The Autonomic Nervous System Flashcards
what are the two large divisions of the autonomic nervous system?
sympathetic and parasympathetic
what do the sympathetic and parasympathetic nervous systems do?
provide link between the central nervous system and peripheral organs. involuntary systems.
what is the basic anatomy of the autonomic nervous system? (which parts?)
cervical, gastrointestinal, lumbar, medullary, sacral, thoracic.
basic sections of sympathetic nerves?
thoracic, lumbar sections of spinal cord.
preganglionic nerves - ganglion - post ganglionic nerve.
basic sections of parasympathetic nerves?
cranial, sacral sections of spinal cord.
Preganglionic nerves – ganglion – postganglionic nerve.
basic difference between sympathetic and parasympathetic nerves?
s: preganglionic nerves short. ganglion located outside of innervated tissue
p: preganglionic nerves long. ganglion located within innervated tissue
name two neurotransmitters of the autonomic nervous system:
acetylcholine, noradrenaline.
noradrenergic neurons: what does it do and where is it located?
synthesize noradrenaline. located in periphery are sympathetic neurons, whose cell bodies lie in sympathetic ganglia.
store noradrenaline in vesicles and release into synaptic cleft. re-uptake of noradrenaline from synaptic cleft by noradrenaline transporter (SLC6A2) to reduce its effect
within the autonomic nervous system, what are cholinergic neurons?
choline taken up into the nerve. free choline within the nerve terminal is acetylated by choline acetyltransferase (CAT), which transfers the acetyl group from acetyl coenzyme A.
what terminates the effect of released acetylcholine?
acetylcholinesterase (AChE)
ACh + AChE –> choline and acetate.
what does botulinum toxin do?
Inhibits acetylcholine release from cholinergic neurons –> prevent exocytosis. progressive parasympathetic and motor paralysis.
name two indications of botulinum toxin poisoning
blepharospasm (persistent eyelid spasm)
urinary incontinence.
Anticholinesterease drugs: effects?
Inhibit acetylcholinesterase.
increases acetylcholine concentration by preventing its metabolism
Anticholinesterease drugs: effects mainly due to?
enhancement of cholinergic transmission at cholinergic autonomic synapses (and neuromuscular junction)
examples of anticholinesterease drugs: short acting and medium duration?
short: edrophonium
medium: neostigmine
indications of anticholinesterase drugs?
myasthenia gravis
(antibodies destroy the communication between nerves and muscle, resulting in weakness of the skeletal muscles. affects voluntary muscles)
simply: what are agonists and receptors of the following: pre-ganglionic nerves, sympathetic nerves, parasympathetic nerves.
- acetylcholine –> nicotinic receptors
- noradrenaline –> adrenoceptors
- acetylcholine –> muscarinic receptors
what releases adrenaline into vascular system to activate adrenoceptors?
adrenal medulla
what are nicotinic receptors activated by?
acetylcholine released from pre-ganglionic nerves
what happens when nicotinic receptors are activated?
tachycardia, an increase in blood pressure, and variable effects on gastrointestinal motility and secretions. salivary and sweat secretions
what are nicotinic receptors blocked by?
hexamethonium –> transmission block. causes hypotension and loss of cardiovascular reflexes (prev used to manage hypertension. ‘hexamethonium man’)
Name an exogenous agonist that activates nicotinic receptors. (what does exogenous agonist mean?)
