antifungal agents - sar (structure activity relationship )

• Fungi are eukaryotic, heterotrophic organisms that live as saprobes or parasites.

• Complex organisms in comparison to bacteria .

• Have nucleus and well defined nuclear membrane, and chromosomes.

• Have rigid cell wall composed of chitin (bacterial cell wall is composed of peptidoglycan)

• Fungal cell membrane contains ergosterol , human cell mebmrane is composed of cholesterol

• Antibacterial agents are not effective against fungi.

• Fungal infections are also called as mycoses

Antifungal Agents, also known as an antimycotic Agents

ANTIFUNGAL AGENTS

1

Introduction

2

• Systemic fungal infections are a major cause of death in patients whose immune system is compromised

– cancer or its chemotherapy,

– organ transplantation

– HIV-1 infection.

• Superficial infections of the skin and other soft tissue structures.

• Antifungal agents target

– distinctive components of the fungal cell membrane

– others alter cell wall synthesis

– nucleic acid synthesis

3

• Superficial : Affect skin – mucous membrane

– Tinea versicolor

– Dermatophytes : affect keratin layer of skin, hair, nail. e.g. tinea pedis, ring worm infection

– Candidiasis : Yeast-like, oral thrush, vulvo-vaginitis , nail infections.

• Deep Infections :

– Affect internal organs as : lung ,heart , brain leading to pneumonia , endocarditis , meningitis.

Types of Fungal Infections

Yeasts

• Fungi may be classified as

Moulds

• Yeasts: Blastomyces, candida, histoplasma, coccidioides,

cryptococcus.

• Moulds: Aspergillus spp. Dermatophytes, mucor

Superficial mycosis

• Clinically classified as:

Deep (systemic) mycosis

4

Antifungal Agents

Fungal skin infections are now the fourth most common disease in the world today- afflicting 1 billion people

The vast majority of fungal infections are caused by Aspergillus and Candida

The number of drug available to treat fungal infections is small compare to the number of drugs available to treat bacterial infections

Fungi are eukaryotes (like mammalian cells), unlike bacteria, which are prokaryotic. With few several biochemical differences

Fungal cells unlike mammalian cells (possess cell membrane), fungal cells have an outer cell wall

They also differ in the sterol component of their membranes

Ergosterol is the sterol found in the cell membranes of fungi whereas cholesterol is found in animal cells

Cholesterol

Animals Ergosterol

Fungi 5

Azoles inhibit

Polyenes (Disrupt membrane structure & function)

Flucytosine inhibits DNA synthesis 6

• Disrupt fungal cell membrane – Polyenes – amphotericin, Nystatin

– Azoles • Imidazole – Ketoconazole, Miconazole, Clotrimazole

• Triazole – Fluconazole, Itraconazole

– Allylamines - Terbinafin

– Echinocandins - Capsofungin

• Inhibit mitosis - Gresiofulvin

• Inhibit DNA synthesis - Flucytosine

• Miscellaneous – Tolnaftate

– Cyclopirox

ANTIFUNGAL AGENTS Mechanism of action of Antifungal agents

4

function Membrane Amphotericin B

Cell Wall Synthesis Capsofungin

acid Nucleic synthesis

Flucytosine synthesis Ergosterol

Azoles synthesis Lanosterol Terbinafine 5

Caspofungin inhibits cell wall synthesis

9

Classification based on mechanism of

action

•

1. Fungal cell wall synthesis inhibition: Caspofungin.

2. Bind to fungal cell membrane ergosterol: Amphotercin–B,

Nystatin.

3. Inhibition of ergosterol + lanosterol synthesis: Terbinafine,

Naftifine, Butenafine.

4. Inhibition of ergosterol synthesis: Azoles

5. Inhibition of nucleic acid synthesis: 5–Flucytosine.

6. Disruption of mitotic spindle and inhibition of fungal mitosis:

Griseofulvin.

7. Miscellaneous:

Ciclopirox, Tolnaftate, Haloprogin, Undecylenic acid, Topical azoles.

