drugs of the ANS

1. SKELETAL MUSCLE RELAXANTS.
•Skeletal muscle relaxants are drugs which act
peripherally at the neuro muscular junction(NMJ)
and centrally in the cerebrospinal axis to relax
muscles.
•The drugs which act at the NMJ or neuro
muscular blocking drugs are used in conjunction
with general anaesthetics to provide muscle
relaxation during surgery.
•The centrally acting muscle relaxants are used
mainly for painful muscle spasms and spastic
neurological conditions.

2. NEURO MUSCULAR BLOCKING AGENTS.
CLASSIFICATION.
• A) Non depolarizing (competitive) blockers.
• Long acting: d-Tubocurarine, Pancuronium,
Doxacurium, Pipecuronium.
• Intermediate acting: Vecuronium, atracurium,
cisatracurium, Rocuronium, Rapacuronium
• Short acting: Mivacurium.
• B) Depolarizing blockers.
• Succinyl choline (suxamethonium).
• Decamethonium.

3. CLASSIFICATION CONT..
• C) Directly acting agents
• Dantrolene sodium.
• Quinine.
Other agents that interfere with neuro
muscular transmission.
• Aminoglycosides, tetracycline, polypeptide
antibiotics: these are not used as muscle
relaxants.

4. MECHANISM OF ACTION OF NON-
DEPOLARIZING NEURO MUSCULAR
BLOCKERS.
• These are competitive inhibitors of acetyl
choline at the motor end plate.
• The motor end plate is found at the
junction of the motor nerve and the
skeletal muscle and it contains nicotinic
Nm or N2 receptors of acetylcholine.
• ACH Combines with these post synaptic
receptors leading to influx of sodium ions
and the development of end plate
potential causing muscle contraction.

5. MECHANISM OF ACTION OF NON-
DEPOLARIZING NEURO MUSCULAR BLOCKERS.
CONT..
• The competitive neuro muscular blockers are
generally bulky in nature and therefore block
access of the nicotinic receptors to ACH with no
generation of end plate potentials and causing
flaccid paralysis.
• ACH also acts presynaptically on cholinergic
neurons and augments its own release(positive
feedback).
• Tubocurarine can reversibly block both
presynaptic and post synaptic receptors while α-
bungarotoxin blocks only post synaptic receptors
but not presynaptic receptors.

6. MECHANISM OF ACTION OF NON-
DEPOLARIZING NEURO MUSCULAR
BLOCKERS. CONT..
• Gallamine also inhibits neuronal release of
ACH by acting on presynaptic cholinergic
M2 receptors.
• 80-90% of nicotinic receptors must be
blocked before neurotransmission fails.
• Anticholinesterases agents like
neostigmine are able to reverse the
effects of neuromuscular blockers by
building up the concentration of the
agonist (ACH).

7. PHARMACOKINETICS OF COMPETITIVE
NEURO MUSCULAR BLOCKERS.
• All competitive neuro muscular blockers are
quaternary ammonium compounds: They are:
• Poorly absorbed after oral administration
• Low volume of distribution because they don’t
cross membranes.
• Do not penetrate placenta or blood brain barrier.
They are safe in obstetrical surgery except
gallamine)
• They are always administered by IV route
although the IM route is also possible.

8. PHARMACOKINETICS OF COMPETITIVE
NEURO MUSCULAR BLOCKERS. CONT..
• The drugs are first distributed to muscles
with higher blood flow and these muscles
are affected first. Redistribution to non-
muscular tissues plays a role in
terminating the activity of the NMJ blocker.
• Duration of muscle relaxation following IV
administration : tubocurarine 30 min,
gallamine 15 mins, pancuronium 60 min,
atracuronium 10 min, alcuronium 30
mins.

