SEM 1 Flashcards
(196 cards)
1
Q
What is occupation and what’s it governed by?
A
Occupation is the tendency for a drug to bind to its receptor, and its governed by affinity
2
Q
What is activation and what’s it governed by?
A
Activation is the ability of the drug to cause an effect, and is governed by efficacy
3
Q
What 4 types of bonds can drugs make with their receptors?
A
Hydrogen bonds
Ionic bonds
Van der Waal’s forces
Covalent bonds
4
Q
What is the law of mass action?
A
The principle that the rate of a chemical reaction is proportional to the concentrations of the reacting substances
5
Q
What’s the KA and when is it?
A
The KA is the equilibrium constant, which is the concentration of the agonist when 50% of receptors are free and 50% are bound by an agonist.
6
Q
What does smaller KA mean?
A
Smaller KA means the agonist has a greater affinity for the receptor (it binds more) than a drug with a higher KA
7
Q
Why is there a maximum number of AR interactions?
A
There’s a finite number of receptors
8
Q
Why can drugs work at small concentrations?
A
Receptors amplify signals, so even a small number of drug-receptor interactions will produce biological effects.
9
Q
How does buprenorphine reduce withdrawal effects and additive ‘highs’?
A
Buprenorphine is a partial agonist that has a high affinity but relatively low efficacy. This means it can reduce heroin-induced highs because the partial agonist has a high affinity and is already bound to the receptors
10
Q
When agonist and antagonist are both present at receptors, what are the 2 equilibrium constants involved?
A
KA and KAnt
11
Q
On a graph of response against log of the agonist concentration, which way does the sigmoid curve of the agonists response shift if antagonist is introduced?
A
The curve shifts right
12
Q
What is surmountable antagonism?
A
Antagonism which can be overcome by increasing the agonist’s concentration
13
Q
What’s non-competitive antagonism?
A
Where the antagonist binds to a different site from the agonist.
14
Q
What’s irreversible antagonism?
A
Antagonism where the antagonist binds irreversibly to either the agonist or non-agonist binding sites on the receptor through covalent bonds
15
Q
Define the term agonist
A
A drug which binds to a receptor to produce a biological response
16
Q
Define the term receptor
A
A specific target molecule with which a drug interacts to produce a cellular response
17
Q
Define the term antagonist
A
A drug which binds to a receptor but does NOT produce a biological response, but rather prevents an agonist from producing effects.
18
Q
What are 4 properties of receptors?
A
Tissue selectivity
Chemical selectivity
Extracellular/intracellular communication
Amplification
19
Q
What are the 4 receptor families?
A
Ligand-gated receptors
G-protein-coupled receptors
Tyrosine kinase receptors
Intracellular receptors
20
Q
Describe the structure of ligand-gated receptors
A
Ligand-gated receptors are composed of 5 protein subunits which each span the membrane 4 times and form an ion channel. The N terminal is a ligand-binding site
21
Q
How fast is the response from ligand-gated receptors?
A
The response takes a matter of milliseconds
22
Q
Describe the structure of G-protein-coupled receptors
A
These receptors are made of 1 single protein that has 7 transmembrane regions. The N terminal is a ligand binding site and the C terminal is a G-protein binding region.
23
Q
How fast is the response from G-protein-coupled receptors?
A
G-protein-coupled receptors give slower responses than ligand-gated receptors. They take seconds or minutes
24
Q
What are G proteins?
A
Guanine nucleotide binding proteins that are composed of 3 subunits: an alpha subunit, a beta subunit and a lamda subunit
25
What do G protein alpha subunits determine?
G protein alpha subunits determine which systems inside the cell are activated
26
Describe the structure of tyrosine kinase receptors
Made of 1 protein subunit with 1 transmembrane domain. The extracellular N-terminal binds the ligand, while the intracellular C- terminal binds the effector.
27
How fast are tyrosine kinase receptors?
The response is slow, taking minutes, hours or days
28
Describe the structure of intracellular receptors
These receptors are monomers made of 1 protein subunit. The N-terminal binds heat shock protein (HSP) and the agonist. The C-terminal controls transcription.
