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3. NMJ.docx

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Kristin Hillman

 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) Neuromuscular Junction:  Synapse between motor neuron and skeletal muscle Human Nervous System:  Anatomical divisions: o CNS o PNS  TODAY = We are in the motor (efferent) system and the somatic (voluntary) system  Psychoactive drugs = drugs that goes into the CNS – not what we are doing today… Why would you want to promote Muscle contraction?  Therapeutically?  Behaviorally?  Addiction?  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?  Therapeutically?  Behaviorally?  Addiction?  If you wanted to paralyse someone for some reason (drugging someone)  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 = Acetylcholine (ACh) Acetylcholine (ACh)  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   ACh System:  Synthesis:  Chlorine + acetyl CoA = ACh  Storage  Vesticular storage loaded into essicle by ACh transporter  Receptors:  Nicotinic: o Ionotropic o 3 subtypes  Muscarinic o Metabotropic o 5 subtpes… (Gq or Gi)  Clearance:  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:  Options:  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)  Physostigmine:  The first widely used agent for contraction extract of physostigma venenosum  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 bean?  Used in the court of law – idea was if guilty they would die, if innocent they would throw up.  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 sick (self-experimentation) 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, Alzheimer’s.  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 into system  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  Why? o Because they are easy to get, they can be easily covered up   MOA = AChE inhibition  How can some AChE inhibitors be therapeutic and others lethal?  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 these things.  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 military operations  Prophylactic (taken ahead of time) pyridostigmine  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 off  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:  Ther
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