ANTI FUNGAL DRUGS.ppt The ppt contains information about Antifungal drugs

ANTI FUNGAL DRUGS
Pharm.D III Yr
Medicinal Chemistry
By
Dr Rakam Gopi Krishna
Marri Laxman Reddy Institute of
Pharmacy

Fungal infection may be
 SUPERFECIAL
 Dermatomycoses affecting skin, hair or nails.
 b) Candidiasis (commonly normal flora of mouth, skin,
intestines and vagina) infection caused by genus candida
affecting skin, mucous membrane of mouth or G.I.T or female
genital tract
 SYSTEMIC
Candidiasis ,cryptococosis, Aspergillosis,
Blastomycosis, Histoplasmosis,

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
iii) Allylamines
Terbinafine
Naftifine
Butenafine

Diagram showing mechanism of action of different anti fungal durgs

Drug classification cot’d
B) Drugs that inhibits mitosis
Griseofulvin
C) Drugs that inhibits DNA synthesis
flucytosine

Superficial Mycosis
 a) Dermatophyte infection (ring worm,tinea).
 Benzoic acid ointement for mild infection.
 Topical imidazole (like miconazole,clotrimazole) is
preferred now a days
 Tioconazole for nail infection
 Griseofulvin orally for extensive scalp or nail tinea
infection.

b) Candida infection.
 Cutaneous infection: by
topical amphotericin,clotrimazole ,econazole,
miconazole or nystatin
 Candidiais of elementary tract mucosa
amphotericin,fluconazole, ketoconazole,
miconazole or nystatin.
 Vaginal candidiasis:
Clotrimazole,econazole,ketoconazole, miconazole or
nystatin

Systemic Mycosis
 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+, causing cell death.
 They bind selectively to ergosterol in fungus but not in mammalian cell
wall.

Mechanism of action of Amphotericin

 Remains in the body for weeks after stopping the
drug.
 Drug of choice for most systemic infections.
 Course of treatment lasts 6-12 weeks.
 Dose .5-1 mgkgday

Adverse reactions
 Most serious is renal toxicity, which occurs in 80% of
patients
 There may occur decrease in glomerular filtration,
and renal function, drop in creatinine clearance,and
loss of potassium and magnesium, nephrotoxcity may
be potenciated by sodium depletion.
 Hypokalaemia in 25% of patients, requiring
potassium supplementation.
 Hypomagnesaemia
 Anemia
 Impaired hepatic function
 Thrombocytopenia

 Anaphylactic shock
 Anorexia, nausea, vomiting, abdominal, joint and
muscle pain, loss of weight, and fever.
 Aspirin, antihistamines (H1) antiemetics may help in
alleviating the symptoms.

NYSTATIN
 It is polyene macrolide,similar in structure to
amphotericin and with same mechanism of
action
 Too toxic for systemic use
 Not absorbed from GIT, skin or vagina,
therefore administered orally

 For vaginal candidiasis in form of pessaries used for
2 weeks
 In Cutaneous infection available in cream, ointment
or powder form and applied 2-3 times a day
 Can be used in combination with antibacterial agents
and corticosteroids

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.

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 constituents.
 They lack selectivity,and also inhibits human gonadal and
steroid synthesis leading to decreased testosterone and cortisol
production. It also inhibits cytochrome P450 –dependant
hepatic drug –metabolizing enzyme.

b).Triazoles.
 Fluconazole,
 itraconazole,
 voriconazole
Voriconazole is under clinical trials.
 They damage the fungal cell membrane by inhibiting enzyme desmethylase
 They are selective
 Resistant to degradation

KETOCONAZOLE:
 First azole that could be given orally to treat systemic fungal infections.
 Well absorbed orally as acidic environment favors its dissolution.
 Only administered orally
 Bioavailability is decreased with H-2 blocking drugs, proton pump
inhibitors and antacids and is impaired with food.
 cola drinks improve its absorption in patients with achlorhydria.
 After oral administration of 200,400 and 800 mg, plasma conc. reaches to
4.8 and 20 ug/ml.
 Half life increases with dose and it is 7-8 hrs with 800 mg

