Drug for systemic mycoses

 Systemic mycoses can be subdivided into

two categories
 Opportunistic infection: candidiasis,
aspergillosis, cryptococcosis,mucormycosis—
it occur in immunocompromised host
 Non-opportunistic infection:
 Histoplasmosis, blastomycosis-----it occur in any
host
Drugs for systemic Mycoses
 Amphotericin B
 Ketoconazole
 Itraconazole
 Fluconazole
 Miconazole
 Flucytosine
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 :
 Dermatophytics referred to as ringworm
[ because of characteritic ring shaped lesion]
 Tinea pedis[ ringworm of foot or athlete’s foot]
 Tinea corporis[ ringworm of body]
 Tinea capitis[ ringorm of scalp]
 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 )
 Amphotericin B is active againt broad spectrum of
pathogenic fungi and is drug of choice for most systemic
mycoses
 Amphotericin B cause renal damage
Pharmacokinetics
 Poorly absorbed orally , is effective for fungal
infection of gastrointestinal tract.
 For systemic infections given as slow I.V.
 Intrathecal injection has been used for fungal
meningitis
 Highly bound to plasma protein, Poorly
crossing BBB,Metabolized in liver
 Excreted slowly in urine over a period of
several 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 modyfing 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.
2- Slower toxicity
 Most serious is renal toxicity (nearly in all
patients )----dose >4gm
 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 and 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.
 Topical drops & direct subconjunctival
injection for Mycotic corneal ulcers &
keratitis.
 3- Local injection into the joint in fungal
arthritis.
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
 More expensive
Drug interaction
 Nephrotoxic drugs: aminoglycosides,
cyclosporin,---risk for kidney damage
 Flucytosine : reduce amphotericin toxicity
 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 ). This results in increased membrane
permeability and leakage of cellular components
 2- Inhibition of mitochondrial cytochrome oxidase
leading to accumulation of peroxides that cause
autodigestion of the fungus.
 3- Imidazoles may alter RNA& DNA metabolism.
 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 & mucocutaneous
candidiasis.
Adverse Effects
 Nausea, vomiting ,anorexia
 Hepatotoxic
 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[ rifampici].
 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
 Conc. 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
 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
 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
 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 from5-FC)
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 2-6weeks 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.
CLOTRIMAZOLE
 Absorption is less than 0.5% from intact skin,
3-10% from vagina (its activity remains for 3
days ).
 Used in dermatophytes , cutaneous candidiasis
& vulvovaginal candidiasis.
 Causes : Erythema, edema, , urticaria & mild
vaginal burning sensation.