SKELETAL MUSCLE RELAXANTS Flashcards
Define 2 types of skeletal muscle relaxants?
• Neuromuscular blockers. Used during surgical procedures and in ICUs to cause paralysis.
• Spasmolytics.
Used to reduce spasticity
in a variety of neurologic conditions.
Division of skeletal muscle relaxants and types?
Neuromuscular blockers
Antagonists (Non depolarizing blockers)
Agonists (Depolarizing blockers)
Spasmolytics
For chronic spasm
For acute spasm
CHEMISTRY: NON-DEPOLARIZING BLOCKERS
CHEMISTRY: DEPOLARIZING BLOCKERS?
• Non-depolarizing blocking drugs are classified
according to their chemical structure into
benzylisoquinolines and ammonio steroids.
• The depolarizing blocker succinylcholine is two
acetylcholine molecules linked end-to-end.
List 4 Benzylisoquinolones and 3 Ammoni steroids
Benzylisoquinolines Ammonio steroids Tubocurarine Atracurium Cisatracurium Mivacurium
Ammonio Steroids
Pancuronium
Rocuronium
Vecuronium
MOA NONDEPOLARIZING BLOCKERS
• They are competitive antagonists.
• Tubocurarine is the prototype.
• Their action can be overcome by increasing the concentration of acetylcholine in the synapse.
• This can be achieved with neostigmine or
edrophonium.
• During anesthesia, nondepolarizing blockers first cause motor weakness
• Ultimately, skeletal muscles become totally
flaccid and inexcitable to stimulation.
MOA: DEPOLARIZING BLOCKERS?
• Succinylcholine activates the nicotinic receptor and depolarizes the junction.
• This causes fasciculations.
• Succinylcholine is not metabolized effectively by
acetylcholinesterase.
• The membrane remains depolarized and unresponsive to additional impulses.
• Flaccid paralysis results.
• The onset of neuromuscular blockade is very
rapid, usually <1 minute.
• Because of its rapid hydrolysis by plasma
pseudocholinesterase, duration of block is 5-10
minutes.
PHARMACOKINETICS OF
NEUROMUSCULAR BLOCKERS?
• Neuromuscular blockers contain quaternary
ammonium groups.
• They are highly polar and poorly soluble in lipid.
• Inactive if given by mouth.
• Penetrate membranes very poorly.
• Do not enter cells or cross the BBB.
• Always given IV or IM.
Non depolarizing duration of action
SHORT ACTING
Mivacurium
INTERMEDIATE ACTING Atracurium Cisatracurium Rocuronium Vecuronium
LONG-ACTING
Tubocurarine
Pancuronium
Metabolism of Non-depolarizing blockers?
• Drugs that are excreted by the kidney typically
have longer half-lives, leading to longer
durations of action.
• Drugs eliminated by the liver tend to have
shorter half-lives and durations of action.
BENZYLISOQUINOLINES Drug, elimination mechanism and duration of action?
Atracurium
Enzymatic & nonenzymatic
ester hydrolysis
45 min
Cisatracurium
Spontaneous (80%) and renal
45min
Mivacurium
Plasma pseudocholinesterase
15 min
Tubocurarine
Renal and hepatic
80 min
AMMONIO STEROIDS Drug, elimination mechanism and duration of action?
Pancuronium
Renal (80%) and hepatic 90
Rocuronium
Hepatic (80%) and renal 30
Vecuronium Hepatic (80%) and renal 45
Metabolism of Atracurium?
ATRACURIUM
• Atracurium is inactivated by hydrolysis by nonspecific plasma esterases and by a
spontaneous reaction.
• No increase in half-life in patients with renal failure.
• One of atracurium metabolites is laudanosine.
• Laudanosine, may cause hypotension and seizures.
Metabolism of Cisatracurium?
CISATRACURIUM
• Cisatracurium, a stereoisomer of atracurium
forms much less laudanosine.
• Cisatracurium also causes less histamine release.
• Cisatracurium has largely replaced atracurium in clinical practice.
Metabolism of Mivacurium?
MIVACURIUM
• Mivacurium is the only nondepolarizing blocker classified as short acting.
• Hydrolysis by plasma butyrylcholinesterase is the primary mechanism for inactivation.
• Not dependent on liver or kidney.
Metabolism of Rocuronium?
ROCURONIUM
• Rocuronium has the most rapid onset among nondepolarizing blockers.
• Can be used as alternative to succinylcholine for
rapid sequence intubation.
Metabolism of Succinylcholine?
SUCCINYLCHOLINE
• Succinylcholine has extremely short duration of
action (5–10 minutes).
• Due to hydrolysis by butyrylcholinesterase.
