (proguanil) are blood schizonticides. Chloridine is a derivative of diaminopyrimidine related to trimethoprim (chapter “Sulfanilamides”). Bigumale is a biguanide derivative. Chloridine and bigumale are dihydrofolate reductase inhibitors (folic acid antagonists, antifols). They have a higher affinity for plasmodial dihydrofolate reductase than the human enzyme. Resistance to them is widespread in certain areas.
Both chloridine and bigumale are slowly but adequately absorbed from the gastrointestinal tract. Chloridine has an elimination half-life 3-4 days and bigumale - 16 hours. Therefore, in prophylaxis, bigumale must be administered daily, whereas chloridine can be given once a week. Chloridine and bigumale are used for personal malaria prophylaxis. Also they are indicated in combination with sulfanilamides or/ and chloroquine in the treatment of malaria. Metakelfin contains chloridine and sulfalen; fansidar includes chloridine and sulfadoxine. Such combination is the example of effect potentiation. Finally, chloridine is used for toxoplasmosis treatment.
Chloridine and biguanide can cause nausea, skin rashes, and alopecia. In the high doses of chloridine used in toxoplasmosis, side effects of folic acid deficiency (megaloblastic anemia, agranulocytosis, and thrombocytopenia) are common. Also in high doses, neurologic symptoms (headache, insomnia, depression, ataxia, tremors, and seizures) may occur. Because chloridine is teratogenic in animals, it should be avoided during the first trimester. Bigumal is considered safe in pregnancy.
Mefloquine is used in prophylaxis and treatment of chloroquine-resistant and multidrug-resistant malaria. Mefloquine hydrochloride is a synthetic 4-quinoline methanol derivative chemically related to quinine. It is well absorbed. The drug is highly bound to plasma proteins and concentrated in red blood cells. Its elimination half-life varies from 13 days to 33 days. Mefloquine is used one time for malaria treatment and once a week for prophylaxis. Drug may leads to gastrointestinal disturbances, headache, and dizziness. In high doses visual disturbances can occur.
Primaquine is a synthetic 8-aminoquinoline derivative. It is active against the primary exoerythrocytic stages and late hepatic stages of Plasmodium. Primaquine is gametocidal against the four malaria species. The mechanism of action based on primaquine's ability to bind to and alter the properties of DNA. At high doses, it may suppress myeloid activity. After oral administration, the drug is usually well absorbed, and then is almost completely metabolized and excreted in the urine. Its plasma half-life is 3-8 hours. Primaquine is widely distributed to the tissues, but only a small amount is bound there. It infrequently causes nausea, epigastric pain, abdominal cramps, and headache. The more serious adverse effects, leukopenia and methemoglobinemia (manifested by cyanosis) are rare. Primaquine may cause hemolysis in persons with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Quinocide is similar in structure and function to primaquine.
Quinine, the principal alkaloid derived from the bark of the cinchona tree, has been used in malaria suppression and treatment for more than 300 years. Although superseded by other antimalarials, following the development of widespread resistance to chloroquine and other drugs, quinine has again become an important antimalarial. Quinine is a rapidly acting, highly effective blood schizonticide. The mechanism of action based on quinine's ability to bind to and alter the properties of DNA. Agent is rapidly absorbed and is widely distributed in body tissues. When taken orally, quinine commonly causes gastric irritation. The drug causes hypersensitivity reactions, myocardial depression and slight increasing of the uterus tonus. A less common effect is cinchonism that includes headache, slight visual disturbances, dizziness, and mild tinnitus. Hemolysis may occur in G6PD-deficient persons.
Acriquine (quinacrine) a 9-aminoacridine, is a blood schizonticide that can effectively suppress all four types of human malaria. The mechanism of action based on acrichine's ability to bind to and alter the properties of DNA. Nowadays acrichine superseded by chloroquine. Its disadvantages include occasional drug deposits that turn the skin yellow and rare psychotic reactions. However, acrichine is indicated in the treatment of lambliasis (giardiasis), leishmaniasis, and cestodosis.