Nicotine
external factors which bind to various receptors. induce biological response.
classification of adrenoceptors? (name first three)
alpha1, alpha2, beta. each splits into three further groups.
noradrenaline: where is it released, what does it activate?
released from sympathetic nerve terminals activates adrenoceptors
activation of a1 adrenoceptor: main effect?
vasoconstriction, gastrointestinal smooth muscle relaxation, salivary secretion, hepatic glycogenolysis
activation of a2 adrenoceptor: main effect?
inhibition of transmitter release (noradrenaline and acetylcholine release from autonomic nerves), platelet aggregation, contraction of vascular smooth muscle, insulin release inhibition.
activation of b1 adrenoceptor: main effect?
increased cardiac rate and force. delayed cardiac hypertrophy
activation of b2 adrenoceptor: main effect?
bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis, muscle tremor
activation of b3 adrenoceptor: main effect?
lipolysis.
can adrenoceptors co-exist? give example and effect.
b1 and b2 adrenoceptors in human heart. increase heart rate and force of contraction.
what family do the adrenoceptors/muscarinic receptors belong to?
G-protein coupled receptors. (GCPRs)
beta1 adrenoceptor: binding pocket: what does GPCR do?
GPCRs form a ‘binding pocket’ where agonists and antagonists enter.
agonists and antagonists bind to specific amino-acids on the GPCR
What does G-protein-coupled receptor (GPCR) act like in the cell? What is the role of the binding pocket in the GPCR?
GPCR receives signals from the outside. The binding pocket is where the receptor grabs onto specific molecules.
What is the function of agonists in GPCR signaling?
Agonists, like adrenaline, stabilize the receptor in a way that activates it and couples it to the cell’s internal G-protein, triggering a response.
How do antagonists, such as cyanopindolol, affect GPCR signaling?
Antagonists stabilize the receptor differently, preventing it from coupling to the G-protein and stopping the signal.
What happens to the pocket around adrenaline in GPCR binding?
There is a 2–3A ° tightening of the pocket around adrenaline, ensuring a strong and clear signal. (antagonists don’t produce this response)
critical anchoring points (endogenous catecholamines): when is beta2 adrenoceptor activated most effectively?
when there are precisely 2 carbon atoms between the ring and the amino group.
catecholamines: (class of neurotransmitter/hormone. e.g. dopamine, noradrenaline, adrenaline). endogenous means produced naturally in the body.
what is the neurotransmitter released from sympathetic nerve terminals and activates adrenoceptors?
noradrenaline
neurotransmitter released from parasympathetic nerve terminals and activates muscarinic receptors:
acetylcholine
neurotransmitter released from pre-ganglionic receptors and activates nicotinic receptors:
acetylcholine
neurotransmitter that is a substrate for SLC6A2
noradrenaline
neurotransmitter synthesized from dopamine by dopamine beta-hydroxylase:
noradrenaline
give three examples of catecholamines:
noradrenaline, adrenaline, isoprenaline.
What are the structural features studied in β1- and β2-adrenoceptors?
structural features: for example, interaction with protonated amine group.
What is the role of the amine group in β-blockers like propranolol in interacting with the β2-adrenoceptor?
works as an anchor.
The amine group of β-blockers like propranolol anchors these compounds to the Asp113 in the β2-adrenoceptor.
what structural substitution results in reduction of agonist activity?
Tertiary amine substitution ex –
N(CH3)2 - reduces agonist activity
name three full agonists of β1AR, β2AR
noradrenaline, adrenaline, isoprenaline.
nicotinic receptors are activated by? where is it released?
activated by acetylcholine released from pre-ganglionic nerves.
what are indirect acting sympathomimetic drugs? what are their classifications? (4)
enter sympathetic nerve terminals and displace noradrenaline from storage vesicles.
phenoethylamines
phenylethanolamines
phenylethylamines
aliphatic amines
indirect acting sympathomimetic drugs: phenoethylamines: give function and example.
tyramine: acts almost entirely by displacing noradrenaline from stores in sympathetic nerve terminals.
indirect acting sympathomimetic drugs: phenylethanolamines: give function and example.
ephedrine: has four isomers. have largely indirect action. ephedrine isomers with same configuration about beta-carbon as noradrenaline have more direct activity on beta adrenoceptors.
indirect acting sympathomimetic drugs: phenylethylamines: example, characteristics and activity?
