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Transcript
ANTI FUNGAL AGENT
FUNGI
• Very large and diverse group of microorganisms
• Classified into yeast and molds
• Yeast is single cell organism, useful for baking and alcohol beverages
• Molds are multicellular, characterized by long, branching filaments called hyphae
FUNGI
• Fungi are eukaryotic, heterotrophic (not self sustaining)
organisms that live as saprobes or parasites.
• They are complex organisms in comparison to bacteria.
Thus antibacterial agents are not effective against fungi.
• Fungal infections are also called as mycoses
• They have nucleus and well defined nuclear
membrane, and chromosomes.
• They have rigid cell wall composed of chitin ( N –
acetylglucosamine )
• Fungal cell membrane contains ergosterol , human cell
mebmrane is composed of cholesterol.
FUNGAL INFECTIONS
• Yeast infections
• Candida species
• Cryptococcus neoformats
• Moulds (filamentous fungi)
•
•
•
•
Aspergillus sp.
Dermatophytes
Trichophyton
Microsporum
MYCOSIS
• A fungal infection of animals, including humans.
• Common and a variety of environmental and physiological conditions can
contribute to the development.
• Initiation of persistent infections:• Inhalation of fungal spores
• localized colonization of the skin
• Therefore, mycoses often start in the lungs or on the skin.
Epidemology:• Skin Fungal infections- the 4th most common disease in 2010
• Affecting 984 million people.
CAUSES
• Individuals being treated with antibiotics are at higher risk of fungal
infections.
• Individuals with weakened immune systems are also at risk of developing
fungal infections.
• This is the case of people with HIV/AIDS, people under steroid treatments, and people
taking chemotherapy.
• People with diabetes also tend to develop fungal infections.
• Very young and very old people, also, are groups at risk.
MAJOR TYPES OF MYCOSES
•
•
•
•
•
Superficial
Cutaneous
Subcutaneous
Systemic
Opportunistic
• Symptoms vary from cosmetic to life threatening
CLASSIFICATION
• Classified according to the tissue levels initially colonized.
Superficial mycoses
• Limited to the outermost layers of the skin and hair.
An example:
• Tinea versicolor
• Affects the skin of young people, especially the chest, back, and upper arms and legs.
• Tinea versicolor
• Caused by a fungus that lives in the skin of some adults.
• It does not usually affect the face.
• This fungus produces spots that are either lighter than the skin or a reddish brown.
CUTANEOUS MYCOSES
• Extend deeper into the epidermis, and also include invasive hair and
nail diseases.
• These diseases are restricted to the keratinized layers of the skin,
hair, and nails.
• Host immune responses may be evoked resulting in pathologic
changes expressed in the deeper layers of the skin.
• The organisms that cause these diseases are called dermatophytes.
• The resulting diseases are often called ringworm (even though there
is no worm involved) or tinea.
• Caused by Microsporum, Trichophyton, and Epidermophyton fungi,
which together comprise 41 species.
• One common disease is the athlete's foot which most commonly
affects children before puberty.
MYCOSES DUE TO
SUBCUTANEOUS MYCOSES SYSTEMIC
PRIMARY PATHOGENS
• Involve the dermis,
• Originate primarily in
subcutaneous tissues,
the lungs and may
muscle and fascia.
spread to many organ
• Infections are chronic
systems.
and can be initiated by
piercing trauma to the
• Organisms that cause
skin which allows the
systemic mycoses are
fungi to enter.
inherently virulent.
• These infections are
difficult to treat.
• May require surgical
interventions such as
debridement.(the
removal of damaged
tissue or foreign objects
from a wound.)
SYSTEMIC MYCOSES DUE TO OPPORTUNISTIC
PATHOGENS
• These are infections of patients with immune deficiencies who would otherwise not
be infected.
• Examples of immunocompromised conditions include AIDS, alteration of normal flora
.
by antibiotics, immunosuppressive therapy, and metastatic cancer
• Examples of opportunistic mycoses include
• Candidiasis (infection caused by yeast Candida, common cause of vaginal
infections in women. )
• Cryptococcosis (systemic infection caused by Cryptococcus that affect the
lungs, skin, or other body organs ,brain and meninges.)
