Catecholamines + Adrenergic antagonists Flashcards
The backbone of all catecholamines is made up of which chemical structure?
Phenylethylamine
Substitution at the Beta carbon of the phenylethylamine (increases/decreases) CNS activity but greatly increases __ activity at both alpha and beta receptors
Substitution at the Beta carbon decreases activity in the CNS but greatly increases agonist activity at alpha and beta receptors
What is the effect of making an alkyl group substitution on the amino group of the phenylethylamine?
Substitution of an alkyl group at the amino group increases beta or alpha selectivity, depending on the size of the alkyl group. Increased alkyl group size = increased beta receptor selectivity; decreased alkyl group size = increased alpha receptor selectivity
Substitution at the alpha carbon blocks metabolism of the drug by ___ (enzyme name) which prolongs the drug’s duration of action
Substitution at the alpha carbon blocks metabolism of the drug by MAOs (monoamine oxidases), which prolongs the drug’s duration of action
What is the structure below?
Catecholamine
**two OH groups and no other substitutions**
___ (drug name) is the prototypical naked catecholamine (hint: its a neurotransmitter)
Dopamine
**think d-OH-pamine = catec-HO-lamine**
Fill in below
Adding the hydroxyl groups:
decreased CNS penetration
greatest alpha and beta receptor activity
active site for the COMT enzyme that degrades catecholamines
Dopamine is considered a weak, non-selective agonist because ___ (3)
Dopamine is considered a weak, non-selective agonist because:
No beta carbon substitution = poor agonist activity at both a and b receptors
No amino group substitution so no selectivity
Substitution of 2 OH groups on phenyl ring + no alpha carbon substitution = susceptible to both COMT + MAO
What is the difference between dopamine and norepinephrine structurally and thus functionally?
Norepinephrine is basically dopamine + on OH group on the beta carbon. That makes Norepi a prototypical alpha agonist b/c:
Again, the hydroxyl group at beta carbon = increased agonis activity at both a and b receptors
No amino group substitution= limited activity at beta receptors
OH group @ beta carbon + no alpha carbon group = susceptible to both COMT and MOA
What is the difference between norepinephrine and epinephrine?
β-carbon hydroxyl group: increased agonist activity
Amine methyl group: increased α-receptor activity (and β-activity)
–OH groups and no α-carbon group: substrate for both COMT and MAO
***Most potent, least selective***
Why are dopa, nor-epi and epi short acting drugs?
All 3 short acting because of susceptibility to MOA and COMT
Draw and describe the synthesis of norepinephrine
What is the rate limiting step of norepinephrine synthesis?
The first step in nor-epi synthesis is the uptake of __ by the Na+ contransporter
Where is dopamine converted to norepinephrine in the neuron?
The rate limiting step in nor-epi synthesis is the conversion of Tyrosine to Dopa (then to dopamine) via tyrosine hydroxylase
The first step in nor-epi synthesis is the uptake of tyrosine by the Na+ contransporter
Dopamine is converted into norepinephrine inside the vesicle in the neuron (uptake of Dopamine fascilitated by the VMAT H+ antiporter)
While Norepinephrine is synthesized at the nerve terminals, epinephrine is synthesized in the ___ (hint: somewhere in the gland that sits right above the kidneys)
While Norepinephrine is synthesized at the nerve terminals, epinephrine is synthesized in the adrenal medulla
Draw and describe the synthesis of epinephrine in the adrenal medulla
What is the first step of synthesis of epi?
What are two major differences between the synthesis of epinephrine and norepinephrine?
**see below**
The first step is the same as that of nor-epi: tyrosine conversion to DOPA (then to dopamine)
Two major differences: epi is made from nor-epi via PNMT in the cytosol, and epi is actually released with nor-epi from the storage complex that forms inside the chromaffin granule
The release of catecholamines is primarily mediated by the activation of ___ (ion channel) following an action potential
The release of catecholamines is primarily mediated by the activation of voltage-gated calcium channel following an action potential
Upon release into the synaptic cleft, norepinephrine and dopamine are taken up by the ___ and ___ transporters, respectively
Upon release into the synaptic cleft, norepinephrine and dopamine are taken up by the norepinephrine (NET) and dopamine transporters (DAT), respectively
____ is located all over the body (cytoplasm) but primarily concentrated in the liver and kidney, and metabolizes most of the IV-administered catecholamines
COMT (catcechol-O-methyltransferase) is located all over the body but primarily concentrated in the liver and kidney, and metabolizes most of the IV-administered catecholamines
Monoamine oxidase is concentrated in the __ and __ but also located in the outer mitochondrial surface in the body.
There a 2 types of MAO enzymes, ___ and ___.
___ is located in the placenta, liver and binds to noradrenergic neurons
___ is found in platelets and binds to serotonergic neurons
MAO metabolizes ___ (endogenous/IV) catecholamines
Monoamine oxidase is concentrated in the liver and kidney but also located in the outer mitochondrial surface in the body.
