2. Autonomic Pharmacology Flashcards
1
Q
Draw out the flow chart from sensory afferent input to final efferent output
A
2
Q
Draw out the synthesis of NE
A
Phenylalanine to tyrosine (phenylalanine hydroxylase - deficiency = PKU)
Tyrosine to DOPA (Tyrosine hydroxylase)
DOPA to Dopamine (Amino acid decarboxylase)
Dopamine to NE (Dopamine-B hyroxylase)
*RLS is the first step
*NE to E occurs within the adrenal medulla
3
Q
What blocks tyrosine hydroxylase?
What blocks dopamine entry into vesicles?
A
Metyrosine
Reserpine
4
Q
How does NE enter nerve terminals?
A
Tyrosine enters a nerve terminal via Na channel and is converted into dopamine. Dopamine then enters a vesicle vai VMAT2 where it is converted into NE
5
Q
What are the three fates of NE after being released into the synaptic cleft?
A
1) Binds to post-synpatic membrane
2) Binds to autoreceptor
3) Reuptake into presynaptic neuron via NET
The three autoreceptors are
- Alpha 2: Inhibits NE release
- M2: Inhibits NE release
- Angiotensin2: Stimulates NE release
6
Q
How can you block NE reuptake? (i.e. NET)
A
Cocaine
TCA
7
Q
What two enzymes metabolize NE?
A
Monoamine oxidase (oxidizes NE)
Cathechol-O-methyl transferase (methylates NE)
8
Q
Why is taking dopamine orally not effective?
A
MOA and COMT are located within the liver and thus taking dopamine will result in significant metabolism
9
Q
How is Ach synthesized?
A
Choline enters the nerve terminal via Na channels and is combined with acetyl Ca via the enzyme choline acetly transferase
10
Q
What drug blocks packaging of Ach inside of vesicles?
A
Vesamicol
11
Q
Name one toxin that stimulates Ach release and another that inhibits Ach release.
A
Stimulates Ach release: Black widow spider toxin (results in spastic paralysis)
Inhibits ACh release: Botulinum toxin (results in flaccid paralysis)
12
Q
What causes NE and Ach to be released from their vesicles?
A
Depolarization resulting in Ca channels opening and Ca influx
13
Q
What inhibits Ach release?
A
Botulism toxin
14
Q
What enzyme metabolizes Ach?
A
Acetylcholinesterase
15
Q
What are the two cholinergic receptors?
A
Nicotinic (ligand-channels)
Muscarinic (GPCR)
16
Q
What are the adernergic receptros?
A
Alpha and beta
17
Q
What NT is released from the CNS in
a. Somatic innervation to skeletal muscle
b. SNS innervation to organs
c. PNS innervation to organs
A
Somatic: Ach
SNS: Preganglion - Ach; Postganglion - NE
PNS: Preganglion - Ach; Postganglion - Ach
*Postganglion SNS release Ach only when targetting sewat glands
*Preganglion SNS release Ach (as expected) at ganglions or at the adrenal medulla to induce E formation
18
Q
What receptor do each of the following hit?
a. Somatic innervation to skeletal muscle
b. SNS innervation to organs
c. PNS innervation to organs
A
Somatic: NM on skeletal muscle
SNS preganglion: NN at adrenal medulla or ganglion
SNS postganglion: Adrenergic (alpha/beta) at organs
SNS postganglion: M receptors at sweat glands
PNS preganglion: NN at ganglion
PNS postganglion: M receptors at organs
19
Q
What effect does SNS have on the body?
A
Increase HR
Increase blood flow to skeletal muscles
Dilate bronchi and pupils
Sweat
20
Q
What effect does PNS have on the body?
A
Decrease HR
Increase GI
Pupil constriction
Poop
21
Q
What inhibits choline uptake into nerve terminals, which otherwise would have gone on to become Ach?
