2. Anti Fungal Drugs
• Fungi constitute an important group of eukaryotic organisms ranging from
unicellular to multicellular organisms, such as yeasts, molds, mushrooms, etc.
• Mushrooms are the largest fungi existing in the universe.
• Pneumocystis jiroveci is also a fungus but does not respond to antifungal agents,
rather anti-protozoal agents.
• Pulmonary manifestations are those of immunocompromised.
• Co-trimoxazole and trimethoprim have some activity.
4/4/2023 2
3. Anti Fungal Drugs
• Fungi are different from bacteria.
• They have larger size and the cell wall is more.
• Sterol part of cell membrane consists of ergot instead of cholesterol.
• Fungi are capable of constituting number of superficial systems known as mycoses.
4/4/2023 3
8. Antifungal drug targets…
• Generally these targets should be different from mammalians.
Both human and fungi are eukaryotic, so not much difference could be found.
The most important difference is the presence of CW for fungi that is not found in humans.
• Other targets are:
Inhibitors of DNA synthesis
Disruption of mitotic spindle
Interfere with metabolism
• The most exploited difference is the nature of sterols:
Important components of cell membrane for proper function of CM enzymes and ion
transporter proteins.
4/4/2023 8
10. Cell membrane synthesis inhibitors
• Amphotericin B
• Source
• Antibiotic obtained from Streptomyces nodosus
• Amphotericin A –no therapeutic application
• Amphotericin B –broader activity, antifungal
• Chemistry
• 7 Polyene macrolide-O-Mycosamine
• Polyene is a term used for agents consisting of large number of double bonds.
• Macrolides are molecules having more than 12 atoms.
4/4/2023 10
11. Amphotericin B…
• General Properties
• Poorly water soluble
• Mostly available as a suspension with sodium desoxycholate
• Amphoteric molecule –amphipathic character in addition.
• Both water and lipid soluble components
• Stable at extremes of pH
• Latest preparation besides colloidal and sodium desoxycholate is Liposomal
amphotericin B to decrease renal toxicity of amphotericin B.
• Hydroxyl groups are capable of producing mechanism of action as antifungal.
4/4/2023 11
12. Amphotericin B…
• Mechanism of Action
• Sterol component in fungal cell membrane is ergot instead of cholesterol.
• Has amphipathic character, both lipophilic (due to choline) and hydrophilic components.
• When administered:
• Preferential binding to ERGOSTEROL, choline part binds
• Pores or channels are formed in membranes of sensitive fungi (lipophilic part)
• Cell is unable to maintain internal environment, expulsion of intracellular ions occur
• Fungicidal action
4/4/2023 12
13. Amphotericin B…
• Resistance
• Resistance occurs because different mechanisms are established:
1. Some defect in binding site of ergosterol for amphotericin B
2. Less affinity for amphotericin B
3. Less synthesis of ergosterol due to which resistance occurs.
• Some binding of AmpB with human tissues is responsible for side effects.
4/4/2023 13
14. Amphotericin B…
• Spectrum of Activity: The broadest spectrum
• Effective against most fungi causing mycotic infection including:
• Candida albicans
• Cryptococcus neoformans
• Histoplasma capsulatum
• Blastomyces dermatitidis
• Coccidioides immitis
• Aspergillus fumigatus
4/4/2023 14
15. Amphotericin B…
• Pharmacokinetics
• Oral absorption poor thus not given orally.
• Locally applied for irrigation of bladder, gut.
• IV 0.6mg/kg/day, with this dose blood levels are maintained at 0.3-1 mcg/ml.
• Protein binding 90%
• Wide distribution (CNS 2-3%) fungal meningitis?
• Thus if required intrathecally administered for achieving higher levels
• having some neurotoxic manifestations (some neurotoxic manifestations).
4/4/2023 15
16. Amphotericin B…
• Excretion in urine and bile.
• Traces in urine are found for several days due to wide distribution and high plasma protein binding
• t1/2 15 days
• Liposomal amphotericin B –newer amphotericin B
• AmBisome 3-5mg/kg/d
• Amphotec 5mg/kg/d
• Abelcet 5mg/kg/d
• Older preparations include colloidal suspensions and sodium desoxychalate.
