ANS Flashcards
Tonically active
There is continuous basal discharge along SNS and PNS nerves established by “pacemaker” neurons in the brainstem
ANS that has postganglionic cholinergic fibers
PNS
ANS that has postganglionic muscarinic receptors
PNS
Postganglionic neurotransmitters of PNS
ACh
Vasoactive intestinal peptide (VIP)
Nitric oxide (NO)
Postganglionic neurotransmitters of SNS
Epi and norepi
ATP
Neuropeptide Y (NPY)
Target cell types for SNS
SNS specific (no PNS)
Sweat glands and piloerector muscles
Liver, adipose, and kidney
Vascular smooth muscle
Lack PNS innervation
What target cells for both SNS and PNS
Smooth muscle
Cardiac muscle
Cardiac conducting tissue
Endocrine/exocrine glandular tissue
Physiologic competition between SNS/PNS and heart
PNS innervate only nodes of the heart - stimulation activates metabotropic AChR and slows HR
SNS innervate nodal cells of the heart, ventricular myocytes, and peripheral vasculature
Physiologic competition between SNS/PNS and lungs
PNS innervation activates metabotropic AChR’s that cause bronchoconstriction and mucous secretion
SNS activate metabotropic adrenergic receptors that induce bronchodilation
PNS - bronchoconstriction and secretions
SNS - bronchodilation
Physiologic competition between SNS/PNS and the eyes
PNS innervation activates metabotropic AChR’s that cause pupillary constriction and allow for accommodation (parasympathetics innervate the iris dilator muscle. Pupils constrict because the iris dilator contracts)
SNS innervation activates metabotropic adreneric receptors that cause pupillary dilation and has no effect on accomodation (SNS innervates the radial muscle - when contracted, the pupil is dilated)
Accomodation refers to the contraction of the ciliary muscles attached to the lens, which allows the lens to become more rounded - better able to focus on near objects (PNS control)
HR w/ and w/o PNS innervation
SA node w/ PNS drive - 60-100 bpm
SA node w/o PNS drive - 100-110 bpm (intrinsic automaticity of SA node)
Thermoregulatory (eccrine) sweat glands
Activated by ACh released by sympathetic nerves (exception to rule that sympathetic nerves are adrenergic)
ANS control of bladder function
Filling - SNS predominates (relaxation of detrusor m. and contraction of internal sphincter)
Micturition - PNS predominates (contraction of detrusor m. and relaxation of internal sphincter)
α1 - in internal sphincter
β 2 , adrenoreceptor in detrusor muscle L1–L3, lumbar segments
M, muscarinic cholinoreceptor in detrusor muscle and internal sphincter S2–S4, sacral segments
Thoracolumbar outflow
Craniosacral outflow
MOA and target tissue of α 1 receptors
MOA and target tissues of α 2 receptors
MOA and target tissues of β 1 receptors
MOA and target tissues of β 2 receptors
MOA and target tissues of nicotinic receptors
MOA and target tissues of muscarinic tissues
Only type of agent that prevents accomodation of the eye?
PNS antagonist
All preganglionic neurons release ______, and all postganglionic neurons have ______ receptors
All preganglionic neurons release ACh and all postganglionic neurons have nicotinic AChR’s
no matter where we are in the body, everywhere and always within the autonomic nervous system, the first synapse from preganglionic to postganglionic tissue uses the neurotransmitter acetylcholine and i tgoes to a nicotinic acetylcholine receptor.
Does the PNS or SNS exit the spinal cord and form a trunk?
SNS forms a sympathetic trunk
PNS nerves stay separate
SNS innervation of adrenal medulla
Specialized sets of preganglionic SNS neurons do not synapse with a postganglionic neuron with a ganglion, but rather continue to the adrenal medulla where the medullary cells act as their ganglion.
The adrenal medullary cells have ACh receptors, just like a ganglionic neuron.
The cells of the adrenal medulla are neuroendocrine
Difference between epi/norepi and what receptors they bind
Epinephrine binds α1, α2, β1, and β2
Epi has access to β2; norepi
doesn’t.
β2 acts as sympathetic tone but also acts to check the norepi signal.
