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Cardio Week 1 > ICL 1.4: Autonomic Nervous System Pharmacology > Flashcards

ICL 1.4: Autonomic Nervous System Pharmacology Flashcards

1
Q

what are the big categories of AND drugs?

A

cholinergic vs. adrenergic

stimulating vs. inhibiting

cholinergic receptors are mostly part of the PSNS while adrenergic are mostly SNS

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2
Q

what are cholinergic receptors?

A

they bind ACh and other substrates

there are 2 types:

muscarinic bind ACh are G-protein coupled receptors (GPCRs) –> M1-M5

nicotinic receptors bind ACh and are ion channels –> Nm and Nn

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3
Q

what are adrenergic receptors?

A

they bind NE, DA, EPI and other substances

there are 3 types: alpha, beta and dopamine

alpha 1 is a Gq pathway and alpha 2 is Gi while all the B receptors are Gs

they are all G-protein coupled receptors

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4
Q

how does G-protein coupled receptor signaling pathways work?

A

there’s Gs (G-stimulatory) and Gi (G inhibitory) receptors and Gq signaling pathways

when Gq pathway is activated, GDP is phosphorylated into GTP and GTP activates phospholipase C –> PLC cleaves PIP2 into DAG and IP3 –> IP3 binds to the ER and releases Ca+2 which leads to depolarization

when a Gs pathway is activated, GDP is phosphorylated to GTP which activates adenylate cyclase to turn ATP into cAMP –> cAMP activates PKA which goes and phosphorylates

when a Gi pathway is activated, adenylate cyclase is inhibited which helps regulate the Gs pathway

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5
Q

what does it mean if an organ has dual innervation from the ANS?

A

it means that the site is dually innervated and receives input from both the SNS and PSNS

most sites that receive ANS input are dually-innervated

however, blood vessels and sweat glands ONLY receive input from the sympathetic nervous system

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6
Q

what is predominant tone?

A

in most organs, the parasympathetic nervous system displays a “predominant tone”, meaning it has a stronger influence on tissue function when the body is at rest, as compared to the sympathetic nervous system 9

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7
Q

when the body is at rest, which drug will have a more substantial impact: a drug that blocks a NE receptor or one that blocks a muscarinic ACh receptor?

A

cholinergic antagonist

because when the body is at rest, the parasympathetic nervous system displays a predominant tone

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8
Q

when the body is in a stressful situation, which drug will have a more substantial impact: a drug that blocks a NE receptor or one that blocks a muscarinic ACh receptor?

A

adrenergic antagonist

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9
Q

how does the ANS effect the eye’s ability to accommodate/focus?

A

PSNS activates muscarinic receptors which contracts the ciliary muscle and changes lens shape to allow for near vision

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10
Q

how does the ANS effect pupil diameter?

A

SNS: α1 activation contracts radial dilator muscle, pulling iris open to cause mydriasis (pupil dilation)

PSNS: M activation contracts circular muscle (iris sphincter), pulling iris shut to cause miosis (pupil constriction)

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11
Q

how does the ANS effect aqueous humor production?

A

SNS: β activation stimulates production of aqueous humor by ciliary epithelium, α2 activation reduces production

α2 receptors are Gi pathways while β are Gs

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12
Q

what is glaucoma?

A

eye disorders that involve damage to the optic nerve, which can cause permanent blindness often resulting from abnormally high pressure inside the eye

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13
Q

what is open angle glaucoma?

A

aqueous humor flows out between cornea and iris, but drainage site is partially blocked, increasing pressure

it’s chronic, slow onset, more common

treatment is pharmacological

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14
Q

what is closed/narrow angle glaucoma?

A

lens is pushed forward against iris blocking outflow –> iris dilation can block drainage site even more

it’s usually acute and is a medical emergency

treatment is mainly surgical

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15
Q

which ANS drug classes might be useful in treating glaucoma?

A
  1. α2 agonists would decrease the rate of fluid production

2. muscarinic agonists would constrict the iris and pull the iris away from the drainage site to let fluid come out

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16
Q

which drugs are useful in treating open angle glaucoma?

A
  1. prostaglandins

first line treatment; increases fluid outflow by relaxing ciliary muscle

ex. latanoprost, bimatoprost
2. β-blockers

second line treatment; decreases fluid production from ciliary epithelium

ex. timolol, betaxolol

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17
Q

how does the ANS effect bronchial diameter?

