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BMPH 1 > Pharmacology of ANS > Flashcards

Pharmacology of ANS Flashcards

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).

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2
Q

Which organs are innvervated by the ANS?

A

ALL

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3
Q

What are the two branches of the ANS?

A

Sympathetic

Parasympathetic

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4
Q

What does the sympathetic nervous system do?

A
  • Alertness
  • Fight or Flight
  • Spend energy
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5
Q

What does the parasympathetic nervous system do?

A
  • Restore energy

- Rest and Digest

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6
Q

How does the ANS regulate organ function?

A

Via release of neurotransmitters that bind to unique receptors on organs

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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)

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8
Q

What are nerves?

A

Bundles of hundreds of axons and/or dendrites

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9
Q

How to ANS synapses work in general?

A
  1. AP propagated down presynaptic axon
  2. AP arrival at terminal induced Ca channels to open so there is an influx on Ca into the cell
  3. Ca induces exocytotic release of vesicles with NT
  4. NT travels across cleft to bind to receptor on post synaptic cell, inducing a function in target cell
  5. NT in cleft needs to be removed so effect on target cell can end: either degraded or reuptaken
  6. NT is brought back in some way to presynaptic and recycled
  7. NT is repackaged into vesicles for next AP
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10
Q

What is the function of presynaptic or prejunctional receptors?

A

Inhibit release of NT vesicles via a negative feedback loop

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11
Q

How are enzymes used with NTs?

A
  • Synthesis
  • Packaging
  • Storage
  • Release
  • Degradation/reuptake
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12
Q

What types of NT receptors are there in the ANS?

A
  • Sympathetic: Adrenergic - Alpha and Beta

- Parasympathetic: Cholinergic - Nicotinic and Muscarinic

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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
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14
Q

What role do organs play in ANS pharmacology?

A

Systems enact a systemic response, which can be normal or pathologic

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15
Q

What role do receptors play in ANS pharmacology?

A
  • Functions via downstream signaling.

- Receptor localization

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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
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17
Q

How do drugs interest with receptors?

A

Receptor molecules can exist in several conformations, which drugs can stabilize.

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18
Q

How can an inverse agonist affect a receptor?

A

Lessen or negate a response

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19
Q

How does an antagonist affect a receptor?

A

Decrease response or negate, depending on basal activity

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20
Q

How does a partial agonist affect a receptor?

A

Partial response

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21
Q

How does a fill agonist affect a receptor?

A

Full response

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22
Q

How do receptors regulate cellular functions?

A
  1. Receptor on plasma membrane facing outside
  2. Drug binds to receptor
  3. Inactive GDP-bound Protein is converted to active GTP-bound protein
  4. Effector inside cell influences second messenger
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23
Q

Receptor desensitization

A

Prolonged stimulation leads to GPCR desensitization via phosphorylation by GRK (G protein-coupled Receptor Kinase)

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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.

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25
Q

Signaling “From Within”

A

There is evidence that GPCRs continue functioning once internalized, so can signal from within.

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26
Q

Downstream Effects of G protein coupling

A
  1. Second messengers activate protein kinases
  2. Phosphorylation of substrates in cells
  3. Function of substrates changes
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27
Q

How does the ANS maintain homeostasis?

A

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
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28
Q

Function of Ganglia in ANS

A
  • All pre-ganglionic secreta ACh
  • Post-ganglionic:
    • Parasympathetic: ACh
    • Sympathetic: NE
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29
Q

What is the effect on ANS of drugs than target ACh?

A

Since ACh is used widely in ANS, its lack of specificity will cause changes across the system.

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30
Q

ANS reflexes in circulatory system

A
  1. Heart pumps blood through blood vessels
  2. Blood vessel tone changes in response
  3. In response, Heart pumping changes
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31
Q

What influences changes in heart pumping?

A
  • Vascular resistance
  • Heart rate and force
  • Blood volume
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32
Q

ANS Regulation of Blood Pressue

A
  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
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33
Q

What is the purpose of autonomic reflexes?

