Pharmacology of ANS Flashcards
(195 cards)
1
Q
What is the purpose of the Autonomic Nervous System (ANS)?
A
To optimize distribution of resources while the body performs different tasks. This must be done EFFECITVELY and WITHOUT thinking (no CNS, tho CNS does innervate).
2
Q
Which organs are innvervated by the ANS?
A
ALL
3
Q
What are the two branches of the ANS?
A
Sympathetic
Parasympathetic
4
Q
What does the sympathetic nervous system do?
A
- Alertness
- Fight or Flight
- Spend energy
5
Q
What does the parasympathetic nervous system do?
A
- Restore energy
- Rest and Digest
6
Q
How does the ANS regulate organ function?
A
Via release of neurotransmitters that bind to unique receptors on organs
7
Q
What is the significance of the way the ANS regulates organ function?
A
We can manipulate the organs by using synthetic chemicals that use autonomic mechanisms (eg, receptor agonists and antagonists)
8
Q
What are nerves?
A
Bundles of hundreds of axons and/or dendrites
9
Q
How to ANS synapses work in general?
A
- AP propagated down presynaptic axon
- AP arrival at terminal induced Ca channels to open so there is an influx on Ca into the cell
- Ca induces exocytotic release of vesicles with NT
- NT travels across cleft to bind to receptor on post synaptic cell, inducing a function in target cell
- NT in cleft needs to be removed so effect on target cell can end: either degraded or reuptaken
- NT is brought back in some way to presynaptic and recycled
- NT is repackaged into vesicles for next AP
10
Q
What is the function of presynaptic or prejunctional receptors?
A
Inhibit release of NT vesicles via a negative feedback loop
11
Q
How are enzymes used with NTs?
A
- Synthesis
- Packaging
- Storage
- Release
- Degradation/reuptake
12
Q
What types of NT receptors are there in the ANS?
A
- Sympathetic: Adrenergic - Alpha and Beta
- Parasympathetic: Cholinergic - Nicotinic and Muscarinic
13
Q
What are some characteristics of receptors in the ANS?
A
- Different downstream biochemistry
- Distinct localization (expressing) in tissues/within cells
- Different subtypes have different localization in body
14
Q
What role do organs play in ANS pharmacology?
A
Systems enact a systemic response, which can be normal or pathologic
15
Q
What role do receptors play in ANS pharmacology?
A
- Functions via downstream signaling.
- Receptor localization
16
Q
What role do drugs play in ANS pharmacology?
A
- Mechanism of action: agonist, antagonist, or other
- What is the effect of the natural NT?
- Many drugs
- Side effects
- Pharacodynamics/Pharmacokinetics
17
Q
How do drugs interest with receptors?
A
Receptor molecules can exist in several conformations, which drugs can stabilize.
18
Q
How can an inverse agonist affect a receptor?
A
Lessen or negate a response
19
Q
How does an antagonist affect a receptor?
A
Decrease response or negate, depending on basal activity
20
Q
How does a partial agonist affect a receptor?
A
Partial response
21
Q
How does a fill agonist affect a receptor?
A
Full response
22
Q
How do receptors regulate cellular functions?
A
- Receptor on plasma membrane facing outside
- Drug binds to receptor
- Inactive GDP-bound Protein is converted to active GTP-bound protein
- Effector inside cell influences second messenger
23
Q
Receptor desensitization
A
Prolonged stimulation leads to GPCR desensitization via phosphorylation by GRK (G protein-coupled Receptor Kinase)
24
Q
Receptor internalization
A
After phosphorylation of receptor due to prolonged stimulation, receptor can be internalized: becomes part of internal vesicle. Will stay there until stimulation stops.
25
Signaling "From Within"
There is evidence that GPCRs continue functioning once internalized, so can signal from within.
26
Downstream Effects of G protein coupling
1. Second messengers activate protein kinases
2. Phosphorylation of substrates in cells
3. Function of substrates changes
27
How does the ANS maintain homeostasis?
