anticholinesterases and anticholinergics Flashcards
what is AChE?
enzyme that hydrolyzes 300,000 ACh molecules per minute
what dos the inhibition of AChE allow?
allows for more ACh to be available to facilitate action at the NMJ (depolarization and contraction)
what are the mechanisms of action of anticholinesterases?
- enzymatic inhibition: inhibit AChE by being hydrolyzed by the AChE, causing carbamylation of AChE or by attaching to the enzyme (ties up or distracts the enzyme)
- presynaptic effects: cause increased availability of ACh, causing spontaneous contractions in the absence of NMB
- avoid in myotonia dystrophica
- direct effect on the NMJ: too much ACh at the NMJ causes decreased sensitivity resulting in blockade effect
- opposite effect of what we want
describe carbamylation of AChE.
- reversible inhibition
- neostigmine, pyridostigmine, and physostigmine are hydrolyzed by AChE, causing chemical change in the enzyme and reversibly inhibiting its ability to hydrolyze ACh
describe electrostatic binding of AChE.
- truly reversible inhibition
- edrophonium forms a reversible electrostatic attachment to AChE to inhibit its ability to hydrolyze ACh
- competes with ACh for the bonding site on AChE
describe organophosphate anticholinesterase agents.
- form an irreversible complex that must be replaced with generation of new enzyme
- echothiophate: eye gtts
- insecticides
- nerve gases: tabum, saran, soman
- there is a massive amount of ACh released hitting muscarinic and nicotinic receptors
- side effects take longer to subside
what are the chemical properties of anticholinesterases?
-quaternary ammoniums
*neostigmine, pyridostigmine, edrophonium
*poor lipid solubility, water soluble
-tertiary amine
*physostigmine
*lipid soluble- crosses the BBB
*not usually used for reversal, but more for post op
delirium
describe neostigmine (Prostigmine) elimination
50% renal, other 50% plasma esterases and hepatic metabolism
*doesn’t matter about renal failure since we want reversal
what is the dose and max dose of neostigmine?
dose: 0.06 mg/kg
max: 5 mg
* if not reversed with max dose, may use about 10 mg of edrophonium
what is the onset of neostigmine?
7-11 minutes
describe edrophonium (Enlon) elimination.
75% renal
what is the dose of edrophonium?
0.5-1 mg/kg (weaker than neostigmine)
what is the onset of edrophonium?
30-60 seconds (presynaptic effect)
describe pyridostigmine (Mestinon) elimination.
75% renal
what is the dose of pyridostigmine?
dose: 0.3 mg/kg
what is the onset of pyridostigmine?
onset: 10-20 minutes
describe physostigmine (Antilirium).
- elimination hepatic and hydrolysis by cholinesterases
- used to treat CNS effects of anticholinergic agents, anesthetics, and reduces shivering
- tx for post op delirium
what is the dose of physostigmine?
dose: 0.5-2 mg/kg (0.01-0.03 mg/kg)
* give slowly, 1 mg/min
* if pushed rapidly, pt. will projectile vomit
what is the onset of physostigmine?
about 5 minutes
what are some considerations when selecting which reversal to use?
- Deep NMB is reversed better with neostigmine
- infusions of atracurium, vecuronium, and pancuronium
- edrophonium better with atracurium
- neostigmine better with vecuronium
what is the ceiling effect of reversal agents?
-once AChE is maximally inhibited, giving more anticholinesterase will not reverse a NMB
what can affect the reversal of NMB?
- antibiotics
- hypothermia
- respiratory acidosis (PaCO2 > 50 mmHg)
- hypokalemia and metabolic acidosis
- hyperventilation causes K+ to move into the cell
when AChE is inhibited, what receptors does ACh affect?
-cholinergic (nicotinic)
*receptors within ANS ganglion and at NMJ
-muscarinic
*M1: CNS, stomach
-post op N/V (neostigmine enhances)
-if at risk, goal is to not use reversal
*M2: mainly heart, also airway smooth muscle
*M3: airway smooth muscles and salivary, contraction
and secretion
*side effects: significant secretions, relaxation of
gut/bladder, relaxation of bronchial smooth muscles,
bradycardia, dysrhythmias
what are some cardiac side effects of anticholinesterases?
- bradycardia
- junctional rhythm
- PVCs
- ventricular rhythm
- asystole
- slowing of conduction- AV node
what are some GI and GU effects of anticholinesterases?