4/4/2023 16
17. Amphotericin B…
• In order to decrease toxicity liposomal preparations are made.
Amphotericin B attaches to lipid carriers.
Liposomes act as a reservoir of amphotericin B.
Most of it is within liposomal preparations, so its attachment to renal cells decreases renal
toxicity.
Enzymes known as lipases cause release of bond from amphotericin B, increasing their
availability for physical effects.
• Free form is made available producing more efficacy.
• These drugs are highly expensive
4/4/2023 17
18. Amphotericin B…
• Toxicity
• Immediate
• Seen when given IV.
• Manifested by: Fever, chills, muscle pain, headache, vomiting, hypotension
Treatment:
1.Test dose:- 1mg amphotericin B IV in 20 ml of 5% dextrose
2.Daily doses decreased if fear for immediate effects
3.Dose has to be administered slowly
4.If such manifestations, then premedication with antipyretics and antihistaminic or
corticosteroids.
4/4/2023 18
19. Amphotericin B…
• Late
1. Renal damage (reversible –deviation of RFTs and decreased GFR) (Irreversible >4g total
dose)
2. Renal Tubular Acidosis –accumulation effect beyond 4g.
3. Severe hypokalemia. Treated by calcium supplements
4. Hypomagnesemia (K+ Mg++ loss)
5. Abnormal liver function test
6. Anemia of renal origin –reversible normocytic normochromic
7. Loss of Erythropoietin formation:
Due to renal damage
When therapy is stopped, anemia is corrected
8. Cerebral damage –Seizures
• When given intrathecally for fungal meningitis, producing neurotoxic effects including
headache and seizures.
4/4/2023 19
20. Therapeutic uses
1. Induction Therapy
• Broad spectrum, mainly used for systemic fungal infections.
• Initially introduced as induction therapy for fungal infections
• Later maintenance with newer azoles
• Fungal pneumonia
• Meningitis
• Immunocompromised; neutropenic patients
• Fungal sepsis
• Dose 0.5-1 mg/kg/d (Total dose 1-2g)
4/4/2023 20
21. Therapeutic uses…
2. Locally –empirical therapy of neutropenia
• Mycotic corneal ulcer,
• keratitis,
• Fungal arthritis (injected directly into joints)
• Candiduria
3. Intrathecal
• Care is taken to avoid neurotoxicity.
4/4/2023 21
22. CM synthesis inhibitors
• Nystatin
• A polyene macrolide obtained from penicillin
• Discovered in New York state lab so named.
• Mechanism of Action
• It is a polyene macrolide ,similar in structure & mechanism to amphotericin B.
• Too toxic for systemic use.
• Used only topically but not recommended for oral use as has very bad taste and serious adverse effects.
• It is available as creams, ointment , suppositories & other preparations.
• Not significantly absorbed from skin, mucous membrane, GIT.
• Very less amount is absorbed systemically, toxicity chances are less
4/4/2023 22
23. Nystatin…
• Uses
• Topically for candidiasis
• Prevent or treat superficial candidiasis of mouth, esophagus, intestinal
tract.
• Vaginal candidiasis
• Can be used in combination with antibacterial agents & corticosteroids
4/4/2023 23
24. Griseofulvin
• Griseofulvin
• Systemic drug used for local infection and not systemic.
• Uses are declining, grouped with antibiotic group.
• Obtained from same source as penicillin.
• Mechanism of action
• When given orally, binds to microtubules comprising the spindles and inhibits mitosis.
• Incorporates into affected keratin –fungistatic
• Inhibit nucleic acid synthesis
• Taken with fatty meal as bioavailability is increased.
• Microfine dosage form or micro crystalline form
4/4/2023 24
26. Griseofulvin…
• Dose: 1g/day dose
• Half life is 24 hours.
• For hair infections administered for 4-6 weeks.
• For nails infections administered for 4-6 months.
• For toe nail infections administered for 8-18 months.
