Pharmacology-4 PHL 425

Sixth Lecture

By

Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

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 Tinea corporis OnychomycosisOnychomycosis

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 CapitisTinea 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 DrugsSystemic 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 BAmphotericin 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

Mechanism of action of AmphotericinAmphotericin

D

K+,Na +

Fungal Cytoplasmic membrane

Ergosterol

Fungal cell

death

Amphotericin binds to ergosterol and forms pores in the membraneAmphotericin 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 hypotensionThey can be ameliorated by slowing the infusion rate or decreasing

the daily dose

Antifungal ActivityDespite 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 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 P450Ergosterol

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 UseThe 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 CSFLess 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 P450 isoenzymes responsible for the synthesis of

adrenal and gonadal steroids leading to gynecomastia, menstrual irregularity and impotence

- liver enzymes

2- FluconazoleWide therapeutic window (few interactions and better GIT tolerance)High oral bioavailability and good CSF penetrationIt lacks the endocrine side effects of ketoconazole (no inhibition of cytochrome P450)

3- Itraconazole It is the most potent azoleItraconazole has a broader spectrum of activity Oral or I.V.More selective for fungal enzymes no endocrinal disturbancesItraconazole is over 99% protein bound and has virtually no penetration into CSF. Therefore, it should never be used to treat meningitis and other CNS infectionsIt 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 Lanosterol Ergosterol

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

Thank You