A

PSNS: M3 activation contracts airway smooth muscle, causing bronchoconstriction

SNS: β2 activation relaxes airway muscle, causing bronchodilation

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18
Q

how does the ANS effect bronchial secretions?

A

PSNS: M3 activation stimulates goblet cells, submucosal glands to increase mucus secretion

SNS: β2 activation has minor effect on secretion, but increases clearance of secretions

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19
Q

how does the ANS effect the smooth muscle walls of the GI tract?

A

PSNS: M3 activation contracts smooth muscle to increase gastric tone and promote movement

SNS: α2 and β2 reduce tone/motility

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20
Q

how does the ANS effect the sphincters of the GI tract?

A

PSNS: M3 receptors relax sphincters and allow for transit

SNS: α1 constrict GI sphincters

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21
Q

how does the ANS effect GI secretions?

A

PSNS: M3 activation promotes secretion (e.g., saliva, acid, pepsin, mucin)

SNS: α2 activation (presynaptic) suppresses vagal ACh release, inhibiting motility, secretion

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22
Q

what are ANS co-transmitters and NANCs?

A

ANS effects (particularly in the GI tract and blood vessels) are often modulated by many other endogenous substances like serotonin, NO, substance P, etc.

when one or more of these substances is packaged into vesicles in adrenergic or cholinergic neurons, they are termed “co-transmitters”

some ANS-innervated organs contain neurons that are non-adrenergic and non-cholinergic (NANC), which release these substances when stimulated

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23
Q

how does the ANS effect the urinary bladder walls?

A

PSNS: M3 activation contracts detrusor muscle to expel urine

SNS: β2 activation relaxes detrusor to retain urine

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24
Q

how does the ANS effect the urethral sphincter?

A

SNS: α1 activation constricts the sphincter to keeps urine in

PSNS: M3 activation relaxes sphincter to allow urine to escape

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25
Q

how does the ANS effect the prostate?

A

SNS: α1A activation contracts prostate smooth muscle, which impedes urine flow

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26
Q

how does the ANS effect the pacemaker cells of the heart?

A

SNS: β1 activation increases rate of AP generation in SA node (+ chronotropy) and rate of action potential transmission in AV node (+ dromotropy) which increases heart rate

PSNS: M2 activation decreases rate of action potential generation in SA node (- chronotropy) and rate of AP transmission in AV node (- dromotropy) which decreases heart rate

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27
Q

how does the ANS increase heart rate?

A

SNS: β1 activation increases rate of AP generation in SA node (+ chronotropy) and rate of AP transmission in AV node (+ dromotropy); these effects increase heart rate

β1: Gs activation –> ↑AC –> ↑ cAMP:

cAMP increases opening frequency of HCN Na+ channels (increases If “funny” current) that brings the cell toward depolarization threshold  ↑ AP firing rate

cAMP increases opening of voltage-sensitive (L-type) Ca2+ channels responsible for rapid depolarization = ↑ AP firing rate

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28
Q

how does the ANS decrease heart rate?

A

PSNS: M2 activation decreases rate of AP generation in SA node (- chronotropy) and rate of AP transmission in AV node (- dromotropy); these effects decrease heart rate

M2: Gi activation  ↓AC  ↓ cAMP, which:

reduces opening frequency of HCN Na+ channels (decreases If “funny” current) that brings the cell toward depolarization threshold  ↓ AP firing rate

decreases opening of voltage-sensitive (L-type) Ca2+ channels responsible for rapid depolarization = ↓ AP firing rate

increases opening of K+ channels; K+ outflow  ↓ membrane potential  slower to reach threshold  ↓ firing rate

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29
Q

how does the ANS effect the force of which the heart pumps?

A

SNS: β1 activation increases the force of cardiomyocyte contraction (increased contractility, or “positive inotropy”) via PKA’s multiple effects on Ca2+ handling

PSNS: does not directly innervate cardiomyocytes

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30
Q

how does the ANS effect blood vessel resistance?

A

SNS: β2 activation causes VSMC relaxation (vasodilation) in skeletal muscle vessels

SNS: α1 (and α2) activation causes VSMC contraction (vasoconstriction) in skin, splanchnic & skeletal muscle vessels

PSNS: no direct innervation of VSMCs, but M3 activation on endothelial cells releases nitric oxide (NO), which diffuses into VSMCs and contributes to relaxation (vasodilation)

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31
Q

what is the RAAS system?