TREATMENT OF AMEBIASIS[edit | edit source]
Amebiasis is infection by the protozoan parasite Entamoeba histolytica. Usually it is lead to amebic dysentery that associated by ulcerative inflammation of the colon. It also may be associated with amebic infection of other organs (liver, lungs). The choice of drug depends on the desired site of drug action, i.e., in the intestinal lumen or in the tissues.
Classification of antiamebic agents
1. Luminal amebicides. These agents are act primarily in the bowel lumen: quiniofone, chlorchinaldole.
2. Agents that act against amebas in the bowel wall and lumen: tetracyclines.
3. Agents that act against amebas in the bowel wall and in liver: emetine.
4. Agents that act against amebas in the liver: chloroquine.
5. Agents that act in any ameba’s localization: metronidazole.
Metronidazole is the drug of choice in treatment of intestinal and extraintestinal amebiasis. The mechanism of action and the pharmacologic features of metronidazole have been discussed in chapter “Imidazole derivatives”. However, it is only partially effective and not adequate as luminal amebicides. That’s why, for amebic dysentery treatment metronidazole is used concurrently with luminal amebicides.
Quiniofone is the derivative of 8-oxyquinolines (see chapter “8-oxyquinolines”). Agent is effective against organisms in the bowel lumen but not against trophozoites in the intestinal wall or extraintestinal tissues. Ninety percent of the drug is not absorbed. Thus, it produces a high amebicidic concentration in lumen. Quinifone is a drug of low toxicity, but still it may cause diarrhea, optic neuritis, and peripheral neuropathy. Intetrix, derivative of 8-oxyquinolines, is a patented drug. One tablet of intentrix includes two active substances, which are similar to chlorchinaldole. It is highly active against both gram-positive and gram-negative microbes in bowel. Also, intetrix is antiamebic and antifungal drug.
Emetine is the alkaloid of ipecacuanha root. It acts on organisms in the bowel wall and other tissues but not on amebas in the bowel lumen. Emetine blocks the synthesis of protein in ameba. The agent is administered parenterally, because oral preparation is absorbed erratically, and may induce vomiting. When given parenterally, it is stored primarily in the liver, lungs, and kidneys. The drug is cumulative; it is eliminated slowly via the kidneys more than month. Serious toxicity is common if they are given for more than 10 days. Therefore, use of this drug for more than 7-8 days is contraindicated. Hospitalization with careful supervision is essential. Pain in the area of the injection is frequent. Nausea and vomiting, which occur infrequently, are thought to be central in origin. The most serious symptoms are depression of cardiac conduction and contraction, which may cause a variety of atrial and ventricular arrhythmias, heart failure, and hypotension. Generalized muscular weakness (tenderness, stiffness, aching, or tremors), paresthesia are often reported. It should not be used during pregnancy.
The oral tetracyclines indirectly affect luminal amebas by inhibiting the bacterial associates of E. histolytica in the bowel lumen. Thus, the contents of oxygen in bowel enhance that is harmful for ameba existing.
ANTILEISHMANIC DRUGS[edit | edit source]
Infection with a species of Leishmania resulting in a clinically ill-defined group of diseases may be divided into two types: visceral leishmaniasis (kala azar) and cutaneous leishmaniasis. Transmission is by various sandfly species. Treatment of leishmaniasis is not satisfactory because of drug toxicity, the long courses required, treatment failures, and the frequent need for hospitalization.
The drugs of choice for visceral leishmaniasis are pentavalent antimony compounds (solusurmine, sodium stibogluconate). Solusurmine is frequently used drug. It binds with thyolic group of leishmania enzymes that lead to their inactivation. Solusurmine is injected i.v. The duration of treatment is about 3-4 weeks. The adverse effects are nausea, headache, skin rashes, and leukopenia. Hypotonia; liver, renal, and heart damages may appear. In case of solusurmine overdosing unithiol can be prescribed. Sodium stibogluconate can be administered i.m. or i.v. Most common adverse effects are gastrointestinal symptoms and rash. For cutaneous leishmaniasis are useful: acriquine or chloroquine (chapter “Antimalarial drugs”), aminoquinole, monomycin (chapter “Antibiotics”), amphotericin B (chapter “Antifungal drugs”). Aminoquinole is the quinoline derivative. It is effective in the treatment of cutaneous leishmaniasis as well as toxoplasmosis, lambliasis, and collagen diseases. Amioquinole is well-tolerated, sometimes gastrointestinal disturbances, headache and allergic reactions may appear.
