Skeletal Muscle RelaxantsSkeletal Muscle Relaxants

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Dr. Rene AnandReference: Bertram Katzung et al, "Basic and Clinical Pharmacology", 12th edition, McGraw-Hill Lange, Chapter 27

Learning Objectives

Describe the pharmacological properties of drugs classified as relaxants

Describe the transmission process at the skeletal neuromuscular end plate and the points at which drugs modify this process

Identify the major non-depolarizing neuromuscular blockers and one depolarizing neuromuscular blocker, compare their pharmacokinetics

Describe the differences between depolarizing and non-depolarizing blockers from the standpoint of tetanic and post-tetanic twitch strength

Describe the reversal of non-depolarizing blockade List drugs for treatment of skeletal muscle spasticity and identify

their sites of action and adverse effects

Skeletal Muscle Relaxants

Skeletal muscle relaxants interfere with the contraction of skeletal muscles:

1. Neuromuscular blockers are used to completely paralyze skeletal muscle during surgical and orthopedic procedures in the controlled environment of a hospital.

2. Spasmolytics are used to elicit a more modulatory effect on muscle contraction and do not completely block the activity of the skeletal musculature. These agents are used to reduce muscle spasms and are commonly used in ambulatory patients.

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Classification of Skeletal Muscle RelaxantsClassification of Skeletal Muscle Relaxants

Peripherally acting drugs Neuromuscular blocking drugs. Direct acting spasmolytic.

Centrally acting spasmolytics.

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I Summary of Neuromuscular TransmissionI Summary of Neuromuscular Transmission

An action potential depolarizes the nerve

terminal and Ca2+ enters. ACh-containing vesicles

fuse with the prejunctional membrane releasing the

ACh by exocytosis into the junctional space.

The released ACh diffuses across the synaptic gap and

binds to nicotinic (Nm) receptors leading to

depolarization of the muscle end-plate region. The nicotinic receptor is a complex of 5 protein

subunits. There are 2 a subunits, and one each of b,

g and d subunits in embryonic muscle. In the adult d is replaced by an e

subunit. When one molecule of ACh binds to each of the

a subunits there is an increase of the fluxes of

Na+ in, Ca2+ in, and K+ out.

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II Summary of Neuromuscular TransmissionII Summary of Neuromuscular Transmission

There is propagation of a muscle action potential through the conducting

system of the myofibrils, with release of Ca2+ from the

sarcoplasmic reticulum. This triggers off the troponin-

actin-myosin interaction and muscle contraction.

Relaxation is associated with restorage of Ca2+ in the

sarcoplasmic reticulum which is driven by energy supplied

by an ATPase. There is a refractory period until

repolarization of the muscle end-plate.

ACh is inactivated by ACh esterase (AChE).

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Quick Review: Model of Nicotinic ReceptorQuick Review: Model of Nicotinic Receptor

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Quick Review

Quick Review Quick Review

Curare

Curare is a generic term that refers to a mixture of naturally occurring alkaloids found in various South American plants and is used to make arrow poison by some South American Indians. The most important alkaloid is d-tubocurarine. First used in surgery in 1942.

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http://waynesword.palomar.edu/ecoph23.htm

Peripherally acting drugsPeripherally acting drugs

Neuromuscular Blocking DrugsChemically most are bisquaternary ammonium compounds

Interaction with the acetylcholine (ACh) receptor appears to be one to one but the exact nature is unknown. It is speculated that the charged compounds span and bind to the nicotinic (Nm) receptor and prevent ACh from reaching it.

-N+______________N+-

+

- -

- -Pancuronium

Characteristics of quaternary compoundsconsidering their positive charge Characteristics of quaternary compoundsconsidering their positive charge

Poorly absorbed from the gut and generally rapidly

excreted

Will not cross the

blood-brain barrier

Will not cross the placenta

Administered IV

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Indications for Neuromuscular Blocking DrugsIndications for Neuromuscular Blocking Drugs

Adjunct for surgery to

reduce muscle tone and

fasciculation at the site of

surgery (permit tracheal

intubation).

Electroshock therapy for psychiatric disorders

(prevent bone breakage).

Control convulsive

disorders (status epilepticus,

tetanus, eclampsia and

toxic reactions to local

anesthetics).

