• Bethanechol 
• Carbachol
•  Pilocarpine
• Acetylcholine
•  Cevimeline 
• "chol"

• Edrophonium 
• Ambenonium 
• Neostigmine
•  Physostigmine
•  Pyridostigmine
•  Isoflurophate
• Echothiophate 
• "Phonium, igmine, and phate"

agents which block or inhibit

actions of cholinesterase

agents which decrease effectiveness of ACh at muscarinic

synapses

agents which mimic activation of the parasympathetic

nervous system, i.e. cholinomimetics 

• Cholinergic Synapses
• Acetylcholine (ACh) released into synapse
• Post-synaptic receptors-muscarinic [M1–M5] or nicotinic [NN, NM]
• NOT in same synapse
• Cholinomimetics increase stimulation of post-synaptic ACh receptors 

• Two classes of cholinomimetic agents which act by entirely different mechanisms
• Cholinergic agonists- cholinomimetic agents directly stimulate postsynaptic ACh receptors.
• Cholinesterase inhibitors block the destruction of ACh by inhibiting ChE.
• These drugs prolong the time of effective receptor stimulation of endogenously secreted ACh, thereby indirectly producing a cholinomimetic effects similar to that of the cholinergic agonists. 

• Acetylcholinesterase (ChE)-synaptic, primary mechanism of inactivation. 
• Therapeutic action of inhibitors due to decrease ChE.
• Butyrylcholinesterase (BuChE)-liver, glia, plasma, inactivates circulating ACh. 

• Systemic sites with muscarinic receptors- primarily M2, M3
• Primarily post-ganglionic synapses of the Parasympathetic Nervous System- Clinically Important Sites of Action
• Also- sweat glands-post-ganglionicsynapse of the Sympathetic Nervous System-Not clinically Important
• Mimic effects of Parasympathetic Stimulation-Parasympathomimetics
• Relative contribution of M2 and M3 differs across organs 

• Nicotinic Neural receptors- Ganglionic Stimulation-
• Neuromuscular Junction-striated muscle-Clinically Important Site of Action
• Stimulates muscle contraction 

• AChReceptorsinBrain
•  Subtypes
•  M1-M5
• NN
• Throughout brain- areas controlling
•  motor
•  cognitive,
• autonomic function
• Can alter other neurotransmitter systems,
• norepinephrine,
•  serotonin,
•  and dopamine. 

• Cognitive effects
•  Altered memory***
• Coma
• Confusion
• Motor responses
• Initial tremors, followed by convulsions*** 

• Different  from  peripheral effects. i.e. NOT equivalent to stimulation of Parasympathetic Nervous System
• depends on area/strength of stimulation 

• Alzheimerʼs Disease --
• ACh neurons important in memory-decrease ACh
• Parkinsonʼs Disease—
• Increase relative to dopamine
• Organophosphate exposure (insecticides, nerve agents)
• increase ACh 

• Increase exogenous ligand
• Distributes non-selectively 

• Most agonists and antagonists are specific for either Muscarinic or Nicotinic receptors.
• However, majority of muscarininc-cholinomimetic agents show little receptor subtype specificity-stimulate M1-M5.
• Most peripheral organs contain M2, M3
• general systemic administration produces responses in a number of organ systems-
• Produces non-specific, non-clinically related side effects.
• Local administration-strategy for specific responses 
• Restricts availability of agent to the desired receptors
• e.g. Pilocarpine topically to eye 
• Resistant to cholinesterase degradation 

• Are alkaloids or choline esters
• Naturally occurring alkaloids--muscarine and nicotine.
• choline esters were synthesized and tested for cholinomimetic activity because of their structural similar to ACh 

• Very short duration of action (<20 sec)-rapidly destroyed by ChE
• Stimulates both muscarinic and nicotinic receptors.
• Used in very specific clinical circumstances where rapid stimulation/degradation required, e.g. cataract surgery or corneal transplant 

• Synthetic carbamoyl choline ester.
• Long acting-NOT hydrolyzed by ChEs
• Only stimulates muscarinic 

Carbachol (Isopto Carbachol, Miostat) 

• synthetic carbamoyl choline ester 
• Long acting-NOT hydrolyzed by ChEs.
• Stimulates BOTH muscarinic and nicotinic
• causes release of ACh from synapses 

• All increase accumulation of endogenous ACh in ALL ACh synapses
• ChE inhibitors, except the organophosphates, are competitive inhibitors of ChE. 