ANTILAMBLIAL DRUGS[edit | edit source]
Lambliasis (giardiasis) is infection caused by protozoan parasite Giardia lamblia that may cause diarrhea, dyspepsia, and occasionally malabsorption in humans. For lambliasis treatment can be used metronidazole (see “Imidazole derivatives”), furazolidone (“Nitrofurane derivatives”), and aminoquinoline.
ANTITRICHOMONADAL DRUGS[edit | edit source]
Trichomoniasis caused by infection with a species of protozoan of the genus Trichomonas; often used to designate trichomoniasis vaginitis. For trichomoniasis treatment can be prescribed metronidazole, trichomonocide, and furazolidone. Trichomonocide is a relative of aminoquinole. It can be taken locally or orally. It has irritate potency. Osarsole, arsenic compound, is seldom used for topical treatment of trichomoniasis.
ANTITOXOPLASMOSIS AGENTS[edit | edit source]
Toxoplasmosis caused by the protozoan parasite Toxoplasma gondii that can produce a variety of syndromes in humans, such as fever, encephalomyelitis, retinopathy, maculopapular rash, myalgia, myocarditis, and lymphadenopathy. For its treatment can be taken chloridine (“Antimalarial agents”), sulfanilamides. During pregnancy sulfanilamides are prefer.
ANTHELMINTIC DRUGS[edit | edit source]
Anthelmintic drugs are used to eradicate or reduce the numbers of helminthic parasites in the intestinal tract or tissues of the body.
According to their localization helminths can be divided into intraintestinal and extraintestinal groups. Also helminths are distinguished as nematodes (roundworms) and platyhelminthes (flatworms). The last one includes cestodes (tapeworms) and trematodes (flukes, sucklings). Most anthelmintics in use today are active against specific parasites. Therefore, parasites must be identified before treatment is started, usually by finding the parasite or eggs in the feces, urine, blood, sputum, or tissues of the host.
Mebendazole (vermox) is a synthetic benzimidazole that has a wide spectrum of anthelmintic activity. It has been approved for use in ascaridosis, trichocephalosis, ancylostomidosis, and enterobiosis. In the treatment of trichinellosis and echinococcosis the drug should be taken with food containing fat, which enhances absorption. Mebendazole inhibits glucose uptake by parasites, decreasing formation of ATP. As a result, intestinal parasites are immobilized or die slowly. Less than 10% of orally administered mebendazole is absorbed. The absorbed drug is rapidly metabolized in the liver. Within 24-48 hours, it is excreted mostly in the urine, either unchanged or as metabolites. A dosage of 100 mg twice daily for 3 days is used for adults. Treatment can be repeated in 2-3 weeks. Cure rates are 90-100% for ascaridosis and trichocephalosis. Mebendazole has a low incidence of adverse effects. Rash, nausea, vomiting, diarrhea, and abdominal pain have been reported infrequently. The drug is contraindicated during pregnancy.
Albendazole is similar in structure and activity with mebendazole. It is also the drug of choice in echinococcosis and cysticercosis. Agent rapidly undergoes first-past metabolism in the liver to active metabolite. In large part, it binds to protein and is distributed to the tissues, including bile and cerebrospinal fluid, and enters hydatid cysts. When used for 1-3 days, albendazole infrequently may cause nausea, diarrhea, headache, dizziness, and insomnia. In 3-month treatment courses for echinococcosis rash or pruritus, leukopenia were observed. Because the drug is teratogenic and embryotoxic in some animal species, it should not be used in pregnancy.
