Review on Antifungal Agents

 

Sangita P. Shirsat, Kaveri P. Tambe, Ganesh G. Dhakad, Paresh A. Patil, Ritik. S. Jain

Ahinas Institute of Pharmacy, Dondaicha 425408

*Corresponding Author E-mail: ritikbadera390@gmail.com

 

ABSTRACT:

There are so many type of daisies are founded because of ‘Fungal’ such daisies given in follow. also the treatment on this particular daisies with the help of ‘Anti-fungal’ drug or anti- fungal agent and anti-fungal medication as follows The four main classes of antifungal drugs are the polyenes, Azoles, allylamines and echinocandins. Clinically useful “older” agents include topical azole Formulations (for superficial yeast and dermatophyte Infections), first-generation triazoles (fluconazole and Itraconazole, for a range of superficial and invasive fungal Infections), amphotericin B formulations (for a broad range of Invasive fungal infections) and terbinafine (for dermatophyte Infections). Clinically important “newer” agents include members of the Echinocandin class (eg, caspofungin) and second-generation Triazoles (eg, voriconazole and posaconazole). Voriconazole and posaconazole have broad-spectrum activity Against yeasts and moulds, including Aspergillus species. Posaconazole is the only azole drug with activity against Zygomycete fungi. Caspofungin and the other echinocandins are effective in Treating Candida and Aspergillus infections. The azoles are relatively safe, but clinicians should be aware Of drug–drug interactions and adverse effects, including Visual disturbances (with voriconazole), elevations in liver Transaminase levels, and skin rashes. Caspofungin has Minimal adverse effects.  Combination antifungal therapy may be appropriate in Selected patients with invasive fungal infections, but is Empiric and driven by individual physician practice.Clinical needs for novel antifungal agents have altered

 

KEYWORDS: Anti-fungal agent, Types of anti-fungal agent, daisies create form Fungus.

 

 


INTRODUCTION:

An antifungal agent is a drug that selectively eliminates fungal pathogens from a host with minimal toxicity to the host. The development of antifungal agents has lagged behind that of antibacterial agents. This is a predictable consequence of the cellular structure of the organisms involved. Bacteria are prokaryotic and hence offer numerous structural and metabolic targets that differ from those of the human host. Fungi, in contrast, are eukaryotes, and consequently most agents toxic to fungi are also toxic to the host.

 

Furthermore, because fungi generally grow slowly and often in multicellular forms, they are more difficult to quantify than bacteria. This difficulty complicates experiments designed to evaluate the in vitro or in vivo properties of a potential antifungal agent. DespiteDespite these limitations, numerous advances have been made in developing new antifungal agents and in understanding the existing ones. This chapter summarizes the more common antifungal agents. Three groups of drugs are emphasized: the polyenes, the azoles, and one antimetabolite. Table 76-1 summarizes the most important antifungal agents and their most common uses. An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete’s foot, ringworm, candidiasis, serious systemic infections such as cryptococcal meningitis, and others. Steadily with the rise and fall of AIDS-related mycoses, And the change in spectrum of fatal disseminated fungal Infections that has accompanied changes in therapeutic Immunosuppressive therapies. The search for new Molecular targets for antifungals has generated con- Severable research using modern genomic approaches, So far without generating new agents for clinical use. Meanwhile, six new antifungal agents have just Reached, or are approaching, the clinic. Three are new Triazoles, with extremely broad antifungal spectra, and three are echinocandins, which inhibit synthesis of fun-Gal cell wall polysaccharides – a new mode of action. In Addition, the sordarins represent a novel class of agents That inhibit fungal protein synthesis. This review Describes the targets and mechanisms of action of all Classes of antifungal agents in clinical use or with Clinical potential.