For all biological parameters, there is a normal level that can increase with activation or decrease with inactivation.
These changes are influenced in two ways by ANS:
- Molecularly: NT release/re-uptake, presynaptic inhibition, receptor activation/desensitization
- Physiologically: Maintains balance by sending on/off signals via reflexes
28
Function of Ganglia in ANS
- All pre-ganglionic secreta ACh
- Post-ganglionic:
- Parasympathetic: ACh
- Sympathetic: NE
29
What is the effect on ANS of drugs than target ACh?
Since ACh is used widely in ANS, its lack of specificity will cause changes across the system.
30
ANS reflexes in circulatory system
1. Heart pumps blood through blood vessels
2. Blood vessel tone changes in response
3. In response, Heart pumping changes
31
What influences changes in heart pumping?
- Vascular resistance
- Heart rate and force
- Blood volume
32
ANS Regulation of Blood Pressue
1. Baroreceptor measures BP, sending info to vasomotor center in CNS
2. CNS sends instructions to PNS and SNS
3. PNS and SNS response
- PNS: affect heart rate --> Cardiac output --> pressure
- SNS: affect multiple parts
- Vascular resistance (smooth muscle) --> pressure
- Heart rate --> cardiac output --> pressure
- Contractile force --> stroke volume --> cardiac output --> pressure
- Venous tone --> venous return --> stroke volume --> cardiac output --> pressure
33
What is the purpose of autonomic reflexes?
Explains how several organs respond to a change in blood pressure in an organized manner: Once an order arrives, ANS executes it in an organized manner, engaging all organs.
34
ANS Reflexes in the eye
1. ANS controls flow of humor, which maintains shape of eye
| 2. Smooth muscles in pupil control diameter
35
ANS regulation of the eye: parasympathetic
Pupil contraction via muscarinic ACh receptor:
- Decrease humor secretor
- Contraction of ciliary muscles
- Focus for near vision
- Open canal of Schlemm
- Reduce intraocular pressure
36
ANS regulation of the eye: sympathetic
Pupil Dilation via alpha adrenergic receptor:
- Increase humor secretion to increase intraocular pressure
- Sharper focus on distant objects --> fight or flight
37
M1 receptor
```
NT: Cholinergic
Type: muscarinic
Sub-type: 1
Location: Nerve endings
Mechanism: Gq-coupled
Major Functions: inc IP3, DAG cascade
```
38
M2 receptor
```
NT: cholinergic
Type: muscarinic
Sub-type: 2
Location: heart, some nerve endings
Mechanism: Gi-coupled
Major Functions: dec cAMP, activate K+ channels
```
39
M3 receptor
```
NT: cholinergic
Type: muscarinic
Sub-type: 1
Location: effector cells - smooth muscle, glands, endothelium
Mechanism: Gq-coupled
Major Functions: inc IP3, DAG cascase
```
40
Nn receptor
```
NT: cholinergic
Type: nicotinic
Sub-type: N
Location: ANS ganglia
Mechanism: Na-K ion channel
Major Functions: depolarizes, evoke AP
```
41
Nm receptor
```
NT: cholinergic
Type: nicotinic
Sub-type: M
Location: neuromuscular end plate
Mechanism: Na-K ion channel
Major Functions: depolarizes, evoke AP
```
42
Alpha 1 receptor
NT: adrenergic - ACh
Type: alpha
Sub-type: 1
Location: effector tissues - smooth muscle, glands
G protein: Gq
2nd Messenger: inc IP3, DAG
Major Functions: inc Ca --> causes contract, secretion
43
Alpha 2 receptor
NT: adrenergic - ACh
