Anti Fungal Drugs -Azoles, Echinocandins, Allylamines and Flucytosine

Flucytosine

Discovered in 1957, a group of scientists working on anti-neoplastic drugs established it to have anti-fungal properties.

Chemistry

Fluorinated pyrimidine  like 5-Fluorouracil (which is anti-metabolite)

Mechanism of Action

Anti-fungal having fungistatic effect.

1. Taken up by fungal cells
2. Deaminated to 5-FU
3. Incorporated  as FUTP in RNA
4. 5-FdUMP  (Inhibitor of thymidylate synthetase)

Cytosine deaminase is absent in mammals, humans are not effected.

Synergy with Amphotericin B and Azoles. Pores are formed or induced which facilitate entry of flucytosine in cell.

Mechanism of resistance

Monotherapy is not recommended due to emergence of resistance, so given in combination slowly.

Resistance is said to be mainly due to altered mechanism of metabolism of flucytosine to 5 fluorouracil, due to mutation in cytosine deaminase.

Pharmacokinetics

• Readily absorbed orally.
• High bioavailability of  >90%
• T_1/2  3-4hours
• Peak plasma levels occur within 1-2 hours.
• Dose: 100-150 mg/kg/day
• Distribution (all parts, CSF high )
• Excretion by glomerular filtration

Dose adjustment has to be done in renal failure as plasma levels higher due to increased half life to 200 hours or more.

Spectrum Of Activity

Narrow spectrum, effective for:         

a.      Cryptococcus neoformans ,
b.      Candida spp

Clinical Uses

1.      Cryptococcal meningitis –with Amphotericin B
2.      Chromoblastomycosis –with Itraconazole

Adverse Effects

As resembles 5-fluroruracil (anti-neoplastic) so may cause:    

1. Bone marrow toxicity as antimetabolite:

• Anemia
• Leukopoenia
• thrombocytopoenia

2. Active metabolites produced by intestinal flora thus enterocolitis can occur.
3. GIT manifestations:

• Nausea
• Vomiting
• Diarrhea
• Abdominal cramps and pain

4.      Liver enzymes elevation
5.      Nephrotoxicity
6.      With prolonged use alopecia may occur as resembles anti-neoplastic drugs.

Azoles

Imidazole

Used specifically for topical infections. Ketoconazole was used as highly effective for most fungal infections previously, but due to higher p450 enzyme drug interactions, newer drugs are preferred. It is reserved only for scalp fungal infections.

High quantity is used to suppress levels of corticosteroids.

Triazoles

Highly effective for most fungal infections.

Mechanism of Action

Most are synthetic.

• Inhibit the fungal cytochrome P450 enzyme, (α-demethylase) which is responsible for converting lanosterol to ergosterol (the main sterol in fungal cell membrane ).
• Inhibition of mitochondrial cytochrome oxidase leading to accumulation of peroxides that cause autodigestion of the fungus.
• Imidazoles may alter RNA& DNA metabolism.

Thus anti-fungal action.

Spectrum Of Activity

1. Most candida species:
2. Candida albicans,
3. C tropica ,
4. C parasilosis,
5. C glabrata
6. Cryptococcus neoformans (Fluconazol)
7. Blastomyces dermatitidis,
8. Histoplasma capsulatum,
9. Coccidioidomycosis
10. Zygomycosis,
11. Mucormycosis (Posaconazole)
12. Ring worm
13. Pseudallescheria boydii ( Amphotericin B resistant)

Although most fungal species are inhibited but have affinity for p450 of humans, which is the main reason why ketoconazole is not recommended now.

Adverse Effects

1. Nausea, vomiting
2. Allergic rash
3. Hormone imbalance
4. Fluid retention
5. Hepatitis
6. Teratogenic
7. Inhibits drug metabolism
8. Absorption reduced by H₂ antihistamines and omeprazole and antacids (KETOCONAZOLE)

	Solulibility	Absorption	Bioavailability	t1/2 hours	Excretion	Route
Ketoconazole	Low	Erratic	Less	7-10	Hepatic	Oral
Itraconazole	Low	Erratic	55 ­food, low pH	24-42	Hepatic	Oral, IV 100-400mg/d
Fluconazole	High	High	>90%	22-31	Renal	Oral, IV 100-800mg/d
Posaconazole	High	High?	­food	___	Hepatic	Oral 800mg/d
Voriconazole	High	High	96¯ food	6	Hepatic	Oral, IV 400mg/d

Ketoconazole

Due to adverse effects used for:

1. Scalp infections
2. Corticosteroid suppression

Itraconazole

Newer triazole, may posses activity against human p450 enzyme, leading to drug interactions. Decreased bioavailability is seen with Rifampicin. Cannot cross blood brain barrier readily, used for:

1. Histoplasmosis
2. Blastomycosis
3. Sporothrix
4. Also used for candidiasis in dermophytosis and oncomycosis

Adverse Drug Reactions

1. May lead to rash
2. Increased levels of hepatic enzymes
3. Hypokalemia
4. Stevens Johnson syndrome in some
5. GIT –nausea, vomiting, abdominal pain

Fluconazole

Has high bioavailability and penetrates BBB, highly water soluble and has high therapeutic index. Drug interactions are less. GI effects are less readily seen with fluconazole as is highly tolerable.

