8/13/2019 6. 54_DT2_NMJ_541018

1/24

SKELETAL MUSCLE RELAXANTS()

SKELETAL MUSCLE RELAXANTS()

. .

. .

8/13/2019 6. 54_DT2_NMJ_541018

2/24

2

1.

Excitation-contraction coupling2. Skeletal muscle relaxants

2.1 Neuromuscular blocking agents

2.1.1 Nondepolarizing agents: d-tubocurarine

2.1.2 Depolarizing agents: succinylcholine

2.2 Spasmolytic drugs

2.2.1 Diazepam

2.2.2 Baclofen

2.2.3 Datrolene

2.2.4 Drugs used to treat acute local muscle spasm

2.2.5 Botulinum toxin

Objective:

8/13/2019 6. 54_DT2_NMJ_541018

3/24

References:

1. E-Book

Brunton LL, eds. Goodman & Gilmans

The Pharmacological Basis of Therapeutics 11 ed.

Katzung BG. Basic & Clinical Pharmacology 11ed.

Rang & Dale. Pharmacology 6 ed.

2. 1

3. Website: http://en.wikipedia.org/wiki/Muscle_relaxant

8/13/2019 6. 54_DT2_NMJ_541018

4/24

4

Impulse(from motor nerve)

Motor end plate( Ca2+ influx)

Exocytosis( ACh release)

Nicotinic receptor(Depolarization)

Action potential

Muscle contraction

Muscle contractionMuscle contraction

1. Presynaptic terminal

2. Sarcolemma

3. Synaptic vesicle4. Nicotinic ACh receptor

5. Mitochondrion

8/13/2019 6. 54_DT2_NMJ_541018

5/24

5

Excitation-Contraction CouplingExcitation-Contraction Coupling

8/13/2019 6. 54_DT2_NMJ_541018

6/24

6

CNS

Motor nerve

Neurotransmission

NMR

Contractile apparatus

Interrupt at:

Events leading to skeletal

muscle relaxation

Events leading to skeletal

muscle relaxation

8/13/2019 6. 54_DT2_NMJ_541018

7/24

7

SKELETAL MUSCLE RELAXANTSSKELETAL MUSCLE RELAXANTS

1. Neuromuscular Blockers:

Interfere ACh neuromuscular transmission, no CNS effect

Used in surgical procedures, ICU & emergency med paralysis

Or centrally acting muscle relaxant, except Dantrolene

To alleviate musculoskeletal pain & spasmand to reduce spasticity in a variety of neurological conditions

2. Spasmolytics

Drug affecting skeletal muscle function and muscle tone Used to alleviate symptoms: muscle spasm, pain, hyperreflexia

Refer to two majortherapeutic groups:

8/13/2019 6. 54_DT2_NMJ_541018

8/24

8

1. Non-depolarizing

blocker

2. Depolarizingblocker

I. Neuromuscular BlockerI. Neuromuscular Blocker

:d-tubocurarine

(curare)

:succinylcholine

(suxamethonium,SCh)

8/13/2019 6. 54_DT2_NMJ_541018

9/24

9

Basic Pharmacology of Neuromuscular Blocking DrugBasic Pharmacology of Neuromuscular Blocking Drug

1. Chemistry1. Chemistry

Structure ~ ACh

Non-depolarizing blocker:

- isoquinoline

- steroid derivative

Have 1 or 2 quaternary amine

polar, BBB no CNS effect

8/13/2019 6. 54_DT2_NMJ_541018

10/24

10

Highly polar- incomplete absorption, given as iv/im injection,

-/-> BBB no central effect

2. Pharmacokinetics:2. Pharmacokinetics:

Nondepolarizing Drugs

- steroid: mainly eliminated by liver, shorter t1/2

- quinoline: mainly eliminated by kidney, longer t1/2

Depolarizing Drug

-rapid hydrolysis by plasma ChE brief duration (5-10min)

- no plasma ChE at motor end plate prolong depolarization

(The neuromuscular blockade of SCh is terminated by diffusion)

M h f

8/13/2019 6. 54_DT2_NMJ_541018

11/24

11

3. Mechanism of Action3. Mechanism of Action

Competit ive with ACh at NM

R

nondepolarization- Phase I block (depolarizing)

- Phase II block (desensitizing)

1.Nondepolarizing Drugs: 2.Depolarizing Drugs:

8/13/2019 6. 54_DT2_NMJ_541018

12/24

12

Depolarizing Blocking Drug, Phase I & II BlockDepolarizing Blocking Drug, Phase I & II Block

5 Adverse Reactions

5 Adverse Reactions

8/13/2019 6. 54_DT2_NMJ_541018

13/24

13

5. Adverse Reactions5. Adverse Reactions

- hyperkalemia cardiac arrest (mechanism ?)

