Antifungal drugs

ERICK ABEDKWENE
Introduction
• Fungal infections are also called mycoses

• They are complex organisms in comparison to bacteria, thus

antibacterial agents are not effective against fungi

• They are generally difficult to treat requiring longer periods of

treatment
Fungal infection may be
1. Superficial
a) Dermatomycoses; affecting skin, hair or nails
•Epidermophyton (Skin & nails)
•Trichopyton (skin, hair & nails)
•Microsporum (skin and hair)
b) Candidiasis;
•Commonly normal flora of mouth, skin, intestines and
vagina
•Infection caused by genus candida; affecting skin,
mucous membrane of mouth, GIT or female genital
tract
2. Systemic
Candidiasis, cryptococcosis, aspergillosis, blastomycosis,
histoplasmosis, coccidiomycosis, paracoccidomycosis, etc
Common Fungal Infections
• Tinea
• Athlete’s Foot
• Ringworm
• Versicolor

• Yeast Infection

• Infection of the Lungs

• Aspergillosis
Athlete's Foot (Tinea pedis)

•Symptoms: scaling,
flaking, and itching of the
feet

•Caused by: Microsporum

and Trichophyton

•Treated with: various

allylamines and azoles,
miconazole nitrate, and
tolnaftate, etc
Ringworm

•Symptoms: Scaling of the

skin, characteristic circular
rash

•Caused by: Microsporum

and Trichophyton

•Treated with: Miconazole,

Clotrimazole,
Ketoconazole, etc
Tinea Versicolor

• Symptoms: Blotches of differing

pigmentation around upper trunk

• Caused by: Malassezia globosa

• Treated with: Topical selenium

sulfide, Clotrimazole, Ciclopirox
olamine, etc
Yeast Infection (Candidiasis)

• Symptoms: Localized infection,

inflammation, discomfort

• Caused by: Yeast Fungi from

genus Candida

• Treated with: nystatin,

ketoconazole, fluconazole, etc
Aspergillosis
• Symptoms: Delirium, failure of
organs, death!

• Caused by: Inhalation of fungal

spores from genus Aspergillus

• Treated with: nystatin,

ketoconazole, fluconazole,
capsofungin
 Drug Classification
A) Drugs that disrupt fungal cell membrane
i) Polyenes: Amphotericin, Nystatin, Natamycin
ii) Azoles
a) Imidazole: Ketoconazole, Butaxonazole,
Clotrimazole, Econazole , Miconazole, Oxiconazole,
Sulconazole
b) Triazole: Fluconazole, Itraconazole, Tioconazole
iii) Allylamines; Terbinafine, Naftifine, Butenafine
iv) Echinocandins; caspofungin

