anti fungal drugs

1. By
Arshad khan
Group - 13
Antifungal Drugs

2. Introduction - Also called antimycotic drugs
⚫Used to treat two types of fungal infection:
◦ Superficial fungal infections - skin or mucous
membrane
◦ Systemic fungal infections - lungs or central nervous
system
⚫Fungi causing mycosis live as commensally or
are present in the environment.
⚫Earlier superficial infections were common and
systemic rather rare.
⚫Recently there is increase in local as well as
systemic fungal infections.
⚫Reason for this is opportunistic infections

3. Opportunistic infections
⚫Immuno-suppression due to
- Cancer chemotherapy
- AIDS
◦ Corticosteroid overuse
⚫Indiscriminate use of broad
spectrum antibiotics

4. Fungal infections
⚫Superficial
◦ Skin
◦ Hair
◦ Nails
◦ Mucous membrane
⚫Deep
◦ Tissues (muscle &
connective tissue)
◦ Organs

5. Types of fungal infections - Mycoses
⚫Superficial mycoses
◦ Affect the skin,hair and nails – ringworm/tinea or
onychomycosis
⚫Subcutaneous mycoses (tropical)
◦ Affect the muscle and connective tissue immediately below
the skin
⚫Systemic (invasive) mycoses
◦ Involve the internal organs
⚫Allergic mycoses
◦ Affect lungs or sinuses
◦ Patients may have chronic asthma,cystic fibrosis or sinusitis
There is some overlap between these
groups

6. MOST COMMON FUNGAL
PATHOGENS
⚫Dermatophytes – Microsporum,
Epidermophyton and Trichophyton
⚫Candida – C. albicans,C.glabrata,
C. tropicalis
⚫Aspergillus
⚫Cryptococcus
⚫Rhizopus

7. Causative fungi
⚫Superficial infections by
◦ D ermatophytes (ring worms): athlete`s foot or
tinea pedis, jock itch or tinea cruris, tinea capitis etc.
◦ Candida: oral thrush, vaginitis and diaper candidiasis
etc.
⚫Deep infections are
◦ Candidiasis:Chronic mucocutaneous candidiasis,
systemic candidiasis etc.
◦ Aspergillosis: broncho-pulmonary aspergillosis
◦ Coccidiomycosis:pulmonary and disseminated
(complications – pneumonia)
◦ Histoplasmosis:H. capsulatum (common in HIV)

8. What are the targets for antifungal therapy?
Cell membrane
Fungi use principally ergosterol
instead of cholesterol
DNA Synthesis
Some compounds may be
selectively activated by fungi,
arresting DNA synthesis.
Cell Wall
Unlike mammalian cells, fungi
have a cell wall

9. Polyene antibiotics-Amphotericin B
⚫
⚫
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Fermentation product of Streptomyces nodusus
High affinity for ergosterol present in fungal cell membrane
Hydrophilic polyhydroxyl chain along one side and a lipophilic
polyene hydrocarbon chain on the other
Binds sterols in fungal cell membrane –
◦
◦
high affinity for ergosterol present in fungal cell membrane
affinity is less for host cell membrane although closely resembles
⚫
⚫
⚫
Creates transmembrane channel and electrolyte leakage.
Active against most fungi except Aspergillus terreus, Scedosporium spp.
Bacteria lack sterols so insensitive to polyenes

10. Cell MembraneActiveAntifungal
Cell membrane
1. Polyene antibiotics
- Amphotericin B, lipid
formulations
- Nystatin (topical)
2. Azole antifungals
Imidazoles:
•
• Topical: Clotrimazole,
econazole, miconazole
Systemic: Ketoconazole
Triazoles: Fluconazole,
itraconazole and voriconazole

11. Antifungal spectrum
⚫Most Toxic antifungal
⚫Fungicide at high and static at low conc.
⚫Effective against
◦ Candida albicans
◦ Histoplasma capsulatum
◦ Cryptococcus

12. Pharmacokinetics
⚫ Insoluble in water
⚫ Unstable at 37degree
⚫ Poorly absorbed from GIT
⚫ Cannot cross BBB
⚫ Highly bound to plasma proteins
⚫ Takes 2 months for complete clearance of drug
⚫ Given as I/V infusion
⚫ For fungal meningitis given intrathecally
⚫ Has immuno-stimulant action also
⚫ Given in immuno-compromised patients for fungal
infections