There a 2 types of MAO enzymes, MAO-A and MAO-B
MAO-A is located in the placenta, liver and binds to noradrenergic neurons
MAO-B is found in platelets (pronounced blatelets) and binds to serotonergic neurons
MAO metabolizes endogenous catecholamines
The final product of catecholamine metabolism is ___
The final product of catecholamine metabolism is Vanillyl mandelic Acid (VMA) (idk like a vanilla looking nelson mandela. not very appealing)
___ is located in peripheral vasculature and causes pupillary dilation and vasoconstriction
Alpha 1 receptor is located in peripheral vasculature and causes pupillary dilation and vasoconstriction
What is the function of alpha 2 receptor?
The alpha 2 receptor is basially for negative feedback/feedback inhibition of norepinephrine release via inhibition of Adenylyl cyclase >> decreased cAMP >> loss of downstream signaling
Alpha 2 agonists, aka ___ work by ___
Alpha 2 agonists, aka sympatholytics work by inhibiting sympathetic outflow (again feedback inhibition of NE release)
The beta 1 receptor is primarily located in the ___ and serves what function?
The beta 1 receptor is primarily located in the heart
*see below*
(activates AC >> + cAMP >> + PKA >> downstream activation of things)
What is the function of beta 2 receptors and where are they located?
Beta 2 receptors are in peripheral organs and vasculature (note that these have opposite effects in the vasculature to alpha 1 receptors)
(activate AC >> + cAMP >> + PKA >> downstream activation of things but in this case the effect is RELAXATION of muscles and blood vessels because you want to increase perfusion to your organs and muscles and also to increase/release glucose stores)
Study this slide
Fill in the blanks
Mr. Ken H is 65 year old overweight male with a history of SSRI-resistant clinical depression who is currently on MAOi
Baseline BP 140/98
Ken is rushed from a wine/cheese party to the hospital by his wife (Ann H.) with a severe headache and a bloody nose.
Presents with BP 230/110
Why did he have this hypertensive crisis?
Dietary interaction between tyramine and MAO inhibitors:
Tyramine (found in cheese, wine etc) is actually broken down by MAO, and it is sort of a, a derivative of Tyrosine (not sure if can be used to synthesize catecholamines) and it causes release of catecholamines from the pre-synaptic cleft
MAO inhibitors block the breakdown of catecholamines so coupled with tyramine, you get a lot of NE release which leads to a hypertensive crisis
The crisis is usually mediated by MAO-A inhibitor since tyramine is primarily broken down by MAO-A
**got info from Wikipedia**
Tyramine causes excess release of NE and subsequent hypertensive crisis via what mechanism?
Tyramine releases norepinephrine thru reversal of the NET (so the NE that’s supposed to be going back into the pre-synaptic neuron’s cytoplasm is going back into the presynaptic cleft)
**reversal NET**
What are sympathomimetics?
Tyramine is a non-catecholamine aka sympathomimetic (contrast that with the alpha 2 agonists = sympatholytics)
**sympathomimetics are basically agonists/things that mimic endogenous catecholamines and enhance the sympathetic system’s effects**
Decreased potency because they don’t bind to the endogenous receptors
Increased duration of action because they’re not taken up and recycled by NET or DAT, and they’re also resistant to metabolism by COMT and MAO
Fill in the blanks
**see below**
Catecholaminies like to DDINE: dopamine, doputamine, isoproterenol, epi and norepi
Beta 2 agonists eat too many FATS: formoterol, albuterol (the asthma med), terbutaline, salmeterol (salmonterol)
Non-catecholamines can be found in what you EAT: ephedrine, amphetamine, tyramine
A 7 year old female presents with dizziness, brief loss of consciousness and vomiting when standing up after swallowing her mother’s unknown pills.
**assume the mother has hypertension. what are the pills likely to be/do?**
Would the child have a normal valsalva maneuver?
The pills are likely NE release blockers (or some drug that inhibits NE function to lower blood pressure)
Kid would have an abnormal valsalva i.e. no phase 4 overshoot which is mediated by NE release
**treat with alpha 2 antagonist**
Fill in the blanks
see below
A 3 year old female presents with labored breathing and lethargy from a common cold. How would you treat this patient (to help the breathing)?
Need to use bronchodilator so beta-2-agonist
There are 2 types of beta 2 agonists, long acting and short acting. ___ and ___ are short acting beta agonists whereas ___ and ___ are long acting beta agonists
Isoproterenol and albuterol are short acting beta agonists whereas formoterol and salmeterol are long acting beta agonists
**note that isoproterenol is non-selective (so binds both beta 1 and beta 2) **
Study this slide
A 46 year old male with a history of hypertension presents with loss of consciousness after taking pseudoephedrine for congestion secondary to common cold. His baseline BP is 180/100 and it rises ro 230/120 after taking pseudoephedrine. What contributed to the increase in blood pressure?
Primary hypertension from taking pseudoephedrine
(remember ephedrine is an NE releaser >> hypertensive crisis)
How does ephedrine/pseudoephedrine work and what are the clinical indications of this drug?
Ephedrine releases norepinephrine through reversal of NET
**see below for indications but basically it raises BP, decongestant, bladder contraction**
