1. ANTIFUNGAL
1

2.  Fungi
are eukaryotes
VIJAy
 Fungal
infections Mycoses
 Less
frequent than bacterial & Virus but
common.
 Anyone
can succumb to fungal infection but
more at risk in older people, diabetics, pregnant
women and burn wound.
2

3. FUNGI MAY BE CLASSIFIED AS YEAST OR MOULDS.
Yeast like pathogenic
 Histoplasmosis

Coccidioidomycosis
Blastomycosis
 Cryptococcosis
 Candida

Mould group of pathogenic
 Aspergillosis
 Dermatophytes
 Mucormicosis

Candida Spp. and Pneumocyst carinii are not pathogenic

pathogenic in immuno compromised patients
OPPORTUNISTIC INFECTION.
3

4. Oropharyngeal
 Vaginal candidiasis
 Sporotrichosis (Granulomatus of skin & Lymph abscess)
 Pityrosporum orbiculare - hyperpigmetnation

4

5. 
Fungal infections classified as Superficial & Deep
mycosis (Systemic)

Superficial affecting skin, hair, nails, mucous
membranes.

Most common: Dermatophytoses
Encouraged by hot (Hygiene)and humid environment
 Dermatophytoses classified according to body site
• Tinea barbae
• Tenia capitis(Scalp)
• Tinea corporis(Body)
• Tinea manuum(Hand)
• Tinea pedis(Foot)
• Tinea unguium(Nails)

5

6. 
Systemic fungal infections: Affect deeper tissues
and organs.

Systemic candidiasis (RTI)

Meningitis, endocarditis

Rhinocerebral mucormycosis (Thrombosis)

Pulmonary aspergillosis

Blastomycosis (lesion of skin)

Histoplasmosis (cough , fever, multiple pneumonic
infiltrates)

Coccidioidomycosis

Pneumocystis carinii pneumonia
6

7. 
Fungal cell structure and function is essential for
understanding the pharmacology of antifungal agents.

Four targets in fungal pathogens:

Fungal Cell Wall

Fungal Cell Membrane

DNA/RNA Synthesis

Inhibition of fungal mitosis
7

8. Fungal Cell Wall contain β- 1,3-D-glucan
 Depletion of glucan  Leads to death

Capsofungin
8

9. Altering membrane permeability
AMPHOTERICIN-B
Leading to cell death.
9

10. MEMBRANE SYNTHESIS

Ergosterol is the predominant sterol in many pathogenic
fungi.
Squalene
Terbinafine
squalene 2,3 epoxide
Lanosterol
Azoles
14-demethylase
Ergosterol
10

11. 
Inhibits DNA synthesis by blocking the functions of
a key enzyme in DNA replication- thymidylate
synthetase.

Fungal cell mitosis by disrupting mitotic spindle
formation-a critical step in cellular division.
11

12. 12

13. CLASSIFICATION BASED ON MECHANISM OF ACTION
Inhibitor of cell wall
synthesis:

Caspofungin
Drugs altering membrane
synthesis
 Inhibition of ergosterol
Drugs altering membrane
permeability
Trimidazoles
 Fluconazle,
 Itraconazole,
 Voriconazole
Imidazoles
 Ketoconazole,
 Miconazole,
 Clotrimazole.
Amphotericin-B,
 Nystatin,
 Hamycin

Inhibit nucleic acid
Synthesis

5 Flucytosine
Disruption of mitotic
spindle

Griseofulvin

Inhibition of ergosterol+
lanosterol

Terbinafine
13

14. Drugs altering membrane permeability

Amphotericin-B
Nystatin
Hamycin
Amphotercin:

First drug introduced in 1950s

Obtained from Strepomyces nodosus

Systemic Antifungal drug

Polyene group- Multi lactone ring with conjugated double
bond .

One end – Hydroxyl group (OH)–polar (Hydrophilc)

Other end – Hydrocarbon group-non polar (Lipophilic)
14

15. 
MOA:
Lipophilc end
Hydrophilc end
Creates ion channel
15
Leading to cell death.

16. PK:

Poor absorbed from GIT- effective against intestinal fungal
infection

For systemic - IV slow infusion

Peak antifungal activity at pH 6.0-7.5.

High con- Fungicidal, low- fungi static

90% plasma protein binding

T1/2- 15days ( binds with sterol)

It is insoluble in water  colloidal suspension with sodium
16
desoxycholate(1:1)

17. Antifungal spectrum & uses:

After advent of azoles groups, the use of AMB declined.