9. PHARMACOLOGICAL ACTIONS OF D-
TUBOCURARINE
• When injected I.V there is immediate onset of
action, peak effect within 5-7 mins. and duration
of action of between 30- 60 mins.
• Effects of d-tubocurarine on skeletal
muscles.
• There is flaccid paralysis of the muscles.
• Muscles of fine movements are more sensitive
than larger and stronger muscles of coarse
movements.
• Small rapidly moving muscles of the face,neck,
eyes and pharynx are affected first, leading to
difficulty in speaking, accumulation of secretions
in throat, and diplopia.

10. PHARMACOLOGICAL ACTIONS OF D-
TUBOCURARINE CONT..
• Other small muscles of fingers, toes,
hands and intercostal muscles are
affected next leading to difficulty in
performing delicate motor tasks.
• Muscles of limb, trunk, abdomen, chest
and finally diaphragm are paralyzed with
cessation of respiration.
• Recovery of paralysis occurs in reverse
order.

11. Effects of d- tubocurarine on other
systems.
• Blocks transmission at autonomic ganglia
and decreases secretion of adrenaline
from the adrenal glands leading to fall in
blood pressure.
• Releases histamine from mast cells leads
to fall in blood pressure and
bronchospasm. Contraindicated in
patients of bronchial asthma and other
allergic states.

12. Important Pharmacological Effects of
Other Agents.
• All are quaternary ammonium compounds
with same pharmacokinetic profile as d-
tubocurarine.
Gallamine.
• Does not release histamine or block
autonomic ganglia.
• Blocks M2 muscarinic receptors of the
heart and releases NA, inducing
tachycardia.

13. Pancuronium
• Does not release histamine or block
autonomic ganglia.
• Blocks M2 muscarinic receptors of the
heart and releases NA leading to
tachycardia.
• Duration-60-120 mins.
• Inhibits plasma cholinesterase.

14. Atracurium
• 4 times less potent than pancuronium and
shorter acting (20-35mins.)
• Neostigmine reversal not required because of
short duration of action.
• It is inactivated by plasma cholinesterase and
spontaneous non enzymatic degradation in the
plasma (Hofmann elimination) therefore duration
of action is not altered by liver diseases.
• Preferred muscle relaxant for patients of hepatic
diseases, neonates and the elderly.
• Releases histamine and may cause
hypotension.

15. Pipecuronium.
• Slow onset and long duration of action
(onset2-4min Duration-50-100mins)
• Recommended for prolonged surgeries.
• Has little cardiovascular action, though
there may be transient hypotension and
bradycardia.

16. Vecuronium.
• A close congener of pancuronium with a shorter
duration (30-60mins) due to rapid distribution
and metabolism.
• Recovery is generally spontaneous not requiring
neostigmine reversal unless repeated dose has
been given.
• Cardiovascular stability is better due to lack of
histamine release and ganglion blockage,
tachycardia occasionally occurs.
• Currently the most commonly used muscle
relaxant for routine surgery.

17. Doxacurium
• Has the least rapid onset (4-8 mins) and the
longest duration of action (60-120 mins).
• Suitable for long surgeries.
• Minimal cardiovascular effects.
• Mivacurium
• Shortest acting (onset 2-4 and duration 12-20
mins).
• Does not need neostigmine reversal.
• Cause slight histamine release leading to fall in
BP but minimal effect on heart rate.
• Hydrolyzed by plasma cholinesterase and
prolonged paralysis can occur in pseudo
cholinesterase deficiency.

18. Rocuronium.
• New compound with rapid onset (1-2 mins) and
intermediate duration of action (25-40 mins).
Onset is dose dependent.
• Can be used as an alternative to succinyl
choline for tracheal intubation without the
disadvantages of depolarizing block and
cardiovascular changes.
• May serve as maintenance muscle relaxant.
• Seldom needs neostigmine reversal.

