Pharmacology-4 PHL 425 Sixth Lecture By Abdelkader Ashour, Ph.D. Phone:

Antifungal Agents

Antifungal Agents, Overview  Fungi are plant-like organisms but, unlike plants, they cannot turn sunlight into food (photosynthesis)  Fungi may exist in colonies of single cells (yeast) or filamentous multicellular aggregates (molds or hyphae)  Many types of fungi live harmlessly in the soil, on food or on our skin  However, some types of fungi can thrive and multiply on the surface of the body, to cause infection of the skin, nails, mouth or vagina  Human fungal infections have increased dramatically in incidence and severity in recent years, due mainly to:  Cancer treatment and the HIV epidemic (why? Is immune system involved?)  Critical care accompanied by increases in the use of broad-spectrum antimicrobials  Immunosuppressive therapy (organ transplantation)

Antifungal Agents, Overview  Fungal infections (Mycosis): can be divided into: 1.Superficial infections (mucocutaneous); affecting skin, nails, scalp or mucous membranes) 2.Systemic infections (affecting deeper tissues and organs)  Fungal infections of the skin, nails, vagina and mouth are quite common, but are rarely serious and do not usually spread deeper into the body (with a normal immune system)  It is rare for fungi to affect internal organs. These internal fungal infections can be serious and, sometimes, life-threatening  Systemic mycoses due to primary pathogens originate primarily in the lungs and may spread to many organ systems  Organisms that cause systemic mycoses are virulent “dimorphic”  Infection occurs in patients with immune deficiencies

Superficial fungal infections  Fungi that cause superficial skin infection are called dermatophytes ( e.g.ring worm);  Tinea infections (scalp, body, foot)  Candidiasis (thrush) Tinea Versicolor Tinea corporis Onychomycosis

Superficial fungal infection Fungi that cause superficial skin infection are called dermatophytes ( e.g.ring worm); Tinea infections (scalp, body, foot) Candidiasis (thrush) Tinea pedis and onychomycosis Tinea Capitis

Antifungal drugs  Oral or parenteral drugs  For systemic infections  For nail or scalp or massive skin infection  For refractory or intractable cases  Topical and oral for mucocutaneous infections

Antifungal preparations  They are used to treat various fungal infections in the form of creams, shampoos, pessaries (topical) and medicines to take by mouth, and injections for systemic effects  The length of treatment depends on the type of the offending fungi and severity of infection  Some courses of treatment can be as short as a few days (vaginal thrush), other can be for ten weeks (ringworm infection of the scalp) or months for onychomycosis  Topical antifungal creams and shampoos: usually cause no side effects and are easy to use

Systemic Antifungal Drugs 1- Amphotericin B 2- Flucytosine 3- Azoles

1- Amphotericin B  Amphotericin B is a polyene antifungal antibiotic produced by Streptomyces nodosus  It is poorly absorbed from the GIT  Oral amphotericin B is thus effective only on fungi within the lumen of the GIT and cannot be used for treatment of systemic disease  For systemic infections, it can be given by slow i.v. injection  Intrathecal for fungal meningitis  It can also be applied topically

Amphotericin B  Mechanism of Action of Amphotericin B Amphotericin B is selective in its fungicidal effect because it exploits the difference in lipid composition of fungal and mammalian cell membranes Amphotericin B binds to ergosterol (a fungal cell membrane sterol) and alters the permeability of the cell by forming amphotericin B- associated pores in the cell membrane …..how? Amphotericin B combines avidly with ergosterol along the double bond- rich side of its structure and associates with water molecules along the hydroxyl-rich side This amphipathic characteristic facilitates pore formation by multiple amphotericin molecules, with the lipophilic portions around the outside of the pore and the hydrophilic regions lining the inside The pore allows the leakage of intracellular ions and macromolecules, eventually leading to cell death

Amphotericin Mechanism of action of Amphotericin D K +,Na + Fungal Cytoplasmic membrane Ergosterol  Fungal cell death Amphotericin binds to ergosterol and forms pores in the membrane