Still it is DOC for

Treatment of Invasive aspergillosis in immune
compromised patients

Mucormycosis

Rapidly progressing histoplasmosis, blastomycosis,
meningeal cocciodomycosis(intrathecal)
Topical use:- 3% cream for oropharngeal candidiasis,
 Reserve drug for resistant case of KALA AZAR. Leishmania
. Splenic enlargement

17

18. Dose: 0.5 mg/kg/day
 Adverse events:


Acute reaction (infusion related events, chills, fever,
headache, nausea, vomiting)

Long term toxicity: nephrotoxicity(>4g), anemia (D. Ery)

azotemia, hypokalemia

CNS toxicity : intrathecal administration-seizures,
headache, vomiting, nerve palsies


Hepatotoxicity rarely
DI:Flucytosine –synergetic action inc. permeability FC
 Aminoglycoside inc. renal toxicity.

18

19. 
3 new formulations available

AMB Lipid complex (ABLC): 35% AMB incorporated in
ribbon like particles of dimyristoyl phospholipids

AMB colloidal dispersion (ABCD): Disc shaped particles
containing 50% each of AMB & cholesteryl ester in
aqueos dispersion

Liposomal AMB (Small Unilamellar Vesicles) : 10% AMB
incorporated in SUV made up of lecithin
19

20.  Special
features of these formulations:

Milder acute reaction

Dec. infusion associated side effects

Can be used in intolerance to conventional
preparations

Lower nephrotoxicity & anemia

Deliver AMB to reticular endothlial cell of liver
spleen so useful in leshmania & immuno
compromised
20

21. 
Nystatin:

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:5 lac U in intestinal moniliasis TDS
 1 lac U in vaginitis (1mg=2000U)
 Can be used in oral, cutaneous, conjunctival candidiasis
 Adverse events: Gastrointestinal disturbances with oral
tablets

21

22. 
Drugs altering membrane synthesis
Azoles: 1970


Broad spectrum

Fungistatic / Fungicidal

Most commonly used


Synthetic anti fungals
Classified as imidazoles & triazoles
Imidazoles: Two nitrogen in structure
Topical: Econazole, Miconazole, Clotrimazole
 Systemic : ketoconazole


Newer : Butaconazole, Oxiconazole, Sulconazole
22

23. 
Triazoles : Three nitrogen in structure 1980



Fluconazole, itraconazole, voriconazole, Terconazole
Topical for superficial infections
Both these groups are

Structurally related compounds

Have same mechanism of action

Have similar antifungal spectrum
23

24. Acetyl CoA
Squalene
Allylamine
Drugs (Terbinafine)
Squalene
monooxygenase
Squalene-2,3 oxide
Lanosterol
Azoles
14-α-demethylase
(ergosterol)

25. 
Miconazole & clotrimazole:
Topical use
 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
25

26. Ketoconazole:
First orally effective broad spectrum antifungal
 Effective against

Dermatophytosis
 Deep mycosis
 Candidiasis


Pharmacokinetics:
 Effective orally
 Requires acidic environment for absorption
 High protein binding
 Readily distributed, not to BBB
 Metabolized in liver, excreted in bile t1/2 = 8-10 hrs
26

27. 
Dose : 200 mg OD or BD

Adverse events:

Nausea , vomiting , anorexia

Headache , paresthesia, alopecia

Reduces steroid, testosterone & estrogen synthesis

Thus can cause gynaecomastia,

oligospermia, loss of libido & impotence in males.

Menstrual irregularities & amenorrhoea in females

Elevation of liver enzymes

Hypersensitivity reaction like skin rashes
27

28. 
Drug interactions: Inhibits CYP450 enzyme

H2 receptor blockers

↑ Sr conc of cisapride, terfenadine, astemizole, quinidine

Phenytoin toxicity

Sulfonylureas: hypoglycemia

Cyclosporine: nephrotoxicity

Warfarin: bleeding

Rifampicin, phenytoin ↑ metabolism of ketoconazole

Should not combine with AMB
28

29. 
Use: Restricted use, most serious mycoses

Dermatophytosis: conc in stratum corneum

Monilial vaginitis : 5-7 days

Systemic mycosis: blastomycosis, histoplasmosis,
Coccidioidomycosis

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

Topical: T.pedis, cruris, corporis, versicolor
29

30. RESISTANCE
May develop by altered
demethylase or
by enhanced removal from
the fungal cell.

30

31. Fluconazole:

Newer water soluble triazole

Oral, IV as well as topical

Broad spectrum antifungal activity

Candida, cryptococcosis, coccidioidomycosis

Dermatophytosis

Blastomycosis

Histoplasmosis

Sporotrichosis
31

32. 
Pharmacokinetics:

94% oral bioavailability

Not affected by food or gastric pH

Primarily excreted unchanged in urine t1/2 = 25 -30 hrs

Poor protein binding (10-12%)

