ANTIMYCOTICS

Drugs used in the treatment of fungal

infections

• Mrs. Fatima Kathrada

• [email protected]
• Room 8Q15, 8TH Floor
• Dept. of Pharmacy & Pharmacology
 Objectives
• Classify the different classes of antifungal agents
• Describe the mechanism of action of each antifungal
• List the adverse effects of each agent
• List the indications for each agent
• Describe the first line and second line treatment
options for each indication
• Describe the mode of administration of each agent per
indication
• Describe the important Pharmacokinetics of each
agent as outlined
 Fungal
Infections
• Difficult to treat
– Slow growing
– occur in tissues that
are poorly penetrated
by antimicrobial agents
(e.g., devitalized or
avascular tissues)
– Require Prolonged
Treatment
Superficial Systemic

Systemic
candidiasis

Dermatomycoses
- Tinea pedis (foot:athletes foot) Cryptococcosis
- Tinea corporis (body)
- Tinea Cruris(groin)
- Tinea capitis (scalp)
Systemic
- Tinea unguium(nails) aspergillosis

Candidiasis Blastomycosis

- Skin
- Mouth (thrush)
- vagina Histoplasmosis

Emergomycosis
 Classification of antifungals

Systemic antifungals Topical Antifungals

• Amphotericin B • Terbinafine
• Azoles • Nystatin
Fluconazole • Clotrimazole
Itraconazole • Miconazole
Voriconazole
• Ketoconazole
Posaconazole
• Econazole
• Echinocandins
Capsofungin
Micafungin,
Anidulafungin
• Griseofulvin
• Terbinafine
 Membrane function
Bind to ergosterol, forming pores
in fungal membrane , altering Inhibit cytP450 enzymes
membrane integrity and causes decreased
ergosterol synthesis

Nuclear division
Griseofulvin
Inhibits fungal mitosis by binding
to intracellular microtubules

Inhibit glucan
synthesis Inteferes with DNA
and RNA synthesis
selectively in Fungi
 AMPHOTERICIN B
SYSTEMIC
INFECTIONS
AMPHOTERICIN B
 AMPHOTERICIN B
- Drug of choice for most serious systemic infections
- Very toxic- monitor patients closely
- Broad spectrum of activity
*Used as induction therapy then replaced by newer AZOLE drug of choice once
fungal burden reduced
Indications
- Disseminated candidiasis: C.albicans
- Cryptococcosis: Cryptococcus neoformans
- Mucormycosis
- Histoplasmosis: Histoplasma capsulatum
- Blastomycosis: Blastomyces dermatitidis
- Aspergillus: Aspergillus fumigatus
- Emergomycosis
- Sporotrichiosis
Pharmacokinetics
• IV (intravenous)
• Not absorbed orally: absorption from GI tract is negligible
• T½= 24hrs but with repeated doses: T½= 15days
• Widely distributed (but poor BBB crossing)
• Eliminated slowly in urine
 AMPHOTERICIN B
Adverse Effects
Infusion reactions:
• fever, chills, headache,myalgia, N&V, hypotension

Cumulative Toxicity: NEPHROTOXIC!

• Renal impairement: pre-renal injury, renal tubular acidosis
• Renal tubular acidosis: K+ and Mg2+ wasting
• Anaemia, abnormalities in liver function reported

Drug Interactions:
- Aminoglycosides, tenofovir, ciclosporin
- Diuretics
- Digoxin

Newer Liposomal Amphotericin B formulations (Ambisome®)

• lipid drug formulation
• Preferential binding- decr toxicity, permits use of larger doses
 AZOLES

Imidazoles Triazoles
Topical use Systemic use

Ketoconazole Itraconazole

Miconazole Fluconazole

Clotrimazole Voriconazole

Posaconazole
 Pharmacologic properties of systemic azole drugs

CSF:Serum T ½ (hrs) Metabolism Formulations

conc. ratio

Itraconazole < 0.01 21 Hepatic Oral (& oral

suspension)

Fluconazole > 0.7 20-50 Renal Oral, IV

Voriconazole > 0.21 6 Hepatic Oral, IV

Posaconazole -- 35 Hepatic Oral suspension

 MOA:
Inhibits fungal CytP450 (14-demethylase) enzymes
AZOLES leading to a reduction in ergosterol synthesis

Imidazoles < selective than triazoles, therefore increased

incidence of A/E & D/I
Broad spectrum of activity against
dermatophytes and invasive yeast
infections (eg: Candida,Cryptococcus)
 AZOLES
ADVERSE EFFECTS: Azole Inhibition of CytP450
- Hepatotoxicity enzymes
- N,V,D,Headache Drug Interactions:
- Skin rash • Ciclosporin Tacrolimus
• Sirolimus Cisapride
• Colchicine Midazolam
• Nevirapine Zidovudine
• Phenytoin Rifampicin
• Digoxin Quinidine
• Nifedipine Omeprazole

