Azole Drugs

Azole antifungal drugs are a class of drugs that represent a wide range of antifungal medications. Azoles have been in use as topical antifungals for decades. Recently, several azole drugs have received accelerated regulatory reviews. One such drug is an orally administered azole called voriconazole, which is currently in phase III clinical trials for the treatment of invasive Candida infections that are refractory to therapy with other antifungal agents. Voriconazole has shown good activity against a diverse group of fungi, and it exhibits modest pharmacokinetic properties. The following article consists of more details on the Azole antifungal drugs.

Azoles

Azole antifungal drugs are a class of drugs that represent a wide range of antifungal medications. Azoles have been in use as topical antifungals for decades.

Effects of Azoles

• Azoles are frequently used for systemic mycoses
• They act by inhibiting the action of sterols in the fungal cell membrane, thus decreasing sterol synthesis
• Azoles’ mechanism of action includes inhibiting fungal ergosterol synthesis and production and decreasing the synthesis of ergosterol-derived substances in certain fungi

Classification of Azoles

Azoles are classified as oil-soluble (e.g., fluconazole, itraconazole, ketoconazole) or water-soluble (e.g., miconazole, clotrimazole). Potency and spectrum of action vary according to the structure of the azole. Azoles are also used topically and generally have a lower incidence of side effects than when they are taken orally. Azole antifungal drugs are classified according to the five-membered heterocyclic ring that they possess.

The major classes include imidazoles, triazoles, and pentazoles. Each member of these classes has been used as a topical antifungal for many years.

• Imidazoles

Imidazoles are employed in a wide range of topical antifungal formulations. Formulations include creams and lotions (terbinafine, naftifine), shampoos (miconazole), and toenail preparations (ciclopirox, econazole). Imidazoles are examples of drugs that have been used for many years as topical antifungals.

• Triazoles

Triazoles are used in topical antifungal preparations for the treatment of a wide range of fungal infections. Examples include clotrimazole (Lotrimin), miconazole, ketoconazole, and fluconazole. The topical application of triazoles is an effective therapy for various skin fungal infections.

Two subclasses are represented. The most widely used class is the imidazoles. These drugs have a polar side chain that is critically important for their activity against fungi. The second class is the triazoles, which contain a five-membered heterocyclic ring.

• Pentazoles

Pentazoles are also used in topical antifungal formulations. These drugs are largely used intravaginally in the treatment of vaginal yeast infections, but they have also been employed in dermatological formulations. Examples include: clotrimazole, econazole, miconazole, and tioconazole

Mechanism of Action

1. Azole antifungal drugs inhibit ergosterol synthesis. 
2. However, certain azoles (e.g., ketoconazole) also modulate ergosterol-dependent fungal hormone production. 
3. They do not inhibit the fungal cell wall synthesis directly but interrupt the cascade of reactions that leads to ergosterol production in fungi. 
4. Unlike many other antifungals, such as amphotericin B or nystatin, azoles do not appear to interfere with hyphal growth or normal cell structure and transport processes.
5. Ergosterol inhibition by azoles is the main mechanism of azole antifungal drugs.
6. Ketoconazole and other imidazoles inhibit fungal and human cytochrome P450-dependent enzymes involved in steroidogenesis. However, their other mechanisms of antifungal activity are not fully understood.

How do Azole Antifungal Drugs Get in the Blood?

1. Azoles are transported into the blood mostly by carrier proteins and plasma proteins to a lesser extent. 
2. Azoles build up in tissues, and tissues can also be a source of infection after local use. Thus, dose optimisation is necessary for the best outcomes.
3. Azole drugs have been found in human breast milk, and there is some evidence that these drugs can be transferred from mother to infant.

Potential Side Effects of Azole Antifungal Drugs

Azoles, especially imidazoles, may cause significant interactions with other drugs. 

• They may also interfere with blood clotting
• Potential systemic side effects include hepatotoxicity, tendon toxicity, and hepatitis
• Because of their antifungal activity, they can also cause fungemia and methemoglobinemia
• Conversely, azoles are non-toxic to humans when used topically as topical antifungals
• Like all antifungals, azoles are potentially toxic in overdose

Ergosterol Inhibition

1. The azole antifungals are all structurally related to each other, and they are all inhibitors of ergosterol formation.
2. Ergosterol is a critical component of the fungal cell membrane. The azoles inhibit the conversion of lanosterol to ergosterol, which results in accumulation within the cell wall.
3. This cellular accumulation is responsible for the antifungal effects of the azoles.
4. The azoles bind to lanosterol (the parent compound) in the biosynthetic pathway and sterically hinder the transformation of lanosterol into ergosterol.
5. Azoles also induce other enzymes that catalyze Stereochemistry: 2-5 of the side chain, which inhibits the synthesis of ergosterol. The result is inhibition of fungal growth. This type of inhibition is called a ‘rapid-binding site’ because it occurs very rapidly and is irreversible.

Conclusion

Azoles act on ergosterol synthesis, decrease the fungal cell wall deposition and decrease ergosterol synthesis by inhibiting various enzymes. Azole antifungal drugs are usually lipid-soluble, have a broad spectrum of antifungal activity, and have relatively good potency. In addition, their activity is additive, which may be important in the treatment of fungal infections. However, their toxicity profile is also substantial, and some azoles can interact with other medications. These points should be considered when they are used as monotherapy or as part of combination therapies. The pharmacodynamic profile of voriconazole can be compared to that of fluconazole, and it has milder side effects.