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.
Selective Toxicity: Higher affinity and binding to nematode beta-tubulin compared to human beta-tubulin.
Spectrum of Activity 1. Thiabendazole Cutaneous larval migrans (15% cream bd, 5/7) S. stercoralis High GIT toxicity thus replaced by other members.
2. Mebendazole GIT nematodes (mixed infections): E. Vermicularis, A. lumbricoides, T. trichiura, Hookworms. Tissue nematodes: T.spiralis Hydatid cyst (Albendazole superior)
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.
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 hours. 3. Albendazole Erratic absorption from GIT. Metabolised to Albendazole sulphoxide (active).
Unwanted Effects GIT disturbances: N, V and D CNS (rare): drowsiness, dizziness, headache Allergic reactions (very rare)
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.
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.
Pharmacokinetics Readily absorbed. Extensive 1 st pass metabolism producing inactive hydroxylated metabolites. Excreted in urine and bile. 80% plasma protein bound. Half life of 1-3 hours.
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.
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.
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.
OXAMNIQUINE MoA Causes DNA intercalation. Selective Toxicity Parasite accumulates drug more than host.
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)
Pharmacokinetics Well absorbed. 1 st pass effect in gut and liver – inactive metabolites. Excreted in urine. Half life of 1-2 hours. Fully eliminated within hours.
Unwanted Effects GIT CNS stimulation – hallucinations, convulsions. Allergic manifestations appearing long after treatment – antigens from dead flukes.
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.
Uses: Drug of choice for O.volvulus Mass chemotherapy in combination with Albendazole where O.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
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.
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.
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.
Uses: Drug of choice for Filariasis caused by: W.b, L.l, B.m, B.t O.v (2 nd choice) Cutaneous larval migrans caused by dog and cat hookworms Visceral larval migrans caused by dog and cat round worms.
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.
Unwanted Effects: 1. 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.
Discuss the rationale for the widespread use of broad spectrum antihelminthics, giving examples of helminths and drugs used against them.