1. ANTIFUNGAL DRUGS
DR SEEMI GULL
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2. 2

3. 3

4. 4

5. 5

6. 6

7. 7

8. 8

9. 9

10. 10

11. 11

12. 12

13. 13

14. Antifungal Agents
Drugs used to treat infections caused by fungi
– Systemic and topical
FUNGI
– Very large and diverse group of microorganisms
14

15. STRUCTURE OF FUNGI
They are eukaryotes consists of :-
1. Cell wall ( chitin) homopolymer of N-
acetylglucogamine
2. Cell memb:- Contains ergosterol & zymiosterol in contrast to
human which contain cholesterol cell memb also contain lipids
glycoprotein & sterols
3. Inside the cell → golgi app. Ribosome’s bond to ER &
cytoskeleton with microtubules, microfilaments & intermediate
filament
4. Nucleus enclosed by nuclear memb.
15

16. TYPES
i. Yeasts
ii. Moulds
iii. Dimorphic
I.YEASTS
 Single cell fungi, ovoid or spherical
 Reproduce by budding & devision
 Some are useful organisms
 Baking
 Alcoholic beverages
II. Molds
 Multicellular characterized by ong, branching filaments called
hyphae → form mycelium
III. Dimorphic
 Have growth characteristics of both
 At body temp glow as yiest in host tissue
 At ambient temp. glow as mold in saprophytic, free living state
16

17. MAGNITUDE OF PROBLEM
 Fungi commonly present in environment
 Hardly cause any serious disease
 Five decades ago most common inf. Were
– Athlete foot
– 1- oral & vaginal through
 Incidence of serious fungal inf. increased after 1970
 Mostly secondary inf. → caused by opportunistic organism
FACTORS WHICH INCREASE RISK:-
 Use of broader spectrum antibiotics which destroy normal
florc which compete fungi
 Immouno compromised pts
 Immunosuppressant
 Anti-cancer drugs
 Increased international travelling
 Pregnancy
 Diabetes
 Oral contraceptives

18. FUNGAL INFECTION (MYCOSES)
Three groups cause human disease
I. Yeasts
II. Moulds
III. Dimorphic fungi
18

19. Common mycotic infection in human:-
A. Cutaneous
1.Dermatophytes (Ring worm, tinea inf)
There are three main genera
Trichophyton → skin, hair & nail
Microsporum → skin & hair
Epidermophyton → skin & nail
Dermatophytes only invade karatin &
zoophilic fungi cause more severe but short
lived inf then anthropophilic fungi
19

20. Various types of ring worms
Tinea capitus (scalp)
Tinea cruris (Groin)
Tinea corporis (body)
Tinea pedia (Feet) → Athlete foot
Managed by :-
White field ointment
Griseofilum
Turbenafine
20

21. 2. Candida albican → candidiasis (moniliasis)
Risk factor
» Antibiotic therapy
» Antineoplastics
» Immunosuppressants
» Prolong neutropenia
» Recent surgery
» Catheterization
» I/V catheter
» Cellular immune deff
 May result in overgrowth and systemic infections
 Oral candidiasis or thrush
 Newborn infants and immune compromised patients
 Vaginal candidacies → preg, diabetes, oral contraceptives
3. Pit versicolor → pityrosporium orbiculare
21

22. B. subcutaneous (deep tissue infections):-
1.mycetoma (medura foot)
 Ch. Fungal inf of deep soft tissue & bones
 Most commonly introduced by thoru. & common in foot
2. other soft tissue inf:-
i. Zygomycosis
• Face, limbs & syst in immunocompromized pts
presented by S/C swelling
ii. ch. Ronoblastomycosis:-on feet presented as nurossy foot
iii. Rhinosporodidiosis:- on nose & cheeks presented by nasal
polysps & S/c mudule
iv. sporothrichosis:- on limbs rarely syst as S/C swelling ulcer,
lymphatic spread → common informers
22