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Classification based on structure

• ANTIBIOTICS

Polyene: Amphotericin, nystatin, hamycin

Hetrocyclic benzofuran: griseofulvin

• ANTIMETABOLITE : Flucytosine

• AZOLES

Imidazoles: Ketoconazole, clotrimazole, oxiconazole,

miconazole,

Triazoles: Fluconazole, itraconazole, voriconazole,

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• ALLYLAMINES

– Terbinafine, butenafine

• ECHINOCANDINS

– Caspofungin, anidulafungin, micafungin

• OTHER TOPICAL AGENTS

– Tolnaftate, Undecyclinic acid, benzoic acid

Classification based on structure

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Polyene antifungals

A polyene is a molecule with multiple conjugated double bonds.

Polyenes are macrocyclic compounds which bear several conjugated double bonds and distinct lipophilic and hydrophilic regions- containing carbonyls, hydroxyls and a sugar

A polyene antifungal is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungals amphiphilic.

Examples of polyenes include Amphotericin B and Nystatin

Amphotericin B 13

14

Polyene antifungals

The polyene antimycotics bind with sterols in the fungal cell membrane (ergosterol)

Polyenes have greater affinity for ergosterol-containig fungal membranes so, in other words, polyenes are more selective for fungal cells

Reduction of the hydrophobic chain may result in it binding to cholesterol, making it toxic to animals.

The lipophilic region of polyenes interacts with sterols via hydrophobic interactions

Polyenes work by inserting themselves into cell membranes

This results a rise in membrane permeability and loss of cytoplasmic constituents which is detrimental to fungal cell viability

15 Amphotericin B

• Antifungal agent with the broadest spectrum of activity

• Produced by Streptomyces nodosus.

• Natural, Amphoteric polyene macrolide –

– Amphoteric = can react as an acid as well as a base

– polyene = many double bonds

– macrolide = containing a large lactone ring

• Heptaene macrolide - large lactone ring with multiple ketone and hydroxyl group)

• Drug of choice for the vast majority of life-threatening systemic fungal infections

• Interacts with ergosterols, forms pores that increase membrane permeability and allow leakage of intracellular ions &

Polyene antibiotics Amphotericin B

6

macromolecules from fungal cDer llrs(Bocrkearll death ).

Polyene antibiotics

Lactone ring

Lipophilic part

• Amphotericin B:

– Obtained from Streptomyces Nodosus

– Amphoteric in nature Hydrophilic part

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• Broad range of pathogenic fungi

• Protozoa, Leishmania braziliensis and Naegleria fowleri

• No antibacterial activity

• Amphotericin A & B are antifungal antibiotics.

• Amphotericin A is not used clinically.

Mechanism of action

18

1 ©

Hydrophobic region

Action of amphotericin B (antifungal agent)

- builds tunnels through membrane and drains cell

Hydrophilic Hydrophilic

Hydrophilic

OOH

HO

OHHOOC

OH

O

Me

OH

OH

Me

OH O OH

Me

O

O

HONH2

HO

Me

H

1 ©

Polar tunnel formed

Escape route for ions

CELLMEMBRANE

TUNNEL

HO

HO

HO

HO

HO

HO

HO

HO2C CO2H

Sugar

OH OH

Sugar

HO

HO

HO

HO

HO

HO

HO

OH

OH

OH

OH

OH

OH

OH

Sugar

OH OH

Sugar

HO2C CO2H

OH

OH

OH

OH

OH

OH

OH

7. Drug Targets - Cell Membrane Lipids

Mechanism of action Amphotericin B

Binds ergosterol in fungal cell membrane

Form pores in cell membrane Cell

contents leak out

Cell death

21

Mechanism of resistance

• Resistance:

– Replacement of ergosterol by other sterols in fungal plasma membrane.

– Resistance is not a problem clinically.

22

Pharmacokinetics

• Poorly absorbed orally, useful for fungal infection of gastrointestinal tract.