β2 receptor activation in vascular smooth muscle
Only activated by epinephrine - induces smooth muscle relaxation (all beta receptors raise cAMP in target tissues)
What causes constriction of smooth muscle arterioles?
Binding of norepinephrine onto alpha-1 receptors
β2 receptors in skeletal muscle only respond to what?
Circulating epinephrine (as opposed to direct innervation)
This is a delayed response relative to the sympathetic activation of alpha-1 receptors (vasoconstriction by binding of norepi) - alpha-1 receptors are also activated by circulating epi
What causes vasodilation in exercising muscle
Local metabolites and autoregulation
What is the response of skeletal muscle vasculature to sympathetic nerve stimulation?
Vasoconstriction
Rate and force of contraction of the heart
ANS control
β1 are the primary receptors and stimulation causes increase in both.
However, the dominant repsonse is cholinergic - causing decrease in both
Predominant tone of all blood vessels
Sympathetic
Predominant tone of bronchial tree
Parasympathetic
Muscarinic vs. nicotinic receptors
What enzyme converts norepinephrine to epinephrine?
Phenylethanolamine-N-methyltransferase
Enzymes that metabolize norepinephrine and terminate its actions
Monoamine oxidase and catechol-O-methyltransferase
NE biosynthesis
Diagram
Adrenergic receptors and their direct response
Diagram
All adrenergic receptors are ______, and activate through ______
All adrenergic receptors are metabotropic and activate through G proteins (Gi, Gs, Gq).
A) site 2
Atropine is a drug that is useful for dilating the pupil and it also paralyzes accommodation. These effects of atropine occur at which of the following sites on the diagram above (in question 1)?
D) Site 6
The flight or fight response is made possible by high levels of epinephrine circulating throughout the body, acting as a hormone, rather than a neurotransmitter. When acting at beta-2 receptors in the vasculature of skeletal muscle, what is the physiologic effect?
Vasodilation
Which enzyme is the rate-limiting step involved with synthesizing acetylcholine?
Choline acetyltransferase
M2 muscarinic receptors act via which second messenger pathways?
Decrease cAMP
ACh biosynthesis
Agonist and antagonist of nicotinic receptors
Agonist - ACh/Nicotine
Antagonist - Trimethaphan (Nn) only and curare (Nnmj) only
Agonist and antagonist of muscarinic recptors
Agonist - ACh and muscarine
Antagonist - atropine
Smooth muscle in vascular endothelium
Constriction of vessel diagram
Smooth muscle in vascular endothelium
Dilation of vessel diagram
Myocardial contractility
Diagram - MOA of norepi
Eccrine sweat glands involved in thermoregulation are innervated by what nerve fiber types?
Cholinergic postganglionic sympathetic fibers
Rapid activation of the sympathetic nervous system as in response to a fight or flight event (a lion walking into your backyard) will stimulate all of the following except one. Which is the exception?
Dilation of arterioles in skeletal muscle
The function of which of the following organs or systems is dominated by the sympathetic nervous system?
Systemic blood vessels
The odd muscarinic receptors (M1, M3, M5) primarily impact which second messenger pathway component?
Activate phospholipase C
What enzyme is the rate-limiting step in norepinephrine biosynthesis?
Tyrosine beta hydroxylase
Stimulation of which adrenergic receptor is associated w/ increased heart rate and increased myocardial contractility?
Beta 1 receptor stimulation
Which of the following is the common link inside vascular smooth muscle cells that is (a) activated when norepinephrine stimulates alpha 1 receptors and is (b) inhibited after epinephrine stimulates beta 2 receptors?
Myosin light chain kinase
If you administer a drug that blocks the nicotinic receptors in the ganglia, what do you expect will happen to heart rate?
