BT_GS 1.38 - Adverse effects and factors modifying responses Flashcards
(17 cards)
Post sux desensitisation blockade only need __/__ of NDMR for same duration of effect as full dose without sux
1/3
In what diseases do you see upregulation of the ACh receptor, time course
UMN lesions
LMN lesions
polyneuropathy in the absence of a complete transection of the nerve can cause a high K+ response to SCh
Muscle trauma
Burn injury
Burn of a single limb (8–9% body surface area) is sufficient to cause lethal hyperkalemia following succinylcholine Immobilisation
Sepsis / infection
Time course
Initiated within hours, takes several days for full proliferation
Describe the pathophysiology of ↑ the Expression of ACh receptor
When innervation and electrical conductivity are established between muscle and nerve, the mature receptors are localized only to the NMJ.
Deprivation of neural influences on muscle –> up regulation AChR + spread of the receptors beyond the neuromuscular junction into the peri- and extrajunctional areas.
Instead of the mature adult receptor with an ε subunit (ε for elderly) (2⍺1, β1, δ, 𝛆) that is expressed in the normal junction. new immature fetal receptors containing a γ subunit (y for young) (2α1β1δγ), are reexpressed, they have an altered ligand sensitivity and affinity. ⍺7 receptors are also expressed.
Immature receptors are referred to as extrajunctional, as they are expressed mostly but not exclusively in the extrajunctional region of the muscle membrane.
⍺7 receptors are homomeric comprised of 5 alpha subunits
Immature receptors (2α1β1δγ)
Smaller conductance per channel
2-10x longer mean channel opening time
Variable sensitivity and affinity e.g. ACh and SCh depolarise this isoform of the immature receptor more easily, requiring only 1-10% of the dose nessecary to depolarise mature receptors.
↓ affinity for NDNMB
⍺7 receptors
Activated by ACh and SCh but also by their metabolites succinylmonocholine and choline
↓ affinity for NDNMB
How does MG affect the use of muscle relaxants?
↓AChR number, loss of post-synaptic fold and voltage gated Na+ channels
Fewer AChRs are opened by each quantum of ACh release, the amplitude of MEPP is ↓
↑ sensitivity to NDMRs
Continuous assessment via NM monitoring advised
renders SCh less capable of depolarizing the endplate effectively and raises the dose requirements of SCh.
For RSI it is advisable to ↑ dose SCh to 1.5–2 mg/kg.
Higher doses may cause a nondepolarizing type block (Phase II block and Desensitation block).
continuation of the treatment of myasthenics with cholinesterase inhibitors during the perioperative interval can cause delayed hydrolysis of SCh and prolong the neuromuscular block.
discontinuation of cholinesterase inhibitor therapy is, however, not recomended.
How does Lambert-Eaton Syndrome affect the use of muscle relaxants?
paraneoplastic disease associated with small-cell carcinoma, usually of lung origin.
antibodies directed against the PQ-type voltage-gated Ca2+ channels, possibly due to a cross-reaction with the calcium channels on the carcinomatous cells
caused by a prejunctional mechanism that results in the decreased quantal release of acetylcholine. there is a ↓ in the number of and size of active zones
↑ sensitivity to both nondepolarizing and depolarizing muscle relaxants
Continuous assessment via NM monitoring advised
In contrast to myasthenia gravis, repetitive (e.g., train-of-four) stimulation results in enhancement, and not fade, of twitch.
How does Botulinum toxin affect the use of muscle relaxants?
7 different serotypes of organisms, each producing different toxins
E.g. toxin types A and B target the SNAP-25 protein of the SNARE complex –> block in release of ACh –> de-nervation –> accompanying muscle paralysis and atrophy
Causes upregulation of muscle NAChRs, with ↑ sensitivity to NMBs
SCh –induced hyperkalaemia, has been reported following
botulinum toxin poisoning
Wound botulinism
Define peak effect
minimum post-tetanic count
Outline the Factors potentiating (↑ depth) of NMB (would correlate with a lower post-tetanic count, or duration of time with no post tetanic count)
Pre-Junctional Mechanisms
Post-Junctional Mechanisms
- Direct blockade
- Desensitisation block
- Channel block
- Inhibits post-junctional membrane potential generation → ↓membrane excitability (membrane stabiliser)
- Dantrolene
Pathological factors
Factors potentiating (↑ depth) of NMB (would correlate with a lower post-tetanic count, or duration of time with no post tetanic count)
Pre-Junctional Mechanisms
Deficiency blockade - drugs can ↓pre-junctional release of ACh via 3 mechanisms
Block pre-junctional ACh receptors → prevent positive feedback → ↓ACh release
Volatile anaesthetics
↓cAMP synthesis → ↓ACh release
Frusemide
Block pre-junctional Ca channels → ↓ACh release
Volatile anaesthetics
Aminoglycosides, clindamycin, polymyxins (main mech of action)
Ca channel blockers (verapamil)
Magnesium
Factors potentiating (↑ depth) of NMB (would correlate with a lower post-tetanic count, or duration of time with no post-tetanic count)
Post-Junctional Mechanisms –> Direct blockade
NDMRs ↑ dose –> ↑[NDMR] at synaptic cleft
E.g. rocuronium 2xED95 (0.6mg/kg) will effect a lower PTC than 1xED95 roc (0.3mg/kg)
NDMRs ↑ potency e.g. vecuronium ED95 0.05mg/kg vs rocuronium ED95 0.3mg/kg (molar potency similar) if you gave the 0.05mg/kg dose of each then you would get a deeper block with vecuronium
volatile anaesthetics: direct nAChR inhibition + ↓affinity of NMB for nAChR
other non-depolarising neuromuscular blockers: same class = additive effect; different class = synergistic effect
Volatile anaesthetics, ketamine, midazolam, barbiturates
Aminoglycosides (secondary mech of action), TCAs, quinidine
↑ ACh concentration caused by AChE inhibitor
Factors potentiating (↑ depth) of NMB (would correlate with a lower post-tetanic count, or duration of time with no post-tetanic count)
Post-Junctional Mechanisms –> Desensitisation blockade
Effects are mediated by allosteric inhibition of receptors by binding of the drug to sites other than ACh binding sites.
