BT_GS 1.39, 1.40 - Reversal Agents Flashcards
(28 cards)
AChE structure and mechanism
Acetylcholine (ACh) is rapidly broken down by the enzyme acetylcholinesterase (AChE) which is present in the NMJ synaptic cleft and also bound to the post-junctional membrane
The AChE enzyme has two functional sites of importance
Anionic site
A negatively charged site that attracts the positively charged quaternary amide head of the ACh molecule
Esteratic site
The acetylcholine molecule is broken at the ester bond to form choline, while the acetyl group is transferred to the esteratic site of the enzyme
The enzyme undergoes rapid spontaneous hydrolysis to release the acetyl group, and go back to its original functional state
During anticholinesterase-facilitated antagonism of a non-depolarising block, recovery from paralysis relies on what 2 processes?
↑ACh at the NMJ → shift the balance of competition between ACh and the NDMR in favour of ACh → successful transmission across NMJ
Ongoing spontaneous recovery as NDMR diffuses away from the NMJ, either due to redistribution after a single bolus or clearance from plasma after repeated doses or infusion
Neostigmine for NDNMB reversal
Minimum TOF count
TOFC 2
Neostigmine for NDNMB reversal
Explain what factors you base your dosing on
Dosing - dependent on depth of blockade and weight
Optimally guided with quantitative measure of residual NMB
Subjective monitoring (visual or tactile assessment of TOF)
TOFC 2–3 = 0.05mg/kg
TOFC 4 = 0.04mg/kg, or 0.015–0.025mg/kg if no fade
Objective monitor (AMG assessment of TOF)
TOFC 2–3 or TOFR < 0.4 = 0.02–0.05mg/kg
TOFR 0.4–0.9 = 0.015–0.025mg/kg
TOFR > 0.9 = Reversal not needed
I would use adjusted body weight or FFM (Vd is 0.4-1L/kg)
Neostigmine for NDNMB reversal
At what dose is the ceiling effect reached and why?
At 70 mcg/kg maximal blockade is reached
Two factors that contribute to the ceiling effect
1/
- There is a finite amount of ACh at the NMJ
- Once all the AChE has been inhibited, further increasing the dose of neostigmine will not result in higher ACh concentration
- This, in and of itself, is sufficient to explain why deep block can’t be reversed with an anti-cholinesterase — it is a completely acceptable exam answer — but there is another factor that contributes:
2/ Biased competition
- NDMRs compete with ACh at the two binding sites on the α subunits of the nACh receptor
- Binding of only one NDMR molecule is required to prevent activation, while simultaneous binding of two ACh molecules is required to activate the receptor → strongly biases the competition in favour of NDMR
- At high concentrations of NDMR, an inordinate amount of ACh would be required to competitively overcome the block
If anticholinesterase is given after spontaneous recovery has already occurred, this may impair NMJ transmission by what mechanisms?
Desensitisation block
Depolarising block
Open channel block
Neostigmine 2.5mg given to non-paralysed patients has been shown to impair pharyngeal muscle and diaphragmatic function and causes airway collapsibility to a degree similar to a TOFR of 0.5
Systemic effects of anticholinesterases
Why
Dose disparity
Agent disparity
Onset disparity
Anticholinesterases → ↑cholinergic transmission at all synapses that use ACh as the neurotransmitter –> muscarinic adverse at low dose, nicotinic at high dose
NMJ (nicotinic)
Parasympathetic post-ganglionic (muscarinic)
Autonomic ganglia (nicotinic)
CNS (if crosses BBB)
Neostigmine and pyridostigmine affect NMJ transmission > autonomic transmission, while physostigmine and organophosphates show the reverse pattern
unsure if these differences reflect different lipid solubility or different AChE enzyme subtypes at different locations
Generally, autonomic muscarinic effects develop before nicotinic effects
Systemic effects of anticholinesterases Cholinergic / Muscarinic Effects: Why are muscarinic effects often termed cholinergic? And what are the effects
The term ‘cholinergic’ refers to anything related to the neurotransmitter acetylcholine (ACh) or substances that mimic or affect ACh’s actions is frequently associated with the parasympathetic nervous system because ACh is the primary neurotransmitter, both pre- and post-ganglionic PSNS receptors. While the SNS also uses ACh in preganglionic neurons, its postganglionic neurons primarily release NE, aside from the sweat gland innervates. This difference in neurotransmitter usage at the postganglionic level makes the parasympathetic system more prominently cholinergic.
muscarinic effects occurred at lower concentrations than nicotinic effects.
