Anti-fungal drug
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Transcript Anti-fungal drug
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