Lec 6- ANS 3 Flashcards
Drugs affecting cholinergic transmission
- Inhibitors of ACh synthesis or release
- Muscarinic agonist/antagonist
- Ganglion stimulating or blocking drugs
- Depolarising or non-depolarising neuromuscular blocking agents
- Cholinesterase inhibitors or stimulants of ACh
Neuromuscular blocking drugs
- Used as an adjunct to anaesthesia- Artificial ventilation required
- Non-depolarising agents- Competitive antagonist at nicotinic ACh receptors
- Depolarising agents- agonists at nicotinic ACh receptors
Non-depolarising agents
- Curare identified in 1856: Most active component is tubocurarine; Arrow poison used by South American Indians
- Synthetic derivatives include: pancuronium; vecuronium and atracurium
- Necessary to block 70-80% of receptors sites before transmission fails
- Case motor paralysis: starting with eye muscles, ending with respiratory muscles; N.B consciousness and perception of pain not affected
Non-depolarising agents 2
- Block reversed by anticholinesterase
- Increased ACh overcomes competitive inhibition
Non-depolarising agents 3
- Side effects of tubocurarine:
- Fall in arterial pressure due to ganglion block
- Release of histamine from mast cells can cause bronchospasm
- Other agents don’t have these side effects
Non-depolarising agents 4
Main differences between drugs are onset and duration of action
- Duration of action of some compounds can be prolonged in hepatic or renal impairment
- Atracurium spontaneously hydrolysed at plasma pH –> short-acting
Depolarising agents
Suxamethonium is only depolarising agent in use; very rapid onset (endotracheal intubation)
-Agonist at nicotinic ACh receptors at NMJ
-Hydrolysed slowly by AChE –> prolonged depolarization in phase 1 block –> loss of electrical excitability
-Causes transient twitching of skeletal muscle (fasciculations) and post-op muscle pain
-Phase 2 block; the receptor is desensitised
-Cannot be reversed by anti-cholinesterase
-Action potential occurs due to suxamethonium binding, thus causing other V.gated ion channels to open and can’t be removed
NB when Na channels are opened via voltage they become inactivated this is reversed when the membrane is repolarised
-This means that the Na channels can’t become reactivated therefore muscle cannot be electrically excited
Depolarising agents
Side effects of suxamethonium
-Bradycardia (muscarinic actions)
-K+ release from muscle
-Increase intraocular pressure (muscle contraction)
-Prolonged paralysis if plasma cholinesterase activity is reduced (genetic deficiency; anticholinesterases)
-Malignant hyperthermia (due to abnormal calcium release in muscles in a subset of patient)
NB Worse treatment for this is to add a anti-cholinesterase which will further desensitise the nicotinic receptors
Cholinesterases
- Two types of cholinesterase exist: AChE; Butyrylcholinesterase (BChE) also known as pseudoACh: Differ in their substrates specificities
- Enzymes are serine proteases: soluble and membrane-bound forms
- Rapid hydrolysis of ACh in plasma
- Acetylcholinesterase enhance cholinergic transmission
Anticholinesterases: effects NB think of rest and digest
- Mainly due to enhanced ACh activity at parasympathetic post-ganglionic synapses: bradycardia, bronchoconstriction, increase secretions; increased peristalsis
- Increased skeletal muscle contraction (can progress to depolarising block)- therefore can be used in myasthenia gravis
- CNS effects used in treatment of dementia
Anticholinesterases (durations)
- SHORT ACTING: e.g.endrophonium used in diagnosis of myasthenia gravis (autoimmune disease –> dec nicotinic receptors at NMJ –> muscle weakness)
- MEDIUM DURATION: e.g. Physostigmine, neostigmine, pyridostigmine; USES-myasthenia gravis; reverse non-depolarising block; atropine poisoning
- IRREVERSIBLE: attach covalently; organophosphates (nerve gases and pesticides- sarin, parathion); Recovery requires synthesis of new enzymes
Acetylcholinesterase: structure
2 Main site
- Anionic site (-ve charge) and Esteratic site (Enzymes)
- ACh is positively charged and so is attracted to -ve charge glutamic acid
- N group on Histidine makes -OH on serine more negative meaning that the acetyl group on ACh will undergo a SN2 reaction and attach onto the serine
- The reaction the reverse caused by a hydrogen then returning back onto O- of serine
Neostigmine
- Anticholineesterase
- This forms a stable intermediate with serine group therefore blocking ACh entering the enzyme
