Antifungal, Antiprotozoal, Anthelmintic Drugs

Dr n. med. Marta Jóźwiak-Bębenista Department of Pharmacology Medical University of Lodz

Fungal infections

• also called mycoses; widespread in the population (e.g. „athlete's foot” or „thrush”) • become a more serious problem (immunocompromised patients – even fetal!) • are more difficult to treat than bacterial infections • therapy of fungal infections usually requires prolonged treatment! • opportunistic infections- Pneumocystis carinii

Fungi

Yeasts Moulds Higher Fungi

1 Clinically important fungi may be classified into:

• (e.g. ) • -like fungi that produce a structure resembling a mycelium (e.g. ) • filamentous fungi with a true mycelium (e.g. spp., Microsporum spp., Epidermophyton spp., Tinea spp., fumigatus ) • „dimorphic” fungi that, depending on nutritional constraints, may grow as either yeasts or filamentous fungi (e.g. , , Blastomyces dermatides)

Fungal infections

Superficial (topical) Systemic („disseminated”) 1. cutaneous surfaces - skin, nails, 2. mucous membrane surfaces - oropharynx, vagina

Fungal infections

Superficial Systemic • Dermatomycoses - infections • of the skin, hair and nails; caused by • Cryptococcal Trichophyton • Pulmonary Microsporum Epidermophyton • (scalp) • (groin) • Coccidiomycosis Tinea pedis (athlete's foot) • Paracoccidiomycosis (body) • Candidiasis, infections of the mucous membranes of the mouth, vagina or the skin; caused by Candida spp.

2 Ringworm an infection of the skin by a .

Antifungal drugs

• Natural (Amphotericin, Nystatin, Natamycin, Griseofulvin) • Synthetic (Azoles)

• Polyenes (Amphotericin, ...) • Azoles (Ketokonazol, ...) • Echinocandins (Capsofungin, ...) • Antymetabolites (Flucytosine)

• used for Systemic mycoses (Amphotericin, Fluconazole) • used for Topical mycoses (Myconazole, Clotrimazole)

Amphotericin (Amphotericin B)

• naturally occurring • polyene macrolide • produced by Streptomyces nodosus

3 Mechanism of action of amphotericin

Activity spectrum of amphotericin

• Candida albicans • Histoplasma capsulatum • Cryptococcus neoformans • Coccidioides immitis • Aspergillus • Blastomyces dermatidis • Leishmania species

Pharmacokinetics of amphotericin

• i.v • p.o (infections in GI tract) • topically • liposome preparation! • bound to plasma proteins • poorly penetrate BBB (!inflammation: used in cryptococcal meningitis + flucytosine) • excreted very slowly via the kidney (even 2 mths), and via the bile

4 Resistance

• decreased ergosterol content of the fungal membrane • rare • synergistic combination (+ flucytosine)

Side effects of amphotericin

• low therapeutic index! • renal toxicity (vasoconstractive effect on afferent renal arterioles) • hypokalaemia (hypotension) • hypomagnesaemia • anemia • thrombophlebitis (heparin) • neurotoxicity (intrathecal injections) • skin rashes (topical applications) • injection: chills, fever, tinnitus, headache, vomiting

Nephrotoxicity of amphotericin can be lessened by: • avoid others nephrotoxic agents (i.e. aminoglycosides) • avoid concomitant diuretic therapy • keeping patients well hydrated (saline infusion prior to amphotericin) • continuous infusion (over 24 h)

5 Nystatin

• a polyene macrolide antibiotic • structure, metabolism of action ~ amphotericin • no absorbed from the GI and from the skin • I: Candida infections of the skin, mucous membranes and the GI tract. • SE: nausea, vomiting and diarrhoea

Griseofulvin

• produced by the Penicillium griseofulvin • fungistatic action, long-term treatment • binds to the fungal microtubulesinterfers cell mitosis • I: dermatophyte infections (Epidermophyton, Microsporum, Trichophyton) • p.o! (poor absorbed from GI) • inducer of Cyt. P450 • SE: GI upsets, headache, photosensitivity, allergic reactions

SYNTHETIC ANTIFUNGAL AGENTS - AZOLES

IMIDAZOLE (2N) TRIAZOLE (3N) • clotrimazole • itraconazole • econazole • fluconazole • fenticonazole • voriconazole • ketoconazole • miconazole The triazoles tend to have fewer side effects, better absorption, • tioconazole better drug distribution in body tissues, • sulconazole and fewer drug interactions!