19. ADVERSE REACTIONS OF COMPETITIVE
NEUROMUSCULAR BLOCKERS
• Hypoxia and prolonged respiratory
paralysis. Managed by artificial
respiration, maintenance of patient’s
airway and injection of neostigmine (1-
3mg i.v) and atropine sulfate (0.6 mg
i.v). Atropine is used to block the
peripheral muscarinic actions of ACH
e.g. bronchospasm and hypotension.

20. ADVERSE REACTIONS OF COMPETITIVE
NEUROMUSCULAR BLOCKERS CONT..
• Bronchospasm due to histamine
release as with tubocurarine.
• Hypotension due to autonomic
ganglion blockage and histamine
release. Less likely with the new
compounds.
• Neuro muscular paralysis especially
in children, myasthenia gravis and
patients with hepatic and renal failure.

21. DRUG INTERACTIONS INVOLVING
COMPETITIVE NEUROMUSCULAR BLOCKERS.
• Neuro muscular block and paralysis are
potentiated by:
• Inhalation anaesthetics (ether, halothane,
cyclopropane, enflurane.
• Lignocaine, quinidine, beta blockers,
calcium channel blockers and lithium
which inhibit ACH release or action.

22. DRUG INTERACTIONS INVOLVING COMPETITIVE
NEUROMUSCULAR BLOCKERS. CONT..
• Antibiotics (aminoglycosides, clindamycin)
which inhibit ACH release.
• Anticholinesterases reverse the action of
competitive blockers. Neostigmine (0.5-
2mg i.v) is routinely used after
pancuronium and other long acting
blockers to hasten recovery at end of
operation.

23. SUMMARY OF ADVANTAGES OF NEW
COMPETITIVE NEURO MUSCULAR BLOCKERS.
• No or minimal ganglionic, cardiac or
vascular effects.
• No or minimal histamine release.
• Many are short acting and easy reversal
• Some are rapid acting: provide alternative
to Succinyl choline without the attendant
complications.

24. DEPOLARIZING BLOCKING AGENTS.
• The group is also referred to as persistent
depolarizing agents and includes succinyl
choline and decamethonium.
• Mechanism of action: the drugs cause persistent
depolarization at the motor end plate and
prevent any response due to acetyl choline
combining with the nicotinic receptors at the
motor end plate.
• Persistent depolarization means there is no
resting phase of the action potential and hence
no response to ACH.
• It is caused by sustained opening of sodium
channels by the depolarizing neuro muscular
blocker.

25. PHARMACOKINETICS OF DEPOLARIZING
NEURO MUSCULAR BLOCKERS.
• Onset of action of succinyl choline is 1-1.5 minutes
after IV injection ad duration of action is 3-6 minutes.
• It is rapidly hydrolyzed by plasma and tissue
pseudo- CHE.
• Duration of action of succinyl choline is prolonged in
patients withpseudo CHE deficiency or with atypical
pseudo –CHE which may lead to respiratory
paralysis or succinyl apnea.
• Decamethonium is not easily metabolized having
longest duration of action, hence not used clinically.

26. PHARMACOLOGICAL EFFECTS OF SUCCINYL
CHOLINE
• It causes transient fasciculation of groups
of muscle fibres for 10-15 seconds
followed by flaccid paralysis. This is called
phase one block.
• In this depolarized state(phase), the block
cannot be reversed by anticholinesterases
like neostigmine or edrophonium.
• Paralysis of neck and limb muscles occurs
before those of face and pharynx.

27. PHARMACOLOGICAL EFFECTS OF
SUCCINYL CHOLINE CONT..
• With continued exposure to Succinyl choline, the initial
depolarization decreases, the membrane is repolarized
but now cannot be depolarized again as long as the
succinyl choline is present in the receptor sites. This is
called phase II or desensitization block, which can be
antagonized by anti cholinesterases.
• Succinyl choline has muscarinic and ganglion stimulating
actions but does not release histamine.
• It may cause bradycardia in therapeutic doses and
tachycardia in larger doses. It may also cause cardiac
arrhythmia (extra systole).
• Muscle power recovery occurs within minutes.