• Aspergillosis ( infections in the ear canal, eyes, nose, sinus cavities, and
lungs)
ANTI FUNGAL AGENT
BASED ON MECHANISM OF ACTION
Fungal
cell
wall
synthesis
inhibition:
• Caspofungin.
Bind to fungal cell membrane
ergosterol:
• Amphotercin–B, Nystatin.
Inhibition of ergosterol + lanosterol
synthesis:
• Terbinafine, Naftifine, Butenafine.
Inhibition of ergosterol synthesis
• Azoles
Inhibition of nucleic acid synthesis
• 5–Flucytosine.
Disruption of mitotic spindle and
inhibition of fungal mitosis
• Griseofulvin.
Miscellaneous
• Ciclopirox, Tolnaftate, Haloprogin,
Undecylenic acid, Topical azoles.
ROUTE OF ADMINISTRATION
SYSTEMIC:
• Amphotericin
Ketoconazole,
Caspofungin
B,
Fluconazole,
Itraconazole,
TOPICAL:
•
Terbinafine,
clotrimazole,
grizeofulvin, nistatin
BASED ON STRUCTURE
1. Antibiotics
A. Polyenes:
• Amphotericin
B
Nystatin, Hamycin
(AMB),
B. Echinocandins:
• Caspofungin,
Anidulafungin
Micafungin,
C. Heterocyclic benzofuran:
• Griseofulvin
3. Azoles
A. Imidazoles
Topical:
• Clotrimazole, Econazole,
Miconazole, Oxiconazole
Systemic:
• Ketoconazole
B. Triazoles: (systemic)
• Fluconazole, Itraconazole,
Voriconazole, Posaconazole
4. Allylamine
2. Antimetabolite:• Flucytosine (5-FC)
• Terbinafine
5. Other topical agents
• Tolnaftate,
Undecylenic
acid,
Benzoic
acid,
Quiniodochlor,
Ciclopirox olamine, Butenafine,
Sod. thiosulfate.
Polyenes (Disrupt membrane structure & function)
Azoles inhibit
Flucytosine inhibits DNA synthesis
POLYENE ANTIBIOTICS
• Amphotericin B
• Obtained from Streptomyces
Nodosus
• Amphoteric in nature
• Polyene group- Multi lactone
ring with conjugated double
bond.
• One end – Hydroxyl group
(OH)–polar (Hydrophilc)
MECHANISM OF ACTION
Amphotericin B
Binds ergosterol in fungal cell membrane
Form pores in cell membrane
• Other end – Hydrocarbon
group-non polar (Lipophilic)
Cell contents leak out
Cell death
MECHANISM OF ACTION
ANTIFUNGAL SPECTRUM
- Fungicidal at high & static at low
conc.
- Broadest spectrum of action
•
Aspergillus
Blastomyces dermatitidis
Candida albicans
Cryptococcus neoformans
Coccidioides immitis
Histoplasma capsulatum
Mucor spp.
Also active against Leshmania
RESISTANCE:
• Replacement of ergosterol by other
sterols in fungal plasma membrane.
PHARMACOKINETICS
• Poorly absorbed orally
• Insoluble in water so colloidal
suspension prepared with sodium
deoxycholate (1:1 complex)
• Plasma proteins bound 90%
• Metabolized in liver
• Slowly excreted in urine
DI:• Flucytosine – synergetic action inc.
permeability FC
• Aminoglycoside inc. renal toxicity.
ADVERSE EVENTS:
– Acute reaction:
– Chills, fever, headache,
pain all over, nausea,
vomiting, dyspnoea
lasting 2-5 hrs because of
release of IL & TNF
– Long term toxicity:
– Nephrotoxicity:
Azotemia ( inability of
the kidneys to excrete
blood urea nitrogen) ,
Hypokalemia, acidosis,
↓ GFR
– anemia
– CNS toxicity : intrathecal
administration, headache, vomiting,
nerve palsies
– Hepatotoxicity rarely
USE:-
Disadvantages of AMB
• Useful drug in nearly all life
threatening
mycotic
Nephrotoxicity
infections
• Treatment
of
invasive
aspergillosis
Acute infusion related reactions
• Rapidly progressive
Blastomycosis (Infection with
a fungus called
Hypopotassemia, anemia, hepatic
Blastomyces dermatitidis) &
dysfunction.