Type: alpha
Sub-type: 2
Location: nerve endings, some smooth muscle
G protein: Gi
2nd Messenger: dec cAMP
Major Functions: dec NT release (nerves) --> causes contract (muscle)
44
Beta 1 receptor
NT: adrenergic - ACh
Type: Beta
Sub-type: 1
Location: cardiac muscle, juxtaglomerular apparatus
G protein: Gs
2nd Messenger: inc cAMP
Major Functions: inc heart rate/force; inc renin release
45
Beta 2 receptor
```
NT: adrenergic - ACh
Type: beta
Sub-type: 2
Location: smooth muscle, liver, heart
G protein: Gs
2nd Messenger: inc cAMP
Major Functions: relax smooth muscle; inc glycogenolysis; inc heart rate/force
```
46
Beta 3 receptor
```
NT: adrenergic - ACh
Type: beta
Sub-type: 3
Location: adipose cells
G protein: Gs
2nd Messenger: inc cAMP
Major Functions: inc lipolysis
```
47
Dopamine 1 receptor
```
NT: adrenergic - dopamine
Type: dopamine
Sub-type: 1
Location: smooth muscle
G protein: Gs
2nd Messenger: cAMP
Major Functions: Relax renal vascular smooth muscle
```
48
ANS effect on:
| Radial muscle of iris (eye)
Sympathetic
- Action: Contracts
- Receptor: alpha 1
Parasympathetic
- Action: none
- Receptor: none
49
ANS effect on:
| Circular muscle of iris (eye)
Sympathetic
- Action: none
- Receptor: none
Parasympathetic
- Action: contracts
- Receptor: M3
50
```
ANS effect on:
Ciliary muscle (eye)
```
Sympathetic
- Action: relaxes
- Receptor: beta
Parasympathetic
- Action: contracts
- Receptor: M3
51
```
ANS effect on:
SA node (heart)
```
Sympathetic
- Action: accelerates
- Receptor: beta 1 and 2
Parasympathetic
- Action: decelerated
- Receptor: M2
52
```
ANS effect on:
Ectopic pacemakers (heart)
```
Sympathetic
- Action: accelerates
- Receptor: beta 1 and 2
Parasympathetic
- Action: none
- Receptor: none
53
ANS effect on:
| Contractility (heart)
Sympathetic
- Action: increases
- Receptor: beta 1 and 2
Parasympathetic
- Action: decreases
- Receptor: M2
54
ANS effect on:
| Skin, splanchnic vessels
Sympathetic
- Action: contracts
- Receptor: alpha
Parasympathetic
- Action: none
- Receptor: none
55
ANS effect on:
| Skeletal muscle vessels
Sympathetic
- Action: relaxes or contracts
- Receptor: beta 2 or alpha
Parasympathetic
- Action: none
- Receptor: none
56
ANS effect on:
| Bronchiolar smooth muscle
Sympathetic
- Action: relaxes
- Receptor: beta 2
Parasympathetic
- Action: contracts
- Receptor: m3
57
ANS effect on:
| Smooth muscle walls (GI)
Sympathetic
- Action: relaxes
- Receptor: beta 2
Parasympathetic
- Action: contracts
- Receptor: m3
58
ANS effect on:
| Smooth muscle sphincters (GI)
Sympathetic
- Action: contracts
- Receptor: alpha 1
Parasympathetic
- Action: relaxes
- Receptor: m3
59
ANS effect on:
| Secretion (GI)
Sympathetic
- Action: inhibits
- Receptor: alpha 2
Parasympathetic
- Action: increases
- Receptor: m3
60
```
ANS effect on:
Myenteric plexus (GI)
```
Sympathetic
- Action: none
- Receptor: none
Parasympathetic
- Action: activates
- Receptor: m1
61
ANS effect on:
| Bladder wall
Sympathetic
- Action: relaxes
- Receptor: beta 2
Parasympathetic
- Action: contracts
- Receptor: m3
62
ANS effect on:
| Sphincter (uro)
Sympathetic
- Action: contracts
- Receptor: alpha1
Parasympathetic
- Action: relaxes
- Receptor: m3
63
ANS effect on:
| Uterus, pregnant
Sympathetic
- Action: relaxes or contracts