Uses

1. AIDS
2. Immunocompromised patients
3. Cryptococcal meningitis
4. Ocular keratitis
5. Candidemia
6. Mucocutaneous candidiasis

No activity against Aspergillosis.

Adverse Drug Reactions

Although GI manifestations not common, but may lead to:

1. Nausea
2. Vomiting
3. Abdominal pain
4. Skin rashes
5. Alopecia
6. Stevens Johnson syndrome

Posaconazole

Newer agent discovered having activity against:

1. Candida
2. Aspergillosis
3. Zygomycosis
4. Liuamycosis

Used for:

1. Prophylaxis in patients of leukemia in which chemotherapy is initiated, such patients are prone to fungal infections.
2. In bone marrow transplant patients especially those undergoing graft cases.

Voriconazole

Less plasma protein binding having less affinity for cytochrome p450 and less interactions.

It is highly effective against aspergillus. It is the drug of choice.

Adverse Drug Reactions

1. Rash
2. Increased hepatic enzymes
3. Visual disturbances –blurring of vision
4. Decreased perception to color is seen especially to bright colors.

Echinocandins

Newly discovered agents.

1. Caspofungin
2. Micafungin,
3. Anidulafungin

• Large cyclic compounds with long chain fatty acids.
• Fungicidal action
• Inhibit 1,3-b-D-glucan synthase, which is required for glucan polymerization in the wall of filamentous fungi

Spectrum of Activity

a.      Candida albicans,
b.       C glabrata,
c.       C tropicalis,
d.      C krusei,
e.       Aspergillus fumigatus,
f.        A  flavus,
g.       A terreus
h.      Pneumocystis  jiroveci*

Anti protozoal agents may have some activity

Pharmacokinetics

Caspofungin

• Given IV only
• Half-life     9-11 hrs
• Protein binding 90%
• Elimination -Renal & GIT

Dose    70mg followed by 50mg daily

Micafungin

• Half life 11-15 hours
• Dose: 50-150 mg/day

Anidulafungin

• Half life longer: 24-48 hours
• Dose: 50-200 mg/day

Mainly used for:

1. Candidiasis
2. In neutropoenic fungal infections disseminated mucocutaneous candidiasis –caspofungin highly effective.

Allylamines

Terbinafine

• Inhibits squalene 2, 3- epoxidase. Squalene is fungicidal to sensitive organisms.
• Systemic agent used orally for dermatophytes
• Metabolized by liver excreted in urine
• Adverse effects include hepatitis and rashes. Both are rare.
• Accumulates in keratin and newly synthesized skin.

Azoles for topical use

In the form of vaginal creams, suppositories, tablets for vaginal candidiasis given once daily .

Miconazole/Clotrimazole

Absorption is less than 0.5% from intact skin, 3-10% from vagina (its activity remains for 3 days).

Used in dermatophytes , cutaneous candidiasis & vulvovaginal candidiasis, oropharyngeal candidiasis and dermatophytic infections like:

1. Tinea corporis
2. Tinea pedis
3. Tinea cruris

Side effects : Erythema, edema, , urticaria & mild vaginal burning sensation.

Tolnaftate

• Effective in most cutaneous mycosis.
• Ineffective against Candida.
• Used in tinea pedis ( cure rate 80% ).
• Used as cream, gel, powder, topical solution.
• Applied twice daily.

Naftifine

• Broad spectrum fungicidal .
• Available as cream or gel.
• Effective for treatment of tinea cruris.

Terbinafine

• Drug of choice for treating dermatophytes (onychomycoses).
• Better tolerated ,needs shorter duration of therapy.
• Inhibits fungal squalene epoxidase, decreases
• The synthesis of ergosterol .(Accumulation of squalene ,which is toxic to the organism causing death of fungal cell).

Ciclopirox Olamine

May block amino acid transport –  penetrates well –

Used:- Candida and Dermatophytes

Haloprogin

Used for dermatophytes and candida, may cause burning at site of application

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