Coccidiomycosis
(caused by inhaling spores of
the fungus Coccidioides immiti
s)
• Cryptococcus neoformans
• Mucormycosis.
• Disseminated
rapidly
progressing Histoplasmosis
• Reserve drugs for resistant
kala
azar
( visceral leishmaniasis caused
by L. tropica)
• Topical uses: for oropharngeal
candidiasis
NYSTATIN:-
 Obtained from S.Noursei
 Similar to AMB
 In antifungal properties
 High systemic toxicity so
used locally only
 Poorly absorbed from
mucus membrane
 Available as ointment,
cream , powder, tablet
USES:
 In
intestinal
moniliasis
(Yeast infection of the
mouth and throat )
 In vaginitis
 Prevention of oral candidiasis
 Can be used in oral,
cutaneous,
conjunctival
candidiasis
ADVERSE EVENTS:
 Gastrointestinal disturbances
HAMYCIN:-
 S. Pimprina
 Hindustan antibiotics Pimpri
 More water soluble, fraction absorbed
orally but unreliable in systemic
infections
 Topical use in thrush (develops on the
mucous membranes of the mouth ),
cutaneous candidiasis, trichomonas &
monilial vaginitis, otomycosis by
aspergillus
Natamycin:
 Similar to nystatin, broad spectrum
 Used topically 1%, 3% ointment
 For Fusarium solani keratitis (ocular
infectious
disease),
trichomonas
(sexually transmitted disease (STD)
caused by a small organism
called Trichomonas vaginalis.)
&
monilial vaginitis (Vaginal Yeast
Infection)
GRISEOFULVIN
• Obtained from Penicillium
griseofulvum
• Fungistatic
• Systemic drug for superficial
fungal infections
• Active
against
most
dermatophytes
• Narrow spectrum
• Dermatophytes concentrate it
actively
hence
selective
toxicity
• Resistance:
• loss of drug concentrating ability
• MECHANISM OF ACTION:
• Griseofulvin
interacts
with
polymerized microtubules and
• Disrupts the mitotic spindles thus
arresting fungal mitosis
PHARMACOKINETICS:
• Irregular absorption
• Increased by fatty food
• Gets conc in keratinized tissue
ADVERSE EVENTS:
• Headache most common
• GIT disturbances
• CNS symptoms: confusion, fatigue,
vertigo
• Peripheral neuritis
• Rashes, photoallergy
• Leukopenia, albuminuria (the
presence of albumin in the urine).
USES:
• Systemically
only
for
dermatophytosis, ineffective topically
• In athletes foot (a fungal infection
affecting mainly the skin between the
toes)
• Systemic azoles more effective and
preferred.
DI :• Induces warfarin metabolisrn
• Reduces
efficacy
of
oral
contraceptives.
• Phenobarbitone reduces the oral
absorption
and
induces
the
metabolism of griseofulvin
• failure of therapy may occur.
:,f
FLUCYTOSINE
• Has useful activity against
Candida and Cryptococcus.
• Synthetic
pyrimidine
antimetabolite
• Fungistatic
MECHANISM OF ACTION
• It is converted to antimetabolite
5-florouracil in a fungal but not
human cell.
• Inhibits thymidylate synthetase
enzyme and
• Thus DNA synthesis.
• Should never be used alone,
resistant may occur.
Uses
• Combination with itraconazole
for
treating
chromoblastomycosis
(chronic
fungal infection of the skin and the
subcutaneous tissue)
• With amphotericin for treating
cryptococcal meningitis in AIDS
patients
UNWANTED EFFECTS
• Neutropenia
• Thrombocytopenia
• Bone marrow depression.
• Nausea, vomiting ,diarrhea,
• Severe enterocolitis (inflammation
of both the small intestine and the colon.)
• Hepatic enzyme elevation.