29
Where are intracellular receptors found?
In the cytoplasm of the cell, rather than embedded in the plasma membrane
30
Are G-proteins more likely to bind GDP or GTP, and why?
GTP, as GTP has a higher affinity than GDP
31
Adrenergic transmission mediates the effects of which nervous system?
The sympathetic nervous system
32
What neurotransmitter is synthesised and released across the synaptic cleft at an adrenergic synapse?
Noradrenaline
33
What 3 receptors can noradrenaline bind to on the post-synaptic membrane?
Alpha 1 receptors, beta 1 receptors or beta 2 receptors
34
What happens to noradrenaline in the synaptic cleft after a biological response has been triggered?
Noradrenaline is broken down by monoamine oxidase enzymes (MAO).
35
What can happen if too much noradrenaline is present in the synaptic cleft for it all to be broken down by MAO?
Some noradrenaline can bind to alpha 2 receptors on the pre-synaptic membrane, triggering negative feedback
36
In what 3 places are noradrenaline and adrenaline mediated?
The sympathetic post-ganglionic fibres, the CNS and the adrenal medulla
37
What's the function of reserpine and what can it be used to treat?
Reserpine prevents the storage of NA in vesicles, so NA in the cytosol is broken down by MAO. This reduces NA release. As a result, there are less sympathetic actions (e.g. less a1-mediated vasoconstriction), so reserpine can be used as treatment for hypertension
38
What is tyramine and how does it facilitate NA release?
Tyramine is an amine found in meats, cheese and chocolate. It enters the terminal and displaces NA into the synaptic cleft. This increases the sympathetic responses and therefore blood pressure.
39
Why can tyramine cause marked hypertension in patients treated with MAO inhibitors for depression?
Usually, tyramine gets broken down by MAO in the GI tract before it can facilitate NA release and increase sympathetic actions. If MAO enzymes are inhibited, less tyramine will be broken down and blood pressure will be increased by NA
40
How do amphetamine and ephedrine facilitate NA release from pre-synaptic adrenergic neurons?
Amphetamine and ephedrine reverse the uptake transporters, causing the release of NA into the synaptic cleft
41
How does guanethidine inhibit NA release?
Guanethidine competes with NA for inclusion into vesicles, which means less NA is released into the synaptic cleft
42
How do clonidine and alpha-methyl-DOPA
Clonidine and AMDOPA stimulate pre-synaptic alpha 2 receptors, which reduces the release of NA because activation of alpha 2 receptors causes negative feedback
43
Name an example of an MAO inhibitor and what it can be used as
Moclobemide is an MAO inhibitor, and MAO inhibitors are used as anti-depressants
44
Which nervous system does cholinergic transmission mediate the effects of?
The parasympathetic nervous system
45
What receptors can Ach bind to on the post-synaptic membrane?
Nicotinic receptors, M2 receptors and M3 receptors
46
What does the binding of Ach to nicotinic receptors change?
When Ach binds to nicotinic receptors, there can be changes in skeletal muscle or in the ganglia of the ANS
47
What does the binding of Ach to M2 receptors affect?
Changes in the heart
48
What does the binding of Ach to M3 receptors affect?
Changes in smooth muscle in airways and eyes etc.
49
Give 3 examples of biological responses to Ach
Decreased heart rate, bronchoconstriction and skeletal muscle contraction
50
How do cocaine and tricyclic anti-depressants such as imipramine affect termination of adrenergic synaptic transmission?
Cocaine and imipramine acts at the uptake transporter, inhibiting the re-uptake of NA back into the pre-synaptic terminal
51
In what 4 places does synthesis of acetylcholine occur?
NMJ's, ganglia, parasympathetic post-ganglionic fibres and the CNS
52
What's the importance of choline acetyltransferase?
ChAT takes the acetyl group from acetyl CoA molecules and adds it to choline to form the acetylcholine neurotransmitters required for cholinergic transmission
53
What bacterium causes botulism?