A

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.

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34
Q

ANS Reflexes in the eye

A
  1. ANS controls flow of humor, which maintains shape of eye

2. Smooth muscles in pupil control diameter

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35
Q

ANS regulation of the eye: parasympathetic

A

Pupil contraction via muscarinic ACh receptor:

  • Decrease humor secretor
  • Contraction of ciliary muscles
  • Focus for near vision
  • Open canal of Schlemm
  • Reduce intraocular pressure
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36
Q

ANS regulation of the eye: sympathetic

A

Pupil Dilation via alpha adrenergic receptor:

  • Increase humor secretion to increase intraocular pressure
  • Sharper focus on distant objects –> fight or flight
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37
Q

M1 receptor

A 
NT: Cholinergic
Type: muscarinic
Sub-type: 1
Location: Nerve endings
Mechanism: Gq-coupled
Major Functions: inc IP3, DAG cascade
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38
Q

M2 receptor

A 
NT: cholinergic
Type: muscarinic
Sub-type: 2
Location: heart, some nerve endings
Mechanism: Gi-coupled
Major Functions: dec cAMP, activate K+ channels
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39
Q

M3 receptor

A 
NT: cholinergic
Type: muscarinic
Sub-type: 1
Location: effector cells - smooth muscle, glands, endothelium
Mechanism: Gq-coupled
Major Functions: inc IP3, DAG cascase
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40
Q

Nn receptor

A 
NT: cholinergic
Type: nicotinic
Sub-type: N
Location: ANS ganglia
Mechanism: Na-K ion channel
Major Functions: depolarizes, evoke AP
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41
Q

Nm receptor

A 
NT: cholinergic
Type: nicotinic
Sub-type: M
Location: neuromuscular end plate
Mechanism: Na-K ion channel
Major Functions: depolarizes, evoke AP
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42
Q

Alpha 1 receptor

A

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

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43
Q

Alpha 2 receptor

A

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)

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44
Q

Beta 1 receptor

A

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

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45
Q

Beta 2 receptor

A 
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
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46
Q

Beta 3 receptor

A 
NT: adrenergic - ACh
Type: beta
Sub-type: 3
Location: adipose cells
G protein: Gs
2nd Messenger: inc cAMP
Major Functions: inc lipolysis
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47
Q

Dopamine 1 receptor

A 
NT: adrenergic - dopamine
Type: dopamine
Sub-type: 1
Location: smooth muscle
G protein: Gs
2nd Messenger: cAMP
Major Functions: Relax renal vascular smooth muscle
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48
Q

ANS effect on:

Radial muscle of iris (eye)

A

Sympathetic

  • Action: Contracts
  • Receptor: alpha 1

Parasympathetic

  • Action: none
  • Receptor: none
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49
Q

ANS effect on:

Circular muscle of iris (eye)

A

Sympathetic

  • Action: none
  • Receptor: none

Parasympathetic

  • Action: contracts
  • Receptor: M3
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50
Q 
ANS effect on:
Ciliary muscle (eye)
A

Sympathetic

  • Action: relaxes
  • Receptor: beta

Parasympathetic

  • Action: contracts
  • Receptor: M3
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51
Q 
ANS effect on: 
SA node (heart)
A

Sympathetic

  • Action: accelerates
  • Receptor: beta 1 and 2

Parasympathetic

  • Action: decelerated
  • Receptor: M2
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52
Q 
ANS effect on: 
Ectopic pacemakers (heart)
A

Sympathetic

  • Action: accelerates
  • Receptor: beta 1 and 2

Parasympathetic

  • Action: none
  • Receptor: none
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53
Q

ANS effect on:

Contractility (heart)

A

Sympathetic

  • Action: increases
  • Receptor: beta 1 and 2

Parasympathetic

  • Action: decreases
  • Receptor: M2
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54
Q

ANS effect on:

Skin, splanchnic vessels

A

Sympathetic

  • Action: contracts
  • Receptor: alpha

Parasympathetic

  • Action: none
  • Receptor: none
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55
Q