Symptoms of ↑activity at parasympathetic postganglionic muscarinic receptors:
(DUMBELLS)
Diarrhoea / ↑GI peristaltic activity
- diarrhoea
- abdominal spasm and pain, possible disruption of bowel anastomosis
Urination — relaxation of internal sphincter muscle of urethra, contraction of detrusor muscle
Miosis — stimulation of the constrictor pupillae muscles
(3 killer Bs)
- Bronchospasm –> ↑work of breathing
- Bronchorrhoea –> ↑Tracheobronchial secretions
- bradycardia –> AV block –> ↓Cardiac output
Emesis –> ↑ PONV
Lacrimation
Lethargic
Sweating, salivation, ↑secretions (↑aspiration risk)
Systemic effects of anticholinesterases: Nicotinic effects
Occur at higher concentrations than muscarinic effects
Days of the Week
Mydriasis
Tachycardia
Weakness
Tremors
Fasciculations
Seizures
Somnolent
Systemic effects of anticholinesterases
Neuromuscular junction effects
Large doses may cause muscle twitches, as spontaneous ACh release → end plate potentials that reach threshold → muscle fasciculations
Can cause muscle weakness independently in the absence of residual blockade due to
Secondary muscle blockade
Administration to fully recovered NMJ or patient with no residual block can cause weakness similar to a TOFR of 0.5
Secondary to desensitisation and open channel blockade 2° ↑[ACh] at NMJ
Does not occur with typical use of NMB as 75% receptors remain occupied when TOFR > 0.9
Thus ongoing blockade of most AChR prevents desensitisation blockade
Neostigmine/Atropine or Neostigmine /Glycopyrrolate? dose ratios
Neostigmine/atropine used to be the common combo because glycopyrrolate was expensive, but neostigmine/glycopyrrolate has now become the routine choice because of 2 advantages
Onset and duration of action
Neostigmine and glycopyrrolate have similar times to onset and durations of action, hence “cancel out” each other better
Atropine has a faster onset and shorter duration than neostigmine → early tachycardia followed by late bradycardia
Central anticholinergic syndrome
Glycopyrrolate is a quaternary amine and cannot cross the blood-brain barrier, while atropine is a tertiary amine and can cross the BBB and potentially cause central anticholinergic syndrome, particularly in elderly patients
5:1 ratio with glycopyrolate (2:1 with atropine)
Outline the clinical uses of AChEis
Reversal of non-depolarising neuromuscular blocker
Mechanism – anticholinesterase drugs ↑ synaptic ACh –> competes with ND-NMB in synapse for nAChR –> reversal of neuromuscular block
Drugs – usu. neostigmine, administered together with glycopyrrolate or atropine
Diagnosis and treatment of myasthenia gravis (MG)
Mechanism – in MG the muscle end plate is less sensitive to the effects of ACh –> ↑[ACh] at NMJ –> improved conduction of action potential across NMJ –> improvement of MG symptoms of weakness and fatigue
Drugs – e.g. edrophonium for diagnosis, pyridostigmine for maintenance
Treatment of cognitive impairment in neurodegenerative diseases (e.g. Alzheimer’s disease, Lewy body dementia, etc)
Mechanism: reversible inhibition of AChE and BChE in the brain –> ↑ synaptic ACh in CNS –> ↑ cholinergic transmission
Drugs – e.g. rivastigmine, galantamine, donepezil
Treatment of glaucoma
Mechanism – constriction of sphincter pupillae and ciliary muscles –> miosis –> facilitate outflow of aqueous humor –> IOP decreases
Drugs – e.g. echothiophate eye drops, physostigmine
Treatment of anticholinergic syndrome
Mechanism – increase synaptic ACh Drugs – e.g. physostigmine (tertiary amine + lipophilic –> readily crosses BBB)
Sugammadex
PC
Modified γ-cyclodextrin
8-sugar ring structure
Side chains extend the molecule
Hydrophobic inner
Hydrophilic outer
needing to be stored below 30°C. Use within 5 days if not protected from light
a clear, colourless or pale yellow solution for injection,
available in 2 ml and 5 ml glass vials, containing 100 mg/ml of sugamma-
dex sodium (equivalent to sugammadex 100 mg/ml), It has a pH of between 7 and 8 and an osmolality of between
300 and 500 mOsm/kg. One ml of solution contains 9.7 mg of sodium. The
Solution may also contain 3.7% hydrochloric acid and/or sodium hydroxide for pH adjustment.
Sugammadex
Mode of action
encapsulates the steroid portion of aminosteroidal molecules within its hydrophobic interior in a 1:1 ratio. The negatively charged carboxyl groups bind to the positively charged nitrogen atom on the aminosteroidal molecule. This binding of the NMB drug ↓ the
amount of free drug within the central compartment, thereby establishing a concentration gradient and resulting in movement of the NMB drug
away from the effector site towards the central compartment. The resultant reduction in competitive antagonism of acetylcholine at nicotinic (N2)
receptors at the post-synaptic membrane of the neuromuscular junction leads to successful binding of acetylcholine and rapid re-establishment of neuromuscular function.