The HR will increase
Steps between norepi binding to an alpha-1 receptor in smooth muscle vasculature and physiologic response of vasoconstriction
- Signal transduction through Gq
- Activation of phospholipase C
- Liberation of inositol triphosphate and diacylglycerol
- Intracellular calcium levels rise
- Calcium combines with calmodulin
- Myosin light chain kinase is activated
- Myosin becomes phosphorylated
- Actin and myosin interact
List steps between epi binding to a beta-2 receptor in smooth muscle of the lung and the physiologic response of bronchodilation
- Signal transduction through Gs
- Activation of adenylyl cyclase
- Formation of cAMP
- Activation of protein kinase A
- Phosphorylation of myosin light chain kinase
List the steps between norepi binding to a beta-1 receptor in heart and the physiologic response of tachycardia
- Signal transduction through Gs
- Activation of adenylyl cyclase
- Formation of cAMP
- Activation of protein kinase A
- Increased intracellular calcium levels
Biochemical function of alpha receptors
alpha-1 = phospholipase C activation, resulting in an increase in intracellular calcium
alpha-2 = inhibition of adenylyl cyclase, resulting in decreased cAMP
Physiological effect of alpha-1 receptor agonistic binding
Contraction of smooth muscles of urinary tract (bladder/prostate)
Exocrine gland secretion
Neuronal excitation
Physiological effect of alpha-2 receptor agonistic binding
Inhibition of norepinephrine release
Decrease in secretion of aqueous humor
Decrease in insulin secretion
Platelet aggregation
CNS effects (sedation)
Physiological effect of beta-1 receptor agonistic binding
Increase in secretion of renin
Increase in HR, contractility, and conduction
Physiological effect of beta-2 receptor agonistic binding
Glycogenolysis
Relaxation of smooth muscles
Uptake of potassium in skeletal muscles
Physiological effect of beta-3 receptor agonistic binding
Lipolysis
Thermogenesis
Relax detrusor
What are the biochemical effects of agonistic binding to beta-1 receptors?
Adenylyl cyclase activation - resulting in increased levels of cAMP and protein kinase A activation
Increases HR and contractility
Also increases secretion of renin
What are the biochemical effects of agonistic binding to beta-2 receptors?
Adenylyl cyclase activation - resulting in increased levels of cAMP and protein kinase A activation
Beta-2 may also begin to couple go Gi in specific situations (i.e. HF)
What are the biochemical effects of agonistic binding to beta-3 receptors?
Adenylyl cyclase activation - resulting in increased levels of cAMP and protein kinase A activation
Results in lipolysis
Where are alpha-1 receptors usually found?
Smooth muscle
Main targets of NE and epi at low doese
NE - alpha receptors
Epi - beta receptors
What receptors are linked to Gq proteins?
Alpha-1 receptors
What receptors are linked to Gi proteins?
Alpha-2 receptors (and sometimes beta-2)
What adrenergic receptor class leads to cellular hyperpolarization upon agonistic binding?
Alpha-2 = linked to Gi - decreases cAMP and promotes efflux of K+
Often autoreceptors
What adrenergic receptor class leads to vasoconstriction upon agonistic binding
Alpha-1 receptors are linked to Gq proteins - which increase Ca2+ levels inside cells, leading to contraction of smooth muscle
Also leads to release of neurotransmitters in neurons
Midodrine
Alpha-1 agonist
Tx low BP in POTS
Phenylephrine
Alpha-1 agonist
Causes rebound congestion (rhinitis medicamentosa) if used incorrectly due to tissue damage from poor blood flow
Phenylephrine can also be used as a vasopressor in emergencies to raise BP
Agonistic binding of what adrenergic receptor causes mydriasis?
Agonistic binding of alpha-1 receptors causes pupil dilation by contracting the radial muscle
Alpha-1 increases phospholipase C activity which usually leads to contraction
Direct-acting presynaptic alpha-2 agonists
List examples
Clonidine
Dexmedetomidine
Methyldopa
Clonidine
Acts on alpha-2 autoreceptors
Inhibits further NE relase
Used as a 3rd or 4th line Tx fo hypertension and also for ADHD
Causes profound sedation
Dexmedetomidine
Direct-acting presynaptic alpha-2 agonist
Often used during surgery or in ICU to provide sedation w/o causing respiratory depression
Methyldopa
Prodrug - converted by dopa decarboxylase and dopamine beta-hydroxylase to a false neurotransmitter - alpha-methylnorepinephrine, which is stored inside vesicles
When neurons depolarize it is released - alpha-methylNE displaces dopamine and NE, acting as an agonist on alpha-2 presynaptic autoreceptors
Ultimately leads to less neurotransmitter release
Used in OB to Tx pregnancy-induced hypertension (pre-eclampsia) becuase of its safety profile
Ezymatic conversion occurs in neurons
What drugs are used to reduce intraocular pressure by decreasing the production of aqueous humor and increasing its drainage?