23. C. Systemic fungal inf:-
i. Histoplasmosis:- caused by histoplasma capsulatum a diamorphic fungus
Symptomatic & resp illness is most common hepatomegaly &
lymphadenopathy rare Common in AIDS
Mode of inf. Is inhalation of conidia → conversion in small budding
in lungs → engulfation by phagocytes → prolif of organism →
carried to for hematology spread
ii. Aspergillosis:-
Caused by aspergillus fumigates
involves lungs → pulmonary aspergillosis leading cause of death in
recipients of bone marrow transplant in pts of asthma & cystic
fibrosis
Colonization of lungs with aspergillus’ cause allergic
bronchopulmonary aspergillosis 23

24. iii. Coccidiodomycosis:-
Influenza like illness with malaise fever backache cough
arthralgia swelling of knees & ankles caused by
conidia of coccidiodes immitis
iv. Paracoccidiodomycosis:-
Caused By Paracoccidiodies Brasilienensis
Mucocut. Lesions with involvement of lymph nodes & lungs
v. Blastomycosis:-
Mostly in men infected during occupational or eroatianal
activities mostly in south central begins in lungs &
mediestimal lymph nodes canidia resemble pulm T.B
vi. Cryptococcasis by C. Neoformans
local grannlomatons lesions of lungs bones brain & meanings
24

25. Vii. Pneumocystosis:- caused by pneumocystitis carinii
Viii. Candidiasis:- by candida albieans in immunocomproin pts
GIT, mucosal dis resopligitis & catheter associated fungenia in
hospilized pts
Ix. Candidal endocarditic:- Caused by non albicans like candida prapsilarus,
cond. Tropicals
Risk factor:- bypass surgery
X. Penicillins marneffie inf:-
Diamorphic organism in south east asia syst inf in both
normal & immunocompr. Persons
XI. sporotrichosis
Caused by sporo thrix schenchii
XII. Chromoblastomycosis:-
Ch. Cut inf caused by phialo
25

26. GEOGRAPHICAL PREVALENCE (INCIDENCE)
UK:-
More incidence of sec inf. Like uryptocococcal meningitis &
endocarditic & aspergillosis.
Other parts of world:-
More common are primary inf. Like blostomycosis
histoplasmosis Coccidiodomycosis
ANTI FUNGAL AGENTS
Systemic
Examples:- Amphotericin B, fluconazole, ketoconazole,
itraconazole
Topical
Examples:- Clotrimazole, miconazole, nystatin
26

27. CLASSIFICATIONS OF ANTI-FUNGAL DRUGS:-
A. According to MOA
1.Drug affecting synts / Function of cell memb:-
i. Synthesis (inhibit synth of ergosterol)
– Ketoconazole
– Fluconazole
– Itraconazole
– Voviconazole
– Miconazole
– Turbenafine (inhibit enzy squaline epoxidase so interfere
ergosterol synth)
ii.Function
• Polyene antibiotics
– Amphotericin B
27
– Nystatin

28. 2. Block nucleic acid synth:-
– Flucytosine
3. Distrupt microtubular function
– Griseofulvin
4. Reduction of fungal cell wall viability
– Pradimicin
– Nikkomycin
5. Fungal protein synth inhib:-
– Jordanians
28

29. B. Acc. To route of admin:-
1. Topical
– Nystatin
– Clotrimazole
– Econazole
– Amphotericin – B
2. Oral
– Miconazole
– Ketoconazole
– Fluconazole
– Itraconazole
– Flucytosine
– Grisofulvin
– Terbenafine
3. I/V
– Amphotercin
– Miconazole
– Flucytozine
– Fluconazole
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30. C. Acc. To chemical structure
1. Polyenes
• Amphotericin B
• Nystatin
2. Pyrimidins:- Flucytosine
3. Azoles, ketoconazole, miconazole, Clotrimazole,
fluconazole, voriconazole, podaconazole
4. Benzofurans:- Griseofulvin
5. Misc. drugs
• Undecylenic acid
• Benzoic acid
• Salicylic acid
• Propionic acid
• Caprylic acid
• Pot iodide
• Vaccines
30