• Should be given for prolonged period so that growth of newer skin, hair are
devoid of fungal infections.
4/4/2023 26
27. Griseofulvin…
• Uses
• Tinea infections of skin, hair and nail due to:
• Microsporum
• Trichophyton
• Epidermophyton
• Athletes foot
• Both systemic drugs used for topical infections.
• Cure rate high given for Weeks to Months
4/4/2023 27
28. NA synthesis inhibitors
• Flucytosine: Discovered in 1957, a group of scientists working on anti-neoplastic drugs established it to have anti-fungal properties.
• Chemistry: Fluorinated pyrimidine like 5-Fluorouracil (which is anti-metabolite)
• Mechanism of Action
• Anti-fungal having fungistatic effect.
1. Taken up by fungal cells
2. Deaminated to 5-FU
3. Incorporated as FUTP in RNA
4. 5-FdUMP (Inhibitor of thymidylate synthetase)
• Cytosine deaminase is absent in mammals, humans are not effected.
• Synergy with Amphotericin B and Azoles.
• Pores are formed or induced which facilitate entry of flucytosine in cell.
4/4/2023 28
29. Flucytosine…
• Mechanism of resistance
• Monotherapy is not recommended due to emergence of resistance, so given in
combination slowly.
• Resistance is said to be mainly due to altered mechanism of metabolism of
flucytosine to 5 fluorouracil, due to mutation in cytosine deaminase.
4/4/2023 29
30. Flucytosine…
• Pharmacokinetics
• Readily absorbed orally.
• High bioavailability of >90%
• T1/2 3-4hours
• Peak plasma levels occur within 1-2 hours.
• Dose: 100-150 mg/kg/day
• Distribution (all parts, CSF high )
• Excretion by glomerular filtration
• Dose adjustment has to be done in renal failure as plasma levels higher due to increased half
life to 200 hours or more.
4/4/2023 30
32. Flucytosine…
• Adverse Effects
• As resembles 5-fluroruracil (anti-neoplastic) so may cause:
1. Bone marrow toxicity as antimetabolite: Anemia, Leucopoenia thrombocytopenia
2. Active metabolites produced by intestinal flora thus enterocolitis can occur.
3. GIT manifestations: Nausea, Vomiting, Diarrhea, Abdominal cramps and pain
4. Liver enzymes elevation
5. Nephrotoxicity
6. With prolonged use alopecia may occur as resembles anti-neoplastic drugs.
4/4/2023 32
33. Azoles
• Imidazole
• Used specifically for topical infections.
• Ketoconazole was used as highly effective for most fungal infections
previously, but due to higher p450 enzyme drug interactions, newer drugs are
preferred.
• It is reserved only for scalp fungal infections.
• High quantity is used to suppress levels of corticosteroids.
4/4/2023 33
34. Azoles…
• Triazoles
• Highly effective for most fungal infections.
• Mechanism of Action
• Most are synthetic.
• Inhibit the fungal cytochrome P450 enzyme, (α-demethylase) which is responsible for
converting lanosterol to ergosterol (the main sterol in fungal cell membrane ).
• Inhibition of mitochondrial cytochrome oxidase leading to accumulation of peroxides that
cause autodigestion of the fungus.
• Imidazoles may alter RNA& DNA metabolism.
4/4/2023 34
35. Azoles…
Spectrum Of Activity
1.Most candida species:
2.Candida albicans,C tropica ,C parasilosis,C glabrata
3.Cryptococcus neoformans (Fluconazol)
4.Blastomyces dermatitidis,
5.Histoplasma capsulatum,
6.Coccidioidomycosis
7.Zygomycosis, Mucormycosis (Posaconazole)
8.Ring worm
9.Pseudallescheria boydii ( Amphotericin B resistant)
Although most fungal species are inhibited but have affinity for p450 of
humans, which is the main reason why ketoconazole is not recommended
now.