- Receptor: beta 2 or alpha
Parasympathetic
- Action: contracts
- Receptor: m3
64
ANS effect on:
| Penis, seminal vesicles
Sympathetic
- Action: ejaculation
- Receptor: alpha
Parasympathetic
- Action: erection
- Receptor: m
65
ANS effect on:
| Pilomotor smooth muscle (skin)
Sympathetic
- Action: contracts
- Receptor: alpha
Parasympathetic
- Action: none
- Receptor: none
66
ANS effect on:
| Thermo sweat glands (skin)
Sympathetic
- Action: increases
- Receptor: m
Parasympathetic
- Action: none
- Receptor: none
67
ANS effect on:
| Apocrine/Stress sweat glands (Skin)
Sympathetic
- Action: increases
- Receptor: alpha
Parasympathetic
- Action: none
- Receptor: none
68
ANS effect on:
| Liver
Sympathetic
- Action: gluconeogenesis or glycogenolysis
- Receptor: alpha and beta 2
Parasympathetic
- Action: none
- Receptor: none
69
ANS effect on:
| Fatcells
Sympathetic
- Action: lipolysis
- Receptor: beta 3
Parasympathetic
- Action: none
- Receptor: none
70
ANS effect on:
| Kidney
Sympathetic
- Action: renin release
- Receptor: beta 1
Parasympathetic
- Action: none
- Receptor: none
71
ANS effect on:
| Sympathetic nerve endings
Sympathetic
- Action: none
- Receptor: none
Parasympathetic
- Action: decreases. NE release
- Receptor: M
72
ANS effect on:
| Parasympathetic nerve endings
Sympathetic
- Action: decreases ACh release
- Receptor: alpha
Parasympathetic
- Action: none
- Receptor: none
73
In fight or flight, sympathetic nerves inc the ___ (firing rate) to release more norepinephrine
Tone
74
Norepinephrine activates ___ receptors.
Adrenergic
75
Modes of indirect action on adrenergic receptors
Influencing NT:
1. Synthesis
2. Degradation
3. Transport
76
What is sympathetic tone?
Rate of SANS firing
77
Which organs respond to flight-or-flight?
- Cardio: heart and different vessels
- Lungs: airway smooth muscle
- Eye
78
Norepinephrine is released by the ___ throughout the body.
Nerves
79
Epinephrine is released by the ___ ___ and goes everywhere
Adrenal gland
80
Adrenergic synapse mechanism
1. Tyrosine enters the presynaptic terminal via membrane bound receptor
2. Converted to DOPA via tyrosine hydroxydase
3. Converted to Dopamine
4. Converted to norepinephrine and packaged into vesicles
5. Influx of Ca due to channel opening from AP
6. NE released from vesicles into synaptic cleft via exocytosis
7. NE binds to alpha or beta receptors on target cell
8. NE leftover in cleft binds to presynaptic alpha-2 receptor for negative feedback (inhibition of NE release) OR
9. Reuptake into presynaptic cell for repackaging OR
10. Degraded in target cell by monoamine oxidase
81
Drug that targets tyrosine hydroxylase
Metyrosine
82
Function of metyrosine
Targets tyrosine hydroxylase, which is involved in conversion of tyrosine to dopa, a step in NE synthesis
83
Drug that targets NE vesicles
Reserpine
84
Drug that interferes with NE reuptake
Cocaine
85
Types of drugs that interfere with target cell receptors
Agonists and antagonists
86
Drugs that interfere with MAO
MAO inhibitors
87
Function of MAO inhibitors
Inhibit the function of MAO, which degrades NE
88
What would be the effect of alpha-2 receptor inhibition on sympathetic outflow & why?
Increase. Alpha-2 is responsible for presynaptic inhibition, so inhibition of inhibition equals stimulation.
