Reversal Agents Flashcards
What is the MOA of anticholinesterases?
increase concentration of acetylcholine at the nicotinic receptors through:
- inhibition of acetylcholinesterase leading to an increase in ACh concentration at both nicotinic and muscarinic receptors
- stimulation of presynaptic nicotinic ACh receptors causing release of additional ACh
What types of cholinesterase do anticholinesterases inhibit?
true cholinesterase
AND
pseudocholinesterase/plasma cholinesterase
What are the implications of inhibiting acetylcholinesterase?
increases ACh activity at nicotinic and muscarinic receptors
What are the implications of inhibiting pseudocholinesterase?
prolonged effect of succinylcholine, ester local anesthetics, and remifentanil
Give 2 examples of anticholinesterases that inhibit pseudocholinesterase:
organophosphates
echothiophate
What is the primary goal of reversing neuromuscular blocking agents?
- maximize nicotinic transmission
- minimize muscarinic side effects
Describe nicotinic cholinergic receptors:
- ligand-gated ion channels
- allow intracellular influx of Na+
- located in the autonomic ganglia, skeletal muscle (NMJ), CNS
- stimulated by nicotine, ACh, and succinylcholine
Describe muscarinic cholinergic receptors:
- G-protein coupled receptors
- 5 subtypes (M1-M5)
- located in CNS, bronchial smooth muscle, salivary glands, SA node
- stimulated by ACh and muscarine
- blocked by atropine, scopolamine, pilocarpine
Stimulation of muscarinic receptors results in (4 things):
1) salivary and sweat gland secretion
2) pupillary constriction
3) increased GI peristalsis
4) slows conduction of SA and AV nodes
AChE inhibitors increase the concentration of ACh at the muscarinic receptor resulting in what predictable set of parasympathetic side effects?
Diarrhea
Urination
Miosis
Bradycardia
Bronchoconstriction
Emesis
Lacrimation
Laxation
Salivation
Which method of AChE inhibition results in a short-acting, reversible bond with a short DOA? Which drug acts in this way?
electrostatic attachment (Edrophonium)
Which method of AChE inhibition results in a slightly tighter, reversible bond with a moderate DOA? Which drug(s) act in this way?
formation of carbamyl esters (neostigmine, pyrido-, and physo-)
Which method of AChE inhibition results in an irreversible bond with a long DOA? Which drugs/substances act in this way?
phosphorylation (organophosphates and echothiophate)
Anticholinesterases have a prolonged effect in which patient population? Why?
renal and liver dz; they are conjugated, hydrolyzed and metabolized in the liver and have some degree of renal elimination
In general, anticholinesterases are _____ amines. Why is this relevant? What is the exception?
quaternary; they do not cross the BBB
exception: physostigmine is a tertiary amine and DOES cross the BBB
Give the dose/onset/duration of edrophonium. What drug is it paired with when used for reversal?
- dose: 0.5-1.0 mg/kg (max 40mg)
- onset: 1-2 min
- duration: 30-60 min
- paired with: atropine (0.014mg per 1mg edro)
Give the dose/onset/duration of neostigmine. What drug is it paired with when used for reversal?
- dose: 0.05 mg/kg (max 5mg)
- onset: <3 min
- duration: 40-60min
- paired with: glycopyrrolate (0.2mg per 1mg Neo)
Give the dose/onset/duration of pyridostigmine. What drug is it paired with when used for reversal?
- dose: 0.1-0.3 mg/kg
- onset: 10-20 min
- duration: 60-120 min
- paired with: glycopyrrolate (0.05mg per 1 pyrido)
What additional clinical issue is neostigmine used for?
treatment of myasthenia gravis
Give the dose/onset/duration of physostigmine.
- dose: 0.5-2mg
- onset: 3-8 min
- duration: 30 min - 5 hours
What is the treatment of choice for anticholinergic syndrome?
physostigmine
What drug reverses the effects of scopolamine?
physostigmine
How is physostigmine metabolized?
plasma esterases
Which anticholinesterase drug is used to treat glaucoma?
echothiophate
What are the symptoms of anticholinesterase poisoning when it comes to nicotinic effects?
- fasciculations
- inability to repolarize cell membrane
- weakness & paralysis
- ventilatory failure
What is the treatment for anticholinesterase poisoning?
