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Pharmacology > Autonomic Nervous System > Flashcards

Autonomic Nervous System Flashcards

1
Q

Autonomic nervous system function

A

control of involuntary activities, i.e. CV responses, respiration, endocrine secretion (smooth muscle around endocrine glands), GI motility and secretions, reproductive and urogenital control

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2
Q

Parasympathetic nervous system (PNS)

A

long pre-ganglionic fibres: ACh–> nicotinic receptors

short post-ganglionic fibres: ACh–>muscarinic receptors

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3
Q

Sympathetic nervous system (SNS)

A

Short pre-ganglionic fibres: ACh–>nicotinic receptors

Long post-ganglionic fibers:

  • Noradrenaline (NA)–>alpha and beta adrenergic receptors
  • ACh–> muscarinic receptors

Autonomic ganglia of adrenal gland; adrenaline–>alpha and beta adrenoceptors

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4
Q

SNS ganglia/cell bodies/ NTS

A

short pre- and long post-synaptic fibres

Cell bodies for pre-synaptic fibres are found at the inter-mediolateral columns of the spinal cord from the 1st thoracic to the 3rd lumbar segment (T1-L3)

Axons synapse at 1) paired paravertebral ganglia 2)pre-vertebral ganglion (near aortic bifurcation) 3) terminal (within end organ itself).

ACh is pre-synaptic NT

NA is post-synaptic NT

Adrenal medulla chromaffin cells (modified neurons) release adrenaline into the peripheral nervous system

Innervations are much more diffuse, with many more ramifications than the PNS.

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5
Q

Functions of SNS

A

If you treat with an SNS agonist (i.e. synthetic analog of NA)

  • mydriasis (pupil dilation)
  • positive chronotropic effect (increase HR)
  • positive inotropic effect (increase force of contraction)
  • positive dromotropic effect (increased speed of conduction within the heart)
  • vasoconstriction or vasodilation depending on the receptor
  • bronchodilation
  • decreased gastric motility
  • increased sphincter tone
  • glycogenolysis
  • gluconeogenesis
  • bladder wall distension (Beta receptors)/bladder neck constriction (alpha receptors)
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6
Q

PNS ganglia/cell bodies/ NTs

A

Cranial outflow: oculomotor, facial, glossopharyngeal and vagus

Sacral outflow: nervi erigentes

Axons of the long pre-synaptic fibres synapse in or near the organ innervated

PNS has a more localized effect than SNS

ACh is pre and post synaptic NT

ANS has tone, can up/down regulate function within a system

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7
Q

Functions of PNS

A

CV system: decrease rate, conduction velocity, force of contraction

vasodilation: INDIRECT physiological effects, as no innervation. ACh induces NO release from vascular endothelial cells, but can’t be stimulated pharmacologically.

Gi system: increased motility, increased secretion

Urinary tract: contraction of detrusor, urethral peristalsis, relaxation of sphincter

Miosis: constriction of pupil

Respiratory: bronchoconstriction (only INNERVATED by PNS) and increased secretion.

Response of lungs to ANS is only driven by PNS- remember SNS affects adrenaline release and adrenaline can have an effect on the lungs. Lungs aren’t bronchodilating in response to SNS nerves, but rather circulating adrenaline release.

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8
Q

Noradrenaline

A

synthesized in the nerve terminal from tyrosine

stored in vesicles until an AP induces its release

Undergoes reuptake and enzymatic degradation

Has an effect on alpha and beta adrenoceptors

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9
Q

Noradrenaline action with the SNS

A

Production of NA: tyrosine–>L-DOPA by tyrosine hydroxylase

L-DOPA–> dopamine–>Noradrenaline

NA is exocytosed out of the pre-synaptic neuron and binds to the receptors.

Extracellular uptake of NA is done either presynaptically or by neuronal cells in the vicinity. There’s also a vesicular uptake mechanism from the cytosol into synaptic vesicles.

Uptake 1: presynpatic uptake by NA transporter- cocaine inhibits this uptake

Uptake 2: by non-neuronal cells- phenoxybenzamine inhibits this uptake

Uptake 3: vesicular uptake mechanism into synaptic vesicles- reserpine inhibits this uptake

Metabolites of NA produced by these enzymes: COMT, MAO, PMNT

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10
Q

SNS receptors

A

NA acts through G-protein coupled receptors (semitransmembrane domains)

Alpha receptors: Alpha 1 and Alpha 2. Alpha 1 receptors broken up into Alpha1a, 1b, 1d

Alpha 3 receptors broken up into Alpha2a, 2b, 2c

Beta receptors broken up into Beta 1, 2, 3, and 4.