B) Drugs that inhibits mitosis: Griseofulvin

C) Drugs that inhibits DNA synthesis: Flucytosine,
Caspofungin
D) Miscellaneous: Haloprogi, Tolnaftate, Whitefield's
ointment, Ciclopirox olamine
Amphotericin B
•Amphotericin A & B are antifungal antibiotics
•Amphotericin A is not used clinically
•It is a natural polyene macrolide originally extracted
from Streptomyces nodosus, a filamentous bacterium
•Pharmacokinetics
•Poorly absorbed orally , is effective for fungal
infection of gastrointestinal tract
•For systemic infections given as slow I.V
•Highly bound to plasma protein
•Poorly crossing BBB
•Metabolized in liver
•Excreted slowly in urine over a period of several days
•Half-life 15 days
Mechanism of action
• It is a selective fungicidal drug
• Disrupt fungal cell membrane by binding to ergosterol, so alters the
permeability of the cell membrane leading to leakage of intracellular
ions & macromolecules (cell death )
• Resistance to amphotericin
• If ergosterol binding is impaired, either by :
• Decreasing the membrane concentration of ergosterol
• Or by modifying the sterol target molecule
Adverse Effects
Immediate reactions ( Infusion –related toxicity )
•Fever, muscle spasm, vomiting ,headache,
hypotension
• Can be avoided by :
•A. Slowing the infusion
•B. Decreasing the daily dose
•C. Premedication with antipyretics,
antihistamines or corticosteroids
•D. A test dose
Slower toxicity
•Most serious is renal toxicity (nearly in all patients ,
Hypokalemia, Hypomagnesaemia, Impaired liver
functions, Thrombocytopenia, Anemia
Clinical uses
•Has a broad spectrum of activity & fungicidal action
•The drug of choice for life-threatening mycotic infections
•For induction regimen for serious fungal infection
•Also, for chronic therapy & preventive therapy of relapse
•In cancer patients with neutropenia who remain febrile on
broad –spectrum antibiotics
Routes of Administration
•1- Slow I.V. (For systemic fungal infections)
•2- Intrathecal for fungal C.N.S. infections
•Topical drops & direct subconjunctival injection for
Mycotic corneal ulcers & keratitis
•3- Local injection into the joint in fungal arthritis
•4- Bladder irrigation in Candiduria
Liposomal preparations of Amphotericin
B
• Amphotericin B is packaged in a lipid- associated delivery system to
reduce binding to human cell membrane , so reducing :
•A. Nephrotoxicity
•B. Infusion toxicity
•Also, more effective
•More expensive
 Nystatin
•It is a polyene macrolide, similar in structure &
mechanism to amphotericin B
•It’s derived from a bacterium Streptomyces noursei
•It is available as creams, ointment , suppositories & other
preparations
•Not significantly absorbed from skin, mucous membrane,
GIT
•Clinical uses
•Prevent or treat superficial candidiasis of mouth,
esophagus, intestinal tract
•Vaginal candidiasis
•Can be used in combination with antibacterial agents &
corticosteroids
Azoles
•A group of synthetic fungi-static agents with a broad
spectrum of activity
•They have antibacterial , antiprotozoal anthelminthic
& antifungal activity
•Mechanism of Action (disruption of cell membrane)
• 1-Inhibit the fungal cytochrome P450 enzyme, (α-demethylase) which is
responsible for converting lanosterol to ergosterol (the main sterol in fungal cell
membrane )
• 2- Inhibition of mitochondrial cytochrome oxidase leading to accumulation of
peroxides that cause autodigestion of the fungus
• 3- Imidazoles may alter RNA & DNA metabolism
 Azoles
• They are antibacterial , antiprotozoal, anthelminthic & antifungal

• They are fungistatic agents

• They are classified into :

• Imidazole group
• Triazole group
 Imidazoles
• Ketoconazole
• Miconazole
• Clotrimazole

• They lack selectivity, they inhibit human gonadal and steroid synthesis
leading to decrease testosterone & cortisol production

• Also, inhibit human P-450 hepatic enzyme

 Ketoconazole
Pharmacokinetics
• Well absorbed orally
• Bioavailability is decreased with antacids, H2 blockers , proton pump
inhibitors & food
• Cola drinks improve absorption in patients with achlorhydria
• Half-life increases with the dose , it is (7-8 hrs)
• Inactivated in liver & excreted in bile (feces ) & urine
• Does not cross BBB
Clinical uses
Uses
•Used topically or systematic (oral route only ) to treat :
•1- Oral & vaginal candidiasis
•2- Dermatophytosis
•3- Systemic mycoses & mucocutaneous candidiasis
•Adverse Effects
•Nausea, vomiting ,anorexia
•Hepatotoxic
•Inhibits human cytochrome P450 enzymes
•Inhibits adrenal & gonadal steroids leading to :
• Menstrual irregularities
• Loss of libido
• Impotence
• Gynaecomastia in males
Contraindications & Drug interactions
• Contraindicated in Pregnancy, lactation ,hepatic dysfunction

• Interact with enzyme inhibitors , enzyme inducers (Inhibits cytochrome

P450 enzymes)