Amphotericin B  Adverse Effects: Toxicity of amphotericin B can be divided into two broad categories: immediate reactions, related to the infusion of the drug, and slow reactions Infusion-Related Toxicity: These reactions consist of fever, chills, muscle spasms, vomiting, headache and hypotension They can be ameliorated by slowing the infusion rate or decreasing the daily dose  Antifungal Activity Despite its high toxicity, amphotericin B remains standard therapy for most life-threatening systemic mycoses  It is used intravenously in the treatment of many systemic mycoses Amphotericin B remains the antifungal agent with the broadest spectrum of action It has activity against the clinically significant yeasts, including Candida albicans, but ineffective against dermatophytes

Amphotericin B Slower Toxicity: Renal damage is the most significant toxic reaction A varying degree of anemia due to reduced erythropoietin production by damaged renal tubular cells is occasionally seen Abnormalities in liver function tests Neurotoxicity, seizures: intrathecal administration

Flucytosine (5-FC) Permease 5-FC Deaminase 5-FU RNA & DNA synthesis inhibits thymidylate 5-FdUMP  A synthetic pyrimidine antimetabolite  It is a prodrug that is converted by fungi to 5 fluorouracil; the latter inhibits thymidine synthesis  5-FC needs certain enzymes in the fungi to enter the cell and be transformed to 5- FU

Flucytosine  FC has a selective toxicity because mammalian cells have low levels of permease and deaminase  It is given by the oral route  Penetrates well into CSF  Flucytosine must not be used as a sole agent in life-threatening fungal infections due to relatively weak antifungal effects and fast development of resistance  Resistance is due to changes in the sensitivity of the target enzymes (decreased activity of fungal permease and deaminase)  Flucytosine with amphotricin B are synergistic, as amphotricin increases cell permeability allowing more 5-FC to penetrate the cell  Adverse effects of 5-FC includes; reversible myelosuppression; anemia, leucopenia, thrombocytopenia, elevated hepatic enzymes, alopecia, GI disturbances; nausea, vomiting and diarrhea

3- Azoles  Mechanism of Action The antifungal activity of azole drugs results from the reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes The specificity of azole drugs results from their greater affinity for fungal than for human cytochrome P450 enzymes Imidazoles (e.g., ketoconazole) exhibit a lesser degree of specificity than the triazoles, accounting for their higher incidence of drug interactions and side effects  Azoles are synthetic compounds that can be classified as either imidazoles or triazoles according to the number of nitrogen atoms in the five-membered azole ring  The imidazoles consist of ketoconazole, miconazole, and clotrimazole. The latter two drugs are now used only in topical therapy  The triazoles include itraconazole and fluconazole

MOA of azoles Lanosterol Blocked by azole Fungal P450 Ergosterol

Azoles  Adverse Effects As a group, the azoles are relatively nontoxic. The most common adverse reaction is relatively minor gastrointestinal upset All azoles have been reported to cause abnormalities in liver enzymes and, very rarely, clinical hepatitis  Clinical Use The spectrum of action of these medications is quite broad, ranging from many candida species, the dermatophytes, to the endemic mycoses They are also useful in the treatment of intrinsically amphotericin- resistant cases

1- Ketoconazole  Oral route, it requires gastric acid for absorption (cola drinks increase acidity)  Does not penetrate into the CSF  Less selective for fungal cytochrome enzymes (can inhibit host cyp450, can inhibit cortisol and testosterone synthesis)  Side effects: - Allergy, GI disturbances most common - It inhibits cytochrome P 450 isoenzymes responsible for the synthesis of adrenal and gonadal steroids leading to gynecomastia, menstrual irregularity and impotence -  liver enzymes 2- Fluconazole  Wide therapeutic window (few interactions and better GIT tolerance)  High oral bioavailability and good CSF penetration  It lacks the endocrine side effects of ketoconazole (no inhibition of cytochrome P 450 )

3- Itraconazole  It is the most potent azole  Itraconazole has a broader spectrum of activity  Oral or I.V.  More selective for fungal enzymes  no endocrinal disturbances  Itraconazole is over 99% protein bound and has virtually no penetration into CSF. Therefore, it should never be used to treat meningitis and other CNS infections  It should be taken after meal, preferably with an acidic drink such as orange juice

