It's very important care of Muscle tension patients

4. Upper motor neuron from
cerebral cortex activated
AP travels in the neuron
AP travels to spinal
cord,release of
epinephrine,glutamate
AP excites lower motor
neuron
Muscle contraction

7. Arrival of an action potential
at the motor nerve terminal
Influx of calcium
Release of acetylcholine
Diffusion of acetylcholine
across the synaptic cleft
Activation of nicotinic
receptors on motor end plate

8. Ach Nicotinic Receptor
(PENTAMER)
2α, 1β, 1γ, 1δ

9. Binding of two acetylcholine molecules to
receptors on the α-β and δ-α subunits
Opening of the channel
Movement of sodium & potassium through
the channel
A graded depolarization of the end plate
membrane - motor end plate potential
Adjacent muscle membrane is depolarized,
and an action potential propagated along
the entire muscle fiber

10. Muscle contraction is
then initiated by
excitation-
contraction coupling
Released
acetylcholine is
quickly removed
from the end plate
region
AP depolarizes muscle
membrane + travels deeply
within the muscle fiber
SR release Ca++
Ca++ initiates attractive
forces between Actin &
Myosin filaments
Ca++ pumped back into SR
Diffusion &
enzymatic
destruction by the
local
acetylcholinesterase
enzyme

11. By interruption of function at several sites
Along the pathway from the central
nervous system (CNS) to myelinated
somatic nerves
Unmyelinated motor nerve terminals
Nicotinic acetylcholine receptors
Motor end plate
Muscle membrane
Intracellular muscular contractile
apparatus

12.  CENTRALLY ACTING
 Spasmolytics
 DIRECTLY ACTING
 Dantrolene
 PERIPHERALLY ACTING
 Neuromuscular Blockers
 Depolarizing
 Non-depolarizing

13.  Spasmolytics
 Diazepam
 Baclofen
 Tizanidine
 Gabapentin
 Progabide
 Glycine
 Idrocilamide, riluzole (for ALS)

14. I- STIMULANTS
Choline esters
Anticholinesterases
II- BLOCKERS
A. Non-Depolarizing
 D-tubocurarine
 Gallamine
 Pancuronium
 Atracurium
 Cisatracurium
 Mivacurium
B. Depolarizing
 Succinylcholine
(Suxamethoniu
m)
 Suxethonium
 Decamethonium

16. Prevent or interrupt muscle spasm
associated with:
 Spastic diseases
 Spinal cord injury
 Overexertion of muscles
Adjunct treatment for:
 Anesthesia
 Intubation
 surgical& orthopedic procedures

17.  Facilitates GABA (inhibitory)
transmission in the CNS
 Diazepam although acts more through
GABAA but through GABAB spasmolytic
effect is more pronounced
 Muscle relaxant activity is due to
inhibition of polysynaptic pathways in
spinal cord
 Sedation
Centrally
Acting
Muscle
Relaxants

20.  Orally effective GABA-mimetic agent
 GABA agonist at GABAB receptors
 MECHANISM OF ACTION:
 Hyperpolarization
 Decrease the release of excitatory
transmitters in both the brain & SC
 Reduce pain in pts with spasticity
(inhibiting the release of substance P in
SC)
 It is as effective as Diazepam having
advantage  causes less sedation
Baclofen
(contd.)

21.  Increases K+ conductance -
hyperpolarization of neuronal
membrane
 Decreases Ca++ influx
 Less sedation & muscular weakness
 Can be given intrathecally in severe
spasms
 Alcoholics to reduce craving
Centrally
Acting
Muscle
Relaxants

23. ADVERSE EFFECTS:
 CNS depression
 Confusion
 Delirium
 Coma
 Impaired renal function

24.  Congener of clonidine
 α2 agonist
 Reinforces both pre & postsynaptic
inhibition in spinal cord
ADVERSE EFFECTS
1. Hypotension
2. Asthenia
3. Sedation
4. CNS depression
Centrally
Acting
Muscle
Relaxants

26. Blocking the effect
of physiological
agonist
Excess of
depolarizing
agonist
Tubocurarine Acetylcholine
Succinylcholine
Non-depolarizing
blockade
Depolarizing
blockade