• Insoluble in water so colloidal suspension prepared with sodium deoxycholate(1:1 complex)

• 90% bound to plasma proteins

• For systemic infections given as slow I/V infusion.

• Locally used in corneal ulcers, arthritis and candidial bladder irrigation

• Penetration through BBB is poor but increases in

inflamed meninges.

• Excreted slowly via kidneys, traces found in

urine for months after cessation of drugs.

• Metabolized in liver slowly excreted in urine

• t ½ = 15 days

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• Adverse events:

– Acute reaction:

– Chills, fever, headache, pain all over, nausea, vomiting, dyspnoea lasting 2-5 hrs because of release of IL & TNF

– can be treated with hydrocortisone 0.6mg/kg

– Long term toxicity:

– Nephrotoxicity: Azotemia, Hypokalemia, acidosis, ↓ GFR

– anemia

– CNS toxicity : intrathecal administration, headache, vomiting, nerve palsies

– Hepatotoxicity rarely

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1. Slow IV infusion for systemic fungal disease.

2. Intrathecal for fungal CNS infections.

3. Topical drops & direct subconjunctival injection for Mycotic corneal ulcers & keratitis.

4. Local injection into the joints in fungal arthritis.

5. Bladder irrigation in Candiduria.

Routes of Administration

SIDE EFFECTS OF AMB

Nephrotoxicity

Acute infusion related reactions

Hypopotassemia, anemia, hepatic dysfunction..

Nystatin

Obtained from S. Noursei

Similar to AMB in antifungal properties, high systemic toxicity so used locally only

Poorly absorbed from mucus membrane

Available as ointment ,cream , powder, tablet

Adverse events: Gastointestinal disturbances with oral tablets

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• Prevent or treat superficial candidiasis of mouth, esophagus, intestinal tract.

• Oral suspension of 100,000 U/ml 4 times a day and tablets 500,000 U are used to decrease GIT colonization with Candida

• Vaginal candidiasis - pessaries used for 2 weeks

• Can be used in combination with antibacterial agents & corticosteroids

• In Cutaneous infection available in cream, ointment or powder form and applied 2-3 times a day

Nystatin/Nysfungin – Clinical uses

Hamycin: S. Pimprina similar in chemical structure to amphotericin B except that

it has an additional aromatic group bonded to the molecule More water soluble, fraction absorbed orally but

unreliable in systemic infections Topical use

Natamycin: Similar to nystatin, broad spectrum Used topically 1%, 3% ointment

Candicidin

Candicidin is an antifungal compound obtained from Streptomyces griseus.

It is active against some fungi including Candida albicans.

Candicidin is administered intravaginally in the treatment of vulvovaginal candidiasis (Gynecological anti-infective)

Named candicidin, because of its high activity on Candida albicans

Griseofulvin • Hetrocyclic benzofuran • One of early antibiotics from penicillium griseofulvum

• Fungistatic, systemic drug for superficial fungal infections

• Active against most dermatophytes

• Dermatophytes concentrate it actively hence selective toxicity

• Resistance: loss of concentrating ability

• Inhibits fungal mitosis

• Mechanism of action: – Griseofulvin interacts with

polymerized microtubules and disrupts the mitotic spindles thus arresting fungal mitosis

• Pharmacokinetics: – Oral administration, irregular

absorption, increased by fatty food and microfine particles

– Gets conc in keratinized tissue

– Metabolized in liver, excreted in urine,t1/2=24 hrs

• Adverse events:

– Headache most common

– GIT disturbances

– CNS symptoms: confusion, fatigue, vertigo

– Peripheral neuritis

– Rashes, photoallergy

– Transient leukopenia, albuminuria

• Interactions: – Warfarin , oral contraceptives

– Phenobarbitone, Disulfiram like reaction

• Uses:

– Systemically only for dermatophytosis, ineffective topically

• Systemic azoles more effective and preferred

• Duration of treatment depends on site, thickness of keratin and turnover of keratin.

• Treatment must be continued till infected tissue is completely replaced by normal skin,hair, nail.

