11.2 Antifungal, Antiviral & Antiparasitic Therapeutics

11.2 Antifungal, Antiviral & Antiparasitic Therapeutics

Independent Study Guide Notice: Independent study guide by OpenExamPrep. This educational resource is developed independently by OpenExamPrep and is not sponsored, endorsed, or affiliated with the National Board of Podiatric Medical Examiners (NBPME) or Meazure Learning.

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Overview of Fungal & Viral Targets in Podiatry

Cutaneous fungal infections (tinea pedis) and onychomycosis represent the most prevalent dermatologic complaints encountered in podiatric practice, affecting up to 10% of the general population and over 30% of diabetic patients. The primary etiologic agents are dermatophytes—predominantly Trichophyton rubrum ($>80\%$), Trichophyton mentagrophytes, and Epidermophyton floccosum—followed by non-dermatophyte molds (Scopulariopsis brevicaulis, Fusarium) and yeasts (Candida albicans).

Unlike human eukaryotic cells that utilize cholesterol as the primary membrane sterol, fungal cell membranes utilize ergosterol. Exploiting the unique enzymes in the fungal ergosterol biosynthesis pathway provides high therapeutic selectivity.

$\text{Squalene} \xrightarrow[\textbf{Inhibited by Terbinafine}]{\text{Squalene Epoxidase}} \text{Lanosterol} \xrightarrow[\textbf{Inhibited by Azoles}]{\text{14}\alpha\text{-Demethylase (CYP51)}} \text{Ergosterol} \xrightarrow[\textbf{Targeted by Polyenes}]{\text{Direct Binding}} \text{Membrane Pores}$

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Ergosterol Synthesis Inhibitors: Allylamines & Azoles

1. Allylamines: Terbinafine (Lamisil)

Terbinafine is a synthetic allylamine and represents the oral drug of choice (first-line therapy) for dermatophyte onychomycosis.

• Mechanism of Action: Terbinafine is a non-competitive, reversible inhibitor of Squalene Epoxidase (squalene monooxygenase). Squalene epoxidase converts squalene to squalene-2,3-epoxide, an obligate precursor to lanosterol and ergosterol. Inhibition yields a dual effect:
  1. Deficiency of ergosterol: Compromises fungal cell membrane structural integrity.
  2. Toxic intracellular accumulation of squalene: Causes lipid droplet accumulation, membrane permeabilization, cellular organelle disruption, and rapid fungicidal cell lysis.
• Dosing in Podiatry:
  • Toenail Onychomycosis: $250\text{ mg}$ orally once daily for $12\text{ weeks}$.
  • Fingernail Onychomycosis: $250\text{ mg}$ orally once daily for $6\text{ weeks}$.
  • Pharmacokinetics: Highly lipophilic and keratophilic; concentrates in the nail matrix, nail bed, and sebum, persisting in the distal nail plate for months following treatment cessation.
• High-Yield Adverse Effects:
  • Hepatotoxicity: Drug-induced liver injury ranging from asymptomatic transaminitis to fulminant cholestatic jaundice and hepatic necrosis. Mandatory baseline Liver Function Tests (LFTs: ALT, AST) must be obtained prior to initiation, with repeat monitoring at 4 to 6 weeks.
  • Taste and Smell Disturbances (Dysgeusia / Ageusia / Anosmia): Can occur abruptly and persist for months after drug withdrawal; patients must be warned immediately.
  • Drug-Induced Lupus Erythematosus (DILE) & Cutaneous Lupus: Induces positive anti-histone antibodies and subacute cutaneous lupus erythematosus (SCLE).
  • Severe Cutaneous Reactions: Stevens-Johnson syndrome, erythema multiforme, and exacerbation of plaque psoriasis.
  • Few CYP3A4 interactions compared with azoles, but terbinafine is a strong CYP2D6 inhibitor that raises levels of tricyclic antidepressants, metoprolol and other CYP2D6 substrates.

2. Azole Antifungals: Imidazoles & Triazoles

Azoles are heterocyclic compounds classified by the number of nitrogen atoms in the azole ring:

• Imidazoles (2 nitrogens): Ketoconazole, Clotrimazole, Miconazole, Econazole, Sertaconazole. (Largely relegated to topical use due to systemic toxicity and high human CYP450 inhibition).
• Triazoles (3 nitrogens): Itraconazole, Fluconazole, Voriconazole, Posaconazole, Isavuconazole. (Enhanced metabolic stability, greater selectivity for fungal CYP over human CYP, primary systemic agents).

