Antifungal

              ANTI FUNGAL

        Classification of Antifungal Agents
• Fungal infections can be divided into two quite different conditions depending on the location of the infection
• The most common fungal infection is superficial and is usually confined to the skin, mucous membrane and nails
• The antifungal agents are classified as follows:
o Systemic drugs for superficial fungal infections
o Drugs for subcutaneous and systemic mycotic infections

• The antifungal drugs are subdivided into the following groups
o Drugs that act by altering cell membrane permeability

Subdivision of antifungal

1.Polyenes ( e.g. Amphotericin)
2.Azoles: such as Imidazoles (e.g. Ketaconazole, miconazole, and clotrimazole) and
3.Triazoles (e.g. fluconazole and itraconazole)
4.Allylamine: Terbinafine
o Drugs that block nucleic acid (DNA) synthesis e.g. Flucytosine
o Drugs that disrupt microtubule function and inhibit mitosis e.g. Griseofluvin

Drugs for Systemic Fungal Infection
• The main drugs used for systemic fungal infection or systemic mycoses are azole antifungal agents (Ketoconazole, Fluconazole and Itraconazole)
Pharmacokinetics of Azole Antimycotic Agents
• Oral bioavailability is variable (normal gastric acidity is required).
• Fluconazole is more reliably absorbed via the oral route than the other azoles.
• Ketoconazole and itraconazole are heavily dependent on acidic gastric conditions in the stomach for absorption.

• The drugs are distributed to most body tissues, but with the exception of fluconazole, drug levels achieved in the central nervous system (CNS) are low.
• Metabolised in the liver.
• Fluconazole is eliminated by the kidneys, largely in unchanged form.

• Mechanism of action:
      The azoles interfere with fungal cell membrane permeability by inhibiting the synthesis of ergosterol (a compound present in many fungi which is converted to vitamin D2 when irradiated with ultraviolet light) which is an essential component of fungal cells.

Clinical Uses
• Ketoconazole
o Has a narrow antifungal spectrum.
o For oesophageal candidiasis, give 200-400mg orally daily until remission is obtained.
o Oral dosages of ketaconazole with or immediately after meals.
• Fluconazole
o The drug of choice in esophageal and oropharyngeal candidiasis
o A single oral dose usually eradicates vaginal candidiasis.
o Fluconazole is now the drug of choice for initial and secondary prophylaxis against cryptococcal meningitis.

• Toxicity
o Adverse effects of the azoles include vomiting, diarrhoea, rash, and sometimes
hepatotoxicity (especially in patients with pre-existing liver dysfunction).
o Ketoconazole inhibits hepatic cytochrome P450 isozymes and may increase the plasma levels of other drugs, including anticoagulants, cyclosporine, oral hypoglycemics, phenytoin, and protease inhibitors.
o Ketoconazole interferes with the synthesis of adrenal and gonadal steroids and may lead to gynecomastia, menstrual irregularities, and infertility.

Systemic Drugs for Superficial Fungal    Infections

Griseofulvin
• Pharmacokinetics
o Griseofulvin is a very insoluble fungistatic drug derived from a species of penicillium.
o Its only use is in the systemic treatment of dermatophytosis.
o It is administered in a microcrystalline form at a dosage of 1 gram/day. Absorption is improved when it is given with fatty foods.
o Because its action is to prevent infection of these new skin structures, griseofulvin must be administered for 2-6 weeks for skin and hair infections to allow the replacement of infected Flucytosine (5-Fluorocytosine, 5-FC)

• Pharmacokinetics
o 5-FC is a pyrimidine antimetabolite related to the anticancer drug 5-fluorouracil.
o It is effective orally and is distributed to most body tissues, including the CNS.
o The drug is eliminated intact in the urine, and the dose must be reduced in patients with renal impairment.

• Mechanism of action
o Flucytosine is accumulated in fungal cells by the action of a membrane permease and converted by cytosine deaminase to 5-FU, an inhibitor of thymidylate synthase.
o Selective toxicity occurs because mammalian cells have low levels of permease and deaminase.

Resistance can occur rapidly and involves decreased activity of the fungal
permeases or deaminases.
o When 5-FC is given with amphotericin B, emergence of resistance is decreased and synergistic antifungal effects may occur.
• Clinical uses
o The antifungal spectrum of 5-FC is narrow; its clinical use is limited to the treatment, in combination with amphotericin B, of infections due to Cryptococcus neofomans and possibly systemic candidal infections.