31. D. Therapeutic classification :-
1. Superficial
i. Dermatoplytes (ringworms)
– Griseofulvin
– Terbanafine
– Ketoconazole
– Nystatin
ii. Candidacies
– Fluconazole
– Miconazole
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32. 2. Systemic
i. Ketoconazole
– Histoplasm
– Blastomycosis
ii. Ketoconazole
– Coccidiodomy
– Para
iii. Amphotericin B cocdidiodo
– Cryptococcus
– Candidacies
– 2ygomycosis
iv. Fluconazole
– Candidiasis
v. Flucytosine
– Candidiasis
– Cryptococcus 32

33. AMPHOTERICIN B
Chemistry
 It is polyene heptanes macrolide
 Amphoteri behavior for which the drug is named is presence of a
‘’ on the main ring & primary ammi group on mycosamine
 Prepared as colloidal susp with Na deoxycholate for I/V inf. Is
called fungizone
33

34. Pharmacokinetics
 Poorly absorbed from GIT so oral ampho B is only used for fungi
within lumen of the tract not for systemic disease
 I/V inj , topical
 90% bound to PP
 Liposomal prep(active drug in lipid delivery vehicles)
 Widely distributed in most tissue ,poorly penetrates BBB
 Some of it excreted in urine slowly over period of several days
 Severe t ½ = 15days
 Hepatic dis, renal disease and dialysis has little effect on drug conc.
And dose adjustment is not required
34

35. MOA
 selective in fungicidal effect
 It binds to ergosterol and form ampho. B associated pores in the
cell membs and alters its permeability
 Its double bond rich side combines with ergosterol and OH rich
side binds to water.
 This pore allows leakage of intercellular ions & macromolecules
and results in cell death
 Some drug may bind to human cells and may lead to prominent
toxicity
 Oxidative damage to fungal cells at least in sites.
Resistance
 If ergosterol binding is impaired either by
 ↓ conc. Of ergosterol reduced affinity of drug d/t modifications of
sterol into precursor sterol d/t mutation
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36. Adverse effects
 Immediate reactions by I/V infusion
 Slow toxicity
Immediate:- / infusion related toxicity
Include
 Fever, chills ,Muscle spasms
 Vomiting, headache, hypotension
 can be lessen by
 slowing infusion rate or ↓ daily dose
 Premedication by
Antipyretics
Antihistaminic
Meperidine or corticosteroid
( test dose of 1mg and should be kept under observation for 2
hours )
36

37. cumulative toxicity
Renal damage
More common with AMB ,SIGNIFICANTLY LESS with
liposomal prep
Reversible,prerenal renal failure
 occur in almost all patients 80% dose dependantd/t ↓
renal perfusion can be reduce by giving inf of N. saline
with daily dose
irreversible
renal tubular acidosis severe K+ and Mg wasting
creatinine Cl- drops and K+ lost with potentiated by
hypo natremia
K= loss can be reversed by KCl
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38. hypochromic, normocytic anemia d/t ↓ production of
erythropoietin
Thrombocytopenia,Leukopenia
Head ach. Nausea, vomiting, malaise
after Intrathecal therapy → seizures and chemical
Hepatic toxicity
Anaphylaxis
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39. Antifungal activity
Broad spectrum fungicidal
No antibact activity
i. Yeast / Candida → Candida albicans Cryptococcus
neofromans
ii. Endemic mycoses → histoplasma capsultive
blastomycoses dermatitides ,coccidioides immitis
iii. Molds → aspergillus furnigatus
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40. Clinical usespectrum
I. All life threatening mycotic infections d/t blood fungicidal action
It is used initially for serious infections and then replace by azoles for
chronic or preventive therapy
Fungal pneumonia status
Empiric therapy systemic fungal inf e.g. cancer patient with neutropenia
who remain febrile on brad spectrum antibiotics
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41. II. Systemic fungal disease
→ slow I/V infusion at dose of 0.5-1mg /kg/d and usually
continued to the total dose of 1-2 mg
→ in AIDS given once daily to prevent replace of cryptococcosis
+ histoplasmosis
III. Intrathecal therapy
 For cryptococcal meningitis not responding to other drugs.
IV. Local use
 Mycotic corneal ulcer + keratitis in form of drops and direct sub
conj. Inj
 Fungal cystitis – bladder irrigation with Amphotericin B
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42. FLUCYTOSINE
Chemistry :- discoursed in 1957 accidently while searching for
anticancer drug
 Pyrimidine derivative related to 5 fluorouracil
 Water soluble
 Spectrum of action less than Amphotericin B
 Synthetic compd.
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43. Antifungal activity
 Candida → Cryptococcus neoformans
 Agents of chromomycosis
Pharmacokinetics
 Well absorbed from GIT ,crosses BBB
 Min pl. protein binding
 80% excreted unchanged in urine
 can. be removed by haemodialysis
MOA
Pyrimidine analog , blocks fungal DNA SYNTHESIS
43