Mechanism of action of ketoconazole

Decrease in the ergosterol in the funagal membrane
By ketoconazle reduces
the fungicidal action of amphotericin

 Metabolized extensively in liver and inactive products appear
in the feces.
 84 % is bound to plasma proteins.
 It does not enter CSF.
 Moderate hepatic dysfunction has no effect on drug
concentration.
 Induction of microsomal enzymes by other drugs reduces the
concentration.

It is not useful for fungal infections of UT
as level of parent drug in urine is very low

Side effects:
 Dose dependant nausea, anorexia ,vomiting
 Liver toxicity is rare but may prove fatal.
 Hair loss
 As it inhibits steroid biosynthesis, several
endocrinological abnormalities may be evident as
menstrual abnormalities, gynecomastia, decreased
libido and impotency.
 Fluid retention and hypertension.

Drug interactions
 cyclosporin,phenytoin ,H1 blockers inhibit its
metabolism and hence increase toxicity.
 Warfarin ,Rifampin increase its metabolism
and hence decrease concentration.
 H2 blockers ,antacids decrease its absorption.
 Contraindicated in pregnancy

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.
 Food increases its absorption

 Metabolized in liver extensively by cytochrome CYP3A4
 It is highly lipid soluble, it is well distributed to bone ,sputum
and adipose tissue.
 Highly bound to plasma protein
 Do not penetrate CSF adequately ,therefore its concentration
is less to treat meningeal fungal infection

 Half life is 30-40 hours
 Steady state reaches in 4 days, so loading doses are
recommended in deep mycosis.
 Dose 100 mg twice daily with food, initially 300 mg thrice
daily as a loading dose.
 Intravenously reserved only in serious infections.200 mg twice
daily in infusion for one hour for two days followed by 200
mg daily for 12 days.
 Side effects: nausea, vomiting, hypertriglyceridemia,
Hypokalaemia, increased aminotransferase, hepatotoxicty rash
leads to drug discontinuation.

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.
 Bioavailability not altered by food or gastric acidity
 It has least effect on hepatic microsomal enzymes.
 Drug interactions are less common.

 Peak plasma concentration 4-8ug/ml with
 It easily penetrate CSF and is a drug of choice in cryptococcal meningitis
and coccido mycosis.
 It can safely be administered prophylactically in patients receiving bone
marrow transplants.
 Resistance not a problem except in patients with HIV
 100mg repetitive dose.
 Renal excretion 90%
 t1/2 25-30 hours.
 Diffuse in all body fluids including CSF concentration 50-90 %.

Uses
 Candidiasis: 200 mg on 1st day then 100 mg daily for 2 weeks.
 Cryptococcosis: 400 mg daily for 8 weeks in meningitis.
 In AIDS 200 mg for life.
 Coccidial meningitis it is drug of choice
 It has also activity against histoplasmosis, blastomycosis,
spirotrichosis ,and ring worm but itraconazole is better in same
dose
 Not effective in aspergillosis.

Unwanted effects :
 nausea, vomiting, headache, skin rash, abdominal
pain, diarrhea, reversible alopecia
 No endocrine adverse effects.
 Hepatic failure may lead to death
 It is highly teratogenic

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.
 mammalian inhibition of P450 less.
 reversible visual disturbances
 it is similar to itraconazole but more potent.

FLUCYTOSINE
 Has useful activity against Candida and Cryptococcus.
 it is synthetic pyrimidine antimetabolite that is often used in
combination with amphotericin B
 it is fungistatic,effective in combination with itraconazole for treating
chromoblastomycosis and with amphotericin for treating
cryptococosis.
 Mechanism of action
It is converted to antimetabolite 5-florouracil in a fungal but not
human cell. This 5-FU inhibits thymidylate synthetase enzyme and
thus DNA synthesis. Resistant mutants may occur, should never be
used alone.