A
Hemicholinium
22
Q
Muscarinic Receptor
*For each, name the receptor involved and the effect
Heart
- SA Node
- AV node
- Atria
- Ventricles
A
M2 receptor invovled
Heart
- SA Node: Decrease HR
- AV node: Decrase conduction
- Atria: Decrease contractility
- Ventricles: No effect
23
Q
Muscarinic Receptor
*For each, name the receptor involved and the effect
Blood vessels
- Arterioles
- Skeletal muscle
- Veins
A
M3 receptor invovled
Blood vessels
- Arterioles: No effect
- Skeletal muscle: No effect
- Veins: No effect
*While there is no PNS innervation, endothelium of blood vessels contain M3 receptors which if acted on by NO, cause vasodilation
24
Q
Muscarinic Receptor
*For each, name the receptor involved and the effect
Lung
- Bronchiols
- Glands
A
M3 receptor invovled
Lung
- Bronchiols: Contraction (bronchospasms)
- Glands: Secretion
25
Muscarinic Receptor
\*For each, name the receptor involved and the effect
GI
* Motility/tone
* Sphincters
* Glands
M3 receptor invovled
GI
* Motility/tone: **Increase**
* Sphincters: **Relax**
* Glands**: Secretion**
26
Muscarinic Receptor
\*For each, name the receptor involved and the effect
Eye
* Radial muscle (dilator pupillae)
* Circular muscle (sphincter pupillae)
* Ciliary muscle
M3 receptor invovled
Eye
* Radial muscle (dilator pupillae): **No effect**
* Circular muscle (sphincter pupillae): **Contract (miosis)**
* Ciliary muscle: **Contract (accomodation near vision)**
27
Muscarinic Receptor
\*For each, name the receptor involved and the effect
Urinary bladder
* Detrusor
* Trigone/sphincter
M3 receptor invovled
Urinary bladder
* Detrusor: **Contract**
* Trigone/sphincter: **Relax**
28
Muscarinic Receptor
\*For each, name the receptor involved and the effect
Glands
* Salivary
* Salivation
* Lacrimation
M3 receptor invovled
Glands
* Salivary: **Secretion**
* Salivation: **Secretion**
* Lacrimation: **Secretion**
29
Muscarinic Receptor
\*For each, name the receptor involved and the effect
Sphincters
M3 receptor invovled
## Footnote
Sphincters
**Relaxation except for lower esophageal (contract)**
30
Muscarinic Receptor
\*For each, name the receptor involved and the effect
Sex organ
M3 receptor invovled
## Footnote
Sex organ
**Erection**
31
PNS acts mainly on M2 and M3 receptors.
Which organs are associated with each?
M2 - Heart
M3 - the rest
32
What are the 3 receptors of the CNS
Major receptors for the CNS
1. NN receptor
1. Found in PNS/SNS ganglions as well as on the adrenal medulla
2. Nm
1. Found on skeletal muscle motor end plate which are innervated by somatic motor neurons
3. M1-3
1. Found on organs that are innervated by the PNS as well as sweat glands which are innervated by SNS
33
Where are the SNS and PNS ganglions located?
SNS: Within the paraventral chains adjacent to the
PNS: Within their target organs
34
What is the equation for BP and CO?
BP = TPR x CO
CO = HR x SV
35
Explain the body's ANS response to an increase in BP
How might you you stop the baroreceptor reflex at the level of the ganglion and at the level of organ?
An increase in BP will cause the baroreceptors to discharge causing an increase in PNS and a decrease in SNS
\*A decrease in BP would have the opposite effect
BP = TPR x CO
CO = TPR x CO
Level of the ganglion: NN antagonist
Level of the organ: Muscarinic antagonist
\*To inhibit tachycardia reflex, you add a B1 antagonist
36
Explain the body's kidney response to an decrease in BP
A decrease in BP would cause reduced blood flow at the level of the kidney. Reduced renal blood means reduced renal pressure. This causes the release of renin which promotes angiotensin II formation. Angiotensin II causes vasoconstriction (increase TPR) and increases aldosterone levels which acts on the kidney to retain salt and water, increasing blood volume (increase CO). This extra volume increases venous return to the heart
\*An increase in BP would cause the opposite
BP = TPR x CO
CO = TPR x CO
37
Name 4 muscarinic agonists?