C/I : * Increase serum concentrations of

- Pregnancy- Teratogenic above co-administered drugs
(CatC: single dose fluconazole 150mg in vaginal
candidiasis)
- Excreted in breast milk- not recommended
 Azoles- Voriconazole
• Voriconazole
Indications
- Treatment of choice: invasive Aspergillosis
- Candida spp. (serious infecs resistant to fluconazole)
- Oropharyngeal & oesophageal candidiasis

Adverse effects:
- Causes visual disturbances (resolves in 30 min)
- Photosensitivity dermatitis (chronic oral)
- Toxicity: rash & raised hepatic enzymes
Blurred vision,
Pharmacokinetics:
changes in colour - well absorbed orally >90% bioavail.
vision & brightness - Absorption reduced by food
- Hepatic metabolism
- Excreted as inactive metabolite
- cytP450 inhibitor
- Available as oral and IV
 Azoles- FLUCONAZOLE
• Fluconazole
Indications:
- vaginal & oropharyngeal candidiasis not
responding to topical tx
- Oesophageal & systemic candidiasis Given as prophylaxis to
immunocompromised pts to
- Cryptococcal meningitis reduce fungal infections
(No activity against aspergillus) Bone marrow transplant pts/AIDS pts

Pharmacokinetics
- Widest therapeutic index from azole group
- Well absorbed orally
- T½: 20-50hrs
- Excreted in urine (80% unchanged)
- Good CSF penetration
- Least effect on hepatic enzymes- less D/I
Azoles- Itraconaozle

Itraconazole
Indications
✓ dermatophytosis
✓ onychomycosis
✓ candidiasis (not responding to conventional tx)
✓ Azole of choice: dimorphic fungi
infections (Histoplasma, Blastomyces,
Sporothrix)
✓ Alternative therapy for aspergillosis (not
responding to standard therapy)

- Oral solution preferred in oropharyngeal or

oesophageal candidiasis
 Azoles- Itraconaozle

Pharmacokinetics
AVOID ANTACIDS..
- Drug absorption of oral capsule
increased by food & low gastric pH
- Poor CSF penetration
- Metabolised extensively by liver
- Low bioavail.-cap
- Oral soln preferred in oropharyngeal
or oesophageal candidiasis

Cyclodextrin carrier-
incr bioavail
 Azoles- Posaconazole
Indications:
✓ Most species of Candida: alternate in oropharyngeal or
oesophageal candidiasis
✓ Has activity against Aspergillosis (only alternate therapy to
standard therapy failure)
✓ Murcomycosis

Pharmacokinetics:
- Available as oral suspension in SA
- Metabolised by liver
- Fatty meal- increases absorption
Echinocandins
✓ Capsofungin
✓ Anidulafungin
✓ Micafungin
 Echinocandins- CAPSOFUNGIN
MOA: specifically inhibits D-glucan synthesis essential to cell wall integrity of fungi,
thus compromising integrity and causing the cell wall to become permeable, causing
cell lysis
 Echinocandins- CAPSOFUNGIN

Indications:
- Candidiasis (oesophageal &oropharyngeal)
- Aspergillus (only as salvage therapy: pts not responsive to Amphotericin
B & voriconazole.)
No activity against Crytococcus neoformans

Pharmacokinetics:
- Only IV
- T½= 9-11 hrs
- highly protein bound (97% plasma protein bound)
- Well tolerated- minor GIT S/E, flushing
 Echinocandins-
Anidulafungin & Micafungin
• Anidulafungan
- Indication: Invasive candidiasis
- Available as IV

• Micafungin
- Indications: invasive candidiasis
- Available as IV
 Griseofulvin

Mechanism of action: inhibits fungal mitosis

Indication
- is limited to treatment of dermatophytic infections of skin, nails & hair
- fungistatic
- Not active against Candida
• Oral : systemic treatment of dermatophytosis
• 2–6 weeks for skin and hair infections
• Months of treatment for nail infections → allow regrowth of the new
protected nail and is often followed by relapse
• Largely been replaced by itraconzaole and terbinafine

Pharmacokinetics:
- Fatty food increases absorption ….(Milk)
A/E: headaches, skin rash, altered taste sensation, dry mouth
 Terbinafine
• MOA:
Inhibits squalene epoxidase which prevents
ergosterol synthesis
 Terbinafine
Indications:
✓ Dermatophytosis of skin, hair & nails
✓ Candida albicans

Pharmacokinetics:
- distributes preferentially to hair, skin, nail bed
- Highly Lipophilic
- Metabolised in liver
- Available in oral and topical formulations

- One tablet po d x 12/52 = cure rate of up to 90% onychomycosis → more

effective than griseofulvin or itraconazole

Adverse effects: GIT upset,headache, skin reactions, arthralgia,

hepatotoxicity, taste disturbances
 Topical antifungals- NYSTATIN

Indications:
✓ oropharyngeal thrush,
✓ vaginal candidiasis,
✓ intertriginous candidal infections

Administration (Topical):
➢ Cutaneous- cream/oint
➢ Vaginal- vaginal tablets
➢ topical oral suspension