Widely distributed crosses BBB


T ½ -27-32hrs
Adverse events:

GIT upset

Headache, alopecia, skin rashes, hepatic necrosis

Teratogenic effect

CYP450 Enzyme inhibiting property less

No anti androgenic & other endocrine effects
32

33. 
Drug Interactions:

Effects hepatic drug metabolism to lesser extent than
Ketoconazole


H2 blockers & PPI do not effect its absorption
Uses:

Candida:



150 mg oral dose  cure vaginal candidiasis with few relapse
Oral candidiasis  2 weeks treatment required
Tinea infections & cutaneous candidiasis:

150 mg weekly  4 weeks, tinea unguim  12 months
33

34. 
Disseminated candidiasis, cryptococcal, coccidiodal
meningitis & other systemic fungal infections:

200-400 mg / day 4- 12 weeks or longer

3 days oral  Candida UTI (100-800mg OD)

Meningitis preferred drug

Eye drops for fungal keratitis
34

35. 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
35

36. 
Adverse events:


Dizziness, pruritis , headache, hypokalemia, hypotension

Increase plasma transaminase


GI Intolerance
Rarely Hepatotoxicity
Drug interactions:

Oral absorption decreased by antacids, H2 blockers

Rifampicin, phenytoin induce metabolism

Potentiates effect of hypnotic drugs

Inhibits CYP3A4 drug interaction profile similar to ketoconazole
36

37. 
Uses:

DOC for paracoccidomycosis & chromoblastomycosis

DOC for histoplasmosis & blastomycosis in AIDS patients

Esophageal, oropharyngeal vaginal candidiasis


Dermatophytosis: less effective than fluconazole


Not superior to fluconazole : 200 mg OD X 3 days
100- 200 mg OD X 15 days
Onychomycosis : 200 mg / day for 3 months

Intermittent pulse regime 200 BD once weekly for 3 months equally
effective

Aspergillosis: 200 mg OD/ BD with meals for 3 months or more
37

38. Voriconazole:


High oral bioavailability, low protein binding

Good CSF penetration

Metabolized by CYP2C19

Doesn’t require gastric acidity for absorption


II generation triazole
T1/2-6 hrs
Uses:

DOC for invasive aspergillosis

Most useful for esophageal candidiasis

First line for moulds like fusarium

Useful in resistant candidal infections
38

39. Dose : 200 mg BD
 Adverse events:


Transient visual changes like blurred vision , altered color
perception & photophobia

Rashes in 5 -6 %

Elevated hepatic enzymes

Prolongation of QT
39

40. Cell wall synthesis inhibitor: Capsofungin

Introduced in 2000s.

Echinocandins

MOA: Inhibits- β-(1,3)-D-glucan

T½-9-11hrs.

P.B- albumin 97%

Excreted through urine(41%) and feces (35%)

Dose: IV infusion (intial 70mg slowly then 50mg/day)
40
»Contd.,

41. 
Active against wide variety of fungi.

Effective treatment for Aspergillus infection and
Candidiasis (Esophageal, intra abdominal
peritontis).

ADR: Sensation of warmth,
flushing,
rashes.

DI:- Cyclosporine hepatotoxicity.
41

42. 5 Flucytosine


Prodrug, pyrimidine analogue, anti metabolite
Mechanism of action
Converted to 5 FU by FUNGAL CYTOSINE DEAMINASE
 5FU  5FUTP RNA DEFECTIVE
 5FU 5dUMP Inhibit Thymidylate synthesis

,
Human cells cant convert it to 5FU
 Adverse events:


Bone marrow toxicity , GIT , Alopecia, skin rashes, itching , rarely
hepatitis

43. 5-flucytosine permease 5-flucytosine
(outside)
(inside)
Cytosine
deaminase
5-fluorouracil
5dUMP
(inhibits
thymidylate
synthase)
RNA
Phosphoribosyl
transferase
5-FUMP

44. 
Uses: in combination with AMB in cryptococcal meningitis

,

Advantages of combination:
Entry of 5 FC
 Reduced toxicity
 Rapid culture conversion
 Reduced duration of therapy & resistance


