Neuromuscular blocking drugs and local anaesthetic agents

1. DRUGS ACTING AT THE
NEUROMUSCULAR JUNCTION
• Action potentials are conducted along the motor nerves to
their terminals where the depolarization initiates an influx
of Ca2+ ions and the release of ACh by exocytosis.
• The ACh diffuses across the junctional cleft and binds to
receptors located on the surface of the muscle fibre
membrane at the motor end-plate.

2. DRUGS ACTING AT THE
NEUROMUSCULAR JUNCTION
The reversible Ach-Receptor combination triggers the
opening of cation-selective channels in the end-plate
membrane, allowing an influx of Na+ ions and a lesser
efflux of K+ ions. The resulting depolarization
(endplate potential; EPP), depolarizes the adjacent
muscle fibre membrane. When large enough, the
depolarization results in an action potential and muscle
contraction. The ACh released into the synaptic cleft is
rapidly hydrolysed by an enzyme, AchE, which is
present in the endplate membrane close to the
receptors.

3. DRUGS ACTING AT THE
NEUROMUSCULAR JUNCTION

4. DRUGS ACTING AT THE NEUROMUSCULAR JUNCTION

5. DRUGS ACTING AT THE
NEUROMUSCULAR JUNCTION
• Neuromuscular transmission may be increased
by anticholinesterase drugs which inhibit
AChE and slow down the hydrolysis of Ach in
the synaptic cleft.
• Neostigmine and pyridostigmine are used in
the treatment of myasthenia gravis and to
reverse competitive neuromuscular blockade
after surgery.

6. DRUGS ACTING AT THE
NEUROMUSCULAR JUNCTION
Neuromuscular transmission can be blocked by
drugs in three ways:-
1. Inhibit Ach synthesis} prejunctional blockade
2. inhibit Ach release } “
3. interfere with postsynaptic action of Ach.
• depolarizing neuromuscular blocking drugs
(NMBs)
• non depolarizing NMBs

7. DRUGS ACTING AT THE NEUROMUSCULAR JUNCTION
DRUGS THAT INHIBIT ACETYLCHOLINE SYNTHESIS
Hemicholinium
- Competitive inhibitor of
choline uptake
- competes for choline acetylase
(Choline acetyltransferase
(abbreviated "ChAT")) through
structural symmetry
- affects peripheral synapses.
- reversal is by administration of
choline.

8. DRUGS ACTING AT THE NEUROMUSCULAR JUNCTION
DRUGS THAT INHIBIT ACETYLCHOLINE SYNTHESIS
• Release of Ach involves the
entry of Ca2+ into the nerve
terminal.
• Local Anaesthetics (L.As)
inhibit the nerve impulse
• Mg2+ ions and
aminoglycoside antibiotics
inhibit Ca2+ entry
• NB - Ca2+ antagonists have
little effect.

9. DRUGS ACTING AT THE NEUROMUSCULAR JUNCTION
DRUGS THAT INHIBIT ACETYLCHOLINE SYNTHESIS
• Botulinum toxin (clostridium
botulinum)
• β-bungarotoxin –snake
venom
• The black widow venom
stimulates Ach release and
causes depletion.
• Prejunctional blockade drugs
are not used clinically in
vet.med.

11. DRUGS ACTING AT THE NEUROMUSCULAR JUNCTION
DRUGS THAT INTERFERE WITH POSTSYNAPTIC
TRANSMISSION OF ACH
(POST. JUNCTIONAL (POST SYNAPTIC) BLOCKADE)
• These drugs cause skeletal muscle relaxation
without anaesthesia (or even analgesia).
• Their main use is as casting agents for large
animals and as adjuncts to anaesthesia.
• The order of muscle relaxation is:
Neck, trunk, limbs, abdomen, intercostals and
diaphragm
• Return of function is in the reverse order.