29.  Curare - arrow poison
 Strychnos species
 Strychnos toxifera
 Quarternary
neuromuscular -
blocking alkaloids

30. Structural resemblance to
acetylcholine
Succinylcholine: 2acetylcholine
molecules linked end-to-end
Presence of one or two
quaternary nitrogens - makes
them poorly lipid soluble and
limits entry into the CNS

31. BENZYL-
ISOQUINOLINES
Natural
 d-Tubocurarine
Synthetic
 Mivacurium*
 Atracurium*
 Doxacurium
 Gantacurium
AMMONIO-
STEROIDS
 Rapacuronium
 Rocuronium*
 Vecuronium*
 Pancuronium*
 Pipecuronium
31
Mixed-onium chlorofumarates
 Gantacurium

32.  Ultra short acting:
Succinylcholine (Dep)
Gantacurium (investigational)
 Short acting: Mivacurium slow onset
 Intermediate acting:
Vecuronium hepatic& billiary exc.
Rocuronium fastest onset
atracurium Hofman elimination
cisatracurium,

33. Long acting:
 D-Tubocurarine* (prototype)
 metocurine
 pancuronium*
 doxacurium

34. Prototype: d, tubocurarine
Mono-quarternary ammonium
alkaloid
 Highly polar
 Not absorbed from GUT
 NOT metabolised in liver
 Excreted unchanged

35.  Atracurium - intermediate-acting
 Hepatic metabolism + Hofmann
elimination
 Breakdown products laudanosine - slowly
metabolized by the liver - longer
elimination half-life (ie, 150 minutes) -
readily crosses BBB - high blood
concentrations: seizures
 Cisatracurium

36.  Site of action: motor end plate
 Competes with acetylcholine for
nicotinic receptors
 Blockade is competitive and
surmountable
 Decrease frequency of channel opening
 Not preceded by fasciculation

38.  Action can be reversed by neostigmine,
edrophonium
 An important clinical consequence:*
 reversal of residual blockade by
cholinesterase inhibitors

39.  Succinylcholine:
 Extremely short duration of action(5–10
minutes)
 Rapid hydrolysis by
butyrylcholinesterase (liver) &
predominantly pseudocholinesterase
(plasma)
 Circulating levels of plasma
cholinesterase influence the duration of
action of succinylcholine
 DIBUCAINE NUMBER

41. Phase-I block (Depolarizing)
 Mimics action of acetylcholine at motor
end plate
 Binds to nicotinic ion channels and opens
 Depolarization of motor end plate –
spreads to adjacent membranes causing
contractions of motor units
 Succinylcholine not metabolized as
effectively as acetylcholine at synapse –
depolarized membrane remains
depolarized & unresponsive to subsequent
impulses

43. Phase-I block (Depolarizing)
 End plate repolarization “repriming”
required for excitation-contraction
coupling and repetitive firing to
maintain muscle tension
 Flaccid paralysis results which is
preceded by fasciculation
 Phase-I block is augmented but not
reversed by anticholinesterases

44. Phase II Block (Desensitizing)
 Persistent depolarization slowly
decreases- repolarization starts –
 can not be depolarized…..desensitization
of the membrane
 Cause: Channel block . channel behaves
like in a prolonged closed state -
 Later in phase II:
 behaves like block by non-depolarizing
drugs and can be reversed by
anticholinesterases

45.  Motor muscle weakness total flaccid
paralysis
 Muscles capable of rapid movement
(eye, jaw, larynx )…….. paralyzed first
 Then neck, limbs, trunk…… paralyzed
 Diaphragm and other respiratory
muscles……. last to be paralyzed
 Recovery occurs in reverse order i.e
diaphragm to be the first to recover and
facial muscles are last of all

46.  Bronchospasm(histamine release)
 Raised intraocular
pressure(succinylcholine)
 Increased intra-gastric pressure
(increased risk of regurgitation &
aspiration of stomach contents)
 Myalgias (succinylcholine)
 HYPERKALEMIA