44. taken up by fungal cells via enzyme deaminase.In fungal cell
converted to 5 FU and then FUTP
 Which inhibit DNA and RNA synthatase respectively
 Drug selective for fungi bcoz human cells are unable to convert
drug to active metabolite.
 Amphotericin B enhances its effect by↑ its entry through
damaged fugal cells membranes
 Action synergistic with azole
44

45. Fungal resistance
 most common when flucytosine used as mononerapy for
Cryptococcus & Candidiasis
 It occur d/t altered metabolism of flucytosine
Adverse effects
d/t conversion of flucytosine to 5FU by microbial flora in
intestinal traction hosts
 Bone marrow depression leading to leucopenia and
thrombocytopenia.
 Rash, nausea, vomiting, diarrhea and severe enterocolitis
 Reversible elevated hepatic enzy in 5% of patients
 Toxicity is more with AIDS and azotemia taking Amphotericin B and
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46. Clinical uses
 Oraly 100-15500 µg/kg/d
 Used in combination with ampho B to ↑ response and ↓ toxicity
 Dose should be adjusted in renal disease
 Cryptococcus neofurmans / meningitis
 Chromoblastomycosis itraconazole + flucytosine
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47. Azoles
 Synthetic comp
 Acc to no. of nitrogen atoms in 5 membered azole ring they are
classified in to 2 groups
1. Imidazoles
2. Triazoles
Imidazole
 Metabolize rapidly
 More effect in human sterol → so more drug interactions
e.g.
ketoconazole
miconazole
Clotrimazole
Econazole
Butoconazole
47

48. Trizole
 Metabolize slowly
 Less effect on human cytochronic P450 i.e. involved in sterol
synthesis less D/F
E.g.
Itraconazole
Terconazole
Fluconazole
New azoles
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49. Antifungal activity
 C. Albican
 C. Glabrates
 C. Immitis
 H. Capsulatern
 C. Tropicalis
 C. Neoformans
Don’t have antibacterial or parasitic effect except antiprotozoal effect
against
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50. MOA
 These drugs act by reducing the synthesis of ergosterol by inhibiting
p450 enzymes i.e. 14x dermetlylase thus acumlating 14x metlylsterol
 These methyl sterols disrupts the cell membrane and impair function
of membrane bound enz e.g. atpase and thus inhibiting growth of
fungi
 Some azoles such as Clotrimazole may directly ↑ the cell membrane
permeability but only in topical use
50

