Antifungal drugs

Antifungal Drugs
 Infectious diseases caused by fungi are called
mycoses, and they are often chronic in nature.
 Fungal infectious occur due to :
 1- Abuse of broad spectrum antibiotics
 2- Decrease in the patient immunity

 They have rigid cell walls composed
largely of a polymer of N-
acetylglucosamine rather than
peptidoglycan (a characteristic component
of most bacterial cell walls).
 The fungal cell membrane contains
ergosterol rather than the cholesterol found
in mammalian membranes.
 These chemical characteristics are useful in
targeting chemotherapeutic agents against
fungal infections

Types of fungal infections
 1. Superficial : Affect skin – mucous
membrane. e.g.
 Tinea versicolor
 Dermatophytes : Fungi that affect
keratin layer of skin, hair, nail. e.g. tinea
pedis ,ring worm infection
 Candidiasis : Yeast-like, oral thrush,
vulvo-vaginitis , nail infections.

2- Deep infections
 Affect internal organs as : lung ,heart ,
brain leading to pneumonia ,
endocarditis , meningitis.

Classification of Antifungal Drugs
1- Antifungal Antibiotics :
 Griseofulvin
 Polyene macrolide : Amphotericin- B &
Nystatin
2- Synthetic :
 Azoles :
A) Imidazoles : Ketoconazole , Miconazole
B) Triazoles : Fluconazole , Itraconazole

Synthetic Antifungal ( contin…)
 Flucytosine
 Squalene epoxidase inhibitors :
e.g.Terbinafine & Naftifine.

Classification According to Route of
Administration
 Systemic :
Griseofulvin , Amphotericin- B , Ketoconazole ,
Fluconazole , Terbinafine.
 Topical
In candidiasis :
 Imidazoles : Ketoconazole , Miconazole.
 Triazoles : Terconazole.
 Polyene macrolides : Nystatin , Amphotericin-B
 Gentian violet : Has antifungal & antibacterial.

In Dermatophytes :
 Squalene epoxidase inhibitors : Terbinafine &
Naftifine.
 Tolnaftate.
 White field ointment : 11% Benzoic acid &
6% Salicylic acid .
 Castellani paint.

Amphotericin B
 Amphotericin A & B are antifungal
antibiotics.
 Amphotericin A is not used clinically.
 It is a natural polyene macrolide
 (polyene = many double bonds )
 (macrolide = containing a large lactone ring )

Pharmacokinetics
 Poorly absorbed orally , is effective for fungal
infection of gastrointestinal tract.
 For systemic infections given as slow I.V.I.
 Highly bound to plasma protein .
 Poorly crossing BBB.
 Metabolized in liver
 Excreted slowly in urine over a period of
several days.
 Half-life 16 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 B
If ergosterol binding is impaired either by :
 Decreasing the membrane concentration of
ergosterol.
 Or by modifying the sterol target molecule.

Adverse Effects
1- 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, antihistamincs or
corticosteroids.
D. A test dose.

2- 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.I. For systemic fungal disease.
2- Intrathecal for fungal C.N.S. infections.
3- 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.
 Too toxic for systemic use.
 Used only topically.
 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 fungistatic agents with a
broad spectrum of activity .
 They have antibacterial , antiprotozoal
anthelminthic & antifungal activity .

Mechanism of Action
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 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
 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).

Ketoconazole (cont.)
 Inactivated in liver & excreted in bile (feces )
& urine.
 Does not cross BBB.

Clinical uses
 Used topically or systematic (oral route only )
to treat :
1- Oral & vaginal candidiasis.
2- Dermatophytosis.
3- Systemic mycoses.

Adverse Effects
 Nausea, vomiting ,anorexia
 Hepatotoxic
 Inhibits human P 450 enzymes
 Inhibits adrenal & gonadal steroids leading to:
Menstrual irregularities
Loss of libido
Impotence
Gynaecomastia in males

Contraindications & Drug interactions
Contraindicated in :
 Prgnancy, lactation ,hepatic dysfunction
 Interact with enzyme inhibitors , enzyme
inducers.
 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 (cont.)
 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
 Concentrated in plasma is same by oral or IV
route
 Has the least effect on hepatic microsomal
enzymes

Fluconazole (cont.)
 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
 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 P450
 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 & itraconazole.
 Systemic fungistatic

Mechanism of action
 Converted within the fungal cell to 5-
fluorouracil (Not in human cell ), 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).

Phrmacokinetics
 Rapidly & well absorbed orally
 Widely distributed including CSF.
 Mainly excreted unchanged through kidney

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

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
 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 26 hours
 Taken selectively by newly formed skin &
concentrated in the keratin.
 Induces cytochrome P450 enzymes
 Should be given for 2-6weeks for skin & hair
infections to allow replacement of infected
keratin by the resistant structure

Griseofulvin(cont.)
 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, fatigue, vertigo,
GIT upset, enzyme inducer, blurred vision.
 Increases alcohol intoxication.

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.

 Highly protein binding
 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 )
 Taste & visual disturbance.

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