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• 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.
10
Classification based on structure
• ANTIBIOTICS
Polyene: Amphotericin, nystatin, hamycin
Hetrocyclic benzofuran: griseofulvin
• ANTIMETABOLITE : Flucytosine
• AZOLES
Imidazoles: Ketoconazole, clotrimazole, oxiconazole,
miconazole,
Triazoles: Fluconazole, itraconazole, voriconazole,
11
• ALLYLAMINES
– Terbinafine, butenafine
• ECHINOCANDINS
– Caspofungin, anidulafungin, micafungin
• OTHER TOPICAL AGENTS
– Tolnaftate, Undecyclinic acid, benzoic acid
Classification based on structure
12
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
17
• 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
23
• 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
25
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
27
• 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
35
• 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
37
• 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
38
• 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
39
• 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
43
• 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
50
• 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
56
• 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
58
• 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
59
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
60
• 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
56
• 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
57
• 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
58
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.
60
• 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