ANS Flashcards
What is signal transduction?
Process by which a cell converts an extracellular stimulus to an intracellular response
Usually by
1) Altering enzymatic activity within the cell
2) Opening or closing an ion channel
First messengers that affect ion channels and G proteins
Ion channels: Glutamate, GABA, and Ach at the nicotinic receptor
G proteins: NE, phenylephrine, and Ach at the MUSCARINIC receptor
Describe G proteins
- 7 transmembrane segments with external N terminus and internal C terminus
- G protein becomes activated when a ligand binds the receptor it’s attached to
- G protein goes on to either activate OR inhibit an effector (either an enzyme or an ion channel)
- G protein has 3 subunits: alpha, beta, and gamma. When ligand binds to the receptor, the alpha subunit detaches. If the G protein is stimulatory, the alpha subunit will activate an effector. If it’s inhibitory, the alpha subunit will inhibit an effector.
- Stimulatory G proteins are Gs and Gq
- Inhibitory G protein is Gi
- Once the first messenger dissociates from the receptor, the alpha unit returns to to the G protein (rejoining the beta and gamma subunits), and it’s effect on the effector ends.
What is the purpose of the effector?
To turn on the second messenger
- The effector is either an enzyme or ion channel
Examples of enzymatic and ion channel effectors
Enzymatic:
- Adenylate cyclase
- Phospholipase C
Ion channel effectors:
- GABA-A
- NMDA
- nAchR
The intracellular response to a second messenger is ____
Tissue specific
- Ex- cAMP may cause different effects in different cell types
5 second messengers we should be familiar with
1) Cyclic adenosine monophosphate (cAMP)
2) Cyclic guanosine monophosphate (cGMP)
3) Inositol triphosphate (IP3)
4) Diacylglycerol (DAG)
5) Ca+2
Stimulation of alpha-1 receptor, results in this
Stimulation of the effector Phospholipase C, which then activates DAT, IP3, and Ca+2
Stimulation of alpha-2 receptor results in
inhibition of the effector adenylate cyclase. As a result, ATP is not converted to cAMP
Stimulation of Beta 1 and 2 receptors results in
Stimulation of the effector adenylate cyclase. As a result, ATP is converted to cAMP.
This is the opposite of the effects of Alpha 2 receptor activation.
Where are Beta 2 receptors located?
Muscles and other vascular beds
Where are Beta 1 receptors located?
The heart
What does cAMP do?
It turns on a variety of protein kinases that instruct the cell to perform a specific function.
How is cAMP metabolized?
Phosphodiesterase III (3) (PDE III)metabolizes cAMP to just AMP. This inactivates cAMP, thus inactivating the protein kinases it had been working on, and tells the cell to stop performing that function.
What will happen if phosphodiesterase III (PDE III) is inhibited?
cAMP will not be metabolized. So cAMP will continue to keep the protein kinases in the “turned on” state
PDE III inhibitors are also called
Inodilators
This is due to their effects on cAMP
cAMP in the heart causes increased inotropy and lusitropy.
cAMP in the vessels causes dilation and decreased SVR.
This medication is a PDE III inhibitor
Milrinone
This is the primary NT in the SNS
NE
Termination of action for NE is due to
1) Reuptake (80%)
- PRIMARY mechanism
- 80% of NE released undergoes reuptake. Most NE is then repackaged into vesicles to be used again, although some gets metabolized by MAO in the terminal.
- Reuptake is blocked by TCAs and cocaine
2) Reuptake by extraneural tissues
- These tissues contain MAO and COMT which metabolize NE
3) Diffusion away from the synapse
- NE enters circulation and is metabolized in the liver and kidney by MAO and COMT
- The kidneys and liver are the primary sites of catecholamine metabolism
The final byproduct of Epi and NE metabolism is
Vanillylmandelic acid (VMA)
This can be measured in the urine as a general measure of SNS activity (used in the diagnosis of pheochromocytoma)
This is the primary NT in the PSNS
Ach
When is Ach used by the SNS?