13. Uses
⚫ Broad spectrum antifungal
⚫ Useful for
1.Candida that causes
◦ oral
◦ vaginal
◦ cutaneous candidiasis
2. Cryptococcus
3. Histoplasma
4. Aspergillosis
5. Also effective for Leishmaniasis(Reserve drug for
resistant cases of KalaAzar)

14. ADRs
 Acute reactions - occurs with each infusion
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◦
Chills, Nausea, Vomiting, Pain, Fever
,Aches, Dyspnoea
So corticosteroids are administered along with the drug
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


Thrombophlebitis
Bone marrow depression - Reversible anemia
On intrathecal injection – Headache,Vomiting,
Nerve paralysis
Renal toxicity leading to – Azotemia,
Decreased GFR, Acidosis, Hypokalemia,
Inability to conc.urine

15. Newer Amphotericin B
They are developed to overcome
1. Side effects
2.To improve tolerability
3.To get the drug at site of action
4.To reduce the toxicity i.e.. Less nephrotoxic and
minimal anemia
Formulations are:
1.Amphotericin B lipid complex
2.Amphotericin B colloidal dispersion
3.Liposomal Amphotericin B
(Only drawback of these formulations is less efficacy)

16. Drug Interactions of Amphotericin B
⚫W ith Flucytocin-synergistic action
⚫Rifampicin and Minocyclin –
◦ Both potentiate Amphotericin B
⚫Vancomycin and Aminoglycoside –
◦ Both increase risk of nephrotoxicity
⚫Preparation and doses:
◦ 50 – 100 mg four times a day orally
◦ 3% ear drops
◦ Systemic: 50 mg vial (one vial diluted in 500 ml of 5%
glucose and initially 1 mg test dose followed by
infusion for 4 – 8 Hrs)

17. Nystatin
⚫Similar to Amphotericin B but more toxic than
Amphotericin B
⚫Used only for superficial candidiasis of
Skin, Mouth,Vagina,Intestine
⚫As ointment ,oral tablets & suppositories
⚫Available as tablets and ointments (1 to 5 lacs
U) – also vaginal tablets
⚫O rally not absorbed but can be used in monilial
diarrhoea

18. Other Polyenes
Hamycin:
⚫Water soluble
⚫Absorption from GIT not reliable
⚫Not used for systemic fungal infections
⚫Used topically for Aspergillus,Candida,Monilial,
Trichomonas vaginalis infections
Natamycin:
⚫Broad spectrum
⚫Used topically for – Keratitis,Monilial
infections, Trichomonas vaginalis

19. Imidazoles and Triazoles
Azole antifungals
⚫ Imidazoles:
◦
◦
Topical: Clotrimazole, econazole, miconazole
Systemic: Ketoconazole
⚫Triazoles: Fluconazole, itraconazole and
voriconazole
⚫Remember that among imidazoles,only
ketocanazole is systemic,other 3 are topical
only
⚫W hile, Triazoles are used systemically and
largely replacing ketoconazole

20. Azole Structures
Fluconazole Ketoconazole

21. Azoles – Common Mechanism
•
•
In fungi, the cytochrome P450-
enzyme lanosterol 14-alpha
demethylase is responsible for the
conversion of lanosterol to
ergosterol
Azoles bind to lanosterol 14α-
demethylase inhibiting the
production of ergosterol
– Some cross-reactivity is seen with
mammalian cytochrome p450 enzymes
leading to
•
•
Drug Interactions
Impairment of steroidneogenesis
(ketoconazole, itraconazole)

22. Individual Agents
Ketoconazole:
⚫Spectrum:yeasts and moulds - poor absorption
limits its role for severe infections,generally
used in mucosal infections only
(dematophytosis)
⚫Pharmacokinetics
◦ Variable oral absorption, dependent on pH (often
given with cola or fruit juice)
◦ T1/2 = 7-10 hours
◦ Protein binding > 99%
◦ Hepatic,bile and kidney elimination