• Dose: 125-250 mg QID

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• Synthetic, water soluble, fluorinated pyrimidine analog

• Often used in combination with amphotericin B and Itraconazole

• Spectrum of antigungal activity is considerably less than that of amphotericin B.

• Amphotericin B increases cell permeability , allowing more 5-FC to penetrate the cell, they are synergistic

• Fungistatic

• Has useful activity against Candida and Cryptococcus.

• Acts by inhibiting synthesis of fungal DNA

Flucytosine

Flucytosine

– Prodrug, pyrimidine analog, antimetabolite

– Converted to 5FU (5-Flurouracil)

– Human cells cant convert it to 5FU

– Adverse events:

• Bone marrow toxicity , GIT , Alopecia, skin rashes, itching , rarely hepatitis

– Uses: in combination with AMB in cryptococcal meningitis

– Narrow spectrum of action

5-fluorocytosine (5-FC) 5-FC 5-FU

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• Absorbed rapidly and well from the GI tract, widely distributed

• Minimally bound to plasma proteins. • Penetrates well into CSF. • Mainly excreted unchanged through kidney • Half life drug normally is 3–6 hours but may reach

200 hours in renal failure. • Dose modification is necessary in renal dysfunction

plasma concentrations should be measured periodically

• Flucytosine is cleared by hemodialysis and peritoneal dialysis

Flucytosine - ADME

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• Given orally at 100 mg/kg/day, in 4 divided doses and is used predominantly in combination with amphotericin B.

• Severe deep fungal infections as in meningitis

• Cryptococcal meningitis: begin with amphotericin B plus flucytosine and change to fluconazole after the patient has improved.

• There is the risk of amphotericin induecd azotemia and flucytocine dose has to be reduced in this situation otherwise the combination will cause bone marrow suppression or colitis

Flucytosine – Uses

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• Hematologic : Leukopenia, thrombocytopenia, bone marrow depression

• Allergic: Rash, nausea, vomiting, diarrhea, and enterocolitis

• Hepatic: Elevation in hepatic transaminases but this reverses when therapy is stopped.

• Toxicity is more frequent in patients with AIDS or azotemia.

• Alopecia

Flucytosine – Adverse effects

Advantages of combination: –Entry of 5 FC

–Reduced toxicity

–Rapid culture conversion

–Reduced duration of therapy

–Decreased resistance

• Differences between AMB & 5 FC • AMB = Active drug, broad spectrum, antibiotic,

fungicidal

• Not absorbed, high protein binding, no BBB, metabolized in liver, highly efficacious, IV, Intrathecal, topical

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• Bivalent chemical group composed of five-membered organic rings (Synthetic antifungals)

• Broad spectrum of activity - Antibacterial, antiprotozoal, anthelminthic and antifungal

• Fungistatic or fungicidal depending on conc of drug

• Group of synthetic fungistatic agents

• Classification: according to the number of nitrogen atoms attached to the ring

– Imidazoles (2 nitrogen atoms): Ketoconazole, Miconazole, Econazole, Clotrimazole, Bifonazole

– Triazoles (3 nitrogen atoms): Itraconazole, Fluconazol, Vorionazole → systemic treatment

ANTIFUNGAL AGENTS Azole Antifungals

• Imidazoles: Two nitrogen in structure

– Topical: econazole, miconazole, clotrimazole

– Systemic : ketoconazole

– Newer : butaconazole, oxiconazole, sulconazole

• Triazoles : Three nitrogen in structure

– Fluconazole, itraconazole, voriconazole

– Terconazole: Topical for superficial infections

• Both these groups are

– Structurally related compounds

– Have same mechanism of action

– Have similar antifungal spectrum

45

Azole Antifungals

•Inhibit the fungal cytochrome P450 enzyme

•Responsible for converting lanosterol to ergosterol ( the

main sterol in fungal cell membrane ).

46

Azole Antifungals- Mechanism of Action

47

• Contain 2 Nitrogen atoms attached to the ring

• Reduce the formation of ergosterol in the cell membrae which become permeable to cellular constituents.

