Drugs that affect skeletal muscle function fall into two major therapeutic groups:
- Neuromuscular blockers
Neuromuscular blockade can be accomplished with drugs acting by two different mechanisms:
- Antagonists (non depolarizing blockers): prevent access of AcH to its receptors – tubocurarine
- Agonists (depolarizing blockers): activate nicotinic receptors leading to desensitization and blockade – succinylcholine (two AcH molecules lined end to end)
Non-depolarizing blockers are classified according to their chemical structure into benzylisoquinolines and ammoniosteroids. what are these drugs?
–Tubocurarine, Atracurium, Cisatracurium and Mivacurium
–Pancuronium, Rocuronium and Vecuronium
What is the MOA of nondepolarizing blockers?
–act at the nicotinic receptor site by competing with AcH.
Their action can be overcome by increasing the concentration of AcH in the synaptic cleft
–can give neostigmine or edrophonium for this
–this strategy is used to shorten the duration of the neuromuscular blockade
In larger doses, nondepolarizing blockers also do what?
Enter the pore of the ion channel
–this causes more intense motor blockade.
Nondepolarizing blockers may also block what?
Prejunctional sodium channels
–they reduce the release of AcH at the nerve ending
What is the MOA of depolarizing blockers?
Succinylcholine (ultrarapid onset/ultrashort duration)
- -binds to the nicotinic receptor and acts like AcH to cause depolarization of the end plate
- -this spreads and depolarizes adjacent membranes, causing transient fasciculations
- -it is not metabolized effectively at the synapse therefor the membrane remains depolarized and unresponsive to additional impulses therefore a flaccid paralysis results this is called phase I block or depolarization block
The onset of neuromuscular blockade is rapid, usually within 1 minute, why?
Rapid hydrolysis by plasma butyrylcholinesterase (pseudocholinesterase)
-duration of neuromuscular block is 5-10 minutes
With a single large dose, repeated doses, or prolonged continued infusion with succinylcholine the membrane repolarizes; despite this repolarization what happens?
The membrane cant be depolarized again because it is desensitized
- -the channels behave as if they are in a prolonged closed state
- -this is called phase II block or desensitization block
- phase II can be reversed
Compare and contrast Tubocurarine (competitive muscle relaxant) and Succinylcholine (depolarizing muscle relaxant). Table page 3
Administration of tubocurarine: Additive
Administration of Succinylcholine: Antagonistic
Effect of Neostigmine: Antagonist
Initial Excitatory effect on skeletal muscle: none
Rate of recovery: 30-60 minutes
Administration of tubocurarine: Antagonistic (phase I) and Augmented (Phase II)
Administration of Succinylcholine: Additive (phase I) and Augmented (Phase II)
Effect of Neostigmine: Augmented (phase I) and Antagonistic (phase II)
Initial Excitatory Effect on Skeletal Muscle: Fasciculations (phase I) and None (phase II)
Rate of Recovery: 4-8min (phase I) and over 20 min (phase II)
All neuromuscular blocking agents contain what?
One or two quaternary ammonium groups
–this makes them highly polar and very poorly soluble in lipid
Neuromuscular blockers are inactive if given by mouth why?
They penetrate membranes very poorly and do not enter cells or cross the blood brain barrier
Classify the non depolarizing blockers according to their duration of action
Short Acting: --Mivacurium (15 min) Intermediate - Acting: --Atracurium (45 min), Cisatracurium (45 min), Vecuronium (45 min) and Rocuronium (30 min) Long Acting --Tubocurarine (80 min) --Pancuronium (90 min)
Classify the non depolarizing blockers according to their elimination mechanism, first Atracurium
Atracurium– enzymatic and nonenzymatic ester hydrolysis. Inactivated by hydrolysis by non specific plasma esterases and by spontaneous reaction (Hoffman elimination). Duration of neuromuscular block is not altered by the absence of renal function
Next non depolarizing blockers are Laudanosine and Cisatracurium
- -Laudanosine is a atracurium metabolite. Causes transient hypotension and even seizures
- -Cisatracurium: undergoes Hoffman elimination to form Laudanosine. More potent drug than atracurium so lower doses required therefore laudanosine concentrations following admin are lower. therefore cisatracurium has replaced atracurium
Next non depolarizing blockers are Mivacurium and Rocuronium
–Mivacurium:hydrolysis by butyrylcholinesterase causes inactivation, not dependent on liver or kidney
–Rocuronium: most rapid onset; can be used as alternative for succinylcholine
Moving on to depolarizing blockers, what is the reason for the extremely short duration of action of succinylcholine?