6 Mechanism of action of azoles

Ketokonazole • the first azole that could be given orally to treat systemic fungal infections • broad spectrum- activity • relapse is common • absorbed from GI (acidic pH) • high doses - CNS • inactivated in the liver and excreted in bile and in urine • SE: liver toxicity, GI disturbances, pruritus, gynaecomastia (inhibits testosterone synthesis) • many interactions with inducers and inhibitors of Cyt. P450

Fluconazole

• p.o ; i.v • widely distribiuted (cerebrospinal fluid, ocular fluids, vaginal tissue, saliva, skin and nails) • first choice for fungal meningitis • SE: mild; nausea, headache, abdominal pain, exfoliative skin lesions or Stevens-Johnson syndrome (AIDS patients) • does not inhibit cyt. P450 and steroid synthesis (ketoconazole!)

7 Itraconazole

• active against a range of . • p.o (absorption is variable!) • extensive metabolized in the liver • does not penetrate the cerebrospinal fluid! • inhibits cyt. P450. • SE: GI disturbances, headache, dizziness, hepatitis and liver damage, hypokalaemia, impotence, allergic skin reactions

Miconazole

• p.o • treating infections of GI tract. • short plasma half-life (every 8h) • therapeutic concentrations in bone, joints and lung tissue but not in the central nervous system • inactivated in the liver. • can be used topically. • SE: relatively infrequent. • inhibits cyt. P450.

Other azoles

• Clotrimazole Clotrimazole • Econazole • interferes with AA • Tioconazole transport into the fungus by an action on • Sulconazole the cell membrane. • active against a wide used only for topical range of fungi, application! including Candida.

8 Flucytosine • a synthetic antifungal agent • Candida infections • Mechanism of action: flucytosine  5-fluorouracil  thymidylate synthetase  DNA synthesis (in fungal cells!) • monotherapy  resistance • politherapy recommended (+amphotericin) • i.v or p.o • SE: infrequent

Terbinafine • highly lipophilic and keratinophilic. • active against a wide range of skin pathogens • nail infections! • Mechanism of action: inhibits squalene epoxidase  squalene (toxic to fungi) • p.o (skin and nails) • topically (skin and mucous membranes) • metabolised in the liver by the cyt. P450 system • excreted in the urine • SE: occur in about 10% of individuals are usually mild and self-limiting • Naftifina ~ terbinafine • Amolorfina ~ topically as nail polish

POTENTIAL NEW ANTIFUNGAL THERAPIES • Echinocandins: • „new generation” triazoles: Micafungin, Anidulafungin Posaconazole, Ravuconazole • Aspergillus and Candida • wide range of fungal pathogens spp., (even in AIDS patients) • SE mild, less than that seen with amphotericin.

9 Fungal infections

• Drugs used for • Drugs used for treating systemic treating topical mycoses mycoses

Case study

Antiprotozoal drugs

Protozoa are motile, unicellular eukaryotic organisms that have colonised virtually every habitat and ecological niche.

10 Protozoa

AMOEBAS FLAGELLATES SPOROZOA CILIATES

Entamoeba Trypanosome Plasmodium Paramecium histolytica brucei brucei falciparum caudatum

Malaria

Plasmodium falciparum

Symptoms of malaria

11 THE LIFE CYCLE OF THE MALARIA PARASITE

• The life cycle of the parasites consists of a sexual cycle, which takes place in the female anopheline mosquito, and an asexual cycle, which occurs in humans.

• The mosquito, not the human, is the definitive host for plasmodia, and the only function of humans is to enable the parasite to infect more mosquitoes so that further sexual recombination can occur.

THE LIFE CYCLE OF THE MALARIA PARASITE

• Plasmodium falciparum  malignant tertian malaria; an 48-hour erythrocytic cycle, does not have an exoerythrocytic stage • Plasmodium vivax  benign tertian malaria; has an exoerythrocytic stage • Plasmodium ovale  rare form of malaria; an 48-hour erythrocytic cycle and an exoerythrocytic stage • Plasmodium malariae  quartan malaria; an 72-hour erythrocytic cycle, does not have exoerythrocytic cycle.

12 People living in areas where malaria is endemic may acquire a natural immunity, but this may be lost if the person is absent from the area for more than 6 months.

Drugs used in the treatment of malaria:

Drugs used in the treatment of malaria: 1. drugs used to treat the acute attack of malaria act on the parasites in the blood; they can cure infections with parasites (e.g. Plasmodium falciparum, P. malariae) that have no exoerythrocytic stage 2. drugs used for chemoprophylaxis act on merozoites emerging from liver cells 3. drugs used for radical cure are active against parasites in the liver 4. some drugs act on gametocytes and prevent transmission by the mosquito.

13 1. Drugs used to treat the acute attack

• quinoline-methanols (e.g. quinine and mefloquine) • 4-aminoquinolines (e.g. chloroquine) • 8-aminoquinolines (e.g. primaquine) • the phenanthrene (halofantrine) • agents that interfere either with the synthesis of folate (e.g. sulfonamide – sulfadoxine; sulfones - dapsone) or with its action (e.g. pyrimethamine and proguanil) • compounds derived from Artemisia (e.g artemisinin)

2. Drugs that effect a radical cure

• 8-aminoquinolines (e.g. primaquine, tafenoquine)

These drugs also destroy gametocytes and thus reduce the spread of infection.