Clostridium botulinum
54
What does the toxin released by 'clostridium botulinum' do to cause botulism?
The toxin enters the terminals and degrades Ach-Containing vesicles. ANS fibres and motor fibres are inhibited, causing paralysis
55
How does botox work?
Very low levels of botulinum toxin are used to produce local paralysis for cosmetic and clinical uses
56
What biological effects do termination inhibitors have?
Termination inhibitors increase cholinergic actions such as bradycardia or hyperhidrosis
57
Where are nicotinic receptors found?
At autonomic ganglia and NMJ's
58
How are the Nic receptors different at the ganglia compared to at NMJ's?
Their ligand-gated receptors are composed of different subunits, so their pharmacology is different
59
Name an agonist and a competitive antagonist at nicotinic receptors
Suxamethonium is an agonist
| Vecuronium is a competitive antagonist
60
Why is it important that suxamethonium has poor dissociation?
This property means suxamethonium stays at the Ach site for a long time and produces a sustained EJP. The sustained depolarisation means voltage-gated Na channels become inactive and cannot open, preventing AP generation, so there's no contraction and the muscle relaxes
61
How does vecuronium act as a competitive antagonist?
Vecuronium outcompetes Ach for the same binding sites on Nic receptors and reduces stimulation of Nic receptors by Ach, therefore causing muscle relaxation
62
For what 2 conditions can muscarinic receptor agonist be useful?
Glaucoma and bladder underactivity
63
What's a parasympathomimetic drug?
A substance that stimulates the parasympathetic nervous system
64
What drug can act on M3 receptors to lessen the symptoms of glaucoma?
Pilocarpine
65
How does pilocarpine help with glaucoma?
Pilocarpine binds M3 receptors and stimulates ciliary muscle contraction. This opens up the aqueous canal and increases aqueous outflow from the eye, to reduce pressure
66
What drug can act to increase bladder activity?
Bethanechol
67
How does bethanechol help bladder underactivity?
Bethanechol acts at M3 receptors and stimulates detrusor muscle contraction, which aids voiding
68
What drug acts as a muscarinic antagonist for motion sickness and how does it work?
Hyoscine acts at M3 receptors to prevent stimulation of the vomiting centre in the brain
69
What drug acts as a muscarinic antagonist for IBS and how does it work?
Hyoscine acts at M3 receptors to reduce intestinal spasm
70
What drug acts as a muscarinic antagonist for bladder overactivity and how does it work?
Solfenacin acts at M3 receptors to decrease detrusor muscle activity to prevent voiding
71
What drug acts as a muscarinic antagonist for asthma and COPD and how does it work?
Inpratropium acts at M3 receptors and causes the relaxation of airway smooth muscle and therefore bronchodilation
72
What drug acts as a muscarinic antagonist for MI-induced sinus bradycardia and how does it work?
Atropine acts at M2 receptors to increase heart rate and counteract the bradycardia
73
What drug acts as an adrenergic agonist for prolonging local anaesthetic and how does it work?
Adrenaline acts at alpha 1 receptors to stimulate vasoconstriction and prevent the loss of the local anaesthetic
74
What drug acts as an adrenergic agonist for anti-obesity development and what receptors does it act at?
BRL37344 is a drug that binds to beta 3 receptors
75
What drug acts as an adrenergic agonist for bladder overactivity and how does it work?
Mirabegion acts at beta 3 receptors to relax the detrusor muscle and decrease voiding
76
What drug acts as an adrenergic agonist for premature labour and how does it work?
Salbutamol acts at beta 2 receptors to relax the myometrium in a pregnant woman's uterus in attempt to prevent premature labour
77
What drug acts as an adrenergic agonist for nasal decongestion and how does it work?
Phenylepherine binds to alpha 1 receptors to trigger vasoconstriction
78
What drug acts as an adrenergic agonist in asthma inhalers and how does it work?
Salbutamol acts at beta 2 receptors to relax airway smooth muscle and cause bronchodilator to relieve symptoms of asthma
79
What drug acts as an adrenergic agonist for heart rate increase and how does it work?