Mechanism of Action

Azoles competitively inhibit the fungal cytochrome P450-dependent enzyme Lanosterol 14-$\alpha$-demethylase (encoded by the $ERG11$ or CYP51 gene). This blocks the demethylation of lanosterol into 14-desmethyl lanosterol, halting ergosterol production. Toxic 14-methylsterols accumulate in the fungal membrane, destabilizing the lipid bilayer, inhibiting membrane-bound enzymes, and stunting fungal growth (predominantly fungistatic).

Cell Membrane Pore Formers & Cell Wall Synthesis Inhibitors

Polyenes: Amphotericin B & Nystatin

Amphotericin B

Amphotericin B is an amphoteric polyene macrolide containing a hydrophobic conjugated polyene chain and a hydrophilic polyol chain.

• Mechanism of Action: Amphotericin B binds directly with high affinity to ergosterol in fungal cell membranes. Several amphotericin molecules aggregate to form a cylindrical transmembrane micropore or ion channel. This creates membrane permeability, permitting rapid efflux of intracellular potassium ($K^+$) and magnesium ($Mg^{2+}$), collapsing electrochemical gradients and causing rapid fungal cell death (fungicidal).
• Selectivity: Preferentially binds fungal ergosterol over human cholesterol; however, cross-binding to human cholesterol in renal tubular cell membranes accounts for profound host toxicity.
• Clinical Indications: Life-threatening systemic mycoses, including invasive mucormycosis (rhinocerebral/lower extremity Rhizopus in diabetic ketoacidosis), disseminated blastomycosis, histoplasmosis, coccidioidomycosis, and severe cryptococcal meningitis.
• Adverse Effects (The "Ampho-Terrible" Profile):
  • Immediate Infusion Reactions: "Shake and bake" cytokine release—severe chills, rigors, fever, headache, nausea, and bronchospasm (prevented by premedication with acetaminophen, diphenhydramine, and meperidine/hydrocortisone).
  • Renal Tubular Toxicity: Binds tubular epithelial cells, causing afferent arteriolar vasoconstriction (prerenal azotemia) and distal renal tubular acidosis (Type 1 RTA). Leads to severe hypokalemia, hypomagnesemia, and tubular nephrocalcinosis.
  • Normocytic Normochromic Anemia: Inhibits renal erythropoietin synthesis.
  • Liposomal Formulations (AmBisome): Packaging the drug in liposomal lipid spheres reduces direct contact with human renal membranes, significantly decreasing nephrotoxicity while preserving antifungal efficacy (at significantly higher drug cost).

Nystatin

Nystatin shares the identical polyene pore-forming mechanism of amphotericin B. However, it is severely toxic if administered parenterally (causes catastrophic systemic hemolysis). It is strictly limited to topical and oral suspension ("swish and swallow") for superficial cutaneous candidiasis, angular cheilitis, and oral thrush (Candida albicans).

Echinocandins: Caspofungin, Micafungin, Anidulafungin

Echinocandins are large, cyclic lipopeptides that inhibit the synthesis of $\beta$-(1,3)-D-glucan, an essential structural polysaccharide component of the fungal cell wall (catalyzed by $\beta$-(1,3)-D-glucan synthase).

• Effect: Weakens the rigid fungal cell wall, leading to osmotic instability and rapid cellular lysis (fungicidal against Candida species, including azole-resistant strains; fungistatic against Aspergillus).
• Human Safety: Because human cells possess cell membranes but completely lack cell walls and glucan polymers, echinocandins display an exceptional safety profile with minimal organ toxicity.
• Route: Administered IV only; not orally absorbed. Minimal CYP450 interactions. Mild histamine release with rapid infusion.

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Topical Therapeutics for Onychomycosis & Tinea Pedis

Topical therapy for onychomycosis avoids the hepatotoxicity and drug interactions of systemic terbinafine/azoles, but is hindered by poor transungual drug penetration through the dense, keratinized dorsal nail plate. Three FDA-approved prescription topicals exhibit specific mechanisms to overcome this barrier:

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Antiviral Therapeutics in Podiatric Care

Podiatric physicians frequently diagnose and manage cutaneous viral infections of the lower extremity, predominantly Herpesviridae (Herpes Simplex Virus [HSV-1, HSV-2] and Varicella-Zoster Virus [VZV shingles]) and Human Papillomavirus (HPV, producing Verruca plantaris).