12. DRUGS ACTING AT THE
NEUROMUSCULAR JUNCTION
DRUGS THAT INTERFERE WITH POSTSYNAPTIC TRANSMISSION OF ACH
(POST. JUNCTIONAL (POST SYNAPTIC) BLOCKADE)
Peripheral acting drugs (also called peripheral acting
muscle relaxants) cause a total paralysis of the
skeletal muscles which often include the respiratory
muscles.
It is therefore preferable that facilities for
mechanical ventilation exist before using these drugs

13. DRUGS ACTING AT THE
NEUROMUSCULAR JUNCTION
DRUGS THAT INTERFERE WITH POSTSYNAPTIC TRANSMISSION OF ACH
(POST. JUNCTIONAL (POST SYNAPTIC) BLOCKADE)
Neuromuscular blocking drugs (NMBs) are of
two types/classes:
a) Competitive muscle relaxants (non‐
depolarization)
b) Depolarization muscle relaxants (non
competitive)

14. COMPETITIVE MUSCLE RELAXANTS
(CURARIZING AGENTS)
Are antagonists of nicotine receptors at the NMJ. They
compete with ACh for the available nicotinic
cholinergic receptors at the post synaptic membrane
(but do not usually initiate ion channel opening).
They induce flaccid paralysis of skeletal muscle.

15. COMPETITIVE MUSCLE RELAXANTS
(CURARIZING AGENTS)
Drugs
•D‐Tubocurarine (Tubarine)
•Gallamine (“Flaxedil”) (Gallamine Triethiodide)
•Atracurium
•Dimethyltubocurarine (Metubine)
•Pancuronium (Pavulon)
•Alcuronium
•Mephenesin
•Vecuronium

16. COMPETITIVE MUSCLE RELAXANTS
(CURARIZING AGENTS)
Pharmacological effects
Skeletal m. relaxation resulting in a flaccid paralysis

17. COMPETITIVE MUSCLE
RELAXANTS (CURARIZING
AGENTS)
Pharmacological effects
Skeletal m. relaxation resulting in a flaccid paralysis
Side and toxic effects
• Inhibition of respiration: respiratory m. paralysis
resulting in apnoea, hypnoxia.
•Histamine release:- causing bronchospasm,
hypotension, salivation, bronchial secretion, a
drop in BP.
•High dose can block autonomic ganglia.

18. COMPETITIVE MUSCLE
RELAXANTS (CURARIZING
AGENTS)
Treatment of overdose
Neostigmine:‐ Curarizing agent overdose/reversal can
be by additional ACh which can be provided by
anticholinesterases.
Best to give after atropine to reduce the autonomic
effects.

19. DEPOLARIZATION MUSCLE
RELAXANTS
Are cholinergic nicotinic agonists. They produce a
long‐lasting depolarization at the NMJ receptors
causing a loss in excitability. The initial depolarization
action causes a transient contraction of muscle cells
(momentary asynchronous muscle twitches and
fasciculations) before the block. They are not in
general, hydrolysed by AChE. Eventually, the drugs
diffuse away (Decamethonium mainly, but not
suxamethonium), the nerve repolarizes and the block
is reversed.

20. DEPOLARIZATION MUSCLE
RELAXANTS
Suxamethonium (Succinylcholine Chloride)
- Readily soluble in water. Stable in acid but not alkali.
- Hydrolysed by pseudocholinesterase (butyrycholinesterase)
present in
plasma.
Duration of action is variable
3-6 minutes (cats)
15-20 minutes (dogs)
Contraction followed by relaxation of skeletal m.
Respiratory muscle are the last to be paralysed.
Only used parenterally – rapidly absorbed from S/C (and
I/M) sites.

21. DEPOLARIZATION MUSCLE
RELAXANTS
Suxamethonium (Succinylcholine Chloride)
Side Effects
•Only use with anaesthesia or the paralysed animal
will not have any CNS depression/analgesia, etc.
•I/M use may cause muscle injury
•IV use can cause AV nodal arrhythmias
•Hypertension
•Occasional liver damage. Raised potassium in serum.

