antifungal agents-mechanism of action-indications-adverse affects.

1. ANTIFUNGAL
AGENTS
-classification
-MOA
-indications
-Adverse effects
Susritha.k
Pg dpt of ent
ASRAMS eluru

2.  Fungi
are eukaryotic, heterotrophic (not
self sustaining) organisms that live as
saprobes or parasites.
 They
are complex organisms in
comparison to bacteria.
 Fungal
infections are also called as
mycoses.

3. 
They have nucleus and
well defined nuclear
membrane, and
chromosomes.

they have rigid cell wall
composed of chitin ( N –
acetylglucosamine )

where as bacterial cell
wall is composed of
peptidoglycan .

fungal cell membrane
contains ergosterol.

4. Fungal infection
SUPERFICIAL
Dermatomycoses
affecting skin, hair
or nails.
SYSTEMIC
Candidiasis
cryptococosis,
Aspergillosis,
Candidiasis
Blastomycosis,
Histoplasmosis,
Coccidioidomycosi
s,
Paracoccidioidomy
cosis

5. 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

6. iii) Allylamines
Terbinafine
Naftifine
Butenafine
vi) Echinocandins
caspofungin

7. B)Drugs that inhibits mitosis
Griseofulvin
C)Drugs that inhibits DNA synthesis
flucytosine
Miscellaneous
Haloprogi
Tolnaftate
Whitefield's ointment
Ciclopirox olamine

8. Diagram showing mechanism of action of different anti fungal durgs

9. POLYENE ANTIBIOTICS
 They
act by:
Binding to sterol in cell membrane.
Deformity in plasma membrane occurs
Interferes with permeability and with transport functions
This allows leakage of intracellular ions and enzymes
especially loss of intracellular k+
cell
death.
 They
bind selectively to ergosterol in
fungus but not in mammalian cell wall.

10. AMPHOTERICIN B

It is macrolide antibiotic large lactone ring.

Poorly absorbed orally, useful for fungal infection of gastrointestinal
tract.

Locally used in corneal ulcers, arthritis and candidial bladder
irrigation

For systemic infections given as slow I/V infusion.

Highly protein bound.

Penetration through BBB is poor but increases in inflamed meninges.

Excreted slowly via kidneys, traces found in urine for months after
cessation of drugs.

Half life 15 days

11.  Drug
of choice for
most systemic
infections.
 Course
of treatment
lasts 6-12 weeks.
 Dose
0.5-1
mgkgday.

12. ADVERSE EFFECTS:

Most serious is renal toxicity, which occurs in
80% of patients.

Hypokalaemia in 25% of patients, requiring
potassium supplementation.

Hypomagnesaemia
Anemia
Impaired hepatic function
Thrombocytopenia




13. Liposomal preparations of
amphotericin B(newer
preparations)



To reduce the toxicity of amphotericin B ,several new
formulations have been developed in which amphotericin B
is packaged in a lipid-associated delivery system, to assume
that they will less bind to mammalian cell.
Lipid vehicle act as a reservoir, reducing binding to human
cell.
In this way it permits a larger doses, even five times more
than colloidal preparation, they have better clearance .

Clinically they have more efficacy , less nephrotoxicity.

But these are very expensive.

15. Nystatin
 It
is polyene macrolide,similar in structure
to amphotericin and with same
mechanism of action.
 Too
 Not
toxic for systemic use
absorbed from GIT /skin therefore
administered orally.

16.  Prevent
or treat superficial candidiasis of
mouth, esophagus or intestinal tract, oral
suspension of 100,000 U/ml 4 times a day
and tablets 500,000 U are used to
decrease GIT colonization with Candida.
 Can be used in combination with
antibacterial agents and corticosteroids.

17. AZOLES:

a bivalent chemical group composed of two nitrogen
atoms.

They are antibacterial, antiprotozoal, anthelminthic and
antifungal.

These are group of synthetic fungistatic agents.

They have broad spectrum of activity.

Inhibit the fungal cytochrome P450 3A enzyme ,
(lanosine 14-desmethylase ),which is responsible for
converting lanosterol to ergosterol, the main sterol in the
fungal cell membrane, this alters fluidity of the
membrane, thus inhibiting the growth of fungi.

18. IMIDAZOLES
 Ketoconazole,
 miconazole,
 clotrimazole,
 isoconazole
,
 Tioconazole
 They
interfere with fungal oxidative enzymes to
cause lethal accumulation of hydrogen peroxide.
 they reduce the formation of ergosterol by
inhibition of fungal cytochrome P450 enzyme,
which become permeable to cellular constituent

19. TRIAZOLES:



Fluconazole,
itraconazole,
voriconazole

They damage the fungal cell membrane by inhibiting
enzyme desmethylase .

They are selective

Penetrate to CNS

Resistant to degradation

Cause less endocrine disturbance.