• H2 blockers & antacids decrease its absorption

 Triazoles
• Fluconazole
• Itraconazole
• Voriconazole

• They are :
•Selective
•Resistant to degradation
•Causing less endocrine disturbance
 Itraconazole
• Lacks endocrine side effects
• Has a broad spectrum activity
• Given orally & IV
• Food increases its absorption
• Metabolized in liver to active metabolite
• Highly lipid soluble, well distributed to bone, sputum, adipose tissues
• Can not cross BBB
Itraconazole…ctd
• Half-life 30-40 hours
• Used orally in dermatophytosis & vulvo-vaginal candidiasis
• IV only in serious infections
• Effective in AIDS-associated histoplasmosis

• Side effects :
• Nausea, vomiting, hypokalemia, hypertension, edema, inhibits the
metabolism of many drugs as oral anticoagulants
 Fluconazole
•Water soluble
•Completely absorbed from GIT
•Excellent bioavailability after oral administration
•Bioavailability is not affected by food or gastric pH
•Conc. in plasma is same by oral or IV route
•Has the least effect on hepatic microsomal enzymes
•Drug interactions are less common
•Penetrates well BBB so, it is the drug of choice of
cryptococcal meningitis
•Safely given in patients receiving bone marrow transplants
(reducing fungal infections)
•Excreted mainly through kidney
•Half-life 25-30 hours
•Resistance is not a problem
Clinical uses
•Candidiasis (is effective in all forms of mucocutaneous
candidiasis)
•Cryptococcus meningitis
•Histoplasmosis, blastomycosis, , ring worm
•Not effective in aspergillosis
Side effects
•Nausea, vomiting, headache, skin rash , diarrhea,
abdominal pain , reversible alopecia.
•Hepatic failure may lead to death
•Highly teratogenic (as other azoles)
•Inhibit P450 cytochrome
•No endocrine side effects
Voriconazole
• A broad spectrum antifungal agent
• Given orally or IV
• High oral bioavailability
• Penetrates tissues well including CSF
• Inhibit cytochrome P450 enzymes
• Used for the treatment of invasive aspergillosis & serious infections
• Reversible visual disturbances
 Flucytosine
•Synthetic pyrimidine antimetabolite (cytotoxic drug)
often given in combination with amphotericin B and
Itraconazole
•Systemic fungistatic
•Mechanism of action
•Converted within the fungal cell to 5- fluorouracil,
that inhibits thymidylate synthetase enzyme that
inhibits DNA synthesis
•(Amphotericin B increases cell permeability ,
allowing more 5-FC to penetrate the cell, they are
synergistic)
Pharmacokinetics
•Rapidly & well absorbed orally, Widely distributed
including CSF, Mainly excreted unchanged through
kidney, Half-life 3-6 hours
•Clinical uses
•Severe deep fungal infections as in meningitis,
Generally given with amphotericin B, For cryptococcal
meningitis in AIDS patients
•Adverse Effects
•Nausea, vomiting , diarrhea, severe enterocolitis,
Reversible neutropenia, thrombocytopenia, bone
marrow depression, Alopecia, Elevation in hepatic
enzymes, (some adverse effects related to 5-FU
formed by intestinal organisms from 5-FC)
Caspofungin
• Inhibits the synthesis of fungal cell wall by inhibiting the synthesis of β
(1,3)-D-glucan, leading to lysis & cell death
• Given by IV route only
• Highly bound to plasma proteins
• Half-life 9-11 hours
• Slowly metabolized by hydrolysis & N-acetylation
• Elimination is nearly equal between the urinary & fecal routes
Clinical uses
• Effective in aspergillus & candida infections
• Second line for those who have failed or cannot tolerate amphotericin B
or itraconazole
• Adverse effects :
• Nausea, vomiting
• Flushing( release of histamine from mast cells)

• Very expensive
Griseofulvin
• Fungistatic, has a narrow spectrum
• Given orally (Absorption increases with fatty meal )
• Half-life 24 hours
• Taken selectively by newly formed skin & concentrated in the keratin
• Induces cytochrome P450 enzymes
• Should be given for 2-6 weeks for skin & hair infections to allow
replacement of infected keratin by the resistant structure
Griseofulvin…ctd
•Inhibits fungal mitosis by interfering with
microtubule function
•Used to treat dermatophyte infections (ring worm of
skin, hair, nails )
•Highly effective in athlete's foot
•Ineffective topically
•Not effective in subcutaneous or deep mycosis