51. Resistance:-
 Many mech, d/t prolong therapy and emerge slowly
 Accumulation of notations' in ERGII the gene coding for 14x sterol
dermetylase
 Cross resistance in all sterols
 ↑ azole efflux by ATP binding casseltc and transporter can add to
fluconazole resistance in C. albicans C. glabruta
 ↑ Production of c 14 x dermatolyse is another cause
 ↑ in no of resistant strains b/c of tis ↑ use in prophylaxis
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52. Ketoconazole
 Given orally
 Cheaper than itraconazole
 More hepatotoxic + corticosteroid depression than itraconazole
Pharmacokinetics
 Oral absorption varies in individuals
 Acidic environment is required for dissolution
 So antacids, proton pump inhibitor etc reduces bioavailability
 t ½ = 7-8 hours
 metabolize extensile in liver and excreted via faces
 84% bound to Albion
 45% of erythrocytes
 1% is free
 Duly 1% penetration to CSF
 Enzyme induces e.g. IND, rifampicin ↑ metabolism
 Water solubility is low
 It was the first oral azole but not used b/c of less selectively for p450
52

53. Adverse effects
 Dose dependent nausea, anorexia voiting so give dose in divided dose
with food and at bed time
 Skin rash, purities
 Hair loss
 As it inhibit cytoch p450 → inhibit steroid synthesis so
endocrinological effects
53

54. ITRACONAZOLE
 Synthetic
 Given orally and I/V
 Dose 100-400mg/d
Pharmacokinetics
 It has equally active metabolite i.e. hydroxyl itraconazole
 99% bound to Pl. protests
 Neither appear in urine, CSF
 t ½ = 24-42 hours
 metabolized in liver extensively first pass state level achieved in 4 days
 I/V is 80-90% excreted in urine
 Teratogenic
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55.  Drug absorption is ↑ by food ad low gastric PH
 Water solubility is low
 Lipid soluble
 Drug absorption ↑ after food and gastric
Adverse effects
 GIT disturbances
 Headache, dizziness
 Rare are hepatitis, hypocalcemia impotence
 Allergic reactions
 Drug interactions b/c interact with hepatic microtonal enz
55

56. Important drug interactions
Rifamycin (Rifampin, rifabutin, rifapeutin)it ↓ bioavailability of
itraconazole
a. Itraconazole conc. ↓ with
Rifamycin, Phenytoin, Pherobalbetone
Drugs that ↓ gastric acidity
b. Itraconazole conc. ↑ with
 Claisthromycin
 Indinavir
 Ritonavil
56

57. c. Other drug ↑
 Diazepam
 Digoxin
 Astemizole
 Quinidine
57

58. Therapeutic uses
Drug of choice for systemic infections d/t (non meningeal infection)
 Blastomyces I/V
 Sporotheix
 S/C Chromoblastomycosis
Alternative T/M for infections caused by
 Aspergillus (outside CNS) I/V
 Coccidioides
 Cryptococcus
 Histoplasma
 In HIV patients with disseminated histoplasmosis → for maintenance
 Bronchopul aspergillosis
Active against some strains of esophageal Candidiasis resistant to fluconazole
(in form of itraconazole solution)
Used in dermatophytoses 58

59. FLUCONAZOLE
Chemistry
 Fluocimated bistriazole
Pharmacokinetics
 Almost completely absorbed from GIT
 Plasma conc. almost same after oral or I/V
 Bioavailability not effected by food or gastric acidity
 Half life 25-30hours
 Excretion of 90% renal and 10% faces
 CSF conc. in 50-90%
 Can also penetrate body fluids e.g. sputum or saliva
 11-12% protein bound
 100-200mg given after haemodialysis
 Water soluble
 Least effect on cytochrome p 450 so less drug interactions
 Dose is 100-800mg/day oral or I/V
 Widest therapeutic index b/c better GIT tolerance and less effect on p450
59

60. Drug interactions
 It ↑ Pl. conc. of astemizole, cyclosporine rifampin, sulfonylurea,
theophylline
 Adverse effects
 Nausea & vomiting above 200mg and above 800mg require
antiemetic
 Headaches, skin rash, vomiting, abd pain, diarrhea after 7days of
therapy
 Reversible alopecia
 Hepatic failure
 Steven syndrome
60