Ach
Bethanechol
Methacholine
Pilocarpine
38
Achetylcholine
## Footnote
1) What receptors does it bind to?
2) Will this be hydrolyzed by AChE?
3) What are its clinical uses?
1. M and N receptors
2. Yes
3. Half life is too short for any clinical uses
39
Bethanechol
1) What receptors does it bind to?
2) Will this be hydrolyzed by AChE?
3) What are its clinical uses?
1. M receptors
2. No (thus longer duration of action)
3. Treats ileus (disruption of GI motility - induced either by postop or neurogenic in origin) and urinary retention
\*Urinary retention (inability to empty bladder)
40
Methacholine
## Footnote
1) What receptors does it bind to?
2) Will this be hydrolyzed by AChE?
3) What are its clinical uses?
1. M \> N receptors
2. Slightly
3. Used to diagnose bronchial hyperreactivity (methacholine is inhaled to induce bronchoconstriction - by measuring the degree of constriction, you can diagnose bronchial hyperreactivity)
41
Pilocarpine
1) What receptors does it bind to?
2) Will this be hydrolyzed by AChE?
3) What are its clinical uses?
1. M
2. No
3. Treats glaucoma (topical) and xerostomia (dry mouth)
42
Name 7 AChE inhibitors
Edrophonium
Physostigmine
Neostigmine and pyridostigmine
Donepezil and tacrine
Organophosphates
43
What is edrophonium used for?
Used to differentiate myasthenia gravis from cholinergic crisis
\*Myasthenia gravis is due to auto-Ig blocking Ach from binding to nicotinic receptors. This causes muscle weakness. Edrophonium, an AChE inhibitor, will increase the concentration of Ach and thus reduce the amount of weakness.
\*Cholinergic crisis is when there is over-stimulation of the nicotinic receptors due to reduced or inhibition of AChE esterase. By increasing the pool of ACh, edrophonium should increase muscle weakness
44
What is physostigmine used for?
Teritary amine (uncharged) and thus can enter CNS
- Treats glaucoma
- Treats atropine overdose
\*Atropine is an Ach receptor antagonist used to dilate pupils (mydriasis) for cosmetic purposes and for urinary hypermotility. \*\*Also results in an inability to focus on near vision and unresponsiveness to light. \*\*\*At low doses, atrophine binds to M1 and causes bradycardia. At high doses, it binds to M2 and causes tachycardia
45
What is neostigmine and pyridostigmine used for?
- Quaternary amine (thus no CNS entry)
- Treats ileus, urinary retention, myasthenia, reversal of nondepolarizing Nm blockers (such as muscle relaxants used during operations, e.g. Rocuronium)
46
What is donepezil and tacrine used for?
- Enter CNS
- Treats alzheimer disease
\*Alzheimer is characterized by neurofibrillary tangles, amyloid plaques, and **loss of ACh neurons** - thus the use of AChE inhibitors
47
Organophosphates
- CNS entry
- Irreverisble inhibitors
- Treats glaucoma
\*Commonly used as an insecticide and as a nerve gas
48
What are two irreverisble AChE inhibitors that can treat glaucoma?
Organophosphates
Echothiophate
49
Excessive muscarinic and nicotinic stimulation causes toxicity.
What are the effects of muscarinic and nicotonic toxicity levels?
Muscarinic
- Diarrhea
- Urrination
- Miosis
- Bradycardia
- Bronchoconstriction
- Lacrimation
- Salivation
- Sweating
- CNS stimulation
Nicotinic
- Skeleta excitation
- CNS stimulation
\*Mnemonic - DUMBBELSS (E for excitation - refers to skeletal and CNS stimulation)
50
How do you treat muscarinic poisoning?
Atropine
51
How do you regenerate AChE in response to organophosphate poisoning?
Pralidoxime (2-PAM)
52
How does 2-PAM work?