1) atropine (1-2mg IV bolus, repeat Q3-5 mins)
2) pralidoxime (15mg/kg IV over 2 mins) - especially for organophosphate
need something that crosses the BBB
What are other names for anticholinesterase poisoning? What does it mean?
central cholinergic syndrome
cholinergic crisis
means: excessive ACh in brain at nicotinic and muscarinic receptors
Describe why we must give anticholinergic drugs in combination with anticholinesterases?
- only the nicotinic cholinergic effects are needed for reversal of a NDMR
- if unaddressed, the muscarinic effects would cause profound bradycardia and excessive salivation
What is the MOA of anticholinergic drugs?
- reversibly bind with muscarinic cholinergic receptors
- prevent ACh from binding
- results in excessive PNS effects
- increasing amounts of ACh can overcome these drugs
What tissues are most sensitive to anticholinergics?
salivary glands, sweat glands, bronchial tissue
What effect to anticholinergics have on HR?
increase
atropine > glyco > scopolamine
What effect do anticholinergics have on bronchial tissue?
bronchodilate
atropine = glyco > scopolamine
What effect do anticholinergics have on sedation?
scopolamine»_space; atropine
*glyco does not cross BBB d/t quaternary amine
What effect do anticholinergics have on salivary glands?
inhibit salivation
scopolamine > glyco > atropine
What effect do anticholinergics have on pupillary response?
mydriasis (dilation) and cycloplegia
scopolamine > atropine
glyco = no effect
What effect do anticholinergics have on motion sickness?
prevent/reduce
scopolamine > atropine
*glyco = no effect
What effect do anticholinergics have on the cardiovascular system?
increase rate of SA node (counteracts bradycardia)
What effect do anticholinergics have on the GI tract?
decrease tone and motility
What effect do anticholinergics have on the urinary system?
decreased tone (retention possible)
Besides concomitant use with anticholinesterases, how else are anticholinergics used clinically?
- Parkinson’s
- motion sickness
- ophthalmologic exams
- CV disorders/bradycardia
- cholinergic poisoning
What is a major adverse effect of anticholinergics?
atropine poisoning/central anticholinergic syndrome
dry as a bone
blind as a bat
red as a beet
mad as a hatter
List 2 contraindications to anticholinergic use:
glaucoma
gastric ulcer
Give the dose/onset/duration of atropine:
- dose: NDMR reversal 0.015 mg/kg
sinus brady 0.4-0.8mg Q3-5min - onset: 45-60 sec
- duration: 1 hour
What are the minimum atropine doses for adult and pediatric bradycardia?
adult: no less than 0.4mg
peds: no less than 0.1mg
What is the dose/onset/duration of glycopyrrolate?
- dose: 0.1mg/kg
(0.2mg for each 1mg of neo) - onset: <1min
- duration: 2hr
What is the dose/onset/duration of scopolamine for anticholinergic effects?
- dose: 0.2-0.6 mg
- onset: <1min
- duration: 2-6 hours
What is the MOA of sugammadex?
- selectively binds to aminosteroid NDMRs (roc>vec>pan)
- encapsulates NMBAs and renders them unable to engage with nicotinic receptors
Sugammadex interacts with which receptors/NT?
NONE - and there are no systemic side effects
How is sugammadex metabolized and excreted?
metab: none
excretion: unchanged by kidneys
How long does sugammadex take to work? Does it depend on how deeply the pt is blocked?
fully restores muscle function to TOF >0.9 from any depth of NMB within 3 minutes
List 3 advantages of sugammadex use:
1) no effect on anticholinesterase
2) no effect on any receptors
3) mechanism is independent of the depth of neuromuscular block
What are the side effects of sugammadex?
- bradycardia (1-5%)
- anaphylaxis (0.3-1%)
- bleeding
- hormonal contraceptives ineffective x7 days
Which 2 patient populations should not be given sugammadex?
kids
kidneys (dialysis or low creat clear)
What dose of sugammadex should be given to patients with a moderate block? What does moderate block mean?
moderate block = 2 twitches
dose = 2mg/kg
What dose of sugammadex should be given to patients with a deep block? What does deep block mean?
deep block = 0 twitches with TOF or 1-2 post-tetanic counts
dose = 4mg/kg
What does of sugammadex should be administered to reverse a patient who received rocuronium 3-4 minutes ago?
16 mg/kg
If a patient was reversed with sugammadex 5 mins to 4 hours ago, what dose of rocuronium is needed to re-paralyze? What about greater than 4 hours ago?
5 mins to 4 hours = 1.2 mg/kg (upper end)
>4 hours = 0.6 mg/kg
