Anti-fungal drugs.pdf

Prof. Shaikh Abusufiyan
Assistant Professor,
AIKTC-School of Pharmacy,
New Panvel-410206
Antifungal Drugs
Pharma Learning Forever

At the end of this e-learning session you are able to…
A. Discuss type of fungal infection and
classify Anti-fungal drugs.
B. Explain pharmacology of anti-fungal
drugs.

●The fungal infection are termed as
mycoses.
2 Types of fungal infection:
1. Superior fungal infection: affecting skin,
nails, scalp or mucous membrane.
2. System infection: affecting deeper tissues
and organ.

● The commonest systemic fungal disease is systemic
candidiasis--> infection with yeast like microorganism.
● Other more serious conditions are:
● Cryptococcal meningitis
● Endocarditis
● Pulmonary aspergillosis

● Colonization of the lungs of patient by
aspergillus --> can lead to allergic
bronchopulmonary aspergillosis.

Prevalence:
Following people are more prone to fungal infections:
● Older people
● Diabetic patients
● Pregnant women
● Burn wound victims

● The superficial fungal infection can be classified as:
● Dermatomycoses- infection of skin, nails and hairs.
● Candidiasis- yeast like MO infect the mucous
membranes of the mouth, vagina or skin.

Anti-fungal drugs
1. Antibiotics:
A. Polyenes e.g Amphotericin B, Nystatin, Hamycin,
Natamycin
B. Heterocyclic benzofuran e.g. Griseofulvin.
2. Antimetabolites e.g. Flucytosine (5-FU)

3. Azoles:
Eg. Imidazole's
- Topical- Clotrimazole, Econazole, Miconazole
- Systemic- Fluconazole, itraconazole
4. Allylamine eg Terbinafine
5. Other topical agents:
● Tolnaflate, benzoic acid, quinido-chlore, sod.
thiosulphate

I. Polyene antibiotics:
A. Amphotericin B:
- It is a macrolide antibiotics of a complex structure-
characterized by many member carbon ring.

MOA:
● Fungal cell contain large amt of ergosterol in the
plasma membrane
Facilitate the attachment of polyene antibiotics
Act as ionophores and cause leakage of the cation

Pharmacokinetics:
● Amphotericin is poorly absorbed and remains in GIT
It is given for the fungal infection of GIT.

● It can also be given topically.
● For systemic infection- it complex with sodium
deoxycholate and given as a suspension by slow IV
injection.

● Other preparation of amphotericin for IV infusion
include amphotericin complexed with–lipid-beta
cyclodextrin
● Or encapsulated in liposome or nanospheres.

Q&A: Activity I
Q.1 What is happen in case of allergic
bronchopulmonary aspergillosis.
Q.2 Name antifungal drug under
Antimetabolites category?
Q.3 Give MOA of Amphotericin
Q.4 In which form Amphotericin is given
for systemic administration?

Activity II: Self learning of e-content

Distribution:
● It is highly protein bound
● It normally crosses BBB poorly --> but penetration is
more when meninges are inflamed

●It is excreted slowly via kidney --> traces are found in
the urine for 2 months or more.

Unwanted effects:
● Renal toxicity: Some degree of reduction of renal
function occurs in more then 80% of patients.
● Hypokalaemia: occur in 25 % of patients
● Hypomagnesemia

● Impaired hepatic functions
● Thrombocytopenia
● Anaphylactic shock
● Frequent injection result in
● Chills
● fever
● tinnitus
● Headache

● Local thrombophlebitis- due to irritant effect of
drug on vein
● Neurotoxicity- with intrathecal injection
● Skin rashes- with topical application

Nystatin
●Nystatin (Also called as fungicidin) is polyene
macrolide antibiotic
●Similar in structure with amphotericin and with same
mechanism of action.

● Not absorb from mucous membrane of the body
or from skin
Use mainly limited to the Candida infections of the
skin, mucous membranes and the GIT.

● Unwanted effects:
● Nausea
● vomiting
● diarrhoea

Griseofulvin
●It is a narrow spectrum antifungal agent --> isolated
from culture of penicillium griseofulvum.
MOA:
● Fungistatic action
● Interreact with fungal microtubule and interfere with
mitosis.

● Used to treat dermatophyte infection of skin or nails
--> when local treatment is ineffective - but treatment
need to be very prolonged.

