PHRM 136: Anthelmintic Drugs – Flashcards

Multicellular (metazoa), parasitic worms; pathogenic to humans Classification: 1. Roundworms (nematodes) 2. Two types of flatworms: flukes (trematodes) and tapeworms (cestodes) These biologically diverse eukaryotes vary with respect to life cycle, bodily structure, development, physiology, localization within the host, and susceptibility to chemotherapy - Helminth infections can cause malnutrition in children

Paralysis followed by expulsion (affects neurosynapses and motion of worms): 1. Ivermectin- Cl- channel opener 2. Piperazine- Cl- channel opener 3. Praziquantel- Ca2+ channel opener 4. Pyrantel- N-receptor agonist, cation channel opener 5. Metrifonate- Cholinesterase inhibitor Direct Inhibition of Growth (cytotoxic): 1. Benzimidazoles- b-tubulin binder 2. Doxycycline- protein synthesis inhibitor 3. Niclosamide- ATP depletion 4. Diethylcarbamazine- unclear 5. Bithionol- unclear

• The major nematode (roundworms) parasites of humans include the filarial (slender) nematodes and the soil-transmitted helminths (STHs; sometimes referred to as "geohelminths"). • The major STH infections, which include ascariasis, trichuriasis (including whipworms), and hookworm infection, are among the most prevalent infections in developing countries.

- The major physiological feature of neurotransmission is the ion channels Na, K, Ca, Cl - Opening of Na channels causes depolarization - Opening of Cl and K channels causes hyperpolarization - Cl and K are inhibitory to depolarization or impulse propagation - Agents work by keeping the ion channel open and causing paralysis because the impulses will not be propagated normally. This can occur during any stage. - Depending on the ion channel that is affected it can cause flaccid paralysis, spastic paralysis, etc.

- NTs are first stored in the vesicles at the synaptic terminal and then released when stimulated - ACh is released into the synapse and binds to the post-synaptic membrane which generates another wave of electron pulses in the post-synaptic cells (may be muscular or neural cells). At the NMJ, ACh excites muscle cells - ACh is quickly hydrolyzed by AChE and recycled back into the pre-synaptic cells. This deactivation is fast! - If you interfere with any of the above steps you will affect ACh at NMJ - Inhibition of AChE will cause the cells to be trapped in the excited state for too long

Natural product from Streptomyces avermitilis. Complex structure. Highly effective against round worm infections as well as some insects (ticks and lice). Used extensively in veterinary medicine. The major drug used to treat onchocerciasis (river blindness) in humans

Binds to and activates certain glutamate-gated chloride channels found only in invertebrates, including the nerve or muscle cells of the affected worm species. This causes the cell hyperpolarization and induces the tonic paralysis of the worm musculature - MOA: Cl channel opener - Overall effect: Tonic paralysis

Highly effective againt pinworms (Ascaris lumbricoides). MOA: Acts as a GABA (g-amino butyric acid) agonist on chloride channels on muscle cell membranes. Produces hyperpolarization and reduced excitability, leading to flaccid paralysis followed by expulsion of worms. Selective toxicity is not clear, but may be a simple distribution phenomenon

Effective against cestodes and trematodes. Used extensively in schistosomiasis.

Mechanism of Action: • Activates voltage-gated calcium channels in/on the worms' surface, leading to rapid Ca2+ influx into schistosomes. Molecular mechanisms of binding to the channels is unknown. Two fold action against the parasite: 1. At lower doses it causes an increase in muscle activity followed by muscle contraction and paralysis of the parasite. 2. At slightly higher doses it causes tegumental damage, leading to exposure of tegumental antigens, which are attacked and eliminated by the host's immune system.

Effective against pinworm, roundworm and hookworm infections. Mechanism of Action: • Induces marked, persistent activation of nicotinic acetylcholine receptors • Also an inhibitor of cholinesterases • Opens nonselective cation channels • Causes a depolarizing neuromuscular block and spastic paralysis in the parasites. - Selectivity is unclear for many of these agents, but most of these agents are oral tothey stay in the GI lumen to kill the worms. There may be differences in ion channel topology between worms and humans.

Insecticide used as an anthelmintic agent. A prodrug, □ Converts to dichlorvos ( active form) in the body Occurs spontaneously ◊ Water reacts with it and causes HCl to be lost

Most OPs have a phosphate with three ester □ Irreversibly inhibits ACh-esterase • Greatly increases amount of ACh in synapse --> way more muscle contraction □ Mechanism • Serine attacks the phosphate group - Covalent bond is formed - Like first step of normal ACh-esterase mechanism • Aging then occurs - Good LG leaves (has the 2 Cl groups on it) - Other alkyl groups may leave as well - The bond between the phosphate and enzyme becomes very stable! - After aging, 2-PAM is ineffective (remember) • The covalent bond is now permanent - Way too stable to be broken via hydrolysis □ Result: Tetany paralysis

Drugs ◊ Albendazole ◊ Mebendazole ◊ Thiabendazole ◊ All end in -bendazole! Used against most worms, especially GI nematodes Structure ◊ Based on a benzene ring + imidazole ring (has 2 N's)

◊ Mechanism of Action • Binds β-Tubulin - Will only bind that found in worms (selectivity) ◊ Won't bind ours • Inhibits polymerization of tubulin • Microtubules can't be formed --> loss of cytoskeleton --> cell death ◊ Resistance • β-Tubulin point mutation may occur - Makes it look like the human one ◊ F at position 200 becomes Y - Results in los s of efficacy (won't attack this form!)

Protein Synthesis Inhibitor

MOA: Inhibits oxidative phosphorylation and/or stimulates ATPase activity. Causes a rapid loss in energy stores (ATP) and cell death follows.