23. Ketoconazole – contd.
⚫Adverse effects
◦ N&V, worse with higher doses (800 mg/day)
◦ Hepatoxicity (2-8%),increase in
transaminases,hepatitis
◦ Dose related inhibition of CYP P450
responsible for testosterone synthesis
🞄Gynecomastia,oligosperma,decreased libido
◦ Dose-related inhibition of CYP P450
responsible for adrenal cortisol synthesis

24. Ketoconazole – contd.
Drug Interaction:
⚫ Potent inhibitor of cytochrome P450 3A4
◦ Rifampin and phenytoin decrease ketoconazole levels
◦ Ketoconazole increases cyclosporin, warfarin, astemizole,
corticosteroid,and theophylline levels
🞄Many of these drug interactions are severe
⚫ Drugs that increase gastric pH will decrease blood
levels of ketoconazole
◦ Antacids,omeprazole,H2 blockers
⚫ Doses:
◦ Serious infections 800 mg/
day PO
◦ Other: 200-400 mg/day PO

26. Fluconazole
⚫ Water soluble having wider range of activity than
Ketoconazole
⚫ Good activity against C. albicans and Cryptococcus
neoformans
⚫ Non-albicans Candida species more likely to exhibit
primary resistance
Sometimes resistant
Always resistant
C. krusei > C. glabrata > C. parapsilosis
C. tropicalis
C. kefyr

27. Resistance
⚫Primary resistance (seen in severely ill or
immunocompromised patients)
◦ Selection of resistant species or subpopulations
◦ Replacement with more resistant strain
⚫Secondary resistance (seen in patients with
AIDS who experienced recurrent
orophayrngeal candidiasis and received long-
term fluconazole therapy)
◦ Genetic mutation
◦ Upregulation of efflux pumps

28. Mechanisms of antifungal resistance
⚫Target enzyme
modification
⚫Ergosterol
biosynthetic pathway
⚫Efflux pumps
⚫Drug import

29. Fluconazole - Kinetics
⚫ Available as both IV and PO
⚫
◦ Bioavailibility > 90%
Pharmacokinetics
◦
◦
◦
◦
t 1/2 = ~24 hours
Protein binding < 12%
Vd 0.85 L/
kg (widely distributed)
>90% excreted unchanged through the kidney
⚫ Dosing
1. Mucosal candidiasis
🞄 100-200 mg/
day (150 mg tablet vulvovaginal candidiasis)
1. Systemic fungal infections
🞄 400-800 mg q24h
🞄 > 800 mg q24h in unstable patient,S-DD isolate, or ifnon-albicans spp.
(except C.krusei)
1. Maintenance for cryptococcal meningitis
🞄 400 mg q24h

30. Fluconazole - ADRs
⚫N&V, rash:
◦ More likely with high doses and in AIDS
patients
◦ Asymptomatic increase in LFTs (7%)
⚫Drug interactions:
◦ May increase phenytoin, cyclosporin, rifabutin,
warfarin,and zidovudine concentrations
◦ Rifampin reduced fluconazole levels to half
(even though FLU is not a major substrate)

31. Itraconazole
Some Features:
⚫Newer orally active triazole
⚫Broader spectrun than KTZ and FCZ –
includes moulds like aspergillus
⚫Fungistatic action but very effective in
immunocompromizrd patients
⚫Steroid hormone synthesis inhibition is
absent and no serious hepatotoxicity

32. Ketoconazole Fluconazole Itraconazole
1 Broad spectrum Still wider range Fungi static
2 Dermatophyte
& deep mycosis
Cryptococcal & coccidial
meningitis
immunocompromised
patients
3 Absorbed at low pH Good oral absorption Varies with food & pH
4 Highly bound to PP Not much Highly bound
5 More S/E, headache, androgen
inhibition
Less S/E, headache & rash Hypokalemia, pruritis &
dizziness
6 Causes hepatic impairment Mild Not hepatotoxic
7 Inhibit cytochrome P450 Inhibit only fungal P450 No effect
8 Used for Monilial vaginitis.
Cushing’s syn
Candidiasis, Keratitis,
Cryptococcal meningitis
Mycosis, meningitis
Chromo & paracocci

33. Local azoles
⚫ Very popular local azoles are – Clotrimazole, Econazole
and Miconazole
⚫ (For Tinea, Ring worm, Athlete’s foot, otomycosis, oral,
cutaneous & vaginal candidiasis)
⚫ Mechanism of action is same as that of Ketoconazole
i.e. ergosterol inhibition by inhibiting CYP450
⚫ Clotrimazole is favoured in vaginitis because of long
lasting residual effect and once daily dosing
⚫ Miconazole causes frequently vaginal irritation & pelvic
cramp.
⚫ Available s lotion, cream, powder, vaginal tablet etc.