Adrenaline or dobutamine both act on beta 1 receptors to increase heart rate and contractility
80
What drug acts as an adrenergic agonist for acute anaphylaxis and how does it work?
Adrenaline acts at alpha 1 and beta 2 receptors to increase heart rate and contractility and contract blood vessels. These changes increase blood pressure
81
What drug acts as an adrenergic antagonist for anti-hypertension and what receptors does it bind to?
Prazosin acts at alpha 1 receptors
82
What drug acts as an adrenergic antagonist against adrenal gland tumours and how does it work?
Phenoxybenzamine acts at alpha 1 receptors and is long-lasting. It prevents excess vasoconstriction due to high adrenaline levels, so it decreases blood pressure
83
What drug acts as an adrenergic antagonist for bladder inactivity and how does it work?
Tamulosin acts at alpha 1 receptors and causes relaxation of internal sphincter muscle to aid voiding
84
What drug acts as an adrenergic antagonist for glaucoma and how does it work?
Timolol acts at beta 2 receptors to reduce secretion of aqueous fluid and therefore reduce pressure
85
What drug acts as an adrenergic antagonist for angina, heart failure and arrhythmia and how does it work?
Atenolol acts at beta 1 receptors to decrease heart rate, conduction and contractility and reduce O2 demand
86
What drug acts as an adrenergic antagonist for hypertension, angina and heart failure and how does it work?
Atenolol acts at beta 1 receptors to reduce renin release and decrease RAAS
87
Name the 5 criteria that encompass a neurotransmitter
* Synthesised in nerves
* Released from nerves
* Stimulates nerves
* Acts at receptors
* Have a mechanism present to terminate their action
88
Name 3 different types of neurotransmitter
Amino acids
Amines
Neuromodulators/ neurotrophic agents
89
Where is neurotransmitter synthesised and stored?
Synthesised in pre-synaptic terminals and stored in vesicles
90
What triggers the release of NT into the synaptic cleft?
The arrival of an AP at the synaptic terminal depolarises the terminal, activating and opening VGCC's leading to an influx of Ca2+ ions. Ca2+ dependent release of NT occurs
91
How does the NT induce a response and complete the synaptic transmission?
The NT binds to specific receptors on the postsynaptic membrane and triggers a chemical change in the postsynaptic neuron
92
What happens to neurotransmitter once it's induced an effect?
The NT is terminated by being re-uptaken into presynaptic vesicles or by being broken down
93
How does a local anaesthetic such as lignocaine work?
Lignocaine prevents AP conduction and synaptic transmission in sensory nerves by binding to VGSC's, stopping inputs to the brain that code for pain, so there's no pain sensation
94
How do anti-epileptic drugs such as phenytoin work?
Phenytoin prevents excess synaptic transmission during the high-frequency firing in the CNS that's associated with seizures.
95
How do analgesics such as ziconotide work?
Ziconotide is potent in blocking VGCC's in presynaptic clefts, which prevents synaptic release of the neurotransmitter involved in conduction of pain signals. This means inputs to the brain that code for pain stop and ziconotide acts as a painkiller
96
How do MAO inhibitors act as anti-depressants?
MAO inhibitors prevent NA from being broken down in the synaptic cleft, therefore potentiating NA levels in the brain
97
How do amphetamines work to suppress ADHD?
Amphetamines bind to and reverse the action of monoamine uptake transporters, which causes the release of NA, dopamine and serotonin. NA and dopamine improve focus
98
How does ephedrine work to decrease nasal congestion?
Ephedrine is a derivative of amphetamine which is used as a decongestant, causing vasoconstriction of nasal blood vessels
99
How does guanethidine work as an antihypertensive drug?
Guanethidine competes with NA for inclusion into vesicles. This leads to decreased or prevented NA release into the synaptic cleft
100
How do clonidine and alpha-methyl-DOPA act as antihypertensive drugs?
Clonidine and alpha-methyl-DOPA stimulate pre-synaptic alpha2 receptors, which reduces NA release and this decreases blood pressure
101
How do cocaine and tricyclic anti-depressants work?