ANS effect on:

Skeletal muscle vessels

A

Sympathetic

  • Action: relaxes or contracts
  • Receptor: beta 2 or alpha

Parasympathetic

  • Action: none
  • Receptor: none
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56
Q

ANS effect on:

Bronchiolar smooth muscle

A

Sympathetic

  • Action: relaxes
  • Receptor: beta 2

Parasympathetic

  • Action: contracts
  • Receptor: m3
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57
Q

ANS effect on:

Smooth muscle walls (GI)

A

Sympathetic

  • Action: relaxes
  • Receptor: beta 2

Parasympathetic

  • Action: contracts
  • Receptor: m3
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58
Q

ANS effect on:

Smooth muscle sphincters (GI)

A

Sympathetic

  • Action: contracts
  • Receptor: alpha 1

Parasympathetic

  • Action: relaxes
  • Receptor: m3
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59
Q

ANS effect on:

Secretion (GI)

A

Sympathetic

  • Action: inhibits
  • Receptor: alpha 2

Parasympathetic

  • Action: increases
  • Receptor: m3
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60
Q 
ANS effect on: 
Myenteric plexus (GI)
A

Sympathetic

  • Action: none
  • Receptor: none

Parasympathetic

  • Action: activates
  • Receptor: m1
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61
Q

ANS effect on:

Bladder wall

A

Sympathetic

  • Action: relaxes
  • Receptor: beta 2

Parasympathetic

  • Action: contracts
  • Receptor: m3
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62
Q

ANS effect on:

Sphincter (uro)

A

Sympathetic

  • Action: contracts
  • Receptor: alpha1

Parasympathetic

  • Action: relaxes
  • Receptor: m3
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63
Q

ANS effect on:

Uterus, pregnant

A

Sympathetic

  • Action: relaxes or contracts
  • Receptor: beta 2 or alpha

Parasympathetic

  • Action: contracts
  • Receptor: m3
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64
Q

ANS effect on:

Penis, seminal vesicles

A

Sympathetic

  • Action: ejaculation
  • Receptor: alpha

Parasympathetic

  • Action: erection
  • Receptor: m
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65
Q

ANS effect on:

Pilomotor smooth muscle (skin)

A

Sympathetic

  • Action: contracts
  • Receptor: alpha

Parasympathetic

  • Action: none
  • Receptor: none
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66
Q

ANS effect on:

Thermo sweat glands (skin)

A

Sympathetic

  • Action: increases
  • Receptor: m

Parasympathetic

  • Action: none
  • Receptor: none
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67
Q

ANS effect on:

Apocrine/Stress sweat glands (Skin)

A

Sympathetic

  • Action: increases
  • Receptor: alpha

Parasympathetic

  • Action: none
  • Receptor: none
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68
Q

ANS effect on:

Liver

A

Sympathetic

  • Action: gluconeogenesis or glycogenolysis
  • Receptor: alpha and beta 2

Parasympathetic

  • Action: none
  • Receptor: none
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69
Q

ANS effect on:

Fatcells

A

Sympathetic

  • Action: lipolysis
  • Receptor: beta 3

Parasympathetic

  • Action: none
  • Receptor: none
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70
Q

ANS effect on:

Kidney

A

Sympathetic

  • Action: renin release
  • Receptor: beta 1

Parasympathetic

  • Action: none
  • Receptor: none
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71
Q

ANS effect on:

Sympathetic nerve endings

A

Sympathetic

  • Action: none
  • Receptor: none

Parasympathetic

  • Action: decreases. NE release
  • Receptor: M
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72
Q

ANS effect on:

Parasympathetic nerve endings

A

Sympathetic

  • Action: decreases ACh release
  • Receptor: alpha

Parasympathetic

  • Action: none
  • Receptor: none
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73
Q

In fight or flight, sympathetic nerves inc the ___ (firing rate) to release more norepinephrine

A

Tone

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74
Q

Norepinephrine activates ___ receptors.

