Another name for cholinesterase inhibitors and what is the primary function of these drugs?
- Reverse NONdepolarizing muscle blockade
Acetylcholine is the neurotransmitter for the entire ____________ nervous system
Parasympathetic nervous system
Acetylcholine the neurotransmitter for what parts of the sympathetic nervous system
- sympathetic ganglions
- adrenal medulla
- sweat glands
Name all of the systems/areas that acetylcholine is the neurotransmitter
- entire parasympathetic nervous system
- parts of sympathetic (sympathetic ganglions, adrenal medulla, sweat glands)
- some neurons in CNS
- somatic nerves innervating skeletal muscle
Neuromuscular transmission is blocked when non-depolarizing muscle relaxants compete with acetylcholine to bind to ____________ ____________ receptors
nicotinic cholinergic receptors
do cholinesterase inhibitors work DIRECTLY or INDIRECTLY? how?
INDIRECTLY - they block acetylcholinesterase, thus allowing acetylcholine to accumulate
True or false: TOO MUCH cholinesterase inhibitors can PROLONG neuromuscular blockade
TRUE - floods the motor end plate with so much acetylcholine, causing fasciculations and flaccid paralysis.
The time required to fully reverse a nondepolarizing block depends on: (4 things)
1) choice of cholinesterase inhibitor administered
2) dose of cholinesterase inhibitor administered
3) muscle relaxant being antagonized
4) extent of blockade before reversal
Another name for acetylcholinesterase
Acetylcholine is synthesized in the nerve terminal by what enzyme?
What is the action of acetyltransferase?
1) catalyzes the reaction between acetylcoenzyme A and choline
2) After its release, acetylcholine is rapidly hydrolyzed by acetycholinesterase (aka TRUE cholinesterase) into ACETATE and CHOLINE
Describe the synthesis and hydrolysis of acetylcholine
1) Acetylcholine is synthesized in the nerve terminal by choline acetyltransferase
2) acetyltransferase catalyzes the reaction between acetylcoenzyme A and choline
3) After its release, acetylcholine is rapidly hydrolyzed by acetycholinesterase (aka TRUE cholinesterase) into ACETATE and CHOLINE
Cholinergic receptors have been subdivided into two major groups based on their reaction to the ______________, which includes ____________ and _____________.
alkaloids: muscarine and nicotine.
What does nicotine stimulate?
1) autonomic ganglia
2) skeletal muscle receptors (nicotinic receptors)
What does muscarine stimulate?
end-organ effector cells in:
1) bronchial smooth muscle
2) salivary glands
3) SA node (muscarinic receptors)
The CNS has both _____________ and _____________ receptors
muscarinic and nicotinic receptors
What are nicotinic receptors blocked by? What are muscarinic receptors blocked by? What neurotransmitter do these receptors have in common?
- Nicotinic receptors are blocked by MUSCLE RELAXANTS (ex roc, vec)
- Muscarinic receptors are blocked by ANTICHOLINERGIC DRUGS (ex atropine)
- these receptors both response to ACETYLCHOLINE
Examples of muscarinic agonists. How do these drugs work?
- Bethanechol and methacholine are MUSCARINIC AGONISTS.
- These drugs work by resisting hydrolysis by cholinesterase
When reversing neuromuscular blockade, the primary goal is to maximize ___________ transmission, and minimize ____________ side effects
maximize NICOTINIC transmission, and minimize MUSCARINIC side effects
_________ has both muscarinic and nicotinic agonist activities (drug name)
carbachol - used for wide angle glaucoma
The _________________ nervous system uses acetylcholine as a preganglionic and postganglionic neurotransmitter
True or false: carbachol is a specific cholinergic agonist
FALSE: carbachol is NON-specific, affecting muscarinic AND nicotinic receptors
True or false: methacholine and bethanchol are primarily muscarinic agonists
Normal neuromuscular transmission critically depends on acetylcholine binding to ____________ ______________ receptors on the __________ _________ _____________
- nicotinic cholinergic receptors
- motor end plate
Describe what spontaneous reversal from nondepolarizing muscle blockers depends on
Reversal of blockade depends on gradual diffusion, redistribution, metabolism and excretion from the body
How do cholinesterase inhibitors work?