61. Therapeutics uses
 Drug of choice in t/m and 2nd prophylaxis
 Cryptococcal meningitis i.e. cryptococcal neofurmans of AIDS
400mg PL 8 wks
 Esophageal & oropharyngeal Candidiasis
 Dose is 200mg on first day twice 100mg -150mg Pl 2 wks
61

62. VORICONAZOLE
 Newest triazole
 I/V & oral formulations
 Dose 400mg/d
Pharmacokinetics
Well absorbed orally with
Bioavailability < 90%
Less protein binding than itraconazole
Hepatic metabolism
Propensity for inhibition of p450 is low
62

63. Adverse effects
Rash
Elevated hepatic enzymes
Transient visual disturbances 30%
Include blurring and changes in color
Vision or brightness these changes occur immediately after
dose of voriconazole and resolve with 30min
Uses
Similar to itraconazole
Excellent activity against Candida (including fluconazole –
resistant species such as & dimorphic fungi
Less toxic and more effective in invasive as
63

64. Systemic azoles
Water Absop CSF: serum t½ Elimination Formulation
conc ratio
Ketoconazole Low Variable <0.1 7-10 Hepatic Oral
Itraconazole Low Variable <0.01 24-42 Hepatic Oral, I/V
Fluconazole High High >0.7 22-31 Renal Oral, I/V
Voriconazole High High >0.7 6 Hepatic Oral, I/V
64

65. ECHINOCANDINS
 Newest class of antifungal to be developed
 They are large cyclic peptides linked to a long chain fatly acid
(Lipophilic) CASPOFUNGIN:- is only licensed agent, others are
under investigation
 Water soluble semi-synthetic lipopeptide derivative
Pharmacokinetics
 Water soluble
 Only available in I/V form
 Administered as a single loading dose of 70mg followed by
50mg/d
 Highly protein bound
 t ½ 9-11hours
 Metabolites are executed by kidneys and GIT
 Dosage adjustment required only in severe hepatic in sufficiency
65

66. Mechanism of action:-
 It acts at the level of fungal cell wall by inhibiting synthesis of B(1-
3)glucan. This results in disruption of cell wal and cell death
 Resistance occur d/t mutations
Adverse effects:-
 Usually well tolerated with mino GIT side effects and flushing reported
infrequently
 Elevated liver enzymes specially in patients taking cospafungis
cyclosporine in combination so avoid it
66

67. Uses
 Salvage therapy in patients with universe aspergillosis who failed to
respond to Amphotericin B
 Active against Candida i.e. mucocutaneous Candidiasis and blood
stream Candida inf
 H. capsulation
 C. albises
67

68. MICAFUNGIN
 Undergoing clinical
 Effective against aspergillus & Candida speches even in pts who
are immunocompromised with AIDS
AMOROLFINE
 Morphemic derivative that interferes with fungal sterol synthesis
 Given locally effective against infections of nails
68

69. SYSTEMIC ANTIFUNGAL DRUGS FOR MUCOCUTANEOUS INFECTIONS
1. Griseofulvin
Chemistry
 Isolated from the culture of penicillin Griseofulvin
 Narrow spectrum antifungal agent
Pharmacokinetics
 Given orally, absorption ↑ with fatly finds
 Poorly soluble in water and absorption varies with type of preparation
specially size of the particle
 Peak Pl. conc. reaches in 5hour
 It is taken up by the newly formed skin and concentrated in the lceratin
drug can be detected in St. corneuna after 4-8 hour of oral adm.
69
 t ½ is 24hour but retained for with higher conc. in upper layer