22. DEPOLARIZATION MUSCLE
RELAXANTS
Suxamethonium (Succinylcholine Chloride)
Uses
•To aid endotracheal intubation
•To aid treatment of luxations
•Surgery – abdominal, thoracic surgery, orthopedic
surgery
•Anaesthetic sparing effects
•Chemical restraint

23. DEPOLARIZATION MUSCLE
RELAXANTS
Suxamethonium (Succinylcholine Chloride)
Contraindications
Contraindicated in animals that have recently been
treated with organophosphates + carbamates since it
would result in increased duration of action.
Neostigmine is contraindicated as an antidote. The
anticholinesterases block Pseudocholinesterase which
is responsible for the breakdown of succinyl choline,
hence the duration of action will be prolonged.

24. DEPOLARIZATION MUSCLE
RELAXANTS
Suxamethonium (Succinylcholine Chloride)
Treatment of overdose
•Ventilate

25. DEPOLARIZATION MUSCLE
RELAXANTS
DECAMETHONIUM
- longer activity
- not broken down by pseudocholinesterase
- eliminated unchanged in urine.

26. CENTRALLY ACTING
MUSCLE RELAXANTS
These drugs selectively depress or block n. impulse
transmission at the internuncial neuron level of the
spinal cord, brain stem and subcortical areas of the
brain. Depending on the dose, graded effects from
mild relaxation to total paralysis of skeletal muscles
can be obtained.

27. CENTRALLY ACTING
MUSCLE RELAXANTS
DRUGS:
•Glyceral Guaiacolate ether (Guaiafenesin) (GGE)
•Benzodiazepine group e.g., Diazepam (valium)
•Xylazine
•Metacarbamol

28. CENTRALLY ACTING
MUSCLE RELAXANTS
GGE
First used for analgesic, antipyretic and expectorant
properties.
Toxicity is associated with haemolysis,
haemoglobinuria and venous thrombosis.
Best administered IV but can be given P.O., widely
distributed including CNS.
Pharmacological effects – muscle relaxation, mild
sedation, mild analgesia, mild antipyretic action,
expectorant properties.

29. CENTRALLY ACTING
MUSCLE RELAXANTS
GGE
Clinical uses
•Used in equines for premedication or for handling,
also for induction (used together with sodium
thiopentone to induce general anaesthesia).
•Used in cough mixtures due to expectorant
properties.

30. LOCAL ANAESTHETICS
Local anaesthetics are drugs used to prevent pain or
reduce sensation of a limited area of the body by
causing a reversible block of conduction along nerve
fibres.
Regional anaesthesia is loss of sensation in a larger,
although limited, area of the body.
General anaesthesia means loss of sensation of the
whole body. Local anaesthetics act as membrane
stabilizers and are able to interfere with the ability of
excitable cells to generate or transmit impulses.

31. LOCAL ANAESTHETICS
Most local anaesthetics are weak bases (B) that exist
mainly in a protonated form (BH+) at body pH.
The pKa is the pH at which the drug is 50% ionized
and 50% unionized. Ionized drugs are poorly lipid
soluble.
The closer the pKa is to local tissue pH (usually 7.4),
the more unionized the drug is, or, the higher the pKa,
the more ionized.
B + H+ BH+
= pH - pKa
BH+
B

32. LOCAL ANAESTHETICS
The drugs penetrate the nerve in a non-ionized
(lipophilic) form, but once inside the axon, some
ionized molecules are formed and these block the Na+
channels preventing generation of action potentials.
They do not interfere with the resting membrane
potential of the cell.
Local anaesthetics also act as membrane stabilizers.

33. LOCALANAESTHETICS
The loss of sensation is in the order pain, cold, heat,
touch and deep pressure. Recovery occurs in the
reverse order.
Commonly used local anaesthetics consist of a
lipophilic end (often an aromatic ring) and a
hydrophilic end (usually a secondary or tertiary amine)
connected by an intermediate chain that incorporates
an ester (ester local anaesthetic) or amide (amide local
anaesthetic) linkage.

34. LOCAL ANAESTHETICS
Aromatic
group
Ester
Or
Amide
Basic side chain
(amine)
The ester linkage is less stable and can be easily
broken down. The amide linkage is stronger. Amide
local anaesthetics are heat stable and can be
autoclaved whereas esters cannot.