•Adverse effects ;
•Peripheral neuritis, mental confusion, headache,
fatigue, vertigo, GIT upset, enzyme inducer, blurred
vision
•Increases alcohol intoxication
 Antifungal Drugs Used For Topical
Fungal Infections
1. Topical azole derivatives
2. Nystatin & Amphotericin
3. Terbinafine
4. Tolnaftate
5. Naftifine
6. Griseofulvin
 Topical Antifungal Agents
•Used in superficial fungal infections , such
as :
•Dermatophytosis; ring worm, candidiasis,
fungal keratitis
•They are not effective in mycoses of the
nails & hair or subcutaneous mycoses
•The preferred formulation for cutaneous
application is cream or solution
Azoles for topical use

•In the form of vaginal creams,

suppositories, tablets for vaginal
candidiasis given once daily for 2 weeks
to one month
Clotrimazole
•Absorption is less than 0.5 % from intact skin, 3-10
% from vagina (its activity remains for 3 days )

•Uses: dermatophytes , cutaneous candidiasis &

vulvovaginal candidiasis

•Causes : Erythema (redness of the skin), edema,

urticaria & mild vaginal burning sensation
Itraconazole

• Effective for treatment of onychomycoses (fungal infection of the

nails)

• Should not be given in patients with ventricular dysfunction

• Evaluation of hepatic function is recommended

Tolnaftate
•Effective in most cutaneous mycosis

•Ineffective against Candida

•Used in tinea pedis ( cure rate 80 % )

•Used as cream, gel, powder, topical solution

•Applied twice daily

Naftifine

• Broad spectrum fungicidal

• Available as cream or gel

• Effective for treatment of tinea cruris

Terbinafine
•Drug of choice for treating dermatophytes
(onychomycoses)
•Better tolerated ,needs shorter duration of therapy
•Inhibits fungal squalene epoxidase, decreases the
synthesis of ergosterol. (Accumulation of squalene
,which is toxic to the organism causing death of fungal
cell)
•Fungicidal, its activity is limited to candida albicans &
dermatophytes
•Effective for treatment of onychomycoses
•6 weeks for finger nail infection & 12 weeks for toe nail
infections
•Well absorbed orally , bioavailability decreases due to
first pass metabolism in liver
Terbinafine…ctd
•Highly protein bound
•Accumulates in skin , nails, fat
•Severely hepatotoxic, liver failure even
death
•Accumulate in breast milk , should not be
given to nursing mother
•GIT upset (diarrhea, dyspepsia, nausea )
•Causes altered taste & visual disturbance
 Uses of antifungal drugs
Drug used Disease

Systemic infections
■ Amphotericin, flucytocin, , fluconazole. ■ systemic candidiasis

■ Amphotericin, flucytocin , fluconazole, ■ Cryptococcosis( meningitis)

itraconazole
■ itraconazole Amphotericin, ■ systemic aspergillosis

■ itraconazole Amphotericin, ■ Blastomycosis

■Amphotericin, itraconazole ,fluconazole. ■ Histoplasmosis

■ fluconazole. itraconazole ,Amphotericin, ■ Coccidiomycosis

■ fluconazole. itraconazole ,Amphotericin, ■ Paracoccidiomycosis

■ Amphotericin, flucytocin ,Amphotericin, ■ Mucormycosis

■ Amphotericin, flucytocin ■ Disseminated sportrichosis
END
• THE MYTHS OF ITCHING;

• HANDS = YOU’RE GETTING MONEY SOON

• FEET = GO SOMEWHERE/TRAVELLING SOON
• EARS = SOMEONE IS TALKING ABOUT YOU
• NOSE = SNEEZE/GET INTO A FIGHT/ANNOYED

• PRIVATE PARTS = SEEK MEDICAL ADVICE