Released by postganglionic fibers on muscarinic receptors that are located at the sweat glands, piloerector muscle, some BVs, and by preganglionic fibers in the adrenal medulla
Ach synthesis
- Choline is transported from the blood into the nerve terminal
- Mitochondria make Acetyl CoA, which is released into the cytoplasm
- In the presence of choline acetyltransferase, Choline + Acetyl CoA = Ach
- Ach is then packaged into vesicles
This is an antagonist of Ca+2 at the presynaptic nerve terminals
Magnesium
This is why Mg can cause muscle weakness. It antagonizes the Ca+2 channels, preventing Ca from entering the cell and releasing Ach to elicit a muscle response.
Type of fiber that pre-ganglionic SNS neurons are
Myelinated B fibers
Type of fiber that post-ganglionic SNS neurons are
Unmyelinated C fiber
Origin of SNS signals
Thoracolumbar output (Sympathetic Chain) T1-L3****
Cell bodies arise from the intermediolateral region of the spinal cord, and axons exit via the ventral root
Origin of PSNS signals
Craniosacral output
- CN X
- S2-4
For each pre-ganglionic neuron in the SNS, there are this many postganglionic
30
Results in signal amplification that contributes to mass response
For each pre-ganglionic neuron in the PSNS, there are this many postganglionic
3
Allows for precise control of each organ
What does the stellate ganglion do?
Provides SNS innervation to the ipsilateral extremity and portion of the head and neck
May be blocked to treat complex regional pain syndrome, upper extremity sympathetic dystrophy, or to increase blood flow to that extremity
2 areas of the adrenal gland and what they make
1) Medulla
- Secretes catecholamines
2) Cortex
- Makes hormones (cortisol, aldosterone, and androgens)
Do catecholamines stay longer in the synaptic cleft or the bloodstream?
5-10x longer in the bloodstream
Function of alpha 2 receptors
Most are on presynaptic nerve terminals and modulate NE release.
However, there are also some located on effector organs.
MOA of alpha 2 receptors
1) Decrease Ca+2 conductance to decrease NT release
2) Increase K+ conductance to cause hyper polarization
BP and Precedex
Precedex will work alpha 2 receptors in both the brain and in the periphery.
Rapid administration will stimulate the post-ganglionic alpha 2 receptors in the arterial and venous circulations leading to vasoconstriction and HTN.
The effect in the brain is what causes vasodilation. This effect is slower, but once it kicks in, it overpowers the effect in the periphery.
Are beta 2 receptors innervated?
As a general rule, no.
They respond to circulating epinephrine in the blood stream
How does beta 2 stimulation by EPI affect the liver?
Stimulating B2 receptors in the hepatocyte results in release of GLUCOSE and POTASSIUM into circulation.
Effect of beta 2 stimulation by EPI on potassium levels
Overall, it causes hypokalemia
There are two phases to potassium response:
1) Initial K+ release from the cell, causing serum levels to rise (very short lived)
2) Epi then binds to beta 2 receptors on skeletal muscle and erythrocytes. This activates the Na/K pump, bringing K+ into the cell.
Baroreceptor reflex
Increase in BP causes:
- Decreased HR, contractility, and SVR
Decrease in BP causes
- Increased HR, contractility, and SVR
Overall, an increase in BP will result in a decrease in SNS output and an increase in PSNS output
Where is the main control center for the baroreceptor reflex?
Vasomotor center in the pons and medulla
4 Key functions of the vasomotor center
Vasoconstriction and dilation
Cardiac stimulation and inhibition
Sevoflurane and the baroreceptor reflex
Sevo decreases the effectiveness of the baroreceptor reflex in a dose dependent fashion
This can result in hemodynamic instability (body unable to compensate for the low BP caused by the VA)
Iso has some mild B-1 stimulation, so it impairs baroreceptors the least
Congestion on the R side of the heart leads to these hormonal changes
1) Decrease in ADH release
2) Release of ANP –> diuresis
These factors will worsen the severity of the OCR
Hypercarbia, hypoxia, and light anesthesia
Muscarinic receptors and their effectors
Even ones (2&4) inhibit adenylate cyclase
Odd ones (1, 3, & 5) stimulate phospholipase
This muscarinic receptor causes bronchial constriction
M3
This muscarinic receptor causes decreased chronotropy
M2
How does the bainbridge reflex work?