20. KETACONAZOLE:
 First
azole that could be given orally to treat
systemic fungal infections.
 Well
absorbed orally as acidic environment favours
its dissolution.
 Only administered orally.
 After
oral administration of 200,400 and 800 mg,
plasma conc. reaches to 4.8 and 20 ug/ml.
 Half
mg
life increases with dose and it is 7-8 hrs with 800

22.  Decrease
in the
ergosterol in the fungal
membrane by
ketoconazle reduces
the fungicidal action of
amphotericin.
 Oral
dose 400 mg daily.

23.  As
it inhibits steroid biosynthesis, several
endocrinological abnormalities may be
evident as menstrual abnormalities,
gynecomastia, decreased libido and
impotency.
 Contraindicated in pregnancy.

24. ITRACONAZOLE




It is a synthetic triazole
it is new drug
It lacks endocrine side effects
of ketoconazole.
It has broad spectrum
activirty

Administered orally as well as
I/V.

Do not penetrate CSF
adequately.
Dose 100 mg twice daily with
food, initially 300 mg thrice
daily as a loading dose
hypertriglyceridemia,
Hypokalaemia, hepatotoxicty


FLUCONAZOLE

It is fluorinated bistriazole.

Completely absorbed from GIT

Excellent bioavailability by oral route.

Concentration in plasma is same by
oral or I/v route
Drug interactions are less common.
It easily penetrate CSF and is a drug
of choice in cryptococcal meningitis
and coccido mycosis
Candidiasis: 200 mg on 1st day then
100 mg daily for 2 weeks.




Cryptococcosis: 400 mg daily for 8
weeks in meningitis.

Hepatic failure may lead to death

It is highly teratogenic.

25. Voriconazole

A new drug available in i.v and oral
fromulations.

recommended dosage is 400 mg/ day

high biological availability when given orally

hepatic metabolism predominant.

it is similar to itraconazole but more potent.

26. FLUCYTOSINE

Has useful activity against Candida and Cryptococcus.

it is synthetic pyrimidine antimetabolite that is often used
in combination with amphotericin B.

Mechanism of action


It is converted to antimetabolite 5-florouracil in a fungal cell.
This 5-FU inhibits thymidylate synthetase enzyme and thus
DNA synthesis.

27. 
dose 100-150 mg /kg per day divided into 4
doses.

Generally use in combination with
amphotericin

For cryptococcal meningitis in AIDS patients
Side effects:


reversible neutropenia, thrombocytopenia and
occasional bone marrow depression.

28. Caspofungin
 It
is echinocandin class of antifungal drugs
 it interferes with the synthesis of fungal cell wall by
inhibiting synthesis of D-glucan.
 especially useful for aspergillus and candida.
 not active orally.
 Has half life of 9-11 hours
 Adverse

effects include nausea ,vomiting, flushing
very expensive

30. GRISEOFULVIN

Isolated from Pencillium griseofulvum

It interacts with microtubules and interferes with mitosis.

31. 
Uses


Mycotic diseases of skin, hair (particularly for
scalp) , nail.
It is also highly effective in athlete's foot
Peripheral neuritis
 Lethargy
 mental confusion
 impairment in performance of routine task
 fatigue, vertigo ,syncope, blurred vision.


32. Comparison of Azoles fungistatic drugs

33. Topical anti fungal
preparations
 Topical






azole derivatives
Ciclopirox olamine
Naftifine
Terbinafine
Butenafine
tolnaftate
Nystatin and Amphotericin

34.  Amphotericin



B
Candida oesphogitis0.15-0.2mg/kg daily.
Invasive aspergillosis1-1.2mg/kg until
progression is arrested.
Candida cystitisbladder irrigation with
50ug/ml.

35.  Itraconazoledeep


mycosis
Divided dosage1st 3 days 200mg three
times(loading dose)
Maitainence dose200mg once daily for
12wks.
 Flucanozole

Oesophageal candidiasis




200mg 1st day.
100mg daily for 2 wks.
Coccidioial meningitis
Cryptococcal meningitis400mg daily 8wks
later 200mg for life

36. Future prospects
 Posaconazole
azoles.
& rabuconazole newer
Very effective in
treatment of
zygomycosis in
immunocompromised
 Nikkomycins
newer antifungals act by
inhibiting chitin synthesis.

37.  Sordarinsupcoming

Inhibits fungal growth by blocking
elongation factor2.
 Two


class of antifungals
new echinocandins
Micafungin
Anidulafungin
Effective in
immunocomprimised pts
against aspergillus &
candida infections.

38.  Recombinant
form of human granulocyte
colony stimulating factors like
 Lenogastrin
increase neutrophil count in
neutropenia pts with fungal infections.
 These
are used along with antifungal
agents to enhance their efficacy in
immunocompromised pts.

39. Bibliography
 Goodmans
gillmans-the pharmacological
basis of therepeutics 10th edition pg:1295.
 Principles of pharmacology –sharma h.s
pg:789-90.
 Tripati