Lecture 37: Catecholamines Part II

Question 1

What is the inactivation process of catecholamine neurotransmitters?

Answer 1

1. Reuptake into nerve terminals
2. Metabolic transformation/catabolism
3. Diffusion out of the junctional cleft and uptake at extraneuronal sites

Question 2

What are the two major systems for neurotransmitter uptake?

Answer 2

1. Uptake 1
   
   • refers to the re-uptake of NE into nerve endings
   • uptake process is high-affinity low-capacity system
2. Uptake 2
   
   • refers to mechanisms of extra-neuronal uptake
   • uptake processes is a low-affinity, high-capacity system
   • important for removing circulating amines

Question 3

What is the catabolic pathway of neurotransmitters?

Answer 3

MAO (monoamine oxidase) inactivates both circulating and intraneuronal amines
-functons as a “safety valve” to inactivate any excess neurotransmitter that leaks into the synaptic cleft when the neuron is at rest
Two isoenzymes of MAO:
i. MAO-A: substrates for MAO A enzyme = 5-HT, NE and Trypatmine
ii. MAO-B: substrates are Dopamine and Tryptamine

Question 4

What are the substrates for MAO-B?

Answer 4

Dopamine and tryptamine

Question 5

What are the substrates for MAO-A?

Answer 5

Serotonin, NE and tryptamine

Question 6

Is MAO the only degrading enzyme in the synaptic cleft?

Answer 6

No (there is also COMT and aldehyde reductase that breaks down the product of NE+MAO)

Question 7

Should you target rate limiting step of catecholamines? Why?

Answer 7

NO
Because this shit is NON-selective…i.e. there is no clinical scenario where you would want to decrease dopamine, NE AND E lol

Question 8

What do you use to inhibit NE synthesis?

Answer 8

1. Alpha-methyl-p-tyrosine
   -competitive inhibitor of tyrosine hydroxylase
2. (alpha) methyldopa
   -inhibits L-aramatic amino acid decarboxylase
   Less dopamine
3. Carbidopa
   Inhibits L-AAD in the periphery
   Less dopamine
4. Tetraethylthiuram (disulfiram)
   -inhibits dopamine beta-hydroxylase
   Less NE

Question 9

What is alpha-methyl-p-tyrosine?

Answer 9

Competitive inhibitor of tyrosine

LESS catecholamines

Question 10

What is alphamethyldopa/carbidopa?

Answer 10

Blocks L-aromatic amino acid decarbaoxylase

Parkinson’s

Question 11

What is reserpine?

Answer 11

Used to block VMAT so dopamine cant get into vesicle
Used for hypertension and SNAKE bite lol
Horrible drug because it is so powerful

Question 12

What is Disulfiram?

Answer 12

Prevents NE FORMATION
Blocks dopamine hydroxylase
Used in alcohol dependence

Question 13

How do you inhibit catecholamine release?

Answer 13

1. Bretylium
   
   • causes NE release initially but THEN inhibits release by preventing Aps from reaching terminals
   • has been used to treat ventricular fibrillation
2. Guanethidine
   
   • inhibits release of NE
   • powerful antihypertensive
   • leads to depletion of catecholamines and degradation of nerve endings
   • must be taken up into nerve terminal to have an effect

Question 14

What is sympathomimetic response?

Answer 14

Increase Sympathetic

Question 15

What is a sympatholytic response?

Answer 15

Decrease sympathetic

Question 16

What are sympathomimetic amine agonists?

Answer 16

1. Dopamine
2. Dobutamine
3. L-DOPA

Question 17

What is important to know about dopamine agonists?

Answer 17

1. Inotropic agent

2. alpha and beta adrenoreceptor agonist

Question 18

What does inotropic mean?

Answer 18

Something that regulates the force and speed of muscle contraction

Question 19

What is Dobutamine?

Answer 19

1. A beta receptor agonist
2. produces inotropic effect
3. used in congestive heart failure

Question 20

What are the two agonists used to treat PD?

Answer 20

L-DOPA
Bromocriptine
-selective D2 receptor agonist
-from lysergic acid

Question 21

What is Bromocriptine?

Answer 21

A D2 receptor agonist used to treat Parkinson’s

-LSD (acid) relative

Question 22

What are the properties of amphetamine/methamphetamine?

Answer 22

Lipid soluble (can penetrate into the brain)
Possess an alpha-methyl group that is RESISTANT to MAO
Promotes neurotransmitter release

Question 23

Why do neuroamines have a short half-life?

Answer 23

Due to the efficiency of MAO

Question 24

What are examples of inhibitors of catecholamine reuptake?

Answer 24

1. Cocaine
   -block uptake-1 channels in presynaptic terminal
   Allows for more neuroepinephrine in the synapse
2. Imipramine, a tricyclic
   Both are sympathomimetic

Question 25

What is Imipramine?

Answer 25

A tricyclic antidepressant

Blocks NE reuptake so amplifies NE response

Question 26

What inhibits catabolism (MAO inhibitors)?

Answer 26

Selegiline

- inhibits MAO-B at low doses
- delays breakdown of dopamine 
- USED IN PARKINSONS SO REMEMBER
- used as antidepressant because of effect on noradrenergic/serotnergic neurons

Question 27

What is Selegiline?

Answer 27

A Parkinson disease treatment
MAO-B inhibition
Delays breakdown of dopamine

Question 28

What are the drugs used for Parkinson’s disease?

Answer 28

1. Seligiline (MAO-B inhibitor)
2. Bromocriptine (D2 receptor agonist)
3. L-DOPA
4. Carbidopa