A

Adrenergic

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75
Q

Modes of indirect action on adrenergic receptors

A

Influencing NT:

  1. Synthesis
  2. Degradation
  3. Transport
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76
Q

What is sympathetic tone?

A

Rate of SANS firing

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77
Q

Which organs respond to flight-or-flight?

A
  • Cardio: heart and different vessels
  • Lungs: airway smooth muscle
  • Eye
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78
Q

Norepinephrine is released by the ___ throughout the body.

A

Nerves

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79
Q

Epinephrine is released by the ___ ___ and goes everywhere

A

Adrenal gland

80
Q

Adrenergic synapse mechanism

A
  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
Q

Drug that targets tyrosine hydroxylase

A

Metyrosine

82
Q

Function of metyrosine

A

Targets tyrosine hydroxylase, which is involved in conversion of tyrosine to dopa, a step in NE synthesis

83
Q

Drug that targets NE vesicles

A

Reserpine

84
Q

Drug that interferes with NE reuptake

A

Cocaine

85
Q

Types of drugs that interfere with target cell receptors

A

Agonists and antagonists

86
Q

Drugs that interfere with MAO

A

MAO inhibitors

87
Q

Function of MAO inhibitors

A

Inhibit the function of MAO, which degrades NE

88
Q

What would be the effect of alpha-2 receptor inhibition on sympathetic outflow & why?

A

Increase. Alpha-2 is responsible for presynaptic inhibition, so inhibition of inhibition equals stimulation.

89
Q

Classes of adrenergic receptors

A

alpha and beta

90
Q

Subclasses of adrenergic receptors

A
  • Alpha: 1 and 2

- Beta: 1, 2, and 3

91
Q

Localization and function of alpha-1 receptors

A

Vascular smooth muscle in skin and gut: Activation constricts vessels

92
Q

Localization and function of alpha-2 receptors

A
  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
Q

Localization and function of beta-1 receptors

A
  1. Heart: increases pacemaker activity, conduction velocity, and contractility = increased cardiac output
  2. Kidney (JG cells): increases renin release
94
Q

Localization and function of beta-2 receptors

A
  1. Vascular smooth muscle of vessels in skeletal muscle, heart, and brain: activation relaxes
  2. Smooth muscle in airways: activation relaxes
95
Q

Localization and function of beta-3 receptors

A

Fat cells increase of metabolism

96
Q

What are the differences between adrenergic alpha 1 and 2 receptors?

A
  1. Different gene products
  2. Different localization in cells (pre/post synaptic) and tissues
  3. They activate different G proteins.
97
Q

G protein adrenergic receptor signaling mnemonic

A

QISSS
Alpha-1: Gq
Alpha-2: Gi
Beta: Gs

98
Q

Gq mechanism

A

Effector enzyme: Adenylate cyclase
2nd Messenger: in cAMP
Example effect: inc heart rate

99
Q

Gi mechanism

A

Effector Enzyme: adenylate cyclase
2nd Messenger: dec cAMP
Example effect: dec heart rate

100
Q

Gs mechanism

A

Effector enzyme: Phospolipase C
2nd Messenger: inc IP3, DAG, Ca2+
Example effect: vasoconstriction

101
Q

Flight-or-Flight response

A

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
Q

Assuming only direct effect of epinephrine, how will it influence blood pressure?

A
  • 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
Q

NE agonist receptor selectivity

A

Somewhat selective: a1=a2=b1»b2

104
Q

NE agonist a1 mechanism

A

Vasoconstriction: skin, gut

105
Q

NE agonist a2 mechanism

A

dec:
- sympathetic outflow
- NE release
- renin release
- vasodilation

106
Q

NE agonist b1 mechanism

A

inc:

