3. I. Peripherally acting agents
1. Neuromuscular blocking agents (NMBs):
• These are the agents which interfere with transmission of
nerve impulses form somatic motor nerve ending to
skeletal muscle fibres.
• These agents blocks NM nicotinic ACh receptors at the
end plate of neuromuscular junction.
A. Non-depolarizing NMBs
Competitive antagonist of Ach at NM nicotinic receptor
They donot depolarize the motor end plates
They all are quarternary ammonium compounds
containing two or more quarternary N+ atoms.
4. Mechanism of Action
Nm nicotinic receptor + Non-depolarizing
NMBs
No conformational changes in Receptor
Na+ channel doesn’t open
Skeletal muscle doesn’t
depolarize
5. On the basis of duration of action, Non-depolarizing NMBs are of following types:
a. Long acting drugs (duration >60 min)
b. Intermediate acting drugs (duration 30-60 minutes)
c. Short acting drugs (duration 10-30 minutes)
a. Long acting drugs (duration >60 min):
i. d-tubocurarine
Pharmacological effects:
Skeletal m/s : Flaccid paralysis
Histamine release: Histamine release from mast cells. Intradermal
injection produce similar to that produced by injection of
histamine.
Autonomic ganglia: Partial blockage at autonomic ganglia and
adrenal medulla
CVS: IV injection causes fall in blood pressure due to ganglionic
blockage and histamine release.
CNS: No action
Other effect: Bronchoconstriction
6. Pharmacokinetics:
Poorly absorbed from GI tract so given by IV
Doesnot cross blood brain barrier and placental
membrane.
Metabolized in liver and kidney.
Onset of action = 3-5 minutes
Termination = 20-45 minutes
7. Side effect:
• Fall in blood pressure
• Regurgitation of food from stomach.
• Bronchospasm ( due to histamine release).
• Paralysis of intercostal muscle and
diaphragm
Antidote:
• Anticholinesterase agents (Neostigmine)
• Antimuscarinic drugs
8. Contraindications:
• Severe hepatic and renal diseases
• Asthmatic and patient with allergies
• Myasthenia gravis patients
Clinical use:
• Surgical exposure and minimize tissue trauma
• Intratracheal intubation
• Use to reduce the severity of muscle spasm in
severe tetanus
• To facilitate orthopaedic manipulations and
fracture reduction
9. Dose:
• Dog and Cat = 0.4 mg/kg b.wt., slow IV
• Cow and lamb = 0.6 mg/kg b.wt, slow IV
• Pig = 0.3 mg/kg b.wt, slow IV
• Horse = 0.22-0.25 mg/kg b.wt, slow IV
• Goat = 0.3 mg/kg b.wt, slow IV
• Sheep = 0.4 mg/kg b.wt, slow IV
Note: The above dose recommendations are maximal and
may elicit respiratory arrest.
10. ii. Pancuronium
Pharmacological effect:
• Muscle relaxant
• Do not release histamine or cause ganglionic
blockage
Pharmacokinetics:
• Inactive orally, must be administered parenterally
• Onset of action: 2-4 minutes
• Duration of action: 30-40 minutes
• 10 to 30 % hepatic metabolism, 40% unchanged
in urine and partially as metabolites
11. Side effect:
• Slight elevation in cardiac rate and blood
pressure
• Salivation
• Muscle weakness
• Respiratory depression
Antidote: Anticholinesterase agents
Contraindications: Similar to Tubocurarine
12. Clinical use:
• Muscle relaxation during surgical procedure
• Mechanical ventilation
• Endotracheal intubation
• In some countries, it is used as euthanasia in animal and
execution in human
Dose:
• Dogs and cats: 0.04 – 0.1 mg/kg, slow IV
• Pigs: 0.1 mg/kg, slow IV (initial dose), followed by increments of 0.02
mg/kg.
• Sheep and goats : 0.025 mg/kg, slow IV (initial dose), followed by
increments of 0.005 mg/ kg
• Cattle: 0.04 mg/kg, slow IV (initial dose), followed by increment of 0.008
mg/kg
• Horses: 0.06 mg/kg, slow IV (initial dose), followed by increment of 0.01
mg/kg
13. iii. Doxacurium
• It has potency approximately twice that of
pancuronium.