89
Classes of adrenergic receptors
alpha and beta
90
Subclasses of adrenergic receptors
- Alpha: 1 and 2
| - Beta: 1, 2, and 3
91
Localization and function of alpha-1 receptors
Vascular smooth muscle in skin and gut: Activation constricts vessels
92
Localization and function of alpha-2 receptors
1. Presynaptic: decreases NE release
2. Brainstem: activation decreases sympathetic outflow
3. Kidney (JG) cells: decreases renin release
4. Vascular endothelium: activation increases release of NO
5. Direct vasoconstriction is minimal
93
Localization and function of beta-1 receptors
1. Heart: increases pacemaker activity, conduction velocity, and contractility = increased cardiac output
2. Kidney (JG cells): increases renin release
94
Localization and function of beta-2 receptors
1. Vascular smooth muscle of vessels in skeletal muscle, heart, and brain: activation relaxes
2. Smooth muscle in airways: activation relaxes
95
Localization and function of beta-3 receptors
Fat cells increase of metabolism
96
What are the differences between adrenergic alpha 1 and 2 receptors?
1. Different gene products
2. Different localization in cells (pre/post synaptic) and tissues
3. They activate different G proteins.
97
G protein adrenergic receptor signaling mnemonic
QISSS
Alpha-1: Gq
Alpha-2: Gi
Beta: Gs
98
Gq mechanism
Effector enzyme: Adenylate cyclase
2nd Messenger: in cAMP
Example effect: inc heart rate
99
Gi mechanism
Effector Enzyme: adenylate cyclase
2nd Messenger: dec cAMP
Example effect: dec heart rate
100
Gs mechanism
Effector enzyme: Phospolipase C
2nd Messenger: inc IP3, DAG, Ca2+
Example effect: vasoconstriction
101
Flight-or-Flight response
Autonomic reflex:
1. CNS sense danger and activates ANS
2. Redirection of blood to brain, skeletal muscle, heart, and away from gut/skin.
3. Airways dilate, energy production increased.
4. Temp inc as muscle work
5. Vision adjusts for distant objects
102
Assuming only direct effect of epinephrine, how will it influence blood pressure?
- Inc BP
- Inc cardiac output
- Stronger effect on alpha1-rich blood vessels in skin and gut
- Effect of vasodilation in other blood vessels via beta-2 receptors is less
103
NE agonist receptor selectivity
Somewhat selective: a1=a2=b1>>b2
104
NE agonist a1 mechanism
Vasoconstriction: skin, gut
105
NE agonist a2 mechanism
dec:
- sympathetic outflow
- NE release
- renin release
- vasodilation
106
NE agonist b1 mechanism
inc:
- cardiac output
- renin release
107
NE agonist b2 mechanism
doesn't really influence so little vasodilation in skeletal muscle, brain
108
Effect of NE agonist
- Inc cardiac output
- inc BP
- subsequent vasovagal reflex
109
EPI agonist receptor selectivity
Non-selective: a1=a2=b1=b2
110
Epi agonist a1 mechanism
Vasoconstriction: skin, gut
111
Epi agonist a2 mechanism
dec:
- sympathetic outflow
- NE release
- renin release
- vasodilation
112
Epi agonist b1 mechanism
inc:
- cardiac output
- renin release
113
Epi agonist b2 mechanism
Dec dilation of the fight/flight vessels: those in the brain, heart, and skeletal muscle
114
Effect of Epi agonist
- Inc cardiac output
| - Inc BP (but not as strong as w/ NE)
115
Use of sympathomimetics in CV system
- Enhance blood flow and pressure
- Hypotension
- Shock
- Heart emergency management
- Reduce blood flow
- In surgery, together w/ anesthetic
- Decongestants
116
Use of sympathomimetics in Anaphylaxis
- Intramuscular epi prior to anti-histamines and glucocorticoids
- Epi to treat bronchospasm, suppress mucus membrane secretion, etc
117
Use of sympathomimetics in asthma
Bronchodilation
118
Use of sympathomimetics in CNS
- Amphetamines treat narcolepsy
| - Ritalin for ADD/sharpen concentration
119
Why is epinephrine used in surgery?
