Antiparasitics: Ivermectin (Topical and Systemic) and Permethrin

Mechanism

Pharmacological Class and Group

Ectoparasitics and acaricides for topical and oral use belonging to the class of Macrocyclic Lactones (Ivermectin, derived from the fermentation of the actinomycete Streptomyces avermitilis) and Synthetic pyrethroids (Permethrin).

Mechanism of Action

Both drugs eliminate target ectoparasites by inducing selective neuromuscular paralysis:

• Ivermectin: It binds selectively and with high affinity to glutamate-dependent chloride channels expressed exclusively in the nerve and muscle cells of invertebrates (parasites, mites, nematodes):

Ivermectin Opening of Glutamate-dependent Cl^- Channels Hyperpolarization and Flaccid Paralysis

This induces a massive and continuous entry of chloride ions through the postsynaptic cell membrane, causing sustained hyperpolarization and the subsequent flaccid motor paralysis and death of the parasite (sarcoptes, lice or the follicular mite *Demodex folliculorum*). Additionally, it has topical local anti-inflammatory properties by inhibiting the degranulation of mast cells and blocking the secretion of inflammatory cytokines stimulated by the mite in rosacea.

• Permethrin: It acts by selectively altering voltage-gated sodium channels in the membranes of mite nerve cells. It prevents the rapid inactivation of sodium channels and prolongs the inward sodium current, inducing a sustained repetitive depolarization that results in spastic paralysis and death of the parasite.

Pharmacokinetics

High Resolution Pharmacokinetics

• Absorption: Oral ivermectin has an absorption of 95%, which increases significantly if it is ingested with foods rich in fats. Topical permethrin has extremely low and insignificant systemic absorption (<1-2%), which gives it an excellent biosafety profile in pediatrics.
• Metabolism: Systemic ivermectin is extensively metabolized in the liver by the CYP3A4 isoenzyme system to inactive metabolites.
• Excretion: Systemic ivermectin is eliminated almost exclusively through the bile and fecal route (99%), recovering less than 1% unchanged in urine. Absorbed topical permethrin is rapidly hydrolyzed and eliminated renally.
• Half-life (t_1/2): Oral ivermectin has a plasma half-life of 16 to 18 hours.

Indicators and dose

Clinical Indications and Off-Label Uses

• Scabies (Sarcoptic Mange): Permethrin 5% cream is the standard topical treatment of first choice. Oral ivermectin is the systemic treatment of choice, ideal for institutionalized community outbreaks or hyperkeratotic forms (Norwegian scabies).
• Pediculosis Capitis (Lice): Topical permethrin in 1% lotion or topical/oral Ivermectin for recalcitrant cases of resistance.
• Papulopustular Rosacea (Ivermectin 1% Cream): Highly effective and excellent local tolerability treatment to reduce papules and erythema by direct elimination of the Demodex follicular mite.

Dosage and Clinical Adjustment

Permethrin Cream 5% (Scabies):

• Apply an entire tube (approximately 30 g in adults) from the neck to the feet continuously, repeating the regimen after 7 days.

Oral Ivermectin (Scabies):

• Dose of 200 µg/kg orally in a single dose (usual equivalent of 2 6 mg tablets for a 60 kg adult). Preferably ingest with water on an empty stomach.
• Mandatory Repetition: Administer a second identical dose 7-14 days after the first dose to ensure total elimination of the newly hatched parasite.
• In forms of crusted or hyperkeratotic Norwegian scabies, an aggressive multiple-dose regimen is suggested (days 1, 2, 8, 9 and 15) in combination with topical local keratolytics and daily permethrin.

Ivermectin Cream 1% (Soolantra - Rosacea):

• Apply a small amount (pea size) to the forehead, chin, nose and both cheeks once a day at night for a minimum period of 3 to 4 months.

Adjustment in Renal and Hepatic Failure: No renal adjustment is required for oral ivermectin. Use with caution and consider dose reduction in advanced liver failure due to impaired primary bile clearance.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to pyrethroids or ivermectin.
• Patients with severe alteration of the blood-brain barrier (for systemic oral ivermectin, due to theoretical risk of penetration into the CNS).

Relative Contraindications

• Children weighing less than 15 kg (for oral ivermectin, due to immaturity of the P-glycoprotein).
• Infants less than 2 months of age (for topical permethrin).

Adverse Effects (ADR) and Specific Toxicity

• Common (1%-10% with topical permethrin): Transient burning sensation, mild local paresthesias, rebound pruritus (secondary to the release of antigens from the dead mite under the stratum corneum, which should not be confused with treatment failure), local dryness or erythema.
• Common (with oral ivermectin): Mild self-limited headache, transient dizziness, myalgia, nonspecific pruritus.
• Rare (<0.1%): Mazzotti-type reaction (in patients co-infected with massive filariasis, due to acute systemic parasitic lysis), transient neurotoxicity with extreme somnolence and ataxia (associated with accidental overdose or immaturity of the GP-P barrier in young infants).

Drug Interactions of Clinical Relevance

Systemic ivermectin is a substrate of the P-glycoprotein (P-gp) transporter. Concomitant use with strong P-gp inhibitors (such as Verapamil, Amiodarone or Quinidine) can dangerously increase the penetration of the antiparasitic agent through the patient's blood-brain barrier, inducing neurotoxicity.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Topical permethrin 5% is of choice and is considered safe and compatible during pregnancy due to its zero systemic absorption. Oral ivermectin should preferably be avoided during the first trimester of pregnancy due to the theoretical risk of bone malformations reported at massive doses in experimental animals.
• Breastfeeding: Topical permethrin is absolutely compatible. Oral ivermectin is excreted in breast milk at low concentrations, so it is recommended to postpone systemic treatment of the mother if the infant is younger than 2-3 months of age or weighs less than 15 kg.

Clinical

Rigorous Application of Permethrin in Scabies

The success of sarcoptes eradication using topical permethrin depends strictly on the correct application technique:

• Preparation: Bath with warm water and completely dry the skin (wait until the skin is cold before applying to avoid excessive systemic absorption and vasodilation).
• Application Area: Spread the cream continuously from the neck to the soles of the feet, paying special attention to the interdigital spaces of the hands and feet, armpits, undermammary folds, inguinal region, intergluteal groove and under the fingernails (previously trim).
• Contact Time: Let the drug act uninterruptedly for a minimum of 8 to 14 hours (preferably at night).
• Removal: Remove the product by showering with warm water and mild soap. It is essential to wash bedding and clothing used in the last 48 hours with hot water (>60 °C) or seal it in plastic bags for 7 days.
• Repetition: A second application must be repeated after 7-10 days to eliminate the nymphs hatched from the surviving eggs that are not completely destroyed by topical permethrin.