It phosphorylates AChE, causing organophosphate to leave
\*If you wait too long organophosphate becomes permenately stuck
53
Name 6 muscarinic receptor antagonists?
Atropine
Tropicamide
Ipratropium
Scopolamine
Benztropine
Trihexyphenidyl
54
What is atropine used for?
Atropine CAUSES the following
Decreases secretion (salivary, sweat)
Mydriasis and cyclopegia
Hyperthermia
Tachycardia
Sedation
Urinary retention and constipation
Behavioral exciation and haullucination
55
What is tropicamide used for?
Dilates the eyes
56
What is ipratropium used for?
Asthma and COPD
57
What is scopolamine used for?
Used in motion sickness
Causes sedation and short term memory block
58
What is benztropine and trihexyphenidyl used for?
Parkinsonism
Acute extrapyramidal symptoms induced by antipsychotics
59
Nicotonic receptors are found on ganglion and skeletal muscles.
What drugs can be used to inhibit ganglion NN receptors?
Hexamethonium
Mecamylamine
60
Why aren't ganglionic blocking agents used today?
Very toxic
61
Even though both PNS and SNS synpase at Nn only the dominant ANS will be inhibited, allowing the other uneffected. In which systems does the SNS and the PNS dominant?
SNS dominates in vascular tone and sweat glands
PNS dominates in everything else
Thus, a block of the heart's NN means PNS is inhibited, resulting in tachycardia
Similarly, a block of a vessel's NN means SNS is inhibited, resulting in vasodilation
62
What are the four main adrenergic receptors?
a1, a2, B1, and B2
63
Where are alpha 1 receptors located and what effect does SNS have on them?
Eye - radial muscle (contraction - mydriasis)
Arterioles (contraction - increase in TPR, diasoltic pres)
Veins (contraction - increase in venous return)
Bladder (contraction - urinary retention)
Penis (ejaculation)
Liver (increase glycogenolysis)
Kidney (decrease renin release)
64
Where are alpha 2 receptors located and what effect does SNS have on them?
Nerve terminals - Decrease NE synthesis
Platelets - Aggregation
Pancreas - Decrease insulin secretion
65
Where are beta 1 receptors located and what effect does SNS have on them?
Heart:
* SA node (increase HR)
* AV node (increase conduction velocity)
* A/V muscles (increase contraction)
Kidney: Increase renin release
66
Where are beta 2 receptors located and what effect does SNS have on them?
Blood vessels (vasodilation - decrease TPR, dias press)
Uterus - Relaxation
Bronchioles - Dilation
Skeletal muscle - Increase glycogenolysis
Liver - Increase glycogenolysis
Pancreas - Increase insulin secretion
67
Where are dopamine 1 receptors located and what effect does dopamine have on them?
Kidney - Vasoilation (increase in RBF, GFT, Na secretion)
68
To what receptors does dopamine bind?
D1 at low doses
B1 at medium doses
Alpha1 at high doses
69
Some drugs exert both alpha and beta effect. Explain when one domaints over the other
At lower doses, drugs tend to effect more beta response while at higher doses, drugs tend to cause more alpha response
70
Name two alpha1 agonists and their effects
Alpha1 agonists
* Increase TPR
* Increase BP
* Potential reflex bradycardia
* NO change in pulse pressure (sys pres - dia pres)
Alpha 1 receptors cause vasoconstriction resulting in increase TPR and thus BP
- Phenlyephrine: Treats nasal decongestant and causes mydriasis
- Methoxamine: Treats paroxysmal atrial tachycardia
71
Name two alpha2 agonists and their effects
Alpha2 agonist binding causes decreased sympathetic output by decreasing NE synthesis
Clonidine - Mild to moderate HTN
Methyldopa - Mild to moderate HTN
72
Name 6 Beta agonists and their effect
B1 cause increase HR, SV, CO, and PP
B2 cause decrease TPR and BP
Isoproterenol (B1=B2) used for bronchospasm, heart block, and baryarrhythmias
Dobutamine (B1\>B2) used for CHF
Salmeterol, alubterol, and terbutaline (B2) for asthma
Ritodrine (B2) for premature labor
73
NE and E are mixed agaonsits. Which receptors do they bind to and what effect do they have?