The piperazine adipinate is alternative drug in the treatment of ascaridosis. Cure rates are over 90% when patients are treated for 2 days. Also it can be used for enterobiosis treatment. Piperazine causes paralysis of nematodes by blocking acetylcholine at the myoneural junction. Thus, the paralyzed roundworms are unable to maintain their position in the host and are expelled live by normal peristalsis. No pre- or posttreatment cathartics are used. Mild adverse effects occur occasionally, including nausea, diarrhea, abdominal pain, and headache. Patients with epilepsy may have an exacerbation of seizures.
Pyrantel (combantrin) is a broad-spectrum anthelmintic highly effective for the treatment of enterobiosis, ascaridosis, and ancylostomidosis. Cure rates are greater than 95%. The drug causes stimulation of ganglionic receptors and worm paralysis, which is followed by expulsion from the host's intestinal tract. Because it is poorly absorbed from the gastrointestinal tract, it is active mainly against luminal organisms. Adverse effects are infrequent and mild. They include vomiting, diarrhea, abdominal cramps, dizziness, headache, insomnia, and rash.
Levamisole is highly active for the ascaridosis treatment. It causes contracture of Ascaris that follows by it paralysis. In addition, levamisole inhibit a succinate dehydrogenase (essential enzyme) of helminth. Agent is rapidly absorbed from gastrointestinal tract. The levamisole half-life is about 3 to 4 hours. It is eliminated mostly via kidney (70% over 3 days). Levamisole is a single dose drug for ascaridosis treatment. Also levamisole has immunomodulating properties. Side effects of levamisole are usually mild and transitory. It may lead to gastrointestinal disturbances and leukopenia.
Naphthammone (bephenium) primarily has been approved for use for ancylostomidosis treatment. It is less useful in the treatment of ascaridosis, trichocephalosis, and enterobiosis infection. Naphthammone causes contracture of nematodes that follows by their paralysis. The agent is badly absorbed in the gastrointestinal tract. There are special tablets of naphthammone, which are dissolved in lower part of small intestine – in the basic place of Ancylostoma localization. Nausea, vomiting, and diarrhea can appear in the period of naphthammone using.
Praziquantel is effective in the treatment of schistosome infections of all species and most other trematode and cestode infections, including cysticercosis. The drug's safety and effectiveness as a single oral dose have also made it useful in mass treatment of several of the infections. Praziquantel is a synthetic isoquinoline derivative. Praziquantel increases cell membrane permeability to calcium, resulting in marked contraction, followed by paralysis of worm musculature. It is rapidly and well absorbed after oral administration. Cerebrospinal fluid and bile concentrations of praziquantel reach 14-20% of the drug's plasma concentration. Most of the drug is rapidly metabolized to inactive products; the half-life of the drug is 0.8-1.5 hours. Excretion is mainly via the kidneys (60-80%). The adverse effects are headache, nausea, vomiting, abdominal pain, loose stools, and myalgia. The only specific contraindication is ocular cysticercosis; parasite destruction in the eye may cause irreparable damage. Because the drug induces dizziness and drowsiness, patients should not drive and should be warned if their work requires physical coordination or alertness.
Phenasale (niclosamide) is a drug of choice for the treatment of most tapeworm infections. It appears to be minimally absorbed from the gastrointestinal tract. Scoleces and segments of cestodes are rapidly killed on contact with phenasale due to the drug's inhibition of oxidative phosphorylation. With the death of the parasite, digestion of scoleces and segments begins. A single 2 g dose of phenasale results in cure rates of over 85% for Diphyllobothrium latum and about 95% for Taenia saginata. Phenasale should be given in the morning on an empty stomach. The tablets must be chewed thoroughly and are then swallowed with water. Posttreatment purges to expel the worm are not necessary. Two hours after Taenia solium treatment an effective purge (such as 15-30 g of magnesium sulfate) should be given to eliminate all mature segments before ova can be released, that will prevent cysticercosis. Adverse effects are infrequent, mild, and transitory. Nausea, vomiting, diarrhea, and skin rash may occur.
