Carbamyl Inhibitors of AChE

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					Carbamyl Inhibitors of AChE (1)

    Their action promoting accumulation of ACh at muscarinic or
     nicotinic receptors is the basis of their pharmacological,
     therapeutic, and toxic actions

    Are derivatives of carbamic acid

    Bind covalently to the esteratic site of AChE, resulting in
     carbamylation of the enzyme

     Carbamic acid                          Carbamic acid ester
Carbamyl Inhibitors of AChE (2)

   Quaternary compounds bind to the ionic binding site of AChE

   Their induce accumulation of AChE at nicotinic and
    muscarinic sites, producing pharmacological responses
    qualitative to cholinergic stimulation

   Inhibition of AChE is reversible, in the order of hours

   Are metabolized in the plasma by plasma esterases
Carbamyl Inhibitors of AChE (3)

   High doses produce skeletal muscle weakness due to
    depolarizing blockade at the end plate of the neuromuscular

   High doses produce a profound fall in cardiac output and
    blood pressure

   Their inhibition of AChE is not reversed by pralidoxime
Carbamyl Inhibitors of AChE (4)

   Quaternary ammonium compounds do not cross the blood-
    brain barrier

   For oral administration, high doses must be given
Neostigmine Carbamylates Acetylcholinesterase
Slow Hydrolysis of Carbamylated-AChE and Enzyme Liberation
Organophosphate Inhibitors of
Organophosphate Inhibitors of Acetylcholinesterase (1)

   Chemical characteristics

   Promote accumulation of ACh at
     NM nicotinic receptor

       NN nicotinic receptor
       Muscarinic receptor
Organophosphate Inhibitors of AChE (2)

      Their action promoting accumulation of ACh at the
       muscarinic receptor of the ciliary muscle is the basis of their
       therapeutic effectiveness in open angle glaucoma

      Only two of these agents are used for therapeutics
        Echothiophate for glaucoma

          Diisopropylflurophosphate (DFP) for glaucoma (?)
Organophosphate Inhibitors of AChE (3)

   Inhibition of AChE by these agents is irreversible
     New enzyme synthesis is required for recovery of
       enzyme function

   They also inhibit pseudocholinesterase

   Metabolized by A-esterases (paroxonases) present in plasma
    and microsomes. They are metabolized by CYP450.

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