 

Antifungal agents Mechanisms of action:

Clinical needs for novel antifungal agents have altered Steadily with the rise and fall of AIDS-related mycoses, And the change in spectrum of fatal disseminated fungal Infections that has accompanied changes in therapeutic Immunosuppressive therapies. The search for new Molecular targets for antifungals has generated con- Siderable research using modern genomic approaches, So far without generating new agents for clinical use. Meanwhile, six new antifungal agents have just Reached, or are approaching, the clinic. Three are new Triazoles, with extremely broad antifungal spectra, and Three are echinocandins, which inhibit synthesis of fun- Gal cell wall polysaccharides – a new mode of action. In Addition, the sordarins represent a novel class of agents That inhibit fungal protein synthesis. This review Describes the targets and mechanisms of action of all Classes of antifungal agents in clinical use or with Clinical potential.1,2 The earliest inhibitory agent specific to fungal species was griseofulvin. The precise mechanism of action of this compound is still unknown but the favoured explanation is that it interferes with microtubule assem- bly. The selective toxicity of griseofulvin for fungi is only moderate (liver toxicity is recognised as an occasional hazard) and its spectrum of action is restricted mainly to the dermatophyte fungi – causes of ringworm and athlete’s foot. However, other types of compound are known to interfere with microtubule assembly and function in pathogenic fungi, such as C. Informants. Effects on microtubules explained the antifungal activity of early compounds, such as benzimidazole. However, unlike the situation in fungicide research against plant pathogens, relatively little research attention seems to have been paid in recent years to microtubules as possible antifungal targets for clinical use3,4

 

Types of antifungal:-

There are two types of antifungals: local and systemic. Local antifungals are usually administered topically or vaginally, depending on the condition being treated. Systemic antifungals are administered orally or intravenously. of the clinically employed azole antifungals, only a handful are used systemically. These include ketoconazole, itraconazole, fluconazole, fosfluconazole, voriconazole, posaconazole, and isavuconazole. Examples of non-azole systemic antifungals include griseofulvin and terbinafine.5,6,7,8

 

Classification of Anti Fungal Drugs

These agents are categorized as:

Topical vs systemic (acting in the bloodstream)

 

Naturally occurring:

Antifungal Antibiotics (mostly produced by Actinomycetes, classified as ‘higher bacteria’). Examples:

Amphotericin B (AMB), a polyene antimycotic, Nystatin

 

Antifungals of fungal origin.

Example: Griseofulvin, a Heterocyclic Benzofuran discovered in 1939 from a type of Penicillium mold

 

Membrane permeability agents

β-Glucan synthesis blockers

Microtubule function inhibitors

Nucleic acid synthesis blockers

Azoles

Terbinafine

Polyenes

Echinocandins

Griseofulvin

Flucytosine

 

Synthetic Agents:

Azoles

Imidazoles: Clotrimazole, Econazole, Miconazole, Oxiconazole, Ketoconazole

Triazoles: Fluconazole, Itraconazole, Voriconazole

Anti-metabolites: Flucytosine (5-FC)

Allylamine: Terbinafine (Lamisil)

 

Newest antifungals:

Echinocandins

Amphotericin B (AMB)

 

It is derived from cultures of Streptomyces Nodosus and is a very large (‘macrolide’) molecule belonging to the polyene group of antifungal agents. 7,8

 

Mechanism of Action:

The molecule has a high affinity for ergosterol present in the fungal cell membrane and combines with it in such a way to make a ‘micropore.’ The basic mechanism of the drug is to disrupt the cell membrane. It is fungicidal at high and fungistatic at low concentrations.

 

Important: Amphotericin is not active against human and bacterial sterols as the predominant sterol found in bacteria and humans are cholesterol.9,10

 

Indication:

Amphotericin B is active against a wide range of yeasts and fungi: Candida Albicans, Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioidesimmitis, Torulopsis, Rhodotorula, Aspergillus, and Sporothrix, etc. It does not have any anti-bacterial property. It is the most effective drug for resistant cases of kala-azar and mucocutaneous leishmaniasis.

 

Pharmacokinetics

Amphotericin B is not absorbed orally; that is why it is administered intravenously and rarely intrathecally (for fungal meningitis). Amphotericin B has a half-life of 15 days. The excretion through urine requires a long time, although excretion occurs slowly both in the urine and bile. Penetration into the CNS is poor; about 60% of AMB is metabolized by the liver.

 

Side Effects:

Nephrotoxicity is the most important side effect. Acute reactions may be triggered by symptoms consisting of chills, fever, aches, and pain, nausea, vomiting, and dyspnea lasting for one hour, probably due to the release of cytokines. To reduce the side effects and improve the tolerability of infusion, formulations of lipid complex, colloidal dispersion, and small unilamellar vesicles have been introduced.

