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34 Cards in this Set

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How are skeletal muscle agents classified?
1. Based on site of action

2. Based on clinical use
Which different sites of action do skeletal muscle agents work?
1. Neuromuscular junction

2. Spinal Interneurons (polysynaptic reflexes)

3. Skeletal muscle contractile process
Examples of neuromuscular jxn skeletal muscle relaxants.
Presynaptic: botulinus toxin

Postsynaptic: (cis)atracurium
vecuronium
succinylcholine
Examples of spinal interneuron skeletal muscle relaxants.
Diazepam
Baclofen
Examples of skeletal muscle contractile process muscle relaxants.
Dantrolene Na
Describe how drugs which block nerve to muscle conduction can be used.
1. facilitate endotracheal intubation by decreasing neck muscle tone and reducing reflex movement
-- EX: succinylcholine

2. as adjunct in surgical anesthesia to decrease reflex mvmt and to relax skeletal muscle to obtain access to operative sites

3. facilitate assisted (mechanical) ventilation during surgery or in the critical intensive care setting where pts cannot breathe on their own due to injury or surgery

4. local injection of botulinum toxin can be used to
-- reduce muscle contractures (blepharospast, strabismus) and decrease local pain reflexes
-- relax facial muscle for cosmetic purposes
Describe how drugs which block spinal interneuronal conduction (central neuronal blockade) can be used.
1. decrease motor reflexes (spasticity)

2. decrease muscle hypertonicity

3. blockade of skeletal muscle contractile processes (peripheral acting)
-- MALIGNANT HYPERTHERMIA PROPHYLAXIS***
-- spasticity
How can agents block PRESYNAPTIC mechanisms of conduction?
1. block by interfering w/ ACh synthesis

2. block by decreasing ACh release
Which drugs interfere w/ ACh synthesis?
1. hemicholinium blocks the uptake of the precursor choline w/ depletion of vesicular ACh (not used clinically)

2. butyrylcholine inhibits choline acetyltransferase

**neither of these drugs are on the list, I just included this for completion
Which drug blocks ACh release?
Botulinus toxin blocks vesicular release of ACh
-- cleaves presynaptic proteins which are involved in the exocytosis of synaptic vesicles containing ACh
What are the two ways in which we can block POSTSYNAPTIC conduction mechanisms?
1. non-depolarizing (competitive) blocking agents
-- “…uroniums”

2. depolarizing (non-competitive) blocking agents
-- succinylcholine
Describe the non-depolarizing (competitive) blocking agents.
-- contain at least one positively charged quartenary ammonium group permitting electrostatic attraction and binding to the negatively charged alpha subunit of the ACh receptor

-- are large, bulky molecules which bind to the ACh receptor to competitively block the access and thus binding of ACh

-- have affinity for the receptors but lack intrinsic activity; agents bind but do not stimulate (hence term “non-depolarizing”)

-- muscle relaxes due to lack of neuronal input; muscle will still contract if directly apply electrical stimulus to surface

-- recent studies suggest these agents may also block prejunctional Na+ (but not Ca++) channels decreasing ACh release
How can we reverse the non-depolarizing (competitive) blocking agents?
Since blockade is competitive, increasing synaptic ACh by inhibiting ACh breakdown can reverse the block
-- acetylcholinesterase inhibitors can increased synaptic ACh and are administered clinically to reverse the block by competitive agents
Describe the depolarizing (non-competitive) blocking agent.
-- SUCCINYLCHOLINE contains two positively charged quaternary ammonium groups (two ACh molecules linked through acetate and methyl groups)

-- binds to alpha subunit of the ACh receptor w/ both affinity and efficacy and as a result depolarizes the postjxnal ACh receptor (hence term “depolarizing”)

-- depolarization of postjxnal mbrn produces transient “disorganized” muscle contraction appearing as fasciculations

-- succinylcholine also appears to enter motor end plate Na+ channels to produce a “flickering” of ion conductance which is sufficient to trigger a propogated action potential in individual fibers also contributing to muscle fasciculations

-- since succinylcholine is not broken down as rapidly as ACh, it remains bound to the receptor and continuously holds the end plate in a depolarized state (ion flow through channels is sustained)

-- muscle contraction requires cycling btwn end-plate repolarization and depolarization; in absence of cycling, a flaccid paralysis results
Compare a PHASE I block with a PHASE II block
PHASE I – initial blockade due to sustained depolarization
-- increased ACh intensifies the blockade
-- POTENTIATED BY ACETYLCHOLINESTERASE INHIBITION

PHASE II – blockade characteristics consistent w/ a competitive blockade
-- continued occupancy by receptors by succinylcholine, produces receptor DESENSITIZATION and as a result, the mbrn depolarizes
-- characteristic of the blockade are now consistent w/ a competitive blockade, this block can now be REVERSED BY EXCESS ACh (acetylcholinesterase inhibition)
Pharmacokinetics of neuromuscular blockades.
1. All agents are administered parenterally. Onset of blockade varies from 1-7 minutes depending on the agent

2. Increasing dose can shorted induction time, especially w/ the longer acting agents

3. Duration of effect of competitive, non-depolarizing agents largely reflects diffusion away from the active site followed by hepatic metabolism and renal elimination of metabolites