3. Drugs used for chemoprophylaxis

• chloroquine • mefloquine • proguanil • pyrimethamine • dapsone (sulfone) • doxycycline

14 4. Drugs used to prevent transmission

• primaquine • proguanil • pyrimethamine

They are rarely used for this action alone

TREATMENT and PREVENTION of malaria

Precautions

• wearing clothes that cover much of the skin • using insect repellents in living, and especially in sleeping, areas! • spraying bed nets with insecticides such as permethrin • chemoprophylactic agents (1 week before the trip)

15 Toxoplasmosis • Toxoplasma gondii • cats - definitive hosts of Toxoplasma gondii; humans inadvertently intermediate hosts. • Dangerous!: pregnant woman - damage the developing fetus and immunosuppressed patients (AIDS) - fatal infection (toxoplasmic encephalitis) • The treatment of choice: pyrimethamine-sulfadiazine trimethoprim-sulfamethoxazole (folic acid!) or parenteral pentamidine is also used and, more recently, azithromycin has shown promise.

Amebiasis

• Entamoeba histolytica • severe diarrhoea, colitis (dysentery) and liver abcesses • main cause: poor hygiene • some people are symptomless „carriers” for Entamoeba

LIFE CYCLE OF Entamoeba histolytica

16 Drugs for amebiasis

• Metronidazole, Tynidazole invasive form in gut and liver but not the cysts • Idoquinol • Paromomycin invasive form in gut and cysts • Chloroquine • Emetine, dehydroemetine invasive form in the liver

Trypanosomiasis

African (sleeping disease) • Trypanosoma gambiense • Trypanosoma rhodesiense

American (Chagas disease) • Trypanosoma cruzi

Drugs for Trypanosomiasis

African • Suramin (i.v.) • Pentamidine isethionate (i.v.) • Melarsoprol (i.v.) • Nifurtimox, Eflornithine (i.v.;p.o.)

American • Nifurtimox (p.o.) • Benznidazole (p.o.)

17 Leishmaniasis

• Leishmania spp. 1. simple skin infection 2. mucocutaneous form 3. serious visceral form „kala-azar”

Drugs for Leishmaniasis

• Drugs of choice - sodium stibogluconate and meglumine antimoniate (parenteral route of administration) • Alternative drugs: – Amphotericin B – Pentamidine – miltefosine

Gardiasis

• Giardia lamblia • an infection of the small intestine • main cause: poor hygiene and sanitation • the drug of choice: Metronidazole

18 Antihelminthic drugs

Nematode Infections Pathogenesis and Treatment TreatmentPathogenInfection Ascariasis Ascaris lumbricoides Pyrantel pamoate or piperazine

Hookworm disease Ancylostoma duodenale or Pyrantel pamoate Necator americanus Enterobiasis Enterobius vermicularis Pyrantel pamoate

Strongyloidiasis Strongyloides stercoralis Albendazole or Thiabendazole

Toxocariasis Toxocara canis (larvae) Thiabendazole

Trichinosis Trichinella spiralis (larvae) Thiabendazole

Angiostrongyliasis Angiostrongylus cantonensis Thiabendazole (larvae) Filariasis Wuchereria bancrofti or Diethylcarbamazine Brugia malayi Onchocerciasis Onchocerca volvulus Ivermectin

Trichuriasis Trichuris trichiura Albendazole or Mebendazole

Capillariasis Capillaria philippinensis Albendazole or Mebendazole

Trematode Infections Pathogenesis and Treatment

TreatmentPathogenInfection Schistosomiasis Schistosoma japonicum, S. mansoni, Praziquantel S. haematobium Clonorchiasis Clonorchis sinensis Praziquantel Opisthorchiasis Opisthorchis viverrini, Praziquantel O. felineus Paragonimiasis Paragonimus spp. Praziquantel or Bithionol Fascioliasis Fasciola hepatica, F. gigantica and other Triclabendazole Fasciola sp. Fasciolopsiasis Fasciolopsis buski Praziquantel Heterophyiasis Heterophyes heterophyes, Praziquantel Metagonimus yokogawai

19 Cestode Infections Pathogenesis and Treatment

TreatmentPathogenInfection Taeniasis saginata Taenia saginata Praziquantel, Niclosamide or Gastrografin Diphyllobothriasis Diphyllobothrium latum Praziquantel, Niclosamide or Gastrografin Taeniasis solium Taenia solium Gastrografin, Praziquantel or Albendazole Cysticercosis T. solium (larvae) Gastrografin, Praziquantel or Albendazole Echinococcosis Echinococcus granulosus, Albendazole E. multilocularis (larvae) Hymenolepsiasis Hymenolepis nana, Praziquantel or Niclosamide H. diminuta

Case study

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