Drugs and ANS Flashcards
Where can we pharmacologically intervene to alter ANS activity?
At the points of chemical communication
Describe the successful ways in which we can target neurotransmission
We can design drugs that interfere with:
- Interaction with Presynaptic receptors
- Interaction with Post synaptic receptors
- Inactivation of transmitter
- Degradation of transmitter
- Reuptake of transmitter (neuronal)
Steps of neurotransmission
What is Acetylcholine synthesised from?
Acetyl Co A + Choline = acetylcholine (+co enzyme A)
Enzyme used to synthesise Ach
Choline acetyltransferase (CAT)
Acetylcholine degradation
acetylcholine –> acetate + choline
Enzyme used for acetylcholine degradation
(acetyl)cholinesterase (AchE)
How are drugs targeted to cholinergic sites? (3)
- nAchR at autonomic ganglia is different to nAchR at somatic neuromuscular junction (they differ in structure)
- Thus, some drugs have actions selective to autonomic ganglia
- You can get ganglion-blocking drugs
Name a ganglion blocking drug and state its use
Trimethaphan
- Used in hypertensive emergencies
- Used to produce controlled hypotension in surgery
How can endogenoulsly released Ach action be enhanced?
Using AchE inhibitors - acetylcholinesterase inhibitors
Give 2 examples of acetylcholinesterase inhibitors and describe their uses
Pyridostigmine for Myasthenia Gravis
Donepezil for Alzheimers
Problem with mAchR agonists/antagonists (4)
- There are 5 muscarinic acetylcholine receptor subtypes M1-M5
- At present, there are few subtype selective mAChR agonists or antagonists that are clinically available
- Not many selective ones
- Most effect all subtypes (M1-M5) so side effects limit use
What are the dangers of a non-selective, muscarinic ACH receptor agonists? (3)
Autonomic side effects:
Heart - Increase in Heart rate and cardiac output (ie could be an issue for an elderly patient in an early stage of heart failure)
Smooth muscle - Increase in bronchoconstriction and GI tract peristalsis
Endocrine gland - Increase in sweating and salivation
What is SLUDGE?
- A mneumonic for the pathological effects indicative of a massive discharge of the PNS
What is SLUDGE syndrome?
Parasympathetic mAchR system overly stimulated Salivation Lacrimation Urination Defectation GI upset (ie diarrhoea) Emesis (vomitting)
Causes of SLUDGE (4)
- Drug overdose - Ingestion of Magic mushrooms - Exposure to Organophosphorous insecticides (parathion) - Exposure to Nerve agents (e.g. sarin, VX,novichok)
What do organophosphate poisoning and nerve agents do? (3)
- Covalently modify acetylcholinesterase
- To irreversibly deactivate the enzyme
- Ach levels rise = continued stimulation of mAchR
Sludge treatment
Atropine
Pralidoxime
Or other anti-cholinergic agents
Name 2 mAchR agonists and state their uses
Pilocarpine (treat glaucome)
Bethanechol (stimulate bladder emptying)
Name 2 mAchR antagonists and state their uses
- Ipratropium
- Tiotropium
Used to treat some forms of asthma and COPD
mAchR antagonists for overactive bladder
Tolterodine
Darifenacin
Oxybutynin
mAchR antagonists for IBS/post op nausea
Hyoscine (aka Scopolamine)
Sympathetic neuroeffector junction
postganglionic neurones = branches axonal network with bulges (VARICOSITIES)
These are specialised site for Ca2+ dependent release of noradrenaline from vesicles
Noradrenaline synthesis
Tyrosine –> DOPA –> dopamine –> Noradrenaline
What happens in adrenal medulla to noradrenaline?
Converted to adrenaline via phenylethanolamine N-methyltransferase)
How is noradrenaline released?
Ca2+ dependent exocytosis
What does noradrenaline do once released?
interacts with post-synaptic adrenoreceptors to signal effector tissue
Interacts with pre-synaptic adrenoreceptors to provide negative feedback to stop release
How is NA removed from cleft?
By high affinity Na+ dependent transporter (NET aka Uptake 1) back to presynaptic terminal
If not recaptured by Uptake 1:
Uptake 2 = low affinity, non neuronal mechanism
What happens to NA once back in presynaptic terminal?
Packaged back into vesicles
Any not packaged metabolised by:
- monoamine oxidase (MAO)
- catechol-O-methyltransferase (COMT)
B2 receptor agonists
Salbutamol treat asthma (reverse bronchoconstriction)
Why is B2 selectivity important?
if just broad beta receptor agonist there are possible cardiovascular side effects (+ve inotropic and chronotropic)
Drugs for hypertension
a1 adrenoreceptor antagonist (Doxazosin)
B1 adrenoreceptor antagonist (atenolol)