• depends on the chemical linkage to ChE.
• Short duration (<15 min)-electrostatic forces, hydrogen bonding
• Intermediate (30 min-6 hr)-covalent
• Extended (days)- phosphorylates binding site, becomes irreversible 
• Recovery depends on synthesis of new ChE 

Neostigmine

(Prostigmine), pyridostigmine (Mestinon, Regonol) 

• Binding mechanism similar to ACh- more slowly removed (0.5-6 hr) 
• Access to CNS
• poor lipid solubility prevents crossing the BBB.
• Targeted at peripheral cholinergic receptors 

• phosphorylate active site of ChE forming a phosphoryl-enzyme complex
• very slowly reverses (hundreds of hours).
• With time bond strength increases -“ages”, and the phosphoryl-ChE link becomes essentially irreversible.
•  Need synthesis of new ChE. 
• Access to CNS
•  Organophosphate ChE inhibitors
• Echothiophate (Phospholine) 
• Charged, not lipid soluble
• DOES NOT readily cross BBB
• Isoflurophate (Floropryl, DFP), insecticides, and nerve gases.
• uncharged, highly lipid-soluble 
•  easily crosses BBB 

Recovery from Neuromuscular

Neuromuscular blockade of NM receptors during surgery to reduce muscle activity, twitches, tone 

Recovery from Neuromuscular

•  After surgery, want recover of muscle function ASAP
• Rapidly overcome (reverse) competitive blockade of Nm receptors at NMJ junction 

Recovery from Neuromuscular

• ChE Inhibitor of moderate duration
• Neostigmine (IV or IM)- increases ACh in neuromuscular junction to overcome competitive blockade
• Antimuscarinic always given to decrease muscarinic side effects 
• Edrophonium

Myasthenia Gravis

• Normal- multiple, closely packed NM receptors at the neuromuscular junction of skeletal muscle
• MG- Autoimmune disease- Decreases number, blocks, and/or spreads functional NM receptors
• Results- marked weakness and fatigability of skeletal muscle 

Myasthenia Gravis

Therapeutic Goal    

Myasthenia Gravis

Treatment

• ChE Inhibitor
• Moderate duration ChE inhibitor which does NOT cross BBB
• Neostigmine, pyridostigmine
• Long lasting ChE inhibitor contraindicated due to rapidly changing dosing requirements
• Antimuscarinic if needed to reduce muscarinic side effects
• Immunosuppressant to reduce disease progression 

• Interruption of neurally mediated micturition reflex
• Anesthesia induced decrease in smooth muscle tone (surgical atonia)
• Neural injury
• Micturition center in cord
• Pelvic Nerves from spinal cord 
• Spinal Shock following spinal injury 

• Head irradiation 
• poorly controlled diabetes
• medication
• infection 
• aging
• Sjogren's syndrome- autoimmune disease- salivary/lacrimal grands 

• Behavioral, life-style
• Avoid drugs which decrease saliva flow, e.g. decongestants, antihistamines
• Chew sugar free gum
• Sip sugar free fluids
• Saliva substitute mouthwash (carboxymethyl cellulose)
• Eye drops
• Cholinomimetic-not primary Rx due to side effects, systemically administered
• Traditionally Pilocarpine (ACh agonist)
• Cevimeline (ACh agonst) New- M3 selective, longer lasting, fewer side effects 

• Acute closed-angle glaucoma, increase pressure is due to blockage of the drainage by dilated iris.
• Chronic open-angle glaucoma presents as a chronic, slowly progressing increase in eye pressure, due to decreased outflow of aqueous humor. 

• Chronic Open Angle 
•  Beta blockers,
• prostaglandins
• Acute Closed Angle-Medical Emergency
• cholinomimetic agonist or ChE inhibitor occasionally used prior to surgery
•  topical (pilocarpine, carbachol) or (echothiophate)
• stimulation of sphincter muscle of iris constricting pupil (miosis) - removing the drainage obstruction in acute closed angle
• induced contraction of the ciliary muscles improves the outflow of aqueous humor in chronic open angle.
• For some cases of complicated glaucoma-echothiophate 

• ChE Inhibitors- slow progression of disease, donʼt reverse
• Donepezil (Aricept) 
• Rivastigmine (Exelon)    
• galantamine (Razadyne)    

• produces modest improvement in some measures of cognitive function in patients with Alzheimerʼs disease.
•  more selective to CNS ChE, less toxic
•  long duration of action – single dose/day is possible. 

•  Recently approved by the FDA (Exelon, 2006; Razadyne, formerly Reminyl, approved 2001).
• Long-acting, but given twice daily
• Pattern of toxicities is less severe, like donepezil, but still includes nausea, vomiting, diarrhea, and insomnia.
• Efficacy similar to that of donepezil 

• Poisoning with
• plant materials,
• atropine,
• antihistamines,
• tricyclic antidepressants,
• Lomotil (antidiarrheal drug) in children
• Antimuscarinic activity-competitive blockade M receptors centrally and systemically 

1. Overcome the muscarinic

   blockade 

• Commonadverseside effects
• Characteristic of systemic and CNS activation of cholinergic receptors
•  Depend on distribution (Route of administation and bioavailability) of the drug, reduced by local application, i.e. logenges, eye drops
• Generally predictable
•  Result from non-specific stimulation of cholinergic receptors in organ systems distant from the site of pathology 

• Pathologies in which increased parasympathetic nervous system activity caused by enhanced cholinergic activity would increase severity.
• Asthma -> can cause broncho-constriction and bronchosecretion
• Coronary insufficiency
• Can cause hypotension
• decreased heart rate
• arteriolar dilation (ACh agonist only)
• Peptic ulcers -> can cause increase of gastric acid secretion
• Incontinence -> increased urination
• Generally predictable