5-flucytosine permease 5-flucytosine
(outside)
(inside)
Cytosine
deaminase
5-fluorouracil
5dUMP
(inhibits
thymidylate
synthase)
RNA
Phosphoribosyl
transferase
5-FUMP
Fdump(fluorodeoxyuridne
monophosphate
Mechanism of action of Flucytosine
TERBINAFINE
 Orally & topically effective drug
 Against candida & dermatophytes
 Fungicidal :
 shorter courses of therapy required
& low relapse rates
 Pharmacokinetics:
 Well absorbed orally 75%
 Highly keratophilic & lipophilic
 High protein bound , poor BBB
permeability
 Negligible effect on CYP450
MECHANISM OF ACTION:
• Acts as a noncompetitive
inhibitor
of
‘squalene
epoxidase’,
• an early step enzyme in
ergosterol biosynthesis by
fungi.
• Accumulation of squalene
within fungal cells appears to
be responsible for the
fungicidal action.
• The mammalian enzyme is
inhibited only by higher
concentration of terbinafine.
Acetyl CoA
Squalene
Allylamine
Drugs (Terbinafine)
Squalene
epoxidase
Squalene-2,3 oxide
Lanosterol
14-α-demethylase
(ergosterol)
ADVERSE EVENTS:
 Nausea , vomiting , Diarrhoea
 Taste disturbances
 Rarely hepatic dysfunction
 Topical: erythema (superficial
reddening of the skin) , itching,
dryness , urticaria, rashes
USES:
• Topically as cream in tinea pedis
(Infection that usually begins
between the toes)/ cruris (fungal
infection of the groin region)
/corporis
(superficial
fungal
infection of the arms and legs,) and
Pityriasis
versicolor
(patches
appear mainly on the chest and
back)
• Oral treatment reserved for
onychomycosis (fungal infection of
the nail.) , tinea capitis (a fungal
infection of the scalp and hair
shafts).
• Efficacy in nail infection is ~80%.
• Less effective against cutaneous
and mucosal candidiasis.
Mechanism of action of terbinafine
ECHINOCANDINS
Caspofungin,
micafungin,
anidulafungin
• A new class of potent semisynthetic
drugs
• With large cyclic peptides linked to a
long chain fatty acid
• Have low toxicity compared to
AMB.
• Active mainly against Candida and
Aspergillus.
• Strains of candida that have become
resistant to azoles are susceptible
to caspofungin.
MECHANISM OF ACTION
• Inhibits the synthesis of β-1, 3glucan
• which is a unique component of the
fungal cell wall.
• Cross linking between chitin and β1, 3-glucan gives toughness to the
fungal cell wall.
• Weakening of the cell wall leads to
osmotic susceptibility of fungal cell,
which then burst out.
USE:• In deep and invasive candidiasis.
• Esophageal candidiasis
• In invasive aspergillosis.
• Now
increasingly
used
in
neutropenic immunocompromised
patients whose fever is not
responding
to
antibacterial
antibiotics.
ADR:• An
acute
febrile
reaction
(reactions are fever, chills, pruritus,
or urticaria,)
• Phlebitis of the injected vein.
• Rash,
vomiting,
dyspnoea,
hypokalemia and joint pain may
occur.
TOPICAL AGENTS USED IN DERMATOPHYTE
Tolnaftate:
• An effective drug for tinea
cruris and tinea corporis
• Poor penetrability
• Resistance does not occur.
• Causes little irritation
Ciclopirox olamine:
• Penetrates superficial layers
and reaches hair roots
• Negligible Systemic absorption.
• No irritation
• Used
in
onychomycosis:Formulated as nail lacquer
• Vaginal candidiasis :- as vaginal
cream.
• Effective in tinea infections,
pityriasis
versicolor
and
dermal candidiasis.
• Undecyclenic acid:
• Generally combined with
zinc salt
• Requires
prolonged
treatment
has
high
relapse rate
• Weaker antifungal action
used in tinea cruris, tinea
pedis and nappy rash
(inflammation of a baby's skin
caused by prolonged contact with
a damp nappy)
• Sodium thiosulfate:
• A weak fungistatic,
• Active against Malassezia
furfur
(a fungus species can cause tine
a versicolor, folliculitis)
• Effective in
versicolor
pitryasis
BENZOIC ACID:
• Fungi
static-weaker
than tolnaftate
• Used in combination
with salicylic acid
• Whitfields
ointment:
( benzoic acid 6% +
salicyclic acid 3 %)
• Salicyclic acid due to its
keratolytic action helps
to remove infected
tissue & promotes
penetration of benzoic
acid in fungal infected
lesion
• Adverse
events:
irritation & burning
sensation
QUINIDIOCHLOR:
• Luminal amoebicide
• Weak
antifungal
&
antibacterial
• External
application
:
Dermatophytosis , mycosis
barbae (Ringworm of the beard) ,
pitryasis versicolor
• Also used in vaginal creams for
monilial and trichomonas
vaginitis
BUTENAFINE
• A benzylamine congener of
terbinafine
• Same mechanism of action.