A

RAAS = Renin-Angiotensin Aldosterone System

SNS: β1 activation on kidney cells stimulates renin release, which ultimately increases blood volume by:

  1. reabsorbing / retaining Na+ (which draws more water into blood)
  2. vasoconstriction
  3. increasing thirst
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32
Q

what is the main way that ACh effects are terminated?

A

acetylcholinesterase

with adrenergic receptors, reuptake is how their effect is terminated

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33
Q

what are the targets for direct-acting drugs?

A

nicotinic and muscarinic receptors

34
Q

how might you increase ACh signaling?

A
  1. increase ACh
  2. acetylcholinesterase inhibitors
  3. ACh agonists
  4. block presynaptic receptors that mediate negative feedback
35
Q

how might you decrease ACh signaling?

A
  1. stimulate acetylcholinesterase
  2. block nicotinic or muscarinic receptors
  3. block the packing of ACh into vesicles
  4. block choline uptake into the cell (ACh precursor)
  5. block vesicle docking and release (this is nonspecific and would block all NTs)
36
Q

where are cholinergic receptors found?

A
  1. autonomic ganglia (nicotinic receptors)
  2. neuromuscular junction (nicotinic receptors)
  3. target organs of the parasympathetic nervous system (muscarinic receptors)

all muscarinic receptors are GPCRs: either Gq or Gi

37
Q

activation of muscarinic receptors results in what responses?

A
  1. mitosis = pupil constriction
  2. decrease in heart rate
  3. bronchial constriction and increased secretions
  4. increased motility and relaxation of sphincters in GI tract
  5. relaxation of sphincters and bladder wall contraction
  6. increased secretions of glands

since selectivity is somewhat limited, cholinomimetics produce most of these effects to some extent (depending on administration site and dose), and the blockers oppose them

38
Q

what are the 2 classes of direct-acting cholinomimetic drugs?

A
  1. choline esters
  2. alkaloids

cholinomimetics increase ACh signaling

39
Q

what are choline esters?

A

a class of direct-acting cholinomimetic drugs that can activate N, M or both receptors

they’re synthetic derivatives of ACh that increase ACh signaling

they have a permanently (+) charged quaternary ammonium group which results in hydrophilicity and low penetration into the CNS

some are rapidly and extensively metabolized in blood by cholinesterase enzymes –> those that are more susceptible to AChE have poor oral bioavailability and brief duration of action

40
Q

what are alkaloids?

A

a class of direct-acting cholinomimetic drugs that can activate N, M or both receptors

they are nitrogenous organic compounds of plant origin which have pronounced physiological actions on humans, including effects at ANS receptors

some are tertiary amines so they’re lipophilic and are well absorbed and readily enter the CNS! the quaternary amines are charged and not absorbed as well

ex. amanita mushroom or lobelia flower

41
Q

which drugs are muscarinic receptor agonists?

A
  1. bethanechol
  2. carbachol
  3. pilocarpine
42
Q

what is bethanechol?

A

a choline ester muscarinic receptor agonist that activates M1-M3 receptors in all peripheral tissues

poor AChE substrate so good bioavailability, doesn’t go to CNS

used to treat ileus and urinary retention by increasing bowel and bladder tone

ex. PO, Urecholine®

43
Q

what is carbachol?

A

a choline ester muscarinic receptor agonist that’s a nonselective M and N agonist

poor AChE substrate so good bioavailability

Treats open-angle glaucoma by increasing fluid outflow

ex. eye drops; Miostat®

44
Q

what is pilocarpine?

A

alkaloid tertiary amine that’s an M3 agonist

crosses BBB because it’s a tertiary amine and isn’t charged

treats glaucoma by increasing fluid outflow (eye drops; Isopto Carpine®)

treats xerostomia in Sjögren syndrome (PO, Salagen®)

45
Q

which drugs are nicotinic receptor agonists?

A
  1. nicotine

2. varenicline

46
Q

what is nicotine?

A

an alkaloid tertiary amine that’s an agonist at the N and M receptors

activates post-ganglionic neurons (SNS, PSNS), skeletal muscle end plates, CNS

used for smoking cessation aid (OTC; gum, lozenge, nasal spray or transdermal patch, e.g., Nicorette®)

47
Q

what is varenicline?

