ANTIFUNGAL AND AGENTS - wickUP - HOME...
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Transcript of ANTIFUNGAL AND AGENTS - wickUP - HOME...
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