Increased venous return stretches the RA.
Info goes to the vasomotor center in the medulla.
PSNS tone to the heart is reduced, resulting in increased HR.
This is the only commonly used beta blocker that uses the kidneys as it’s primary route of elimination
Atenolol
Most others depend on the liver. Think about how so many liver patients are on atenolol (for varices –> liver is shot, so use the one that’s eliminated via kidneys)
Vasopressin and seizures
Overdose of vasopressin can lead to hyponatremia and resultant seizures
TCAs have this effect on NE
They decrease the repute of NE –> can lead to excessive SNS activation
Epi dose ranges
Low dose epi
- 0.01-0.03 mcg/kg/min
- B1 and B2 stimulation results in decreased SVR and increased CO
Intermediate epi
- 0.01-0.15 mcg/kg/min
- Mixed alpha and beta effects
High Dose Epi
- > 0.15 mcg/kg/min
- Mostly alpha effects
- SVT can also occur here (limits it’s usefulness)
This BB has great membrane stabilizing properties
Propanolol
This BB has intrinsic sympathomimetic properties
Labetalol
What does it mean to say that a medication has membrane stabilizing properties?
Means that the drug has local anesthetic-type effects
Includes propanolol and acebutolol
S/S of central anticholinergic syndrome
Sedation Stupor Coma Restlessness Anxiety Hallucinations Confusion Flushed skin Dry mouth Blurred vision Fever
Diphenhydramine and promethazine both have anticholinergic qualities and can cause central anticholinergic syndrome (I believe atropine and scopolamine can also do this)
These are selective beta 1 blockers
Atenolol Acebutolol Betaxolol Bisprolol Esmolol Metoprolol
These are some non-selective BBs
Carvedilol Labetalol Nadolol Timolol Propanolol Pindolol
2 Types of MAO and what they metabolize
1) MAO-A
- Metabolizes catecholamines (EPI, NE, DA, and Serotonin)
2) MAO-B
- Metabolizes tyramine, DA, and phenylethylamine
Dopamine is metabolized by both forms of MAO
Name 3 drugs that block nicotinic Ach receptors at autonomic ganglia
Trimethephan
D-Tubocurarine
Metocurine
What happens in response to blocking nicotinic autonomic receptors?
Hypotension 2/2 arterial and venodilation
This occurs because sympathetic impulses are blocked
How does EPI increase BP?
1) Arterial and venoconstriction
2) Increased HR
3) Increased contractility
This dose of EPI is very good for producing bronchodilation
LOW dose EPI is the most effective bronchodilator available
025-0.50 mcg/min
Effect of cocaine on SNS
Increases SNS activity by blocking reuptake of EPI and NE
Effect of phenylephrine
Activates A1 and A2 receptors
Veins > arteries
Stimulates baroreceptor reflex (will decrease HR and CO)
Effects of Dobutamine
Mostly B1 Stimulation
Minimal B2 and Alpha stimulation
Overall, produces increased contractility and CO with minimal increases in HR and BP
Effects of isoproterenol
Works on B1 and B2
Causes increased contractility and HR and thus CO
Also decreases BP 2/2 B2 effects.
Can cause dysrhythmias and increased O2 demand, resulting in MI.
Good clinical use as chemical pacemaker for complete HB
What is the most common clinical use of dopamine?
For it’s positive inotropic effects
Where are B2 receptors most commonly found?
In the SM of blood vessels in skeletal muscle
Receptors that phentolamine blocks
A1 and A2
Receptors blocked by labetalol
B1, B2, and A1
Avoid labetalol in these isorders
Asthma and CHF (will further decrease inotropy and CO)
Risk of giving a BB to a diabetic patient
Beta blockade may mask the s/s of hypoglycemia