Infants
 Topical antifungals- NYSTATIN

- Indications: Candida yeast infections

- Not effective against Dermatophyte skin infections
- Too toxic for parenteral admin. – used for suppression of
local candidial infections
- Treatment for 14 days is usually adequate but prolonged
therapy needed in some cases
- Poorly absorbed through skin, mucous membranes or
GIT- low toxicity Topical: Low
- Unpleasant taste toxicity
- Safe for use in infants
 TOPICAL
Topical ANTIFUNGALS
antifungals-AZOLES
Azoles
• Clotrimazole & Miconazole (most common topical)

• Indications:
✓ vulvovaginal candidiasis,
✓ dermatophytic infections (incl. Tinea species)
✓ oral candidiasis
 Topical antifungals-AZOLES
Agent formulation Indication
Clotrimazole,econazole, Cream Dermatophytosis (Tinea)
miconazole, ketoconazole
Clotrimazole,econazole, Vaginal cream, vaginal Vaginal candidiasis
miconazole tablet

Miconazole Oral gel Oral candidiasis (oral

thrush)
Ketoconazole shampoo Pityriasis versicolor,
seborrheic dermatitis
Clotrimazole lozenges Oral Candidiasis (oral
thrush)
 Ketoconazole

Seborrhoeic dermatitis

Tinea versicolor
 First line topical and systemic options

Vaginal Candidiasis Oral candidiasis Tinea infections Onychomycosis Aspergillus Cryptococcal

Meningitis

Topical ✓ Clotrimazole ✓ Nystatin ✓ Clotrimazole -- -- --

✓ nystatin ✓ Clotrimazole troches ✓ Terbinafine
✓ Ketoconazole
(seborrheic derm,
pityriasis versicolor)

Systemic ✓ fluconazole ✓ Fluconazole ✓ Itraconazole ✓ Terbinafine ✓ Amphotericin B ✓ Amphotericin B

✓ Itraconazole (oral ✓ fluconazole ✓ Itraconazole ✓ Voriconazole ✓ Fluconazole
suspension & oral tabs)
 Antifungals summary
Drug Primary Indication Route of administration Adverse effect Drug interactions Notes

AZOLES
MOA: Inhibits fungal P450 enzymes, inhibits ergosterol synth (cell membrane) by inhibiting 14-demethylase

Fluconazole - Systemic candidiasis - IV - N, V, rash Inhibits CytP450 enzymes Half life: 20-50 hr
- Vaginal & oropharyngeal - Oral Good CSF penetration
candidiasis (not resp to topical tx)
- Cryptococcal Meningitis

Itraconazole - Oropharyngeal & oesophageal - Oral - Hepatotoxic Inhibits CytP450 enzymes Requires acid medium for
candidiasis (not resp to topical tx) - Oral solution Antacids, PPI absorption- avoid antacids
- Dematophytes (Tinea)
- Onychomycosis
- Dimorphic fungi infecs
(Histoplasma, Blastomyces,
Sporothrix)

Voriconazole - Aspergillosis - Oral - Visual disturbance Inhibits CytP450 enzymes Well absorbed orally>90%
- Candidiasis - Hepatotoxic
- PS dermatitis

Ketoconazole Dermatophytes - Topical -- -- * Due to toxicity- only used

- Seborrhoeic dermatitis topically now
- Pityriasis versicolor (Tinea)

Clotrimazole - Dermatophytes (Tinea) - Topical -- -- Clotrimazole lozenges are

- Oral candidiasis - Topical troches pleasant tasting- alt to
- Vaginal candidiasis (lozenges) nystatin
- Topical- vaginal cream
 Antifungals summary
Drug Primary indication Route of Adverse effect Drug interactions Notes
administration

Polyene Macrolide
MOA: Binds to ergosterol – forms pores in fungal cell membrane

Amphotericin B Systemic Candida, Cryptococcus, - IV - Nephrotoxicity Aminoglycosides, digoxin, * Used for serious systemic
Aspergillus, Histoplasma, Blastomyces, - Hypokalalemia diuretics infections than changed to
Coccidioidis - hypomagnesaemia azole of choice once fungal
load decreased

Nystatin - Superficial Candidiasis - Topical - Unpleasant taste -- Safe to use in Infants- oral
(Oral candidiasis, vaginal candidiasis) Topical oral soln, vag soln
No activity against dermatophytes tab, cream/oint

Echinocandins
MOA: inhibits fungal cell wall synthesis by inhibiting D-glucan

Capsofungin - Candidiasis (oesophageal, - IV - Minor GIT effects High plasma protein binding
oropharyngeal) - Well tolerated
- Aspergillus

ALLYL AMINE
MOA: inhibits ergosterol synth (cell membrane) by inhibiting squalene epoxidase

Terbinafine - Onychomycosis (only treated with - Topical Oral: Taste disturbances, Orally: Most effective in
oral agents) - Oral hepatotoxic, arthralgia, GIT,H onychomycosis (daily, 12/52)
- Dermatophytosis (Tinea pedis,
cruris, corporis)
- Candida albicans