 

Important:

Irreversible renal toxicity can result in prolonged administration (more than 4g cumulative dose).

 

Am Bisome (liposome-based), Amphotec (a complex of amphotericin B and cholesteryl sulfate), Abelcet (consists of amphotericin B complexed with two phospholipids) are the lipidic formulations available to reduce the renal toxicity of the conventional amphotericin B; however, these are very costly.11,12

 

Nystatin

It is also called fungicidin with a similar structure to that of Amphotericin B. It is derived from Streptomyces noursei and has high systemic toxicity, hence, it is commonly used as a topical agent.

 

Mechanism of Action:

The molecule also has a high affinity for ergosterol present in fungal cell membranes and it disrupts the cell membrane.

 

Indication:

It is used against monilial vaginitis, corneal, conjunctival and cutaneous candidiasis in the form of an ointment but is ineffective in dermatophytosis. Nystatin can be added to tetracycline to prevent monilial overgrowth caused by the destruction of the bacterial microflora of the intestine during tetracycline therapy

 

Pharmacokinetics:

It is given in the form of vaginal tablets and pastilles for local application only. Nystatin will treat gut candidiasis and is used in a ‘swish and swallow’ routine for oral candidiasis.

 

Side Effects:

The common side effects associated are itching, irritation and burning. Rarely, nystatin can cause diarrhea and nausea.12,13

 

Griseofulvin

Griseofulvin is a narrow-spectrum antifungal agent isolated from cultures of Penicillium griseofulvum, and is active against dermatophytes, including Epidermophyton, Trichophyton, Microsporum, but not against fungi causing deep mycosis.

 

Mechanism of Action:

The mechanism of action of griseofulvin is not clear. It is thought to interfere with mitosis during the fungal hyphae formation. It also causes abnormal metaphase in the division of cells by acting in a way that the daughter nuclei fail to move apart, or move only a short distance during division. It does not inhibit polymerization of tubulin, but binds to polymerized microtubules and disorients them.

 

Pharmacokinetics:

The absorption of the drug is improved by taking it with a fatty meal and by microfining the drug particles. Griseofulvin gets deposited in keratin forming cells of skin, hair, and nails; concentrating in tinea infected cells because it is fungistatic and not cidal. The newly formed keratin is not affected by the fungus.

 

Side Effects:

Effects with griseofulvin use are infrequent, but the drug causes gastrointestinal upsets, headache, and photosensitivity. Allergic reactions (rashes and fever) may occur. The drug is contraindicated in pregnant women.14,15

 

Azoles and Triazole Agents:

These are synthetically derived antifungal agents, both used orally and topically. They are used for treating a large number of infections caused by dermatophytes, Candida, other fungi involved in deep mycosis, Nocardia, some gram-positive and anaerobic bacteria, e.g., Staphylococcus aureus, Enterococcus faecalis, Bacteroides fragilis and Leishmania.

 

Mechanism of Action:

The azoles constitute imidazoles and triazoles subgroups and act by inhibiting CYP P450 14 α- demethylase enzyme in fungi which causes the conversion of lanosterol to ergosterol. Other P450s in sterol biosynthesis may also be affected.

 

The nitrogen of the azole ring forms a bond with the heme iron of the fungal P450 preventing substrate and oxygen binding, leading to changes in shape and physical properties of the fungi membrane, leading to permeability and fluidity changes. They also inhibit the transformation of yeast cells into hyphae, the invasive and the pathogenic form of the parasite.

 

Ketoconazole (KTZ)

It is available in the form of a cream or in shampoos at a strength of 1 or 2 % for treating tinea pedis, tinea corporis, tinea cruris, and cutaneous candidiasis. It can also be administered orally.

 

Pharmacokinetics:

The oral absorption of KTZ is improved by gastric acidity because it is more soluble at lower pH. Hepatic metabolism is extensive for the drug; metabolites are excreted through urine and feces. The half-life is short and varies from 1.5-6 hours.