- Causes local vasoconstriction by acting on skin vessel a1 receptors
- Reduces bleeding
120
Clonidine - drug type
Highly selective a2 receptor agonist
121
Clonidine - mechanism
Presynaptic inhibition:
- drop in NE release
- dec sympathetic outflow
- dec rening release
Postsynaptic:
- inc vasoconstriction: little contribution
122
Clonidine - use
Decreased BP
123
What effect would a sudden drop in dose of clonidine have on patient?
High BP crisis:
- a2 receptor desensitized by continuous presence of agonist
- NE in synapse not enough to self-inhibit release
- Sympathetic outflow will be strong
- Peripheral vasoconstriction and HTN
124
Which sympathomimetics are not agonists?
Cocaine and tyramine
125
Mechanism of cocaine
Blocks re-uptake of NE --> NE effects lasts longer
126
Mechanism of tyramine
MAO inhibitors --> accumulation of tyramine --> spike in BP --> (maybe) drop in BP
127
Non-catecholamine sympathomimetics
- Pseudoephedrine
- Phenylephrine
- Amphetamine
128
Pseudoephedrine
- decongestant
| - high bioavailability
129
Phenylephrine
- a1 agonist
| - decongestant
130
Amphetamine
- Not catecholamine: enters CNS easily
- Strong stimulator.
- Inc activity
- Inc false sense of well-being
- suppresses appetite (anorexic)
Mechanism:
1. Takes place of catecholamine in vesicles
2. Promotes release of NE into cleft
3. Depletion of NE stores
4. "Crash" until NE is re-synthesized and restored
131
Adrenergic agonists selective for b2
- Albuterol
- Tertbutaline
- Salmeterol
132
Albuterol
bronchodilation
133
Why is activation of b2 adrenergic receptor beneficial in asthma?
- B2 abundant in smooth muscle airways
| - Elevate cAMP --> bronchodilation
134
Adrenergic antagonists
Reduce demand for O2 not by reducing load (systemic BP) but by reducing heart rate
135
Propanolol
Adrenergic antagonist selective for beta
Blocks:
- b1: dec cardiac output/renin release
- b2: vasoconstriction in skeletal muscle, bronchoconstriction
Result: dec BP
136
How can propanolol influence a person with asthma?
Worsen condition of precipitate an attack
Non-selective beta-blocker --> antagonize b2 receptors --> prevent bronchodilation
137
Adrenergic antagonists, b1 selective
- Metoprolol
| - Atenolol
138
Mechanism of B1 blocker
- dec cardiac output
| - dec renin release
139
Effect of B1 blocker
dec BP
* better for asthma since does not affect b2 so keeps bronchodilation in place
140
A1-selective antagonists
- Prazosin
| - Terazosin
141
Mechanism of a1-selective antagonists
- Blocks sympathetic tone and vessel constriction in large vascular beds of skin and gut
- Lowers resistance to blood flow
142
Effect of a1-selective antagonists
Dec BP
143
Non-selective Alpha antagonist
Phentolamine
144
Fight/Flight in eye
beta receptors in ciliary epithelium:
- inc humor secretion
- inc intraocular pressure
- sharper focus on distant objects
- via beta receptors
alpha agonist:
- allow more light to enter eye
- open pupil via dilator muscle
- Myadriasis
145
Myadriasis
pupil dilation
146
What will happen with the pupil upon inhalation of conn?
Dilation (mydriasis)
- Block reuptake of NE at dilator muscle
- Constriction via alpha AR, Gq, Ca
147
Mnemonic for PNS
DUMBELLS:
- Diarrhea
- Urination
- Miosis (pupil contraction)
- Bronchospasm
- Emesis
- Lacrimation
- Salivation
148
Does the PNS innervate all tissues?
No, very few blood vessels are innervated by it.
149
What is the main NT of PNS?
