Pharmacology of the Neuromuscular Junction

Question 1

What are the main steps at which drugs can influence synapse?

Answer 1

1. uptake of precursor
2. synthesis of transmitter, which normally occurs locally in nerve terminals itself
3. packaging of transmitter into vesicles (applicable mainly to adrenergic neurones where drugs may inhibit uptake into vesicles or release stored transmitter from vesicles)
4. release by exocytosis
5. combination of transmitter with receptors (competitive block)
6. 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

7. enzymatic destruction of transmitter

Question 2

what type of receptors are the ACh receptors at ganglia?

Answer 2

nicotinic - however they both function quite separately

Question 3

what is a ganglionic stimulant?

Answer 3

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

Question 4

what are the main acute effects of absorbing nicotine?

Answer 4

1. CNS stimulant effect
2. 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

Question 5

what is a ganglion blocking drug?

Answer 5

hexamethonium

Question 6

how does hexamethonium work?

Answer 6

it affects sympathetic and parasympathetic ganglia indiscriminately.
generally stated to act by competition but may also block channels rather than receptors

Question 7

what is the action of ganglion blocking drugs?

Answer 7

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

Question 8

what effects does ganglion block from drugs like hexamethonium have?

Answer 8

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.

Question 9

what was hexamethonium originally introduced for?

Answer 9

originally introduced to treat hypertension

Question 10

what is hemicholinium and how does it act?

Answer 10

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

Question 11

what is botulinum toxin and how does it work?

Answer 11

NMJ blocking drug

Protein produced by anaerobic bacillus (clostridium botulinum), - food poisoning

BLOCKS RELEASE OF ACH FROM NERVE TERMINALS

Question 12

What is streptomycin and how does it work?

Answer 12

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

Question 13

how do clinically useful NMJ drugs work?

Answer 13

1. Competition with ACh for receptor sites (step 5)

2. Depolarisation of endplate region of muscle fibre, causing membrane to become inexcitable (6b)

Question 14

in which setting are NMJ blocking drugs used?

Answer 14

these drugs are used in general anaesthesia to cause muscle relaxation, and hence reduce the amount of general anaesthetic required

Question 15

what is tubocurarine and how does it work?

Answer 15

tubocurarine - NMJ blocking agent

COMPETITIVE BLOCKING AGENT

Question 16

what is pancuronium and how does it work?

Answer 16

NMJ blocking agent

COMPETITIVE BLOCKING AGENT

Question 17

what is gallamine and how does it work?

Answer 17

NMJ blocking agent

COMPETITIVE BLOCKING AGENT

Question 18

What is suxamethonium?

Answer 18

NMJ blocking agent

DEPOLARISING BLOCK AGENT - causes sustained activation of ACh receptors

Question 19

what are the features of competitive block?

Answer 19

1. causes relaxation without preliminary excitation of muscle
2. relaxant effect anatagonised by anticholinesterases
3. tetanic response (sustained contraction) of muscles poorly sustained
4. myasthenia gravis patients (autoimmune loss of ACh receptors) are normally sensitive

Question 20

what are the features of depolarising block?

Answer 20

1. initial fasciculation (ie twitching) as endplate depolarisation causes excitation of muscle fibres- could cause postoperative muscle pain
2. block not relieved by anticholinesterases
3. myasthenia gravis patients are insensitive to blocking action
4. action at endplate causes release of K causing hyperkalaemia.

Question 21

what are the features of suxamethonium?

Answer 21

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

Question 22

what are the two forms of cholinesterases found?

Answer 22

1. acetylcholinesterase - membrane bound- specific
2. 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

Question 23

what is endrophonium?

Answer 23

short acting anticholinesterase

Question 24

what is neostigmine?

Answer 24

medium/ long acting reversible anticholinesterase

Question 25

what is eserine?

Answer 25

medium/ long acting reversible anticholinesterase

Question 26

what is dyflos?

Answer 26

long acting irreversible anticholinesterase

Question 27

what is parathion?

Answer 27

long acting irreversible anticholinesterase

Question 28

what is pralidoxime?

Answer 28

cholinesterase reactivator