• No Cardiovascular effect
• Eliminated by kidney and contraindicated in
patient with renal diseases
• Used during surgery, mechanical ventilation and
tracheal intubation
Dose:
• Dog and cat: 0.008 mg/ kg, slow IV
14. b. Intermediate acting drugs (duration 30-60 minutes)
Atracurium
• Similar to above but medium acting
• It possess unique property that it undergoes spontaneous non-
enzymatic breakdown at 370C and PH 7.4 due to temperature and PH
dependent process called Hoffmann elimination
• Can be administered to animals with hepatic and renal failure
• It should be stored at 40 C
Dose:
Dog/ Cat: 0.2 mg/kg b.wt (initial dose), slow IV and increment of 0.15
mg/kg
Sheep: 0.5 mg/kg b.wt (initial dose), slow IV and increment of 0.2
mg/kg
Horse: 0.15 mg/kg b.wt (initial dose), slow IV and increment of 0.06
mg/kg
15. c. Short acting drugs (duration 10-30 minutes)
Mivacurium
• Facilitate endotracheal intubation, mechanical
ventilation and skeletal muscles relaxation of
short duration during surgery
• Hydrolysed by plasma cholinesterase
Dose:
• Dogs and cats: 0.03 mg/kg (initial dose), slow
IV, increment of 0.01 mg/kg
16. B. Depolarizing NMBs
• They have two quaternary Nitrogen atoms
• Produce neuromuscular blockage by
persistent depolarization of the end plates at
neuromuscular junctions
Mechanism of action:
It occurs in two phases:
a) Phase I ( depolarising phase)
b) Phase II (desensitizing phase)
17. Depolarizing agent + Nm nicotinic receptor
Conformational changes in receptor
Open Na+ channel
Cause depolarization
Long time presence of drug at receptor
Receptor desensitization
No action of drugs or ACh
Sodium Channel closed
Repolarisation
Muscle relaxation
18. i. Suxamethonium/ Succinyl choline
Pharmacological effect:
• Skeletal muscle: At first muscle contraction
and then relaxation
• CVS: Bradycardia followed by Tachycardia
• Eye: Contraction of extra occular muscles and
transient dilation of choroidal blood vessels
• Other effect: Weak histamine release in
action, Hyperkalaemia
19. Pharmacokinetics
• Rapid onset of action after IV, 30 seconds.
• Metabolised by plasma and tissue
pseudocholinesterase enzyme not by AChE
• About 10 % of suxamethonium is excreted
unchanged in urine
• Cattle are more susceptible than horses
20. Side effect:
• Painful muscle contraction
• Bradycardia
• Excessive salivation
• Hyperkalaemia
• Increased occular pressure
Contraindications:
• Patient with liver disease, Chronic anaemia, glaucoma,
increased CPK value
• Patient having traumatic wounds or burns
• Quinidine, digitalis or organophosphate agent therapy
Clinical use:
• Surgical purpose
• Endotracheal intubation
21. Dose:
• Dog: 0.3 mg/kg , slow IV
• Cat: 1.5 mg/kg, slow IV
• Pig: 2 mg/kg, slow IV
• Cattle and sheep: 0.02 mg/kg, slow IV
• Horses: 0.1 mg/kg, slow IV
• Primates: 1 mg/kg, slow IV
ii. Decamethonium
• Similar to suxamethonium but used only for
research purpose.
22. 2. Direct acting
i. Dantrolene:
• Different from NMBs as it has no action on
nerve conduction or neuromuscular
transmission.
Mechanism of action:
Interferes with the release of Ca++ from
sarcoplasmic reticulum
23. Dantrolene + Ryanodine receptor
Block the receptor
Inhibit the release of calcium
Block excitation contraction coupling in
skeletal muscles cell
Leading to muscle relaxation
Mechanism of action of Dantrolene
24. Pharmacological effect:
• Skeletal muscle relaxation
• No action on respiratory and CVS
Pharmacokinetics:
• Slowly and incompletely absorbed after oral
adminstration (5 hours in human and 1.5 hours in
horse)
• Cross blood brain barrier and produce some sedation.
• Metabolised in liver and excreted in urine
• Half life: Human = 8 hours, Horse = 2 hours
25. Side effect:
• M/s weakness, drowsiness, dizziness, vertigo,
nausea, vomiting, constipation, increased
urinary frequency and hypotension
• Hepatotoxicity
Antidote: Supportive and Symptomatic therapy
Contraindications: Pre-existing liver, cardiac and
pulmonary diseases
26. Clinical uses:
• Treatment of malignant hyperthermia
• Treatment of functional urethral obstruction
• Treatment of equine post anasthetic myositic and equine
exertional rhabdomyolysis.
• Treatment of bites form black widow spiders
• Treatment of porcine stress syndrome
Dose:
Dogs: 1.5 mg/kg , PO, 3 times daily
Cats: 0.5-2 mg/kg, PO, 2 times daily
ii. Quinine
• Antimalarial drug
• Increases refractory period however seldom used as muscle
relaxant
27. II. Centrally acting drugs/ Spasmolytic
Reduce skeletal muscles tone by selective action in the
cerebrospinal axis without altering consciousness
i. Diazepam:
Mechanism of action:
It promotes the binding of GABA to GABAA –
receptors and results in hyperpolarisation of neuron
by opening chlorine channel.
Clinical use:
• Control of seizures skeletal muscle spasm and
spasticity
28. Dose:
• Cattle: 0.5 – 1 mg/kg b.wt, IM/ IV
• Horse: 20 – 50 mg (total), IV
• Dog: 1- 4 mg/kg b.wt, IV
• Sheep: 0.55 – 1.1 mg/kg b.wt, IM
• Pig: 0.5-1.5 mg/kg b.wt, IM/IV
29. ii. Baclofen
Mechanism of action:
Selective agonist on GABAB receptors. Open K+ channel
and block Na+ and Ca++ channel from opening which
finally results in hyperpolarisation.
Side effect:
• Drowsiness, weakness and atoxia
• Vomiting, slow breathing, seizures
• Unusual pupil size and coma
Clinical use:
• Treatment of spasm, pain and stiffness. Also used to
treat hiccups.