Cocaine and tricyclic anti-depressants inhibit dopamine uptake transporters by blocking them, potentiating adrenergic transmission and increasing sympathetic actions
102
How can SSRIs such as fluoxetine relieve symptoms of depression?
SSRIs prevent the reuptake of 5-HT (serotonin), leading to increased serotonin in the synapse and increased 5-HT neurotransmission
103
Describe the relative lengths of the pre- and post-ganglionic fibres in the parasympathetic nervous system
In the parasympathetic NS, pre-ganglionic fibres are long and post-ganglionic fibres are short
104
What neurotransmitter is released at the ganglionic synapse in the parasympathetic nervous system?
Acetylcholine
105
What neurotransmitter is released from post-ganglionic fibres onto muscarinic receptors?
Acetylcholine
106
Describe the relative lengths of pre- and post-ganglionic fibres in the sympathetic nervous system
In the sympathetic NS, pre-ganglionic fibres are short and post-ganglionic fibres are long
107
What neurotransmitter is released at ganglionic synapses in the sympathetic nervous system?
Acetylcholine
108
What neurotransmitter is released from post-ganglionic fibres in the sympathetic nervous system?
Noradrenaline is released onto adrenoreceptors
109
What type of receptor are ß1, ß2 and ß3 receptors in the sympathetic nervous system?
They are all Gas G-protein coupled receptors
110
What type of receptors are a1- and a2-adrenoreceptors in the sympathetic nervous system?
a1-adrenoreceptors are Gaq G-protein coupled receptors, while a2-adrenoreceptors are Gai G-protein coupled receptors
111
What G-protein subtype is associated with a1-adrenoreceptors?
Gaq
112
What G-protein subtype is associated with a2 adrenoreceptors?
Gai
113
What G-protein subtype is associated with ß1, 2 and 3 adrenoreceptors?
Gas
114
Where are a1 receptors found?
In blood vessels, the bladder and the eyes
115
Where are a2 receptors found?
Presynaptic membranes
116
What does a1 stimulation do?
Vasoconstriction, venoconstriction, pupil dilation and bladder sphincter constriction
117
What does stimulation of a2 receptors do?
Triggers negative feedback to reduce neurotransmitter release from the presynaptic neurone
118
Where are ß1 receptors found?
In the heart and kidneys
119
What does ß1 stimulation do?
Increase heart rate, contractility and electrical impulse conductivity in the heart, and stimulate renin release from juxtaglomerular cells in the kidney
120
Where are ß2 receptors found?
In blood vessels (coronary arteries and skeletal muscle), the lungs, and bladder detrusor muscle
121
What are ß2 receptors responsible for?
Dilation of blood vessels, bronchodilation and relaxation of bladder detrusor muscle
122
Where are ß3 receptors found?
In adipose tissue, the gallbladder and the urinary bladder
123
What are ß3 receptors for?
Activation of lipolysis
| Relaxation of the bladder
124
What activity does sympathetic nervous system activity decrease?
GI tract activity
125
What pathway does Gas affect?
Gas activates AC, leading to increase in cAMP and PKA
126
What pathway does Gai affect?
Gai deactivates AC, leading to decrease in cAMP and PKA
127
What pathway does Gaq affect?
Gaq activates PLC, leading to increase in IP3 and DAG
128
Describe the effects of ß1 stimulation in the kidney in detail
ß1 stimulation triggers renin release from juxtaglomerular cells, which leads to increase in Ang II and then aldosterone. Aldosterone increases Na+ and H2O retention (reabsorption), increasing blood volume and pressure and CO. Ang II causes vasoconstriction, increased TPR and increased BP and CO
129
What does ß2 stimulation do?
It causes relaxation of smooth muscle, so dilation of coronary and skeletal vessels, bronchodilation and relaxation of bladder detrusor muscle
130
What does ß3 stimulation do in adipose tissue?
Enhances lipolysis and thermogenesis
131
What are sympathomimetics?
