Pharmacology of Skeletal muscle relaxants

Ref: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 relaxants

CNS Centrally acting

Peripherally acting 1. 2. Competititive Depolarizing

3.

Directly acting

Classification of skeletal muscle relaxants

Peripherally acting muscle relaxants:

I. Neuromuscular blocking agents:
A. Non depolarizing (Competitive
blockers)blockers:

B.

Depolarizing blockers:




Long acting: d-Tubocurarine, Pancuronium, Doxacurium, Pipecuronium. Intermediate acting: Vecuronium, Atracurium, Cisatracurium, Rocuronium, Rapacuronium. Short acting: Mivacurium

Succinylcholine (SCh, Suxamethonium),

Decamethonium (C-10)

II.Directly acting
Dantrolene sodium, Quinine

Chemistry

1.Structural resemblance to acetylcholine 2. One or two quaternary nitrogens, poorly lipid-soluble and limits entry into the CNS

PKNon depolarizing[Competitive] Depolarizing 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.

Those excreted by kidneyLong acting Excreted by liver-Short Atracurium-Spontaneous elimination[Hofmann elimination] Mivacurium-Shortest[Late onset] Gantacurium- very rapid onset and short duration

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

Normal activity

Mechanism of action:
Competitive blockers combine with the nicotinic-NN 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

Depolarizing block Phase II Block (Depolarizing)

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

What is phase II block?

Phase I Phase II

Immediate onset Lower drug doses Rapid recovery Depolarization of motor end plate Muscle is paralysed

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,--limbsneck--- 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 release Reduced venous return  Heart rate may increase Succinylcholine Cardiovascular effects are variable- Ganglionic stimulation-parasympathticsympathetic

Other effects[ADEs]
CNS-Does not cross BBB Hyperkalemia-Patients with burns, nerve damage or neuromuscular disease, or trauma[SCh] Respiratory paralysis[both] Flushing Fall in BP[dtc] Precipitation of asthma[dtc] Muscle Pain-Myalgias are a common postoperative complaint [SCh] Increased Intraocular Pressure[SCh] Increased Intragastric Pressure-Fasciculations Malignant hyperthermia [mutation of Ca channels]

Drug Interactions with Neuromuscular Blocking Agents Volatile anesthetics Increased duration of action of competitive blockers, malignant hyperthermia[SCH] Antibiotics potentiation of competitive and noncompetitive blockers
Acid-base balance acidosis potentiates some competitive blockers (e.g. tubocurarine) Potassium Elevated potassium reverses blockade. Succinylcholine may cause hyperkalemia

Reversal of Nondepolarizing Neuromuscular Blockade

By Neostigmine and pyridostigmine Reversal may be required for longer acting agents Novel cyclodextrin reversal drug, Sugammadexinactivate steroidal[Rocuronium] neuromuscular blocking drugs by forming an inactive complexexcreted in urine

Uses
Surgical relaxation Tracheal Intubation Control of Ventilation-to reduce chest wall resistance on ventilators Treatment of Convulsions-Only abolishes peripheral action SCH - brief procedures endotracheal intubation, laryngoscopy, esophagoscopy, reduction of fractures and dislocations. Convulsions & trauma due to ECT.

Hoffman

Parameters
MOA Onset & duration Type Neostigmine NM blockers Histamine release BP Respiratory effects GIT Serum K IOT Pharmacogenetic variation

d-TC
Competitive blockers-NM 4-5 & 30-50mts Flacid Reversal potentiation ++ Hypotension Bronchospasm Constipation No change No change -

SCh
Persistent depol-desensitization 1 & 6 mts Fasciculation flacid Potentiation No effect No Variable No effect Nausea, vomiting Hyperkalaemia Raised Apnoea, Maignant hyperthermia

Directly acting muscle relaxant:Dantrolene

MOA Binds and blocks RyR1[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++ with Some 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 injury inflammation [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 acting
Causes 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 non depolarizing blockade of NM rec

i.v

Inhibit poly synaptic reflexes Oral/parenteral No paralysis/reduced tone/ no loss of voluntary power

Reduced release of Ca

Route Type of paralysis

Oral/parenteral No paralysis/reduced tone/ partial loss of voluntary power

Flacid

CNS effects Use

Do not cross BBB During surgery

Cross/sedation Spastic conditions

Cross/less sedation Spastic conditions And malignant hyperthermia & neuroleptic malignant syndrome Diarrhea, hepatic tox

Side effects

Not serious