Use:• Topically in dermatophytosis.
• Efficacy in tinea cruris /
corporis / pedis
AZOLES
• Synthetic anti fungals
• Broad spectrum
• Fungistatic / Fungicidal
• Most commonly used
• Classified as imidazoles & triazoles
• Both these groups are
• Structurally related compounds
• Have same mechanism of action
• Have similar antifungal spectrum
• Imidazoles:
• Two nitrogen in structure
• Topical:
• Econazole,
Miconazole,
Clotrimazole
• Systemic :
• ketoconazole (topically also)
• Triazoles :
• Three nitrogen in structure
• Fluconazole,
itraconazole,
voriconazole, Terconazole
• Fluconazole and itraconazole -----largely replaced ketoconazole for
systemic mycosis
• Because of greater efficacy, longer t½,
as well as fewer side effects.
• Some newer triazoles have been
added.
• Newer
:
Butaconazole,
Oxiconazole, Sulconazole
• Covering dermatophytes, Candida,
other fungi involved in deep mycosis
(except mucor), Nocardia and
Leishmania
THE MECHANISM OF
ACTION
• They inhibit the fungal cytochrome
P450 enzyme ‘lanosterol 14demethylase’
• Thus impair ergosterol synthesis.
• Leading to a cascade of membrane
abnormalities in the fungus.
• The lower host toxicity :-
• Lower affinity for
mammalian CYP450
enzymes
• Lesser propensity to
inhibit mammalian sterol
synthesis.
RESISTANCE:• Mutation of the gene
• Encoding for fungal 14demethylase enzyme.
• By enhanced removal
from the fungal cell.
Acetyl CoA
Squalene
Allylamine
Drugs (Terbinafine)
Squalene
monooxygenase
Squalene-2,3 oxide
Lanosterol
Azoles
14-α-demethylase
(ergosterol)
MICONAZOLE & CLOTRIMAZOLE
KETOCONAZOLE
• Topical use
• First orally effective broad spectrum
antifungal
• Effective against
• Cream, gel, spray, lotion, solution ,
pessary
• Dermatophyte
infections
(pedis, cruris, corporis, versicolor)
• Candida: oral pharyngeal, vaginal,
cutaneous
ADVERSE EVENTS:
• Local irritation , itching or burning
• Miconazole shows higher incidence of
vaginal irritation & pelvic cramps
• No systemic side effects
• Dermatophytosis
• Deep mycosis
• Candidiasis
PHARMACOKINETICS:
• Requires
environment
absorption
acidic
for
USE:
• Restricted use, most serious mycoses
• Dermatophytosis
• Monilial vaginitis
• Systemic mycosis: blastomycosis (Parasitic fungi affecting the skin or the internal
organs), histoplasmosis (infection by a fungus confined to the lungs but can be
fatal if spread throughout the body), Coccidioidomycosis (a serious fungal disease
of the lungs and other tissues)
• Less efficacious than AMB & produces slower response
• Efficacy low in immunocompromized and meningitis
• Lower toxicity than AMB higher than triazoles
• So triazoles have replaced it in systemic mycosis
• High dose used in cushings syndrome (a metabolic disorder caused by
overproduction of corticosteroid hormones)
• Topical: T.pedis, cruris, corporis, versicolor
38
DRUG INTERACTIONS:
• Inhibits CYP450 enzyme
ADVERSE EVENTS:
• Nausea , vomiting , anorexia
• ↑ Sr conc of cisapride, terfenadine,
• Headache , paresthesia, alopecia
• Reduces steroid, testosterone
estrogen synthesis
astemizole, quinidine
&
• Thus
can
cause
gynaecomastia
(enlargement of a man's breasts, usually
due to hormone imbalance),
• Oligospermia (deficiency of sperm cells
in the semen), loss of libido (loss of sex
drive)
& impotence ( sexual
dysfunction) in males.