Substances that mimic or modify the actions of endogenous catecholamines of the sympathetic nervous system. This includes adrenergic receptor agonists and any indirect drugs that increase neurotransmitter in the synaptic cleft
132
What can adrenergic receptor agonists be used as?
Cardiac stimulants, asthma inhalers, nasal decongestants. They can also be used for overactive bladder, prolonging of local anaesthetic and acute anaphylaxis
133
What can adrenergic receptor antagonists be used for?
Underactive bladder, hypertension, angina, heart failure, glaucoma and adrenal gland tumours
134
What kind of receptor are nicotinic receptors?
Ligand-gated cholinergic receptors
135
What kind of receptors are muscarinic receptors?
G-protein coupled cholinergic receptors
136
Why are G-protein coupled receptors slower at inducing a response than ligand-gated receptors?
They involve a second messenger
137
Where are nicotinic receptors found?
NMJ's, all autonomic ganglia and the adrenal glands
138
How does NMJ nervous transmission lead to muscle contraction?
Ach is released and binds to nAchr on the sarcolemma, causing an excitatory junction potential (EJP). If the threshold is reached, VGNa+ channels open and there's an influx in Na+. Depolarisation spreads down the T-tubules and opens VGCCs, leading to Ca2+ influx and muscle contraction
139
What is an important exception to all autonomic ganglia using nicotinic receptors at pre-ganglionic nerve endings?
In the adrenal medulla, there are no post-ganglionic fibres in the sympathetic innervation to the adrenal glands. Ach binds directly to nicotinic receptors on the adrenal medulla
140
Where are muscarinic receptors found?
In post-ganglionic parasympathetic fibres and in sweat glands
141
What is an exception to post-ganglionic parasympathetic nerves releasing Ach onto muscarinic receptors on target organs?
In erectile tissue there's NANC innervation
142
What G-protein are M2 and M4 coupled with?
Gai
143
What muscarinic receptors are Gaq-linked?
M1, M3 and M5
144
Where are M1 receptors found?
In glands
145
Where are M2 receptors found?
In the heart
146
Where are M3 receptors found?
In smooth muscle, the lungs, pancreas and brain
147
What is ChAT?
Choline acetyltransferase, an enzyme that catalyses formation of ACh and CoA from choline and acetyl CoA
148
How do ChAT inhibitors regulate cholinergic activity?
They indirectly regulate cholinergic activity by preventing resynthesis of Ach from choline that's reuptaken into the presynaptic terminal from ACh broken down in the synaptic cleft
149
What is AChE?
Acetyl cholinesterase- an enzyme that breaks down excess ACh in the synaptic cleft after it's stimulated postsynaptic receptors. AChE breaks ACh down into choline and an acetyl group, and choline is then reuptaken to regenerate Ach
150
How do AChE inhibitors work?
They prevent resynthesis of ACh by preventing ACh breakdown in the cleft, therefore indirectly inhibiting cholinergic transmission
151
What drugs directly regulate cholinergic activity?
AChr agonists and antagonists regulate cholinergic transmission by binding to post-synaptic ACh receptors
152
What are the 4 notable Anti-cholinesterases?
Edrophonium- short-lasting
Neostigmine- medium-acting
Sarin gas- irreversible
VX agent- irreversible
153
Name a drug that acts at muscarinic receptors for asthma treatment and how it works
Ipratropium binds to M3 receptors to relax airway smooth muscle and induce bronchodilation
154
Name a drug that works at muscarinic receptors to treat MI-induced sinus bradycardia
Atropine binds to M2 receptors and increases heart rate
155
Give 3 examples of receptors that are ligand-gated
Nicotinic receptors
Glutamate receptors
GABA receptors
156
Describe the mechanism of action of ligand-gated receptors
The ligand binds to the receptor
This causes conformational change in the subunits
This opens an ion channel (pore)
The opening of the ion channel allows for influx of ions, changing cell excitability
157
Give 3 examples of G-protein coupled receptors
Alpha-adrenoreceptors
Beta-adrenoreceptors
Muscarinic receptors
158
What's the mechanism of action of G-protein coupled receptors?
