80. Anthelminthic drugs

Helminths

Helminths are parasitic worms. They’re categorized like this:

• Helminths (worms)
  • Plathelminths (flatworms)
    • Cestodes (tapeworms)
    • Trematodes (flukes)
  • Nemathelminths (roundworms)
    • Nematodes (threadworms)
      • Intestinal nematodes
      • Filariae

Antihelminthic drugs

Classified according to mechanism of action:

• Drugs against flatworms
  • Drugs which bind tubulin
    • Benzimidazoles
  • Drugs which interfere with energy production
    • Niclosamide
  • Drugs which act on Ca2+ receptors
    • Praziquantel
• Drugs against roundworms
  • Drugs which bind tubulin
    • Benzimidazoles
  • Neuromuscular blocking drugs
    • Pyrantel
    • Oxantel
    • Levamisole
  • Drugs acting on GABA receptors
    • Piperazine
  • Drugs acting on GABA receptors and glutamate-gated chloride channels
    • Ivermectin
  • Drugs which interfere with energy production
    • Pyrvinium
  • Other
    • Diethylcarbamazine

Benzimidazoles

Benzimidazoles, also called bendazoles, are antihelminthic drugs derived from benzimidazole.

Drugs

• Mebendazole
• Albendazole

Indications

These are broad-spectrum antihelminthics. Albendazole is more efficacious than mebendazole.

Some sensitive worms:

• Enterobius
• Ascaris
• Ancylostoma
• Trichuris
• Intestinal trichinella

Mechanism of action

Benzimidazoles inhibit the polymerization of β-tubulin, thus interfering with microtubule-dependent functions like glucose uptake, motility and DNA replication.

Mechanisms of resistance:

• Mutation in β-tubulin, decreasing the affinity to benzimidazoles
• Lower expression of β-tubulin

Pharmacokinetics

Benzimidazoles are very lipophilic. Their oral absorption is poor but increases substantially with concurrent intake of fat-rich food. They have strong plasma protein binding.

Adverse effects

• Both
  • GI symptoms
  • Neutropaenia
• Albendazole
  • Mild hepatotoxicity

Piperazine

Indications

• Nematodes
  • Ascaris (roundworm)
  • Enterobius (threadworm)

Mechanism of action

Piperazine is a GABA receptor agonist. It opens GABA-gated chloride channels in nematodes, which causes flaccid paralysis of the worms. They are then excreted by normal peristaltic movements.

Adverse effects

• Neurotoxicity (seizures)

It’s contraindicated in epileptics.

Levamisole

Indications

• Ascaris (roundworm)

Also used to cut cocaine, because its crystals are similar to those of cocaine.

Mechanism of action

Levamisole is a nicotinic receptor agonist, causing overstimulation of the neuromuscular junction and resulting paralysis, just like depolarizing muscle relaxants.

Adverse effects:

• CNS toxicity
• Agranulocytosis

Pyrantel and oxantel

(Not among the most important antihelminthics to know, according to the seminar teacher).

Indications

Intestinal parasites, parasites in the GI lumen.

Mechanism of action

These drugs are nicotinic receptor agonists and cholinesterase inhibitors, thereby acting as depolarizing muscle relaxants.

Pharmacokinetics

These drugs are not orally absorbed and are therefore only effective against parasites in the GI lumen.

Niclosamide

Indications

Intestinal forms of tapeworms.

Mechanism of action

Niclosamide inhibits glucose uptake, oxidative phosphorylation and the citric acid cycle.

Pharmacokinetics

Niclosamide is not orally absorbed and is therefore only effective against tapeworms in the GI lumen.

Praziquantel

Praziquantel is a quinoline derivate.

Indications

• Schistosomiasis
• Cysticercosis

Mechanism of action

Praziquantel increases the permeability of Ca2+ across the parasite’s membranes. This causes tonic paralysis.

Pharmacokinetics

Praziquantel is well absorbed but has significant first-pass effect in the liver, so very little reaches the systemic circulation.

Adverse effects

• Rare
• GI symptoms

Contraindications

Worm infections of the eye.

Unlike what the seminar says, praziquantel is safe in pregnancy, a property which is important for its role in national disease control programs.

Pyrvinium

(Not among the most important antihelminthics to know, according to the seminar teacher).

Indications

Enterobius.

Mechanism of action

Pyrvinium inhibits glucose absorption.

Pharmacokinetics

Pyrvinium is not absorbed in the GI tract.

Diethylcarbamazine

Indications

• Loiasis
• Lymphatic filariasis

It is no longer used to treat patients with onchocerciasis (river blindness) because it can cause the Mazzotti reaction.

Mechanism of action

Poorly understood. Parasites exposed to diethylcarbamazine in vitro seem unbothered. It is thought that the drug changes the parasite so that it becomes more susceptible to phagocytosis. It also inhibits arachidonic acid metabolism in the host.

Adverse effects

Using diethylcarbamazine to treat onchocerciasis can cause the Mazzotti reaction, a potentially life-threatening reaction with pruritus, adenopathy, etc. This reaction can be treated with steroids.

Ivermectin

Not among the most important antihelminthics to know, according to the seminar teacher, but has recently been receiving renewed interest because some (erroneously) believed it could be used to treat COVID-19.

Indications

• Filariae
  • Especially onchocerciasis (river blindness)
• Cutaneous larva migrans
• Strongyloides
• Scabies

Mechanism of action

Ivermectin opens glutamate-gated Cl– channels, which causes pharyngeal paralysis. It also activates GABA receptors, causing tonic paralysis.

Adverse effects

Ivermectin can cause a Mazzotti reaction, especially when used to treat onchocerciasis.