Antifungal

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Transcript Antifungal

Antifungal
 Antifungal agents:
These drugs are used for superficial or deep systemic fungal
infection .
 Fungal infection termed as mycoses.
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FUNGI AND FUNGAL INFECTION:
 Fungi are Eukaryotic cells. They possess mitochondria, nuclei & cell
membranes.
 They have rigid cell walls containing chitin as well as polysaccharides,
and a cell membrane composed of ergosterol.
 While bacterial cells are prokaryotic. So, antibacterial agents can exhibit
Selective toxicity.
 In contrast, similarity between fungal & mammalian cells makes
Antifungal drugs non-selective.
 Thus, Antifungal drugs are in general more toxic than antibacterial
agents.
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 Exampels of Fungi:
 Yeasts
 Molds
 Mushrooms
 Puffballs
 Shelf fungi
 Animal pathogen
 Plant pathogen
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 Clinically important fungi may be classified into four main types:
1.yeasts(cryptococcus neoformans)
2.yeast like fungi that produce a structure resembling a
mycelium(candida albicans)
3.filamentous fungi with true mycelium(Aspergillus fumigatus)
4.Dimorphic fungi that,depending on nutritional consraints,may grow as
either yeasts or filamentous fungi(histoplasma capsulatum)
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1) Superficial fungal infections can be classified into
1.dermatomycoses:
 Infection of hair,skin,nails
 Most commonly caused by Trichophyton,Microsporum or
Epidermophyton,giving rise to various types of ‘ring worm’ or tine.
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2.candidiasis:
 Yeast like organisam may infect the mucous membranes of the mouth
or vagina(thrush) or the skin.
2) Systemic fungal infection:
 Blastomycosis,histoplasmosis,coccidiomycosis and
paracoccidomycosis;thses are the primary infections.
 Involve the internal organs
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Classification:
1)

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Antibiotics:
Polyenes:
- Amphotericin B(AMB)
- Nystatin
- Hamycin
- Natamycin

Heterocyclic benzofuran:
- Griseofulvin
2)
Antimetabolite:
- Flucytosine(5-FC)
3) Azoles:
a)imidazoles:
Topical -Clotrimazole
-Econazole
-Miconazole
systemic – Ketoconazole
b)Triazoles:
systemic –Fluconazole
- Itraconazole
4) Allylamine:
- Terbinafine
- Naftifine
- Butenafine
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5) β-glucan synthase inhibitors:
-Caspofungin
-Micafungin
-Anidulafungin
6)
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Other topical agents:
- Tolnaftate
-Undecylenic acid
-Benzoic acid
-Quiniodochlor
-Ciclopirox olamine
-Sodium thiosulfate
Action of antifungal agents:
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 Polyenes, triazoles, and imidazoles target ergosterol destroying
the cell membrane’s integrity.
 Allylamines inhibit ergosterol synthesis.
 flucytosine inhibit DNA/RNA synthesis.
 griseofulvin inhibit fungal cell mitosis preventing cell proliferation
and function.
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1.Antibiotics:
A. Polyenes:
1.
Amphotericin B(AMB):
 It is the drug of choice used in the treatment of the systemic
mycoses although it is toxic.

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It is sometimes used in combination with flucytosine to decrease
the toxicity of amphotericin B.
M/A:
 It binds with ergosterol(component of fungal cell membrane)
AMB-ergosterol complex alter the membrane permeability
creates pore in the membrane
pores allows the leakage of inracellular ions,amino acid &
micromolecules
cell death
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Pharmacokinetics:
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
i.v.(t½ - 24 hours)

mostly metabolized

some is excreted by kidney

does not readily pass the blood brain barrier

extensively bound to plasma proteins, and is distributed
throughout the body. However, amphotericin B does cross the
placenta; some is also eliminated via the bile. Liposomal
preparations of amphotericin B are available and have shown
therapeutic efficacy.
 Clinical use:

•
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topically applied for ,
oral,vaginal, cutaneous candidasis
otomycosis
 leishmaniasis:it is a reserve drug for resistant cases of kala azar
and mucocutaneous leishmaniasis.
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 Adverse effects:

Infusion related: fever,chills,aches ,nausea,vomiting and
dyspnoea and can be alleviated partly by pretreatment with
NSAIDs,antihistamines,meperidine and adrenal steroids.
Dose dependent:
• Nephrotoxicity includes reduce g.f.r,acidosis, hypokalemia and
inability to concentrate urine.
• anemia:it is due to bone marrow depression(decrease
erythropoietin)
• CNS toxicity:occurs only on intrthecal injection –
headache,vomiting,nerve palsies.