Mechanism of action of Flucytosine
Fdump(fluorodeoxyuridne
monophosphate

 Ph/kinetics
 Absorbed rapidly and well from GIT
 Widely distributed in body and penetrates well into CSF.
 Minimally bound to plasma protein
 Peak plasma con. reaches 70-80 ug /ml in 1-2 hours.
 80% dose is excreted unchanged in urine.
 t 1/2 3-6 hours in renal failures it may be 200 hours

 Uses
 dose 100-150 mg /kg per day divided into 4 doses.
 Generally use in combination with amphotericin
 For cryptococcal meningitis in AIDS patients

 Unwanted effects:
 reversible neutropenia, thrombocytopenia and
occasional bone marrow depression.
 Nausea ,vomiting ,diarrhea, severe enterocolitis
 Hepatic enzyme elevation in 5% patients is
reversible.

Caspofungin
 It is echinocandin class of antifungal drugs
 it interferes with the synthesis of fungal cell wall
by inhibiting synthesis of D-glycan.
 especially useful for aspergillus and candida.
 not active orally
 Higly bound to serum proteins
 Has half life of 9-11 hours

 slowly metabolized by hydrolysis and N-
acetylation.
 eliminated equally by urinary and fecal
route.
 Adverse effects include nausea ,vomiting,
flushing
 very expensive

Anti fungal drugs used for topical
fungal infections
 Topical anti fungal preparations
1. Topical azole derivatives
2. Ciclopirox olamine
3. Naftifine
4. Terbinafine
5. Butenafine
6. tolnaftate
7. Nystatin and Amphotericin

Oral anti fungal agents used for
topical infections
1. Griseofulvin
2. oral azoles
3. Terbinafine

TOPICAL ANTIFUNGAL AGENTS
 In superficial fungal infections those drugs are
preferred which get confined to stratum
corneum, squamous mucosa, or cornea.
 Such disease includes dermatophytosis (ring
worm), candidiasis tinea and fungal keratitis.

 Topical administration of antifungal agents is usually
not successful in mycoses of the nails and hair and
has no place in the treatment of subcutaneous
mycoses.
 The efficacy of topical agents in the superficial
mycoses depends not only on the type of lesion and
the mechanism of the drug action but also on the
viscosity, hydrophobicity and acidity of the
formulation.
 The preferred formulation for cutaneous application
usually is a cream or solution.

IMIDAZOLE AND TRIAZOLES FOR TOPICAL
infections
 These are synthetic and used both topically and
systemically
 Selection depends on cost and availability
 Should be applied twice a day for 2-3 weeks.
 Vaginal creams, suppositories and tablets for vaginal
candidiasis used once a day preferably at bed time.

CLOTRIMAZOLE
 Absorption less than 0.5 % from intact skin, 3-10 %
from vagina and activity in vagina remains for 3 days.
 Oral dose of 200 mg per day give rise to 0.2-0.35ug/ml
concentration.
 Stigma, erythema, edema, vesication, pruritus, urticaria
mild vaginal burning sensation may occour.
 Cure dermatophytes.it is effective in 60-100%.cutaneous
candidiasis is80-100% and vulvovaginal candidiasis is
80%.

Itraconazole
 Itraconazole is effective for treatment of
onychomycosis in a dose of 200 mg daily after
food for 3months
 Should not be given in patients with ventricular
dysfunction
 Routine evaluation of hepatic function is
recommended.
 should not be used concurrently with
midazolam, triazolam and HMG-CoA.

TOLNAFTATE
 Effective in most cutaneous mycosis.
 It is ineffective against Candida.
 In tinea pedis cure rate is around 80%.
 Available in 1% con.as cream,gel,powder and topical
solution.
 Applied locally twice a day.

NAFTIFINE
 It is broad spectrum, fungicidal.
 Available as 1% cream or gel
 Effective for tropical treatment of tinea cruris.

