GIT 3

Antiparasitics for GIT Infections

• Topic: Antiparasitics for GIT infections
• Presenter: Dr Brooke Storey-Lewis, Discipline of Pharmacology, University of Sydney

Learning Outcomes

• Identify antiparasitic drugs used for gastrointestinal tract infections
• Review mechanism of action (MOA), pharmacokinetics (PK), and adverse effects (AE) of metronidazole/tinidazole for intestinal protozoal infections
• Describe the MOA of benzimidazoles (e.g., albendazole, mebendazole)
• Describe the MOA of ivermectin
• Describe pharmacokinetic considerations for benzimidazoles and ivermectin
• Describe adverse effects and contraindications for benzimidazoles and ivermectin

Revisiting Metronidazole

• Indications: Giardiasis ( Giardia lamblia), Amoebiasis (Entamoeba histolytica)
• MOA: Amoebicidal tissue active agent (metronidazole/tinidazole) + luminal cysticidal agent (paramomycin). Paramomycin is an aminoglycoside available via SAS, only for asymptomatic cases.
• Tinidazole has a longer half-life and is better tolerated.

Indications (AMH Online)

WormTreatmentHookwormSingle dose albendazole or 3d course pyrantel* or mebendazoleRoundwormSingle dose albendazole or pyrantel or 3d course mebendazoleStrongyloidiasisSingle dose ivermectin or 3d course albendazoleFasciola hepatica (Liver fluke)Usually resistant, Triclabendazole via SASThreadwormSingle dose albendazole, mebendazole, pyrantel, Treat all family membersWhipworm3d course albendazole or mebendazole(Pyrantel is a neuromuscular blocker causing spastic paralysis and expulsion of the worm from the GIT)

Mechanism of Action - Benzimidazoles

• MOA: Interferes with microtubule assembly, affecting cytoskeleton structure, organization, transport, motility (cilia/flagella) and mitotic division (mitotic spindle).
• Benzimidazoles bind to beta subunit, and formation of the protofilament and decreasing integrity of microtubule, resulting in cell death.
• Alpha & beta subunits dimers form long protofilaments arranged in cylindrical shape with central lomen.

Pharmacokinetic Considerations - Benzimidazoles

• Variable absorption: Take on empty stomach to minimize absorption (intestinal), with food (fatty meal) for increased systemic absorption to increase efficacy.
• Absorption: Albendazole > mebendazole absorption
• Metabolism: Liver; eliminated in bile

Adverse Effects & Contraindications - Benzimidazoles

• More common with high doses and extended treatment
• Death of parasite and heavy parasite burden
• Gastrointestinal upset
• Headache
• Liver enzyme abnormalities, low red blood cell count (long-term use)
• Albendazole pregnancy category D (teratogenic, embryotoxic in animal studies)
• Use contraception for 1 month post-treatment

Mechanism of Action - Ivermectin

• MOA: Ivermectin hyperpolarizes cells (neurons or muscle cells) leading to paralysis and cell death.
• The drug targets glutamate-gated chloride channels, disrupting ion flow, creating hyperpolarization.

Pharmacokinetic Considerations - Ivermectin

• Administration: Oral or topical only
• Bioavailability: ~50%, increases to 2.5x with fatty meals
• PK data less well-established in humans compared to veterinary medicine
• Metabolism: Liver, possibly CYP3A4
• Elimination: Faecal

Adverse Effects & Contraindications - Ivermectin

• Infrequent: Fatigue, dizziness, gastrointestinal upset, rash, itching
• Avoid concomitant use of drugs enhancing GABA activity (e.g., barbiturates, benzodiazepines, sodium valproate)
• Pregnancy/breastfeeding safety not established
• No studies in hepatic/renal impairment; exercise caution