  • cardiac output
  • renin release
107
Q

NE agonist b2 mechanism

A

doesn’t really influence so little vasodilation in skeletal muscle, brain

108
Q

Effect of NE agonist

A
  • Inc cardiac output
  • inc BP
  • subsequent vasovagal reflex
109
Q

EPI agonist receptor selectivity

A

Non-selective: a1=a2=b1=b2

110
Q

Epi agonist a1 mechanism

A

Vasoconstriction: skin, gut

111
Q

Epi agonist a2 mechanism

A

dec:
- sympathetic outflow
- NE release
- renin release
- vasodilation

112
Q

Epi agonist b1 mechanism

A

inc:

  • cardiac output
  • renin release
113
Q

Epi agonist b2 mechanism

A

Dec dilation of the fight/flight vessels: those in the brain, heart, and skeletal muscle

114
Q

Effect of Epi agonist

A
  • Inc cardiac output

- Inc BP (but not as strong as w/ NE)

115
Q

Use of sympathomimetics in CV system

A
  • Enhance blood flow and pressure
    - Hypotension
    - Shock
    - Heart emergency management
  • Reduce blood flow
    - In surgery, together w/ anesthetic
    - Decongestants
116
Q

Use of sympathomimetics in Anaphylaxis

A
  • Intramuscular epi prior to anti-histamines and glucocorticoids
  • Epi to treat bronchospasm, suppress mucus membrane secretion, etc
117
Q

Use of sympathomimetics in asthma

A

Bronchodilation

118
Q

Use of sympathomimetics in CNS

A
  • Amphetamines treat narcolepsy

- Ritalin for ADD/sharpen concentration

119
Q

Why is epinephrine used in surgery?

A
  • Causes local vasoconstriction by acting on skin vessel a1 receptors
  • Reduces bleeding
120
Q

Clonidine - drug type

A

Highly selective a2 receptor agonist

121
Q

Clonidine - mechanism

A

Presynaptic inhibition:

  • drop in NE release
  • dec sympathetic outflow
  • dec rening release

Postsynaptic:
- inc vasoconstriction: little contribution

122
Q

Clonidine - use

A

Decreased BP

123
Q

What effect would a sudden drop in dose of clonidine have on patient?

A

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
Q

Which sympathomimetics are not agonists?

A

Cocaine and tyramine

125
Q

Mechanism of cocaine

A

Blocks re-uptake of NE –> NE effects lasts longer

126
Q

Mechanism of tyramine

A

MAO inhibitors –> accumulation of tyramine –> spike in BP –> (maybe) drop in BP

127
Q

Non-catecholamine sympathomimetics

A
  • Pseudoephedrine
  • Phenylephrine
  • Amphetamine
128
Q

Pseudoephedrine

A
  • decongestant

- high bioavailability

129
Q

Phenylephrine

A
  • a1 agonist

- decongestant

130
Q

Amphetamine

A
  • 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
Q

Adrenergic agonists selective for b2

A
  • Albuterol
  • Tertbutaline
  • Salmeterol
132
Q

Albuterol

A

bronchodilation

133
Q

Why is activation of b2 adrenergic receptor beneficial in asthma?

A
  • B2 abundant in smooth muscle airways

- Elevate cAMP –> bronchodilation

134
Q

Adrenergic antagonists

A

Reduce demand for O2 not by reducing load (systemic BP) but by reducing heart rate

135
Q

Propanolol

A

Adrenergic antagonist selective for beta

Blocks:

  • b1: dec cardiac output/renin release
  • b2: vasoconstriction in skeletal muscle, bronchoconstriction

Result: dec BP

136
Q

How can propanolol influence a person with asthma?

A

Worsen condition of precipitate an attack

Non-selective beta-blocker –> antagonize b2 receptors –> prevent bronchodilation

137
Q

Adrenergic antagonists, b1 selective

A
  • Metoprolol

- Atenolol

138
Q

Mechanism of B1 blocker

A
  • dec cardiac output

- dec renin release

139
Q

Effect of B1 blocker

A

dec BP

  • better for asthma since does not affect b2 so keeps bronchodilation in place
140
Q

A1-selective antagonists

A
  • Prazosin

- Terazosin

141
Q

Mechanism of a1-selective antagonists

A
  • Blocks sympathetic tone and vessel constriction in large vascular beds of skin and gut
  • Lowers resistance to blood flow
142
Q

Effect of a1-selective antagonists

A

Dec BP

143
Q

Non-selective Alpha antagonist

A

Phentolamine

144
Q

Fight/Flight in eye

A

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
Q

Myadriasis

A

pupil dilation

146
Q

What will happen with the pupil upon inhalation of conn?

