All ANS neurotransmission and pharmacology Flashcards
(98 cards)
1
Q
What are afferent neurons in the peripheral nervous system important for?
A
- Afferent = sensory
- Physiologic control of involuntary organs (reflex arcs, blood pressure, respiration rate)
- Fewer drugs available targeted to these neurons
2
Q
Do most clinically useful drugs for ANS modulation target efferent or afferent neurons?
A
• EFFERENT
3
Q
What are efferent neurons in the peripheral nervous system important for?
A
- Major pathway for information transmission from the CNS to involuntary effector tissues
- Smooth muscle
- Vascular endothelium
- Cardiac muscle
- Exocrine (secretory) glands
- MOST clinically useful ANS drugs target efferent neurons
4
Q
In terms of numbers of neurons, what is different between somatic nervous system and autonomic nervous system?
A
- The number of neurons in the chain of information
- Somatic = single neuron connection
- Autonomic = two neuron connection, pre-ganglionic to post-ganglionic
5
Q
What is special about the adrenal medulla in our discussion of the ANS?
A
• Adrenal medulla is embryologically and functionally a sympathetic ganglion, innervated by typical sympathetic preganaglionic neurons (ach release, so they have cholinergic receptors)
6
Q
Where are the ganglia of the ANS located?
A
- Para - mostly on or in the innervated organs
- Symp - two paravertebral chains along spinal cord or prevertebral ganglia in abdomen
- Adrenal medulla is embryologically and functionally a sympathetic ganglion, innervated by typical sympathetic preganaglionic neurons
7
Q
From where in the CNS does the parasympatic and sympathetic nervous system originate?
A
- Para - cranial nerve nuclei (tectal region of brain stem) and sacral segments of spinal cord (S2-4)
- Symp - thoracic and lumbar segments of spinal cord (T1-12), L1-5
8
Q
What is different about the para and symp nervous system neuron ratios?
A
- Ratio of pre-ganglionic to post-ganglionic
- PNS is usually 1:1, so it funcitons in a discrete or localized fashion
- SNS ratio is more like 1:20-50 (way more widespread in action/function)
9
Q
If the neuron has the name “cholinergic” what does that mean?
A
• Acetylcholine is the NT used at that synapse
If the neuron is called “adrenergic” what does that mean?
• Norepinephrine is released from that neuron
10
Q
What are the two types of cholinergic receptor?
A
• Nicotinic and muscarinic
11
Q
What are the two types of adrenergic receptor?
A
• Alpha and beta adrenergic receptors
12
Q
What is the PNS NT and it’s receptors?
A
• PNS = parasympathetic nervous system • Pre-ganglionic ○ Ach, at ganglia ach is bound by nicotinic cholinergic receptors (N-n) ○ Same as in SNS • Post-ganglionic ○ Ach, end organs ach is bound by muscarinic cholinergic receptors ○ M1-5) ○ Heart, lungs, GI, GU, eye
13
Q
What are the SNS NT’s and receptors?
A
• Preganglionic
○ Ach, at ganglia and adrenal medulla ach with nicotinic cholinergic receptors - same as PNS
• Postganglionic
○ NE - effector organs, with alpha1-adrenergic and beta1-adrenergic receptors
§ Alpha1 = blood vessels, eye, GI
§ Beta1 = heart
○ Super low affinity for beta2
○ Ach - sweat glands with muscarinic cholinergic receptors
○ DA - renal vascular smooth muscle cells with D1 receptors
• Adrenal medulla
○ Releases EPI (epinephrine) and some NE into general circulation that interacts at adrenergic synapses with alpha1, beta1 and beta2 receptors
14
Q
What adrenergic receptors bind epinephrine?
A
- Released from adrenal medulla
- Alpha1, beta1, beta2 all are capable of binding epinephrine
- Thus the wide-reaching effects
15
Q
While most organs are dually innervated by the PNS and SNS, what is the most notable and important exception?
A
- Blood vessels are only innervated by sympathetic nervous system
- Thus, having parasympomimetics will not do much to the blood vessels
- You either have to antagonize the sympathetic nervous system OR agonize it
- They do possess non-innervated muscarinic cholinergic receptors though that can be utilized in pharmacologic therapy
16
Q
While the PNS and SNS usually exert opposite effects, what is the notable exception?
