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Neuro > All ANS neurotransmission and pharmacology > Flashcards

All ANS neurotransmission and pharmacology Flashcards

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
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2
Q

Do most clinically useful drugs for ANS modulation target efferent or afferent neurons?

A

• EFFERENT

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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
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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
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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)

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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
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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
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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)
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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

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10
Q

What are the two types of cholinergic receptor?

A

• Nicotinic and muscarinic

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11
Q

What are the two types of adrenergic receptor?

A

• Alpha and beta adrenergic receptors

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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
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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

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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
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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
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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)
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17
Q

While most organs have predominant parasympathetic tone, what is the notable exception?

A

• Blood vessels. They have sympathetic tone

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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
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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

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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)
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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
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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
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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
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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

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25
Q

What kind of drugs are able to by-pass the BBB and enter the CNS?

A

• Lipid-soluble tertiary agents

* quarternary agents are permenantly charged and cannot enter CNS

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26
Q

What are the physiologic effects mediated by activation of peripheral adrenergic receptors in the vasculature?

A
  • 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
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27
Q

What are the physiologic effects mediated by activation of peripheral adrenergic receptors in the heart?

A
  • 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
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28
Q

What do each of the 4 adreneric receptors do to blood pressure?

A
  • 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
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29
Q

What broad effects in the CNS does the activation of Nicotinic neuronal receptors have

A

• 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)

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30
Q

What is bethanechol?

A

• 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
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31
Q

What is the difference between an indirect and direct agonist?

A

direct - binds and activates the receptor

indirect- somehow increases the amount or activity of the neurotransmitter (NT)

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32
Q

At the level of the effector organ, is cholinergic PNS or SNS? Adrenergic?

A

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

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33
Q

What class of drug is Pilocarpine?

A

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?
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34
Q

What class of drug is Bethanechol?

A

cholinergic agonist (muscarinic)

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35
Q

What class of drug is Neostigmine?

A

cholinergic agonist - indirect - ache inhibitor

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36
Q

What class of drug is pyridostigmine

A

cholinergic agonist - indirect - ache inhibitor

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37
Q

What receptors are important for Adrenergic agonists?

A

alpha1, beta1, beta2 (to a mild extent alpha2)

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38
Q

what is meant by the mneumonic SLUDGE BB (basketball)

A

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)
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39
Q

What are the worries you have with organophosphate toxicity?

A

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
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40
Q

What is the target of phenylephrine?

A

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
Q

With any pharm question in neuro, what is the first questions you need to ask yourself?

A

What is overactive or underactive? What receptors are being targeted?

42
Q

What is the mneumonic for PNS antagonist effects?

A

*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
Q

what class of drug is edrophonium?

A

indirect cholinergic agonist - ache antagonist

44
Q

what class of drug is donepezil?

A

indirect cholinergic agonist - ache antagonist

45
Q

what class of drug is an organophosphate?

A

indirect cholinergic agonist - ache antagonist (irreversible)

46
Q

what is important to note about a tertiary ion?

A

both uncharged and charged species are in existence and thus some will make it into the brain

47
Q

when you see stigmine what do you think?

A

cholinergic agonists

48
Q

Can you get a depolarization blockade from a muscarinic receptor activation?

A

• Nope. There are de-sensitization mechanisms in place to keep this from happening

49
Q

what is the most common mechanism of indirect agonist for the SNS?

A

that would be adrenergic agonist, indirect - in the ANS that is from increasing release of NE
*in the CNS it’s reuptake

50
Q

What kind of receptor is M2?

A

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
Q

what class of drug is atropine?

A

cholinergic antagonist, direct muscarinic receptor block

52
Q

what class of drug is scopolamine?

A

cholinergic antagonist, direct muscarinic receptor block

53
Q

what class of drug is benztropine

A

cholinergic antagonist, direct muscarinic receptor block

54
Q

what class of drug is oxybutynin

A

cholinergic antagonist, direct muscarinic receptor block

55
Q

what class of drug is tolterodine

A

cholinergic antagonist, direct muscarinic receptor block

56
Q

what class of drug is ipratroprium

A

cholinergic antagonist, direct muscarinic receptor block

57
Q

what class of drug is tiotropium

A

cholinergic antagonist, direct muscarinic receptor block

58
Q

Why does an M3 receptor lead to vasodilation?

A

• Gq receptor on the endothelial cell will end up leading to NO release which in turn will relax associated blood vessels

59
Q

what does an adrenergic agonist do to GI motility?

A

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
Q

what is the consequence of overstimulating N-m receptors?

A

depolarization block and skeletal muscle paralysis

61
Q

what does pralidoxime do?

A

treatment for NMJ overactivity, it will treat depolarization block and skeletal muscle block

62
Q

what is the result of over-stimulation of N-n receptors?