A

partial agonist at specific N subtype

it blocks nicotine activation of CNS reward pathways

used for smoking cessation aid (Chantix)

48
Q

how can a drug with nicotine receptor-activating effects like varenicline block nicotines effects?

A

varenicline is a partial agonist at specific nicotinic receptor subtypes

so since it’s a partial agonist, it occupies the receptors and activates them a only a little bit

this way, you can smoke as much as you want and put as much nicotine into your body but that nicotine won’t be able to get to the receptors and activate the reward pathway

49
Q

what are indirect-acting cholinergic drugs?

A

increase/decrease ACh everywhere

they ALL work by inhibiting acetylcholinesterase enzyme which increases ACh levels

classes differ in duration of action, which is a function of their bonding to the target site = reversible vs. irreversible

more widespread drug effects

50
Q

what are reversible indirect-acting cholinergic drugs? what are the 2 classes?

A
  1. alcohols

quaternary, charged, lipid-insoluble –> short-acting due to weak reversible binding to AChE active site (3 minutes)

  1. carbamates

tertiary or quaternary –> intermediate-acting; drug-enzyme complex persists for 1-6 hr

51
Q

what are irreversible indirect-acting cholinergic drugs?

A

organophosphates

most are well-absorbed from skin, lung, gut, eye, and distribute into most organs including CNS

long-acting due to covalent binding to AChE active site; drug-enzyme complex persists for hundreds of hours; can become nearly irreversible (“aging”)

52
Q

which drugs are reversible indirect-acting cholinergic drugs that do not enter the CNS?

A
  1. edrophonium
  2. pyridostigmine
  3. neostigmine
53
Q

what is edrophonium?

A

an indirect-acting cholinergic drug that does not enter the CNS

it’s an alcohol that increases ACh concentrations

was used to diagnose MG but now an antibody test is used

54
Q

what is pyridostigmine?

A

a quaternary carbamate indirect-acting cholinergic drug that does not enter the CNS

it increases ACh concentrations

1st-line symptomatic treatment for myasthenia gravis (PO; Regonol®)

cholinergic side effects can be dose-limiting; treated with antimuscarinics

55
Q

what is neostigmine?

A

a quaternary carbamate indirect-acting cholinergic drug that does not enter the CNS

it increases ACh concentrations and is used to treat myasthenia gravis and urinary retention

56
Q

which drugs are reversible indirect-acting cholinergic drugs that enter the CNS?

A
  1. physostigmine

2. rivastigmine

57
Q

what is physostigmine?

A

tertiary carbamate indirect-acting cholinergic drug that crosses the BBB

it increases ACh concentrations and it’s the antidote for anticholinergic toxicity

58
Q

what is rivastigmine?

A

tertiary carbamate indirect-acting cholinergic drug that crosses the BBB

Increases ACh concentrations by preferentially inhibiting AChE and BuChE isoforms in memory regions of brain

used to treat Alzheimer’s

donepezil, galantamine and tacrine are structurally-unrelated anticholinesterase drugs also used in treatment of Alzheimer’s disease (tacrine is no longer used to hepatotoxicity)

59
Q

which drugs are irreversible indirect-acting cholinergic drugs?

A
  1. carbaryl
  2. parathion
  3. malathion
  4. sarin
  5. VX

these drugs are basically poisons because they’re designed to be extremely lipid-soluble, highly distributed in the body, and long-lasting

60
Q

what is carbaryl?

A

irreversible indirect-acting cholinergic drug

it’s a carbamate insecticide (Sevin®) for home use

61
Q

what is parathion?

A

irreversible indirect-acting cholinergic drug

it’s an organophosphate insecticide that’s extremely toxic and limited to just some agricultural uses

62
Q

what is malathion?

A

irreversible indirect-acting cholinergic drug

it’s an organophosphate insecticide that’s highly toxic to in secret and non-target species like fish

it’s less toxic to birds and mammals due to rapid metabolism to inactive products

treats head lice (topical; Ovide®)

63
Q

what is sarin and VX?

A

irreversible indirect-acting cholinergic drugs

they’re chemical warfare agents

64
Q

what’s the pneumonic for the side effects of muscarinic drugs?