Rapid hydrolysis by plasma butyrylcholinesterase
–may be prolonged in patients with abnormal variant of butyrylcholinesterase (needs to be treated with mechanical ventilation until muscle function returns)
Moving on to Adverse effects of Non-depolarizing blockers. What are some of these?
- Tubocurarine, Mivacurium and Atracurium: produce hypotension as a result of histamine release
- -erythema at the face and upper chest, a transient decrease in blood pressure and an increase in heart rate
- -more severe includes bronchospasm and circulatory collapse
- -give antihistamines before blockade
- Tubocurarine: causes blockade of nicotinic receptors of the autonomic ganglia and adrenal medulla, therefore fall in BP and tachy.
- Pancuronium: tachy due to blockade of cardiac muscarinic receptors
Moving on to adverse effects of depolarizing blocker. There is stimulation of nicotonic receptors in both sympathetic and parasympathetic ganglia and muscarinic receptors in heart. therefore what are some adverse effects?
Bradycardia: activation of muscarinic receptors
Hyperkalemia: loss of tissue potassium during depolarization
Increased Intraocular Pressure
Increased Intragastric Pressure
Malignant Hyperthermia: AD disorder of skeletal muscle
(usually arise from succinylcholine and an halogenated anesthetic ; treat with dantrolene)
CNS: do not penetrate BBB so none
What are the drug interactions for non and depolarizing blockers?
Inhaled anesthetics: increase neuromuscular blockade evoked by nondepolarizing muscle relaxants
Aminoglycosides: produce neuromuscular blockage by inhibiting AcH release from the preganglionic terminal
Tetracyclines: produce neuromuscular blockade
Several diseases can decrease or increase the neuromuscular blockade caused by nondepolarizing muscle relaxants, what are these?
- Myasthenia Gravis: increases neuromuscular blockade
- Advanced Age: prolonged duration of action from non depolarizing relaxants
- Patients with severe burns and those with upper motor neuron disease are resistant to nondepolarizing muscle relaxants
Succinylcholine is therefore contraindicated in whom?
- Persons with personal or familial history of malignant hyperthermia, skeletal muscle myopathies
- Patients with major burns, multiple trauma, extensive denervation of skeletal muscle, or upper motor neuron injury (may lead to severe hyperkalemia)
How are nondepolarizing neuromuscular blockade reversed?
- Neostigmine, Pyridostigmine and Edrophonium
- -acteylcholinesterase inhibitors
- -used in tx with overdose
- -used to reverse and decrease duration of competitive neuromuscular blockade
- -atropine is used to prevent stimulation of muscarinic receptors and avoid bradycardia
What is the main clinical use of neuromuscular blockers?
Adjuvants in surgical anesthesia
–obtain relaxation of skeletal muscle
Succinylcholine is used to facilitate endotracheal intubation during induction of anesthesia
Briefly lets discuss spasmolytic drugs. First are drugs for chronic spasm and within this category are drugs that act in the CNS. what are these ?
- Diazepam: facilitate action of GABA at GABAa receptors
- -muscle spasm of almost any origin
- Baclofen: orally active GABA agonist at GABAb receptors
- -useful for spasticity from MS
- Tizanidine: agonist at alpha 2 adrenergic receptors in the CNS
- -acts by increasing presynaptic inhibition of motor neurons
- -used in MS and spinal cord injury
The other category in chronic spasm drugs are drugs that act on the skeletal muscle, what are these?
- Dantrolene: interferes with release of Ca2+ by binding to the ryanodine receptor in the SR of skeletal muscle
- -AE: generalized muscle weakness, sedation and hepatitis
- -used in malignant hyperthermia
- Botulinum Toxin
- -injected locally into muscles to treat a form of persistent disabling eyelid spasm
Now drugs used for acute local muscle spasm
- -relief of muscle spasm associated with acute, painful musculoskeletal conditions
- -not effective for cerebral palsy or spinal cord injury
- -related to TCA structurally, therefore has strong antimuscarinic side effects