Pharmacokinetics:
●It is given orally.
●It is poorly soluble in water
●Peak plasma concentration is reached in about 5 hrs.
●It is taken up selectively by newly formed skin and
concentrate in the keratin.

Unwanted effect: Are frequents and includes:
● Gastrointestinal upsets
● Headache
● Photosensitivity
● Allergic reaction (rashes, fever)
● Drug should not be given to pregnant women.

Q&A: Activity III
Q.1 Enlist unwanted effects of
Amphotericin.
Q.2 What is category of Nystatin?
Q.3 Give MOA of Griseofulvin

Echinocandins:
● It consist of a ring of six amino acid linked to the
lipophilic side chain.
MoA:
● It inhibit the synthesis of 1,3 beta glucan (a glucose
polymer necessary for maintaining the structure of
fungal cell walls).
In the absence of this polymer fungal cells loss
integrity (and lead to lysis of the cell)

Azoles:
● The azole are grp of synthetic fungistatic agents with a
broad spectrum of activity.
● They are classified as:
A. Imidazole (Topical) eg. Clotrimazole,
econazole, ketoconazole, miconazole etc
B. Triazole nucleus (Systemic) Eg.
Itraconazole, fluconazole etc.

MoA:
●It inhibit the fungal
● Cytochrome P450 3A enzyme
● Lanosine 14 alpha demethylase
These enzymes are responsible for converting the
lanosterol to ergosterol (The main sterol in the fungal
cell membrane)

MoA:........
●The resultant depletion of ergosterol alter the
fluidity of the membrane.
Inhibition of replication

MoA:.......
● It also inhibit the transformation of candidal yeast
cells
into hyphae (The invasive and pathogenic form of the
parasite).

Ketoconazole:
● Ketoconazole was the first azole --> that can be
given orally to treat systemic fungal infection.
● It is effective against --> several different type of
organism

Activity IV: Self learning of e-content

Pharmacokinetic:
● It is well absorbed from GIT
● It is distributed widely --> throughout the tissue and
tissue fluid
● But it does not reach the therapeutic concentration in
the central nervous system unless high dose is given.

Pharmacokinetic........
● It is inactivated in the liver
● It is excreted in the bile and urine

Unwanted effect:
● Liver toxicity- it is rare but some time fatal
● GIT disturbance, pruritus.
● Inhibition of adrenocorticoid
● Inhibition of testosterone – resulting in gynecomastia

Adverse interaction with the drugs:
Cyclosporine, terfenadine, and astemizole- interfere
with drug metabolizing enzymes.
Causing increase plasma concentration of ketoconazole.

●Rifampicin, histamine H2 receptor antagonist and
antacids decreases the absorption of ketoconazole.

Q&A: Activity V
Q.1 Explain mechanism of action of
Echinocandins.
Q.2 ------ was the first azole that can be
given orally to treat systemic fungal
infection.
Q.3 Enlist few unwanted effect of
ketoconazole

Flucytosine:
MoA:
● Converted to antimetabolites --> 5 Fluorouracil in fungal
but not in human cell
● 5 fluorouracil --> inhibits thymidylate and DNA
synthesis

Terbinafine:
● it is a highly lipophilic fungicidal compound
● active against a wide range of skin pathogen.
● it is particularly useful against nail infections.

- it act by selective inhibition of --> enzyme squalene
epoxidase
involve in the synthesis of --> ergosterol from squalene
in the fungal cell wall.
- the accumulation of --> squalene within the cell is
toxic to the organism.

Pharmacokinetics:
● It is given orally.
● It is rapidly absorbed and is taken up by the skin,
nails, and adipose tissue.

● Given topically --> it penetrate the skin and mucous
membranes.
● Metabolised in the liver --> by cytochrome p450
system.
● Metabolites --> excreted in the urine.

Unwanted effects:
● GIT disturbance
● Rashes
● Pruritis
● Headache
● Dizziness
● Joint and muscle pains
● And more rarely hepatitis.

Q&A: Activity VI
Q.1 Explain mechanism of action of
Flucytosine.
Q.2 Identify the drug which act by selective
inhibition of enzyme squalene epoxidase.
Q.3 Discuss Pharmacokinetic of Terbinafine.

Reference:
• H.P Rang. M M Dale, J.M Ritter, R.J Flower, G
Henderson. Pharmacology, Seventh Edition. Elsevier
Churchill Livengston Publication. Page no:649-654

Anti-fungal drugs.pdf

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