Neuromuscular Blockade Flashcards
NMJ Neurotransmission-ACh Release?
Ach is released from pre-synaptic vesicle into the synapse
How do the cation channels get opened?
binding (2 ACh) of Nicky R opens cation channels and INCREASES Na+ and K+ conductance.
What is a muscle twitch?
AP-dependent increase in intracellular calcium followed by an Cai fall due to sequestration by SR
Why does the axon get so close to the target?
ensure that NT release creates a response
What is Clonus?
reduced ability to lower Ca between stimulations due to inreased frew of stimulation leads to incomplete relaxation
Define tetanic contraction
no appreciable reduction in Cai between stimuli leads to physiological mu contraction.
Why is the availability of fast Na channels important?
propagation of AP is dependent on it. channel must be in a RESTING STATE (to maintain AP)…linked to way of inducing paralysis
(proper skeletal mu contraction requires 5 things)
- Ach release
- available Nicky R
- summation of EPPs to produce AP
- activation of fast Na+ channels
- increased intracellular calcium
What are the two types of neuro.mu relaxants acting on nicky R?
non-depolarizing agents (curare drugs)-competitive antagonist of Nm receptor
AND depolarizing agents-bind to nicky R, stay there; prolonged activation of Nm and membrane DEpolarization (Succinylcholine)
What are three examples of non-depolarizing blocking drugs?
D-TUBOCURARINE
PANCURONIUM
VECURONIUM
What is the mech of action of ND Drugs?
- mech of action: competitive ANTagnist at nicky ACH R
- overcome by excess ACh thru: tetanic stimulation and AChE inhibitors
- At higher concentrations blockade (plugging) of channel pore develops less sensitive to excess ACh inhibitors-wont to avoid this because drug will act in a NON-COMPETITIVE manner)…therefore use stimulus to know how many receptors are being used so that you dont go overboard
Clinical Characteristics
competitive binding of curare-likeD to the nicky R prevents opening of nicky R ion channel thus preventing membrane depolarization and end-plate potentials
What does choice of drugs depend on?
desired PK parameters
- short vs. long t1/2 (depends on route of elimination…)
- renal > hepatic clearance > plasma cholinesterase
Curare Info
rapid distribution (dont cross BBB) t1/2 depends on how drug is eliminated
Fun drugs
(**know how long they act RELATIVE TO EACHOTHER)
PANCURONIUM: 75-107…renal 30-80%
TUBOCURARINE: 107-237
VECURONIUM: 61.1…>25 renal (good for pt with liver failure)
MIVACURIUM: ~3-5..cholinesterase (use for renal/liver probs)
ROCURONIUM: ~60…80-90 liver
(tub>pancuro>vecuro=rocuro>miva
(two ~1hr but one eliminated by liver vs kidney)
Why is Receptor Reserve relevant?
significant R occupancy by antagonist is required before an effect (to prevent muscle twitch)=large RR (for agonist)
RR
biological t1/2 of the curare compounds tend to be longer than their therapeutic effect (**duration of action)
What about ANTAGONIST?
percentage of R that must be occupied by an ANTAGONIST to inhibit contraction is directly related to the RR.
Clinical Uses of ND NM relaxants
- surgical procedures (many diff drugs); adjuvant to anesthesia during surgery-choice depends on length of surgery and liver/renal function
- relaxation of larynx for endotracheal intubation (rocu and micu)
- relaxation of chest during mechanical ventilation (choice depends on liver and renal fxn)
Side Effects
non-analgesic-with these blockers wont respond to pain
apnea-paralyze respiratory muscles-MUST ventilate pt
histamine release (mivacurium)
-hypOtension, bronchospasm
musky blockade (pancuronium, rocuronium)
-increased HR and CO, troublesome for pt with CHD
Muscle weakness followed by paralysis
- affects small muscles first then large muscles of limb and trunk
- *-order: extraocular, hands and feet, head and neck, abdomen and extremities, diaphragm-respiratory muscle (recovery is in reverse order)
Drug Interactions
Inhalation anesthetics (enhaned effect) AB (enhance efects, particularly aminoglycosides)
Chemical Antidotes
Cholinesterase inhibitors-neostigmine (can also work at musky)
Muscarinic blocker-to minimize effet of ChE inhibitor–glycopyrate
Depolarizing Blocking D-AGONISTS major example?