34. Heterocyclic Nitrofurans - Griseofulvin
⚫Used for superficial fungal infections by
dermatophytes
⚫Derived from Penicillium griseofulvum
but no antibacterial activity
⚫Effective against most dermatophytes,but
not against candida causing deep mycosis
⚫Dermatophytes actively concentrate it –
accounts for selective toxicity against
them
⚫Taken up by newly formed keratin

35. Griseofulvin - MOA
⚫Interferes with mitosis – results in
multinucleated and stunted hyphae
(In most fungi, hyphae are the main mode of vegetative growth, and are
collectively called a mycelium yeasts are unicellular fungi that do not grow as
hyphae)
⚫Abnormal metaphase configurations leading to
failure of daughter nuclei to fall apart
(Colchicine and vinca alkloids also mitotic inhibitors but they cause arrest of
mitosis)
⚫ Disorientation of polymerized microtubules

36. Griseofulvin – contd.
Pharmacokinetics:
⚫ Given orally and fats improve absorption
⚫ Absorption depends on the particle size
⚫ Duration of treatment depends upon tissue turn over
1. 3-6 wks for skin & hair
2.3-6 months for nails
⚫ Treatment should continue till whole infected tissue is
shed off.
Doses: Used orally only for dermatophytosis (125 to 250
mg 4 times daily
, but depends on site of infection

37. Griseofulvin - ADRs
⚫ Safe with mild side effects
1.GIT upsets
2.CNS symptoms
3. Hepatotoxicity
4. Leucopenia
5. Photosensitivity
6. Allergy etc.
⚫ Microsomal enzyme inducer
⚫ Causes decrease in activity of anticoagulants
⚫ Cause intolerance to alcohol
⚫ Phenobarbitone reduces its oral absorption so failure of
therapy

38. Flucytosin
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Fluorinated pyrimidine related to flurouracil
Restricted spectrum of activity.
Acquired Resistance due to > result of monotherapy
Due to:
1) Decreased uptake (permease activity)
2)Altered 5-FC metabolism (cytosine deaminase or UMP
pyrophosphorylase activity)
Kinetics:
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Orally absorbed
W idely distributed even in CSF
Exc.in urine.
Converted in fungal cell to 5-FU which is antimetabolite.
Mammalian cells remain unaffected except few bone marrow cells

39. Flucytosin
Monotherapy :Never

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Candidiasis
Cryptococcosis
Aspergillosis
} In combination with amphotericin B or
fluconazole.
Doses:
1. Vaginal candidiasis: 200 mg OD for 3 days
2. Dermatophytosis; 100-200 mg OD for 7-15 days
3. Onychomycosis: 200 mg per day for 3 months
ADRs: 1.Mild BM depression
1. Loss of hair
2. Dose should be decreased in the presence of renal impairment

40. Terbinafine
⚫ Belongs to a newer allylamine class of antifungals
⚫ Given both orally & locally
⚫ Lipophillic so widely distributed
⚫ Fungicidal in contrast to azoles (fungistatic)
⚫ Acts by non-competitive inhibition of “squalene
epoxidase” (early step enzyme in ergosterol synthesis
(Image in Slide No. 22) – accumulation of squalene in
fungal cells – cidal effect
⚫ Used for dermatophytes & candida
⚫ Dose is 250mg OD for
2-6 wks
⚫ Locally 1% ointment.

41. Terbinafine – contd.
ADRs
⚫ With oral
GIT upset
Hepatic dysfunction
Rash
Taste disturbance
◦
◦
◦
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◦ No interaction with CYP450
⚫ Preparations and doses:
◦ 1% cream 125/250 mg tablets etc.
◦ Tinea pedis:250 mg OD for 2-6 weeks
◦ Onychmycosis: 3-12 months (alternative to fluconazole)
•On local application -
dryness, Erythema, Rash,
itching etc.

42. Thank you