Control respiration when

the patient is unable to

ventilate.

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Classification of Neuromuscular Blocking DrugsClassification of Neuromuscular Blocking Drugs

Nondepolarizing Blocking Drugs

(competitive, stabilizing, or

antidepolarizing drugs).

Depolarizing Blocking Drugs.

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1. Nondepolarizing Blocking Drugs1. Nondepolarizing Blocking Drugs

Block neuromuscular

junction nicotinic receptors

competitively. They compete for the receptor with

ACh.

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I Classification of some neuromuscular blocking agents based on duration of actionI Classification of some neuromuscular blocking agents based on duration of action

Drug Effect on Autonomic Ganglia

Effect on Histamine Release

Effect on Cardiac Muscarinic Receptors

Nondepolarizing DrugsLong-acting (>35 min) Pancuronium Intermediate-Acting (20-35 Min) Vecuronium Atracurium Rocuronium Cisatracuium

None

NoneNoneNoneNone

None

NoneSlightNoneNone

Moderate Blockade

NoneNoneNoneNone

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(-ium)

Nondepolarizing Blocking DrugsNondepolarizing Blocking Drugs

Because they are competitive

blockers their action can be reversed by

increasing the concentration of

endogenous ACh at the NMJ.

Use ChE inhibitors such as

neostigmine, physostigmine, edrophonium together with

atropine to protect muscarinic

receptors against excessive

stimulation by increased levels of

ACh.

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II Classification of some neuromuscular blocking agents based on duration of actionII Classification of some neuromuscular blocking agents based on duration of action

Drug Effect on Autonomic

Ganglia

Effect on Histamine Release

Effect on Cardiac

Muscarinic Receptors

Depolarizing DrugsShort-Acting (5-15 min) Succinylcholine

Stimulation Slight Stimulation

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Succinylcholine (Anectine®) structurally looks like two molecules of ACh end-to-end. It is a relatively short duration (5-15 min) ACh-like agonist at nicotinic receptors.

Progression of pharmacological response to succinylcholineProgression of pharmacological response to succinylcholine

• Initial depolarization of the end-plate region. Transient muscle fasciculation followed by relaxation.

Phase 1

Block.

• Desensitization of the receptor to ACh. End-plate repolarization possibly do to conformational change of the receptor molecule.

Phase 2

Block.

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Note. Cholinesterase inhibitors will intensify the response to succinylcholine during Phase 1 block. They may reinitiate muscle contraction if administered during late Phase 2 block.

Metabolism of succinylcholineMetabolism of succinylcholine

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ACh

(CH3)3-N-CH2-CH2-O-OC-CH3

Succinylcholine

(CH3)3-N-CH2-CH2-O-OC-CH2-CH2-CO-O-CH2-CH2-N-(CH3)3

plasma ChE

succinylmonocholine 1/2 activity

plasma ChE

succinic acid + choline

Note. ACh metabolism takes place primarily in the NMJ, while succinylcholine metabolism takes place in the plasma

+

+ +

Plasma ChE

Plasma ChE is synthesized in the liver and therefore patients with liver dysfunction, decreased hepatic blood flow or genetic abnormalities would show prolonged responses to succinylcholine. Neonates have low plasma ChE. A clinical dose of 1-2 mg/kg usually lasts <15 min while an atypical patient may respond for >2 hr. • About 1:3000 patients have a genetic related decrease of

plasma ChE.• Treatment- mechanical respiration

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I Adverse Effects of neuromuscular blocking drugsI Adverse Effects of neuromuscular blocking drugs

Do not enter brain - CNS fully functional, pain is not dulled.

Depolarizing Drug (Succinylcholine)

Fasciculation can result in:• Post operative muscle stiffness and pain.• Increase of intraocular pressure-contraction of the extraocular

muscles.• Increased intragastric pressure – occasionally leading to emesis.• Hyperkalemia – in some patients especially with burns, nerve

damage, closed head injury, renal failure.

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II Adverse Effects of neuromuscular blocking drugsII Adverse Effects of neuromuscular blocking drugs

Nondepolarizing Drugs

• Atracurium (occasionally succinylcholine)

Release of endogenous histamine into the circulation- bronchospasm, increased excretions, vasodilation resulting in decreased blood pressure.

