Lecture 9.1: Pharmacology of the Autonomic Nervous System Flashcards
Basics Steps in Neurotransmission (10)
1) Uptake of precursors
2) Synthesis of transmitter
3) Vesicular storage of transmitter
4) Degradation of transmitter
5) Depolarisation by propagated action potential
6) Depolarisation-dependent influx of Ca2+
7) Exocytotic release of transmitter
8) Diffusion to post-synaptic membrane
9) Interaction with post-synaptic receptors
10) Inactivation of transmitter
Acetylcholine Synthesis
- Acetyl CoA + choline —> acetylcholine + coenzyme A
- Facilitated by choline acetyltransferase (CAT)
Acetylcholine Degradation
- Acetylcholine —> acetate + choline
- Facilitated by (acetyl) cholinesterase (AChE)
Nicotinic acetylcholine receptors(nAChRs) at autonomic ganglia and the neuromuscular junction differ in structure, how is this clinically relevant?
Therefore, some drugs have actions selectively at autonomic ganglia (e.g. the ganglion-blocking drug
trimetaphan)
What drugs can enhance the actions of endogenously released ACh?
- AChE inhibitor
- Pyridostigmine (used to treat myasthenia gravis)
- Neostigmine (to reverse muscle relaxation)
- Donepezil
How many muscarinic acetylcholine receptor (mAChR)
subtypes are there?
- 5
- M1-M5
A relative lack of selectivity of cholinergic drugs means that unwanted ‘side-effects’ often limit their usage, what side effects is a non-selective, muscarinic ACh receptor agonist is likely to cause?
- HEART: bradycardia, reduced cardiac output
- SMOOTH MUSCLE: bronchoconstriction, increased GI
tract peristalsis - EXOCRINE GLANDS: increased sweating & salivation
mACh receptor agonists and antagonists have some
clinical uses, especially when they can be administered….?
locally rather than systemically
What muscarinic ACh receptor agonist is used to treat glaucoma?
Pilocarpine
What muscarinic ACh receptor agonist is used acutely to stimulate bladder emptying?
Bethanechol
What muscarinic ACh receptor antagonists are used to treat some forms of asthma and COPD? (2)
- Ipratropium
- Tiotropium
What muscarinic ACh receptor antagonists are used to treat an overactive bladder? (3)
- Tolterodine
- Darifenacin
- Oxybutynin
What is an orthosteric binding site?
Active site
What is an allosteric binding site?
Site elsewhere to active site
How do benzodiazepines increase GABA(A) receptor/ion channel activity?
By acting as positive allosteric modulators(PAMs)
The vast majority of post- ganglionic sympathetic neurons are ….?
Noradrenergic
What are the Steps of Noradrenergic Transmission following Ca2+-dependent exocytotic release of NA?
1) NA diffuses across the synaptic cleft and interacts
with adrenoceptors in the post-synaptic membrane to
initiate signalling in the effector tissue
2) NA interacts with pre-synaptic adrenoceptors to
regulate processes within the nerve terminal e.g. NA
release
3) NA has only a very limited time in which to influence
pre- and post-synaptic adrenoceptors as it rapidly
removed from the synaptic cleft by noradrenaline
transporter proteins
Noradrenergic Termination: Termination
- NA actions are terminated by re-uptake into the pre-
synaptic terminal by a Na+- dependent, high affinity
transporter - NA not re-captured by Uptake 1 is taken up by a lower
affinity, non-neuronal mechanism
Noradrenergic Termination: Metabolism
- Within the pre-synaptic terminal NA not taken up into
vesicles is susceptible to metabolism by two enzymes - Monoamine oxidase (MAO)
- Catechol-O-methyltransferase (COMT)
Presynaptic G protein-coupled receptors (e.g. the α2- adrenoceptor) can regulate neurotransmitter release by…?
inhibiting Ca2+-dependent exocytosis
How do GPCRs inhibit Ca2+-dependent exocytosis?
G protein βγ subunits inhibit specific types of voltage- operated Ca2+ channels (VOCCs) reducing Ca2+-influx and neurotransmitter release
Side Effects of Anticholinergic Drugs? (8)
- Dry Mouth
- Constipation
- Urinary Retention
- Bowel Obstruction
- Dilated Pupils
- Blurred Vision
- Tachycardia
- Decreased Sweating
What type of drug is Atropine?
Anticholinergic, competitive antagonist
What is Atropine used for?
Emergency bradycardia, it increases heart rate by blocking the inhibitory effects of the parasympathetic neurotransmitter acetylcholine on heart rate
What is excess bronchoconstriction caused by?
- Increase parasympathetic tone (mAch receptors)
- Decreased sympathetic stimulation (β-adrenoceptors)