4/4/2023 35
36. Azoles…
• Adverse Effects
1.Nausea, vomiting
2.Allergic rash
3.Hormone imbalance
4.Fluid retention
5.Hepatitis
6.Teratogenic
7.Inhibits drug metabolism
8.Absorption reduced by H2 antihistamines and omeprazole and antacids (KETOCONAZOLE)
4/4/2023 36
37. Azoles…
Agents Solulibility Absorption Bioavailability t1/2 hours Excretion Route
Ketoconazole Low Erratic Less 7-10 Hepatic Oral
Itraconazole Low Erratic 55 food, low pH 24-42 Hepatic Oral, IV
100-400mg/d
Fluconazole High High >90% 22-31 Renal Oral, IV
100-800mg/d
Posaconazole High High? food ___ Hepatic Oral
800mg/d
Voriconazole High High 96¯ food 6 Hepatic Oral, IV
400mg/d
4/4/2023 37
38. Azoles…
• Ketoconazole
• Due to adverse effects used for:
1. Scalp infections
2. Corticosteroid suppression
• Itraconazole
• Newer triazole, may posses activity against human p450 enzyme, leading to drug interactions.
• Decreased bioavailability is seen with Rifampicin.
• Cannot cross blood brain barrier readily, used for:
1.Histoplasmosis, Blastomycosis, Sporothrix
2.Also used for candidiasis in dermophytosis and oncomycosis
4/4/2023 38
39. Azoles…
• Adverse Drug Reactions
• May lead to rash
• Increased levels of hepatic enzymes
• Hypokalemia
• Stevens Johnson syndrome in some
• GIT –nausea, vomiting, abdominal pain
4/4/2023 39
40. Azoles…
• Fluconazole
• Has high bioavailability and penetrates BBB, highly water soluble and has high therapeutic
index.
• Drug interactions are less.
• GI effects are less readily seen with fluconazole as is highly tolerable.
• Uses
1.AIDS
2.Immunocompromised patients
3.Cryptococcal meningitis
4.Ocular keratitis
5.Candidemia
6.Mucocutaneous candidiasis
• No activity against Aspergillosis.
4/4/2023 40
41. Azoles…
• Adverse Drug Reactions
• Although GI manifestations not common, but may lead to:
1.Nausea, Vomiting, Abdominal pain, Skin rashes, Alopecia
2.Stevens Johnson syndrome
4/4/2023 41
42. Azoles…
• Posaconazole
• Newer agent discovered having activity against:
• Candida, Aspergillosis, Zygomycosis, Liuamycosis
• Used for:
1.Prophylaxis in patients of leukemia in which chemotherapy is initiated, such patients
are prone to fungal infections.
2.In bone marrow transplant patients especially those undergoing graft cases.
4/4/2023 42
43. Azoles…
• Voriconazole
• Less plasma protein binding having less affinity for cytochrome p450 and less
interactions.
• It is highly effective against aspergillus.
• It is the drug of choice.
• Adverse Drug Reactions
1.Rash
2.Increased hepatic enzymes
3.Visual disturbances –blurring of vision
4.Decreased perception to color is seen especially to bright colors.
4/4/2023 43
44. Azoles…
• Azoles for topical use
• In the form of vaginal creams, suppositories, tablets for vaginal candidiasis given
once daily .
• Miconazole/Clotrimazole
• Absorption is less than 0.5% from intact skin, 3-10% from vagina (its activity
remains for 3 days).
• Used in cutaneous candidiasis & vulvovaginal candidiasis, oropharyngeal candidiasis
and dermatophytic infections like:
• Tinea corporis, Tinea pedis, Tinea cruris
• Side effects : Erythema, edema, , urticaria & mild vaginal burning sensation.
4/4/2023 44
45. Cell wall synthesis inhibitors
• Echinocandins
• Newly discovered agents.
• Caspofungin, Micafungin, Anidulafungin
• Large cyclic compounds with long chain fatty acids.