70.  Potent inducer of p450 so many drug interactions specially warfarin,
phenobenbital so largely replaced by itraconazole and terburafine
 Reductive in particle size greatly ↑ the absorption
 Formulation that contain the smallest particle size are labeled
“ULTRAMICRONISED” it adueues bioequivalent PL> levels with half the
dose of micronized drug
 In addition solubilizing Griseofulvin in polyethylene glycol enhances
absorption even further
 Micronized grisesfuliun is available as 250mg, 500mg tab
 Ultra micronized as 125mg, 165mg, 250mg and 330mg tab and 250mg
capsule
 Adult done of micronized is 500mg/day in single or divided doses with
meals & occasionally 1g/d in t/m of recalcitrant infections
70

71.  The pediatric dose is 10mg/kg body wt daily in single or divided
dose with meals
 Oral suspension is also available
 50% of oral dose can be detected in urine within 5days mostly in
the form of metabolites mainly 6 methlgaseofulvin
 Barbiturate ↓ its absorption
 The drug is deposited in keratin precursor cell
 The antibiotic present in cells when they differentiate is tightly
bound to and persist in keratin & makes this substance resistant to
fungal infection → so new growth of hair & nail is first to become
free of disease, as the fungus containing keratin is shed it is
replaced by normal tissue.
71

72. Antifungal activity
Fungi static
 Various species of dermetophytes i.e. Mycospoum,
epidermophyton and trichophyton
 Most effective in twice inf of scalp and glabrous skin
 In scalp response in 4-6 weeks glabrous skin 3-4 weeks
 dermatophyte inf of nail need prolong therapy – finger nail 6
weeks towards 8-18 month
 No effect on bacteria & other fungi i.e. Candida & p. Orbicular
72

73. Mechanism of action
 It inhibit mitosis so these is production of multinucleate cells
 It causes disruption of mitotic spindle by interacting with
polymerized microtubules of spindle and cytoplasmix
microtubules result in the impaired processing of newly
synthesized cell wall at the growing tips oc hyphare
 antifungal activity is
 Inhibiting of hyphal cell wall synthesis
 Nuc acid synthesis
 Inhibition of mitosis
73

74. Adverse effects
Serious effects are rare
CNS:- Headache disappears when therapy is continued
 Peripheral neuritis
 Lethargy
 Mental confusion
 Impairment of performance of routine tasks, fatigue,
syncope, vertigo
 Blurred vision transient macular edema
 Augmentation of the effects of alcohol
GIT:- Nausea, vomiting, diarrhea, flatulence, dry mouth, angular
stomatitis, hepatotoxicity
 Haematological leucopenia
 Neutropenia
 Punctarte basoplilia
 Monocytosis 74

75. Skin :- Cold & worm urticaria
 Erythema, photosensitivity
 Serum sickness like syndrome angioedema
 Estrogen like effects in children
 Induces hepatic p450 → cry inducer ↑ metabolism of
warfarin + oral contraceptives
 Cross sensitivity with penicillin may occur
C/I:-
 Prophria
 Hepatic failure
 Hypersensitivity to guisofuloxia in post
75

76. Precaution:-
 If prolong therapy then routine evaluation of
 Hepatic
 Renal
 Haemopoitic system
Uses:-
 Recommended daily dose
 5-15mg/kg --- children
 500mg – 1g/d –adults
 1.5-2g fore severe infection
 Best results if repeated 6 hourly but mostly given twice daily
 Not effective for S/C or deep mycosis
 T/M should be gives until diseased portro is replaced by wound
twice skin of nails,
 Normal hair, skin, nails → I µ for scalp & hair ring worm
 6-9µ for finger nails
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77. TERBINAFINE
Chemistry
 Synthetic allylanuire, similar to naftifure
Pharmacokinetics:-
 Well absorbed
 Bioavailability is 40% d/t first pass effect
 Protein bound 99%
 Drug accumulates in skin walls and fat
 Initial half life is 12hour but extends to 200-400hour at steady state
 Drug can be found in plasma for 4-8weeks after prolong therapy
 Hepatic metabolism P450, excreted by urine
 If given topically then can penetrate the skin & M. memb
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78. Mechanism of action
 Fungicidal
 Keratophilic like griseofuluir
 Like azoles interfere with ergosterol biosynthesis
 Inhibits fungal enz squalene epoxidase instead of P450
 This leads to accumulative of sterol squalene which is toxic to the
organism
Adverse effects
 Rare & self limiting
 GIT upset
 Headache, dizziness
 Rashes, purities
 Rarely hepatitis
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 Don’t effect p450, so no drug restrictions