REVERSIBLY binding to acetylcholinesterase, which INDIRECTLY allows for the accumulation of acetylcholine at the motor end plate (since acetylcholinesterase cannot break down AcH)
Describe the bonding differences of edrophonium and neostigmine and pyridostigmine
Edrophonium - electrostatic attraction and hydrogen bonding creates a short-lived duration of action. binding to anionic site is stabilized by hydrogen bonding at esteratic site.
Neostigmine + pyridostigmine - covalent bonds create a longer lasting effect
Describe the bonding in organophosphates
form very stable, irreversible bonds to acetycholinesterase
The clinical duration of cholinesterase inhibitiors used in anesthesia is probably more influence by what?
the rate of drug disappearance from the plasma.
besides inactivation of acetycholinesterase, edrophonium also appears to work in a different way. describe its other mechanism of action
prejunctional effects that enhance the release of acetycholine
neostigmine inactivates acetylcholinesterase but also has what action, which enhances its ability to restore neuromuscular function?
a direct (but weak) agonist effect on nicotinic receptors.
also, acetylcholine mobilization and release by the nerve may also be enhanced (a presynpatic mechanism)
In high doses, neostigmine may cause ____________ ___________ blockade
acetylcholine channel blockade
How do cholinesterase inhibitors PROLONG depolarization blockade?
1) an increase in acetylcholine (which increases motor end plate depolarization)
2) inhibitor of pseudocholinesterase activity (except edrophonium which has little to no effect on pseudocholinesterase)
Describe physostigmine's effect on the CNS
crosses the BBB and can cause diffuse activation of the EEG by stimulating muscarinic and nicotinic receptors within the CNS.
What are the muscarinic side effects of cholinesterase inhibitors?
1) CV: bradycardia, bradyarrthymias
2) Pulm: bronchospasm, secretions
3) CNS: diffuse excitation (PHYSO only)
4) GI: intestinal spasm, increased salivation
5) GU: increased bladder tone
6) Eyes: pupillary CONSTRICTION (MIOSIS)
Clearance of cholinesterase inhibitors is due to...
1) hepatic metabolism (25-50%) **** primary metabolism
2) renal excretion (50-75%) **** primary excretion
When you have a patient with renal or hepatic insufficiency do you need to decrease your dose of cholinesterase inhibitors?
Not necessarily because when the nondepolarizing agent is likely to be prolonged, the cholinesterase inhibitor will be prolonged as well, so it evens out.
True or false: the posttetanic count (# of palpable twitches after tetanus) generally correlates with the time of return of the first twitch of the TOF
A palpable posttetanic twitch appears about ________ minutes before spontaneous recovery of agents such as atracurium and vecuronium
structure of neostigmine
- carbamate moiety --> provides for covalent bonding to acetylcholinesterase
- quaternary ammonium group --> makes molecule lipid INsoluble
Dose and concentration of neostigmine, and recommended anticholinergic and anticholinergic dose
- dose: 0.04-0.08mg/kg
- concentration: 1mg/ml typically, but also 0.5mg/ml, 0.25mg/ml
- recommended anticholinergic: glycopyrrolate
- anticholinergic dose: 0.2mg glyco per 1mg neostigmine
Dose and concentration of pyridostigmine, and recommended anticholinergic and anticholinergic dose
- dose: 0.1-0.4 mg/kg
- concentration: 5mg/ml
- recommended anticholinergic: glycopyrrolate
- anticholinergic dose: 0.05mg glyco per 1mg pyridostigmine
Dose and concentration of edrophonium, and recommended anticholinergic and anticholinergic dose
- dose: 0.5-1mg/kg
- concentration: 10mg/ml
- recommended anticholinergic: atropine (packaged together as ENLON PLUS)
- anticholinergic dose: 0.014mg atropine per 1mg edrophonium
Dose and concentration of physostigmine, and recommended anticholinergic and anticholinergic dose
- dose: 0.01-0.03mg/kg
- concentration: 1mg/ml
- recommended anticholinergic: NOT NECESSARY
- anticholinergic dose: N/A
NOT USED TO REVERSE MUSCLE RELAXANTS
Onset, peak and duration of neostigmine
Onset: 5-10 min
peak: 10 min
duration: > 1 hr
Onset and duration of pyridostigmine
Onset: 10-15 min
duration: > 2 hours
Onset and duration of edrophonium
Onset: 1-2 min
duration: with higher doses can be > 1 hr
Onset, peak and duration of
When reversing the pregnant patient with neostigmine, which anticholinergic should you use and why?