47. PROLONGED APNEA
 Airway obstruction
 Neuromuscular depressant effect of
excessive neostigmine
 Low plasma butyrylcholinesterase
 Presence of latent myasthenia gravis
 Decreased elimination: hepatic
dysfunction (cisatracurium, rocuronium,
vecuronium) or renal dysfunction
(pancuronium)

48. MOA:
 Interferes with the release of calcium from
its stores in the sarcoplasmic reticulum of
the sarcomere & thus reduces the muscle
strength by affecting excitation-contraction
coupling in the muscle fibre
 Calcium exits out of sarcoplasmic reticulum
through Ryanodine channels
 Dantrolene probably combines with the
same channel and interferes with the
release of the Ca++
 Cardiac &smooth muscles are depressed
slightly

50. CLINICAL USES
Malignant hyperthermia
ADVERSE EFFECTS
 Sedation
 Muscular weakness
 Fatigue
 Rashes
 Jaundice/hepatitis
 Diarrhea
 Should be used with caution in
concomitant hepatic, renal ,cardiac and
pulmonary disorders.

51.  Chemodenervation
& local paralysis in
muscle
 Cosmetic
 Cerebral palsy
 Dystonia
 Overactive bladder
incontinence
 Chronic migraine

52.  Cyclobenzaprine* (prototype),
antimuscarinic effects – sedation,
transient visual hallucinations
 Carisoprodol
 Chlorphenesin*
 Chlorzoxazone
 Metaxalone
 Methocarbamol
 Orphenadrine*

53.  Succinylcholine, halothane
 Life threatening condition
 Contracture, rigidity & heat production
from skeletal muscle -hyperthermia,
metabolic acidosis, tachycardia
 Uncontrolled release of Ca+2 from SR
(Ryanodine receptor)
 Genetic predisposition
 Dantrolene, rapid cooling 100% oxygen,
control of acidosis

55.  Skeletal muscle relaxant during surgery
 Orthopedic manipulations
 Facilitate endotracheal intubation
 Facilitate laryngoscopy, bronchoscopy,
esophagoscopy
 Tetanic convulsions & Status epilepticus
 In Modified ECT
 As a treatment of crush injures of chest
 Rx of poisoning due to convulsant drugs
e.g. strychnine

56.  Myasthenia gravis
 Concomitant use of aminoglycosides
 Asthmatic patients
 Hypotensive states
 Succinylcholine in children
 Hyperkalemia (caution with other
conditions/drugs)
 Severe liver/kidney disease
 Atypical pseudocholinesterase in
patients

57. THANK YOU!

58. d-Tubocurarine Suxamethonium
Source: Natural Synthetic
Chemistry Alkaloid, Monoquaternary
Ammonium Compound
Two molecules of
acetylcholine joined
together
Mechanism of
action
Non-depolarizing;
competitive antagonism
with ACH at nicotinic
receptors of motor end
plate
Persistent depolarizing
(action like ACH)
followedby desensitization
of area around motor end
plate.
Initial
fasciculations
Absent Present

59. d-Tubocurarine Suxamethonium
Onset of action 4 minutes 1 minute
Duration of action 20-30 minutes 4-10 minutes
Effect on histamine
release
Moderate Slight
Metabolism Not metabolised Rapidly hydrolysed by
pseudocholinesterase.
Excretion Mainly through kidney
as unchanged
Only a small proportion is
excreted unchanged
Effect of
administration of
neostigmine
Antagonistic Augmented during Phase
I; Antagonistic during
Phase II

60. d-Tubocurarine Suxamethonium
Effect of
administration
of tubocurarine
Antagonistic during
Phase I; Augmented
during Phase II
Pharmacogeneti
cs
No genetic problem Prolonged apnea due
to atypical
pseudocholinesterase
Main Uses As adjuvant to
anesthesia for
moderate to
prolonged operations
For rapid endotracheal
intubation for
operations of short
duration

61. Non depolarizing blockade:
 Cholinesterase inhibitors
 Neostigmine
 Pyridostigmine
 Edrophonium
 Suggammadex(for rocuronium)
Depolarizing blockade
 Phase1:cannot be reversed
 Phase2: same as non depolarizing
blockade

62. THANK YOU!