ANTIFUNGAL AND ANTIPARASITIC AGENTS

Dr Deliwe Nkosi

Microbiology

Type Body site Disease Aetiological agent

SUPERFICIAL hair, skin, nail skin

Tinea (ringworm) Ptyriasis/tinea versicolor

Microsporum, Trichophyton, Epidermophyton Malessezia furfur

SUBCUTANEOUS below skin sporotrichosis mycetoma

Sporothrix schenkii many species

SYSTEMIC & OPPORTUNISTIC

Internal organs Cryptococcosis Pneumocystis pneumonia Histoplasmosis Mucormycosis Aspergillosis

Cryptococcus neoformans Pneumocystis jiroveci ■ Histoplasma capsulatum ■ Mucor ■ Aspergillus fumigatus

FUNGAL INFECTIONS

ANTIFUNGAL DRUGS ■ POLYENES (Amphotericin B, Nystatin) ■ AZOLES (Imidazole, Triazoles)

■ ECHINOCANDINS (Caspofungin) ■ FLUCYTOSINE ■ ALLYLAMINES ■ OTHERS (Griseofulvin, Potassium iodide)

Echinocandins- inhibit glucan synthesis

AMPHOTERICIN B It is obtained from Streptomyces nodosus

Mechanism of action ■ It has affinity for ergosterol present in the cell membrane and forms a micropore thus disrupting membrane function and resulting in cell death. Pharmacokinetics ■ It is not absorbed orally ■ Half life is ~ 15 days ■ Metabolized in liver and excreted in urine and bile ■ Relatively safe in pregnancy.

ADMINISTRATION ■ It can be given intravenously and intrathecally ■ New formulations have reduced nephrotoxicity

ABCD - amphotericin B colloidal dispersion ABLC - amphotericin B lipid complex ADVERSE REACTIONS ■ Acute reactions – fever and chills ■ Long term - nephrotoxicity, anaemia, CNS toxicity

AMPHOTERICIN B

NYSTATIN ■ It is very toxic when given systemically and used only for local anti-fungal effect

■ It is not absorbed orally

■ Used only for mucosal candidiasis - topically

AZOLES Mainly fungistatic in nature EXAMPLES ■ Ketoconazole, ■ Fluconazole, ■ Itraconazole, ■ Voriconazole, ■ Posaconazole ■ Clotrimazole, Econazole, Miconazole

KETOCONAZOLE First orally effective broad spectrum azole anti-fungal MECHANISM OF ACTION : ■ It inhibits C -14 demethylase thus blocking the demethylation

of lanosterol to ergosterol – sterol of fungal membrane.

ADVERSE EFFECTS ■ Nausea and vomiting ■ Hepatitis ■ Hair loss, gynaecomastia, loss of libido, oligospermia -- decrease androgen production. ■ Menstrual irregularities in women

FLUCONAZOLE Not active against dermatophytes (Aspergillus)

It has good activity against – Cryptococcus & Candida Oral absorption is very good – not dependent on gastric

acidity

Fungicidal concentration in CNS, saliva and nails

Used in combination with amphotericin B for treatment of Cryptococcal meningitis

ECHINOCANDINS Echinocandins inhibit the synthesis of glucan in the cell wall, via the enzyme 1,3-β glucan synthase: e.g. Caspofungin, Anidulafungin, Micafungin Caspofungin is semisynthetic, synthesized from Glarea lozyensis ■ Fungicidal against Aspergilli, Candida and P. jiroveci ■ No cross resistance amongst strains resistant to Amphotericin B

or azoles ■ NB: No activity against Cryptococcus neoformans, Fusarium &

Rhizopus

ALLYAMINES TERBINAFINE ■ Inhibits squalene epoxidase (key

enzyme in sterol synthesis)

■ Used orally & topically for dermatophytes

■ Metabolized then excreted in urine

■ Adverse effects include hepatitis and rashes - both are rare.