35. LOCAL ANAESTHETICS
Local anaesthetics are weak bases; pKa 8 to 9. They
are largely ionized at pH 7.4 (80-90 % of the local
anaesthetic is ionized). Anaesthetic activity is strongly
pH-dependant. Increased activity when in alkaline pH;
reduced activity in acid pH. (Therefore local
anaesthetics are less active in acidic pus).
NH
C O
C O
O
Ester Amide

36. LOCAL ANAESTHETICS
• Local anaesthetics are weak bases; pKa 8 to 9.
• They are largely ionized at pH 7.4 (80-90 % of
the local anaesthetic is ionized).
• Anaesthetic activity is strongly pH-dependant.
• Increased activity when in alkaline pH; reduced
activity in acid pH. (Therefore local
anaesthetics are less active in acidic pus).
C C C C N
R1
R2

37. LOCAL ANAESTHETICS
• The lipophilic group is necessary to allow
membrane (especially nerve sheath)
permeability of the local anaesthetic.
C C C C N
R1
R2

38. LOCAL ANAESTHETICS
Pharmacological effects
1. Peripheral nerves – conduction blockade
2. CNS – Stimulation (restlessness, tremors),
convulsions, depression, death. Decreased arterial
pH means reduced dose of local anaesthetic
required produce convulsions.
3. CVS – Possible initial stimulation – increased
heart rate, plus arterial blood pressure due to CNS
stimulation.

39. LOCAL ANAESTHETICS
Pharmacological effects
3. CVS – Possible initial stimulation – increased
heart rate, plus arterial blood pressure due to CNS
stimulation.
-Myocardial depression: Sodium current in cardiac
muscle is decreased
Less [Na+] → ↓[Ca2+] → Reduced force
of contraction.
-Vasodilation – direct effect on smooth muscle;
inhibition of somatic nervous system.
4. Local tissue toxicity: none at clinical doses.

40. LOCAL ANAESTHETICS
Pharmacokinetics
• Blood concentration is related to toxicity.
-depends on absorption rate, distribution and
metabolism.
• Tissue concentration – dependent on blood flow
and lipid solubility.
• Local anaesthetics vary in ability to penetrate
tissue, e.g. procaine has poor penetration, whereas
bupivacaine (pKa 8.1) has good penetration.

41. LOCAL ANAESTHETICS
Pharmacokinetics
Absorption may be altered by addition of
vasoconstrictor, e.g. adrenaline. N.B. High
concentration of adrenaline may cause local
ischaemia. (Adrenaline 1:1000 contains 1 gram of
adrenaline per 1000 mls solution i.e. 1mg/ml)
Hyaluronidase- can be added to improve diffusion
through subcutaneous tissues.

42. LOCAL ANAESTHETICS
Metabolism
• The liver is the major site of inactivation by
esterases, amidases, conjugation reactions.
• Esters (except cocaine) are broken down
rapidly by plasma esterases to inactive
compounds and consequently have a short half
life.
• Cocaine is hydrolysed in the liver.
• Ester metabolite excretion is renal.

43. LOCAL ANAESTHETICS
Metabolism
• Amides are metabolised hepatically by
amidases. This is a slower process, hence their
half-life is longer and they can accumulate if
given in repeated doses or by infusion.
• Prilocaine is also metabolised extra-hepatically.
• Procaine is degraded by plasma esterases as
well as hepatic esterases (and other esterases).
• Extrahepatic site of inactivation for amide
group.

44. LOCAL ANAESTHETICS
Toxicity
Generally occurs after accidental IV or IA (intra-
arterial) injection.
CNS – Treat with barbiturate or diazepam
CVS – Bupivacaine > lignocaine ; support
circulation.
Myocardial depression, and reduced blood
pressure.
Occasional anaphylactoid reactions and skin
sensitizations. Metabolism of most esters results in
the production of para-aminobenzoic acid (PABA)
which is associated with allergic reactions.

45. LOCAL ANAESTHETICS
Routes of Administration of Local Anaesthetics
Surface anaesthesia – topical application-mucous
membranes, skin.
Infiltration – Subcutaneous injection to act on
local nerve endings, usually with a vasoconstrictor.
IVRA (Intravenous regional anaesthesia):
anaesthetic is injected IV into an exsanguinated
limb. A tourniquet prevents the agent reaching the
systemic circulation.