Succinylcholine
Succinylcholine mech of action P1?
Phase I: Depolarization Block
- depolarization of mu with sustained contractions (opens cation channel to cause EPP)
- flickering of channel due to channel blockade
- flaccid paralysis
- **ChE inhibitors augment blockade
Succinylcholine mech of action P2?
- *prolonged exposure to succinycholine (>~30 min, membrane becomes REPOLARIZED) leads to PII
- mechanism unknown, may deal with R desensitization
- R gets INSENSITIVE to ACh (and other agonists)
***What causes DEPOLARIZATION of the membrane?
Plasma ChE is not available at the synapse, therefore DEPOLARIZATION of the membrane is prolonged. This results in inactivation of voltage-gated Na+ channels. The Na+ channels cant regain their resting state until the membrane is REPOLARIZED…consequently: nor further AP can be propagated=FLACCID PARALYSIS!
PK of DEpolarizing Drugs
- more rapid onset of action than non-depolarizing agents
- rapidly metabolized inplasma by cholinesterase (not at synapse)
- action terminated by diffusion of drug away from motor end plate
- ***genetic variant in ChE can prolong drug action (t1/2-longer for it to be broken down)
Clinical Uses of Succinylcholine
-endotracheal intubation
-control convulsion during ECST (electro-convulsive shock therapy)
(only two because of all the side effects)
Side Effects of Succinylcholine
- non analgesic
- apnea
- muscle pain (from fasciculations)
- exacerbate problems if they have glaucoma or intestinal block-could be damaged because of excessive intestinal motility
- stimulation of nicky R of autonomic ganglia and cardiac musky R in sinus node (arrhythmia, hypErtension. bradycardia)
- hypErkalemia due to K+ release from motor end plate (associated with burns or nerve damage)
- can initiate malignant hyperthermia (in children with undiagnosed muscle myopathies)
Antidotes Phase I Succinylcholine
(no chemical ones) time for diffusion (5-10 mins) away from synapse and hydrolysis by plasma ChE
Antidote Phase II Succinylcholine
Can just use ChE inhibitor to reverse paralysis
Ci of Succinycholine
-fam history of malignant hyperthermia
-burns (immediate aftermath)
-major soft tissue injury (over past 7-10 days)
skeletal mu myopathies (associated with genetic variants that may initiate malignant hyperthermic response)
(What are the indications of Spasmolytic Drugs?)
heightened skel.mu tone due to:
- release from inhibitory supraspinal control
- increased activity of facilitory pathways
- heightened excitability of alpha and gamma motor systems
Types of Spasmolytic Drugs: BACLOFEN
Mech of action: GABAb agonist, reduces Ca influx, therefore reduces the release of excitatory transmitters (at that skeletal.mu)
Clinical Usages: spinal spasticity due to MS
Toxicity: drowsiness (crosses BBB)
(**intrathecal catheter-passed by spinal cord, can reduce side effects, less of drug in the brain)
Tx of spasticity
- reduce activity of Ia fibers that excite the primary motor neuron
- enhance activity of inhibitory internuncial neurons (innervated by cutaneous afferents-heat, pain)
Types of Spasmolytic Drugs: Benzodiazepines (DIAZEPAM
Benzo=positive allosteric modulators of GABAa R INCREASE GABA-mediated Cl- influx
MOA: facilitate GABA-mediated pre-synaptic inhibition
Clinical usages: spinal spasticity, MS
Side Effects: sedation and drowsiness
Types of Spasmolytic: TIZANIDINE
Mech of action: alpha TWO adrenergic agonists
Clinical Use:
Side Effects: drowsiness and hypotension
Types of Spasmolytic: DANTROLENE
Mech of Action: blocks ryadonine receptor
Clinical Usages: spasticity and malignant hyperthermia
toxicity: muscle weakness, sedation, hepatitis (inflames the liver–therefore not used that often)