45. SYSTEMIC ALLY FOR TOPICAL INFECTIONS

Terbinafine:
Orally & topically effective drug against candida &
dermatophytes
 Fungicidal : shorter courses of therapy required & low
relapse rates

Mechanism of action:
 Inhibition of Lanosterol + Ergosterol production
 Pharmacokinetics:






Well absorbed orally 75%
Highly keratophilic & lipophilic
High protein bound , poor BBB permeability
Metabolized in liver excreted in urine & feces t1/2- 15
days
Negligible effect on CYP450

46. Adverse events:
 Nausea , vomiting , Diarrhoea
 Taste disturbances
 Rarely hepatic dysfunction
 Topical: erythema , itching , dryness , urticaria,
rashes
Uses:
 Dermatophytosis: topically/ orally 2- 6 weeks
 Onychomycosis: first line drug 3- 12 months
 Candidiasis: less effective 2- 4 weeks therapy
may be used as alternative 250 mg OD

47. Griseofulvin :

Systemic administration for topical infections

Fatty meal inc. BV

T1/2- 24hrs


Obtained from Pencillium griseofulvum


Fungistatic
Drug binds to keratin in stratum corneum of the skin
Mechanism of action:-
Interact with polymerised microtubles causing
disruptions of mitotic spindle and arrest mitosis
metaphase
47

48. 
Uses:-

Dematophytosis caused by Microsporum

Trichophyton, Epidermatophyton

Duration of therapy depend open the body area

TINEA CORPORIS – 2-4 WEEKS



TINEA CAPITIS -4-6WEEKS
TINEA PEDIS – 4-8 WEEKS
Dose- 500-1000mg/day/in 2doses
48

49. OTHER DRUGS
 Ciclopirox
olamine - may block amino acid
transport - penetrates well - useful for Candida
and dermatophytes
 Haloprogin
- useful for dermatophytes and
Candida, may cause burning
 Tolnaftate
- useful for dermatophytes - inhibits
synthesis of macromolecules
 Undecylenic
 KI
acid - dermatophytes
- taken orally for cutaneous sporotrichosis may cause a rash and irritation of salivary and
lacrimal glands

50. Disease
1st choice drugs
2nd choice drugs
Candiasis
oral/vaginal/cutaneous
disseminated
FLU/NYS/CLO
AMB/VOR
ITR
FLU
Cryptococcosis
AMB+/- 5-FC
FLU
Histoplasmosis
ITR/AMB
FLU
Coccidioidomycosis
AMB/FLU
ITR/KTZ
Blastomycosis
ITR/AMB
KTZ/FLU
Sporotrichosis
AMB
ITR
Paracoccidioidomycosis
ITR
AMB
Aspergillosis
AMB/VORI
ITR
Mucormycosis
AMB
-
Chromomycosis
ITR
VIJAY
KTZ/5-FC
50

51. Topical
Ketoconazole
Miconazole
Clotrimazole
Terbinafine
Nystatin
VIJAy
Systemic
administration
Griseofulvin
Ketoconazole
Fluconazole
Itraconazole
Terbinafine
51

52. SPECTRUM OF ACTION
AMB
5FC
KTZ
FLU
ITR
Aspergillus
--
--
--
Y
Blastomycosis
--
Y
Y
Y
cryptococcus
Y
--
Y
Y
Coccidiodo
--
Y
Y
Y
candida
Y
Y
Y
Y
Histoplasma
--
Y
Y
Y
Mucor
--
--
--
--
Sporotrichosis
--
--
Y
Y
chromoblast
dermatophyte
52
Fusarium

53. TOPICAL AZOLES
 Clotrimazole
 Terconazole
 Miconazole
 Sulconazole
 Econazole
 Tioconazole
 Oxiconazole
 Butoconazole
 Sertaconazole

54. 
Nystatin:
Candidiasis only

Griseofulvin: Dermatophytosis only

Terbinafine : Dermatophytosis & candidiasis

Caspofungin: Aspergillosis & candidiasis
54

55. Some important characteristics:

Broad spectrum: AMB, KTZ, FLU, ITR

Resistance: 5 FC

Nephrotoxic/ Anemia: AMB

LEUCOPENIA: 5 FC

GIT upset: All

Over all toxicity: highest for AMB lowest for fluconazole,
itraconazole
55

56. 
Grisofulvin K M C
VIJAy
For SYSTEMIC
F I T Nystatin
For Topical
56

57. TH
VIJAy
57