1. Antifungal Agents
Most of the fungal infections are superficial invasion of skin or mucosal membrane of the body orifices. It can be controlled by local application of antifungal agent.
Antifungal infections are divided into two groups
Dermatophytoces- (tinea infection) it is a superficial skin infection caused by Epidermophytons, Microsporum and Trichophyton species.
Mycoces- it is contagious usually superficial infection involving skin and mucous membrane caused by pathogenic yeast, under certain condition it invade deeper body cavities causing systemic mycoces.

2. Fatty acids are found to be fungistaic in action so copper and zinc salt are used.
Aromatic acids- salicylic acid – keratolytic activity
Certain alkylated and halogenated phenols are also found to be topical fungistatic in action.
Imidazole possess highly antifungal activity analogues to 1,2,4 triazole.
Allylamines – Nafitifine, Terbinafine are also used in local infections.
Azoles – early members of azole were highly substituted with imidazole ring. Later isosteric replacement of imidazole with1,2,4 triazole ring retained the activity. Hence general term azole is applied to antifungal agents.

3. Classification Polyene Antibioics
Amphoterecin B, Nystatin, Griseofulvin
Azoles
Imidazole- Clotrimazole, Ketokonazole, Miconazole
Triazoles- Fluconazole and Itraconazole
Allylamines- Naftifine, Butenafine, Terbinafin
thiocarbamate- Tolnaftate
Antimetabolite- Flucytocin

4. Polyene Antibiotics
Before 1950’s undecyclenic acid i.e. mixture of benzoic acid and salycyclic acis was used.
Polyene antibiotics are used against deep seated infections.
Polyene are macrocyclic lactone with distinct hydrophilic and lipophilic region. Hydrophilic region constitute of several alcohol, carboxylic acid and sugar while lipophilic region constitute of chromophore of four to seven conjugate double bonds.
Number of conjugate bond is directly proportional to antifungal activity. Amphotericin B is 10 fold fungitoxic with 7 conjugate double bond.

5. Mechanism of action polyene antibiotics
The polyene have an affinity for the ergosterol, insert into membrane, disrupt the function.
The lipophilic polyene portion cross the lipid bilayer forming pore in cell membrane.
As a result the cell membrane become leaky and cell die due to loss of essential amino acids, ions and small organic molecule.
Polyene have great affinity for the ergosterol containing cell membrane than the cholesterol containing cell membrane.

6. Amphotericin B
Amphotericin B low toxicity to mammalian cells so can be administered IV.
A/E- fever, shaking chills, hypotension and kidney toxicity.
It’s a safe drug for systemic infection as it does not cross BBB

7. Nephrotoxicity is a serious drawback of this as it is sparingly soluble in water. It is formulated as a complex with deoxycholic acid for it IV administration.
Recently liposomal encapsulation and lipid soluble complex is formed which reduced this A/E.

8. Nystatin It is isolated from culture of streptomyces noursei.
It is effective against the topical fungal infection. It is available in cream and ointment.

9. It is too toxic to use systematically but due to low oral bioavailability it is used in the treatment of oral and GIT fungal infection.

10. Griseofulvin
7-chloro-2’,4,6- trimethoxy-6’-methyl-spiro[benzofuran-2(3H)-1’-[2]cyclohexene]-3,4’dione.
It is antibiotic obtained from fungus penicillium griseofulvum.
It is a natural spiro compound.
It is used to treat systemic ringworm infection of body, hair, nails, feet caused by trichophyton, microsporum, epidermophyton.

11. A/E are allergic reactions like rash, articaria, headache, dizziness, insomnia.
Oral bioavailability is very poor as it is lipophilic drug. Bioavailability is increased by micronized form of drug.
Patient is advice to take griseofulvin with fatty meal.
MOA-
Griseofulvin is mitotic spindle poison. It cause rapid reversible dissolution of mitotic spindle apparatus probably binding to the tubulin dimer that is required for microtubule assembly. Its high conc. Found in tissue rich in keratin, to treat dermatophytes infection.

13. Ergosterol biosynthesis inhibitor.
Non steroidal precursor to both ergosterol and cholesterol is squalene.
It is converted to squalene epoxide by enzyme squalene epoxidase which is cyclized to lanosterol.
Key step in conversion of lanosterol to both ergosterol and cholesterol is removal of 14α methyl group. This step is carried out by CYP 450 enzyme 14α demethylase.
The mechanism is three successive hydroxylation converting hydrocarbon into the alcohol, then aldehyde and carboxylic acid oxidation.
Methyl group is eliminated as formic acid and double bond is formed between C14 and C15 of ring D.