- increased secretions
- increased motility
- sometimes used in treatment of paralytic ileus
- post of N/V
what are some pulmonary effects of anticholinesterases?
- bronchoconstriction
- increased secretions
what are some ophthalmic effects of anticholinesterases?
- miosis (pupil constriction)
- constriction of ciliary muscle (far-sighted)
- decreased intraocular pressure
what are some muscular effects of anticholinesterases?
- contractions, fasciculations similar to SCh
* use with caution with myotonia, muscular dystrophies, spinal cord transection, and burns
how can you prevent the muscarinic effects of anticholinesterases?
- pretreat with an anticholinergic drug
- atropine
- glycopyrrolate (Robinul)
- scopolamine
what are the symptoms of anticholinesterase overdose?
*side effects are amplified
-nicotinic: weakness ranging to paralysis
-muscarinic: miosis, inability to focus vision near,
salivation, bronchoconstriction, bradycardia, abdominal
cramps, loss of bladder/bowel control
-CNS: confusion, ataxia, seizures, coma, respiratory
depression
what is the treatment for anticholinesterase OD?
- atropine: muscarinic blocker
- pralidoxime: needs to be given within minutes of exposure
- ventilatory support
- control of seizures
what is the mechanism of action for anticholinergic agents?
- compete with ACh for all MUSCARINIC receptors
- bind reversibly with receptors
- belladonna plants- atropine, scopolamine
describe atropine.
-tertiary ammonium
*lipid soluble, crosses the BBB
-elimination by both liver metabolism and renal
*always want to see an increase in HR before giving
anticholinesterase, especially in infants
*used with edrophonium
what is the dose of atropine?
0.03 mg/kg
what is the onset of atropine?
1 minute
describe Robinul.
- quaternary ammonium
- lipid insoluble, no CNS effect
- excreted unchanged by renal
- want to start seeing an increasing HR before giving anticholinesterase
- used with neostigmine
what is the dose of Robinul?
0.015 mg/kg
what is the onset of Robinul?
2-3 minutes
describe scopolamine.
- tertiary amine
- crosses BBB
- causes sedation, amnesia
- treats post of N/V
- elimination hepatic
- no hemodynamic effect, no significant change in HR, may be used as an amnestic
what is the dose of scopolamine?
0.4 mg IM/IV
what is the onset of scopolamine?
onset IV: 10 minutes
onset IM: 30-60 minutes
describe anticholinergic pre op clinical use?
- antisialagogue effect (drying effect of secretions)
- scopolamine > glycopyrrolate > atropine
- sedation
- scopolamine > atropine
- prophylactic for vagal response
- atropine > glycopyrrolate > scopolamine
- *be aware glaucoma pts. may have problems and if the drug crosses the BBB, it crosses the placental membrane and may increase fetal HR
describe anticholinergic clinical use to treat bradycardia.
-block the effect of ACh on the SA node (shortens the P-R interval
*underlying vagal tone determines response
higher vagal tones (like athletes) have a better effect
*atropine has a greater onset than glycopyrrolate
*dose of atropine for bradycardia 0.015-0.070 mg/kg IV
*with CAD, you want a slower onset, so use Robinul
**if you under dose, enhances bradycardia
describe anticholinergic clinical use for bronchodilation.
-atropine dose 1-2 mg in 3-5 ml of NS
ipratropium- aerosol
what are other clinical uses of anticholinergics?
- antispasmotic: biliary and ureteral
- mydriasis and cycloplegia
- prophylaxis for PONV and motion sickness
describe central anticholinergic syndrome.
- CNS effects from scopolamine and atropine
- restlessness and hallucinations, to somnolence and unconsciousness
- treatment: physostigmine 0.015-0.060 mg/kg
what causes an increased for aspiration with anticholinergics?
- lower esophageal sphincter is relaxed by both atropine (can last 40 min) and glycopyrrolate (can last 60 min)
- not sure of clinical significance
- at small doses, there is no bronchodilation effect
describe Org 25969 (sugammadex)
- encapsulates the steroid NMB and forms a stable (wont break down) complex, preventing NMB action on the NMJ- excreted unchanged with NMB renally
- no action at the NMJ
- not an anticholinesterase, does not require an anticholinergic
- reversal of deep block early (rocuronium)
- don’t need twitches to reverse
- helped stop anaphylaxis with rocuronium
- *affects the immune system
what is the dose of sugammadex?
dose: 2-4 mg/kg when given with 2/4 on TOF
what is the onset of sugammadex?
onset: 1-3 minutes