A
- Salivary glands. Both activate saliva production though just different kinds
- PNS - profuse and watery
- SNS - scant and viscous (dry mouth)
17
Q
While most organs have predominant parasympathetic tone, what is the notable exception?
A
• Blood vessels. They have sympathetic tone
18
Q
What are the diffuse symptoms of an activated sympathetic nervous system?
A
- Increased heart rate
- Increased blood pressure
- Blood flow shifts from skin and splanchnic regions to skelatal muscles
- Rise in blood glucose
- Dilation of broncioles and pupils
- Decrease in activity of GI and GU systems
19
Q
What are the 5 tissue effects of muscarinic receptors at postganglionic effector organs?
A
• Cardio - decreased heart rate and av conduction rate, vasodilation (indirect from NO and increased cGMP), decreased blood pressure
○ Muscarinic receptors are not innervated and activation of PNS does not result in vasodilation
• Respiratory - bronchial muscle contraction, stimulation of mucus glands
• GI - increase in secretions and motor activity, relaxation of sphincters
• GU - promotes voiding b/c of detrusor muscle contraction and sphincter muscle relaxation
• Eye - miosis or pupil constriction, accomodation, outflow of aqueous humor
20
Q
What are the broad effects of nicotinic neuronal receptors being activated at autonomic ganglia?
A
- Cardio - chiefly sympathetic effects (vasoconstriciton, tachycardia, elevated BP)
- GI/GU - parasympathetic effects (nausea, vomiting, diarrhea, urination)
21
Q
What kind of receptor is the alpha1 adrenergic receptor?
A
- Adrenergic = NE or EPI
- Sympathetic nervous system
- Alpha1 = Gq - activates PLC which forms IP3 which raises intracellular calcium and activates DAG, activating PKC
- End result is smooth muscle contraction - often a rise in total peripheral resistance
22
Q
What kind of receptor is the beta-adrenergic receptor?
A
- Adrenergic = NE or EPI
- Sympathetic nervous system
- Beta1 and Beta2 are Gs - stimulate AC, increasing cAMP levels, activating PKA
- Beta1 also stimulates calcium movement through L-type calcium channels
- End result is smooth muscle contraction
23
Q
What kind of receptor is the alpha2 adrenergic receptor?
A
- Adrenergic = NE or EPI
- Sympathetic nervous system
- Alpha1 = Gi - inhibits AC, which reduces cAMP and/or opens K channels, leading to hyperpolarization and less nerve firing
- Also couples to Go which inhibits calcium movement through ion channels
- End result is smooth muscle relaxation, or inhibition of whatever alpha1 does
24
Q
What role, besides increasing cAMP levels, does activation of the beta1-adrenergic receptor have? (think Ca)
A
Beta1-adrenergic receptor activation (by epi way more than NE) will increase cAMP levels (Gs protein) and will INCREASE Ca conductance through L-type calcium channels
25
What kind of drugs are able to by-pass the BBB and enter the CNS?
• Lipid-soluble tertiary agents
| * quarternary agents are permenantly charged and cannot enter CNS
26
What are the physiologic effects mediated by activation of peripheral adrenergic receptors in the vasculature?
* Effects are either alpha1 or beta2 mediated
* Alpha1 = vasoconstriction
* Beta2 = vasodilation
* The effect of a given drug will depend directly on receptor densities for the tissue in question
* Cutaneous, mucous membranes, splanchnic vasculature - primarily alpha1, thus vasoconstriction and increase in TPR
* Skelatal muscle - has both, but with pharmacological levels of epi, you can activate beta2 receptors enough to decrease TPR
* Renal vasculature - dopamine mediated relaxation is balanced by alpha1 constriction
* Coronary - physiological levels of catecholamines tend to increase blood flow
27
What are the physiologic effects mediated by activation of peripheral adrenergic receptors in the heart?
* Direct effects on the heart are largely mediated by Beta1 receptors
* Small beta2 and alpha1 as well
* SA node - positive chronotropy
* AV node - increased conduction velocity
* Atrial and ventricular cardiac muscle - positive inotropy
28
What do each of the 4 adreneric receptors do to blood pressure?