No commercially available veterinary drugs that can target B3, B4 or any alpha 1 and 2 subtypes.

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11
Q

Alpha 1 adrenoceptors

A

Alpha 1a, 1b, 1d subtypes

Couple mainly to Gq

2nd messenger: activation of phospholipase C leading to formation of IP3 and diacylglycerol (DAG)

IP3 induces release of intracellular calcium from SR and DAG activates protein kinase C.

IP3 results in stimulation of tissues carrying alpha 1 receptors

Alpha 1 receptors are widely distributed:

  • VSM: vasoconstriction
  • Myocardium: positive inotropic effect (increased force of contraction)
  • prostatic smooth muscle: contraction
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12
Q

Alpha 2 adrenoceptors

A

Alpha 2a, 2b, 2c subtypes

Alpha 2 receptors couple to Gi and Go

Inhibit adenylate cyclase and thus decrease cAMP.

Inhibit voltage gated calcium channels, and activate Ca2+ dependent K+ channels–> inhibit activity of any system which predominantly expresses alpha 2 receptors

Functions: located prejunctionally (on synaptic fibres) and inhibit NT release

-CNS: mediate sedation and analgesia- inhibit prejunctionally, decreased activity of CNS (i.e. sedation).

Postjunctionally, in VSM–> vasoconstriction- principle side effects of alpha 2

also present in uterus, gut and platelets

nb: alpha 2a presynaptic subtype: sedative effects without effects on VSM

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13
Q

Beta 1 adrenoceptors

A

Couple mainly to Gs

Stimulation of adenylate cyclase which increases cAMP.

Increased cAMP increases protein kinase A

Beta 1 found mainly in the heart.

Activation leads to: increased force of contraction, conduction and rate of impulse formation

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14
Q

Beta 2 adrenoceptors

A

Mediative activity through Gs and Gi

Can stimulate or inhibit cAMP production

Main effects:

  • VSM relaxation- inhibitory effect
  • bronchodilation- inhibitory effect
  • stabilize respiratory mast cells.
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15
Q

Recap of SNS receptors

A

Alpha 1 (stimulatory)–>increase IP3 and DAG–>increase Ca2+–>vasconstriction of SM except in GIT

Alpha 2 (inhibitory)–>decrease AC–>decrease cAMP–>presynaptic inhibition (lots of alpha 2 in CNS), contratction of VSM

Beta 1 (stimulatory)–>increase AC–>increase cAMP–> increase protein kinase A–> increase Ca2+–> increase force of contraction, conduction and increase HR

Beta 2–> increase or decrease cAMP–> inhibitory: relaxation of smooth muscle (e.g. bronchodilation and vasodilation in skeletal muscle).

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16
Q

Cholinergic receptors- Nicotinic

A

Ligand-gated ion channel–> Nmusc, Ngang, Nneur

these don’t particularly affect ANS atthe level of the end organ

They increase permeability to Na+ and K+ (stimulatory)

3 types: found in skeletal muscle, ganglia and brain

17
Q

Cholinergic receptors- Muscarinic

A

G-protein coupled receptor–> M1, M2, M3, M4, M5

Used to manipulate ANS

M1 (neural): ganglia, CNS, gastric parietal cells: activate protein lipase c (PLC)–> formation of IP3 and DAG–>decreased K+ conductance. M1 agonist is STIMULATORY

M2 (cardiac): All areas of heart and also in brain-stem. Pre-synaptic inputs to peripheral autonomic neurons. Inhibit AC and open K+ channels, inhibiting Ca2+ channels. M2 agonist would DECREASE activity.

M3 (glandular/smooth muscle): smooth muscle and glandular tissue and in cerebral cortex: activate PLC. Relaxation of vascular smooth muscle d/t Nitric Oxide (NO). Bind drug to M3, get activation, but decrease of VSM activity (i.e. decreased contraction) d/t NO.