amphetamine, methylamphetamine. taken up into sympathetic nerve terminal. cause displacement of noradrenaline from storage vesicles. have alpha-chiral carbon.
absence of meta- and para-hydroxyl and beta hydroxyl groups reduce direct beta adrenoceptor activity.
example of partial agonist? + structure.
dobutamine: absence of beta hydroxyl and inclusion of bulky N-substitution cause reduction in efficacy at beta adrenoceptors.
dobutamine has chiral carbon.
what does propranolol do? (effects on the body)
decrease heart oxygen demand by blocking beta receptors, decrease heart workload. manage coronary artery disease.
properties of beta blockers: competitiveness?
all beta blockers are competitive antagonists.
Name the categories of β-blockers based on selectivity.
Non-selective β-blockers (First generation)
Selective β-blockers (Second generation)
β-blockers with vasodilatory effects (Third generation)
Give an example of a β-blocker with intrinsic sympathomimetic activity (ISA).
Oxprenolol (partial agonist)
Provide examples of β-blockers with inverse agonist activity.
Metoprolol, Nadolol (though not used in Australia)
What structural feature in propranolol results in a loss of agonist activity at β-adrenoceptors?
–O-CH2- bridge between the aromatic ring and β-hydroxyl carbon and absence of meta- and para-hydroxyl groups on the aromatic ring.
What structural features do all clinically used β-blockers share?
–O-CH2- bridge and lack meta- and para-hydroxyl groups.
what drug are beta1 selective blockers based on? what are the significant structural aspects? give some examples of blockers.
isoprenaline (synthetic catecholamine)
-O-CH2- oxymethylene group
- para aromatic ring substitution
- absence of a meta aromatic ring substitution
ex. atenolol, metoprolol, bisoprolol.
beta adrenoceptor antagonists with vasodilatory activity: example, what does it block and why, and effect.
carvedilol.
blockade of alpha1 adrenoceptors –> relax smooth muscle.
highly lipophilic –> persistent blockade of beta-adrenoceptors.
beta adrenoceptor antagonists: beta blockers. therapeutic indications and examples?
- hypertension (metoprolol, atenolol)
- coronary artery disease (metoprolol, atenolol)
- heart failure (metoprolol, carvedilol, bisoprolol, nebivolol)
- arrhythmias (atenolol, esmolol) (sometimes sotalol, but also potassium ion channel blocker)
the endogenous agonists for alpha1 adrenoceptors are?
noradrenaline and adrenaline.
What structural feature characterizes drugs like phenylephrine and metaraminol in activating alpha-1 adrenoceptors?
characterized by a meta-hydroxyl or a meta-substituent on the aromatic ring.
What is the effect of activating alpha-1 adrenoceptors?
vasoconstriction.
Name two drugs that activate alpha-1 adrenoceptors and have a meta-hydroxyl.
Phenylephrine and metaraminol
What is the primary action of imidazolines on adrenoceptors?
direct agonists on α1A adrenoceptors
Why do most imidazoline compounds have poor intrinsic activity?
due to different binding patterns compared with noradrenaline. additionally, most do not have chiral centres.
For what purpose are imidazolines commonly used?
‘nasal ‘decongestants.’
alpha 1 adrenoceptor: selective antagonist. give two examples:
prazosin, terazosin.
nature of alpha2 adrenoceptors? what does it do?
Pre-junctional alpha2-adrenoceptors are autoinhibitory
-reduce the amount of (-)-noradrenaline released from sympathetic nerve terminals
location of the following? (cardiovascular control)(pre/post junctional and effects?)
beta1 adrenoceptor, beta2 adrenoceptor, alpha2 adrenoceptor.
beta1 adrenoceptor: postjunctional (increase force of heart contraction and heart rate)
beta2 adrenoceptor: prejunctional (increase noradrenaline release), postjunctional (decrease vascular tone)
alpha2 adrenoceptor: prejunctional (decrease noradrenaline release)
mechanism of imidazoline antihypertensive drugs? function and effect.
reduce release of sympathetic transmitter (noradrenaline).
decrease vascular resistance, heart rate, force of contraction.
five members of muscarinic receptors and G protein coupling?