• Adverse effects
o Bone marrow depression, aplastic anaemia, nausea, GIT disturbances, elevated hepatic enzymes, vertigo, hypokalaemia, skin reaction, and hypoglycaemia. by the resistant structures.
o Nail infections may require therapy for months to allow regrowth of the new
protected nail and is often followed by relapse.
o It potently induces cytochrome P450 enzymes and causes several clinically important drug interactions.

• Mechanism of action
o Griseofulvin interferes with microtubule function in dermatophytes and may also
inhibit the synthesis and polymerization of nucleic acids.

• Clinical uses
o The drug is indicated for severe dermatophytoses of the skin, hair, and nails.
o Griseofulvin has been largely replaced by newer antifungal medications such as
itraconazole and terbinafine.

• Adverse effects
o Headaches
o Mental confusion
o Gastrointestinal irritation
o Photosensitivity
o Changes in liver function
o A drug interaction may enhance coumarin metabolism, resulting in decreased anticoagulant effect

• Contraindications: Should not be used where there is severe hepatic impairment, or during pregnancy

                         Azoles
(Ketoconazole, Itraconazole and              Fluconazole)
• All three of the azoles used for systemic antifungal infections have activity against dermatophytes.
• Intermittent dosing with itraconazole is as effective in onychomycoses as continuous dosing because the drug persists in the nails for several months.
• Choice of which antifungal to use will depend on the cost, and interaction to other drugs.

Topical Drugs for Superficial Fungal  Infections
• A number of antifungal drugs are used topically for superficial infections caused by Candida albicans and dermatophytes.

A. Nystatin
• A polyene antibiotic (related to amphotericin) that disrupts fungal membranes by binding to ergosterol.
• Effective against infections caused by a wide range of yeast and yeast like fungi.
• It executes its killing effects on the organism’s cells by affecting cell permeability.

• Therapeutic uses
o Oral , vaginal and cutaneous candidiasis
o Has no beneficial effects against fungal nail infections
o Commonly used topically to suppress local candida infections and has been used orally to eradicate gastrointestinal fungi in patients with impaired defence
mechanisms
• Dose
o For oral candidiasis, 1-2ml suspension four times daily.
o Vaginal candidiasis, use 100,000IU as pessaries or 100,000IU (1g) of cream inserted with an applicator high into the vagina at night for at least 2 weeks.
o For cutaneous candidiasis, a thin layer of cream or ointment is applied to all affected areas twice daily for two weeks.
o Other topical antifungal agents include the azole compounds miconazole and
clotrimazole.
     B.   Miconazole and clotrimazole are both synthetic imidazoles which are active against fungi (both dermatophytes and yeast) and gram positive (staphlylococcus and streptococcus species).
   
   Miconazole and clotrimazole are used for the topical treatment of most common fungal infection of the skin and vagina.
      Specific indication includes ringworm, diaper dermatitis, vaginal candidiasis, and fungal infection of the outer ear.
        Miconazole is used in the treatment of and prevention of oral candidiasis and
denture stomatitis.

    Important Drug Interactions of Ketoconazole and Griseofulvin to other
Drugs
Ketoconazole Interactions with Cimetidine
• Absorption of ketoconazole from the GIT is pH dependent therefore; avoid administering simultaneously with drugs that reduce gastric secretion and increase gastric pH (e.g. Histamine H2 receptor antagonists and other antacids) because they will delay to reach the therapeutic threshold and hence the failure of drug to function.
       Ketoconazole Interaction with Anti-Retroviral
• Ketoconazole interacts with nevirapine by inhibiting the enzyme cytochrome P450 and hence increase the levels of nevirapine in the blood.
• Also the nevirapine is a liver enzyme inducer and so they may cause high level of liver enzymes which may fasten the metabolism and excretion of the ketoconazole in the blood before it has reached the therapeutic threshold.
• Efavirenz can induce P450 metabolism of ketoconazole and reduce ketoconazole levels and its efficacy.
• Both Ketoconazole and nevirapine are hepatotoxic and hence giving them together they multiply the Liver toxicity and patient cannot well tolerate the medicine.
Avoid using the combination of ketoconazole and nevirapine together.
• Ketoconazole can increase levels of protease inhibitors (e.g. unboosted SQV, indinavir, amprenavir, nelfinavir, darunavir). A bi-directional interaction can also occur with PI so that ketoconazole levels can increase, requiring a dosage reduction to prevent
ketoconazole toxicity.

