sk musc relax

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Pharmacology of Skeletal muscle relaxantsRef:Priniciples of pharmacology, 2nd Ed.

HL Sharma

KK Sharma



Classify

MOA of depolarizing & Non depolarizing

Uses Differences

Centrally acting drugs & uses



Classification of skeletal muscle

relaxantsCNS

Centrally acting

Peripherally acting

1. Competititive

2. Depolarizing

3. Directly acting

Classification of skeletal muscle relaxants



Peripherally acting muscle

relaxants:

A. Non depolarizing (Competitive

blockers)blockers:

Long acting:d-Tubocurarine,

Pancuronium,

Doxacurium,

Pipecuronium.

Intermediate acting:Vecuronium, Atracurium,

Cisatracurium, Rocuronium,

Rapacuronium.

Short acting:

Mivacurium

B. Depolarizing blockers:

Succinylcholine (SCh,

Suxamethonium), Decamethonium (C-10)

II.Directly actingDantrolene sodium, Quinine

I.Neuromuscular blocking agents:



Chemistry

1.Structural resemblance to acetylcholine

2. One or two quaternary nitrogens,

poorly lipid-soluble and limits entry

into the CNS



Non

depolarizing[Competitive]

Those excreted by kidney-

Long acting

Excreted by liver-Short

Atracurium-Spontaneouselimination[Hofmann

elimination]

Mivacurium-Shortest[Late

onset]

Gantacurium- very rapid

onset and short duration

Rapid hydrolysis by

cholinesterases

Extremely short acting

Small percentage reaches

NMJ

No plasma cholinesterase at

motor end plate

Termination of action by

diffusion Action prolonged - genetically

abnormal variant of plasma

cholinesterase

Measured by Dibucaine No.

PK-

Depolarizing



MOA: d-Tubocurarine[Non depolarizing-Non competitive]

Normal activity



Mechanism of action:

Competitive blockers combine with the nicotinic-N N

receptors on the motor end plate

and block the action of acetylcholine

by competitive blockade. Surmountable

Depolarizing blockers ± Produce depolarizing block

[Phase I]

Sometimes followed by [Phase II block]



MOA:Depolarizing block

Phase I Block (Depolarizing)Succinylcholine [SCh] has affinity and partial agonistic action on NM receptors

[Depolarization]Initially produce twitching and fasciculation [acts like Ach].

SCh do not dissociate rapidly from the receptor.

[Not hydrolyzed by true cholinesterase]

Prolonged depolarization & Sodium channel gets inactivated[no repolarization].

ACh is unable to generate action potential.

Muscle paralysis[flaccid paralysis].

Augmented, not reversed, by cholinesterase inhibitors



1. When fluorinated anaesthetics are administered

2. When SCh is injected in high doses, or continuous

infusion

3. In individuals with deficient pseudocholinesterase.

SCH-Remains at the rec. for extended periods

Membrane potential gradually-recovers

Transmission remains blocked[Rec.desensitized] Nature of block-Depolarizing to non-depolarizing

Characters of non-depolarizing block

Depolarizing block

Phase II Block (Depolarizing)



What is phase II block?

Phase I

± Immediate onset

± Lower drug doses ± Rapid recovery

± Depolarization of

motor end plate ± Muscle is

paralysed

Phase II

± Slower onset

± Higher drug doses ± Slow recovery

± Desensitization of

motor end plate ± Muscle is

paralysed



Order of paralysis Competitive

& Depolarizing block Competitive block

Finger, eyes,--limbs²neck-

--- face---trunk---respiratory

muscles.

Depolarizing block

Neck, limbs----face, jaw, eyes,

pharynx-----trunk -----

respiratory muscles.



