Pharmacology 10 - Neuromuscular Blocking Drugs Flashcards
Describe the innervation of skeletal muscle by the somatic nervous system
- Single axon
- Releases Acetylcholine
What type of receptors are at the neuromuscular junction?
- Muscarinic acetylcholine receptors (type 1 - ion channels)
- They are slightly different to the nicotinic acetylcholine receptors at the ganglia, so therefore can selectively be blocked by antagonists
List the main competitive (non-depolarising) neuromusclar drugs. What are these drugs?
- Tubocurarine
- Atracurium
Competitive antagonists
Give an example of a depolarising neuromuscular blocking drug. What are these drugs?
Suxamethonium
Agonists
What are the subunits of the nicotinic receptor?
- 2 alpha, where acetylcholine binds (2 molecules of acetylcholine needed)
- beta
- gamma
- delta
What is the result of opening of nicotinic receptor channel?
- Sodium influx
- Some potassium efflux
Where can different drugs act to block neuromuscular junctions?
- Central processes (generation of action potentials in the spinal cord)
- Conduction of nerve action potential in motor neurone
- ACh release
- Depolarisation of the motor end plate and action potential initiation
- Propagation of action potential along the muscle fibre and muscle contraction
Which drugs act on the central processes to relax smooth muscles?
- Spasmolytics
- Eg. Diazepam and Baclofen
Which drugs reduce conduction of the nerve action potential in the motor nerve to relax smooth muscle?
Local anaesthetics
Which drugs reduce acetylcholine release to relax smooth muscle?
- Hemicholinium
- Ca2+ entry blockers
- Neurotoxins (eg. butolium toxin)
Which drugs reduce depolarisation of the motor-end plate and initiation of an action potential to relax smooth muscle?
- Tubocurarine
- Suxamethonium
Which drugs reduce propagation of action potentials along muscle fibres and muscle contraction to relax smooth muscle?
- Spasmolytics
- Eg. dantrolene
What do neuromuscular blockers not affect?
- Consciousness
- Pain sensation
- When administered, respiration must be assisted until drug is inactive
Where do neuromuscular blocking drugs act?
- Postsynaptic action
Why can tubocurarine bind to the nicotinic receptors?
- As it has 2 quaternary amine groups
- Acetylcholine also has one of these groups
Why can suxamethonium bind to the receptor and activate it?
- Structure is more similar to acetylcholine
- Flexible and has rotation
Describe the mechanism of action of suxamethonium
- Nicotinic receptor agonist
- Produces an extended end plate depolarisation (also called a phase 1 depolarisation block). Therefore, the receptor is overstimulated and shuts down
- Fasciculations are seen as the drug is administered and muscle is stimulated, followed by flaccid paralysis (muscles relax)
Describe the pharmacokinetics of suxamethonium
- IV administration
- Paralysis lasts around 5 minutes (short acting)
- Metabolised by pseudocholinesterase (butyrylcholinesterase) in the liver and plasma
List the uses of suxamethonium
- Endotracheal intubation (used in bronchoscopy and administer anaesthesia)
- Muscle relaxant for ECT (electroconvulsive therapy - used to treat severe clinical depression)
List the unwanted effects of suxamethonium
- Post-oerative muscle pains (due to fasciculations)
- Bradycardia (due to direct muscarinic action on the heart - solved by atropine administration premed)
- Hyperkalaemia
- Increased intraocular pressure (not used in eye injurys or glaucoma)
Why can suxamethonium not be administered to patients with soft tissue injury or burns?
- Soft tissue injury or burns decreases sensitivity to acetylcholine
- End plate responds by increasing nicotinic receptors, attempting to amplify reduced input
- This is denervation supersensitivity, leads to increased potassium efflux and sodium influx
- Hyperkalaemia can lead to ventricular arrhythmias or cardiac arrest
What is tubocurarine?
- Naturally occurring tertiary ammonium compound found in plants
Describe the mechanism of action of tubocurarine
- Competitive nicotinic acetylcholine receptor antagonist
- 70-80% block necessary
List the effects of tubocurarine
- Causes flaccis paralysis
- Double vision when the patient is conscious, small muscles of face limbs and pharynx relax, then respiratory muscles relax
- Recovery occurs in the reverse of the order off occurrence of those effects
Describe the effect of tubocurarine on neuromusclar transmission
- ACh released at end plate, but tubocurarine is blocking the nicotinic receptors
- Therefore, the end plate potential generated is not sufficient to stimulate muscle contraction
- No propagation from the end plate
List the uses of tubocurarine
- Relaxation of skeletal muscles during surgical operations (therefore, less anaesthetic is needed)
- Permit artificial ventilation, as the respiratory muscles are relaxed
How can actions of non-depolarising blockers be reversed?
- By acetylcholinesterases
- Eg. neostigmine (+atropine to prevent overstimulation of muscarinic receptors)
Describe the pharmacokinetics of tubocurarine
- IV administration
- Does not cross the blood brain barrier/placenta
- Duration of paralysis is 1-2 hours (long)
- Not metabolised, excreted 70% in urine and 30% bile (therefore, be careful if there is impairment of renal/hepatic function - use atracurium instead)
What is atracurium?
- Chemically unstable non-depolarising blocker
- Breaks down spontaneously after 15 minutes to two inactive fragments
- Therefore, it can be used in patients with impairment of renal/hepatic function
- Same mechanism of action as tubocurarine
List the side effects of tubocurarine
- Hypotension (due to ganglion blockade decreasing TPR and histamine release - histamine is a vasodilator)
- Tachycardia (potentially can give rise to arrhythmias, a reflex to tachycardia, or blockade of vagal ganglia)
- Bronchospasm and excessive secretions (histamine bronchoconstrictor)
- Apnoea (always assist respiration)
What causes side effects of tubocurarine?
- Ganglion blockade
- Histamine release from mast cells, as tubocurarine is so basic
How does tubocurarine affect the log dose-response curve showing response of skeletal muscle to increasing concentration of ACh?
- The curve will shift right
- Max will be reached as tubocurarine is surmountable
- Competitive antagonist
