Catecholamines + Adrenergic antagonists

Question 1

The backbone of all catecholamines is made up of which chemical structure?

Answer 1

Phenylethylamine

Question 2

Substitution at the Beta carbon of the phenylethylamine (increases/decreases) CNS activity but greatly increases __ activity at both alpha and beta receptors

Answer 2

Substitution at the Beta carbon decreases activity in the CNS but greatly increases agonist activity at alpha and beta receptors

Question 3

What is the effect of making an alkyl group substitution on the amino group of the phenylethylamine?

Answer 3

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

Question 4

Substitution at the alpha carbon blocks metabolism of the drug by ___ (enzyme name) which prolongs the drug’s duration of action

Answer 4

Substitution at the alpha carbon blocks metabolism of the drug by MAOs (monoamine oxidases), which prolongs the drug’s duration of action

Question 5

What is the structure below?

Answer 5

Catecholamine

**two OH groups and no other substitutions**

Question 6

___ (drug name) is the prototypical naked catecholamine (hint: its a neurotransmitter)

Answer 6

Dopamine

**think d-OH-pamine = catec-HO-lamine**

Question 7

Fill in below

Answer 7

Adding the hydroxyl groups:

decreased CNS penetration

greatest alpha and beta receptor activity

active site for the COMT enzyme that degrades catecholamines

Question 8

Dopamine is considered a weak, non-selective agonist because ___ (3)

Answer 8

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

Question 9

What is the difference between dopamine and norepinephrine structurally and thus functionally?

Answer 9

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

Question 10

What is the difference between norepinephrine and epinephrine?

Answer 10

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***

Question 11

Why are dopa, nor-epi and epi short acting drugs?

Answer 11

All 3 short acting because of susceptibility to MOA and COMT

Question 12

Draw and describe the synthesis of norepinephrine

Answer 12

Question 13

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?

Answer 13

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)

Question 14

While Norepinephrine is synthesized at the nerve terminals, epinephrine is synthesized in the ___ (hint: somewhere in the gland that sits right above the kidneys)

Answer 14

While Norepinephrine is synthesized at the nerve terminals, epinephrine is synthesized in the adrenal medulla

Question 15

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?

Answer 15

**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

Question 16

The release of catecholamines is primarily mediated by the activation of ___ (ion channel) following an action potential

Answer 16

The release of catecholamines is primarily mediated by the activation of voltage-gated calcium channel following an action potential

Question 17

Upon release into the synaptic cleft, norepinephrine and dopamine are taken up by the ___ and ___ transporters, respectively

Answer 17

Upon release into the synaptic cleft, norepinephrine and dopamine are taken up by the norepinephrine (NET) and dopamine transporters (DAT), respectively

Question 18

____ is located all over the body (cytoplasm) but primarily concentrated in the liver and kidney, and metabolizes most of the IV-administered catecholamines

Answer 18

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

Question 19

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

Answer 19

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

Question 20

The final product of catecholamine metabolism is ___

Answer 20

The final product of catecholamine metabolism is Vanillyl mandelic Acid (VMA) (idk like a vanilla looking nelson mandela. not very appealing)

Question 21

___ is located in peripheral vasculature and causes pupillary dilation and vasoconstriction

Answer 21

Alpha 1 receptor is located in peripheral vasculature and causes pupillary dilation and vasoconstriction

Question 22

What is the function of alpha 2 receptor?

Answer 22

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

Question 23

Alpha 2 agonists, aka ___ work by ___

Answer 23

Alpha 2 agonists, aka sympatholytics work by inhibiting sympathetic outflow (again feedback inhibition of NE release)

Question 24

The beta 1 receptor is primarily located in the ___ and serves what function?

Answer 24

The beta 1 receptor is primarily located in the heart

*see below*

(activates AC >> + cAMP >> + PKA >> downstream activation of things)

Question 25

What is the function of beta 2 receptors and where are they located?

Answer 25

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)

Question 26

Study this slide

Answer 26

Question 27

Fill in the blanks

Answer 27

Question 28

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?

Answer 28

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**

Question 29

Tyramine causes excess release of NE and subsequent hypertensive crisis via what mechanism?

Answer 29

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**

Question 30

What are sympathomimetics?

Answer 30

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

Question 31

Fill in the blanks

Answer 31

**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

Question 32

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?

Answer 32

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**

Question 33

Fill in the blanks

Answer 33

see below

Question 34

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)?

Answer 34

Need to use bronchodilator so beta-2-agonist

Question 35

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

Answer 35

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) **

Question 36

Study this slide

Answer 36

Question 37

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?

Answer 37

Primary hypertension from taking pseudoephedrine

(remember ephedrine is an NE releaser >> hypertensive crisis)

Question 38

How does ephedrine/pseudoephedrine work and what are the clinical indications of this drug?

Answer 38

Ephedrine releases norepinephrine through reversal of NET

**see below for indications but basically it raises BP, decongestant, bladder contraction**