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Alternative Formulations to Decrease Toxicity
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LIPID amphotericin B formulations in use
 Amphotericin B Lipid Complex: (ABLC; Abelcet®)
 Amphotericin B Colloidal Dispersion: (ABCD; Amphocil® or
Amphotec®)
 Liposomal Amphotericin B:(L-AMB; Ambisome®)
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2.Nystatin(fungicidin):
 It is similar in structure to amphotericin and same mechanism
action.
 No absorption from the mucous membranes of the body or from
skin
use:
 Use limited to candida infection of skin,git,mucous membrane
 unwanted effects:
nausea,vomiting,diarrhoea.
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B. Hetrocyclic benzofuran:
Griseofulvin:
 It is isolated from Penicillium griseofulvum and cure infections due to
dermatophytes(ringworm) when administered orally.
 It is ineffective against candida albicans.
M/A:
 It interacts with microtubules of miotic spindle and with cytoplasmic
microtubules
disorientation of miotic microtubules and interfere in the mitosis
inhibit the growth of fungal hyphae.
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 It is very low water soluble drug,low absorption,absorption
improved by taking with fatty meals and microfine the drug
particles.
 Adverse effects:
 Headache,GIT disturbances,peripheral
neuritis,rashes,leukopenia.
 Interaction:
 It induces warfarin metabolism and reduces efficacy of oral
contaceptives.
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2.Antimetabolite:
Flucytosine(5-fc):
 It is pyrimidine analogue related to the chemotherapeutic agent 5-FU
(5 Fluorouracil).
M/A:
 This permeates the fungal cell wall and converts into 5-FU
phosphorylation of 5-FU and formation of UDP and UTP
which inhibits to thymidylate synthesis
inhibitn the DNA and RNA synthesis
inghibit fungal cell grpwth
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 Adverse effects:
 Bone marrow depression
 Leucopenia
 Rash
 Diarrhoea
 Hepatitis
 Use:
 In cyptococcosis its synergistic action with AMB is utillized to reduce the
total dose of the more toxic latter dose.
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3.Azoles :
M/A:
Inhibit the fungal cytochrome P450 enzyme lanosterol 14-methylase
impair ergosterol synthesis
membrane abnormalities in fungus.
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Ketoconazol:
 Orally used for mucocutaneous candidiasis or dermatophytoses.
 Pharmacokinetics
• Variable oral absorption, dependent on pH (often given with cola or
fruit juice)
• T1/2 = 7-10 hours
• Protein binding > 99%
• Hepatic, bile and kidney elimination
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•
A/E:
 Decrease androgen production and displace testoterone from protein
binding sites gynaecomastia,loss of libido and oligospermia.
 Menstrual irregularities in female.
 Dose-related inhibition of CYP P450 .
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 Interaction:
 Potent inhibitor of cytochrome P450 3A4
 Rifampin and phenytoin decrease ketoconazole levels
 Ketoconazole increases cyclosporin, warfarin and terfenadine levels.
 Drugs that increase gastric pH will decrease blood levels of
ketoconazole
 Antacids, omeprazole, H2 blockers
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Fluconazole:
 Fluconazole is clinically important because of its lack of the
endocrine side effects of ketoconazole, and its excellent penetrability
into the CSF & ocular fluids.
•
Water soluble having wider range of activity than Ketoconazol
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Drug of choice in fungal meningitis
•
Non-albicans Candida species more likely to exhibit primary
resistance
 ItraconazoleL:
 Uses:
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•
Histoplasmosis
•
Sporotrichosis (This fungal disease usually affects the skin, although
other rare forms can affect the lungs, joints, bones, and even the brain).
•
Aspergillosis
•
Blastomycosis
 Voriconazole:
 Posaconazole & Ravuconazole:
• For Invasive candidiasis, and aspergillosis infections
• Only orally available
• Inhibits CYP3A4
• Adverse effects include: GI effects, dizziness, cardiac arrhythmias,
abnormal liver function
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local azoles
 Very popular local azoles are – Clotrimazole, Econazole and
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Miconazole
(For Tinea, Ring worm, Athlete’s foot, otomycosis, oral, cutaneous &
vaginal candidiasis)
Mechanism of action is same as that of Ketoconazole i.e. ergosterol
inhibition by inhibiting CYP450
Clotrimazole is favoured in vaginitis because of long lasting residual
effect and once daily dosing
Miconazole causes frequently vaginal irritation & pelvic cramp.
Available as lotion, cream, powder, vaginal tablet etc.
4.Allylamine:
Terbinafine:
M/A:

