Antifungal drugs

Infection disease caused by fungi are called Mycoses. Fungi unlike bacteria they have rigid cell wall contain keratin as well as polysaccharide and cell membrane contain ergosterol rather than cholesterol in mammalian membran.

Fungi cause slowly progressive chronic infections,however,they may cause life-threatening acute infections in immunoompromised patients (Aids, cancer, Transplant tissuses)so called opportunistic infection.

Human mycoses divided into: Superficial mycoses involve (skin, hair, nail). Subcutaneous involve,subcut. Tissues. Systemic mycoses involve internal organs (serious and difficult to treated ).

Drugs used for treatment of fungal infections Drugs used for subcutaneous and systemic fungal inf.

Amphotercin B Naturaly polyene macrolide ,antibiotic produce by Strptomyces nodosus.

Mechanism of action Bind to ergosterol in plasma membrane of sensitive fungal cell they form pores (channels)disrubt membrane function allawing electrolyte k to leak from the cell resulting in cell death.

Spectrum Either fungicidal or fungi static depending on organism and concentration of drug, Its acts against Candida albicans and histoplasma capsulatum., Cryptococcus neoformans, Blastomyces dermatitidis, and many strains of aspergillus. [Note: Amphotericin B is also used in the treatment of the protozoal infection, leishmaniasis.]

Kinetics It bound to plasma protein extensively. Excreated by urine and bile. Not cross CSF. Cross placenta

Given I. V infusion(Sodium loading with infusions of normal saline Given I.V infusion(Sodium loading with infusions of normal saline. therefore, the lipid-based amphotericin B products are alternatives utilized to minimize nephrotoxicity).

Side effects Low therapeutic index so may cause Fever and chills Renal impairment Hypotension(A shock-like fall in blood pressure accompanied by hypokalemia may occur, requiring potassium supplementation).

5.Anemia (Normochromic, normocytic anemia caused by a reversible suppression of erythrocyte production may occur. This may be exacerbated in patients infected with HIV who are taking zidovudine. 6.Neurological effects(Intrathecal administration ). 7.Thrombophlebitis

Flucytosine Its synthetic anti fungal agent used only in combination with amphotericin for treatment of systemic mycoses and meningitis caused by cryptococcus neoformans and candida.

M. Of action Flucytocin is taken by fungal cell and its converted intracellurally to 5 FluorouraciL )5-FU)which is inhibit DNA andRNA synthesis.

Flucytosine spectum Its fungistatic,effective in treatment of cryptococcus noeforman and candida infection.

PK of Flucytosine Well absorbed orally Cross CSF. Excreted in urine.

Side effect GIT disturbance Hepatic dysfunction Enterocolitis Neutropenia,thrombocytopenia, bone marrow depression.

Azoles      Ketoconazole Itraconazole Fluconazole Voriconazole . . .

Ketaconazole M. of action Block the demethylation of lanosterol to ergosterol which the principle sterol of fungal membrane thereby inhibit fungal cell growth.

PK. Only given orally. Food and antacid impair its absorption. Not enter CSF. Metabolize in liver. Excreted via urine, bile .

Spectrum Its either fungistatic or fungicidal depending on the dose. The spectrum of action of azole medications is broad, including many candida species, C neoformans, (blastomycosis, histoplasmosis), the dermatophytes in the case of itraconazole and voriconazole, even aspergillus infections.

Side effect Allergic reaction GIT disturbance Hepatic dysfunction Endocrine effect result from blocking androgen and adrenal steroid synthesis so may cause gynaecomastia and decrease libido ,impotence in men and menstrual irregularities in women.

Drug Interaction Inhibit P450 Cytochrome can potentiate the toxicity of cyclosporin,phenytoin warfarin. Rifampin, H2 Inhibitors decrease the action of ketaconazole .

Fluconazole M. of action Its same as ketoconazole. Its effective against all form of candidiasis Given orally or I.V. Penetrate CSF therefore indicated for treatment of meningitis. Excreted via kidney. Lack of endocrine effect of ketoconazole.