46. LOCAL ANAESTHETICS
Routes of Administration of Local Anaesthetics
Nerve Block – Techniques range from infiltration
around a single nerve to epidural and spinal (or
intrathecal) anaesthesia.
In spinal anaesthesia, the anaesthetic is injected
into the cerebrospinal fluid in the subarachnoid
space.
In epidural anaesthesia, the anaesthetic is injected
outside the dura i.e. into the epidural space.

47. LOCAL ANAESTHETICS
Commonly used local anaesthetics
Procaine (Diethylaminoethyl
paraaminobenzoic acid) (“Novocaine”;
“Planocaine”)
It is an ester type of anaesthetic. Has a pKa of
8.9. Used in concentrations of 0.5 – 5%
(usually 5% in Vet. Med.). Used with or
without adrenaline.

48. LOCAL ANAESTHETICS
Commonly used local anaesthetics
Procaine (Diethylaminoethyl paraaminobenzoic
acid) (“Novocaine”; “Planocaine”)
It is rapidly inactivated by pseudocholinesterases. Onset of
action is 5-10 minutes, with a duration of about 15
minutes. Its action is brief and it is a vasodilator, so
adrenaline is used as a local vasoconstrictor. It is non-
irritant. Do not use with sulphonamides as PABA inhibits
sulphonamide action. Has no addictive properties, and can
be sterilized by boiling. Acidification of urine hastens
excretion.

49. LOCAL ANAESTHETICS
Commonly used local anaesthetics
Procaine (Diethylaminoethyl paraaminobenzoic
acid) (“Novocaine”; “Planocaine”)
It is used in infiltration, nerve blocks, epidural anaesthesia.
Has been used IV for the treatment of spasmodic colic in
horses and control of various forms of pruritus in dogs.
Because of its CNS stimulant and analgesic properties
procaine has been used illegally in race horses to improve
performance and/or mask lameness in track and racing
events. Psittacine birds (e.g. budgies) are very sensitive to
procaine. Procaine penicillin suspension can cause micro-
embolism if injected IV.

50. LOCAL ANAESTHETICS
Commonly used local anaesthetics
Lignocaine
(USA=Lidocaine;“Xylocaine”;”Xylotox”)
An amide type of local anaesthetic. Has a pKa of 7.9, which is
close to the tissue pH than procaine and therefore spreads
better. Very stable, fairly insoluble compound (hydrochloride
salt is more so). Available as aqueous solutions (0.5-5%) with
or without adrenaline, and as spray aerosols and as gels.
Resistant to plasma esterases but is metabolized in the liver
first by de-ethylation and then by sulphate conjugation. It is
double the potency of procaine (but slightly more toxic).
Does not cause vasodilation.

51. LOCAL ANAESTHETICS
Commonly used local anaesthetics
Lignocaine
(USA=Lidocaine;“Xylocaine”;”Xylotox”)
USES: specific nerve blocks, infiltration and topical
anaesthesia in small and large animals; as a spray for
endotrachial intubation of cats; antiarrhythmic agent in dogs.
It is used as a supplement to inhalation anaesthesia in
humans. Used together with halothane, it decreases the
minimum alveolar concentration of the anaesthetic in dogs as
much as 25%.

52. LOCAL ANAESTHETICS
Commonly used local anaesthetics
Benzocaine – used in powders and ointments
topically.
Bupivacaine – used in human obstetrics; regional
nerve blocks and epidurals.
Proxymetacaine – corneo-conjuctival anaesthesia in
animals. 0.5% Solution. Rapid onset, non-irritant,
brief action.
Amethocaine – used topically. pKa 8.5.
Mepivacaine – nerve blocks; epidural anaesthesia in
the dog, infiltration and regional nerve blocks in man.

53. LOCAL ANAESTHETICS
Other local anaesthetics
Cocaine
• Was first used in 1884 for local anaesthesia of the
eye.
• It is toxic and addictive so it is not used now.
• It has its own vasoconstrictor action (inhibits
noradrenaline uptake 1).
• It is slowly metabolized.