- increase intraocular pressure,

- muscle pain, by unsynchronized contractions of muscle fibers

- malignant hyperthermia: metabolism & muscle spasm(genetic related)

- prolonged neuromuscular blockade & apnea

(abnormal ChE, genetic-based variation).- CVS (bradycardia) & RS (respiratory depression) effects

- ganglionic blockade: hypotension, tachycardia- histamine release: hypotension, bronchoconstirction

Nondepolarizing Drugs:

Depolarizing Drugs:

6 Clinical Uses:

6 Clinical Uses:

8/13/2019 6. 54_DT2_NMJ_541018

14/24

140.435

20-35

Kidney (80%)

Liver (75-90%) & kidney

Pancuronium

Vecuronium

Steroid derivatives

1.5

64

1

20-35

>3510-20

>35

Spontaneous

KidneyPlasma ChE

Kidney (40%)

Atracurium

DoxacuriumMivacurium

Tubocurarine

Isoquinolinederivatives

Potency relativeto Tubocurarine

Duration(min)EliminationDrug

Some Properties of Neuromuscular Blocking Drugs

6. Clinical Uses:6. Clinical Uses:

- Surgical relaxation, - Tracheal intubation,

- Control of ventilation, - Treatment of convulsions

8/13/2019 6. 54_DT2_NMJ_541018

15/24

15

-Enhance inhibition or

- Reduce excitation

II Spasmolytic DrugsII Spasmolytic Drugs

by endogenous inhibitorysubstances: GABA

Sedation,

Drowsiness,Dependence

Principle of Actions

Mechanism of Action

Mechanism of Action

8/13/2019 6. 54_DT2_NMJ_541018

16/24

161. Diazepam

2. Baclofen

4. Dantrolene

3. Tizanidine

Mechanism of ActionMechanism of Action

8/13/2019 6. 54_DT2_NMJ_541018

17/24

17

http://www-hsc.usc.edu/~ddavies/GABAA.gif

1. Diazepam (benzodiazepine)1. Diazepam (benzodiazepine)

Act at GABAA receptor open Cl channel

hyperpolarization

neuronal signaling Muscle spasm of

almost any origin

Sedation (side effect)

2 B l f GABA i

2 B l f : GABA i t

8/13/2019 6. 54_DT2_NMJ_541018

18/24

18

2. Baclofen: GABAB agonist2. Baclofen: GABAB agonist

Pre-synaptic Post-synaptic

GPCR:postsynaptic open K channel hyperpolarization

presynaptic - Ca influx excitatory NT releasein brain & spinal cord

Effective as diazepam, less sedation -/-> general muscle relaxant as dantrolene

Analgesic effect(- substance P release in spinal cord)

Increased seizure activity (caution)

3 Cl nidin nd D i ti

3 Clonidine and Derivatives

8/13/2019 6. 54_DT2_NMJ_541018

19/24

19

2-adrenergic agonist central activity depresses excitatory feedback from muscles that

would normally increase muscle tone spasticity Efficacy diazepam, baclofen & dantrolineA/Rs: drowsiness, hypotension, dry mouth

3. Clonidine and Derivatives3. Clonidine and Derivatives

Tizanidine, Clonidine analog

spasticity (hypotensive effcet

8/13/2019 6. 54_DT2_NMJ_541018

20/24

20

Direct muscle relaxants

Binding to ryanodine receptor - Ca release from SR

Treatment:

- Malignant hyperthermia

life-threatening disorder, triggered by general anesthesia

- Muscle spasticitye.g. after strokes, spinal cord injury, cerebral palsy, multiple

sclerosis

-Major A/R : muscle weakness,

sedation, &

hepatitis (occasionally)

4. Dantrolene4. Dantrolene

5 Drugs used to treat

5 Drugs used to treat

8/13/2019 6. 54_DT2_NMJ_541018

21/24

21

Wide spread CNS depression with mild analgesic effect

Relief acute muscle spasm caused by local tissue

trauma/ muscle strain

S/E: dizziness, malaise, nausea, liver dysfunction

5.Drugs used to treatacute local muscle spasm5.Drugs used to treat

acute local muscle spasm

: Carisoprodol, chlorphenesin, chlorzoxazone

cyclobenzaprine, metaxalone, methocarbamol,

orphenadrine

6 Botulinum Toxin (Cl tidi m b t li m t xin)

6 Botulinum Toxin (Closstidium botulinum toxin)

8/13/2019 6. 54_DT2_NMJ_541018

22/24

22

6. Botulinum Toxin (Closstidium botulinum toxin)6. Botulinum Toxin (Closstidium botulinum toxin)

Botulinum Toxin Type A (BoTox)

- ACh release from presynaptic axon of cholinergic neurons

(SNAPS proteins ACh, ~3 mo)

local injection in spastic disorder, cosmetics, migraine

Tend to occur 12 weeks after injection & usually transient.

Localised pain, tenderness or bruising Rare events include skin rash, pruritus and allergic reaction.

Adverse Reactions:

Clinical Uses:

Mechanism of Action:

Summary

Summary

8/13/2019 6. 54_DT2_NMJ_541018

23/24

23

- Blepharospasm ()- Cosmetic purposes

3. Motor nerve blocker Botulinum toxin

muscle spasms inneurological disorders

2. Antispasmodic drugs Baclofen Diazepam Dantrolene Methocarbamol Tizanidine

- Endotracheal intubation- Muscle relaxation: surgery, ICU: in patient on ventilation electroconvulsive therapy

1. Neuromuscular blockers Atracurium Pancuronium Vecuronium Succinylcholine

Therapeutic UsesMuscle relaxants

SummarySummary

8/13/2019 6. 54_DT2_NMJ_541018

24/24

24

Questions?Questions?