 

Side Effects:

The drug causes inhibition of adrenocortical steroid and testosterone synthesis with high doses, leading to gynecomastia, loss of hair and libido in male patients. In females, menstrual irregularities may occur. Hepatotoxicity is also a side effect but is rarely fatal.16,17

 

Clotrimazole

The topical application of the drug is useful in treating tinea pedis, ringworms, otomycosis, and oral/cutaneous vaginal candidiasis. It is the preferred drug for treating vaginitis because of a long residual effect after a once-daily application. The drug is also combined sometimes with glucocorticoids, which are anti-inflammatory in nature.

 

Side Effects:

The drug is well tolerated; however, causes a local irritation with a stinging and burning sensation occurring in some. No systemic toxicity is seen after topical use.

 

Fluconazole

It is marketed in the form of a tablet or suspension to treat yeast infections of the vagina, mouth, throat, esophagus, abdomen, and lungs.

 

Important: it is a drug of choice for esophageal and invasive candidiasis and coccidioidomycoses.

 

Pharmacokinetics:

Fluconazole is 94 % absorbed; oral bioavailability is unaffected by food or gastric pH. It is primarily excreted unchanged in the urine with a t1/2 of 25—30 hours.

 

Side Effects:

Prominent side effects are nausea, vomiting, abdominal pain, rash, and headache. Elevation of hepatic transaminase has been noted in AIDS patients. As compared to other azoles, it has the least effect on liver microsomal enzymes.

Voriconazole

The drug is present in the form of oral suspension, tablets or parenteral injection. It is used to treat serious fungal infections and may be used in patients who have not responded to other antifungal agents.

 

Rashes, visual disturbances, QT prolongation and an acute reaction on the IV injection are the significant adverse effects.

 

Flucytosine (5-FC)

It is an antifungal drug, which acts by blocking the pyrimidine and DNA synthesis in fungi. It is converted to its active metabolite (5-FU) by fungal cells.

 

The pathway of conversion is below:

Flucytosine → (5-FC) →5-Fluorouracil (5-FU) → 5-fluorodeoxyuridine monophosphate

 

No toxicity in humans due to 5-FC as human cells can’t convert 5-FC to 5-FU.

 

It is not used as a single agent for fungal infections but is used with other antifungal agents such as amphotericin B (cryptococcal meningitis) and itraconazole (chromoblastomycosis).

 

Side-effects are reversible bone marrow depression, liver dysfunction, and alopecia.

 

Terbinafine

It is fungicidal and is given in shorter course therapy and the relapse rates are low. It is particularly useful against Dermatophytes, especially nail infections, along with the treatment of candida infection. It is available for oral, as well as topical use.

 

Mechanism of Action:

It acts as a non-competitive inhibitor of ‘squalene epoxidase’, an enzyme in ergosterol biosynthesis by fungi. Accumulation of toxic squalene within fungal cells leads to the fungicidal action.

 

Pharmacokinetics:

Approximately 75 % of oral terbinafine is absorbed. The drug is lipophilic and is widely distributed in the body, strongly plasma protein bound and concentrated in sebum, stratum corneum and nail plates. Elimination t1/2 of 11—16 hours is prolonged to 10 days after the repeated dosing schedule.

 

Side Effects:

The common side effects are gastric upset, rash and taste disturbance. Some cases of hepatic dysfunction, hematological disorder, and severe cutaneous reaction also occur.

 

Echinocandins:

These are recently discovered antifungal drugs. Examples of drugs in this class are caspofungin and dulafungin.

 

They act by blocking the synthesis of β (1—3)-glucan in fungus.

 

They are active against Candida spp., Aspergillus spp., pneumocystis carinii; however, they are not active against Cryptococcus neoformans.

 

They are poorly absorbed from the GI tract, thus they are only available as intravenous formation.