28. ADVERSE EFFECTS OF SUCCINYL CHOLINE.
• Muscle fasciculation and post-operative
muscle pain are common and are due to
depolarizing effect of the drug.
• Muscarinic effects are manifested as
bradycardia, hypotension, salivation and
increases gut motility.
• Raised intra ocular tension due to
prolonged contraction of extra- ocular
muscles and transient dilation of choroidal
blood vessels. It may be dangerous in
acute glaucoma.

29. ADVERSE EFFECTS OF SUCCINYL
CHOLINE. CONT..
• Hyperkalemia may be due to persistent
depolarization, especially in patients of deep
burns and muscle damage. Cardiac arrhythmias
and arrest can also be caused.
• Succinyl apneas in patients with atypical pseudo
–CHE (genetic variant) which does not hydrolyze
succinyl choline.
• Malignant hyperthermia, a rare congenital
abnormality characterized by intense muscle
spasm and sudden rise in body temperature.
Treated with dantrolene.

30. DRUG INTERACTIONS INVOLVING SUCCINYL
CHOLINE
• The action of Succinyl choline is
potentiated by:
• Drugs which inhibit neuro muscular
transmission-aminoglycosides, quinidine,
calcium channel blockers, local
anaesthetics and magnesium ions.
• Drugs which inhibit pseudo
cholinesterase-anticholinesterases, MAOI
and cytotoxic agents.

31. FACTORS TO BE CONSIDERED WHEN
CHOOSING AN NMB.
• Neuromuscular blockers are used whenever
relaxation of skeletal muscles is desirable.
• The following factors must be considered when
selecting appropriate NMBs
• The duration of the surgical procedure: Succinyl
choline (duration of action 3-6 mins) is employed for
brief procedures e.g. endotracheal intubation,
laryngoscopy, bronchoscopy, esaphogoscopy,
reduction of fractures, dislocations and to treat
laryngospasms.
• Onset of action of the NMB.
• Cardiovascular effects of the drug.
• Patient’s hepatic, renal and hemodynamic status.

32. THERAPEUTIC USES OF NMBs
• As an adjunct to general anaesthetics: For skeletal
muscle relaxation, both non-depolarizing and
depolarizing neuro muscular blockers are used
clinically.
• For operations lasting more than 30 minutes e.g.
intra-abdominal operations or orthopedic
manouvres, d –tubocurarine is used for these
reasons:
• It relaxes muscle tone
• It reduces the dose of anaesthetic agents and the
post anaesthetic complications and keeps the blood
pressure on the lower side.
• D- Tubocurarine has been largely replaced by
synthetic derivatives which have fewer side effects
(atracurium-duration 20-35 mins, pipecuronium 50-
100 mins, vecuronium, 30-60 mins).

33. THERAPEUTIC USES OF NMBs CONT..
• b. In obstetric conditions- any of the non-
depolarizing drugs (except gallamine) can be
used.
• c. In selected cases of arterial surgery,
pancuronium is used.
• d. For producing transient muscle relaxation
as required in endotracheal intubation,
bronchoscopy, direct laryngoscopy,
esophagoscopy and electroconvulsive therapy
(ECT).
• Succinyl choline is the drug of choice as the
onset of action is immediate and recovery is
within 5 minutes.

34. THERAPEUTIC USES OF NMBs CONT..
• The intravenous muscle relaxant doses in mg
are: tubocurarine 10-15, gallamine1-2,
pancuronium, 1-2, pancuronium1-2 and
altracurium 0.5-1.
• 2. In the treatment of painful muscle spasm-
as in tetanus, muscle relaxation is the key to
therapy and mild sedation is also desirable.
• Diazepam i.v as a running drip is given in adults
(60-240 mg /24 hours, in children (30-40 mg/24
hours) and in neonates (20-40mg/24 hours).
Maintenance on intermittent positive pressure
respiration is necessary.