• Fungicidal action
• Inhibit 1,3-b-D-glucan synthase, which is required for glucan polymerization
in the wall of filamentous fungi
4/4/2023 45
47. CW synthesis inhibitors…
• Spectrum of Activity
A. Candida albicans,C. glabrata, C. tropicalis, C. kruzei
B. Aspergillus fumigatus, A. flavus, A. terreus
C. Pneumocystis jiroveci*
• Anti protozoal agents may have some activity
4/4/2023 47
48. Echinocandins…
• Pharmacokinetics
• Caspofungin
• Given IV only
• Half-life 9-11 hrs.
• Protein binding 90%
• Elimination -Renal & GIT
• Dose: 70mg followed by 50mg daily
• Micafungin
• Half life 11-15 hours
• Dose: 50-150 mg/day
• Anidulafungin
• Half life longer: 24-48 hours
• Dose: 50-200 mg/day
4/4/2023 48
50. Allylamines
• Terbinafine
• Inhibits squalene 2, 3- epoxidase. Squalene is fungicidal to sensitive
organisms.
• Systemic agent used orally for dermatophytes
• Metabolized by liver excreted in urine
• Adverse effects include hepatitis and rashes. Both are rare.
• Accumulates in keratin and newly synthesized skin.
4/4/2023 50
51. Allylamines…
• Terbinafine
• Drug of choice for treating dermatophytes (onychomycoses).
• Better tolerated ,needs shorter duration of therapy.
• Inhibits fungal squalene epoxidase, decreases the synthesis of ergosterol .
• Accumulation of squalene ,which is toxic to the organism causing death of fungal cell
4/4/2023 51
52. Allylamines…
• Naftifine
• Broad spectrum fungicidal
• Available as cream or gel
• Effective for treatment of tinea cruris
4/4/2023 52
53. Thiocarbamates
• Squalene epoxidase inhibitor
• Tolnaftate:
• Effective in most cutaneous mycosis
• Ineffective against Candida
• Used in tinea pedis ( cure rate 80% ).
• Used as cream, gel, powder, topical solution.
• Applied twice daily.
• Liranaftate: topical antifungal drug,
• Used as a 2% cream used to treat tinea pedis, tinea corporis, and tinea cruris
4/4/2023 53
54. Other Antifungal Drugs
• Ciclopirox Olamine
• May block amino acid transport – penetrates well
• Iron chelators
• Ciclopirox cream, gel, or lotion are applied to the skin to treat
• Used:- Candida and Dermatophytes
• Haloprogin
• Used for dermatophytes and candida, may cause burning at site of application
4/4/2023 54
55. Summary
• Polyenes
• The polyenes nystatin and amphotericin B are lipophilic and bind to ergosterol
• Cytoplasmic Membrane synthesis inhibitors
• Ergosterol binding forms membrane channels
• Active against most fungi
• Insoluble compound must be infused in suspension
• Therapy must be titrated against toxicity
4/4/2023 55
56. Summary..
• Polyenes are bind with ergosterol, the sterol in fungal membranes
• Creating membrane pores and
• Causing Leakage of cell metabolites
• Amphotericin B
• Is a polygene anti fungal agent administered intravenously (IV)
• Causes nephrotoxicity
• Is the drug of choice in most life-threatening fungal infections
4/4/2023 56
57. Summary…
• Azoles
• Inhibit enzyme crucial for synthesis of membrane ergosterol
• Less toxic than amphotericin B
• Itraconazole and voriconazole prime systemic agents
• Flucytosine
• Enzymatically modified form makes defective RNA
• Inhibits DNA synthesis
• Active against yeasts but not molds
• Resistance develops during therapy if used alone
4/4/2023 57
58. Summary…
• Allylamines
• Inhibit ergosterol synthesis
• Terbinafine used in the treatment of dermatophyte (ringworm) infections
• Echinocandins
• Inhibit cell wall Synthesis
• Inhibit synthetase crucial for glucan synthesis
• Current use is Candida, Aspergillus
• Caspofungin, micafungin and anidulafungin
4/4/2023 58
59. Resistance to antifungal agents
• Concepts are similar to bacterial resistance
• Laboratory methods are variable
• Mechanisms of resistance
• Polyene Resistance
• Membrane ergosterol decreased
• Flucytosine Resistance
• Multiple enzymes can mutate
4/4/2023 59
