Pharmacology of the neuromuscluar junction Flashcards
How can neuromuscluar transmission be blocked?
a
* Ways to block neuromuscular transmission:
1) Presynaptically, by inhibiting Ach Synthesis (rate-limiting step is choline uptake)
2) Presynaptically by inhibiting Ach release
3) Postsynaptically by interfering with the actions of Ach on the receptor
What are the methods of presynaptic blockade?
- Local anaesthetics
- General inhalation anaesthetics
- Inhibitors of calcium
- Magnesium ions
- Some antibiotics
- AMinoglycosides
- Neuro toxins
- β-Bungarotoxin (Taiwanese banded krait)
- Botulinum toxin (clostridium botulinum):
- Musclespasticityu
- Cosmetic
- Hyperhydrosis - inhibits ACh in nautonomic nervous system
What are the clinical uses of neuromuscular blocking drugs
- Endotracheal intubation
- During surgical procedures:
- To allow surgical access to abdominal cavity
- To ensure immobility
- Allow relaxation to reduce displaced fracture or dislocation]Decrease of concentration of general anaesthetic needed
- Infrequently in intensive care
- Mechanical ventilation at extremes of hypoxia
- During electroconvulsive therapy
What is the structure of an Nicotinic ACh Receptor
The nicotinic Ach receptor consists of 5 subunits and 2 ACh binding sites
What is the Nicotinic ACh receptor?
- It is a pore that allows the movement of sodium and potassium ions across the membrane of a cell when ACh binds to both binding sites and causes a conformation shape change
- This allows sodium to come into the cell and potassium to move out of the cell
- When there is a sufficient influx of sodium, it will result in depolarisation of the target muscle cell, allowing an action potential to be generate din the NMJ of the target muscle cell
- This can then spread across the muscle fibre and induce contraction
What do competitive antagonists do?
bind to receptors without activating them and compete with the natural ligand (e.g., acetylcholine) for receptor sites.
How do Competitive antagonists of Nicotinic ACH receptors at the NMJ work?
- Prevents ACh binging to receptor by occupying site
- Decreases the motor end plate potential
- Decreases depolarisation of the motor end plate region
- No activation of the muscle action potential
How do agonists of Nicotinic ACh receptors work?
- Persistent depolarisation of the motor end plate
- Prolonged End Plate potential
- Prolonged depolarisation of the muscle membrane
- Membrane potential above the threshold for the resetting of the voltage- gated sodium channels
- Sodium channels remain refractory
- No more muscle action potentials generated
What are the phases in which depolarising blockade works?
Phase 1
- Muscle fasciculations observed then blocked
- Repolariosation inhibited
- Voltage gated Na+ channels kept inactivated
Phase 2
- Prolonged/ Increased exposure to drug
- Desensitization blovkade
- Depolarisation cannot occur even in absence of drug
How is Atracurium metabolised?
Hofmann elimination and ester hydrolysis
What drugs are metabolised by plasma cholinesterases?
Mivacurium
Suxamethonium
What is the clinical concern behind plasma cholinesterases?
Some patients (due to genetic variations) may have deficient or atypical cholinesterase activity, leading to prolonged paralysis (apnea).
4% of the population: Paralysis lasts about 10 minutes.
0.04% of the population: Paralysis may last hours.
What drugs are metabolised by Hepatic Metabolism (liver breakdown)
- Pancuronium
Vecuronium - Metabolised in the liver
What drug is not heavily metabolised?
- Rocuronium
- Unchanged in bile and urine
List the non-depolarising blockers of the NACh receptors
- Pancuronium
- Vecuronium
- Rocuronium
- Atracurium
- Mivacurium
What is the depolarising blocker of the NACh receptor?
Suxamethonium
For PANCURONIUM state:
- Onset
- Duration
- Main side effects
- Medium
- Long
- Tachycardia
For VECURONIUM state:
- Onset
- Duration
- Main side effects
- Medium
- Medium
- Few side effects
For ROCURONIUM state:
- Onset
- Duration
- Main side effects
- Fast
- Medium
- Tachycardia
For ATRACURIUM state:
- Onset
- Duration
- Main side effects
- Medium
- Medium
- Hypotension
- Bronchospasm
For MIVACURIUM state:
- Onset
- Duration
- Main side effects
- Fast
- Short
- Hypotension
- Bronchospasm
For SUXAMETHONIUM state:
- Onset
- Duration
- Main side effects
- fast
- Short
- Bradycardia
- Cardiac dysrhythmias
- Raised intraocular pressure
- Postoperative myalgia
- Malignant hyperthermia
Describe Acetylcholinesterase
- True cholinesterase, specific for hydrolysis of Ach
- Present in conducting tissue and RBCs
- Bound to basement membrane in the synaptic cleft
Describe Plasma cholinesterase
- Pseudocholinesterase, broad spectrum of substrates
- Widespread distribution
- Soluble in plasma
What are the benefits of Anticholinesterase drugs?
Are all inhibitors of cholinesterase enzymes
- Therefore increased availability of ACh at NMJ by decreased degradation
- Increases duration of activity of ACh at NMJ
- More ACh to compete with non-depolarising blockers
What is the duration of action of neostigmine
Medium
What is the mechanism of action for Neostigmine?
- Formation of carbamylated enzyme complex
What is the duration of action of Pyyridostigimine
- Medium
What is the mechanism of action of Pyridostigmine?
Formation of carbamylated enzyme complex
List anticholinesterase drugs
- Neostigmine
- Pyridostigmine
- Dyflos
- Parathion
What does carbamylation do?
Carbamylation slows the rate of hydrolysis
What is the duration of action of Dyflos?
Long
What is the duration of action of parathion?
Long
What is the mechanism of action of dyflos?
Irreversible inhibition
What is the mechanism of action of parathion?
Irreversible inhibition
Describe phosphorylation by dyflos/parathion
-highly stable
- recovery depends on synthesis of new enzyme
- Can be coaxed off by pralidoxime
What are the effects of anticholinesterases in the CNS?
- Initial excitation with convulsions
- Unconsciousness and respiratory failure
What are the effects of anticholinesterases in the ANS?
- Salivation
- Lacrimation - secretion of tears
- Urination
- Defecation - movement of feces
- Gastrointestinal upset
- Emesis - Vomiting
- Bradycardia
- Hypotension - Low BP
- Bronchoconstriction
- Pupillary constriction
How are anticholinesterases used in anaesthesia?
- Reverse non-depolarising muscle blockade
- Given with atropine or glycopyrrolate to counteract parasympathetic effects
How are anticholinesterases used in Myasthenia Gravis?
- Increase neuromuscular transmission
- Autoantibodies may be produced against the ACh receptor blocking the interaction of the ACh receptor with its ligand (ACh) and leading to increased muscle weakness and death
How are anticholinesterases used in glaucoma
Decrease intraocular pressure
How are anticholinesterases used in alzheimer’s disease?
Enhance the choligernic transmission in the CNS
What does sugammadex do?
Selective binding agent(SRBA); Reverses effects of rocuronium and vecuronium