• They lack selectivity, and also inhibits human gonadal and steroid synthesis leading to decreased testosterone and cortisol production

• Ketoconazole,

• miconazole,

• clotrimazole,

• isoconazole ,

• Tioconazole

Azole Antifungals- Imidazoles

Ketoconazole

– First orally effective broad spectrum antifungal

– Effective against

• Dermatophytosis, Deep mycosis , Candidiasis

Pharmacokinetics • Effective orally

• acidic environment favours absorption

• High protein binding

• Readily distributed, not to BBB

• Metabolized in liver, excreted in bile

• t1/2 = 8- 10 hrs

• Dose : 200 mg OD or BD

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• Inhibits adrenal and gonadal steroids which leads to menstrual irregularities, loss of libido, impotency and gynaecomastia in males.

• Efficacy is poor in immunosuppressed patients and in meningitis.

• Hepatotoxic - rare but may prove fatal.

• Dose dependant nausea, anorexia ,vomiting

• Hair loss

• Fluid retention and hypertension.

• Not used in Pregnancy, lactation ,hepatic dysfunction

Imidazole – Ketoconazole – Adverse Effects

Drug Interactions

Mechanism of action

Ketoconazole

52

53

Used topically or systematic (oral route only ) to treat

1. Oral & vaginal candidiasis.

2. Dermatophytosis.

3. Systemic mycoses & mucocutaneous candidiasis.

Imidazole – Ketoconazole – Clinical uses

54

• Bioavailability is low by taking orally.

• Used topically.

• Absorption less than 0.5 % from intact skin, 3-10 % from vagina

• Activity in vagina remains for 3 days.

• Stigma, erythema, edema, vesication, pruritus, urticaria mild vaginal burning sensation may occour.

• Cure dermatophytes, cutaneous candidiasis and vulvovaginal candidiasis

Imidazole – Clotrimazole

Miconazole & clotrimazole • Topical use:

– Miconazole 2 % and clotrimazole 1 % applied BD for 2 weeks in pityriasis versicolor, 4 weeks in cruris, capitis and corporis

• Uses:

– Dermatophyte infections

– Candida: oral pharyngeal, vaginal, cutaneous

• Adverse events:

– Local irritation , itching or burning

– Miconazole shows higher incidence of vaginal irritation & pelvic cramps

Miconazole

Clotrimazole

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• Damage the fungal cell membrane by inhibiting enzyme desmethylase

• They are selective

• Penetrate to CNS

• Resistant to degradation

• Cause less endocrine disturbance.

• Fluconazole,

• itraconazole,

• voriconazole

Azole Antifungals- Triazoles

57

• It is a synthetic triazole, new drug

• Lacks endocrine side effects of ketoconazole.

• Broad spectrum activity (Fungistatic)

• Administered orally as well as I/V.

• Food increases its absorption

• Metabolized in liver to active metabolite

• Highly lipid soluble ,well distributed to bone, sputum, adipose tissues.

• Can not cross BBB

• Does not inhibit steroid hormone synthesis and no serious hepatoxicity

Azole antifungals – Itraconazole

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• Food increases its absorption (50 -60% bioavailability, absorption is variable, enhanced by food & gastric acidity)

• Metabolized in liver extensively

• It is highly lipid soluble and well distributed to bone, sputum and adipose tissue.

• Highly bound to plasma protein ( 99 % )

• Well distributed accumulates in vaginal mucosa, skin, nails but CNS penetration is poor

• Half life is 30-40 hours

• Does not penetrate CSF adequately

• The capsule is better absorbed with food, but the oral solution is better absorbed in the fasting state

Itraconazole- ADME

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Azole antifungals – Itraconazole - Therapeutic Uses

• Available as a capsule and solutions for oral or intravenous administration

• Oral solution is 60% more bioavailable than the capsules

• IV only in serious infections.