* Alpha1 - vasoconstriction, increasing TPR and BP causing reflex bradycardia
* Alpha2 - decrease in SNS outflow causing a decrease in BP (via action in CNS)
* Beta1 - increased heart rate and increased force of contraction increases CO and BP
* Beta2 - vasodilation decreases TPR and BP causing reflex tachycardia
29
What broad effects in the CNS does the activation of Nicotinic neuronal receptors have
• N-n receptor activation in the CNS
• Mild alerting effect
○ Tremor, emesis, respiratory stimulation
• Activates reward pathway
○ Limbic system, contributes to addiction
• Convulsions (toxic doses)
30
What is bethanechol?
• Cholinergic, muscarinic agonist
* would have the effect of acting like a parasympathetomimetic
* synthetic analog of ach
* can be specific for muscarinic receptors and can be slightly resistent to ache hydrolysis
31
What is the difference between an indirect and direct agonist?
direct - binds and activates the receptor
| indirect- somehow increases the amount or activity of the neurotransmitter (NT)
32
At the level of the effector organ, is cholinergic PNS or SNS? Adrenergic?
cholinergic = PNS
adrenergic = SNS
*at the level of the effector organ
*cholinergic receptors are for ach, which only postganglionic parasympathetic neurons release at effector organs
*adrenergic receptors are for NE and EPI, which are postganglionic sympathetic neuron release
33
What class of drug is Pilocarpine?
cholinergic agonist (muscarinic)
* it is an analog of ach
* naturally occuring alkaloid that acts with strong selectivity for muscarinic receptors
* highly lipophilic so it gets everywhere?
34
What class of drug is Bethanechol?
cholinergic agonist (muscarinic)
35
What class of drug is Neostigmine?
cholinergic agonist - indirect - ache inhibitor
36
What class of drug is pyridostigmine
cholinergic agonist - indirect - ache inhibitor
37
What receptors are important for Adrenergic agonists?
alpha1, beta1, beta2 (to a mild extent alpha2)
38
what is meant by the mneumonic SLUDGE BB (basketball)
PNS agonists and the effect on the patient. In toxic doses you add the BB (basketball)
* salivation
* lacrimation
* urination
* defecation
* GI - cramping, nausea, vomiting
* Eye (miosis/constriction)
* Bradycardia
* Bronchorrhea (secretion in the bronchioles is increased)
39
What are the worries you have with organophosphate toxicity?
SLUDGE BB is the rule of thumb with organophosphate toxicity
* the main reason is the high lipophilicity of the organophosphate, which activates N-n receptors in the CNS and also activates both the SNS and PNS in the periphery
* these are irreversible ache inhibitors
40
What is the target of phenylephrine?
alpha1 receptor agonist
*reflex bradycardia
*TPR increase because of smooth muscle contraction
*Alpha1 = Gq - activates PLC which forms IP3 which raises intracellular calcium and activates DAG, activating PKC
• End result is smooth muscle contraction - often a rise in total peripheral resistance
41
With any pharm question in neuro, what is the first questions you need to ask yourself?
What is overactive or underactive? What receptors are being targeted?
42
What is the mneumonic for PNS antagonist effects?
*take SLUDGE BB and reverse it
*dry mouth
*hesitation
*constipation
*pupillary dilation
*blurry vision b/c lack of focusing ability
no pee, no see, no spit, no shit
43
what class of drug is edrophonium?
indirect cholinergic agonist - ache antagonist
44
what class of drug is donepezil?
indirect cholinergic agonist - ache antagonist
45
what class of drug is an organophosphate?
indirect cholinergic agonist - ache antagonist (irreversible)
46
what is important to note about a tertiary ion?
both uncharged and charged species are in existence and thus some will make it into the brain
47
when you see stigmine what do you think?
cholinergic agonists
48
Can you get a depolarization blockade from a muscarinic receptor activation?
• Nope. There are de-sensitization mechanisms in place to keep this from happening
49
what is the most common mechanism of indirect agonist for the SNS?
that would be adrenergic agonist, indirect - in the ANS that is from increasing release of NE
*in the CNS it's reuptake
50
What kind of receptor is M2?