Pharmacological actions:

Skeletal muscles:

Autonomic ganglia:

Histamine release:



C.V.S:

D-Tubocurarine produces significant fall in BP

Ganglionic blockade

Histamine releaseReduced venous return

Heart rate may increase

Succinylcholine ± Cardiovascular effects arevariable- Ganglionic stimulation-parasympathtic-

sympathetic



Drug Interactions with Neuromuscular

Blocking Agents

Volatile anesthetics ± Increased duration of action of

competitive blockers, malignant hyperthermia-

[SCH]

Antibiotics ± potentiation of competitive and non-

competitive blockers Acid-base balance ± acidosis potentiates some competitive blockers (e.g. tubocurarine)

Potassium ± Elevated potassium reverses blockade. Succinylcholine may cause hyperkalemia



By Neostigmine and pyridostigmine

Reversal may be required for longer acting

agents

Novel cyclodextrin reversal drug, Sugammadex-

inactivate steroidal[Rocuronium] neuromuscular

blocking drugs by forming an inactive complex-

excreted in urine

Reversal of Nondepolarizing

Neuromuscular Blockade



Uses

Surgical relaxation

Tracheal Intubation

Control of Ventilation-to

reduce chest wall

resistance ±on ventilators

Treatment of

Convulsions-Onlyabolishes peripheral

action

SCH - brief procedures ± endotracheal intubation,laryngoscopy,

esophagoscopy, reductionof fractures anddislocations.

Convulsions & traumadue to ECT.



Hoffman



Parameters d-TC SCh

MOA Competitive

blockers-NM

Persistent depol-desensitization

Onset & duration 4-5 & 30-50mts 1 & 6 mts

Type Flacid Fasciculation ±flacid

Neostigmine Reversal Potentiation

NM blockers potentiation No effect

Histamine release ++ No

BP Hypotension Variable

Respiratory effects Bronchospasm No effect

GIT Constipation Nausea, vomiting

Serum K No change Hyperkalaemia

IOT No change Raised

Pharmacogenetic variation - Apnoea, Maignant hyperthermia



Directly acting muscle

relaxant:Dantrolene

MOA

Binds and blocks RyR 1[ryanodine receptor ] receptor

It inhibits with intracellular release of calcium needed

for excitation-contraction coupling.Uses:

Spasticity due to upper motor neurone disorders,hemiplegia, paraplegia, cerebral palsy.

Malignant hyperthermia.[Massive release of Ca++ withSome anesthetics/SCH]

Neuroleptic malignant syndrome.

ADE

Muscular weakness, Sedation, Diarrhoea, Liver toxicity



Quinine[directly acting]

Increases refractory period and decreases

excitability of motor end plates.

Uses: Nocturnal leg cramps



Centrally acting muscle relaxants:

Selectively depress spinal and supraspinal

polysynaptic reflexes[Stretch] involved in the

regulation of muscle tone [also wakefulness].

They also have sedative property.



Classification: Centrally acting

Mephenesin congeners:

Mephenesin, Carisoprodol, Chlorzoxazone,Chlormezanone, Methocarbamol.

Benzodiazepines:Diazepam and others.

GABA derivative:

Baclofen-GABAB receptor agonist

Central 2 agonist:Tizanidine

Others

Botulin toxin[local spasm]



Uses of centrally acting muscle

relaxants:

Severe spasticity due to cerebral palsy,

mulitple sclerosis, stroke [Baclofen]

Acute spasm due to muscle injuryinflammation [Mephenesin etc.]

Chronic spasm due to cerebral palsy, stroke,

spinal cord injury acute spasm due to muscle

injury [Diazepam]

Spasm due to multiple sclerosis, stroke,

amyotrophic lateral sclerosis [Tizanidine]



Comparison

Skeletal Muscle Relaxants Centrally acting

No reduction in voluntary

power

Inhibits polysynaptic

reflexes in CNS

Causes CNS depression

Usually given orally

Used in chronic spastic

conditions, acute muscle

spasms, tetanus.

Peripherally actingCauses muscle paralysis

Blocks neuromuscular

transmission

No effect on CNS

Given by

I

.V. route

Used for short term purposes



Parameters Peripheral

[d-TC or SCh]

Central

[Baclofen]

Direct

[Dantrolene]

MOA Depolarizing or nondepolarizing blockade of

NM rec

Inhibit poly synapticreflexes

Reduced release of Ca

Route i.v Oral/parenteral Oral/parenteral

Type of

paralysis

Flacid No paralysis/reduced

tone/ no loss of voluntary power

No paralysis/reduced

tone/ partial loss of voluntary power

CNS effects Do not cross BBB Cross/sedation Cross/less sedation

Use During surgery Spastic conditions Spastic conditions

And malignant

hyperthermia &

neuroleptic malignant

syndrome

Side effects Not serious Diarrhea, hepatic tox

sk musc relax

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