Pharmacology of the Neuromuscular Junction Flashcards
What are the main steps at which drugs can influence synapse?
- uptake of precursor
- synthesis of transmitter, which normally occurs locally in nerve terminals itself
- packaging of transmitter into vesicles (applicable mainly to adrenergic neurones where drugs may inhibit uptake into vesicles or release stored transmitter from vesicles)
- release by exocytosis
- combination of transmitter with receptors (competitive block)
- produciton of postsynaptic response (inhibition or enhancement)
at an excitatory synapse, such as the autonomic ganglion or the neuromuscular junction, step 6 consists of:
- increase in ionic conductance of the postsynaptic membrane
- depolarisation of postsynaptic cells
- initiation of action potential in postsynaptic cells
- enzymatic destruction of transmitter
what type of receptors are the ACh receptors at ganglia?
nicotinic - however they both function quite separately
what is a ganglionic stimulant?
nicotine - absorbed through mucous membranes (back of mouth and alveoli) - in small doses actions are central - larger doses stimulate ganglia and still larger doses block ganglia
what are the main acute effects of absorbing nicotine?
- CNS stimulant effect
- Increased parasympathetic and sympathetic activity, causing rise in blood pressure, tachycardia, inhibition of gastric motility and bronchial secretion.
the vasoconstrictor effect of nicotine, by reducing placental blood flow, may be responsible for the increased incidence of coronary attacks in smokers
what is a ganglion blocking drug?
hexamethonium
how does hexamethonium work?
it affects sympathetic and parasympathetic ganglia indiscriminately.
generally stated to act by competition but may also block channels rather than receptors
what is the action of ganglion blocking drugs?
these drugs are selective for autonomic ganglia and do not affect neuromusclar transmission
they do not distinguish between ganglia of sympathetic and parasympathetic systems, and consequently produce a large number of effects
what effects does ganglion block from drugs like hexamethonium have?
Cardiovascular: effects depend mainly on block of sympathetic system. dilatation of arterioles and veins causes a substantial fall in blood pressure and loss of cardiovascular reflexes (causing postural hypotension, exercise hypotension).
GI Tract: effects mainly due to block of parasympathetic system. inhibition of motility and secretion, leading to constipation
Genito-urinary: block of parasympathetic lead to impairment of micturition and erection. block of sympathetic leads to failure of ejaculation - impotence
Eye: accommodation is impaired, causing blurred vision. loss of pupillary reflex can cause photophobia.
what was hexamethonium originally introduced for?
originally introduced to treat hypertension
what is hemicholinium and how does it act?
Hemicholnium is a neuromuscular junction blocking drug
similar to choline, inhibits competitively the uptake of choline by cholinergic nerve terminals.
this is an active carrier mediated transport. inhibition causes the nerve terminal to run short of choline, so that ACh synthesis cannot keep up with release. highly active synapses preferentially affected. not much clinical use
what is botulinum toxin and how does it work?
NMJ blocking drug
Protein produced by anaerobic bacillus (clostridium botulinum), - food poisoning
BLOCKS RELEASE OF ACH FROM NERVE TERMINALS
What is streptomycin and how does it work?
streptomycin is an aminoglycoside antibiotic
this inhibits the release of ACh from nerve terminals - preferentially by blocking Ca entry
can cause weakness as a side effect and potentiates the action of NM blocking drugs in anaesthesia
how do clinically useful NMJ drugs work?
- Competition with ACh for receptor sites (step 5)
2. Depolarisation of endplate region of muscle fibre, causing membrane to become inexcitable (6b)
in which setting are NMJ blocking drugs used?
these drugs are used in general anaesthesia to cause muscle relaxation, and hence reduce the amount of general anaesthetic required
what is tubocurarine and how does it work?
tubocurarine - NMJ blocking agent
COMPETITIVE BLOCKING AGENT
what is pancuronium and how does it work?
NMJ blocking agent
COMPETITIVE BLOCKING AGENT
what is gallamine and how does it work?
NMJ blocking agent
COMPETITIVE BLOCKING AGENT
What is suxamethonium?
NMJ blocking agent
DEPOLARISING BLOCK AGENT - causes sustained activation of ACh receptors
what are the features of competitive block?
- causes relaxation without preliminary excitation of muscle
- relaxant effect anatagonised by anticholinesterases
- tetanic response (sustained contraction) of muscles poorly sustained
- myasthenia gravis patients (autoimmune loss of ACh receptors) are normally sensitive
what are the features of depolarising block?
- initial fasciculation (ie twitching) as endplate depolarisation causes excitation of muscle fibres- could cause postoperative muscle pain
- block not relieved by anticholinesterases
- myasthenia gravis patients are insensitive to blocking action
- action at endplate causes release of K causing hyperkalaemia.
what are the features of suxamethonium?
Suxamethonium is rapidly hydrolysed by plasma cholinesterase so only lasts about 5 minutes
if plasma cholinesterase level is low - action can be greatly prolonged - up to several hours.
- a genetic abnormality with low or absent ChE occurs in 1 in 3000 individuals.
other causes of low plasma ChE is liver disease and malnutrition or use of anticholinesterases
what are the two forms of cholinesterases found?
- acetylcholinesterase - membrane bound- specific
- butylcholinesterase - plasma, unspecific
genetic abnormality leading to loss of this means greatly reduced hydrolysis of sunxamthonium and reduced sensitivity of enzyme to inhibition by dibucaine
high dibucaine number means very sensitive to suxamethonium
what is endrophonium?
short acting anticholinesterase
what is neostigmine?
medium/ long acting reversible anticholinesterase