FLUCYTOSINE PYRIMIDINE ANTIMETABOLITES

■ Block fungal DNA synthesis ■ Selective toxicity because mammalian cells do not accumulate and do not deaminate flucytosine ■ Well absorbed orally and penetrates into CSF Adverse effects ■ Reversible bone marrow suppression-therefore not used in

HIV/AIDS patients ■ Liver dysfunction Therapeutic uses ■ Candida infections (in combination with amphotericin B) ■ Cryptococcal meningitis(in combination with amphotericin B)

GRISEOFULVIN It is obtained from Penicillium griseofulvum It is active against Dermatophytes Pharmacokinetics ■ Absorption from the GIT is irregular better with ultramicrofine granules ■ Better absorption with high fat meals Mechanism of action ■ It gets deposited in the keratin forming cells of the skin, hair and nails – especially concentrated and retained in the tinea infected cells ■ Newly formed keratin is not invaded by the fungus

OTHER ANTI-FUNGAL AGENTS

Other TOPICAL anti-fungal agents : ■ Tolnaftate: effective drug for dermatophytes and Tinea

versicolor

■ Benzoic acid (Whitfields ointment): anti-fungal agents and anti-bacterial property

■ Salicylic acid: acts as keratolytic action

SUMMARY 1 AGENT MECHANISM OF

ACTION ROUTE CLINICAL USES

Nystatin Cell membrane - pores TOPICAL Most fungi

Amphotericin B Cell membrane - pores Intra-venous Most fungi

Ketoconazole Ergosterol synthesis (demethylase)

oral Candida, dimorph, dermatophytes,

Fluconazole Ergosterol synthesis (demethylase)

Oral, I/V Candida, dimorph, Cryptococcus,

Itraconazole Ergosterol synthesis (demethylase)

Oral, I/V

Candida, dimorph, Sporothrix, Aspergillus

Voriconazole Ergosterol synthesis (demethylase)

Oral, I/V

Candida, Aspergillus, yeasts & moulds

Posaconazole Ergosterol synthesis (demethylase)

Oral, I/V Candida, Aspergillus

Clotrimazole Ergosterol synthesis (demethylase

TOPICAL Candida, dermatophytes

SUMMARY 2 AGENT MECHANISM OF

ACTION ROUTE CLINICAL USES

ECHINOCANDIN Caspofungin

Glucan synthesis (glucan synthetase

I/V Candida, Aspergillus

FLUCYTOSINE DNA synthesis oral Candida & Cryptococcus

ALLYLAMINES Terbinafine

Ergosterol synthesis (squalene epoxidase)

oral Dermatophytes

GRISEOFULVIN Microtubule destruction

oral Dermatophytes

Potassium iodide unknown oral Sporothrix schenkii

Tolnaftate unknown Topical Dermatophytes

ANTIPARASITIC

AGENTS

FIVE FAMILIES OF ANTI-PARASITIC DRUGS

■ Anti-helminths

■ Schistosomicides

■ Anti-malarials

■ Protozoacides

■ Parasiticides

PROTOZOAL DISEASES

DRUGS

Chagas disease Trypanosoma cruzei

Nifurtimox

African Sleeping sickness – T. gambiense

Suramin & Pentamidine

African Sleeping sickness – T. rhodesiense

Melarsoprol

Leishmaniasis Stibogluconate

Toxoplasmosis Toxoplasma gondii

Pyrimethamine, Sulfadiazine

ANTI - AMOEBIC DRUGS

METRONIDAZOLE : Broad spectrum cidal activity against :

Protozoa E. histolytica, T. vaginalis, G. lamblia

Anaerobic bacteria B.fragilis, C. perfringes, H. pylori, Cl. difficile

ANTI - AMOEBIC DRUGS Metronidazole : Mechanism of action : ■ Nitroimidazole group is reduced to an intermediate

compounds which causes destruction of DNA Pharmacokinetics : ■ Well absorbed from the intestine ■ Widely distributed in the body secretions – semen,

saliva and CSF

ANTI - AMOEBIC DRUGS Metronidazole : Uses ■ Amoebiasis

■ Giardiasis

■ Trichomonas vaginalis

■ Anaerobic infections

■ Pseudo-membranous enterocolitis ■ Ulcerative gingivitis

■ Helicobacter pylori

ANTI - AMOEBIC DRUGS Paromomycin ■ Aminoglycoside which is not absorbed from GIT.