Aminoacrichine is relative of acrchine (see “Antimalarial drugs”). It has been used for the treatment of diphyllobothriosis, hymenolepiosis, and taeniosis, however it less effective agent than phenasale and praziquantel. In addition, aminocrichine is used for the treatment of trichomoniasis vaginitis. It has high irritate potency, thus after ingestion aminocrichine can cause stomachache, nausea, and vomiting.
Ditrazine citras (diethylcarbamazine citras) is a drug of choice in the treatment filariatosis (wuchereriasis, loiasis). It alters microfilariae surface structure, making them more susceptible to destruction by host defense mechanisms. Adult parasites are killed more slowly. Ditrazine is rapidly absorbed from the gastrointestinal tract. Adverse reactions may caused by to the agent itself and also occur as a result of the release of foreign proteins from dying worms in sensitized patients. For instance, headache, weakness, anorexia, nausea, vomiting, dizziness, and sleepiness have observed. Antihistamines may be given for the first 4-5 days of ditrazine therapy to reduce the incidence of allergic reactions.
Ivermectin also indicated for filariatosis (onchocercosis) treatment. In comparison studies, ivermectin is more effective than ditrazine. Ivermectin appears to paralyze nematodes by intensifying GABA-mediated transmission of helminths. Ivermectin is given only orally. The drug is rapidly absorbed; it has a wide tissue distribution. It apparently enters the eye slowly and to a limited extent. The adverse effect of ivermectin includes the reaction which caused by killing of microfilariae: fever, headache, dizziness, weakness, rash, diarrhea, joint and muscle pains, hypotension, lymphadenitis, and peripheral edema.
Chloxyle is the drug of choice for the treatment of fasciolosis and opisthorchosis. The agent is slowly absorbed from gastrointestinal tract; mainly it excreted with feces. Two days before and during treatment fat-food and alcohol are prohibited for patients. It has been taken 2 g of chloxyle powder every 10 minutes (total dose – 10 g). Adverse effects are drowsiness, pain in liver region, arrhythmia, and hypersensitivity reactions.
Bithionol is the drug of choice for the treatment of fasciolosis. The agent is well absorbed in gastrointestinal tract. Excretion appears to be mainly via the kidney. Adverse effects are generally mild. Diarrhea and abdominal cramps are most common. Anorexia, nausea, vomiting, dizziness, and headache may also occur.
Antimony sodium tartrate was for many years the principal drugs for the treatment of schistosomosis, but because of it toxicity and difficulty of administration, using of antimony sodium tartrate is limited. Adverse effects are strong vomiting, skin rashes, arthralgia, and anaphylactic reactions. In case of overdosing, unithiol is indicated. Niridazole is the drug of choice for the treatment of schistosomosis. It is readily absorbed orally. The most frequent adverse effects are neurotoxicity (dizziness, headache, drowsiness), gastrointestinal disorders, and allergic reactions.
ANTIFUNGAL AGENTS[edit | edit source]
Antifungal agents can be divided into three main groups. They are the next -
1. Agents for the treatment of system mycosis (histoplasmosis, blastomycosis, coccidomycosis) - amphotericin B, amphoglucamine, mycoheptine, azole derivatives.
2. Agents for the treatment of dermatomycosis (epidermophytya, microsporya, and trichophytya):
a) antibiotic – griseofulvin;
b) azole derivatives - miconazole, itraconazole and fluconazole;
c) derivatives of undecylenic acid (“Zincundane”, “Undecine”);
d) different chemical groups representatives – terbinafine, octicyle, nitrofungin, and iodine including agents.
3. Agents for the treatment of candidamycosis:
a) antibiotics – nystatin, levorin;
b) other agents – clotrimazole, decamine.