Alpha-2 agonists:
Brimonidine or apraclonidine
Ephedrine
Indirect-acting sympathomimetic
Stimulates release of catecholamines from nerve terminals
Relatively resistant to MAO and COMT
Also pseudoephedrine
Tyramine
Indirect-acting sympathomimetic
Found in food
Stimulates release of pre-formed catecholamines
Normally degraded rapidly by MAO in gut - hypertensive crisis when MAO is compromised
What indirect-acting sympathomimetic inhibits norepinephrine reuptake transporters?
Cocaine bitch
What indirect-acting sympathomimetic causes reverse transport of norepi/dopamine out through the reuptake transporters?
Amphetamine/Methylphenidate
Phentolamine
Non-selective alpha antagonist (block both alpha-1 and 2)
Short-acting and reversible blocker (name is shorter than other non-selective alpha antagonist)
Administered IV
Phenoxybenzamine
Non-selective alpha antagonist
Long-acting and irreversible blocker
Administered orally
What drugs block the effects of epinephrine, and when would it be pertinent to do so?
Phentolamine and phenoxybenzamine are both non-selective alpha antagonists
They are used primarily to Tx Pt’s w/ pheochromocytoma (adrenal tumor that releases excess catecholamines) - especially important during surgery - where manipulation of the tumor can release epi
Also used to Tx Pt’s w/ frostbite: IV phentolamine vasodilates quickly to restore perfusion
Selective alpha-1 antagonists
Prazosin/doxazosin/terzosin - vasodilation (3rd/4th line antihypertensives due to side-effects)
Side-effects:
First-dose syncope (esp. Pt’s that are dehydrates or sodium-deplete [diuretics], due to sudden venous pooling)
Reflex tachycardia due to baroreceptor activation as BP drops
Miosis - pupillary constriction
Tamsulosin/alfuzosin/sildosin - Tx BPH and have greater selectivity for alpha-1 receptors in prostate gland
Where are beta-1 receptors primarily found?
Heart and kidneys
Where are beta-2 receptors primarily found?
Lungs, blood vessels, and smooth muscles (i.e. the uterus)
Baroreceptors
Pressure-sensors in the carotids and aortic arch
Send signal to the ventrolateral medulla, nucleus of the solitary tract - activate the sympathetic nervous system to raise HR and BP
Selective alpha-1 antagonist can trigger reflex tachycardia (TPR decreases - increasing CO w/ increase in HR)
What happens to heart rate when phenylephrine is infused?
HR decreases
What is the mechanism of pseudoephedrine?
Promote release of preformed catecholamines
Which G protein do alpha-2 receptors couple to?
Alpha-2 receptors couple to Gi proteins
Give an example of a cardioselective antihypertensive
Metoprolol
Clonidine and methyldopa share some similarities in terms of actions at which of the following receptors?
Alpha 2
What drugs cause reflex tachycardia?
Drugs that induce vasodilation - alpha-1 antagonists and beta-2 agonists
When NE is administered after pre-Tx w/ atropine (prototypical muscarinic receptor antagonist) what is the response in HR?
Increase in HR caused by direct cardiac action
A possible effect of administering a beta-2 agonist to a patient is?
C. Skeletal muscle tremor
A possible effect of administering a beta-1 agonist to a patient is?
A. Direct stimulation of renin release
Pindolol
Partial beta-1 and 2 agonist (intrinsic sympathomimetic activity) - does not slow HR as much as a pure antagonist
Which of the following produces the traces shown in B?
A. Epi
B. Isoproterenol
C. Norepi
Epinephrine is associated with trace B
Norepinephrine is associated with trace A
Isoproterenol is associated with trace C
M1, M3, and M5 muscarinic receptors
Are linked to Gq proteins, which generally cause smooth muscle contraction
M2 and M4 muscarinic receptors
Linked to Gi proteins, which usually inhibit cells by hyperpolarizing them
Where are M1 receptors found?
In nerves
Where are M2 receptors found?
