Drug of the week (Ketoconazole) Series 9

General
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Ketoconazole

Mechanism of Action

As we all know, ketoconazole is an antifungal drug. But how it works is a question here .

It mainly inhibits the growth of ergosterol, which helps the structure and function of fungal cell membrane s.

Synthesis of ergoste rol

1. Formation ofHMG-CoA

  • Two molecules of acetyl-CoA combine to form HMG-CoA

  • Acetoacetic-CoA + Acetyl-CoA → HMG-CoA (3-hydroxy-3-methylglutaryl-CoA)

2. Formation of Mevalonate

  • HMG-CoA reductase converts HMG-CoA into mevalonate.

3. Formation of Isoprene Units

  • Mevalonate undergoes phosphorylation and decarboxylation to form : isopentenyl pyrophosphate (IPP).
  • IPP can isomerize to: Dimethylallyl pyrophosphate (DMAPP) These are the 5-carbon building blocks of sterols.

4. Formation of Farnesyl Pyrophosphate (FPP)

  • IPP and DMAPP condense to form Farnesyl pyrophosphate (FPP, 15 carbons)

5. Farnesyl pyrophosphate (FPP, 15 carbons)

  • Two molecules of FPP combine: 2 FPP → Squalene (30 carbons) (enzyme responsible is squalene synthase)

6. Formation of Lanosterol

  • Squalene epoxide cyclizes: Squalene epoxide → Lanosterol (First sterol in the pathway)

7. Conversion of Lanosterol to Ergosterol

  • Conversion of lanosterol to ergosterol by isomerization / reduction.

  • Enzyme responsible is Lanosterol 14-α-demethylase (CYP51)

Why was it necessary to know?

Ketoconazole binds to the heme iron of CYP51 (14-α-demethylase). Due to this, the 14α-methyl group cannot be removed from lanosterol. Ergosterol is not formed, which results in the deactivation of the cell membrane.

The fungal cell membrane becomes defective, less stable, and more permeable due to which essential cellular functions are distorted. It acts as fungistatic.

Conclusion: Ketoconazole It is a systemic fungistatic that inhibits the formation of ergosterol, which is a main component of cell wall formation.

Ketoconazole exerts its antifungal action by inhibiting:

  • Squalene epoxidase
  • DNA gyrase
  • Lanosterol 14-α-demethylase (CYP51)
  • Dihydrofolate reductase
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The pharmacophoric group responsible for binding to fungal CYP51 is:

  • Piperazine ring
  • Dioxolane ring
  • Imidazole ring
  • Chlorophenyl ring
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MBH/PS