Acetylcholinesterase inhibitors cholinergic effects

Galantamine (Razadyne) [Cholinesterase Inhibitor] Uses Alzheimer Dz Action Acetylcholinesterase inhibitor Dose 4 mg PO bid, T to 8 mg bid after 4 wk may T to 12 mg bid in 4 wk Caution [B, ] T Effect w/ suc-cinylcholine, amiodarone, dildazem, verapamil, NSAIDs, digoxin X- effect w/ anticholinergics, T risk of death vs placebo Contra Severe renal/hepadc impair Disp Tabs, soln SE GI disturbances, wt loss, sleep disturbances, dizziness, HA Interactions T Effects W/ amitriptyline, cimeddine, erythromycin, fluoxetine, fluvoxamine, ketoconazole, paroxetine, quinidine EMS Use succinylcholine w/ caudon, may need a reduced dose monitor ECG for induced conduction abnormalities OD May cause cholinergic Sxs (SLUDGE), muscle weakness, resp depression, and Szs atropine may be used as antidote... 

There are no effective therapies for Alzheimer s disease and no cure. Treatment aims to enhance cholinergic transmission. The most useful drugs are central acetylcholinesterase inhibitors, for example donepezil. Acetylcholinesterase is the enzyme that normally breaks down acetylcholine after it has interacted with its receptors at the synapse. Inhibition of this enzyme in the brain increases the amount of acetylcholine available and prolongs its action. These drugs produce a modest improvement in memory or slow progression of symptoms in some patients. The response to anti-cholinesterase drugs may take several weeks. Their use is limited by side effects, which can be severe. 

It appeared that cholinergic transmission performed other new functions. It can modulate various aspects of immune function, both innate and adaptive. Cholinergic transmission influences immune cell proliferation, cytokine production, differentiation of T-helper cells, and antigen presentation. These effects are mediated by cholinergic mAChR and nAQiR and other cholinergic components present in immune cells, for example, a7 nAQiR has the ability to induce anti-inflammatory activity [89]. This is probably one of the reasons why acetylcholinesterase inhibitors (AChEIs) act far broader than just to the inhibition of AChE. 

The pro-cholinergic effect by inhibition of acetylcholinesterase has been proven, but is not the only action of these compounds (Table 1.4). In their review of the subject, Wagstaff and McTavish [1] discussed the therapeutic potential of the different properties of tacrine and recalled that it is impossible to attribute the clinically observed phenomena exclusively to one or other of this drug s properties. Certain features would suggest there is a possible cytoprotector action (anti-glutamate effect [166, 167], an MAO inhibitor effect and a cytoskeleton effect) associated with the symptomatic effect currently in the limelight resulting from the action initially described for neurotransmitters. 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

Pharmacology Galantamine is a competitive and reversible inhibitor of acetylcholinesterase. While the precise mechanism of galantamine s action is unknown, it may exert its therapeutic effect by enhancing cholinergic function. Pharmacokinetics ... 

Mechanism of Action A cholinesterase inhibitor that inhibits the enzyme acetylcholinesterase, thus increasing the concentration of acetylcholine at cholinergic synapses and enhancing cholinergic function in the CNS. Therapeutic Effect Slows the progression of Alzheimer s disease. 

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