Cholinergic system Class 6-Skeletal muscle relaxants

Pharmacology ofSkeletal muscle relaxants

Dr.U.P.RathnakarMD.DIH.PGDHM

www.scribd.comwww.pharmacologyfordummies.blogspot.com

What is the link?• Cholinergic drugs

[Agonists of Ach Rec.]Cholinomimitics OR

Directly acting cholinergics OR

Indirectly acting Cholinomimitics

Musc.Rec.Antagonists

Antagonists at N.M.Junction

Anti-Cholinesterases

Antagonists Anti-cholinergics

N.M.Blockers

Ganglion blockers

Skeletal muscle relaxants

South American arrow poison

Normal Neuromuscular Function

Nicotinic receptorNeuromuscular

junction

Impulse

Ca++ influx

Release Ach

Binds to REC

Na channel opens

Depolarization

MEPP & AP

Impulse propogation&

Muscle contraction

Muscle relaxants

Classification of skeletal muscle relaxants

CNSCentrally 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 acting Dantrolene 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-Spontaneous

elimination[Hofmann elimination]

• Mivacurium-Shortest[Late onset]

• Gantacurium- very rapid onset and short duration

• Rapid hydrolysis by cholinesterases[Plasma & Liver]

• 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

Normal activity

Mechanism of action:

Competitive blockers combine with the nicotinic blockers on the motor end plate and block the action of acetylcholine by competitive blockade.

Surmountable

MOA:Depolarizing block Phase I Block (Depolarizing)

Succinylcholine has affinity and partial agonistic action on Nm

receptors, so initially they produce twitching and fasciculations.

↓

These drugs do not dissociate rapidly from the receptor.

↓

Prolonged depolarization & Sodium channel gets inactivated.

↓

ACh is unable to generate action potential.

↓

Muscle paralysis.

[Augmented, not reversed, by cholinesterase inhibitors]

1. When fluorinated anaesthetics are administered

2. When SCHis 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

• In abnormal individuals not reversed by anticholinesterases

Depolarizing block Phase II Block (Depolarizing)

Drug EffectCompetitive(Curare)

Depolarizing(Succinylcholine)

Initial effect at receptor Inhibition Activation

Effect of cholinesterase inhibition

Reversal Enhancement

Duration of action Variable by drug Very short

Phase II Block? No Yes

Competitive VS Depolarizing

What is phase II block?

• Phase I– Immediate onset–Lower drug doses–Rapid recovery–Depolarization of motor end plate–Muscle is paralyzed

• Phase II–Slower onset–Higher drug doses–Slow recovery–Hyperpolarization of motor end plate–Muscle is paralyzed

Order of paralysis Competitive & Depolarizing block

Competitive block• Finger, eyes,--limbs—neck---- face---trunk---respiratory

muscles.

Depolarizing blockNeck, limbs----face, jaw, eyes, pharynx-----trunk -----respiratory

muscles.

Assessment of Neuromuscular Transmission

Pharmacological actions:

• Skeletal muscles:

• Autonomic ganglia:

• Histamine release:

C.V.S:

• D-Tubocurarine produces significant fall in BPGanglionic blockadeHistamine releaseReduced venous return Heart rate may increase• Succinylcholine – Cardiovascular effects are

variable- Ganglionic depolarization

Other effects

• CNS-Does nor cross BBB• Hyperkalemia-Patients

with burns, nerve damage or neuromuscular disease, or trauma

• Respiratory paralysis• Flushing• Fall in BP• Precipitation of asthma

• Muscle Pain-Myalgias are a common postoperative complaint

• Increased Intraocular Pressure

• Increased Intragastric Pressure-Fasiculations

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

• Unsuspected residual block may result in hypoventilation, leading to hypoxia and even apnea

• Neostigmine  and pyridostigmine  antagonize nondepolarizing neuromuscular by inhibition of acetylcholinesterase

• 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-Only abolishes peripheral action

• SCH - brief procedures – endotracheal intubation, laryngoscopy, esophagoscopy, reduction of fractures and dislocations.

• Convulsions & trauma due to ECT.

Directly acting muscle relaxant:Dantrolene

MOA• Binds and blocks RyR1[ryanodine receptor ] receptor• It interferes 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

• 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 wakefullness].

• They also have sedative property.

Classification: Centrally acting

Mephenesin congeners: Mephenesin, Carisoprodol, Chlorzoxazone,

Chlormezanone, Methocarbamol.Benzodiazepines:Diazepam and others.GABA derivative:Baclofen-GABAB receptor agonistCentral α2 agonist:TizanidineOthersBotulin 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]

ComparisonSkeletal 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