A ligand binds to the G-protein coupled receptor site
This causes conversion of GDP bound to the G-protein to GTP
This conversion activates the alpha subunit of the G-protein
The alpha subunit diffuses across to the enzyme, which is either adenylate cyclase or phospholipase C
159
Give 2 examples of tyrosine kinase receptors
Insulin receptors and EGF receptors
160
Give the mechanism of action of tyrosine kinase receptors
```
The ligand binds
Dimerization
Autophosphorylation
Activation of signal proteins
Cellular function
```
161
Give an example of an intrinsic (nuclear) receptor
Steroid hormone receptor
162
Give the mechanism of action of intrinsic receptors
Drug binds, displacing heat-shock protein
The complex enters the nucleus and binds to the HRE of DNA
Modulation of gene expression and transmission
163
What's an HRE of DNA?
A hormone response element is a short length of DNA within the promoter of a gene that is able to bind to a specific hormone receptor complex and regulate transcription
164
What outflow does the parasympathetic NS have?
Craniosacral outflow
| the neurones originate from cranial nerves (CN3, CN7, CN9, CN10) and the sacral spinal cord (S2, S3, S4)
165
What cranial nerves have parasympathetic action?
CN3, CN7, CN9, CN10
166
Describe parasympathetic innervation of the heart
Vagus nerve stimulation leads to binding of Ach to M2 receptors in the SAN and AVN, decreasing SAN firing frequency and HR. Stimulation of M2 receptors in the conducting tissue decreases electrical conduction through the AVN, which balances reduction in heart rate to contraction. SV and TPR aren't affected because parasympathetics don't innervate most blood vessels. With decrease in HR, CO therefore is reduced
167
What's the mechanism for parasympathetic control of CO?
Ach binds to M2, activating G-protein by GDP-GTP swap, activating the Gai subunit. The G-protein deactivates adenylate cyclase, leading to decrease in cAMP and PKA, so fewer ion channel open. This means decreased SAN pacemaker potentials, less Ca2+ channels opening and less Ca2+ influx, so contractility is decreased as less TnC is displaced by Ca2+
168
Describe the parasympathetic actions on the eye
Ach binds to M3 receptors, causing miosis- constriction of the pupil- via constriction of smooth muscle of the iris (constrictor pupillae), so pupil diameter decreases. Ach binding to M3 receptors also stimulates ciliary muscle contraction, which opens up the aqueous canal (canal of Schlemm) and increases aqueous humour outflow from the eye to reduce pressure
169
What is the canal of Schlemm?
A drainage system at the back of the pupil that opens on constriction of the pupil
170
How does ciliary muscle of the eye control vision?
Ciliary muscle is attached to the lens by suspensory ligaments. Relaxation of the muscle makes the suspensory ligaments taut, so the lens is long and thin and has a long focal length for distance vision. For close vision, the ciliary muscle contracts to relax suspensory ligaments, as the ciliary body moves upwards and forwards, so the lens has a bulged shape and focal length is reduced
171
Describe parasympathetic action on the bladder
When afferent sensory fibres detect bladder wall stretch, parasympathetic activity leads to Ach binding to M3 receptors to cause contraction of detrusor muscle and micturition
172
Describe the sympathetic action that keeps the bladder relaxed for storage of urine
NA binds to ß2 receptors to keep detrusor muscle relaxed. NA binds to a1 receptors to keep the internal sphincter closed
173
What is detrusor muscle?
Smooth muscle in the walls of the bladder that determines urine storage and micturition
174
Describe parasympathetic action on the GI tract
The vagus nerve acts directly, and indirectly via the enteric NS on the GI tract. Activation of M3-Gaq receptors causes increased contraction of smooth muscle and therefore increased motility by longitudinal and circular smooth muscle contraction. Parasympathetics also increase secretions of amylase, gastric acid, insulin and pancreatic secretions
175
Describe parasympathetic activity on the lungs and airways
Ach binds to M3 receptors to cause bronchoconstriction.
176
What's the importance of M3 receptors in the airways for COPD patients?