A

seizures, treated with diazepam

63
Q

What is succinylcholine used for?

A

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
Q

what is the mneumonic for the adverse reactions for overactive nicotinic receptors?

A 
MATCH
Muscle weakness N-m
Adrenal medulla activity increase - N-n
Tachycardia N-n
Cramping of skeletal muscle N-m
Hypertension N-n
65
Q

what does pralodoxime do (mechanism)?

A

cholinesterase regenerator, increases Ach breakdown and termination of the cholinergic signal

66
Q

What class of drug is atracurium?

A

cholinergic antagoinst, N-m receptor direct

67
Q

what class of drug is rocuronium?

A

cholinergic antagoinst, N-m receptor direct

68
Q

In general, when do you use an adrenergic antagonist?

A

• Chronic, increased cholinergic activity

69
Q

In general, when do you use cholinergic agonists?

A

• For ACUTE, decreased cholinergic activity

70
Q

When, in general, do you use adrenergic agonists?

A

acute decreased activity

*according to French it’s not a great idea to goose a system for a long time

71
Q

have you teased out the adrenergic agonist slide yet?

A

it’s marked with a memorize this slide tag

72
Q

What is the major action that terminates the synaptic activity of norepinephrine?

A

• Reuptake into neuron by NE transporter (NET) on nerve terminal

73
Q

what are actions of the beta1 receptor?

A

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
Q

What might Beta1 adrenergic stimulation result in?

A
  • Increase in cardiac output

* Common treatment during acute heart failure

75
Q

What do the alpha1 and beta2 adrenergic receptors do in the respiratory tract?

A
  • Bronchial smooth muscle dilates via beta2 receptors

* Mucosal blood vessels constrict with alpha1 activation

76
Q

What receptor should be activated to get pupillary dilation?

A

• 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
Q

What does beta2 receptor activation cause in skeletal muscle?

A
  • Marked tremor
    • Action on contractile proteins via beta2 receptors
    • Causes increased blood glucose
78
Q

What do antimuscarinics, neuromuscular blockers and ganglionic blockers all have in common?

A
  • 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
Q

What does hemicholinium do?

A
  • 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
Q

What drug can block the storage of Ach in a quantal vesicle?

A

• Vesamicol blocks ach vesicular packaging

81
Q

Ach release from the nerve terminal upon influx of calcium can be blocked by what substances?

A
  • Botulinum toxin

* Black widow spider toxin

82
Q

What neuronal mechanism can modulate the release of ach?

A

• If NE interacts with the alpha2 heteroreceptor, this tells the presynaptic cholinergic neuron to decrease ach release

83
Q

What is the drug Butyrylcholinesterase supposed to do?

A
  • “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
Q

Where do you find M1 receptors?

A
  • 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
Q

Where do you find M3 receptors?

A 
• 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
Q

What modifications done to bethanechol can either make it more specific for muscarinic receptors or otherwise make it resistent to ache?

A
  • Adding a methyl group will add selectivity for muscarinic receptors
    • Replacing the acetyl group with carbamyl group increases resistence to ache
87
Q

Where in the body would you expect bethanechol to go?

A

• Low lipid solubility so it stays pretty much in the plasma compartment

88
Q

What does nicotine as a drug do?

A

• 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
Q

What do toxic doses of nicotine do?

A
  • 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
Q

What is alarming as it is an irreversible ache inhibitor?

A
  • Nerve gas, isofluorophate

* Organophosphate insectisides

91
Q

What are the two reversible, intermediate to long acting ache inhibitors?

A
  • Neostigmine and phyostigmine

* Phyostigmine is the lipid soluble one is lipid soluble and the other is less so

92
Q

An antimuscarinic that blocks M1 receptors will have effects in what systems?

A
  • CNS,
    • gastric parietal
    • SNS postganglionic cells
93
Q

An antimuscarinic that blocks M3 receptors selectively is going to affect the function of what cells?

A

• Smooth muscle organs and glands

94
Q

An antimuscarinic that blocks M2 receptors selectively is active in what tissue?

A

• Cardiac tissue

95
Q

What is the rate-limiting step in the biosynthesis of norepinephrine?

A
  • Tyrosine (precursor) conversion to DOPA by tyrosine hydroxylase
    • Inhibited by metyrosine
96
Q

What molecule is transported into the catecholamine storage vesicle in the norepinephrine synthesis pathway?

A

• Dopamine is first packaged in the vesicle and then converted to NE by dopamine beta-hydroxylase

97
Q

What is MAO and where is it?

A

• In the neuron, attached to mitochondrial membrane
• Degrades norepinephrine and dopamine
Bretylium can block what?
• Release of catecholamines in a ca dependent manner

98
Q

What is the most important termination mechanism in the NE signaling pathway?

A
  • 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

Neuro (59 decks)

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