Primarily the heart
Where are M3 receptors found?
They are found in glands, smooth muscle of the lungs and bladder, blood vessels, and the eye
Where are M4 and M5 receptors found?
Mainly in the CNS
Ng (aka Nn) receptors
Nicotinic receptors found in nicotinic ganglia
Ng = nicotinic ganglia
Nn = nicotinic neuronal receptors
How do indirect-acting muscarinic agonists work?
By inhibiting acetylcholinesterase (AChE) - breaks down ACh
Allows more ACh to remain in synapse, increasing stimulation of both muscarinic and nicotinic receptors
Muscarinic agonist effects
Mnemonic: SLUD + Miosis
Salivation
Lacrimation
Urination
Defecation
Other effects: hypotension (due to vasodilation), and bronchoconstriction
Three main classes of indirect-acting cholinergic agonists
- Alcohols (i.e. edrophonium): Bind to AChE and are rapidly broken down by hydrolysis
- Carbamates (i.e. pyridostigmine, physostigmine, neostigmine): Bind to AChE and are broken down more slowly than alcohols
- Organophosphates (i.e. echothiophate, insecticides, nerve gases): Bind to AChE and hdryolyze very slowly or form covalent bonds with the enzyme
Pralidoxime
Used to treat organophosphate poisoning - to regenerate AChE - only works if Tx is given before aging occurs
Aging - the formation of covalent bond to AChE
Muscarinic receptor antagonist
- Red as a beet
- Dry as a bone
- Blind as a bat
- Mad as a hatter
- Block sweating - causes flushing
- Reduced secretions (saliva/mucous) - dry mouth/skin
- Impair visions by blocking accomodation (focusing close up)
- In higher doses - confusion or delerium
Muscarinic antagonist used to treat bradycardia
Atropine
Muscarinic antagonist used to treat athma/COPD
Drugs like ipratopium and tiotropium block M3 receptors in the lungs - bronchodilation and decreased mucus production
Muscarinic antagonist used to treat diarrhea/IBS
Drugs like dicyclomine - slow down GI motility and reduce cramping
Muscarinic antagonist used to treat overactive bladder
Drugs like oxybutynin - block contractions of the detrusor
Muscarinic antagonist used to treat motion sickness
The scopolamine patch - blocks ACh in the brain’s vomiting center
What conditions do muscarinic antagonists worsen?
Cognitive decline in the elderly - esp. Alzheimer’s or dementia
Hyperthermia - antimuscarinics prevent sweating
Muscarinic antagonists effects on the eyes
Mydriasis (pupil dilation due to relaxation of the iris sphincter (tropicamide dilates pupil)
Dry eyes
Worsening of glaucoma - they reduce aqeous humor outflow and can increase intraocular pressure (contraindicated in Pt’s w/ angle-closure glaucoma)
Cycloplegia (loss of accomodation due to relaxation of the ciliary muscle which causes the lens to flatten)
Varenicline
Partial agonist/antagonist at nicotonic receptors - helping satisfy cravings while simultaneously blocking full effects of nicotine
Nicotinic Antagonists
Neuromuscular junction blockers: succinylcholine (depolarizing blocker)
Non-depolarizing blockers (Curare derivatives): atracurium, rocuronium, vecuronium
Succinylcholine
Initially activates nicotinic receptors (Nnmj) causing Na+ to influx, depolarizing the cell and resulting in muscle contraction (fasciculations). However, it stays bound to the receptor, preventing repolarization, which leads to prolonged muscle paralysis
Adverse effects: hyperkalemia and malignant hyperthermia (Tx with dantrolene - prevents Ca2+ from SR)
Short duration of action (~8 min.) and is metabolized by plasma cholinesterase (aka butrylcholinesterase)
Competitive antagonists at the Nnmj
Atracurium, rocuronium, and vecuronium are non-depolarizing Nnmr blockers
~25-120 min duration (depends on drug)
Indirect-acting muscarinic agonists can be administered to increase the level of ACh in the synapse
B. Neuromuscular end-plate
A. Increase bladder tone
B. M3
D. Both may increase GI motility
C. Increase GI motility
B. Increased cardiac rate
Physostigmine
A. Increased intraocular pressure
Receptor specificity of bethanecol
Muscarinic
Used for GI and urinary stimulation
Receptor specificity for carbachol
Muscarinic and nicotinic receptors
Used to induce miosis during ophthalmic surger
Receptor specificity for pilocarpine
Muscarinic receptors
Applied topically to the eye to Tx glaucoma (lowers intraocular pressure)
Also oral Tx for xerostomia (dry mouth)
Side effect: decrased night vision caused by miosis and difficulty focusing on distant objects (lens is accomodated for near vision)
Why don’t choline esters distribute to the CNS?
