33.6 Antifungal and Antiviral Therapeutics

Antifungal Therapeutics in Oral Medicine

Oral candidiasis is an opportunistic infection predominantly caused by the dimorphic fungal pathogen Candida albicans, presenting clinically as acute pseudomembranous candidiasis (thrush), acute or chronic erythematous candidiasis, denture-induced stomatitis, or angular cheilitis.

1. Nystatin Oral Suspension (Polyene)

• Mechanism of Action: A topical polyene macrolide. It binds irreversibly to ergosterol, the principal sterol in fungal cell membranes. This binding forms transmembrane channels and pores, allowing leakage of essential intracellular potassium ($K^+$), magnesium, and sugars, leading to fungal cell death.
• Dosing & Administration: 100,000 units/mL (1 mL) four times daily (qds) held in the mouth for several minutes after meals and then swallowed, continued for 7 to 14 days (or 48 hours after clinical resolution).
• Pharmacokinetics: Not absorbed across intact mucous membranes or the gastrointestinal tract. Acts topically with virtually no systemic drug interactions.

2. Miconazole Oral Gel (Imidazole)

• Mechanism of Action: Inhibits the fungal cytochrome P450 enzyme lanosterol 14-$\alpha$-demethylase. This halts the conversion of lanosterol to ergosterol, leading to defective fungal cell membranes and toxic methylated sterol accumulation.
• Dosing: 24 mg/mL gel; 2.5 mL applied topically to oral lesions with a clean finger four times daily (qds) after food, retained in the mouth for as long as possible.

[!CAUTION] CRITICAL MHRA BLACK-TRIANGLE ALERT — Miconazole and Warfarin: Even when applied topically to the oral cavity, miconazole undergoes significant systemic absorption across the oral mucosa and down the gastrointestinal tract. Systemic miconazole is an exceptionally potent inhibitor of hepatic CYP2C9, the primary enzyme responsible for clearing the biologically active S-enantiomer of Warfarin.

Co-administration halts warfarin clearance, leading to uncontrolled, catastrophic spikes in the International Normalized Ratio (INR > 10–18), which can cause fatal spontaneous internal, gastrointestinal, and intracranial haemorrhage. Miconazole oral gel is strictly contraindicated in any patient receiving Warfarin. For oral candidiasis in warfarin-anticoagulated patients, Nystatin oral suspension is the compulsory, safe first-line choice.

3. Fluconazole (Triazole)

• Mechanism of Action: Systemic triazole that selectively inhibits fungal lanosterol 14-$\alpha$-demethylase.
• Dosing: 50 mg capsules once daily for 7 to 14 days.
• Interactions: Inhibits CYP2C9 and CYP3A4. Like miconazole, it significantly enhances warfarin anticoagulation and prolongs sulfonylurea hypoglycaemic effects; it must be used with caution.

Antiviral Therapeutics in Dentistry

Viral infections of the oral mucosa are most frequently caused by Herpes Simplex Virus Type 1 (HSV-1), presenting as Primary Herpetic Gingivostomatitis (PHGS) or recurrent herpes labialis (cold sores), and Varicella-Zoster Virus (VZV), presenting as herpes zoster (shingles) affecting the trigeminal divisions.

                               Aciclovir Bioactivation Pathway
                                              │
                                              ▼
                                   Aciclovir (Prodrug)
                                              │
                    Viral Thymidine Kinase    │ (Selective to HSV/VZV-infected cells)
                                              ▼
                                Aciclovir Monophosphate
                                              │
                    Host Cellular Kinases     │ (Guanylate kinase, etc.)
                                              ▼
                                 Aciclovir Triphosphate
                                              │
                 ┌────────────────────────────┴────────────────────────────┐
                 ▼                                                         ▼
    Competitive Inhibition of                                 Obligate DNA Chain Termination
      Viral DNA Polymerase                                  (Lacks 3'-OH group for elongation)

• Pharmacodynamics of Aciclovir:
  • Aciclovir is a synthetic acyclic purine (guanosine) nucleoside analogue. It is a prodrug requiring a three-step intracellular phosphorylation cascade.
  • Initial Phosphorylation: Catalyzed exclusively by viral-specific thymidine kinase within infected cells. Host cell enzymes cannot phosphorylate native aciclovir, conferring high selectivity with minimal host toxicity.
  • Cellular Phosphorylation: Cellular kinases convert the monophosphate into aciclovir triphosphate.
  • Polymerase Inhibition: Aciclovir triphosphate competitively inhibits viral DNA polymerase. Because it lacks a $3'$-hydroxyl group on its acyclic side chain, its incorporation into replicating viral DNA halts further nucleotide addition, resulting in obligate viral DNA chain termination.
• Clinical Indications & Prescribing:
  • Primary Herpetic Gingivostomatitis: 200 mg tablets orally five times daily (spaced every 4 hours while awake) for 5 days in adults (paediatric suspension dosed according to age). Treatment must be initiated within the first 48 to 72 hours of onset to provide significant clinical benefit.
  • Herpes Zoster (Trigeminal Shingles): Requires higher dosing to overcome lower VZV thymidine kinase affinity: 800 mg orally five times daily for 7 days, commenced within 72 hours of rash onset to reduce the incidence of post-herpetic neuralgia.

Prescribing Safely and Treating the Cause

Two safety points dominate the antifungal section. Miconazole, although applied topically as an oral gel, is absorbed sufficiently to inhibit CYP2C9 and potentiates warfarin, producing a dangerous rise in INR; it also interacts with statins. Fluconazole shares that interaction and additionally interacts with phenytoin and with some antipsychotics, and it prolongs the QT interval. Both are contraindicated or used with great caution in patients taking those drugs, and the examinable safe choice for a patient on warfarin is nystatin suspension, which is not appreciably absorbed.

Equally examinable is that antifungal treatment alone fails if the predisposing factor remains. Denture-induced stomatitis requires denture hygiene, overnight removal and disinfection of the denture as well as treatment of the mucosa; angular cheilitis requires correction of the vertical dimension, treatment of intraoral candidosis, and consideration of haematinic deficiency; persistent or unexplained candidosis requires investigation for diabetes, immunosuppression, HIV infection, inhaled corticosteroid use without rinsing, or an underlying haematological disorder. Recurrent or unusually extensive candidosis in a previously healthy adult is a red flag rather than a simple prescribing problem.