35. THERAPEUTIC USES OF NMBs CONT..
• 3. In very small doses (1/10) atracurium
may be used for diagnosis of myasthenia
gravis.
• 4. Severe cases of status epilepticus
which are not controlled by diazepam or
other drugs may be paralyzed by an NMB
(repeated doses of competitive blocker)
and maintained on intermittent positive
pressure respiration till the disease
subsides.

36. INDIRECTLY ACTING MUSCLE RELAXANTS.
• DANTROLENE.
• It exerts a direct action on the skeletal
muscle by interfering with the release of
calcium from the sarcoplasmic reticulum.
• It interfers with the excitation- contraction
coupling
• Cardiac and smooth muscles are not
affected by dantrolene as the mechanism
of calcium entry is different in these
tissues.
• It has no effect on CNS and neuro
muscular junction.

37. PHARMACOKINETICS OF DANTROLENE
• It is absorbed after oral administration, but
the absorption is slow and incomplete.
• It penetrates the brain and produces some
sedation, but has no selective action on
polysynaptic reflexes responsible for
spasticity.
• It is metabolized in the liver and excreted
by the kidneys with a half- life of 8-12
hours.

38. THERAPEUTIC USES OF DANTROLENE.
• 1. Neurological spastic disorders e.g. multiple
sclerosis, cerebral palsy, spinal injury,
hemiplegia and paraplegia.
• The initial oral dose is 25mg once a day which is
gradually increased to 100mg QDS daily. The
dose limiting toxicity is generalized muscle
weakness.
• 2. Malignant hyperthermia following use of
succinyl choline or halothane in genetically
predisposed people.
• Dantrolene is given initially 1 mg /kg IV and
repeated up to 100 mg/kg IV which is followed
by 50-100mg QDS for 2-3 days.

39. ADVERSE EFFECTS OF DANTROLENE.
• Muscle weakness is the dose limiting toxicity.
• Sedation, malaise lightheadedness and other
central effects occur, but are less pronounced
than centrally acting muscle relaxants.
• Troublesome diarrhea.
• Long term use cause dose dependent liver
toxicity in 0.1-0.5 % of patients. This has
restrictedits use in chronic disorders.

40. QUININE.
• It increases refractory period and
decreases excitability of motor end plates,
thus reducing response to repetitive nerve
stimulation.
• It reduces muscle tone in myotonia
congenita.
• When taken at bedtime (200-300mg) it
may abolish nocturnal leg cramps in some
patients.

41. CENTRALLY ACTING MUSCLE
RELAXANTS.
• These are drugs which reduce skeletal
muscle tone by a selective action in the
cerebrospinal axis, without altering
consciousness.
• They selectively depress spinal and supra
spinal poly synaptic reflexes involved in
the regulation of muscle tone.
• Polysynaptic pathways in the ascending
reticular formation which are involved in
wakefulness are also depressed, though
to a smaller extent.

42. CENTRALLY ACTING MUSCLE
RELAXANTS. CONT..
• All centrally acting muscle relaxants cause
sedation.
• They have no effect on neuro muscular
transmission and on muscle fibres but
reduce decelebrate rigidity, upper motor
neuron spasticity and hyperreflexia.
• Note the differences between peripherally
and centrally acting muscle relaxants in
table 25.3.

43. CLASSIFICATION OF CENTRALLY ACTING
MUSCLE RELAXANTS.
• Mephenesin congeners: Mephenesin,
Carisoprodol, Chlozoxazone,
Chlormezanone, Methocarbamol.
• Benzodiazepines: Diazepam. Trizolam
and others.
• Gabba derivative: Baclofen
• Central α2agonist: Tizanidine

44. PROPERTIES OF CENTRALLY ACTING
• MUSCLE RELAXANTS.
• MEPHENESIN
• First drug to be discovered as a muscle
relaxant.
• Modulates reflexes maintaining muscle
tone.
• It is not used clinically because it causes
gastric irritation, and when administered IV
it causes thrombophlebitis, hemolysis and
marked fall in BP.