presence of desensitized receptors –> ↓ functional receptor channels available to induce a transmembrane current –> ↓ margin of safety of neuromuscular transmission –> ↑ the susceptibility to antagonists, i.e., NDMRs.
If many receptors are desensitized, insufficient nondesensitized normal receptors are left to depolarize the motor endplate, and effective neuromuscular transmission will not occur.
Desensitised ACh receptors are in a conformational state whereby they cannot be activated to open their channel, even when bound by an agonist
This state may be induced by high concentrations of agonists or other drugs
Mechanism unclear, possibly receptor phosphorylation
Desensitisation block can be induced by
Volatile agents, barbiturates
Verapamil, phenothiazines, alcohols
↑ ACh concentration caused by AChE inhibitor
Factors potentiating (↑ depth) of NMB (would correlate with a lower post-tetanic count, or duration of time with no post-tetanic count)
Post-Junctional Mechanisms –> Channel block
Drugs may block the flow of ions through the NAChR cation channel (similar to the mechanism of how calcium channel blockers and local anaesthetics work)
Closed-channel block – drug sits at mouth of closed channel
Open-channel block – drug enters channel while it is opened by ACh activation and binds within channel, hence is a use-dependent block
As this causes non-competitive antagonism of ACh at the NAChR it is not relieved by anticholinesterases
Drugs that can cause channel block include
NDMRs (in addition to their classic action)
Neostigmine
Antibiotics
Cocaine/LA
Naloxone, TCA, quinidine
Factors potentiating (↑ depth) of NMB (would correlate with a lower post-tetanic count, or duration of time with no post-tetanic count)
Post-Junctional Mechanisms –> Inhibits post-junctional membrane potential generation
↓membrane excitability (membrane stabiliser)
Local anaesthetics
Magnesium
lithium
Factors potentiating (↑ depth) of NMB (would correlate with a lower post-tetanic count, or duration of time with no post-tetanic count)
Post-Junctional Mechanisms –> Dantrolene
↓ release of Ca from SR → ↓mechanical response of muscle to stimulation → indirect potentiation of non-depolarising NMBs
Factors potentiating (↑ depth) of NMB (would correlate with a lower post-tetanic count, or duration of time with no post-tetanic count)
Pathological factors
Prejunctional
Lambert-Eaton Syndrome
antibodies directed against the PQ-type voltage-gated calcium channels
↓ quantal release of ACh
Post Junctional
Myasthenia Gravis
Autoantibody production in thymus against ACh receptors –>
↓ number of post junctional ACh receptors
↑ sensitivity to NDMRs (avoid or 10% of usual dose)
Resistance to SCh (↑ dose)
Potentiation of NMB action by volatile anaesthetic rank order
Rank order of potentiation: Desflurane > sevoflurane > isoflurane > halothane > nitrous oxide
Factors that ↓ peak the effect
Physiological
Male: ↑muscle mass
Muscle type –> central muscles e.g. Larynx & diaphragm: ↑blood flow, ↑vesicles, ↑receptors
↑K+ –> Pre-synaptic depolarisation threshold more likely to be achieved -> ↑ACh release
Pathology
Obesity -> ↑pseudocholinesterase
Upregulated foetal type receptor: ααβγδ e.g. in burns, denervation injury (for NDMRs)
Drug factors
↓ dose –> ↓[NDMR] at synaptic cleft
E.g. 1xED95 roc (0.3mg/kg) will produce a higher PTC / max depth than rocuronium 2xED95 (0.6mg/kg)
↓ potency e.g. vecuronium ED95 0.05mg/kg vs rocuronium ED95 0.3mg/kg (molar potency similar) if you gave the 0.05mg/kg dose of each then you would get a less deep block / higher PTC with roc
Drug interactions
Anaesthetic type –> e.g. propofol cf. volatile anaesthetic -> less potentiation
Reversal drug
neostigmine -> ↑[ACh] at NMJ -> displacement from receptors (for NDMRs only)
Sugammadex –> chelates aminosteroids in the plasma –> ↓ aminosteroid in the plasma –> diffuses out of synapse down concentration gradient