Amphotericin B is a polyene antifungal antibiotic produced by Streptomyces nodosus. It remains the drug of choice for nearly all life-threatening mycotic infections. Amphotericin B is selective in its fungicidal effect. The agent binds to ergosterol, a cell membrane sterol, and alters the permeability of the cell by forming pores in cell membrane. The pore allows the leakage of intracellular ions and macromolecules, eventually leading to cell death. Amphotericin B is poorly absorbed from the gastrointestinal tract; thus it is used intravenously. The serum half-life is approximately 15 days. The drug is widely distributed in tissues, but only 2-3% of the blood level is reached in cerebrospinal fluid, thus occasionally necessitating intrathecal therapy for certain types of fungal meningitis. Anemia, hypokalemia, renal function impairment are the most significant toxic reactions. Fever, muscle spasms, vomiting, and hypotension can appear during infusion of the drug. Amphotericin B should be given only to hospitalized patients, so as to provide constant supervision by a physician.
Amphoglucamine is a synthetic derivative of amphotericin B. It is well absorbed from gastrointestinal tract and less toxic than parental agent. Mycoheptine is similar in structure and function to amphotericin B.
Azoles are synthetic compounds that can be classified as either imidazoles or triazoles. The imidazoles consist of ketoconazole, miconazole, and clotrimazole. The triazoles include itraconazole and fluconazole. The antifungal activity of azole drugs results from the reduction of ergosterol synthesis. The effect is fungistatic or may be fungicidal, depending on agent concentration. The most common adverse reaction is relatively minor gastrointestinal upset. All azole drugs inhibit the mammalian cytochrome P450 system of enzymes to some extent. For instance, the metabolism of cumarine anticoagulants, oral antidiabetic drugs and diphenine in liver will slow down; thus the therapeutic effects of those agents will enhance and prolong.
Miconazole can be used in enteral way or i.v. in the treatment of systemic (endemic) mycoses. Also it is useful for local treatment of dermatomycosis (dermatophytosis, tinea) and candidamycosis. The adverse effects are burning and redness of skin, rash, or other sign of skin irritation, thrombophlebitis in site of injections. The systemic using of miconazole is prohibited during pregnancy and hepatitis. Ketoconazole is prescribed for oral and topical usage. The agent is variable absorbed from intestine; the serum half-life is 7-8 hours. Ketoconazole has the same indication as miconazole, however ketoconazole is more toxic. Ketoconazole inhibition of human cytochrome P450 enzymes interferes with biosynthesis of adrenal and gonadal steroid hormones, producing endocrine effects such as gynecomastia, infertility, and menstrual irregularities.
Itraconazole is available in an oral formulation. Like ketoconazole, its absorption is increased by low gastric pH and it poorly penetrates into the cerebrospinal fluid. Itraconazole is the most potent of the available azoles. It is the azole of choice in the treatment of dermatomycosis, systemic mycoses. It interacts with hepatic microsomal enzymes to a lesser degree than ketoconazole. Fluconazole is distinguished from the other azole medications by good cerebrospinal fluid penetration and excellent bioavailability by the oral route. That’s why, it is the azole of choice in the treatment of mycotic meningitis. It is also effective for mucocutaneous candidamycosis. Fluconazole has the least effect on hepatic microsomal enzymes. As a result, this drug has a wide therapeutic window, which permits more aggressive dosing than with any other azole.
Griseofulvin is a fungistatic drug derived from a species of Penicillium. Its only use is in the systemic treatment of dermatomycosis. Griseofulvin inhibits the synthesis of mycotic nucleic acids. Absorption is variable and improved being given with fatty foods. Griseofulvin is deposited in newly forming skin where it binds to keratin, protecting the skin from new infection. It must be administered for 2-6 weeks for skin and hair infections to allow the replacement of infected keratin by the resistant structures. The serum half-life is approximately 24 hours. Adverse effects are diarrhea, nausea, headache, dizziness, insomnia, allergic reactions, and hepatitis. Griseofulvin is not recommended during pregnancy since it has been shown to be embryotoxic and teratogenic in rats.
Terbinafine, a fungicidal agent, is used in the treatment of dermatomycosis, especially onychomycosis. It is available in an oral formulation. Like griseofulvin, terbinafine is a keratophilic medication. It inhibits the ergosterol biosynthesis. One tablet given daily for 12 weeks achieves an up to 90% cures rate for onychomycosis and is more effective than griseofulvin or itraconazole. Adverse effects are rare, consisting primarily of gastrointestinal upset and headache.