M2 and M4 are Gi or Go receptors
* ach receptors, decrease AC activity, increase K influx and decrease Ca conductance
* important in the heart and CNS
51
what class of drug is atropine?
cholinergic antagonist, direct muscarinic receptor block
52
what class of drug is scopolamine?
cholinergic antagonist, direct muscarinic receptor block
53
what class of drug is benztropine
cholinergic antagonist, direct muscarinic receptor block
54
what class of drug is oxybutynin
cholinergic antagonist, direct muscarinic receptor block
55
what class of drug is tolterodine
cholinergic antagonist, direct muscarinic receptor block
56
what class of drug is ipratroprium
cholinergic antagonist, direct muscarinic receptor block
57
what class of drug is tiotropium
cholinergic antagonist, direct muscarinic receptor block
58
Why does an M3 receptor lead to vasodilation?
• Gq receptor on the endothelial cell will end up leading to NO release which in turn will relax associated blood vessels
59
what does an adrenergic agonist do to GI motility?
adrenergic agonist will decrease GI motility.
| *remember that BB SLUDGE shows that overactive PNS is diarrhea, so the opposite is what an adrenergic agonist would do
60
what is the consequence of overstimulating N-m receptors?
depolarization block and skeletal muscle paralysis
61
what does pralidoxime do?
treatment for NMJ overactivity, it will treat depolarization block and skeletal muscle block
62
what is the result of over-stimulation of N-n receptors?
seizures, treated with diazepam
63
What is succinylcholine used for?
a NMJ blocker. causes depolarization block with rapid onset and rapid termination (diffusion)
* too big for ache, so it stays longer than ach alone
* two ach bridged together
64
what is the mneumonic for the adverse reactions for overactive nicotinic receptors?
```
MATCH
Muscle weakness N-m
Adrenal medulla activity increase - N-n
Tachycardia N-n
Cramping of skeletal muscle N-m
Hypertension N-n
```
65
what does pralodoxime do (mechanism)?
cholinesterase regenerator, increases Ach breakdown and termination of the cholinergic signal
66
What class of drug is atracurium?
cholinergic antagoinst, N-m receptor direct
67
what class of drug is rocuronium?
cholinergic antagoinst, N-m receptor direct
68
In general, when do you use an adrenergic antagonist?
• Chronic, increased cholinergic activity
69
In general, when do you use cholinergic agonists?
• For ACUTE, decreased cholinergic activity
70
When, in general, do you use adrenergic agonists?
acute decreased activity
| *according to French it's not a great idea to goose a system for a long time
71
have you teased out the adrenergic agonist slide yet?
it's marked with a memorize this slide tag
72
What is the major action that terminates the synaptic activity of norepinephrine?
• Reuptake into neuron by NE transporter (NET) on nerve terminal
73
what are actions of the beta1 receptor?
Actions of the β1 receptor include:
stimulate viscous, amylase-filled secretions from salivary glands
Increase cardiac output
Increase heart rate[5] in sinoatrial node (SA node) (chronotropic effect)
Increase atrial cardiac muscle contractility. (inotropic effect)
Increases contractility and automaticity[5] of ventricular cardiac muscle.
Increases conduction and automaticity[5] of atrioventricular node (AV node)
Renin release from juxtaglomerular cells.[5]
Lipolysis in adipose tissue.[5]
Receptor also present in cerebral cortex.
74
What might Beta1 adrenergic stimulation result in?
* Increase in cardiac output
| * Common treatment during acute heart failure
75
What do the alpha1 and beta2 adrenergic receptors do in the respiratory tract?
* Bronchial smooth muscle dilates via beta2 receptors
| * Mucosal blood vessels constrict with alpha1 activation
76
What receptor should be activated to get pupillary dilation?
• Mydriasis = dilation, happens through constriction of radial pupillary dilator muscle
• Alpha1 receptor activation results in dilation
In terms of aqueous humor, what receptors are important?
• IOP = intraocular pressure
• Major effect - increased production via beta2 receptors, increasing IOP
• Minor effect - increased outflow via alpha1 receptors causing vasoconstriction and decreased IOP
77
What does beta2 receptor activation cause in skeletal muscle?
* Marked tremor
* Action on contractile proteins via beta2 receptors
* Causes increased blood glucose
78
What do antimuscarinics, neuromuscular blockers and ganglionic blockers all have in common?