• Dose – Cap 200 to 400 mg/day

• doses exceeding 200 mg/day are given in 2 divided doses

• Loading dose: 200 mg 3 times daily can be given for the first 3 days

• The only agent with significant activity against aspergillus species

• It can safely be administered prophylactically in patients receiving bone marrow transplants

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• Dermatophytoses and onychomycosis.

• Onychomycosis - 200 mg daily after food for 3 months

• For deep mycoses, loading dose of 200 mg three times daily for 3 days. Thereafter, two 100-mg capsules are given twice daily with food.

• Histoplasmosis : AIDS-associated histoplasmosis maintainance therapy - 200 mg once daily

• It easily penetrate CSF and is a drug of choice in cryptococcal meningitis and coccido mycosis

• Cryptococcosis: 400 mg daily for 8 weeks in meningitis, In AIDS

200 mg for life.

Azole antifungals – Itraconazole - Therapeutic Uses

61

• Itraconazole solution - for oropharyngeal and

esophageal candidiasis.

• Taken fasting in a dose of 100 mg once daily and swished

vigorously in the mouth before swallowing to optimize

topical effect.

• 100 mg of the solution twice a day for 2–4 weeks.

• Candidiasis: 200 mg on 1st day then 100 mg daily for 2 weeks.

• Not effective in aspergillosis.

• Used orally in dermatophytosis & vulvo-vaginal candidiasis.

Azole antifungals – Itraconazole - Therapeutic Uses

Adverse events

• GI Intolerance

• Dizziness, pruritis , headache , hypokalemia

• Increase plasma transaminase

• Hepatotoxicity

• Fatal cardiac arrhythmias.

• Congestive heart failure in patients with impaired ventricular function

• Drug interactions:

– Oral absorption ↓by antacids, H2 blockers

– Rifampicin, phenytoin induce metabolism

– Inhibits CYP3A4 drug interaction profile similar to ketoconazole

– Interactions can cause serious toxicity

46

• It is fluorinated bistriazole (water soluble )

• The widest therapeutic index of the azoles.

• Excellent bioavailability by oral route.

• Bioavailability not altered by food or gastric acidity

• Not hepatotoxic

• It can safely be administered prophylactically in patients receiving bone marrow transplants.

• Maximum excretion by kidney

• Half life is 25-30 hours.

• Oral, IV as well as topical

Fluconazole - ADME

Pharmacokinetics

• Fluconazole is almost completely absorbed from the GI tract irrespective of food or gastric acidity (94% oral bioavailability)

• Not affected by food or gastric pH

• Concentration in plasma is same by oral or I/v route.

• Only 10% of drug in circulation is protein bound (Poor

protein binding)

• Readily diffuses into body fluids, including breast milk,

sputum, saliva, and CSF.

Primarily excreted unchanged in urine

Half life= 25 -30 hrs

Widely distributed crosses BBB

Adverse events

GIT upset

Headache, alopecia, skin rashes, hepatic necrosis

Teratogenic effect

CYP450 Enzyme inhibiting property less Interactions:

Effects hepatic drug metabolism to lesser extent than

Ketoconazole

H2 blockers & PPI do not effect its absorption

No anti androgenic & other endocrine effects

Uses

Candida:

150 mg oral dose can cure vaginal candidiasis with few relapse

Oral candidiasis- 2 weeks treatment required

Tinea infections & cutaneous candidiasis: 150 mg weekly for 4 weeks, tinea unguim : 12 months

systemic fungal infections: Disseminated candidiasis, cryptococcal, coccidiodal meningitis 200-400 mg / day 4- 12 weeks or longer

Meningitis: preferred drug

Eye drops for fungal keratitis

Triazoles

Itraconazole

- Varied absorption.

- Metabolized by cyt P450

- less endocrine effects but occur at high doses

- Less penetration in CSF

- Many drug interactions (due to inhibition of CYT P450/ 3A4)

Fluconazole

- Completely absorbed and better tolerated, Renal excretion

- Less endocrine effects

- Penetrates well into CSF

- Drug Interactions

SAR

Varying polar functional groups to vary polarity

A polar functional group could be added to a drug to increase polarity.