inhibit the enzyme squalene epoxidase
inhibit synhesis of ergosterol.
 Possible superior to greiseofluvin in onchomycoses.
 A/E:
 GI distress,rash,headache,possible hepatotoxicity.
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5. β-glucan synthase inhibitors:
1) Caspofungin
 Metabolized by hydrolysis and N-acetylation
 Not inhibitor/inducer/substrate of CYP
 Enzymes induced by carbamazepine, cyclosporine, dexamethasone,
efavirenz, nelfinavir, nevirapine, phenytoin, rifampin
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2)
Micafungin:
 Substrate 3A4 minor; weak inhibitor of 3A4
 Increased levels of nifedipine
 Increased monitoring for toxicity and dosage adjustment needed.
3)
Anidulafungin:
 Not inhibitor/inducer/substrate of CYP
 Degrades at normal pH and condition to an open-ringed peptide
6.Other topical agents:
All these drugs are used in dermatophytosis.
1) Tolnaftate:
 Effective drug fof tinea cruris and tinea corporis.
 It causes little irritation and is better than other topical agents.
2) Ciclopirox olamine:
 It used in tinea infections,pityriasis versicolor , dermal candidiasis
and vaginal candidiasis.
3) Undecylenic acid:
 It used for tinea pedis,nappy rash and tinea cruris.
 Used in combination with its zinc salt.
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4) Benzoic acid:
 Antifungal+Antibacterial
 Used in combination with salicyclic acid,its kerolytic action helps to
remove the infected tissue and promotes the penetration of benzoic
acidinto the lesion.
5) Quiniodochlor:
 Weak antifungal+antibacterial
 Used in dermatophytosis,mycosis barbae,seborrhoeic dermatitis,
infected eczematricomonas vaginitis.
6) Sodium thiosulphate:
 It is effective in pityriasis versicolor.
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Future Targets
Moving into the cell:
 Aspartate pathway:
Fungi must synthesize Met, Ile, Thr.
 Siderophore biosynthesis:
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Iron importation mechanism
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Fungi must scavenge for iron inside host
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Siderophores bind soluble iron with high affinity
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Actively transported through cell wall
Summary of Treatments
Pathogen
Primary
Secondary
Cryptococcus neoformans
Amphotericin B +
Flucytosine followed by
Fluconazole
Itraconazole or
Amphotericin B
Histoplasma capsulatum
Itraconazole or
Amphotericin B
Fluconazole
Mucomycosis
Amphotericin B
Posaconazole
Sporothrix schenckii
Amphotericin B
Itraconazole
Saturate solution of
potassium iodide
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 References:
1)Tripathi KD.Essentials of medical pharmacology,Jaypee brother
medical publisher,5th edition(2005),p.p:715-724
2)Rang H.P.,Dale M.M,Ritter J.M.,Flower R.J.,Churchill livingstone
Elsevier,6th edition(2007),p.p:692-697
3) Goodman and Gilman, The pharmacological basis of therapeutics, 11th
Edition,2008,p.p:800-811
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