Five members, M1, M2, M3, M4, M5
- G-protein coupled receptors
- M2, M4 coupled to Gi/Go proteins
- M1, M3, M5 coupled to Gq/11 proteins
types of muscarinic receptors and type (e.g. cardiac)
M1 = neural
M2 = cardiac
M3 = glandular
M4, M5 = molecular mAChR subtypes. mainly occur in CNS
muscarinic receptor agonists: example
acetylcholine. hydrolysed by cholinesterase. effect of muscarinic receptor agonists mimic the effects of acetylcholine.
muscarinic receptors: agonists: effects on the heart.
decreased heart rate, force of atrial contraction, force of ventricular contraction.
muscarinic receptors: agonists: effects on the blood vessels.
relaxation: endothelium dependent. NO mediated.
contraction: smooth muscle dependent.
muscarinic receptors: agonists: effects on the smooth muscle, sweating, lacrimation, salivation and bronchial secretion:
contraction: ^peristaltic activity in gastrointestinal tract, bronchial constriction.
increase secretions
muscarinic receptors: agonists: effects on acid release from parietal cells in gastrointestinal system:
increased acid release –> decrease pH of stomach lumen.
muscarinic receptors: agonists: effects on the the eye and example of drug? what is it used to treat?
constrictor pupillae muscle –> constrict pupil. lowers IOP in patients with glaucoma.
pilocarpine eye drops used for glaucoma.
ciliary body contraction –> lens bulges more induce decrease focal length.
what structural change occurs when M2 receptor is activated?
transmembrane helix 6 (TM6) rotates outward, Tm7 moves inward. G-protein binding site formed intracellularly.
types of muscarinic receptor antagonists. give example of each.
1 irreversible muscarinic receptor antagonist: phenoxybenzamine
2 reversible (competitive receptor antagonists): atropine.
muscarinic receptors: antagonists: effects on the heart, gastrointestinal tract smooth muscle
increase heart rate
decrease motility and acid release (more basic)
muscarinic receptors: antagonists: effects on other smooth muscles and secretions. (effects on eye the opposite of agonist)
bronchial, biliary and urinary tract smooth muscle relaxation
decrease salivary, lacrimal, bronchial and sweat glands –> dry mouth and skin.
decrease acid release from parietal cells (increase pH of stomach lumen (gastrointestinal))
what type of drug is atropine?
muscarinic receptor antagonist.
peripheral indications (meaning apart from primary use): bradyarrhythmia.
selectivity of muscarinic receptor antagonists?
relative lack of selectivity for individual receptors.
“development of drugs of other clinical applications held back possibly due to lack of small molecule ligands that can inhibit/activate specific mAChRs with high selectivity.”
what are the two binding sites of muscarinic receptors? what binds to each?
orthosteric and allosteric
orthosteric: conventional muscarinic receptor ligands
allosteric site: newer compounds can bind to one or both simultaneously (bitopic ligands)
what are bitopic ligands referring to?
compounds which can bind to both allosteric and orthorsteric binding sites of muscarinic receptors simultaneously.
what do allosteric ligands do?
promote conformational changes in receptor that manifest as alternation in properties of ligand bound to orthosteric (classic) site.
orthosteric vs. allosteric?
orthosteric relates to original binding site directly, while allosteric is another site that cause conformational changes and cause indirect effects.
types of allosteric modulators:
positive allosteric modulator (PAM): enhance orthosteric activity
negative allosteric modulator (NAM): inhibit orthosteric activity
neutral allosteric modulator (NAL): do not change orthosteric activity.
compared to muscarinic ligands, what is one reason allosteric modulators may be better for treatment?
provide more selective muscarinic ligands than those currently available –> fewer side effects.