You should use ATROPINE because neostigmine will cross placenta and cause fetal bradycardia. Glyco will NOT cross placenta to counteract the bradycardia. so you must use ATROPINE
Which cholinesterase inhibitor has been used intrathecally and why?
Neostigmine (50-100 mcg) has been used as an adjunct to intrathecal anesthesia, causing a prolongation of sensory and motor blockade, presumably by inhibiting the breakdown of spinal cord acetylcholine
What is the structural difference between pyridostigmine and neostigmine?
Pyridostigmine's quaternary ammonium is incorporated into the phenol ring.
Which cholinesterase inhibitor lacks a carbamate group? What affect does this have?
Edrophonium - must rely on NONcovalent bonding to acetylcholinesterase enzyme.
What is the only available cholinesterase inhibitor that crosses the BBB?
Why is it beneficial to have physostigmine cross the BBB?
1) effective in tx of central anticholinergic toxicity caused by overdoses of atropine or scopalamine
2) reverses some of CNS depression and delerium associated with use of benzos and volatile anesthetics
3) effective in preventing postop shivering
Which cholinesterase inhibitor is almost COMPLETELY metabolized by PLASMA ESTERASES? Why is this important?
Physostigmine is almost completely metabolized by plasma esterases
Renal excretion is NOT important (aka OK to use in ARF/CRF)
What are the other names for butyrocholinesterase?
- plasma cholinesterase
- nonspecific cholinesterase
Where is butyrocholinesterase found? (3 places)
Function of butyrocholinesterase
hydrolyzes succs, mivacron, and ester-type local anesthetics
Classification of acetylcholinesterase drugs
reversible (edrophonium, neostigmine, pyridostigmine)
Drugs with a carbamate group? How do these drugs bond?
physostigmine, neostigmine, pyridostigmine
- covalently bond to acetylcholinesterase and CARBAMYLATE (the enzyme at the esteratic site)
- this decreases the ability to hydrolyze acetylcholine
How long does it take acetylcholinesterase to be reactivated when it combines with acetylcholine? carbamyl ester? organophosphorus agents?
AChE + acetylcholine = milliseconds
AChE + carbamyl ester = 15-30 minutes
AChE + organophosphorus = days to weeks
Describe the mechanism of action of irreversible inactivation of acetylcholinesterase. What drugs cause this?
Organophosphates (aka NERVE GASES)
- forms irreversible phosphorylated bond at esteratic site, which is resistant to hydrolysis
- lasts until spontaneous generation of enzyme occurs (days to weeks)
Side effects of nerve gas (include muscarinic and nicotinic stimulation)
diarrhea, urination, miosis, bronchoconstriction/bradycardia, emesis, lacrimation, salivation
nicotinic - fasiculations and flaccid paralysis (d/t mass accumulation of ACh)
Describe the physical properties of chemical warfare gases
clear, colorless, odorless, evaporate at room temperature and highly lipid soluble (can even go thru clothing)
Dosages of medications used to treat organophosphate poisoning and where the drugs work
1) Atropine - treats muscarinic symptoms ONLY
- 35-70mcg/kg every 3-10 minutes until symptoms resolve.
2) pralidoxime (PAM Protopam)
- 15 mg/kg IV over 2 minutes
- treats NICOTINIC effects at NMJ
- repeat dose in 20 min if weak
- if anticipated gas exposure, pretx w/ pyridostigmine 30mg TID
Steps for treatment of organophosphate poisoning
1) removal from site
2) removal from clothing
3) bath and shampoo to remove agents from skin and hair
- supportive measures
3) seizure control (benzo or barbs)
Where does hydrolysis occur?
Esteratic site - splits into choline and acetic acid
Where does the choline go after its been hydrolyzed from acetylcholine?
Choline is returned to prejunctional motor nerve terminal
What binds to the anionic site?