Undecylenic acid and undecylenate salts (e.g., ointments “Zincundane”, “Undecine”) are topical antidermatomycosis agents. The drugs usually are used in combination. Preparations containing the drugs are applied topically twice daily after cleansing the affected area. In addition, iodine including agents, nitrofungin, and octicyle are indicated for the topical treatment of dermatomycosis.
Nystatin is active against most Candida species and is most commonly used for suppression of local candidal infections. Some common indications include oropharyngeal thrush, gastrointestinal and vaginal candidiasis, and skin candidal infections. Candida, a species ordinarily a part of humans normal gastrointestinal flora, but which becomes pathogenic when there is a disturbance in the balance of flora or in debilitation of the host from other causes. Nystatin is a polyene antibiotic much likes amphotericin B and has the same pore-forming mechanism of action. It is currently available in tablets, ointments, and suppositories for application to skin and mucous membranes. Nystatin is not absorbed from gastrointestinal tract. As a result, it produces a high antifungal concentration at intestine. Nystatin has a little significant toxicity. Sometimes, it can cause gastrointestinal disturbances (diarrhea, nausea or vomiting, stomach pain). Levorin is similar in mechanism of action and indications to nystatin. It has higher anticandidamycosis activity, than nystatin. However, levorin is more toxic.
For candidamycosis treatment as well are used clotrimazole, decamine. Clotrimazole, an imidazole derivative, is active against Candida species and dermatophytes. In connection with it high toxicity, clotrimazole is now used only in topical therapy. Decamine (dequalinium), a quaternary ammonium compound, possess antibacterial and antifungal (Candida, dermatophytes) activity. It can be prescribed in ointment or caramel. The last one has to be taken under the tongue or beyond of cheek. Decamine is well-tolerated agent.
ANTIVIRAL AGENTS[edit | edit source]
Viruses are obligate intracellular parasites; their replication depends primarily on synthetic processes of the host cell. Consequently, antiviral agents must be active inside the host cell. Nonselective inhibitors of virus replication may interfere with host cell function and produce toxicity.
According to the chemical structure, antiviral agents are classificated as:
a. synthetic agents - analogs of nucleosides (acyclovir, idoxuridine, ribamidil, zidovudine), amantadine derivatives (rimantadine), and different chemical groups representatives (oxolin, florenal);
b. biological preparations – interferons.
Acyclovir is an acyclic guanosine derivative with clinical activity against herpes simplex viruses and against varicella-zoster virus. Agent requires three phosphorylation steps for activation and is converted to the mono-, di- and triphosphate compounds. Because it requires the viral kinase for the first phosphorylation, acyclovir is selectively activated and the triphosphate accumulates only in infected cells. Acyclovir triphosphate inhibits the viral DNA polymerase and incorporates into the viral DNA. Oral and topical acyclovir is effective for treatment of primary infection and recurrences of genital and labial herpes. Intravenous acyclovir is the treatment of choice for herpes simplex encephalitis. The bioavailability of the oral formulation is 20%. Acyclovir is cleared primarily by kidneys. The half-life is 3-4 hours. Agent well diffuses into most tissues and body fluids, including cerebrospinal fluid. Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have occasionally been reported. Intravenous infusion may be associated with renal insufficiency or neurologic toxicity (the latter may include tremors or delirium).
Ganciclovir is similar in structure, mechanism of action, and activity to acyclovir. However, its activity against cytomegalovirus is up to 100 times greater than that of acyclovir. Ganciclovir is available in i.v. formulations. The oral bioavailability of ganciclovir is poor (6-9%). Ganciclovir is indicated for the treatment of cytomegalovirus retinitis and colitis in-patients with AIDS. The most common side effect of treatment with ganciclovir is myelosuppression, particularly neutropenia. Central nervous system toxicity (headache, changes in mental status, seizures) has been reported also. Due to the high toxicity and mutagenic and teratogenic potential of ganciclovir, use during pregnancy should be avoided.
Idoxuridine is a thymidine analog. It has the similar mechanism action with acyclovir. Idoxuridine is used topically in the treatment of herpes keratitis, because it is too toxic for systemic administration (leukopenia).
