Classification by origin and chemical structure
The classification of antifungal agents is based on two key principles: their method of production (origin) and the features of their chemical structure. There are three main categories of drugs:
- Antibiotics (natural substances). This group includes polyene antibiotics such as amphotericin B, nystatin, levorin, and natamycin. Griseofulvin is also classified separately as an independent natural agent.
- Semi-synthetic agents. This category is represented by the echinocandin class, the main representative of which is caspofungin.
- Synthetic agents. This is the most extensive group, which is grouped in detail by chemical structure:
- Antimetabolites: flucytosine.
- Imidazole derivatives: ketoconazole, clotrimazole, miconazole, econazole.
- Triazole derivatives: fluconazole, itraconazole, voriconazole.
- N-methylnaphthalene derivatives (allylamines): terbinafine, naftifine.
- Benzylamine derivatives: butenafine.
- Morpholine derivatives: amorolfine.
- Undecylenic acid derivatives: undecin, zincundan, mycoseptin.
- Bis-quaternary ammonium salts: dequalinium chloride.
- Iodine preparations: potassium iodide.
Clinical classification of mycoses and choice of therapy
All known fungal diseases are divided into three main groups. It is the clinical form of mycosis that determines the final choice of pharmacotherapy.
1. Systemic (deep) mycoses This group is characterized by severe visceral damage to internal organs, as well as involvement of the central nervous system (CNS). Typical nosologies include aspergillosis, coccidioidomycosis, cryptococcosis, histoplasmosis, and blastomycosis.
- Drugs of choice: among antibiotics, amphotericin B is used; among antimetabolites, flucytosine; among synthetic agents (azoles and others), fluconazole, itraconazole, voriconazole, ketoconazole, and miconazole are prescribed.
2. Dermatomycoses (superficial mycoses) The etiology of these diseases is associated with dermatophyte fungi. The infection is localized exclusively on the skin and skin appendages (nails and hair are affected). Typical nosologies include trichophytosis, microsporum infection, and epidermophytosis.
- Drugs of choice: griseofulvin and terbinafine are used for systemic and local action. As local agents, azoles (clotrimazole, econazole, miconazole, ketoconazole), as well as allylamines and other drugs (naftifine, butenafine) are used.
3. Candidiasis Diseases of this group are caused by yeast-like fungi belonging to the genus Candida. The most common representative and pathogen is Candida albicans. The specific feature of the course of candidiasis is that it can occur in both superficial and systemic forms.
- Superficial forms affect the mucous membranes of the gastrointestinal tract, bronchi, genital organs, and the skin.
- Systemic forms involve internal organs (lungs, urogenital system, CNS, joints), and in the most severe cases, generalization of the process occurs with the development of septicemia.
- Drugs of choice: polyene antibiotics (nystatin, levorin, amphotericin B) and synthetic azoles (fluconazole, clotrimazole).
Briefly: answers to topical questions
What is the mechanism of action of polyene antibiotics?
The mechanism of action of polyene antibiotics involves disrupting the permeability of the fungal cytoplasmic membrane. The lipophilic part of the molecule binds to pre-formed ergosterol in the membrane, forming a channel (pore) lined by the hydrophilic parts of the antibiotic. Through the formed pores, ions ($K^+$, $Mg^{2+}$) and low-molecular-weight substances exit the cell. The loss of intracellular contents leads to the death of the fungal cell, providing a fungicidal effect. Drugs in this group do not inhibit sterol synthesis, but interact directly with ergosterol molecules.
What is the mechanism of action of azole derivatives (imidazoles and triazoles)?
The mechanism of action of azole derivatives is based on the inhibition of ergosterol biosynthesis at the stage of lanosterol conversion. The drugs bind to the iron atom in the heme and inhibit the 14-$\alpha$-demethylase enzyme, which is dependent on the cytochrome P-450 system. This leads to a blockade of ergosterol synthesis and the accumulation of abnormal precursors (lanosterol and 14$\alpha$-methylsterols) inside the cell. The accumulated methylsterols disrupt the tight packing of phospholipid acyl chains, causing membrane destabilization, dysfunction of membrane-bound enzymes, and fungal cell death.
Which drugs belong to the echinocandin class?
The echinocandin class includes semi-synthetic amphiphilic lipopeptides. This group includes the following drugs:
- Caspofungin (Caspofungin) — used to treat esophageal candidiasis and for prophylaxis in neutropenia.
- Micafungin (Micafungin) is a semisynthetic derivative of the fungus Coleophoma empedri.
- Anidulafungin (Anidulafungin) is a semisynthetic derivative of the fungus Aspergillus nidulans.
What are the main side effects caused by amphotericin B?
Amphotericin B has high toxicity and causes a number of severe side effects.
- Acute reactions — "cytokine storm" with chills, fever, and hypotension within the first hours of infusion.
- Nephrotoxicity — renal tissue ischemia, hypokalemia, hypomagnesemia, acidosis, and cylindruria.
- Hematotoxicity — thrombocytopenia and anemia due to decreased erythropoietin synthesis.
- Neurotoxicity — headache, tremor, seizures, polyneuropathy, paresis, and visual disturbances.
- Other reactions — dyspepsia, allergy, and injection-site thrombophlebitis.
How does fluconazole cross the blood-brain barrier?
Fluconazole freely penetrates all body fluids, including cerebrospinal fluid (CSF), sputum, urine, and saliva. The drug can be administered orally and intravenously, is well absorbed when taken orally, has a bioavailability of about 100%, its absorption does not depend on gastric juice pH, and it is excreted primarily by the kidneys.
To remember synthetic azoles: drugs ending in "-conazole" are divided into imidazole derivatives (ketoconazole, clotrimazole, miconazole) and triazole derivatives (fluconazole, itraconazole, voriconazole).
Class and exam questions
What groups are mycoses divided into in clinical practice?
There are three main groups that determine the choice of therapy: systemic (deep) mycoses, dermatomycoses (superficial), and candidiasis.
Which drugs belong to polyene antibiotics?
This group of natural substances includes amphotericin B, nystatin, levorin, and natamycin.
What is used to treat systemic (deep) mycoses?
Drugs of choice include amphotericin B, flucytosine, and a number of synthetic azoles such as fluconazole, itraconazole, voriconazole, ketoconazole, and miconazole.
Which organs are affected in superficial forms of candidiasis?
In superficial candidiasis, the pathological process involves the skin and mucous membranes of the gastrointestinal tract, bronchi, and genitalia.
What else to study on this topic
- Mechanism of action of various groups of antifungal agents
- Spectrum of antimicrobial activity of specific drugs
- Toxicity and side effects of antimycotics
- Pharmacokinetic features of amphotericin B and fluconazole
- Generalized forms of candidiasis (septicemia)
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