For example: Tioconazole (antifungal) is used only for skin infections because it is non-polar and poorly absorbed in blood.

Introducing a polar hydroxyl group and more polar heterocyclic ring led to the orally active antifungal agent Fluconazole.

In contrast, the polarity of an excessively polar drug could be lowered by removing polar functional groups.

It is important not to remove functional groups which are important to the drug's binding interactions with its target.

Strategies to improve absorption

Voriconazole

II generation triazole

High oral bioavailability, low protein binding

Good CSF penetration

Metabolized by CYP2C19

Doesn’t require gastric acidity for absorption

T1/2= 6 hrs

Uses:

DOC for invasive aspergillosis

Most useful for esophageal candidiasis

First line for moulds like fusarium

Useful in resistant candida infections

Dose and Adverse effects

• Dose : 200 mg BD

• Adverse events:

– Transient visual changes like blurred vision , altered color perception & photophobia

– Rashes in 5 -6 %

– Elevated hepatic enzymes

– Prolongation of QT

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• Topical treatment is useful in superficial fungal infections confined to the stratum corneum, squamous mucosa, or cornea, including dermatophytosis (ringworm), candidiasis, tinea versicolor, piedra, tinea nigra, and fungal keratitis.

• Unsuccessful for mycoses of the nails (onychomycosis) and

hair (tinea capitis)

• No place in subcutaneous mycoses, such as sporotrichosis and chromoblastomycosis.

• Efficacy of topical agents depends not only on the type of lesion and the mechanism of drug action, but also on the viscosity,

hydrophobicity, and acidity of the formulation.

Topical Antifungal Agents

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• Regardless of formulation, penetration of topical drugs into

hyperkeratotic lesions often is poor.

• Removal of thick, infected keratin may be a useful adjunct to

therapy.

• Preferred formulations are

– Creams

– Solutions

– Powders, whether applied by shake containers or aerosols, largely are used for the feet and moist lesions of the groin and other intertriginous areas

Topical Antifungal Agents

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1. Topical azole derivatives

2. Nystatin& Amphotericin

3. Terbinafine

4. Tolnaftate

5. Naftifine

6. Griseofulvin

Topical Antifungal Agents

Used in superficial fungal infections:

Dermatophytosis ( ring worm)

Candidiasis

Fungal keratitis.

Not effective in mycoses of the nails & hair or subcutaneous mycoses.

Preferred formulation for cutaneous application is cream or solution.

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• Indications for topical use include

– tinea corporis

– tinea pedis

– tinea cruris

– tinea versicolor

– cutaneous candidiasis.

• Agents for topical use should be selected based on cost and availability.

• They are applied twice daily for 3–6 weeks.

• Preparations for cutaneous use are effective for

Topical Antifungal Agents - Azoles

61

• Creams, suppositories, and tablets for vaginal candidiasis

• 5 gm, Used once daily for 1–7 days, preferably at bedtime to facilitate retention.

• Three vaginal formulations—

– clotrimazole tablets,

– miconazole suppositories,

– Terconazole cream

• Come in both low- and high-dose preparations.

• Shorter duration of therapy is recommended for the higher doses.

• The action is local and only little is absorbed

• Most common side effect is vaginal burning or itching.

• A male sexual partner may experience mild penile irritation.

Topical Antifungal Agents – Vaginal Applications

61

Antifungal Agents - Allylamine

Terbinafine

Orally & topically effective drug against candida & dermatophytes

Fungicidal : shorter courses of therapy required & low relapse rates

Mechanism of action:

Pharmacokinetics: Well absorbed orally 75%

Highly keratophilic & lipophilic

High protein bound , poor BBB permeability

t1/2- 15 days

Negligible effect on CYP450

Adverse events and uses

Adverse events: Nausea , vomiting , Diarrhoea

Taste disturbances

Rarely hepatic dysfunction

Topical: erythema , itching , dryness , urticaria, rashes

Uses: Dermatophytosis: topically/ orally 2- 6 weeks

Onychomycosis: first line drug 3- 12 months

Candidiasis: less effective 2- 4 weeks therapy may be used as alternative 250 mg OD