Quaternary nitrogen of ACh
Compare the lipid solubilities of the cholinesterase inhibitors
Poorly lipid soluble: neostigmine, edrophonium, pyridostigmine
Highly lipid soluble: organophosphates and physostigmine
the liver metabolizes what percentage of a dose of neostigmine, edrophonium, and pyridostigmine
50% of neostigmine dose
30% of edrophonium dose
25% of pyridostigmine dose
Renal clearance of neostigmine, edrophonium and pyridostigmine (% clearance)
75% edrophonium and pyridostigmine
How should your neostigmine dosing change for children and infants?
You should use a lower dose in infants and children or at least be precise with the weight based calculation.
sympathetic nervous system originates in what region?
the postganglionic fibers of the SNS innervate what two receptors? what are the neurotransmitters for these receptors?
adrenergic receptors - NE/EPI
cholinergic receptors (sweat glands) - ACh
parasympathetic nervous system originates in what region? and exits thru which cranial nerves?
CN III, VII, IX, X
postganglionic fibers of the parasympathetic nervous system innervate what type of receptors and what is the neurotransmitter for this receptor?
cholinergic receptors - ACh
Clinical uses of anticholinesterase agents
1) reversal of NDMB
2) physostigmine reverses undesirable CNS effects
3) Edrophonium used to differentiate between phase I and Phase II block
4) glaucoma (echothiophate)
5) myasthenia gravis (pyridostigmine)
6) paralytic ileus and atonic bladder
7) postop analgesia (intrathecal admin)
8) alzheimer's disease
Factors that may enhance neuromuscular blockade and affect reversal
1) hypothermia **
2) respiratory acidosis **
3) metabolic alkalosis
4) hypermagnesemia **
7) renal and hepatic disease
8) drug interactions -- aminoglycosides, Ca ch blkrs, locals, volatiles, quinidine, lithium
9) Neuromuscular diseases (MG, musc. dystrophy, GB, ALS)
A larger dose of neostigmine leads to a ___________ reversal but can be limited by the ___________ effect
faster reversal, ceiling effect
what are the two suggested end points for recovery?
1) sustained tetanus for 5s to 100Hz stimulus in anesthetized patient
2) sustained head lift
What are Muravchick's (Upenn ologist) opinions on reversal?
- if they have a few twitches, they get full reversal neostigmine (0.07mg/kg)
- if the pt has all 4 twitches but cannot sustain tetanus, they have half a dose (0.035mg/kg)
- if they spontaneously recover sustained tetanus, they DO NOT get neostigmine
Dose of physostigmine to reverse restlessness and confusion. Mechanism of action?
15-60mcg/kg --> increases concentration of AcH in brain, especially muscarinic receptors in RAS
Which drug should you avoid if the patient has an asprin allergy?
physostigmine -> contains sodium bisulfate, sensitivity in asthmatic patients especially
pathophysiology of myasthenia gravis
antibodies attack the nicotinic receptors, decreasing the number on the post-synaptic membrane.
anticholinesterase agents increase concentration of ACh available to stimulate receptor and improve strength
Describe the tensilon test and what it is used to diagnose
edrophonium 1mg IV admin over 1-2 min.
if strength increases --> myasthenia gravis.
if weakness increases --> cholinergic crisis (TOO MUCH anticholinesterase therapy on board)
Who should you avoid using anticholinesterase drugs in?
anyone you wouldnt give succs o
- muscular dystrophy
- spinal cord transection
- extensive burns
Describe the use of anticholinesterases in glaucoma (what types of glaucoma, how it works to benefit glaucoma patients, long-term use complication)
- used in: narrow and wide angle glaucoma
- how it works: decrease synthesis and/or resistance of outflow of aqueous humor
- complication: may lead to cataract formation
how does acetylcholine change in alzheimer's disease
senile plaques and neurofibrial tangles --> damage to cholinergic fibers leads to decreased AcH
treatment of alzheimer's disease
centrally acting cholinesterase inhibitors
- donepezil (aricept)
- rivastigmine 9exelon)
- galantamine (reminyl)
Describe the use of neostigmine in intrathecal and epidural administration, including dosages
mechanism of action: increased concentrations of acetylcholine CSF produces analgesia
- reduces dose of local anesthetic or opioid