cholinergic system class 6-skeletal muscle relaxants
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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
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