Bronchoconstriction is unhelpful in COPD patients, so we can block the M3 receptors with muscarinic agonists such as ipratropium
177
Give 2 side effects of muscarinic M3 antagonists
Reduced micturition
| Increased intra-ocular pressure (therefore, M3 antagonists are contraindicated in glaucoma patients)
178
How do M3-Gaq receptors cause contraction of vascular smooth muscle in airways?
M3-Gaq stimulates conversion of PIP2 to DAG and IP3. IP3 releases Ca2+ from the SR of VSMCs. VGCCs open and there's a further influx of Ca2+. Ca2+-calmodulin complexes form, which activate MLCK. This leads to contraction via phosphorylation of light chains in myosin heads
179
Describe the parasympathetic action on the male genitalia
NO is released from parasympathetic nerves to act on M2-Gai receptors to cause relaxation of VSMCs composing the corpus cavernosum. This vasodilation allows the corpus cavernosum to dilate and fill with blood, producing and maintaining an erection
180
Where is the sympathetic outflow?
Sympathetic outflow is thoracic-lumbar, originating from spinal nerve roots T1-L2
181
What's the pre- and post-ganglionic arrangement of sympathetic fibres?
Short pre-ganglionic fibres release ACh onto nicotinic receptors. Long post-ganglionic fibres release NA onto adrenoreceptors
182
Where are paravertebral ganglia found?
In the sympathetic chain
183
Where are prevertebral ganglia found?
Away from the spinal cord, between the paravertebral ganglia and the end structures
184
What's the arrangement of sympathetic fibres at sweat glands?
Ach acts at muscarinic receptors at end structures
185
What's the arrangement of sympathetic fibres in the adrenal medulla?
Pre-ganglionic fibres release Ach to stimulate adrenaline secretion from the gland
186
What metabolic effects does sympathetic activity have?
Increased metabolism for energy break down and provision- glycogenolysis and gluconeogenesis
187
Describe sympathetic activity on the heart
NA stimulates ß1 adrenoreceptors, giving a chronotropic effect due to increased SAN firing frequency and heart rate. There's an inotropic effect due to increase in contractility and SV as more Ca2+ is released. Both effects increase CO from 5L/min to over20L/min in exercise.
188
Describe sympathetic action on the lungs and airways
There's no direct sympathetic action on the lungs. Bronchioles contain ß2 receptors and are activated by circulating adrenaline to cause bronchodilator by relaxing airway smooth muscle. This allows more airflow and increased gas exchange
189
Describe sympathetic activity on the blood vessels
NA and adrenaline act on a1 adrenoreceptors in blood vessels to cause vasoconstriction. There's an increase in BP and therefore TPR.
190
Describe sympathetic activity on the kidney
Stimulation of ß1 adrenoreceptors by NA causes renin secretion from granular cells. Renin indirectly triggers production of Ang II, which causes vasoconstriction and increases BP and CO. Ang II also causes aldosterone release from the adrenal cortex, which increases Na+ and H2O reabsorption, increasing blood volume and pressure
191
How do ß1-blockers work to decrease BP?
ß1-blockers prevent renin release
192
Describe the effects of sympathetic activity in the GI tract
GI motility is inhibited when ß2 receptors are stimulated
193
Describe the sympathetic activity in the bladder
a1-receptors are stimulated to constrict the internal bladder sphincter, and ß2 receptors are stimulated to relax the bladder detrusor muscle
194
Describe the sympathetic activity in the liver
Stimulation of a and ß receptors cause decrease in insulin release from beta cells, decreased global glucose uptake, prevents insulin from inhibiting glycogenolysis, gluconeogenesis and lipolysis, and increases glucagon secretion from alpha cells, increasing glycogenesis
195
Describe sympathetic activity in the eye
Stimulation of a1-adrenoreceptors on dilator pupillae causes dilation of the pupil
196
Describe sympathetic activity in adipose tissue
Stimulation of ß3 adrenoreceptors increases lipolysis, where triglycerides are broken down into free fatty acids and glycerol. Increased lipolysis leads to increased ATP yield