Acetylcholine ACh
150
Name of receptors that use ACh
Cholinergic
151
Cholinergic synapse mechanism
1. AP to synaptic terminal
2. Opening of Ca channels for Ca influx
3. ACh vesicle exocytosis
4. ACh release into cleft
5. ACh bind to target cell receptor & induce function
6. ACh bind to presynpatic receptor for NE release inhibition
7. ACh degradation by acetylcholinesterase into acetate and choline
8. Choline reuptake in presynaptic terminal
9. ACh re-synthesize and repackaged
152
Vesamicol
Inhibit ACh packaging into vesicles
153
Acetylcholinesterase inhibitors
Neostigmine, Sarin
154
Direct acting cholinomimetics
- Nicotine: tobacco
- Muscarine: poisonous mushrooms
- Pilocarpine: plant - induce salivation/sweating
155
First NT discovered
ACh
156
Synthetic cholinergic agonists
- Carbachol
| - Methacholine
157
Carbachol
Cholinergic agonist
- Not sensitive to acetylcholine esterase
- lower muscarine action
- same nicotinic action
158
Methacholine
Cholinergic agonist
- lower sensitivity to acetylcholine esterase
- inc muscarinic action
- no nicotinic action
159
Indirect cholinomimetics - action
Inhibit acetylcholine degradation --> effect similar to agonist
160
Cholinesterase inhibitors
Indirect cholinomimetics
- Edrophonium
- Neostigmine
- Organophosphates: isoflurophate
161
Edrophonium Action
Cholinesterase inhibitor
- Reversible
- Binds to AChesterase enzyme
- Competes with ACh
162
Neostigmine Action
Cholinesterase inhibitor
- Reversible
- Hydrolyzed very slowly
- Use myasthenia gravis (reduction of nicotinic ACh receptors)
163
Organophosphates (Isoflurophate)
Cholinesterase inhibitor
- Irreversible
- Covalently attaches to a Set residue in active center of AChesterase
164
Malathion
Cholinesterase inhibitor
- Insecticide
- Metabolized in mammals but not insects
- Toxic in large doses
165
Sarin
Cholinesterase inhibitor
| - Chemical weapon
166
Cholinergic receptors and mechanism
- Nicotinic: ligand-gated ion channels
| - Muscarinic: GPCRs
167
M2 and M4 action
- G protein: Gi
- Effector enzyme: adenylate cyclase
- 2nd messenger: dec cAMP
- example effect: dec heart rate
168
M1, M3, and M5 action
- G protein: Gq
- Effector Enzyme: phospholipase C
- 2nd messenger: inc IP3, DAG, Ca2+
- example effect: smooth muscle contraction
169
Gq cascade
A1, M1, M3, M5
- Effector enzyme: Phospholipase C
- 2nd messenger: inc IP3, DAG, Ca2+
Example effects:
- vasoconstriction (SANS)
- smooth muscle contraction (PANS)
170
Gi cascade
A1, M2, M4
- Effector enzyme: adenylate cyclase
- 2nd messenger: dec cAMP
Example effects:
- dec heart rate (SANS/PANS)
171
Gs cascade
B1-3
- effector enzyme: adenylate cyclase
- 2nd messenger: inc cAMP
Example effect:
- inc heart rate (SANS only)
172
Muscarinic receptors location
- M1/4/5: brain
- M2: heart, presynaptic nerve terminals in lung
- M3: GI, glands, smooth muscle in airways, vasculature
173
M2 location
- Heart: activation dec pacemaker activity, conduction velocity, and contractility
- Presynaptic nerve terminals in lung (Asthma = too much ACh)
174
M3 location
- GI: motility (rest/digest)
- Glands: stimulates secretion
- Airway smooth muscle: contraction
- Vasculature: activation --> dilation
175
Effect of cholinesterase inhibitors on CV
Examples: edrophonium, neostigmine
Ganglia:
- Strengthen PANS (M2)
- Weaken SANS (B1/2)
- Result: presynaptic inhibition of NE release
- Clinical effect: bradycardia
Blood vessels:
- Few innervated by cholinergic neurons
- Direct effect minimal
- Constant BP (or small reduction)
176
Effect of direct cholinomimetics on CV