They contain a quartenary ammonium derivative
Cevimeline
Muscarinic agonist to Tx dry mouth
What drug is used to Dx myasthenia gravis?
Edrophonium IV
Echothiophate
Applied topically to the eye to Tx glaucoma and accommodative estropia (binds to cholinesterase quasi-reversibly)
Miosis
Contracts ciliary muscle (improves focus through “spasm of accommodation”)
MOA of acetylcholinesterase hydrolyzing acetylcholine
MOA of acetylcholinesterase hydrolyzing neostigmine
What type of receptors are the nicotinic receptors found at the ganglia?
Ionotropic
Which of the following is a depolarizing nicotinic receptor blocker?
Succinylcholine
What is the site of action of vecuronium
Nicotinic receptors at the neuromuscular junction (Nnmj)
Competitive Zach antagonist
Which of the following is used as an antidote for organophosphate poisoning?
Praladoxime
MOA of scopolamine
MOA of bethanechol
Muscarinic receptor agonist
GI and urinary stimulation
MOA of atropine
Muscarinic receptor antagonist
Increase HR
MOA of neostigmine
Acetylcholinesterase inhibitor
Muscarinic receptor agonist effect on the eye
Muscarinic receptor antagonist effect on the eye
When is norepi used
To Tx warm shock: when BP is low and HR is high; mainly used clinically as a vasopressor
When is epi used
When BP is high and HR is low (cold shock); used for anaphylaxis to bronchodilate, increase HR, and vasoconstrict to counteract widespread vasodilatio; ACLS to stimulate heart; bronchospask
When is isoproterenol used
To increase myocardial contractility (i.e. decompennsated heart failure, cardiogenic shock)
Cycloplegia
Paralysis of accomodation due to relaxation of the ciliary muscle (cannot see up close, only far away)
Physiologic consequence of anti-muscarinics
Antimuscarinic effect on intraocular pressure (IOP)?
Increases IOP
-olol drug effects on the eye
Beta blockers decrease the production of aqueous humor
Why Dx myasthenia gravis w/ IV atropine and edrophonium
Atropine - antimuscarinic
Edrophonium - acetylcholinesterase inhibitor
Blocking - SLUD syndrome with atropine
What is used IV to reverse muscle paralysis?
Neostigmine
What is the drug used for maintenance of myasthenia gravis?
Pyridostigmine
Cholinergic crisis is common during initial Tx - too much stimulation of Nnmj receptors does not allow for repolarization
What type of drug (class) is used to Tx urinary retention?
Muscarinic receptor agonist
Which of the following drugs is used to Tx open-angle glaucoma and has a side-effect profile of: difficulty with far vision and problems seeing in dim light.
A. Pilocarpine
B. Timolol
C. Apraclonidine
D. Epinephrine
E. Phenylephrine
A. Pilocarpine
Pilocarpine is a muscarinic receptor agonist
Pilocarpine causes the ciliary muscle to contract, which increases tension on the scleral spur and opens the trabecular meshwork. This allows aqueous humor to drain from the eye, which decreases intraocular pressure while also decreasing one’s ability for far vision.
What type of receptors control sweat glands and what are they innervated by?
The SNS innervates M3 receptors at sweat glands
When pupillary dilation but not cycloplegia is desired, the best drug to use would be a drug that has a similar MOA as which of the following?
A. Isoproteronol
B. Phenylephrine
C. Pilocarpine
D. Tropicamide
B. Phenylephrine
Alpha-1 agonist will produce mydriasis without cycloplegia. Cholinergic antagonist drugs will also produce pupil dilation along with cycloplegia.