14. Mechanism of action azoles
All the azoles act by inhibiting ergosterol biosynthesis through inhibition of 14α demethylase enzyme.
Basic N3 of azole form bond with heme iron of CPY 450 in position normally occupied by activated oxygen.
This cause inhibition of demethylase result in accumulation of fungal cell membrane of sterol that still bear 14 methyl group which does not have shape and physical properties of normal cell membrane sterol.
This result in permeability change, leaky membrane and malfunction of embedded proteins.
This leads to fungal cell death.
The relative strength of same enzyme differ in different species hence mammalian enzyme is not affected.

15. Clotrimazole
It is broad spectrum antifungal agent used to treat tinea infection and candidiasis.
It is active against many pathogenic yeast it cause severe GIT disturbance.

16. Miconazole
It is available in free base form for injection, solubalized in PEG and castor oil.

17. Ketoconazole

18. It is widely used to treat systemic infection
It is widely used to treat systemic infection. It need low stomach PH for its absorption.
Antacid or drug that rise that PH of stomach will lower the conc of ketokonazole.
CYP 3A4 play significanr role I metabolism of ketoconazole (CYP3A4 inducer drug like phenitoin, carbamezepin and rifampin ) reduce the conc by 50%.
Ketokonazole is inhibitor of CYP3A4 cause increase in conc of triazolam.
Ketoconazole is weak inhibitor of CYP2C9 cause metabolism of warfarin and phenytoin.

20. Itraconazole

21. Itraconazole along with fluconazole is first triazole introduced into clinical use.
It require strongly acidic PH for its absorption.
Like ketoconazole it is extensively metabolised by CYP3A4.
Its oral bioavailability is greatly reduce by co administration of CYP3A4 inducer Phenytoin, carbamazepin, rifampin
This has significance because risk of development of rhabdomylosis followed by co administration of lovastatin and simvastatin

22. Fluconazole
Fluconazole is introduced at the same time that if itraconazole and ketoconazole.
It is equally bioavailable when given orally or IV.
It has two advantages over other antifungal agents that it can cross BBB and it is weak inhibitor of CYP 3A4.
It is strong inhibitor of CYP 2C9 by which it increase the conc of warfarin to extreamly harmful level.

23. Structure activity relationship
The basic structural requirement is weak basic imidazole ring or 1,2,4-triazole ring bonded by N-C linkage to rest structure.
At molecular level N3 of imidazole and N4 of triazole bind to the heme iron of enzyme CYP450 to inhibit activation of molecular oxygen.
Most potent azole possess 2 or 3 aromatic ring at least one of which is halogen substituted.
Nonpolar functional group at 2 or 2,4 yield effective azole compound.
The halogen atom that yield most potent compound is fluorine.
Sulfonic acid substitution yield potent drug.
Substitution at other position leads to inactive compound.
nonpolar functionality increase lipophilicity.

24. Allylamines
The group of agents generally known as allylamines strictly include nafitifine and terbianfine.
The benzyl group of butenafine to be bioisosteric with allyl group of nafitifin and terbinafine.
Tolnaftate a much older drug chemically it is thiocarbamatebut has same mechanism of action of allylamines.
It has limited spectrum of activity than azole, therefor employed in the treatment of skin and nail fungal infection.

25. All the drug act by inhibition of squalene epoxidase.
MOA
All the drug act by inhibition of squalene epoxidase.
It result in decrease in total fungal sterol content of cell membrane.
It change the physicochemical properties of membrane.
It cause malfunction of membrane embedded protein involved in nutrient transport and PH balance.
Secondly it result in formation of cell wall with squalene, which itself is toxic when present in high amount.

26. Nafitifin
First allylamines discovered and marketed subject to first pass metabolism to orally active. It is bioavailable only in topical preparation. Used in tinea infection.

27. Butenafine Used in treatment of topical dermatophyte infection.
It has wide spectrum of activity than tolnaftate.
Butenafine is effective against superficial C. albicans infection which is not treated by tolnaftate.

28. Terbinafin
it is available in oral and topical form. Used in the treatment of onychomycoses i.e. nail infection.
It is given orally, redistribute from plasma to nail bed.

29. Tolnaftate
Tolnaftate is a thioester of β-naphthol is fungicidal against dermatophytes that cause tinea infection.
It is available in 1% cream, powder, gel, solution to treat ringworm infection.
It is inhibitor of squalene epoxidases so it is classified under allylamines.
It is formulated into artificial fingernails to counteract the ringworm infection of nail bed.

30. Flucytosine
it is a powerful antifungal used in the treatment of systemic fungal infection as cryptococcus neoformus, candidia sp.
It is cytotoxic, is a prodrug which is metabolized to 5FU, which is converted to 5-fluorodeoxyuridine.
5-fluorodeoxyuridine is thymidylate synthase inhibitor that interfere both protein and RNA synthesis.
Resistance rapidly develops so it is given in combination of amphotericin B.
Now fluconazole is used in place of flucytosine.