2. Benzimidazole- Introduction-1912
Pharmacological Agent.
Bicyclic consists of the fusion of benzene and imidazole
Most prominent benzimidazole compound in nature is N-ribosyl-
dimethylbenzimidazole.
Presence of benzimidazole nucleus in numerous categories of
therapeutic agents for development of new therapeutic agents
Antimicrobials
Antivirals,
Antiparasitic,
Anticancer,
Anti-inflammatory,
Antioxidants,
Proton pump inhibitors,
Antihypertensives,
Anticoagulants,
Immunomodulators,
Hormone modulators,
CNS stimulants
CNS depressants,
Lipid level modulators,
Antidiabetics, etc
3. Benzimidazole- Antiparasitic
Group of Broad-Spectrum anthelminthic drugs
Nematocidal drug
Primarily used for the control of GI nematodes not
only for livestock's (Cattle, Sheep, Goat, Swine and
Poultry) but also Horse, dog, cat and human as
well.
Also used in agriculture to control the helminth
parasite in plants.
Before 1960s Benzimidazoles are used as fungicide
in plants.
Worldwide use over a four decades due to its
safety and spectrum.
5. Chemistry
All of BZDs,, have a side chain at
position 2 and 5, which prevents
hydroxylation of position 5 of the BZD.
Therefore, these compounds are more
potent than thiabendazole as
nematicides
except thiabendazole
It has been postulated that the
presence of a carbamate group in the
2- position is essential for potent
microtubule inhibitory activity.
6. MOA
BZDs inhibit microtubule
synthesis in nematode cells by
interfering with
polymerization of β-tubulins
Microtubule are hollow
tubular organelle that is
composed of dimeric protein
comprised of α and β subunit.
used for
Cell division,
Maintenance of cell shape,
Cell motility,
Cell secretion,
Nutrient absorption
Intracellular transport.
7. MOA
The microtubule loss observed at
tegumental
intestinal level in cestodes and nematodes
followed by
loss of transport of secretory vesicles
decreased glucose uptake.
Additionally,
the inhibition of secretion of nematode acetylcholinesterase
some enzymatic activities (such as fumarate reductase, malate dehydrogenase,
phosphoenol pyruvate reductase, and succinate dehydrogenase)
BZDs do not affect microtubule synthesis in animal cells, therefore these drugs are
relatively safe in animals- Rate constant for dissociation.
8. BZ-susceptible nematodes have the amino acid
Phenylalanine at positions 167 and 200,
Glutamate at position 198 of the ß tubulin protein and this results in a
high affinity binding site for BZs.
In contrast, vertebrates
commonly have tyrosine at codon 200, and lack a high affinity BZ
binding site and are not susceptible to significant toxicity from BZ
drugs.
Why these drugs does not affects the Vertebrates……?
9. Administration
lack of water solubility is an important
limitation for the formulation of BZD
compounds, which mainly allows their
preparation as
suspensions,
pastes, or
granules for
orally or intraruminal administration
One dose in Cattle and horses
2-3 doses to the carnivores and
omnivores.
10. Pharmacokinetics
Absorption:-
Absorption depend upon water solubility.
Methylcarbamate's BZD have only limited water
solubility and small differences in drug solubility may
have a major influence on their absorption and
resultant pharmacokinetic behavior.
Poor absorption.
Albendazole and oxfendazole have better GI
absorption
Animal should feed fiber before oral dose because
BZDs bind to fiber to preventing them from passing
through the GIT Tract and Facilitating absorption.
11. Metabolism and Excretion :-
All BZDs except thiabendazole are resistant to metabolism.
Parent Drug (TBZ) is short lived and metabolic products predominate in plasma and
all tissues and excreta of the host, as well as in parasites recovered from BZD-
treated animals.
Other Drugs: Pass first pass metabolism in Intestinal, liver, and lung metabolism in
most of animals.
Additionally GI metabolism is an important concern in ruminant species.
Phase I: Primary Metabolites:
Oxidative and hydrolytic processes and are all more polar and water soluble than
the parent drug.
Phase II: Primary metabolites are conjugated with glucuronide and/or sulfate to
increase their polarities, which facilitates urinary or biliary excretion.
Albendazole are converted to its sulfone, sulfoxide metabolites which are active.
Pharmacokinetics
16. Resistance
Cross Resistance
loss of high affinity BZ-parasite tubulin
interactions.
MOA:
Mutation:-,
At codon 167 and 200 (phenylalanine to
tyrosine),
sometimes at codon 198 (glutamate to
alanine) result in BZ resistance
17. Adverse Effect
Safe
Except Albendazole have teratogenic and
embryotoxic effect.
In High dose cause toxicity in liver and bone
marrow