Affinity for rocuronium > vecuronium»_space; pancuronium. Binding of vecuronium is 1/3 as tight as for rocuronium, but because an equipotent dose of vecuronium has 6 times less molecules than rocuronium, effectiveness of reversal is similar for both drugs
Sugammadex dosing + Onset
IV single boolus injection
TOFC > 2, 2mg/kg in 3 minutes
deep block (only post-tetanic twitches are present) PTC > 2, 4 mg/kg
Profound blockade (no PTC) e.g. post 1.2 mg/kg rocuronium, 16 mg/kg
Use (40%CBW) = IBW + 0.4 (TBW − IBW) for obese patients
onset 1-3 mins
Slightly faster w roc than vec
Sugammadex Duration + delay recommended prior to use of amino steroid relaxant again
Elimination half-life 1.8 hours - 90% excreted in 24 hours
24 hour delay recommended prior to use of amino steroid relaxant again
May require longer delay if pt has ↓ renal function
Sugammadex Effects / toxicity / side effects
Inadequate reversal
If an insufficient dose is given, may result in partial reversal or seemingly adequate reversal followed by recurarization, as previously redistributed NDMR is mobilized back to NMJ
If a patient needs to be reparalysed < 2hrs after sugammadex administration, eg for reintubation, a higher dose of rocuronium > 0.6mg/kg may be required or alternatively suxamethonium could be used instead
Possibly beneficial in rocuronium anaphylaxis
Also causes anaphylaxis at similar rate to rocuronium - 1 in 2500
Bradycardia
Lower risk than that of neostigmine - minimal effect overall
Binds to (steroid hormones) progesterone in oral contraceptive pill → equivalent to missing one dose of OCP, non-hormonal contraception should be used for a period of 7 days after sugammadex administration
? May interfere with pregnancy in the early stages
Binds factor Xa, No clinical increase in bleeding, Transient prolongation of APTT/PT/INR
Dysgeusia (bad taste)
No muscarinic effects, no need for co-adminstration of anticholinergics (antimuscarinics)
Much greater cardiovascular and autonomic stability
Caution use in renal failure
Anaphylaxis rate ~ 1/2500
displacement of bound neuromuscular block from sugammadex may theoretically occur, leading to reoccurrence of neuromuscular blockade if the following drugs are administered within 6 hours of a patient receiving sugammadex: toremifene, flucloxacillin, fusidic acid
Sugammadex
PK
biologically inactive
not bound to protein
VD is 11–14 L
minimally metabolized
excreted unchanged in the urine
clearance is 88–120 ml/min, and the elimination half-life is
1.8 hours. More than 90% of a given dose is excreted within 24 hours.
Ninety-six percent of the dose is excreted in the urine, with up to 95% as
unaltered drug. Excretion via faeces or expired air was <0.02% of the dose
in clinical studies.
Clearance ↓ and half-life ↑ in renal failure
Lack of safety data in ESKD so should be avoid unless absolutely necessary
Overview of determinants of speed and adequacy of recovery
TTPE varies with presynaptic Ach reserve and spontaneous rate of recovery from NMB
Rate of spontaneous recovery depends on
NMBA used
Dose administered
Patient factors- e.g. temperature
Pathological processes
e.g. as hypokalaemia
Drug factors
Is the time since the last dose a reliable indicator that spontaneous recovery has occurred
Time since last dose of relaxant is not a reliable indicator that spontaneous recovery has occurred
In one study of healthy volunteers given 0.1mg/kg vecuronium, at the 3hr mark, 3 out of 10 still had a reduced TOFR of 0.6 – 0.7
Cholinergic crisis
Causative agents
organophosphates
carbamate insecticides
physostigmine
edrophonium
mushrooms
sarin nerve gas
Cholinergic crisis
Symptoms
DUMBELLS
Diarrhoea / ↑GI peristaltic activity
diarrhoea
abdominal spasm and pain, possible disruption of bowel anastomosis
Urination — relaxation of internal sphincter muscle of urethra, contraction of detrusor muscle
Miosis — stimulation of the constrictor pupillae muscles
(3 killer Bs)
Bronchospasm –> ↑work of breathing
Bronchorrhoea –> ↑Tracheobronchial secretions
bradycardia –> AV block –> ↓Cardiac output
Emesis –> ↑ PONV
Lacrimation
Lethargic
Sweating, salivation, ↑secretions (↑aspiration risk)
Cholinergic crisis
Treatment
atropine: 0.02mg/kg boluses -> double the dose every 3-5 minutes, treats bradycardia, hypotension and excess secretion production
benzodiazepines: midazolam 0.2mg/kg, seizures or agitation
CVVHDF: not recommended
NaHCO3 can be used to correct acidosis (?shortens ventilation time)
Organophosphate –> pralidoxime chloride 30mg/kg IV -> 8mg/kg/hr: muscle weakness, which promotes hydrolysis and removes the phosphate group, however it must be administered early, as within a few hours the phosphorylated enzyme undergoes a chemical change (‘aging’) that renders it no longer susceptible to reactivation
What is this molecule?
Neostigmine