* They are cholinergic antagonists, just have different names when directed at different places
* PNS end organs - antimuscarinic
* NMJ - neuromuscular blockers
* Ganglionic blockers - autonomic ganglia
79
What does hemicholinium do?
* This is the drug that blocks the choline active transport system
* Dependent on sodium and is the rate limiting step for re-uptake in the ach NT system
80
What drug can block the storage of Ach in a quantal vesicle?
• Vesamicol blocks ach vesicular packaging
81
Ach release from the nerve terminal upon influx of calcium can be blocked by what substances?
* Botulinum toxin
| * Black widow spider toxin
82
What neuronal mechanism can modulate the release of ach?
• If NE interacts with the alpha2 heteroreceptor, this tells the presynaptic cholinergic neuron to decrease ach release
83
What is the drug Butyrylcholinesterase supposed to do?
* "pseudo" cholinesterase
* Widely distributed, non-neuronal tissues and serum
* Biological function UNKNOWNS
* It does hydrolyze longer chain esters like succinylcholine
* In patients who don't have this enzyme then use of succinylcholine (rare) could be problematic
84
Where do you find M1 receptors?
* M1 receptors are neuronal and are in CNS and ENS and GI glands
* M1 receptors are Gq proteins and increase the activity of PLC
85
Where do you find M3 receptors?
```
• Exocrine glands and smooth muscle
• Gq protein, increases activity of PLC
Where do you find M2 and M4 receptors?
• M2 and M4 are the Gi proteins, which inhibit adenylyl cyclase
• Found in the heart and CNS
```
86
What modifications done to bethanechol can either make it more specific for muscarinic receptors or otherwise make it resistent to ache?
* Adding a methyl group will add selectivity for muscarinic receptors
* Replacing the acetyl group with carbamyl group increases resistence to ache
87
Where in the body would you expect bethanechol to go?
• Low lipid solubility so it stays pretty much in the plasma compartment
88
What does nicotine as a drug do?
• It directly stimulates ganglionic neurons, both in PNS and SNS
• Thus the effects are quite complex
• In the doses achieved by smoking it works as a nicotinic receptor agonist
• Cardio - increase BP, HR, vasoconstriction
○ From EPI release from adrenal gland and subsequent SNS activation
• Gut - increased GI motility
○ Ganglionic stimulation of PNS end organs
• CNS - euphoria, arousal, relaxation, increased attention/learning
89
What do toxic doses of nicotine do?
* May result in depolarization blockade
* Secondary membrane unresponsiveness and thus secondary antagonism
* The end result is that nicotine toxicity will result in a temporary depolarizing blocking agent
90
What is alarming as it is an irreversible ache inhibitor?
* Nerve gas, isofluorophate
| * Organophosphate insectisides
91
What are the two reversible, intermediate to long acting ache inhibitors?
* Neostigmine and phyostigmine
| * Phyostigmine is the lipid soluble one is lipid soluble and the other is less so
92
An antimuscarinic that blocks M1 receptors will have effects in what systems?
* CNS,
* gastric parietal
* SNS postganglionic cells
93
An antimuscarinic that blocks M3 receptors selectively is going to affect the function of what cells?
• Smooth muscle organs and glands
94
An antimuscarinic that blocks M2 receptors selectively is active in what tissue?
• Cardiac tissue
95
What is the rate-limiting step in the biosynthesis of norepinephrine?
* Tyrosine (precursor) conversion to DOPA by tyrosine hydroxylase
* Inhibited by metyrosine
96
What molecule is transported into the catecholamine storage vesicle in the norepinephrine synthesis pathway?
• Dopamine is first packaged in the vesicle and then converted to NE by dopamine beta-hydroxylase
97
What is MAO and where is it?
• In the neuron, attached to mitochondrial membrane
• Degrades norepinephrine and dopamine
Bretylium can block what?
• Release of catecholamines in a ca dependent manner
98
What is the most important termination mechanism in the NE signaling pathway?
* Reuptake of NE into nerve endings by NE transporter
* NET is the transporter
* Some is put back into vesicles, some is degraded by MAO
* Cocaine and tricyclic antidepressents inhibit this process and are indirect adrenergic agonists
* Amphetamines and pseudoephedrine reverse NE transporter, leaving NE in synapse longer
