Pharmacology of antifungal agents

Strangely, the raw untreated pharmacology does occasionally come up in this otherwise very pragmatic clinical-based exam. Antifungal pharmacology has come up as a broad theme in  Question 13from the first paper of 2010, albeit briefly. More disturbingly, in Question 3 from the first paper of 2004 the college demanded some significant discussion of fluconazole.

The topic is discussed in full by Russell E. Lewis in his 2011 article for the Mayo Clinic Proceedings ("Current Concepts in Antifungal Pharmacology"). However, my main source for this information was Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12^th Ed.

All molecule images are from Wikimedia Commons.

The drugs below are presented by class (in order of chronological appearance).

In brief summary:

• Polyenes like amphotericin and nystatin weaken fungal cell walls by binding to ergosterol. They are active against virtually all fungi and yeasts
• Azoles like fluconazole and voriconazole prevent the synthesis of ergosterol from lanosterol by inhibiting lanosterol 14 α-demethylase. Early generation azoles are only effective against C.albicans.
• Echinocandins like caspofungin inhibit fungal cell wall synthesis by blocking the synthesis of glucan by 1,3-β glucan synthase.
• Exotic drugs include pyrimidine analogues (flucytosine for cryptococci) and microtube inhibitors (eg. griseofulvin for skin-based dermatophytes)

Polyenes

Polyenes weaken fungal cell walls by binding to ergosterol. The cell wall becomes permeable, and the fungal cells swell with fluid and die. There are probably about 200 different polyenes with some sort of antifungal activity.

Amphotericin

• A heptaene macrolide
• Available in the (slightly) less toxic liposomal formulation (you are able to use higher doses, but you end up needing higher doses due to decreased efficacy)
• Active against virtually all fungi and yeasts
• Large volume of distribution, no reliance on renal clearance mechanisms
• Toxicity:
  • Nephrotoxicity
  • Hypokalemia
  • Fever and chills upon administration
  • Renal tubular acidosis
  • Hypochromic normocytic anemia

Nystatin

• Active against Candida species, and virtually nothing else
• Not available in a systemic preparation: systemic toxicity was prohibitive (even more toxic than amphotericin)

Microtubular inhibitors

Griseofulvin is the only member of this group. It is essentially colchicine for fungi: it binds to tubulin, impairing synthesis of microtubules and thus preventing the formation of the mitotic spindle.

 

Griseofulvin

• Active only against dermatophytes: Microsporum, Epidermophyton, and Trichophyton
• Binds to keratin, and lodges there permanently, offering long-term antifungal activity
• Usually a topical agent
• Metabolites are excreted in the urine, but the drug itself is almost completely insoluble in water
• Only notable toxicity is neuritis

Pyrimidine analogues

Flucytosine is the only real member of this group. Fungi deaminate  flucytosine to 5-fluorouracil which results in impaired DNA synthesis.

Flucytosine

• Active against cryptococcus and candida species
• Resistance develops readily when it is used on its own; it is usually combined with another agent
• Small volume of distribution; relies on renal clearance and is readily cleared by dialysis
• Toxicity:
  • Bone marrow suppression
  • Enterocolitis
  • Thrombocytopenia

Early-generation Azoles

Azoles in general inhibit 14-α-sterol demethylase, an enzyme involved in the synthesis of ergosterol for the fungal cell membrane. This results in the accumulation of 14-α-methylsterols, the presence of which disrupts the organisation and integrity of fungal cell walls and impairs membrane-bound enzymes.

Fluconazole

• Active against Candida albicans, but most non-albicans species are resistant
• Also active against Cryptococcus; no activity against Aspergillus
• Penetrates well into the CSF
• Interacts with many drugs: an inhibitor of CYP3A4 and CYP2C9
• Small volume of distribution; relies on renal clearance and is readily cleared by dialysis
• Toxicity:
  • LFT derangement
  • Alopecia
  • Drug interactions

Advantages

• Most species of Candida albicansare susceptible
• For susceptible organisms, fluconazole is at least equal (if not superior) to amphotericin.
• It has good oral bioavailability
• It has relatively low toxicity
• It seems to enhance the bactericidal activity of neutrophils

Disadvantages

• Most species of non-albicans Candida and most other fungi are not suceptible.
  • If one were called upon to mindlessly repeat rote-learned names of fluconazole-resistant yeasts, one would say C.kruzei, C.glabrata, and C.parapsilosis
• Fluconazole needs adjustment in renal failure
• It interacts with numerous other drugs by inhibiting the CYP450 system of metabolism
• It may cause LFT derangement and QT prolongation.

Evidence for (against) routine post-operative use

• Fluconazole prophylaxis for surgical patients does not reduce mortality.
• Fluconazole as a co-antibiotic in septic shock seems to reduce mortality according to one small trial.
• In 2008, a similar trial compared empirical fluconazole to placebo, and was terminated due to a lack of primary endpoint difference (i.e. placebo was equally effective)

Late-generation Azoles

The major generational change with azoles has been slower metabolism and less effect on human ergosterol synthesis.

Voriconazole

• Just like fluconazole, but with an extended spectrum.
• Covers Candida albicans and non-albicans species, as well as Cryptococcus and Aspergillus
• Highly protein bound and offering good tissue penetration
• Volume of distribution is massive; not dependent on renal excretion, and not dialysable.
• Also inhibits CYPs 2C19, 2C9, and CYP3A4 (thus, interacts with everything)
• Toxicities:
  • Long QT interval
  • Hallucinations
  • Psychosis
  • Drug interactions

Posaconazole

• Just like itraconazole, but with an extended spectrum.
• Antifungal spectrum is simialr to voriconazole; Candida albicans and non-albicans species, as well as Cryptococcus and Aspergillus.
• Active against agents of mucormycosis
• Like voriconazole, it is highly protein bound, not dependent on renal excretion, and not dialysable.
• Inhibits CYP3A4
• Toxicities:
  • Remarkably few! Generally well tolerated.

Echinocandins

These drugs inhibit fungal cell wall synthesis by blocking the synthesis of glucan by 1,3-β glucan synthase. This leads to increased permeability, osmotic bloat, and cell death.

Caspofungin

• Active against Candida albicans and non-albicans species
• Useless againt Cryptococcus, and sub-optimal against Aspergillus
• Highly protein bound, not dependent on renal excretion, and not dialysable.
• Minimal toxicity (perhaps LFT derangement)

Anidulafungin

• Active against Candida albicans and non-albicans species.
• Also useless againt Cryptococcus and sub-optimal against Aspergillus.
• Exotic clearance mechanism:  degraded slowly first by opening the hexapeptide ring and then proteolysis of peptide bonds. Thus, requires no dose adjustment in any sort of organ system failure, be it renal or hepatic. Its the cisatracurium of antifungals.
• Well tolerated, essentially without any systemic toxicity.