They are well tolerated and have only minor gastrointestinal side-effects such as nausea and vomiting. Other side-effects are headache and flushing.17,18

 

Class of Antifungal:-

Polyenes:-

A polyene is a molecule with multiple conjugated double bonds. A polyene antifungal is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungals amphiphilic. The polyene antimycotics bind with sterols in the fungal cell membrane, principally ergosterol. This changes the transition temperature (Tg) of the cell membrane, thereby placing the membrane in a less fluid, more crystalline state. (In ordinary circumstances membrane sterols increase the packing of the phospholipid bilayer making the plasma membrane more dense.)18 As a result, the cell’s contents including monovalent ions (K+, Na+, H+, and Cl−) and small organic molecules leak, which is regarded one of the primary ways a cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. However, at therapeutic doses, some amphotericin B may bind to animal membrane cholesterol, increasing the risk of human toxicity. Amphotericin B is nephrotoxic when given intravenously. As a polyene’s hydrophobic chain is shortened, its sterol binding activity is increased. Therefore, further reduction of the hydrophobic chain may result in it binding to cholesterol, making it toxic to animals.19

 

Amphotericin B:- various formulations are available to treat aspergillosis, blastomycosis, cryptococcosis, histoplasmosis (off-label), mucosal or invasive Candida infections, and coccidioidomycosis

·         Candicidin

·         Filipin – 35 carbons, binds to cholesterol (toxic)

·         Hamycin

·         Natamycin – 33 carbons, binds well to ergosterol

·         Nystatin:- Candida infections of the skin and mouth

·         Rimocidin

Azoles:

Imidazole

Bifonazole

Butoconazole

Clotrimazole

Econazole

Fenticonazole

Isoconazole

Ketoconazole

Luliconazole

Miconazole

Omoconazole

Oxiconazole

Sertaconazole

Siliconizes

Tioconazole

 

Triazoles:

The azoles are commonly used for subacute clinical presentations, chronic suppression, and meningitis (especially fluconazole), with amphotericin B often reserved for the initial management of fulminant infections.

Albaconazole

Efinaconazole

Epoxiconazole

Fluconazole

Isavuconazole

Itraconazole

Posaconazole

Propiconazole

Ravuconazole

Terconazole

Voriconazole

 

Thiazoles:

Abafungin

 

Allylamines

Allylaminesinhibit squalene epoxidase, another enzyme required for ergosterol synthesis. Examples include butenafine, naftifine, and terbinafine. Like the azole antifungals, allylamines interfere with an enzyme that’s involved in the creation of the fungal cell membrane. One example of an allylamine is terbinafine, which is often used to treat fungal infections of the skin. 20,22

 

Echinocandins:

Echinocandins inhibit the creation of glucan in the fungal cell wall by inhibiting 1,3-Beta-glucan synthase: Echinocandins are a newer type of antifungal drug. They inhibit an enzyme that’s involved in the making of the fungal cell wall.

Anidulafungin: mucosal and invasive Candida infections

Caspofungin: mucosal and invasive Candida infections, aspergillosis

Micafungin: mucosal and invasive Candida infections

 

Echinocandins are administered intravenously, particularly for the treatment of resistant Candida species.

 

Triterpenoids

Ibrexafungerp

 

Pharmacology of Systemic Antifungal Agents:-

Traditionally, many invasive fungal infections were associated with a poor prognosis, because effective ther- Apeutic options were limited. The recent development of new antifungal agents has significantly contributed to the successful treatment of fungal diseases. These drugs offer novel mechanisms of action and expanded Spectrums of activity over traditional treatment options. However, with these new agents comes the need for Increased awareness of the potential interactions and toxicities associated with these drugs. Therefore, an Understanding of the pharmacokinetic and pharmacodynamics properties of the classes of antifungal compounds Is vital for the effective management of invasive fungal infections. This review provides a summary of the Pharmacologic principles involved in treatment of fungal disease.21,22,23

 

Antifungal medicines:

Antifungal medicines are used to treat fungal infections, which most commonly affect your skin, hair and nails. YouYou can get some antifungal medicines from a pharmacy without needing a GP prescription.

 

Infections antifungals can treat:

Fungal infections commonly treated with antifungals include:

Ringworm

Athlete’s foot

Fungal nail infection

Vaginal thrush

Some types of severe dandruff

Some fungal infections can grow inside the body and need to be treated in hospital.

 

Examples include:

Aspergillosis, which affects the lungs

Fungal meningitis, which affects the brain

 

You’re more at risk of getting one of these more serious fungal infections if you have a weakened immune system–for example, if you’re taking medicines to suppress your immune system.