Side effect Side effect GIT disturbance. Teratogenic effect.

Itraconazol M. of action Same as other azole. Its drug of choice for treatment of blastomycosis,histoplasmosis,AIDS. Given orally require acid for dissolusion. Metabolize by liver.

Side effects Nausea ,vomiting. Rash Hypertension Edema Headache

Voriconazole Broad spectrum Good tissue penetration including CNS Elimination by metabolism It cause visual disturbances

Caspofungin M. of action Inhibit synthesis of B-1,3-D glucan enzyme leading to lyses and cell death.

How do they work? Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Uses Uses in aspergillus and candida species. PK. I.V used, highly bound to protein. Duration 11-15 hours. Excreted via urine and fecal route.

Side effect Nausea Fever Phlebitis Rash ,flushing due to release of histamin From mast cell.

Drugs for superfacial mycotic infection

Terbinafine M.Of action Inhibit fungal squalen peroxides thereby decresing the synthesis of ergosterol which result in cell death.

How do they work? Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Sepctrum Fungicidal against candida albicans which need prolog therapy about 3 months. Used in treatment of onychomycosis(fungal infection of nail) which need short duration of action.

Kineitcs Oral biovialability only40% due to first pass metabolism. Deposite in skin ,nail ,fat. Avoid in pregnancy Excreted in urin.

Side effect GITdisturbance. Headach,rash. Increase liver enzyme. Loss of visual disturbance.

Griseofulvin M. of action Accumulation in newly synthesized keratin containing tissue where it cause disruption of miotic spindle and inhibition of fungal mitosis.

Spectrum Fungistatic and its effective against dermatophytes.

kinetics Absorped from GIT, more absorption with fat diet. Its given orally.(adminstered2-6 weeks for skin and hair infection). Metabolize and excreted by kidney.

Side effect GITdisturbance. Allergy. Hepatic toxicity. Induce cytocrome P450 (anticoagulant).

Nystatin Its polyene macrolide much like amphotercin B,and has the same mechanism of action.

Ergosterol binding drugs (nystatin) Nystatin bind to ergo. In fungal plasma membrane, increase permeability and result in leakage of essential cellular components leading to cell death. Limited use for superficial Candidal infections of skin, oral , vaginal mucosa topically Liquid and lozenges should contact with infection for 5-7 min

PK Uses topicaly Never used parenterally because of its toxicity. Excreted in feces.

Side effect Rare , nausea and vomiting.

Topical agent Clotrimazole,miconazole,terconazole All are used topically not given parenterally because of its toxicity. Same action as ketoconazole. .

Treatment of oral candidiasis

Treatment of oral candidiasis Topical nystatin which used in oral moniliasis ,thrush, denture stomatitis.(2,3ml)suspension,100,000 units ml swished for 5 minute every 6 hours. Or lozenges(2oo,ooo)units 1-2 lozenges 4or5 times daily. Nystatin ointment(100,000units g)every 6 hours applied to tissue surface for treatment denture stomatitis .

Nystatin cont. *for infants the nystatin suspension is administered in dose of 200 000 units \ 4 times aday i.e 1 ml (15 drops) is administered by dropper in each side of mouth \ 4 times \ day

Clotrimazole Oral troches(10mg) 1 for 5 times daily for two weeks used in treatment of oral candidiasis. Candidiasis with lichen planus need topical cotrimazole with topical steroid. Replaced nystatin in case of liver disease and alcoholism.

Ketoconazole Systemic antifungal 100 or200mg per day in sever cases of oral candidiasis in AIDS. I n case of liver toxicity ,fluconazole or itraconazole.

Topical Rx Patients need follow up appointment ,if no response is seen ,systemic agents should be used Rx for 7 days or continue for at least twice the time required to produce resolution of clinical signs and symptoms

Denture stomatitis