■ Effective against luminal forms of E. histolytica – directly ■ It acts indirectly by reducing the intestinal flora also.

ANTI-HELMINTHIC DRUGS

Three major groups of helminths (worms) ■ Nematodes

■ Trematodes

■ Cestodes

ANTI-HELMINTHIC DRUGS Drugs for helminths Nematodes :

■ Albendazole, ■ Mebendazole, ■ Pyrantel pamoate, ■ Diethylcarbamazine, ■ Ivermectin

Trematodes : Praziquantel Cestodes : Praziquantel, Albendazole

ANTI-HELMINTHIC DRUGS Benzimidazole : Mebendazole, Albendazole ■ Effective against wide spectrum of nematodes

■ It acts by binding and interfering the assembly of microtubules (Vinca alkaloids)

ANTI-HELMINTHIC DRUGS Praziquantel : ■ It acts by increasing the permeability of tegument to calcium – leads to paralysis of the parasite.

■ Well absorbed orally ■ Penetrates CNS.

■ Used for trematodes and cestodes

ANTI-MALARIAL DRUGS Malaria is caused by the five species of protozoa – ■ Plasmodium vivax

■ Plasmodium falciparum

■ Plasmodium malariae

■ Plasmodium ovale ■ Plasmodium knowlesi

ANTI-MALARIAL DRUGS Drugs for the Exo-erythrocytic phase (liver) and gametocytes : ■ Primaquine

Drugs to suppress erythrocytic phase/Schizontocides / Clinical cure : ■ Chloroquine, ■ Quinine, ■ Pyrimethamine, ■ Mefloquine, ■ Artemisinin

ANTI-MALARIAL DRUGS ■ Chloroquine – most common

■ Quinine – Chloroquine resistant

■ Pyrimethamine / Sulfonamides

■ Primaquine – Radical cure ■ Newer drugs Mefloquine, Artimisinin, Halofantrine

ANTI-MALARIAL DRUGS Quinine : ■ It is a levo-rotatory alkaloid from cinchona bark (dextro isomer-Quinidine)

■ It is an erythrocytic schizontocide (acts at erythrocyte stage) ■ It is basic and gets concentrated in acidic schizonts and kills by inhibiting haem polymerase ■ It is orally well absorbed ■ It has antipyretic action, affects hearing and vision at high dose

ANTI-MALARIAL DRUGS Quinine : adverse effects

■ Cinchonism – ringing in ears, nausea , difficulty in hearing, visual defects

■ Hypersensitivity reactions ■ Haemolysis – can result in hemoglobinuria

ANTI-MALARIAL DRUGS Primaquine : ■ Primary indication is radical cure of malaria. ■ It is more active against exo-erythrocytic phase

(liver stage) of vivax and ovale

■ It is highly active against non-growing forms - gametocytes and hypnozoites.

AGENT MECHANISM OF ACTION

ROUTE CLINICAL USES

Metronidazole

Blocking/damaging DNA

I/V, oral

Amoeba histolytica Tichomonas vaginalis Giardia lambia

Paromomycin Inhibits protein synthesis

Oral Amoeba histolytica

Pentamidine Interfere with RNA,DNA, proteins

I/V, aerosol Trypanosoma Leshmania

Mebendazole Albendazole

Binding & interfering assembly microtubules

Oral Nematodes Cestodes

Praziquantel Paralysis of muscle Oral Trematodes

Quinine Schizontocide Gametocytocidal

Oral , IMI Malaria

Primaquine Alters properties of DNA

Oral Radical cure of Malaria

mefloquine Schizontocide

Oral Malaria