lecture 18: parasympathetic nervous system pharmacology Flashcards
acetylcholine role in synaptic neurotransmission
–> ACh plays a primary role in the voluntary (somatic) and involuntary (autonomic nervous system)
somatic nervous system:
- released from neurons to directly stimulate muscle tissue
autonomic nervous system
- stimulates neurons and tissue to directly or indirectly regulate organ function
what kind of receptors does ACh bind to
- ligand gated ion channels
- GPCRs (Gi and Gq)
ACh receptors found in the nervous system
ACh receptors include both stimulatory and inhibitory receptors
–> Nicotinic receptors
- ligand gated ion channels that allow sodium to enter the cell when activated (stimulatory)
–> muscarinic receptors
ACh has a higher affinity for muscarinic receptors
mAChR 1,3,5 –> GPCRs that ACH bind to
stimulatory Gq - coupled GPCR
mAChr 2,4
Inhibitory Gi-coupled receptors
- located on pre and post-synaptic neurons
ACh neurotransmission in the autonomic nervous system
–> ACh regulates both the sympathetic and parasympathetic nervous system
ACh directly stimulates the parasympathetic nervous system
ACh indirectly stimulates the sympathetic nervous system
how can one neurotransmitter control both the parasympathetic and sympathetic nervous systems (opposing physiology)
all depends on where the ACh is being released from
sympathetic = eyes receive the signal, sends to spinal cord to specifically activate sympathetic neurons which activate release of adrenaline
ACh regulation in the parasympathetic nervous system
- ACh activates nicotinic receptors (N or nAChR) in the ganglion
- ACh activates muscarinic receptors (M or mAChR) at the target tissues
ACh regulation in the sympathetic nervous system
- ACh activates nicotinic receptors in the ganglion
Noradrenaline (NA) = norepinephrine (NE) activates a and B receptors in the target organs - nAChR activation in the adrenal gland leads to systemic release of NE/NA and adrenaline (EPI)
types of ACh receptors
- nicotinic receptors and muscarinic receptors both bind acetylcholine
- nicotinic receptors also bind nicotine
- muscarinic receptors bind muscarine
M1,3,5 receptor effects in tissues
Gq-coupled GPCRs
- M1 is found in the brain, salivary glands, tear ducts
- M3 is found in GI smooth muscle
- M5 is found in the brain and the eye
M2,4 receptor effects in tissues
Gi - coupled GPCRs
- M2 is found in the heart and the brain
- M4 is found in the brain
Muscarinic receptors in muscle tissue
–> M3
- M3 activation activates PLC (phospholipase C)
- produce DAG and IP3
- increases intracellular calcium
- initiates smooth muscle contraction (rest and digest)
muscarinic receptors in tissues (M2)
–> M2
- M2 decreases cAMP activity
- prevents PKA from activating calcium channels
- calcium does not enter the cell
- decrease in contractility in the heart
- decreases heart rate
muscarinic receptor effects in the brain
–> M4
- schizophrenia is caused by too much dopamine release in the VTA
- M4 receptors inhibit neurons from firing
- M4 receptors prevent the release of ACh
= less activation of nicotinic receptors
= less depolarization of dopaminergic neurons in the VTA
= decreases schizophrenia
what are the muscarinic agonists drugs for schizophrenia
- xanomeline has an effect size of 0.6 = medium range of effect size for how good a drug is at reducing symptoms
- the most most efficacious drug clozapine has an effect size of 0.89 = many undesirable side effects
physiological effects of other mAChR drugs in the parasympathetic nervous system (agonist and antagonist)
Agonist eg: xanomeline
- non selective agonist
uses:
1. post anaesthesia
- stimulates GI activity
- stimulates bladder emptying
2. atrial tachycardia
Antagonist eg: trospium, atropine, hyoscine (scopolamine)
- non selective competitive antagonist
uses:
1. eye exam
2. anaesthesia
- prevents slowing of HR
- decreases salivary and bronchial secretions
- reduce intestinal spasm
3. anti-motility (motion sickness)
4. bradycardia
5. insecticide/nerve gas poisoning
example of natural anticholinergics ( mAChR antagonists)
- atropa belladonna
- mandrake
- jimsom weed
what receptors stimulate muscle tissue in the somatic nervous system
ligand gated ion channels are the receptors that stimulate muscle tissue because its a rapid response
nAChR structure
- a ligand gated ion channel
- present in sympathetic and parasympathetic ganglia
nAChR function
- when ACh binds, channel opens
= sodium ions enter the cell
= after prolonged activation, channel closes (desensitization) - throughout CNS
–> diverse effects-cognition, locomotion, behaviour
nAChRs impact at the neuromuscular junction
–> somatic nervous system connects the CNS directly to skeletal muscle
- controls voluntary muscle movements
- composed of nAChRs with a unique combination of protein subunits
- unique subunit arrangement allows for drug targeting at the neuromuscular junction
- when we release ACh at neuromuscular junction, we open nicotinic ACh receptors which increases influx of sodium which causes influx of intracellular calcium
neuromuscular depolarising block
- nAChR agonist eg: suxamethonium
- phase 1: sustained activation/depolarisation
- phase 2: nAChR becomes desensitised, closing the channel
- lack of sodium entering the cell = muscle becomes relaxed
neuromuscular non-depolarising block
- nAChR antagonist eg: tubocurarine
–> competitive antagonism (competes with ACh) - effect can be reversed
–> eg: with AChE inhibitor
what happens during nAChR desensitization
- prolonged opening of the nAChR leads to extended depolarization
- calcium is taken up by endoplasmic reticulum
- muscle relaxation occurs
ACh breakdown
- ACh is degraded by acetylcholinesterase (AChE) into choline and acetate
–> rapid enzyme activity - approx. 25,000 mol/sec - AChE inhibitors eg: donazepil
–> reduced ACh breakdown = increase ACh at the synapse
–> similar effects to AChR agonists (but will increase ACh at all AChRs)
used for:
- alzeimers disease
- reversal of muscle relaxants = increases ACh at the synapse