 

Types of antifungal medicines:

You can get antifungal medicines as:

A cream, gel, ointment or spray

A capsule, tablet or liquid

An injection

A pessary: a small and soft tablet you put inside the vagina

 

Common names for antifungal medicines include:

Clotrimazole

Econazole

Miconazole

Terbinafine

Fluconazole

Ketoconazole

Amphotericin

 

Antifungal medicines for children:

Some antifungal medicines can be used to treat children and babies – for example, miconazole oral gel can be used for oral thrush in babies. But different doses are usually needed for children of different ages. Speak to a pharmacist or GP for more advice.24,25

 

Side effects of antifungal medicines:-

Antifungal medicines may cause side effects. These are usually mild and do not last long. TheyThey can include:

Itching or burning

Redness

Feeling sick

Tummy (abdominal) pain

Diarrhoea

A rash

 

Occasionally, antifungal medicines may cause a more severe reaction, such as:

An allergic reaction – your face, neck or tongue may swell and you may have difficulty breathing

A severe skin reaction – such as peeling or blistering skin

Liver damage (very rarely) – you may have loss of appetite, vomiting, nausea, jaundice, dark pee or pale poo, tiredness or weakness. Stop using the medicine if you have these severe side effects, and see a GP or pharmacist to find an alternative.26,27,28

 

Overview of Fungal Infections

Fungi are non-motile eukaryotic single-celled or multinucleate organisms formerly classified as plants that lack chlorophyll and cannot perform photosynthesis, hence parasitic in nature. Thousands of species have been identified, out of which some are the cause for local or systemic fungal infection (mycoses) in patients with AIDS, or humans whose immune systems are compromised by drug therapy or other means. This may cause serious, sometimes life-threatening infections.

 

Introduction into the host’s body is mainly through wounds or inhalation into the lungs and nasal passages. Diseases caused by fungi are mainly due to the Microsporum, Trichophyton or Epidermophyton genera.

 

Various Types of Fungal Infections

Athlete’s Foot

Tinea pedis (Athlete’s foot): The infection is caused by Trichophyton mentagrophytes and Trichophyton rubrum. It is often located between the toes, with the space between the fourth and fifth digits most commonly afflicted; however, it can spread if not treated in time.

 

Ringworm Infection

Tinea corporis (ringworm): The infection is caused by Microsporum canis, Trichophyton mentagrophytes via direct skin contact with an infected individual, or by using the personal care products of the affected individual.

 

Brazilian Blastomycosis

It is caused by Paracoccidioides brasiliensis and is a systemic infection involving mucous membranes, lymph nodes, bone and lungs and prevalent in South America. Amphotericin B, Itraconazole or ketoconazole are effective in treating the infection.

 

Candidiasis:

Candidiasis is caused by yeast Candida Albicans. It is commonly present as a saprophyte in the GI tract and genitourinary system of human beings. However, it can infect locally or systemically and cause serious systemic infections with multi-system organ failure.

 

Mucormycosis:

The infection is caused by the genera Mucor, Rhizopus, Absidia, and Cunninghamella with the affected areas being sinuses, eyes, blood, and brain.

 

CONCLUSION: -

There are so many type of daisies are create form fungal that type daisies are also mansion here and the which kind of particular anti-fungal agent are use on this daisies are given, Antifungal medicines are used to treat fungal infections, which most commonly affect your skin, hair and nails. You can get some antifungal medicines from a pharmacy without needing a GP prescription. Antifungal medicines work by either: Killing the fungus Preventing the fungus from growing. And there are so many use of antifungal agents in the formation of medication, and antifungal have so many type for each antifungal disease give proper treatment. Amphotericin B is the mainstay antifungal agent for treatment of life-threatening mycoses and for most other mycoses, with the possible exception of the dermatophytes. Some regular problem are given in this particular details and what kind of anti-fungal medication are use on that particular problems are also mansion here so all particular type information about the antifungal are mentioned in this review paper.

 

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Received on 16.10.2021         Modified on 28.10.2021

Accepted on 10.11.2021       ©A&V Publications All right reserved

Res. J. Pharmacology and Pharmacodynamics.2021;13(4):147-154.

DOI: 10.52711/2321-5836.2021.00028