TERBINAFINE
 It is synthetic allylamine
 it is a drug of choice for treating dermatophytes
 it is better tolerated , requires shorter duration of therapy
 it inhibits fungal sequalene epoxidase ,decreases synthesis of
ergosterol
 Also accumulation of toxic amounts of squalene causes cell
death.
 it is fungicidal but activity is limited to C.albicans and
dermatophytes.

 quite effective for the treatment of onychomycosis
250 mg daily for 6weeks for finger nail infection and for 12
weeks in toe nail infection
 Well absorbed orally ,bioavailability decreases due to first pass
metabolism in liver.
 Protein binding more than 99% in plasma.
 Drug accumulates in skin,nails and fat.
 severely hepatotoxic , liver failure even death.

Mechanism of action of terbinafine

 Initial half life 12 hrs but extends to 200-400 hrs ,which
reflects it slow release from the tissues
 Can be found in plasma for 4- 8 weeks after prolong therapy.
 Clearance is reduced in moderate and hepatic impairment.
 Not recommended in azotemia or hepatic failure.
 Dose 250 mg for 3 months/for local infection applied twice
daily.
 unwanted effects include GIT disturbance ,Taste and visual
disturbance ,transient rise in serum liver enzymes.
 Rifampicin decreases it serum and cimetidine increases

GRISEOFULVIN
 it has largely been replaced by terbinafine for treatment of
dermatophytic infections of the nails.
 very insoluble in water
 It is useful for dermatophytes
 It is fangistatic for species of dermatophytes. it has narrow
spectrum.
 Isolated from Pencillium griseofulvum
 It interacts with microtubules and interferes with mitosis.

 Pharmacokinetics
 Peak plasma concentration of 1ug/ml in about 4 hours
 Absorption increases with fatty meal
 It is ineffective topically.
 Barbiturates decreases the absorption from GIT.
 Extensivly metabolized in liver.
 Induce CYP450.
 t 1/2 1day.
 Drug is deposited in keratin and nail and hair are 1st
to get rid of disease.

 Uses
 Mycotic diseases of skin, hair (particularly for
scalp) , nail.
 It is also highly effective in athlete's foot

 Dose
 5-15 mg /kg for children and 0.5 -1 gram for adults.
 Treatment required is 1 month for scalp and hair
ringworm, 6-9 months for finger nails, and at least 1
year for toe nails.
 Not effective in subcutaneous or deep mycoses.

Unwanted effects.
 Headache
 Peripheral neuritis , lethargy , mental
confusion, impairment in performance of
routine task, fatigue, vertigo ,syncope, blurred
vision.

Comparison of Azoles fungistatic drugs
Itraconazole
Fluconazole
Ketoconazole
expanded
expanded
narrow
spectum
oral
Oral, i.v
Oral
Route of administration
30-40
30
6-9
T 1/2
no
yes
no
Csf penetration
no
yes
no
Renal excretion
occasional
Occasional
frequent
Interaction with other
drugs
NO inhibition
no inhibition
Dose dependent
inhibitory effect
Inhibition of
mammalian sterol
synthesis

Uses of antifungal drugs
Drug used
Disease
 Amphotericin, flucytocin, , fluconazole.
 Amphotericin, flucytocin , fluconazole,
itraconazole
 itraconazole Amphotericin,
 itraconazole Amphotericin,
Amphotericin, itraconazole ,fluconazole.
 fluconazole. itraconazole ,Amphotericin,
 fluconazole. itraconazole ,Amphotericin,
 Amphotericin, flucytocin ,Amphotericin,
 Amphotericin, flucytocin
Systemic infections
 systemic candidiasis
 Cryptococcosis( meningitis)
 systemic aspergillosis
 Blastomycosis
 Histoplasmosis
 Coccidiomycosis
 Paracoccidiomycosis
 Mucormycosis
 Disseminated sportrichosis

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