Azoles

Definitions & Key takeaways

Azoles are synthetic antifungals with broad spectrum activity against various fungal infections. Azoles bind to the ergosterol molecule in the fungal cell membrane and cause holes to form, which damages the cell membrane and eventually kills the fungus. Examples of azoles include drugs like clotrimazole, fluconazole, and itraconazole. Some of the side effects of azoles include nausea and vomiting, gynecomastia, and hepatotoxicity.

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Introduction0:00–0:39

The “azole” antifungals are a family of medications used to treat mycoses, or fungal infections. Mycoses can be superficial, like on the skin or hair, or develop into systemic infections in immunodeficient people.
Antifungals work either through fungistatic action, meaning that they inhibit fungal growth, or through fungicidal action, meaning they kill the fungi.
Azoles are divided into two major families of antifungals: imidazoles and triazoles. Most fungal cells have a tough outer cell wall and an inner cell membrane.

Pathology0:39–1:43

The cell membrane is mostly made of phospholipids with some sterol or modified steroid molecules mixed in. Humans have cholesterol, while fungi have ergosterol.
Both sterol molecules help keep the cell membrane stable at a wide range of temperatures. Now, the precursor to both molecules is lanosterol.
Fungi have a cytochrome p450 enzyme called fourteen-alpha-demethylase in their mitochondria and endoplasmic reticulums, which converts lanosterol to ergosterol.
Without ergosterol, the structure of the cell membrane will be disrupted. This will cause membrane-bound proteins, like ion channels, to stop working properly.
The membrane also becomes fragile, which eventually leads to inhibition of fungal growth. The azole antifungals include imidazoles, like clotrimazole, isoconazole, miconazole, butoconazole, fenticonazole, and ketoconazole; as well as triazoles like fluconazole, itraconazole and voriconazole.

Mechanism of action1:43–3:26

The only difference between the two groups is the imidazoles contain an imidazole ring, while triazoles contain triazole rings.
These medications work by inhibiting the fourteen-alpha-demethylase enzyme. However, they also inhibit human cytochrome P450 enzymes to a lesser degree.
Because of this, the vast majority of azoles come in topical form, and they’re commonly used to treat superficial mycoses.
Azole creams are used for treating dermatophytosis, or ringworm, which is a red, itchy, scaly, circular rash, on the feet, groin, or armpit area, caused by Trichophyton fungus.
These fungi are also responsible for the more common “athlete’s foot” or “jock itch”. Additionally, azoles can be used to treat tinea versicolor, caused by Malassezia globosa.
This disease is characterized by hypopigmentation or hyperpigmentation in patches of skin. Last but not least, topical azoles are also used to treat yeast infections, such as oral or vaginal candidiasis caused by Candida species.
Topical use of azole antifungals is generally considered to be safe, since absorption through the skin is minimal, and the most common side effect is skin irritation.
Now, certain azoles can also be taken perorally or through IV for the treatment of systemic mycosis; and orally or vaginally for candidiasis.

Indications3:26–4:57

But due to their effect on cytochrome p450, they are usually 2nd or 3rd line therapy after other medications like amphotericin B.
The azole with the narrowest spectrum of activity is ketoconazole, which is only used for candidiasis. Next, fluconazole is effective against candida species, as well as cryptococcus neoformans, so it’s often given as a prophylaxis medication for the prevention of cryptococcal meningitis in people with AIDS.
Wider spectrum azoles like itraconazole and voriconazole can also treat the previous fungi, but in addition, they are effective against Histoplasma and Coccidioides species.
Itraconazole is the first line treatment against blastomyces, while voriconazole is more effective against aspergillus. The broadest spectrum azoles like isavuconazole can be used to prevent a variety of fungal infection in the immunocompromised, or for the treatment of serious aspergillosis infections.
They are the only azoles that are effective against Mucor and Rhizopus species, which can cause mucormycosis, a serious infection of the sinuses that could spread to the surrounding bones, blood, and brain.

Side effects4:57–5:32

If used to treat systemic infections, the azoles are hepatotoxic meaning they damage the liver. They also inhibit cytochrome p450, which leads to the build up of medications like warfarin and phenytoin, which are metabolized by these enzymes.
These medications, particularly ketoconazole, also inhibit the synthesis of androgens in the adrenal gland and testes, leading to gynecomastia and infertility.
Finally, voriconazole can cause visual disturbances in rare cases. Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts!

Memory palace5:32–8:33

For the indications of topical azole creams, let’s have a soccer player that just got out of the shower. On his body are red rings for ring worms.
His feet are on fire representing athlete’s foot, but more worrying is that his jockstrap is also on fire, representing jock itch.
His soccer ball has patches of light and dark colors so it represents tinea versicolor, which causes hyper and hypopigmentation.
There are tiny candy mushrooms growing on top of the ball to represent Candida. Now for the systemic azoles, let’s have a street that’s narrow on one end, and wide at the other for the different spectrum of the azoles.
On the narrow end is a gate and the gatekeeper has a giant key for ketoconazole. The gatekeeper is sitting on a giant candy mushroom since candidiasis is the only indication for this drug today.
Out of all the azoles, ketoconazole has the most anti androgenic side effects, like gynecomastia, so let’s put a large bra on the gatekeeper.
Behind the gate is a man playing a magic flute for fluconazole. The problem is that his flute playing has raised an undead rooster, or cock, from a nearby crypt, for Cryptococcus.
The rooster is hungrily pecking at a brain, since it causes cryptococcal meningitis. Next, we have the wider spectrum azoles in the middle part of the street.
Here we have a duel between an italian plumber, for itraconazole, and a grizzled warrior, for voriconazole. The warrior has an eye patch to help you remember voriconazole causes visual disturbances.
The two are fighting over a rare cockatoo, for Coccidioides. The bird is sitting on a history book, for Histoplasma, and it could quote random historical fact.
Both medications are effective against these two species. The warrior is using a large asparagus, since it’s the preferred drug for Aspergillus, while the Italian is holding a stick of dynamite, since it’s the more effective drug for Blastomyces.
Finally, the widest part of the street is connected to an island for isavuconazole. Living here is a kid with cancer undergoing chemotherapy.
His only companion is a rhino covered in mucus, for Rhizopus and Mucor species. The only vegetation here is giant asparagus, for serious aspergillosis.
For side effects of systemic azoles, let’s put a large liver shaped rock for hepatotoxicity. It’s crushing a chrome colored cell, since it’s a cytochrome p450 inhibitor.
All right, as a quick recap. The azole antifungals can be split into imidazoles or triazoles based on their molecular structure.

Review8:33–9:10

They inhibit a cytochrome p450 enzyme called fourteen-alpha-demethylase, which is in charge of making ergosterol for the cell membrane.
Most azoles are used topically for superficial mycosis, and can cause mild skin irritation. Some, can be used for systemic mycosis, but they cause hepatotoxicity and inhibit cytochrome p450.
Ketoconazole in particular, has a strong anti androgenic effect. But wait, there's more: Here's a mind map with all of the mnemonics from this video.

Mind map9:10–9:22

Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers at the end.