4. Short duration of action of succinylcholine is due to hydrolysis via plasma cholinesterase and diffusion from a receptor
How can we estimate a neuromuscular blockade?
1. Neuromuscular transmission can be monitored by observing the force of muscle contraction evoked by indirect stimulation of a motor nerve

2. “Trans of four” supramaximal stimuli are applied to the ulnar nerve to evoke thumb adduction (contraction of the adductor policis muscle)

3. The estimate of the % neuromuscular transmission is based on the ration of the amplitude of the 4th to the 1st evoked response in the same train provides for assessment of neuromuscular transmission
Which are the non-depolarizing (competitive) agents?
“uroniums”
-- VECURONIUM
-- depending on agent, metabolized by liver or excreted unchanged
-- onset and offset of effects in large part determine utility

CISATRACURIUM
-- purified form of one of the isomers of atracurium
-- both agents undergo spontaneous metabolism in-vivo at normal body temp and pH by Hofmann elimination (base-catalyzed hydrolysis)
-- approx 80% of cisatracurium is cleared by Hoffman elimination w/ the remaining renal mechanisms (thus good to use w/ liver transplants)
Which are the depolarizing (non-competitive) agents?
SUCCINYLCHOLINE CHLORIDE
-- used primarily for brief surgical procedures through the optimal dose varies considerably
-- rapidly hydrolyzed by plasma cholinesterase such that only a small amount reaches the neuromuscular jxn
-- diffusion away from the motor end plate accounts for its brief duration of action
-- patients who have an atypical cholinesterase or low cholinesterase exhibit a prolonged blockade w/ succinylcholine
Adverse reactions to succinylcholine?
Bradycardia
Cardiac dysrhythmias
Increased intraocular, intragastric and intracranial pressures
Myalgia
Myoglobinuria

Should be used in caution in patients w/ ocular disorders

Patients w/ burn injuries or trauma (especially CNS) respond w/ marked hyperkalemia to succinylcholine
Which patients are resistant to the effects of succinylcholine?
Patients with myasthenia gravis are resistant to the effects of succinylcholine
Drug interactions to consider in non-polarizing (competitive) agents?
1. inhalational anesthetic agents augment neuromuscular blockade in a dose-dependent fashion

2. antibiotics, especially aminoglycosides, can augment blockade

3. cholinesterase inhibitors antagonize blockade
Drug interactions to consider in depolarizing (non-competitive) agents?
Very few clinically significant interactions have been reported
-- agents w/ lower serum K+ should be used w/ caution since dosage requirements may increase
What is the MOA of centrally acting muscle relaxants?
1. agents depress activity of spinal and supraspinal interneurons in motor reflex pathways (not at the neuromuscular jxn)

2. though the exact mechanism is unknown, studies suggest that these agents may:
-- enhance GABA-mediated pre- and post-synaptic inhibition to decrease neuronal signal strength in motor circuits
-- decrease the release of excitatory neurotransmitters (glutamate) to decrease neuronal signal strength in motor circuits
What is the clinical use of centrally acting muscle relaxants?
1. agents are palliative and do not alter the clinical course of the primary lesion

2. Used primarily to relieve spasticity due to excessive neuronal reflex activity resulting from sprains, arthritis, myositis, and fibrositis

3. both muscle hypertonicity and rigidity are reduced
What are the centrally acting muscle relaxants?
Benzodiazepines
-- diazepam

Baclofen
How do benzodiazepines work?
Increase GABA mediated inhibitory synaptic transmission to decrease spinal interneuronal signaling

DOES NOT relax muscle with NORMAL tone
S/E’s of benzodiazepines?
Sedation

With continued use: tolerance and dependence
How does Baclofen work?
1. although an agonist at the GABA-B receptor, the action on the basis of GABA receptor-dependent processes is questionable

2. does reduce the release of glutamate from spinal neuronal circuits thereby reducing interneuronal excitatory conduction

3. particularly effective in treating flexor spasms and skeletal muscle rigidity assoc w/ MS and spinal cord injury
S/E’s of Baclofen?
Sedation
Mental confusion
Weakness

Sudden w/d of therapy can lead to auditory and visual hallucinations
What is the peripherally acting muscle relaxant?
Dantrolene Na
What is Dantrolene’s MOA?
Has direct effects on the excitation-contraction coupling mechanisms of skeletal muscle (not at neuromuscular jxn)

Decreases Ca++ release from sarcoplasmic reticulum thereby permitting relaxation of hypertonic skeletal muscle

DOES NOT relax muscle w/ NORMAL tone
Clinical use of Dantrolene Na?
1. spasticity assoc w/ UMN lesion is reduced

2. skeletal muscle relaxation in pts w/ strokes, MS, postencephalitic athetosis and dystonia

3. prophylaxis for anesthetic-induced malignant hyperthermia****
-- pts experience severe muscle spasms and contractures when challenged by a triggering agent (anesthetic agents, muscle relaxants, etc.)
-- pts usually treated prior to potential trigger exposure
-- admin during an episode of anesthetic-induced malignant hyperthermia may also reduce the muscle contracture
S/E’s of Dantrolene Na?
Generalized muscle weakness

Fatigue