Talks in St David Lecture Theatre:
Saturday 16 thMarch
- 10am Tinnitus: What’s the buzz
- 11.15am Caring for the caregiver in Alz D.
- 12pm Potential effects of brain stimulation for chronic pain
What are neuromuscular agents?
Drugs that target the neuromuscular junction, work to increase
(make you have more strength etc) or decrease (paralyse you,
make you fall over) muscular contraction.
Where are muscles located in the body?
3 types of muscles:
o Skeletal muscle (biceps etc.)
o Smooth muscle (line tubes of sorts, found all around
vessels, GI tract, glands)
o Cardiac muscle (heart – to contract/beat = have to
squeeze those muscles)
Functions of muscles?
2 main functions:
Movement (either of body – locomotion, or because of
smooth muscles, things within your body as well – e.g.
helping food move thorugh body etc.)
Posture (helps us stay upright)
Synapse between motor neuron and skeletal muscle
Human Nervous System:
TODAY = We are in the motor (efferent) system and the somatic
Psychoactive drugs = drugs that goes into the CNS – not what
we are doing today…
Why would you want to promote Muscle contraction?
To reduce secretion (e.g. sweat less, salivate less, cry less)
Blood pressure (smooth muscles line vessels, if promote
contraction you would make blood pressure higher)
Post-surgery – bladder and bowels (promote contraction to be
able to go to the toilet after surgery) Myaesthenia gravis (MG) – would want a drug that helps
contraction if you have an immune disease such as MG
Why would you want to promote Muscle relaxation?
If you wanted to paralyse someone for some reason (drugging
Surgical purposes – need muscle relaxed to do something in
surgery, can give muscle relaxer.
How would you do it?
Need to work with the neurotransmitter that’s at the junction =
The first neurotransmitter
Henry Dale and Otto Loewi (1920s)
o Altered muscle tonicity in isolated preps
Same neurotransmitter can cause different effects because there
are different subtypes of it…
ACh + cardiac muscle = slowed rate of contraction
ACh + skeletal muscle = promoted contraction
ACh + most smooth msucles = promoted contraction
Chlorine + acetyl CoA = ACh
Vesticular storage loaded into essicle by ACh transporter
o 3 subtypes
o 5 subtpes… (Gq or Gi)
To get it out of system, AChE
Today, talking about nicotinic receptors (i.e. ionotropic) because
that’s what on the skeletal muscles
How would you manipulate the cholinergic system?
You would want to promote synthesis
For clearance – you want to inhibit it Agents that Contract:
1. Promote synthesis
2. Force release of ACh from vesicles
3. Agonism of of nACh receptor
4. Prevent enzymatic breakdown of ACh.
Some predators and plants use these to target their enemies
(e.g. black widow)
The first widely used agent for contraction extract of
How was it discovered?
o Episodes in the story of physostigmine
o Exploration abroad – William Daniels expedition in
1845 to Africa – What was his account of the calabar
Used in the court of law – idea was if guilty
they would die, if innocent they would throw
1. Younger = more likely to survive
2. Psychology account = if guilty, they would
be hesitant to take it and it would eventually
kill them, if innocent, they would swallow it
fast and throw it up.
o Robert Christison
He ate it himself, he started to get immediately
o Thomas Fraser
Started to be used for medical purposes (first
use of it was for glaucoma)
What is its mechanism of action? – to inhibit
AChE (blocks enzyme)
How did Mary Walker use physostigmine? = to
help MG – made her muscles work much better
MG = loose control of muscle system
Mechanism of Action = inhibitor of AChE
Where it works = neuromuscular junctions in the PNS
It can cross the BBB and can go into the CNS…
Mode of action = muscular tonicity/spasticity
How would we classify it?
Therapeutically? – YES = for MG, glaucoma etc.
Behaviorally – YES = initially it was used maliciously
Addictively – NO
Physostigmine derivatives are in use today: Main uses = MG, glaucoma,
also gut motility, counteracting a neuromuscular block,
for AD, don’t want to have to inject everyday – patches have
been a good advancement
AChE – also have another use…POISON
Toxic AChE Inhibitors:
Main use = pesticide, insecticides, nerve gases
These drugs are extremely potent (only need small amount to be
effective) and they can be volatile (inhaled).
Can be taken orally, transdermally, inhalational
Transdermal = If touched, they can effect you – can go
Dangerous because these things can be absorbed
unknowingly (if working in the field where pesticide has
been used, could be touching infected areas)
These drugs are a common culprit in drug-related homicide,
suicide, and accidental death
o Because they are easy to get, they can be easily
MOA = AChE inhibition
How can some AChE inhibitors be therapeutic and others
When we talk about toxic AChE – they are permanent – they
bind to enzyme and they never let go – not a lot of drugs do
that…. The toxic versions of AChE irreversibly inhibit.
Therefore it is really important to prevent exposure to
How do you prevent exposure?
E.g. gas poisoning:
o Where a gas mask (inhalational)
o Don’t let it touch your skin (transderminally)
o Now = take a pill before you leave the base in
Prophylactic (taken ahead of time)
Is also a AChE inhibitor
Has a much shorted half life than nerve
gases (because they stay there forever)
This half-life allows it to stick then comes
If taken ahead of time, some of enzyme
is caught up with this drug, so toxic drug
will not bind to those enzymes. Pharmacological manipulation of muscle tone:
If we want to promote muscle contraction: