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ANTIHELMINTHICS

ANTIHELMINTHICS. By: Samuel Mwaniki. BACKGROUND. Parasitic worms Two broad phyla: 1.Platyhelminthes Cestodes Trematodes 2.Nematodes. DRUGS. Classified into Benzimidazoles : Albendazole , Thiabendazole , Mebendazole . Prazinoisoquinolines : Praziquantel .

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ANTIHELMINTHICS

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  1. ANTIHELMINTHICS By: Samuel Mwaniki

  2. BACKGROUND • Parasitic worms • Two broad phyla: 1.Platyhelminthes • Cestodes • Trematodes 2.Nematodes

  3. DRUGS • Classified into • Benzimidazoles : Albendazole, Thiabendazole, Mebendazole. • Prazinoisoquinolines: Praziquantel. • Organophosphates: Metrifonate. • Piperazines: Piperazine, Diethylcarbamazine. • Others: Pyrantel, Niclosamide, Levamisole, Ivermectin, Oxamniquine,

  4. BENZIMIDAZOLES MoA Various biochemical changes in susceptible nematodes (both adults and larvae) • Inhibition of mitochondrial fumarate reductase in TCA cycle. • Reduced glucose transport. • Inhibit microtubule polymerization by binding to beta-tubulin, hence immobilizing parasite and causing slow death.

  5. Selective Toxicity: • Higher affinity and binding to nematode beta-tubulin compared to human beta-tubulin.

  6. Spectrum of Activity • Thiabendazole • Cutaneous larval migrans (15% cream bd, 5/7) • S. stercoralis High GIT toxicity thus replaced by other members.

  7. 2. Mebendazole • GIT nematodes (mixed infections): E. Vermicularis, A. lumbricoides, T. trichiura, Hookworms. • Tissue nematodes: T.spiralis • Hydatid cyst (Albendazole superior)

  8. 3. Albendazole • Mixed infections • Hydatid cyst; pre- and post surgery • S.stercoralis (Ivermectin and Thiabendazole preferred) • Neurocysticercosis caused by larva of T.solium. Give glucocorticoids to prevent reaction from death of cysticerci. • With DEC or Ivermectin to control lymphatic Filariasis.

  9. Pharmacokinetics 1.Thiabendazole • Rapidly absorbed from the GIT, metabolized in liver and excreted in urine. 2.Mebendazole • Only 10% absorbed from GIT, fatty meal increases absorption. Rapidly metabolized and excreted in bile and urine within 24-48 hours. 3. Albendazole • Erratic absorption from GIT. Metabolised to Albendazolesulphoxide (active).

  10. Unwanted Effects • GIT disturbances: N, V and D • CNS (rare): drowsiness, dizziness, headache • Allergic reactions (very rare)

  11. PRAZIQUANTEL MoA • Cestodes: At low concentrations, causes increased muscular activity followed by contraction and spastic paralysis, hence detachment of the worm from the host’s intestines. • Trematodes: At high concentrations, causes influx of calcium ions across tegument resulting in damage and exposure of antigens. Host mounts immune response against the parasite.

  12. Clinical Uses • Cestodes: T.saginata, T.solium, D.latum, H.nana ;10-20mg/ kg stat, repeat after 7-10 days. • Liver, lung and intestinal flukes: F.hepatica, P.westermani, F.buski; 25mg/kg tds, 1 day. • Blood flukes: Schistosomes; 40-60mg/kg single dose. • Nematodes not affected.

  13. Pharmacokinetics • Readily absorbed. • Extensive 1st pass metabolism producing inactive hydroxylated metabolites. • Excreted in urine and bile. • 80% plasma protein bound. Half life of 1-3 hours.

  14. Unwanted Effects: • Abdominal discomfort • CNS • Others (rarely): fever, priritis, urticaria, rashes, arthralgia and myalgia

  15. METRIFONATE MoA • An orgnophophate. • Prodrug; converted to dichlorvos in vivo. • Potent inhibitor of cholinesterase enzyme resulting in paralysis. Moves from venous plexus to small arteries and finally to lungs where they are encased hence death. • Ova not affected.

  16. Uses • S.haematobium: 10mg/kg stat, repeat twice at 2 week intervals. Pharmacokinetics • Rapidly absorbed. • Metabolized non enzymatically at physiological PH. • Cleared from plasma within 8 hours.

  17. Unwanted Effects: • GIT disturbances. • CNS effects. • Inhibition of host’s cholinesterase enzyme (no significant effects) • Foetal damage? CAUTION! – administer with Atropine to prevent organophosphate toxicity in host.

  18. OXAMNIQUINE MoA • Causes DNA intercalation. Selective Toxicity • Parasite accumulates drug more than host.

  19. Uses: • S.mansoni: both immature and mature forms affected. Adult male more than female. • Sensitivity differs geographically hence wide range of doses. Tropical Africa (30-60 mg/kg in 2 divided doses), S. America ( 15 mg/kg)

  20. Pharmacokinetics • Well absorbed. • 1st pass effect in gut and liver – inactive metabolites. • Excreted in urine. • Half life of 1-2 hours. Fully eliminated within 10-12 hours.

  21. Unwanted Effects • GIT • CNS stimulation – hallucinations, convulsions. • Allergic manifestations appearing long after treatment – antigens from dead flukes.

  22. IVERMECTIN MoA • Blocks glutamate, GABA and other ligand gated chloride channels in the microfilaria, hence inducing tonic paralysis, immobilization and death . • Prevents egression of microfilaria from uterus of the female. Selective Toxicity • 100 fold higher affinity for nematode GABA activity compared to host.

  23. Uses: • Drug of choice for O.volvulus • Mass chemotherapy in combination with Albendazole whereO.volvulus, W.bancrofti, L.loa infections co-exist. Single annual dose for 4-6 years. • S.stercoralis, A.lumbricoides, T.trichiura, E.vermicularis • Scabies • Head lice • Cutaneous larval migrans

  24. Pharmacokinetics • Rapid absorption reaching peak plasma concentrations in 4-5 hours. • Distributed in liver and adipose tissue. • Metabolized to inactive metabolites in liver. • Excreted in bile.

  25. Unwanted Effects: • Mild Mazzoti like reactions due to antigenic materials released by dead microfilaria – mild (itching); use H1 antagonists, severe (fever, hypotension, headache, myalgia); use glucocorticoids. • C/I in late stage HAT; compounds CNS depression.

  26. DIETHYLCARBAMAZINE MoA • Inhibition of microtubule polymerization and destruction of preformed microtubules. • Causes release of antigens by microfilaria, hosts mounts immune response hence killing parasite. • Interferes with parasite’s arachidonate metabolism. • Rapidly clears microfilaria from blood. No effect on adult worms.

  27. Uses: • Drug of choice for Filariasis caused by: W.b, L.l, B.m, B.t • O.v (2nd choice) • Cutaneous larval migrans caused by dog and cat hookworms • Visceral larval migrans caused by dog and cat round worms.

  28. Pharmacokineticss: • Rapid absorption. • Disributed in all body tissue s except adipose tissue. • Partial metabolism in liver. • Excreted in urine. Cleared from body within 48 hours.

  29. Unwanted Effects: • Drug related • GIT • CNS 2. Antigens released from dead microfilaria (Mazzoti reaction) • Mild: rash, urticaria • Severe: intense itching, lymphadenopathy, fever, tachcardia, hypotension, headache, arthralgia. Management: H1 antagonists, Glucocorticoids.

  30. Discuss the rationale for the widespread use of broad spectrum antihelminthics, giving examples of helminths and drugs used against them.

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