• Menstrual irregularities & amenorrhoea
(an abnormal absence of menstruation)
in females
• Elevation of liver enzymes
• Hypersensitivity reaction like skin
rashes
• Itraconazole or fluconazole, that have
largely replaced it for systemic use.
• Phenytoin toxicity
• Sulfonylureas: hypoglycemia
• Cyclosporine: nephrotoxicity
• Warfarin: bleeding
• Rifampicin, phenytoin ↑ metabolism of
ketoconazole
• Should not combine with AMB
TRIAZOLE
FLUCONAZOLE
• Newer water soluble
triazole
• Oral, IV as well as topical
• Broad
spectrum
antifungal activity
• Candida, cryptococcosis,
coccidioidomycosis
• Dermatophytosis
• Blastomycosis
• Histoplasmosis
• Sporotrichosis
PHARMACOKINETICS:
• 94% oral bioavailability
• Not affected by food or gastric pH
• Primarily excreted unchanged in urine
• Poor protein binding (10-12%)
• Widely distributed
• Crosses BBB
• T ½ -27-32hrs
ADVERSE EVENTS:
USES:
• GIT upset
• Headache,
• Candida
alopecia,
skin
rashes,
hepatic necrosis
• Teratogenic effect
• CYP450 Enzyme inhibiting property
less
• No anti androgenic & other endocrine
effects
DRUG INTERACTIONS:
• Effects hepatic drug metabolism to
lesser extent than Ketoconazole
• H2 blockers & PPI do not effect its
absorption
• Tinea
infections
candidiasis
&
• Disseminated
cutaneous
candidiasis,
cryptococcal, coccidiodal meningitis &
other systemic fungal infections
• Candida UTI
• Meningitis preferred drug
• Eye
drops for fungal keratitis
(infection of the cornea)
ITRACONAZOLE
•
Broadest spectrum of activity also against aspergillus
•
Fungistatic
PHARMACOKINETICS:
•
50-60% bioavailability
•
Absorption is variable, enhanced by food & gastric acidity
•
High protein binding 99 %
•
Well distributed accumulates in vaginal mucosa, skin, nails
but CNS penetration is poor
•
Metabolized in liver CYP3A4
•
Excreted in feces
•
T1/2= 30- 64hr
ADVERSE EVENTS:
• GI Intolerance
• Dizziness,
pruritis
,
hypokalemia, hypotension
• Increase plasma transaminase
• Rarely Hepatotoxicity
headache,
DRUG INTERACTIONS:
• Oral absorption decreased by antacids, H2
blockers , and proton pump inhibitors
• Rifampicin, phenobarbitone , phenytoin
induce metabolism
• Clarithromycin and HIV protease inhibitors
reduce the metabolism of itraconazole and
raise its blood levels.
• Potentiates effect of hypnotic drugs
• Inhibits CYP3A4 drug interaction profile
similar to ketoconazole
USES:
• For paracoccidomycosis (a fungal infection caused by the
fungus Paracoccidioides brasiliensis. )& chromoblastomycosis
• For histoplasmosis, sporotrichosis (infection caused by a fungus
called Sporothrix schenckii )& blastomycosis in AIDS patients
• Esophageal, oropharyngeal, vaginal candidiasis
• Dermatophytosis: less effective than fluconazole
• Onychomycosis
• Aspergillosis
43
VORICONAZOLE
ADVERSE EVENTS:
• Second generation triazole
• Transient
• High oral bioavailability,
• Low protein binding
visual
• Good CSF penetration
changes
• Metabolized by CYP2C19
vision , altered color
• Doesn’t require gastric acidity
absorption
for
• T1/2-6 hrs
USES:
• DOC for invasive aspergillosis
• Most useful for esophageal candidiasis
• First line for moulds like fusarium
(infestation with any of the fusaria or
related moulds.)
• Useful in resistant candidal infections
like
blurred
perception
&
photophobia
• Rashes in 5 -6 %
• Elevated
hepatic
enzymes
• Prolongation of QT
THANK YOU
-PHARMA STREET