Transcript Antifungal Drugs

Antifungal Drugs



Fungal infectious occur due to :
1- Abuse of broad spectrum antibiotics
2- Decrease in the patient immunity
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 : 12% 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 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 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.
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.
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 lipidassociated 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 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




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 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 & vulvovaginal 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
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 5fluorouracil( 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)
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 & Nacetylation.
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 2-6weeks 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.
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 .
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.
ITRACONAZOLE



Effective for treatment of onychomycoses.
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.






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.