Zidovudine (azidothymidine) is a deoxythymidine analog. After entering the cell by passive diffusion, zidovudine is phosphorylated via three cellular kinases; the triphosphate is an inhibitor of the reverse transcriptase. Zidovudine has activity against human immunodeficiency virus. Resistance typically occurs after prolonged therapy. Zidovudine is available in i.v. and oral formulations. It is well absorbed from the gut and distributed to most body tissues and fluids, including the cerebrospinal fluid. Substantial first-pass metabolism to an inactive glucuronidated metabolite results in a systemic bioavailability of approximately 65%. The serum half-life is only 1 hour. Clinical efficacy is limited by the relatively rapid development of resistance, particularly when used as monotherapy. The combination of zidovudine with one or two other agents, such as a protease inhibitor, is one strategy to enhance antiviral activity and retard the development of resistance. The most common adverse effect is myelosuppression, resulting in anemia or neutropenia.
Indinavir is a specific inhibitor of the human immunodeficiency virus protease, an enzyme essential for the production of mature, infectious virions. It is approved for the treatment of individuals with human immunodeficiency virus infection. Oral bioavailability is excellent. The most common adverse effects reported thus far are indirect hyperbilirubinemia and nephrolithiasis. Indinavir is inhibitor of as well as substrate for cytochrome P450. Thus, numerous complex drug interactions can occur.
Rimantadine, an amantadine derivative, inhibit uncoating of the viral RNA of influenza A within infected host cells, thus preventing its replication. It is effective in the prevention of influenza A virus infection. The most common side effects are gastrointestinal intolerance and central nervous system effects (e.g., nervousness, drowsiness).
Ribamidil (ribavirin) is a guanosine analog that is phosphorylated intracellularly by host cell enzymes. Its mechanism of action appears with synthesis of guanosine triphosphate and inhibition of RNA polymerase of certain viruses, including influenza A and B, parainfluenza, and respiratory syncytial virus. Ribavirin is administered in aerosolized form to patients with respiratory syncytial virus bronchiolitis or pneumonia, reducing the severity and duration of illness. I.v. ribavirin decreases mortality in Lassa fever and other viral hemorrhagic fevers. Aerosolized ribavirin is generally well tolerated but may cause conjunctival or bronchial irritation. Systemic administration of ribavirin is associated with dose-dependent anemia and bone marrow suppression. The drug is contraindicated in pregnancy due to possible teratogenicity.
Oxolin and florenal are the topical agents that adopted for the treatment of skin and mucous membrane virial infections (mostly herpes). These agents have direct virucidal activity. They are too toxic for systemic administration. Oxolin and florenal can cause irritation in place of their application.
Interferons are a group of endogenous proteins that exert virus-nonspecific antiviral activities. Three major classes of interferons are now recognized: - (leukocyte), - (fibroblast), and -(immune, T-lymphocyte). Each type can function as a potent cytokine with complex antiviral and immunomodulatory activity. They are not directly antiviral but appear to function by causing elaboration of effector proteins in infected cells, resulting in such effects as inhibition of viral penetration or uncoating, mRNA synthesis and translation, or virion assembly and release. Agents of natural -interferon as well as recombinant -interferon (reaferon, itron A), which produced by genetic engineering, are mostly used in clinics. Natural -interferon have been used an intranasal route for prophylaxis and treatment of the common cold viruses infections (interferon) and an intraconjunctival way for the treatment of herpes keratitis (inerlock).
Recombinant -interferon is approved for the treatment of hepatitis B and C, leukemia, bladder and renal carcinoma, and malignant melanoma. Recombinant -interferon (betaferon) is used for the treatment of multiple sclerosis. Adverse effects of inetrferons include neutropenia, anemia, skin rashes, fever, myalgia, and fatigue. Poludan, amixin stimulates the synthesis of endogenous interferon and thus possess antiviral activity. Poludan is a topical agent for the treatment of virial eyes diseases. Amixin is active in case of virus’s hepatitis B and C.