Guanosine Analogs: Acyclovir, Valacyclovir & Famciclovir

                    Activation Cascade of Acyclovir / Valacyclovir
    
          Acyclovir (or Valacyclovir prodrug)
                         │
                         ▼   ◄── Viral Thymidine Kinase (TK) [RATE-LIMITING]
              Acyclovir Monophosphate
                         │
                         ▼   ◄── Host Cellular Kinases
              Acyclovir Diphosphate
                         │
                         ▼   ◄── Host Cellular Kinases
              Acyclovir Triphosphate (Active Form)
                         │
             ┌───────────┴───────────┐
             ▼                       ▼
    Competitive Inhibition    Obligate DNA Chain Termination
    of Viral DNA Polymerase   (Lacks 3'-OH group for phosphodiester bond)

Mechanism of Action

1. Monophosphorylation by Viral Thymidine Kinase (TK): Acyclovir is an acyclic guanosine nucleoside analog. It is taken up by virus-infected cells and converted to acyclovir monophosphate exclusively by viral Thymidine Kinase. Uninfected human cells lack this enzyme, providing exquisite drug selectivity.
2. Triphosphate Generation: Host cellular kinases convert the monophosphate into acyclovir diphosphate, and finally into the active compound: Acyclovir Triphosphate.
3. Dual Inhibition:
   • Competitively inhibits viral DNA Polymerase.
   • Incorporates into the replicating viral DNA strand. Because acyclovir completely lacks a 3'-hydroxyl (3'-OH) group, the viral DNA polymerase cannot form the next 3'-to-5' phosphodiester bond, resulting in obligate, irreversible chain termination.

Agents & Pharmacokinetics

• Acyclovir (Zovirax): Poor oral bioavailability ($F \approx 15 - 20\%$); requires frequent dosing (5 times daily for acute outbreaks).
• Valacyclovir (Valtrex): L-valyl ester prodrug of acyclovir. Rapidly hydrolyzed by first-pass hepatic esterases into active acyclovir, delivering 3- to 5-fold higher oral bioavailability ($F \approx 55\%$) with convenient BID to TID dosing. First-line oral therapy for Herpes Zoster (Shingles) involving lower extremity dermatomes (L4, L5, S1) to prevent postherpetic neuralgia.
• Famciclovir (Famvir): Diacetyl prodrug of penciclovir; prolonged intracellular half-life.

Adverse Effects & Toxicities

• Obstructive Crystalline Nephropathy: High-dose IV acyclovir exceeds urinary solubility in the renal collecting duct, precipitating insoluble acyclovir needle-shaped crystals within the renal tubular lumen. Manifests as rapid acute kidney injury with elevated creatinine within 24 to 48 hours. Prevention: Maintain aggressive intravenous hydration and slow IV infusion over $\ge 1$ hour.
• Neurotoxicity: Confusion, delirium, visual hallucinations, and myoclonus; observed primarily in elderly patients or patients with renal failure without dose reduction.

Mechanism of Acyclovir Resistance & Foscarnet

Resistance develops almost exclusively through mutations in the viral genome producing deficiency or structural alteration of viral Thymidine Kinase (TK-negative strains). Because TK-negative strains cannot monophosphorylate acyclovir, the drug remains inactive.

• Foscarnet (Foscavir): An inorganic pyrophosphate analog that directly inhibits viral DNA polymerase by reversibly binding to the pyrophosphate-binding site without requiring ANY intracellular phosphorylation or viral thymidine kinase. Drug of choice for acyclovir-resistant, TK-negative HSV and VZV (also treats CMV retinitis). Highly toxic: severe nephrotoxicity and electrolyte chelation (hypocalcemia, hypomagnesemia, hypokalemia).
• Cidofovir: Acyclic nucleoside phosphonate; already contains a phosphate-mimicking phosphonate group, requiring only host cellular kinases (independent of viral TK).

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Plantar Verrucae (HPV) Pharmacotherapy

Plantar warts (Verruca plantaris) are intraepidermal benign neoplasms caused by infection of basal keratinocytes with Human Papillomavirus (primarily HPV types 1, 2, 4, 27, and 57). Podiatric management combines mechanical debridement, chemical cautery, antineoplastic agents, and immunomodulators:

Antiprotozoal and Antiparasitic Agents

Scabies management. Treat the patient and close contacts at the same time. Apply permethrin from the neck to the soles and repeat in 7–14 days. Wash bedding and clothing in hot water. Itching can persist for weeks after cure because of hypersensitivity to mite remnants.