45. • CARIS0PRODOL.
• Has favorable muscle relaxant, sedative,
analgesic antipyretic, and anticholinergic
properties.
• It is used in musculo skeletal disorders
associated with muscle spasm.
• CHLOZOXAZONE.
• Pharmacologically similar to mephenesin, has a
longer duration of action and is better tolerated
orally.
• CHLORMEZANONE.
• Has anti- anxiety and hypnotic actions and is
used for tension states associated with
increased muscle tone.

46. • METHOCARBAMOL.
• Less sedative and longer acting than
mephenesin.
• Orally used in reflex muscle spasm and
chronic neurological diseases.
• It can be given IV without producing
thrombophlebitis and hemolysis-used for
orthopedic procedures and tetanus.

47. DIAZEPAM.
• A benzodiazepine (BDZ) which acts in the brain on
specific receptors, enhancing transmission by the
inhibitory amino acid neurotransmitter GABA.
• Muscle tone is reduced by supraspinal rather than spinal
action.
• It has more sedative activity than muscle relaxation and
sedation limits the dose that can be used for muscle
relaxation.
• Diazepam is particularly valuable in tetanus and spinal
injuries.
• When combined with analgesics, it is useful for
rheumatic disorders associated with muscle spasm.

48. • BACLOFEN.
• Is a GABA B receptor agonist which depresses
both polysynaptic and monosynaptic reflexes in
the spinal cord.
• It does not produce muscle weakness like
diazepam because it does not affect chloride
conductance.
• ( BDZs facilitates the effect of GABA on GABA
A receptors increasing chloride conductance
while baclofen acts on GABAB receptors,
hyperpolarizing neurons by increasing K+
conductance and altering Ca2+ flux.).

49. BACLOFEN. CONT..
• It reduces spasticity in many neurological
disorders like multiple sclerosis, spinal
injuries and flexor spasms.
• It is relatively in effective in stroke,
cerebral palsy, rheumatic and traumatic
muscle spasms and Parkinsonism.

50. • TIZANIDINE.
• It is a new skeletal muscle relaxant which
is a congener of clonidine.
• It is a central α2-adrenergic agonist which
inhibits the release of excitatory amino
acids e.g. aspartate in the spinal
interneurons while facilitating the inhibitory
amino acid neurotransmitter glycine.

51. TIZANIDINE. CONT..
• It inhibits polysynaptic reflexes; reduce
muscle tone and frequency of muscle
spasms without reducing muscle strength.
• Efficacy similar to baclofen and diazepam
has been noted in multiple sclerosis,
spinal injury and stroke with fewer side
effects.
• It is well absorbed and is administered as
tablets of 2 and 4 mg.

52. ADVERSE EFFECTS OF CENTRALLY
ACTING MUSCLE RELAXANTS (CAMs)
• Gastric irritation except for diazepam.
Baclofen and tizanidine.
• All CAMs cause drowsiness and sedation.
• Baclofen can cause tachycardia,
hypotension and rarely visual and auditory
hallucinations. It can also cause ataxia
and elevation of serum transaminase.

53. ADVERSE EFFECTS OF CENTRALLY ACTING
MUSCLE RELAXANTS (CAMs) CONT..
• Tizanidine may cause dry mouth, drowsiness,
night time insomnia and hallucinations. Dose
dependent elevation of liver enzymes has been
noted.
• No consistent effect on BP has been noticed but
should still be avoided in patients receiving anti
hypertensives, especially clonidine.
END.
DR. OCHOLA.F.O, DEPT OF PHARMACOLOGY AND
TOXICOLOGY- MOI UNIVERSITY, SCHOOL OF
MEDICINE.