79. Uses
 More effective than griseofuluin
 Itraconazole in treating onychromycosis i.e. cure rate is 90% when
one 250mg tabled given for 12 weeks
 Ringworm else where in body
 No pediatric formulation is available
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80. TOPICAL ANTIFUNGAL THERAPY
I. Polyene antifungal antibiotic
a) Nystatin
 It is a polyene maesolide produced by streptomyces noursei
 Same structure and mechanism as Amphotericin B
Pharmacokinetics
 it is not absorbed from GIT skin or vagina
 A liposomal preparation is in clinical trial for candidemia
 Too toxic for parental administration only used topically
 It has little toxicity as absorption is poor
 Oral use is limited by unpleasant taste and may cause nausea
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81. Use:-
 Active against candida species i.e orophangeal
 Vaginal Candidiasis
 Intertrigurious candidal inf
 Powder form twice daily for wet lesions
 Vaginal tablets once daily for 2 weeks for vaginal Candidiasis
 Zoles are more effective
 Oral suspensions 4 times /day
 Premature babies 1ml
 Children 2ml
 Adults 4 -6ml per dose
B) Amphotericin B
 In the form of ointment, lotion, cream all contain 3% ampho B
applied 2-4twice daily for cretaceous and mucocutaneous lesions
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82. II. Topical azole
Indications are :-
 Mucocutauous caudidiasis
 T. versicolor
 Ring worm
Vaginal application
 Creams, suppositories, ballets for vaginal Candidiasis
 3 preparations are available
 Clotomazole tablets
 Miconazole supporitory
 Terconazole cream
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83. Oral use
 Orally indication is orophangeal Candidiasis
 There is only local conc. of the drug and no systemic effect
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84. 1. CLOTRIMAZOLE
Kinetics:- Absorption from intact skin 0.5%
 Absorption from vagina 3-10%
 Metabolized in liver & excreted in bile
Adverse effect:-
Skin:- Stinging, Erythema, edema, vesication,
desquamation, pruitis, urtecaria
Vagina:- Burning, ↑frequency of urine, skin rash
Oral :- GIT inhibition
Uses:- Available as OTC
(Cream) dermatophyte infections 60-100% cure rate
Coetaneous Candidiasis 80-100%
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85. 2. MICONAZOLE
Structurally related to econazole
 Penetrates readily st. couneum of the skin and therefore more
than 4 days
 Less than 10% is absorbed in to blood
 Absorption is 1.3% from vagina
Adverse effects
 Burning, itching, irritation. Pelvic cramps, headache, hives, skin rash
safe in pregnancy but avoid is 1st trimester
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86. Uses:-
Available as cream, lotion, ointment powder vaginal cream +
suppository
In t/m of T. curis pedis, versiolor 90%
Vulmoraginal Candidiasis 80-95%
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87. 3. Econazole
 Penetrate at. Corneum upto mid dermis reat is same as above
(miconazole)
 Terconazole + butoconazole + tioconazole
– Terconazole resemble ketoconazole used → in vaginal Candidiasis
– Butoconazole → comparable to clotimazole in vaginal Candidiasis
 Oxiconazole + sulconazole
– For deratophytes
 Ciclopirox olamine
– Blood spectrum
– Cutaneous Candidiasis
– T. coxposis, cursis, pedis & versicolor
 Haloprogin fungicidal
– T. pedis 80% T. crunis corpsis cersicotor
 Tolnaftate
– Cutaneous mycosis
– T. Pedis
 Allylamines
i. Naftifuie
» Allyeamine
» Fungicidal, inhibit swualene 2,3 epoxidese
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