Azoles: Pulse dosing  Pulse dosing refers to taking medicine daily for 1 week a month (1 week treatment and 3 weeks without drug) for 2, 3, or 4 months  Pulse dosing with itraconazole tablets is as effective for treatment of onychomycosis as continuous dosing  The drug persists in nail for several months  Some people find it easier, cheaper and less toxic

Antifungal Agents for superficial fungal infections  The treatment of superficial fungal infections caused by dermatophytic fungi may be accomplished with: 1.Topical antifungal agents, e.g. clotrimazole, miconazole, terbinafine, ketoconazole 2.Orally administered agents, e.g., griseofulvin, fluconazole, terbinafine, ketoconazole  Superficial infections caused by candida species may be treated with topical applications of clotrimazole, miconazole, ketoconazole, nystatin or amphotericin B  Chronic generalized mucocutaneous candidiasis is responsive to long-term therapy with oral ketoconazole

Oral Drugs for cutaneous mycotic infection  Azoles; ketoconazole, fluconazole, itraconazole  Griseofulvin  Terbinafine

Griseofulvin Fungistatic Treat fungal infections of the skin and nails Ineffective topically Replaced by new agents which are more tolerated & with less side effects & interactions (terbinafine) Griseofulvin is reserved for cases with nail, hair or large body surface involvement

Griseofulvin: MOA The drug binds to tubulin, Disrupts the mitotic spindle, inhibits fungal mitosis

Griseofulvin: adverse effects  Headache, confusion, dizziness, fatigue  Allergic reactions; urticaria  GIT irritation (N, diarrhea, dyspepsia)  Impairment of liver enzyme activity  Can reduce the effectiveness of oral contraceptives as it is a cytochrome p450 enzyme inducer

Terbinafine  Synthetic allylamine, keratophilic fungicidal drug  It is deposited in skin and nails  For treatment of dermatophytes, especially onychomycoses (fungal infection of the nails)  It is more effective than griseofulvin and itraconazole  It is also used for candida albicans infection

Terbinafine: MOA Squalene LanosterolErgosterol Squalene epioxidase Terbinafine inhibits Squalene Fungal cell death

Side effects of Terbinafine GIT; nausea, constipation, diarrhea Rashes, urticaria CNS; headache, dizziness, vertigo Hepatobiliary dysfunction: elevated liver enzymes Changes in taste sensation Visual disturbances

Topical drugs for mucocutaneous fungal infections Polyenes –Nystatin (Nilstat ; Mycostatin) Azoles –Clotrimazole (Canesten) –Ketoconazole (Nizoral); Antifungal shampoo –Miconazole (Daktarin) Allylamine –Terbinfine (Lamisil)

Nystatin  Nystatin is a polyene antifungal drug to which many molds and yeast infections are sensitive, including Candida spp.  MOA: Like amphotericin B, nystatin binds to ergosterol, a major component of the fungal cell membrane. When present in sufficient concentrations, it forms pores in the membrane that lead to K+ leakage and death of the fungus

Nystatin  Nystatin is too toxic for parenteral administration and is only used topically  It is currently available in creams, ointments, suppositories and other forms for application to skin and mucous membranes  Nystatin is not absorbed to a significant degree from skin, mucous membranes, or the gastrointestinal tract. As a result, it has little toxicity  Nystatin is active against most candida species and is most commonly used for suppression of local candidal infections  Some common indications include oropharyngeal thrush and vaginal candidiasis

Miconazole  An azole used only topically for treatment of oropharyngeal and vaginal candidiasis  It is a potent inhibitor of warfarin metabolism and causes bleeding in warfarin – treated patients even when applied topically

Preparations for vaginal infections Nystatin (Nilstat® vaginal cream & pessaries) Clotrimazole (Canesten® vaginal cream & ovules) Miconazole Failure of therapy could be due to:  Diabetes Mellitus  Broad spectrum antibiotics  Immunosupression

Mechanisms of action of antifungal drugs

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