A

Dilation (mydriasis)

  • Block reuptake of NE at dilator muscle
  • Constriction via alpha AR, Gq, Ca
147
Q

Mnemonic for PNS

A

DUMBELLS:

  • Diarrhea
  • Urination
  • Miosis (pupil contraction)
  • Bronchospasm
  • Emesis
  • Lacrimation
  • Salivation
148
Q

Does the PNS innervate all tissues?

A

No, very few blood vessels are innervated by it.

149
Q

What is the main NT of PNS?

A

Acetylcholine ACh

150
Q

Name of receptors that use ACh

A

Cholinergic

151
Q

Cholinergic synapse mechanism

A
  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
Q

Vesamicol

A

Inhibit ACh packaging into vesicles

153
Q

Acetylcholinesterase inhibitors

A

Neostigmine, Sarin

154
Q

Direct acting cholinomimetics

A
  • Nicotine: tobacco
  • Muscarine: poisonous mushrooms
  • Pilocarpine: plant - induce salivation/sweating
155
Q

First NT discovered

A

ACh

156
Q

Synthetic cholinergic agonists

A
  • Carbachol

- Methacholine

157
Q

Carbachol

A

Cholinergic agonist

  • Not sensitive to acetylcholine esterase
  • lower muscarine action
  • same nicotinic action
158
Q

Methacholine

A

Cholinergic agonist

  • lower sensitivity to acetylcholine esterase
  • inc muscarinic action
  • no nicotinic action
159
Q

Indirect cholinomimetics - action

A

Inhibit acetylcholine degradation –> effect similar to agonist

160
Q

Cholinesterase inhibitors

A

Indirect cholinomimetics

  • Edrophonium
  • Neostigmine
  • Organophosphates: isoflurophate
161
Q

Edrophonium Action

A

Cholinesterase inhibitor

  • Reversible
  • Binds to AChesterase enzyme
  • Competes with ACh
162
Q

Neostigmine Action

A

Cholinesterase inhibitor

  • Reversible
  • Hydrolyzed very slowly
  • Use myasthenia gravis (reduction of nicotinic ACh receptors)
163
Q

Organophosphates (Isoflurophate)

A

Cholinesterase inhibitor

  • Irreversible
  • Covalently attaches to a Set residue in active center of AChesterase
164
Q

Malathion

A

Cholinesterase inhibitor

  • Insecticide
  • Metabolized in mammals but not insects
  • Toxic in large doses
165
Q

Sarin

A

Cholinesterase inhibitor

- Chemical weapon

166
Q

Cholinergic receptors and mechanism

A
  • Nicotinic: ligand-gated ion channels

- Muscarinic: GPCRs

167
Q

M2 and M4 action

A
  • G protein: Gi
  • Effector enzyme: adenylate cyclase
  • 2nd messenger: dec cAMP
  • example effect: dec heart rate
168
Q

M1, M3, and M5 action

A
  • G protein: Gq
  • Effector Enzyme: phospholipase C
  • 2nd messenger: inc IP3, DAG, Ca2+
  • example effect: smooth muscle contraction
169
Q

Gq cascade

A

A1, M1, M3, M5

  • Effector enzyme: Phospholipase C
  • 2nd messenger: inc IP3, DAG, Ca2+

Example effects:

  • vasoconstriction (SANS)
  • smooth muscle contraction (PANS)
170
Q

Gi cascade

A

A1, M2, M4

  • Effector enzyme: adenylate cyclase
  • 2nd messenger: dec cAMP

Example effects:
- dec heart rate (SANS/PANS)