M4 (CNS): inhibit AC- inhibitor system unclear

M5 (CNS): activate PLC- stimulatory receptor

18
Q

Drug classes

A

Direct acting: bind specifically to receptors which get activated by ANS

Agonists= sympathomimetics, parasympathomimetics

Antagonists= sympatholytics, parasympatholytics

Indirect acting: change amount of NT release–> indrect effects on end-organ via manipulation of ANS

Sympathomimetics- displace NA from terminal itself (not the AP stimulated)

Parasympathomimetics: anticholinesterases, displace ACh

19
Q

Pharmacological maniupation of ANS relative to the eye

A

Mydriatics: dilate pupil

Glaucoma: increased build-up of fluid. Control of fluid production is very important.

Horner’s syndrome: condition that affects SNS–can use drug intervention to prove where the lesion is

20
Q

ANS receptors in the eye

A

M3 in constrictor pupillae (constriction)

Alpha 1 in dilator pupillae (dilation)

Alpha 1 in ciliary body blood supply (constrict VSM)

B1, B2, Alpha 2, M3 in ciliary body- nb: aqueous humor produced in ciliary body.

Beta receptors in ciliary muscle–> slight relaxation

M3 in ciliary muscle–> contraction

Humor flows from ciliary body through pupil, across pupillary muscles to the trabecular meshwork and into the canal of schlemm.

21
Q

Mydriatics (dilate eye)

A

diagnostic: short-acting

Treatment of uveitis (prevent synechia- lens sticking to cornea): long-acting

M3 receptors on constrictor pupillae–>antagonism of M3 receptors will lead to mydriasis (dilation)

Parasympatholytic/cholinergic antagonist- bring about dilation of pupil. No M3 specificc drugs available

Atropine, tropicamide, cyclopentone–> all non-specific muscarinic drugs

Give topically to reduce systemic effects.

Side effects can be predicted: accomodation paralysis (cyclopegia), hypersalivation, GI ileus— contraindicated with glaucoma (because it’s opposite of what we want to achieve).

Alternative: alpha 1 adrenoceptors located on dilator pupillae. Can give sympathomimetic, ideally alpha 1 adrenergic agonist i.e. phenylephrine–> give topically to avoid systemic effects.

22
Q

Glaucoma

A

problem= increase intraocular pressure

Open angle glaucoma: occurs slowly over time due to an obstruction of trabecular meshwork by neoplasm/inflammation. No passage of fluid leaving trabecular mesthwork.

Closed angle glaucoma: acute–> iris is displaced against cornea and fluid can’t get out

Primary glaucoma: no hx of trauma or ocular disease

Secondary glaucoma: ocular inflammation, lens dislocation, introcular tumours or trauma

Different ways of treating due to different nature of underlying problem

Open angle: can move via dilation

Closed angle: need to stop fluid production

IOP: blindness due to compression of nerve

23
Q

Glaucoma treatment 1: closed- angle glaucoma

A

Aim: decrease aqueous humour production (no effect on pupil)

Sympatholytics:

  • Timolol (non-specific beta adrenoceptor antagonist)–> decreased aqueous production, possibly via B2 receptors
  • Betaxolol (B1 adrenoceptor antagonist)

Sympathomimetics:

  • epinephrine: non-specific adrenoceptor agonist–> decreases aqueous production via alpha 1 vasoconstriction of ciliary blood vessels (change VSM, decrease Q, decrease aqueous humor production)
  • apraclonidine: alpha 2 adrenoceptor agonist (also weak alpha 1 agonist–>capitalizing on this action)
24
Q

Glaucoma treatment 2: open angle glaucoma

A

Miosis (pupillary constriction) will open the drainage angle

Direct parasympathomimetic: non-specific muscarinic agonists (local application to bring about effect) e.g. pilocarpine, carbachol

Indirect parasympathomimetic: acetylcholinesterase inhibitors–>increase [ACh]–targets NT rather than receptor e.g. demecarium bromide

25
Q

Glaucoma treatment 3: decrease aqueous production

A

Carbonic anhydrase inhibitors: decreased aqueous production- not affecting ANS

26
Q

Horner’s syndrome symptoms

A

Ptosis (lowering/drooping of eye), protrusion of 3rd eyelid, elevation of lower lid, miosis (not pronounced in farm animals), enophthalmia (not pronounced in farm animals), unilateral heat increase/sweating

Cause: damage to SNS- local inflammation, nerve damage, neoplasia–> can occur in any of the neuron orders

1st order: central lesion

2nd order: pre-ganglionic

3rd order: post-ganglionic

ANS pharmacological intervention is principally diagnostic

27
Q

Horner’s syndrome lesion diagnosis

A

Mydriasis should occur after noradrenaline binds to alpha adrenoceptors on dilator pupillae. Can use an alpha 1 agonist e.g. phenylephrine.

if there’s a lesion in the CNS (1st order): dilation occurs in about 60-90 minutes

if there’s a lesion in the 2nd order (preganglion), dilation occurs in 45 minutes

If there’s a lesion in the 3rd order (postganglion), dilation occurs in 20 minutes

The time taken to dilate relates to denervation hypersensitivity–when you lose normal neuronal control, body becomes hypersensitive to NT. Reuptake is disrupted, so drug remains in cleft longer, leading to an exaggerated response.