Consequence of POLYMORPHISMS OF
BUTYRYLCHOLINESTERASE?
• Neuromuscular blockade by succinylcholine and
mivacurium may be prolonged in patients with an abnormal variant of butyrylcholinesterase.
• Treated with mechanical ventilation until muscle function returns to normal.
ADVERSE EFFECTS:
NON-DEPOLARIZING BLOCKERS?
• Some benzylisoquinolines may cause hypotension due to histamine release and
ganglionic blockade.
• Some ammonio steroids may produce tachycardia due to blockade of muscarinic receptors, which may lead to arrhythmias.
ADVERSE EFFECTS:
NON-DEPOLARIZING BLOCKERS in regards to histamine release?
HISTAMINE RELEASE
• Tubocurarine, and to a lesser extent, mivacurium and atracurium may release
histamine.
• Antihistamines are useful particularly if given before the neuromuscular blocker.
ADVERSE EFFECTS:
NON-DEPOLARIZING BLOCKERS in regards to ganglionic blockade?
GANGLION BLOCKADE
• Tubocurarine may block nicotinic receptors of
the autonomic ganglia and the adrenal medulla.
• This causes hypotension and tachycardia.
ADVERSE EFFECTS: NON-DEPOLARIZING BLOCKERS
in regards to BLOCKADE OF CARDIAC M2 RECEPTORS
BLOCKADE OF CARDIAC M2 RECEPTORS
• The ammonio steroid pancuronium causes
moderate tachycardia due to blockade of cardiac
M2 receptors.
• The cardiovascular effects of pancuronium are
usually not a problem.
AE of depolarizing blockers? List 7
• Succinylcholine activates all autonomic cholinoceptors:
• Nicotinic receptors in both sympathetic and
parasympathetic ganglia
• Muscarinic receptors in the heart.
- Bradycardia
- Histamine Release
- Muscle Pain
- Hyperkalemia
- Increased Intraocular Pressure
- Increased Intragastric Pressure
- Malignant Hyperthermia
• No CNS effects due to their inability to penetrate the blood-brain barrier.
• Drugs that enhance neuromuscular blockade:?
- Inhaled Anesthetics
- Aminoglycosides
- Tetracyclines
EFFECTS OF DISEASE AND AGEING ON DRUG RESPONSE?
• Several diseases can decrease or increase the
neuromuscular blockade caused by nondepolarizing muscle relaxants.
• Myasthenia gravis increases neuromuscular blockade.
• Advanced age prolongs blockade, probably due
to decreased drug clearance.
• Patients with severe burns and those with upper motor neuron disease are resistant to nondepolarizing muscle relaxants. Due to proliferation of extrajunctional receptors.
DEPOLARIZING BLOCKERS:
CONTRAINDICATIONS? List 6
- History of malignant hyperthermia
- History of skeletal muscle myopathies.
- Major burns.
- Multiple trauma
- Denervation of skeletal muscle
- Upper motor neuron injury.
USES OF NEUROMUSCULAR BLOCKERS
• Main clinical use: adjuvants in surgical
anesthesia to obtain relaxation of skeletal muscle.
• Succinylcholine is used to facilitate endotracheal intubation during induction of anesthesia. Also used during ECT.
REVERSAL OF NONDEPOLARIZING
NEUROMUSCULAR BLOCKADE?
• Upon completion of a surgical procedure neostigmine or edrophonium can be given to reverse competitive blockade.
• Atropine or glycopyrrolate are
used concomitantly to prevent bradycardia.
DRUGS FOR CHRONIC SPASM two divisions?
• DRUGS THAT ACT IN THE CNS
• DRUGS THAT ACT ON THE SKELETAL
MUSCLE
3 drugs that act on cns and moa?
DIAZEPAM
• Facilitates action of GABA at GABAa receptors.
BACLOFEN
• GABA agonist at GABAb
receptors.
TIZANIDINE
• Agonist at alpha2-adrenoceptors in the CNS.
DRUGS THAT ACT ON THE
SKELETAL MUSCLE and moa?
DANTROLENE
• Interferes with the release of Ca2+ by binding to the ryanodine receptor in the
SR of skeletal muscle.
• Also used in malignant hyperthermia.
BOTULINUM TOXIN
• Botulinum toxin is now finding increased application in the treatment of more
generalized spastic disorders, e.g. cerebral palsy.
DRUGS FOR ACUTE SPASM?
• Centrally acting drugs. • Used for relief of acute muscle spasm caused by local trauma or strain. • It has been suggested that these drugs act primarily at the level of the brainstem. • Cyclobenzaprine is the prototype. • Structurally related to the TCAs. • Strong antimuscarinic side effects.
