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Skeletal Muscle Relaxants (■ CLINICAL PHARMACOLOGY OF NEUROMUSCULAR…
Skeletal Muscle Relaxants
■ SPASMOLYTIC & ANTISPASMODIC DRUGS
Chronic use
CNS action
TIZANIDINE
mech of action: an imidazoline
related to clonidine w/ significant α2 agonist activity
-->
decr norepi release
,
decr Glu release
; also
potentiates GABA A and B
; reinforces presynaptic inhibition in spinal cord.
Toxicity: may cause
asthenia, drowsiness, dry mouth, and hypotension
OTHERS; gabapentin, pregabalin
Baclofen
mech of action:
reduce Ca influx presynaptically--> decr release of glutamic acid at postsynaptic Rs; facilitates action at GABAB Rs; Reduce pain by inhibiting release of substance P (neurokinin-1) in spinal cord
Toxicity:
less sedation than diazepam
Diazepam: muscle relaxant in low doses
!!!
Muscle action
DANTROLENE
mech of action:
acts in skeletal muscle cell to reduce release of activator Ca from SR
Toxicity:
muscle weakness
BOTULINUM TOXIN: used before to decr muscle tone
ANTISPASMODICS: DRUGS USED TO TREAT ACUTE LOCAL MUSCLE SPASM
cyclobenzaprine, metaxalone, methocarbamol, orphenadrine
Most of these drugs are sedatives or act in
brain stem.
■ BASIC PHARMACOLOGY OF NEUROMUSCULAR BLOCKING DRUGS
Pharmacokinetics:
All highly polar compounds & inactive orally; must be administered parenterally
A. Nondepolarizing Relaxant Drugs: Tubocurarine, Atracurium, Rocuronium, Pancuronium
duration of action
Long: tubocurarine
Short: mivacurium
do not cross BBB
metabolized by plasma cholinesterase
(mivacurium)
bile
(vecuronium);
kidney
(tubocurarine)
atracurium
clearance involves
rapid spontaneous breakdown
(
Hofmann elimination
) to form
laudanosine
. At
high blood levels, laudanosine--> seizures
B. Depolarizing Relaxant Drugs: Succinylcholine
metabolized by cholinesterase (pseudocholinesterase) in liver & plasma
duration of action: only a few minutes
composed of two AChs, resistant to acetylcholinesterase
Mechanism of Action: Blockade of nicotinic cholinergic transmission
A. Nondepolarizing Relaxant Drugs
1) Competitive blockade of nicotinic Ach R
2) Can enter ion channel so cholinesterase inhibitors (neostigmine) can not antagonize them readily
B. Depolarizing Relaxant Drugs: tension cannot be maintained in skeletal muscle w/o periodic repo & depo of end plate--> continuous depo--> muscle relaxation & paralysis
**1. Phase I block (depolarizing):
neuromuscular effects like those of ACh except longer effect at myoneural junction: Prolonged depolarization of muscle fiber, no repo, muscle contracted
Acetylcholinesterase inhibitors augment this phase**
**2. Phase II block (desensitizing)
channel desensitizes
Later stage identical to nondepolarizing drugs
muscle relaxed**
■ CLINICAL PHARMACOLOGY OF NEUROMUSCULAR BLOCKING DRUGS
Cardiovascular and NS Effects:
Succinylcholine stimulates autonomic ganglia and cardiac M2 Rs--> bradycardia
pancuronium: only M R blocking agent in heart among non depolarizants, causes tachycardia; [no effect on autonomic ganglia]
atracurium, vecuronium, [cisatracurium, mivacurium], don't affect autonomic ganglia or heart M2 Rs--> good drugs
tubocurarine: weak block of autonomic ganglia
Other Adverse Effects of Depolarizing Blockade
D. Muscle Pain bc of primary contraction
C. Increased Intragastric Pressure
B. Increased Intraocular Pressure
A. Hyperkalemia
Assessment of Neuromuscular Transmission
B. Depolarizing Relaxant Drugs
A. Nondepolarizing Relaxant Drugs
Interactions with Other Drugs
D. Other Neuromuscular Blocking Drugs
C. Local Anesthetics and Antiarrhythmic Drugs: antiarrhythmic drugs (prolong relaxant effect)
B. Antibiotics: Aminoglycoside antibiotics (prolong relaxant effect)
A. Anesthetics: succinylcholine (and possibly tubocurarine) w/ inhaled anesthetics--> malignant hyperthermia
Skeletal Muscle Paralysis
Effects of Diseases & Aging on the Neuromuscular Response:
Older pxs (>75) & myasthenia gravis more sensitive to actions of nondepolarizing blockers
-
Myasthenia gravis pxs less sensitive to succynilcholine
pxs w/ severe burns or who suffer from upper motor neuron disease less responsive (prolif of extrajunctional nicotinic Rs)
Reversal of Nondepolarizing Neuromuscular Blockade
Uses of Neuromuscular Blocking Drugs
B. Endotracheal Intubation
C. Control of Ventilation
A. Surgical Relaxation
D. Treatment of Convulsions
histamine release from mast cells, allergic reactions, anaphylactic shock; ex succinylcholine (mild release), atracurium (weak), tubocurarine (moderate), vercuronium (none)