28
Q

Horner’s diagnosis: cocaine drop test and hydroxyamphetamine test

A

Cocaine eyedrops block the reuptake of NA, resulting in dilation of the normal pupil. In Horner’s syndrome, the lack of NA in the synaptic cleft causes failure to dilate.

Hydroxyamphetamine: this test helps to localize cause of miosis. If the third order neuron (post-ganglionic) is intact, then the amphetamine causes NT vesicle release, thus releasing NA into the cleft and resulting in a robust dilation of the pupil. If the lesion itself is in the third order neuron, then the amphetamine will have no effect and the pupil will remain constricted.

29
Q

Pharmocological manipulation of the ANS relative to micturition

A

Disorders of storage: urinary incontinence

  • hypercontractile detrusor (wall of bladder too active)
  • hypocontractile sphincter/urethea (sphincter isn’t closing)

Disorders of storage: urinary retention

  • hypocontractile detrusor (not voiding)
  • hypercontractile sphincter/urethra (can’t urinate)
30
Q

Receptor distribution in urinary system

A

M3 (stimulatory): large amounts in detrusor

Some M2 on detrusor/sphincter; large M2 on where SNS inputs (M2 is inhibitory)

B2 on detrusor and sphincter (inhibitory)

Alpha 1 only on sphincter (stimulatory)

Storage: sympathetic dominance + alpha 1 (constriction of sphincter) + B2 (relaxation of detrusor)

Voiding: parasympathetic stimulation + M3 (increase in M3 actively contracts detrusor) + M2 (relaxes sphincter, inhibits SNS input); sympathetic relaxation (alpha 1- relax sphincter)

31
Q

Detrusor hypercontractility/spasticity (urinary incontinence)

A

Cause: bladder infections, neurogenic disorders, over-activity of detrusor wall itself

Aim: decrease destrusor activity (M3 receptor)- Antimuscarinic

Oxybutalin, propantheline, flavoxate, atropine- non-specific muscarinic antagonists given systemically

side effects: low saliva, GI stasis, tachycardia, excitement, sedation, increased IOP, mydriasis, anti-spasmodic effects on GI

32
Q

Detrusor atony- urinary retention

A

decrease in activity of detrusor wall itself, can be caued by neurogenic disorders, over-distension

Aim: increase detrusor activity–> cholinergic agonists

Bethanechol- non-specific muscarinic agonist, but higher affinity for M3.

nb: if dose is too high, will bind to other M reeptors

Oral admin side effects: GI stimulation, hypersalivation, defecation

Antidote: Atropine

33
Q

Urethral sphincter incompetence

A

Common in spayed bitches- etiology not fully characterized

Steroids: estradiol is common tx (not directly ANS), eventually fails to work

Aim: increase sphincter tone–> alpha 1 agonists

Oral phenylpropanolamine (non specific alpha adrenergic agonists) and ephedrine (stimulates NA release, less predictable- binds to alpha and beta receptors)

note: systemic distribution

side effects: hypertension, restlessness, increased IOP

34
Q

Urethral spasticity

A

too much activity in urethra

cause: infections, inflammatory neurological disorders, urethral obstructions, bethanacol treatment

Phenoxybenzamine- non-selective alpha antagonist but preferential binding to alpha 1–IRREVERSIBLE

Side effects: hypotension, reflex tachycardia, increased IOP, GI upset

Prazosin, terazosin- selective alpha 1 antagonist

Side effects: hypotension, GI upset

35
Q

Co-transmission

A

transmitters released from nerve terminals other than ACh and NA

non-peptides: ATP, GABA, 5HT3 (serotonin), dopamine, NO

peptides: NPY, VIP, substance P, GnRH and CGRP
example: ATP is released from post-ganglionic sympathetic nerve terminals in conjunction with NA

Advantages: duration/distribution and variation in response.

Pharmacology (12 decks)

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