NE binds to a1,a2,B1
A1: Increase TPR, BP
B1: Increase Hr, SV, Co, PP
E binds to all adrenergic receptors
Low dose
* B1: Increase HR, SV, CO, PP
* B2: Decrese TPR, BP
Medium dose
* B1: Increase HR, SV, CC, PP
* B2: Decrease TPR, BP
* A1: Increase TPR, BP
High dose
* A1: Increase TPR, BP
* Potential reflex bradycardia
74
What are NE and E used for?
Cardiac arrest
Adjunct to local anesthetic
Hypotension
E is also used for asthma and anaplhyaxis
75
What is tyramine
Found in red wine and cheese
Can cause hypertensive crisis by stimulating the release of NE from its vesicles
\*Tyramine is inhibited by MAO-A and therefore its concentration is greatly limited when taken orally
76
What is amphetamine
Used to treat narcolepsy and ADHD
77
What is epherdrine?
Used for cold medication
78
What are three drugs that act as indirect adrengeric receptor agonists? (In other words, they stimulate the release of NE into the synpatic cleft)
What two drugs inhibit NE release into the synaptic cleft?
**Stimulate release**
Tyramine (stimulates NE release)
Amphetamine (stimualtes DA, NE, 5HT release)
Ephedrine
**Inhibit release**
* Bretylium
* Guanethidine
79
Where is MAO A and B found?
MAO A - Liver but also anywhere (metabolizes NE, 5HT, and tyramine)
MAO B - Brain (metabolizes D)
80
What do alpha receptor antagonists do and what are some examples?
They decrease TPR and BP and are thus used to treat HTN, pheocromocytoma (eye tumor due to excess NE release), and BPH
Nonselective blocks
* Phentoalmine
* Phenoxybenzamine
A1 blockers
* Prazosin, doxazosin, terazosin, tamsulosin
A2 blockers
* Yohimbine (orthostatic hTN and impotence)
* Mirtazipine (antidepressant)
81
What do beta receptor antagonists do and give some examples
B1 antagonists: Decrease HR, SV, CO, renin, aqu humor
B2 antagonist: Vasoconstriction of blood vessels and bronchiols, decrease glycogenolysis
Acebutolol
Atenolol
Metoprolol
Pindolol
Propranolol
Timolol
82
What is the difference between open-angle and closed-angle glaucoma?
Open - Decreased reabsorption of aqueous humor from the posterior chamber out between the lens/iris muscle and into the Canal of Schlemm
Closed - Blockage of canal - EMERGENCY
\*Use beta blockers to decrease aq. secretion and use muscarinic activators to imrpove drainage through canal
- Pilocarpine and echthiophate: Activate M receptors to cause ciliary muscle contraction which increases flow through canal of Schlemm; echthiophate is an organophoshpate (AChE inhibition will increase outflow)
- Timolol: Beta blocker taht will block NE and thus decrease aqueous humor formation
83
What are three examples of zero-ordered drugs?
PEA looks like a zero
Phenytoin
Ethanol
Aspirin
84
How would you treat aspirin and amphetamine toxicity?
Aspirin is a weak acid and thus you would need to give sodium bicarbonate to promote acid elimination
Amphetamine is a weak base and thus you would nee to give ammonium chloride to promte basic elimination
85
What are the enzymes involved in breaking down ethanol into acetate? What drugs can inhibit this?
Ethanol to acetylaldehyde via alcohol dehydrogenase; inhibited by fomepizole
Acetylaldehyde to acete via acetylaldehye dehydrogenase; inhibited by disulfiram
\*Disulfirm allows for the accumulation of acetylaldehye dehydrogenase which leaves the person with hang-over effects
86
Besides ethanol, what else can fomepizole metabolize?
Methanol (otherwise would be broken down by alcohol dehydrogenase into formaldehyde which is very toxic and can cause blindness or keto acidosis)