Griseofulvin Interactions with other drugs
• Griseofulvin induces hepatic enzymes, thus increasing the rate of metabolism of warfarin; adjustment of the dosage of warfarin agent may be necessary in some patients.
• The drug may reduce the efficacy of low-estrogen oral contraceptive agents, probably by a similar mechanism.
• Barbiturates e.g., phenobarbital decrease the Gastro Intestinal Tract absorption of Griseofulvin.

Polyene antibiotic
• The polyene antibiotics bind with sterols in the fungal cell membrane, principally
ergosterol.
• This causes the cell's contents to leak out and the cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible.
o Nystatin
o Amphotericin B

• Amphotericin B
o Naturally occurring polyene macrolide antibiotic, produced by Streptomyces nodosus.
o Is the drug of choice used in the treatment of the systemic mycoses
o It is sometimes used in combination with flucytosine so that lower (less toxic) levels of amphotericin are possible

• Pharmacokinetics
o Administered I.V.
o Extensively bound to plasma proteins, and is distributed throughout the body
becoming highly tissue bound, does cross the placenta
o Adjustment of dose is not required in patients with compromised renal or hepatic function
o Liposomal preparations of amphotericin B are available and have shown therapeutic efficacy
• Indications
o Oesophageal and oral candidiasis, crytococcus meningitis, histoplasmosis,
coccidioidomycosis
• Dose
o Management and Treatment of Cryptococcal meningitis
      Amphotericin B 0.7 mg/kg/day IV, + flucytosine 100 mg/kg/day PO in 4 divided doses x 14 days, followed by Fluconazole 400 mg/day x 8-10 weeks.
       Then maintenance Î Fluconazole 200mg/day for life
o Alternate regimen:
         Amphotericin B 0.7 mg/kg/day IV + flucytosine 100mg/kg/day in 4 divided doses po x 14 days followed by itraconazole 200mg bid for 8 weeks
• Mode of action
o Bind to ergosterol present in cell membranes of sensitive fungal cells to form pores or channels that involve hydrophobic bonds between the lipophilic segment of the polyene antibiotic and the sterol
o This disrupts membrane function, allowing electrolytes (particularly potassium) and small molecules to leak from the cell, resulting in cell death
o Polyene antibiotics have a higher affinity for ergosterol versus cholesterol, the sterol found in mammalian membranes explains their toxicity to the fungal cell

• Antifungal spectrum
o Amphotericin B is either fungicidal or fungistatic
• Adverse effects
• Fever, chills, muscle spasms, vomiting, headache, and hypotension, peripheral
neuropathy, pain and thrombophlebitis at injection site, renal failure, hypokalemia,
hypomagnesemia, anaemia

Flucytosine (5-Fluorocytosine, 5-FC)
• Pharmacokinetics
o 5-FC is a pyrimidine antimetabolite related to the anticancer drug 5-fluorouracil.
o It is effective orally and is distributed to most body tissues, including the CNS.
o The drug is eliminated intact in the urine, and the dose must be reduced in patients with renal impairment.

• Mechanism of action
o Flucytosine is accumulated in fungal cells by the action of a membrane permease and converted by cytosine deaminase to 5-FU, an inhibitor of thymidylate synthase.
o Selective toxicity occurs because mammalian cells have low levels of permease and deaminase.
    Resistance can occur rapidly and involves decreased activity of the fungal permeases or deaminases.
o When 5-FC is given with amphotericin B, emergence of resistance is decreased and synergistic antifungal effects may occur.

• Clinical uses
o The antifungal spectrum of 5-FC is narrow; its clinical use is limited to the treatment, in combination with amphotericin B, of infections due to Cryptococcus neofomans
and possibly systemic candidal infections.

• Adverse effects
o Bone marrow depression, aplastic anaemia, nausea, GIT disturbances, elevated hepatic enzymes, vertigo, hypokalaemia, skin reaction, and hypoglycaemia.

POSTED BY
welfare Jambo