Caspofungin acetate

Semisynthetic antifungal ( lipopeptide antifungal)

MOA: Inhibits B (1,3) D glucan an essential component of fungal cell wall

Uses: Treatment of invasive aspergillosis & candidiasis (esophageal, intraperitoneal)

Dose: IV 70 mg slowly then 50 mg daily infusion

Adverse events:

Flushing rashes , nausea, vomiting, phlebitis

Topical agents used in dermatophytosis

Tolnaftate:

Tinea, cruris, corporis, 1- 3 weeks treatment

Not effective in hyperkeratinized lesions

Salicylic acid aids its effect by keratolysis

• Tolnaftate a synthetic thiocarbamate • The exact mechanism of action is not entirely known, it is

believed to inhibit squalene epoxidase, an important enzyme in the biosynthetic pathway of ergosterol (a key component of the fungal membrane) in a similar way to allylamines

Topical agents used in dermatophytosis

Ciclopirox olamine:

Tinea infections, pitryasis versicolor ,dermal candidiasis, vaginal candidiasis

Penetrates superficial layers

Acts by inhibiting membrane uptake of precursors of macromolecules needed for fungal growth

Ciclopirox is a hydroxypyrimidine

• Undecyclenic acid: 5% (Tineafax)

– Generally combined with zinc (20%)

– Requires prolonged treatment has high relapse rate

– Weaker antifungal action used in tinea cruris and nappy rash

Topical agents used in dermatophytosis

unsaturated fatty acid

Na2S2O3.

• Benzoic acid:

– Used in combination with salicylic acid

– Whitfields ointment: ( benzoic acid 6% + salicyclic acid 3 %)

– Salicyclic acid due to its keratolytic action helps to remove infected tissue & promotes penetration of benzoic acid in fungal infected lesion

–Adverse events: irritation & burning sensation (Ring cutter ointment)

• Quinidiochlor;

– Luminal amoebicide

– Weak antifungal & antibacterial

– External application : dermatophytosis , mycosis barbae, pitryasis versicolor

• Selenium sulfide: T versicolor

• Potassium iodide: Dermatophytic infection

Topical agents used in dermatophytosis

Systemic administration

Topical

Griseofulvin Ketoconazole

Ketoconazole Miconazole

Fluconazole Clotrimazole

Itraconazole Terbinafine

Terbinafine Nystatin

Spectrum of action

AMB 5FC KTZ FLU ITR

Aspergillus -- -- -- Y

Blastomycosis -- Y Y Y

cryptococcus Y -- Y Y

Coccidiodo -- Y Y Y

candida Y Y Y Y

Histoplasma -- Y Y Y

mucor -- -- -- --

Sporotrichosis -- -- Y Y

chromoblast dermatophyte Fusarium

• Broad spectrum: AMB, KTZ, FLU, ITR

• Resistance: 5 FC

• Nephrotoxic/ Anemia: AMB

• Leucopenia: 5 FC

• GIT upset: All

• Over all toxicity: highest for AMB lowest for fluconazole, itraconazole

Important characteristics

Spectrum of action

• Nystatin: Candidiasis only

• Griseofulvin: Dermatophytosis only

• Terbinafine : Dermatophytosis & candidiasis

• Caspofungin: Aspergillosis & candidiasis

87

Tioconazole Fluconazole Fosfluconazole

88

Echinocandins

Echinocandins (cyclic peptides) may be used for systemic fungal infections in immunocompromised patients

they inhibit the synthesis of glucan in the cell wall via the enzyme 1,3-Beta-glucan synthase:

Anidulafungin

Caspofungin

Micafungin

Echinocandins are poorly absorbed when administered orally.

When administered by injection they will reach most tissues and organs with concentrations sufficient to treat localized and systemic fungal infections

Anidulafungin

Caspofungin Micafungin

89