Example: bethanecol
Heart:
- Slowing heart rate via M2 directly
- Presynaptic inhibition of sympathetic fibers
- Baroreflex: sense vasodilation (M3 on blood vessels) and causes sympathetic stimulation
Blood vessels:
- M3 in smooth muscle contracts via Gq and Ca inc
Endothelial cells:
- M3 activation --> NO release --> smooth muscle relaxation
Endothelial>blood vessel so relaxation more prevalent
177
Effect of muscarinic receptors on smooth muscle and endothelial cells
M3 Activation causes opposite contractility
- Smooth blood vessels: contraction
- Endothelial: relaxation
178
Muscarinic agonists
- Acetylcholine
- Pilocarpine
- Bethanechol
- Muscarine
179
Major effects of muscarinic agonists on CV
```
M1=M2=M3=M4=M5
dec heart rate
+ inc NO release by endothelium
= bradycardia + hypotension
*This is toxic
```
180
Excessive activation of muscarinic receptors
Example: mushrooms with muscarine
- M2: Bradycardia
- M3: Bronchoconstriction, GI motility, Pupil constriction, Sweating, Salivation, and vasodilation
181
Clinical relevance of Cholinergic stimulation in eye
- Stimulation of m3 receptors in glands
- Dry eye and mouth syndrome
- Pilocarpine
- Treatment of glaucoma w/ topical pilocarpine
182
Clinical relevance of cholinergic stimulation in pulmonary
- Metacholine test to diagnose asthma
| - Bronchioles overreact in a person with asthma
183
Clinical relevance of cholinergic stimulation in GI/urinary tracts
- stimulate peristaltic and secretory activity
- overcome urinary retention
- bethanecol
184
Clinical relevance of cholinergic stimulation in NMJ
- Neostigmine to diagnose myasthenia gravis
185
PNS regulation of the eye
1. Diagnostics
- Miosis (pupil contraction) via MR
- Indicate organophosphate intoxication, muscarine poisoning, brain injury, drug overdose, etc.
2. Glaucoma pharmacotherapy
- Cholinomimetics: pilocarpine
- stimulate contract of ciliary muscle
- opening of canal of schlemm
- reduce intraocular pressure (IOP)
- Suppression of SANS terminals
- Dec humor secretion
186
Cholinergic receptor antagonists
- Act on all muscarinic receptors
- multiple effects on CNS/PNS
- Can be overcome by muscarinic agonists
- Example: Scopolamine and Atropine
187
Clinical use of cholinergic-blocking drugs in CNS
Some patients: blocking ACh receptors works for Parkinson's by blocking tremors
188
Clinical use of cholinergic-blocking drugs in GI
- Main: suppress emesis
| - Scopolamine: motion sickness, amnesia
189
Clinical use of cholinergic-blocking drugs in eye
- Atropine: long-term mydriasis (open pupil) for examination
** do not use to diagnose narrow-angle glaucoma
190
Clinical use of cholinergic-blocking drugs in CV system
- Hypertension
- Trimethaphan: nicotinic antagonist
- Used to block sympathetic system at ganglionic level
- Block sympathetic outflow --> vasodilation
- Toxic: orthostatic hypotension + parasynaphtoplegia (constipation, urinary retention, blurred vision, etc)
191
Clinical use of cholinergic-blocking drugs in lung
- Prevent bronchoconstriction
| - Bronchitis, COPD, etc
192
Clinical use of cholinergic antagonists
Peripheral: asthma - inhaled
Central: Parkinson's - suppress tremors
193
Ipratropium
Cholinergic antagonist
- Blocks bronchoconstriction constriction
- Keeps airways open
- Peripheral: Asthma - inhaled
194
Benztropine
Cholinergic antagonist
| - Central effect: Parkinson's suppress tremors
195
What two drugs are used together for asthma
Ipratropium + albuterol
- Albuterol = b2 agonist: stimulate bronchodilation
- Ipratropium: inhibits inhibitor of chronchodilation