A

DUMBBELSS

Diarrhea
Urination
Miosis
Bronchospasm
Bradycardia
Emesis
Lacrimation
Sweating
Salivation

basically the parasympathetic nervous system is going crazy

65
Q

what are the side effects of nicotinic drugs?

A
  1. fasciculations
  2. weakness
  3. paralysis from ACh effects at NMJ
66
Q

what is the antidote for anticholinesterase poisoning?

A

atropine and 2-PAM

so basically there’s too much ACh and you need to get rid of it

or else you’ll get severe muscarinic and nicotinic effects like DUMBBELSS and fasciculations, weakness, paralysis

67
Q

what is atropine?

A

the antidote for anticholinesterase poisoning!

it’s a competitive muscarinic antagonist in CNS and periphery

you don’t give a nicotinic antagonist because that’s the NT at NMJ and it’s literally what doctors use to paralyze people during surgery

68
Q

what is pralidoxime?

A

2-PAM is the antidote for anticholinesterase poisoning!

it regenerates active AChE by hydrolyzing phosphorylated AChE

it reverses nicotinic and muscarinic effects but does NOT cross the BBB

69
Q

what is the MOA of antimuscarinic drugs?

A

all antimuscarinic agents are competitive antagonists at muscarinic ACh receptors

70
Q

what are the 2 classes of antimuscarinic drugs?

A
  1. alkaloids

plant derived, tertiary amine structure, lipophilic, well-absorbed

ex. deadly nightshade used for cosmetic purposes to dilate pupils
2. synthetic tertiary and quaternary amines

most tertiary amines penetrate CNS; quaternary amines were developed to produce mainly peripheral effects

the synthetic antimuscarinics tend to block a wider range of receptors (relative to the alkaloids)

71
Q

what are the side effects of antimuscarinic drugs?

A

mad as a hatter

hot as hell

red as a beat

dry as a bone

blind as a bat

confused, hyperthermia, flushed skin, dry mouth/urinary retention, dilated pupils

most clinically- used M antagonists lack receptor subtype selectivity; their actions are very similar to those of atropine

72
Q

which drugs are antimuscarinics used for the eye and CNS?

A
  1. tropicamide
  2. benztropine/trihexyphenidyl
  3. scopolamine
73
Q

what is tropicamide?

A

an antimuscarinic drug that is used to produce mydriasis and cycloplegia to facilitate eye exams or surgery

aka it makes the pupils dilate!

74
Q

what are benztropine/trihexyphenidyl?

A

antimuscarinic drugs used to relieve acute dystonia in Parkinson’s disease, and can also counteract dystonias caused by antipsychotics

effects are due to improving the balance between ACh and DA in basal ganglia

75
Q

what is scopolamine?

A

antimuscarinic drug that’s first-line treatment for motion sickness

76
Q

which drugs are antimuscarinics used for the GI and respiratory systems?

A
  1. dicyclomine
  2. oxybutyinin
  3. ipratropium
77
Q

what is dicyclomine?

A

antimuscarinic used to treat irritable bowel syndrome

dicyclomine and hyoscyamine are used for their antispasmodic effects in irritable bowel syndrome for short-term symptomatic relief

78
Q

what is oxybutyinin?

A

antimuscarinic used to treat urgency incontinence/overactive bladders

oxybutynin, solifenacin, tolterodine and others are first-line pharmacologic treatment for bladder spasms and overactive bladder

79
Q

what is ipratropum?

A

antimuscarinic used to treat asthma and COPD

Ipratropium, tiotropium and others are used for their bronchodilating effects in COPD and asthma (not first-line)

few antimuscarinic side effects due to localization in lung since it’s given via inhaler

80
Q

what is glycopyrrolate?

A

antimuscarinic used to reduce glandular secretion

reduces salivary, tracheobronchial, pharyngeal and gastric secretions during induction of anesthesia and intubation (IV, IM; Robinul®)

treats primary axillary hyperhidrosis and primary focal hyperhidrosis (drooling)

81
Q

which 3 drugs are the antidote for acetylcholinesterase inhibitor overdose?

A

glycopyrrolate, atropine, pralidoxeme

  1. glycopyrrolate

reverses bradycardia (intraoperative) and muscarinic effects of cholinergic agents (AChEIs) given to reverse neuromuscular blockade after surgery

  1. atropine

muscarinic antagonist in CNS and periphery

  1. pralidoxeme

regenerates active AChE in periphery (does not cross BBB); must be given early

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