ANTIFUNGAL AND AGENTS - wickUP - HOME PAGEwickup.weebly.com/uploads/1/0/3/6/10368008/antifungals...Tolnaftate: effective drug for dermatophytes and Tinea versicolor Benzoic acid (Whitfields

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