• Treatment - antihistamines

Pharmacological response Potentiated by:

Some general anesthetics (methoxyflurane) and local anesthetics.

Antibiotics (aminoglycosides; neomycin and streptomycin have a tendency to inhibit Ca2+ fluxes).

Fluid and electrolyte imbalance.

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Direct-Acting (myotropic) Spasmolytics Direct-Acting (myotropic) Spasmolytics

Dantroline

• Interferes with release of Ca2+ from the sarcoplasmic reticulum which is required for muscle contraction.

Indications

• Chronic disorders characterized by muscle spasms.• Spinal cord injury• Stroke• Cerebral palsy• Multiple sclerosis• ( Potential toxicity: Hepatotoxicity)

Malignant Hyperthermia: Genetic disorder, autosomal dominant. Triggered by halogenated anesthetic and/or succinylcholine. Sudden rise of Ca2+ in muscle fiber with increase of body temperature, rigidity.- 50% mortality.

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I Centrally Acting Spasmolytics Antispastic action

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Exerted mainly on the spinal cord by inhibiting mono- and poly-synaptic activation of motor neurons.

Baclofen. GABAB receptor agonist. Activates GABAB receptors on nerve endings that release excitatory neurotransmitters and prevents the release of the excitatory neurotransmitters (glutamate) onto motor neurons.

Diazepam. Belongs to the benzodiazepine class of drugs. Enhances the actions of the inhibitor neurotransmitter GABA in the spinal cord.

Indications: Chronic disorders characterized by muscle spasticity.

• spinal cord injury• stroke• cerebral palsy• multiple sclerosis

Side effects: Sedation and drowsiness

II Centrally Acting SpasmolyticsII Centrally Acting Spasmolytics

Tizanidine.

• Mechanism of action is unclear. • Derivative of clonidine and has significant α2- adrenoceptive

agonist activity. • Appears to reinforce pre- and postsynaptic inhibition in the

cord. • Also inhibits nociceptive transmission in the cord.

Indications:• Chronic disorders characterized by muscle spasticity.

Side effects: Sedation, drowsiness, hypotension, dry mouth, and asthenia.

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I Drugs used for acute local muscle spasmI Drugs used for acute local muscle spasm

There are a large number of sedative

drugs that are promoted for the relief of acute

temporary muscle spasm caused by local

trauma or strain.

The drugs include: • Carisoprodol • Chlorzoxazone • Cyclobenzaprine • Metaxalone • Orphenadrine

Side effects: Most are sedative

hypnotics and some have

antimuscarininc activity.

II Drugs used for acute local muscle spasmII Drugs used for acute local muscle spasm

Botulinum Toxin • Inhibits the release of

ACh from cholinergic nerve terminals.

• Local injection is finding increasing use in the treatment of spastic disorders due to neurologic injury.

• Benefits may persist for weeks after a single injection.

Potential toxicity• May spread beyond

injection site and lead to difficulty swallowing and breathing.

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Botulinum Toxin (Types A-G).

Botulinum Toxin (Types A-G).

The heavy chain is similar for all types,

the light chains differ.

Botox approved to treat:Botox approved to treat:

Strabismus (Cross-eyes)

Uncontrollable blinking

Cervical dystonia (a neurological disorder that

causes severe neck and shoulder

contractions)

Moderate to severe frown lines

between eyebrows

Unintended consequence: Appears to be

effective for the treatment of some forms of headache

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Muscle Relaxants Quiz

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Summary of Key Points to Remember

Two therapeutic groups of muscle relaxants:

A. Neuromuscular blockers (nondepolarizing and depolarizing)

- Act on nicotinic acetylcholine receptors at neuromuscular junction

- Used in surgical relaxation, endotracheal intubation, control of ventilation and treatment of convulsions

B. Spasmolytics (typically act on targets in the spinal chord)

- Used to treat spasticity associated cerebral palsy, multiple sclerosis, and stroke

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Thank you for completing this module

Reference: Bertram Katzung et al, "Basic and Clinical Pharmacology",

12th edition, McGraw-Hill Lange, Chapter 27

Email: Anand.20@osu.edu

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