171
Q

Gs cascade

A

B1-3

  • effector enzyme: adenylate cyclase
  • 2nd messenger: inc cAMP

Example effect:
- inc heart rate (SANS only)

172
Q

Muscarinic receptors location

A
  • M1/4/5: brain
  • M2: heart, presynaptic nerve terminals in lung
  • M3: GI, glands, smooth muscle in airways, vasculature
173
Q

M2 location

A
  • Heart: activation dec pacemaker activity, conduction velocity, and contractility
  • Presynaptic nerve terminals in lung (Asthma = too much ACh)
174
Q

M3 location

A
  • GI: motility (rest/digest)
  • Glands: stimulates secretion
  • Airway smooth muscle: contraction
  • Vasculature: activation –> dilation
175
Q

Effect of cholinesterase inhibitors on CV

A

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
Q

Effect of direct cholinomimetics on CV

A

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
Q

Effect of muscarinic receptors on smooth muscle and endothelial cells

A

M3 Activation causes opposite contractility

  • Smooth blood vessels: contraction
  • Endothelial: relaxation
178
Q

Muscarinic agonists

A
  • Acetylcholine
  • Pilocarpine
  • Bethanechol
  • Muscarine
179
Q

Major effects of muscarinic agonists on CV

A 
M1=M2=M3=M4=M5
dec heart rate 
\+ inc NO release by endothelium 
= bradycardia + hypotension
*This is toxic
180
Q

Excessive activation of muscarinic receptors

A

Example: mushrooms with muscarine

  • M2: Bradycardia
  • M3: Bronchoconstriction, GI motility, Pupil constriction, Sweating, Salivation, and vasodilation
181
Q

Clinical relevance of Cholinergic stimulation in eye

A
  • Stimulation of m3 receptors in glands
  • Dry eye and mouth syndrome
  • Pilocarpine
  • Treatment of glaucoma w/ topical pilocarpine
182
Q

Clinical relevance of cholinergic stimulation in pulmonary

A
  • Metacholine test to diagnose asthma

- Bronchioles overreact in a person with asthma

183
Q

Clinical relevance of cholinergic stimulation in GI/urinary tracts

A
  • stimulate peristaltic and secretory activity
  • overcome urinary retention
  • bethanecol
184
Q

Clinical relevance of cholinergic stimulation in NMJ

A
  • Neostigmine to diagnose myasthenia gravis
185
Q

PNS regulation of the eye

A
  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
Q

Cholinergic receptor antagonists

A
  • Act on all muscarinic receptors
  • multiple effects on CNS/PNS
  • Can be overcome by muscarinic agonists
  • Example: Scopolamine and Atropine
187
Q

Clinical use of cholinergic-blocking drugs in CNS

A

Some patients: blocking ACh receptors works for Parkinson’s by blocking tremors

188
Q

Clinical use of cholinergic-blocking drugs in GI

A
  • Main: suppress emesis

- Scopolamine: motion sickness, amnesia

189
Q

Clinical use of cholinergic-blocking drugs in eye

A
  • Atropine: long-term mydriasis (open pupil) for examination

** do not use to diagnose narrow-angle glaucoma

190
Q

Clinical use of cholinergic-blocking drugs in CV system

A
  • 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
Q

Clinical use of cholinergic-blocking drugs in lung

A
  • Prevent bronchoconstriction

- Bronchitis, COPD, etc

192
Q

Clinical use of cholinergic antagonists

A

Peripheral: asthma - inhaled
Central: Parkinson’s - suppress tremors

193
Q

Ipratropium

A

Cholinergic antagonist

  • Blocks bronchoconstriction constriction
  • Keeps airways open
  • Peripheral: Asthma - inhaled
194
Q

Benztropine

A

Cholinergic antagonist

- Central effect: Parkinson’s suppress tremors

195
Q

What two drugs are used together for asthma

A

Ipratropium + albuterol

  • Albuterol = b2 agonist: stimulate bronchodilation
  • Ipratropium: inhibits inhibitor of chronchodilation

BMPH 1 (8 decks)

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