Adrenergic Transmission And Its Presynaptic Modification

Question 1

What are sympathomimetics?

Answer 1

they are adrenergic drugs that act directly on adrenergic receptors by activating them

Question 2

What are sympatholytics?

Answer 2

Adrenergic drugs that block the action of the NT at there receptor or they can interrupt the release of NE from adrenergic neurons

Question 3

What is the rate limiting step of NE synthesis?

Answer 3

tyrosine hydroxylase

Question 4

What is the co-factor of tyrosine hydroxylase?

Answer 4

Vit C

Question 5

What is the mechanism of action of Reserpine?

Answer 5

It inhibits VMAT2

Question 6

What is the mechanism of action of Guanethidine?

Answer 6

It inhibits the release of vesicles containing NE into the synaptic cleft

Question 7

What is NET?

Answer 7

It is the Na+/Cl- dependent NE transporter

Question 8

What inhibits NET?

Answer 8

TCA e.g., Imipramine

Serotonin-NE reuptake inhibitors e.g., duloxetine, cocaine

Question 9

What is the action of methyl-p-tyrosine?

Answer 9

Inhibits tyrosine hydroxylase

Question 10

What is the mechanism of action of MAO inhibitors?

Answer 10

it leads to increased NE in the mobile pool

Question 11

What is the result of releasers?

Answer 11

it leads to the release of NE from the mobile poo.

Question 12

What is the effect of an alpha 2 agonist on the pre-synaptic neuron?

Answer 12

Negative feedback

Reduced NE in the synapse

Question 13

What is the effect of an alpha 2 antagonist on the pre-synpatic neuron?

Answer 13

Prevention of negative feedback

Increased NE synthesis and release

Question 14

Both the skeletal muscles and vasculature have alpha and beta receptors, which predominates?

Answer 14

Beta receptors

Question 15

What is desensitisation of adrenergic receptors?

Answer 15

Prolongued exposure to catecholamines leads to decreased responsiveness of these receptors

Question 16

What are the possible mechanisms of desensitisation of adrenergic receptors?

Answer 16

1. Sequestration of the receptors so that they are unavailable for interaction with the ligand
2. Down regulation
3. Inability to couple to H protein because the receptor has been phosphorylated on the cytoplasmic side

Question 17

What is the result of OH substitutions in the 3rd and 4th position of the benzene ring?

Answer 17

Increased potency
Decreased absorption and distribution of the drugs
decreased lipophility

Question 18

What are the characteristics of catechomaines with 3,4-IH substituents?

Answer 18

Most potent sympathomimetics
Bad pharmacokinetics: poor absorption, bad distribution, short duration of action.
They must be given parenterally for systemic use - they don’t penetrate the BBB
They are substrates of COMT, this further decreases their bioavailability

Question 19

What are the characteristics of 3-OH, 4-OH or 3,5-OH derivatives?

Answer 19

Weaker sympathomimetics than the catecholamines but they have better pharmacokinetics
They are not substrates of COMT, but still polar drugs - they may be given orally with low bioavailability

Question 20

What are the characteristics of non-substituted derivatives?

Answer 20

They have no hydroxyl groups
Very weak direct or only indirect (NE releasing) sympathomimetic action (bad pharmcodynamics)
They have very good pharmacokinetics: good absorption and penetration through the BBB (resulting in CNS effects)

Question 21

What are the possible substitutions on the amino group?

Answer 21

Methylation

Large substitution

Question 22

What is the effect of methylation on the amino group?

Answer 22

Methylation increases the relative potency on the Beta 2 receptors (NE/EPI)

Question 23

What is the effect of large substitution of the amino group?

Answer 23

Large substitution on the amino group increases significantly the beta 2 receptor affinity

Question 24

What is a precursor substance of adrenergic synthesis?

Answer 24

Levodopa

Question 25

Name the reuptake inhibitors

Answer 25

Cocaine TCA Amitryptyline Desipramine

Question 26

Name the MAO inhibitors

Answer 26

Tranylcypromine Selegiline Moclobemid

Question 27

What are the side edicts of guanethidine and debrisoquine?

Answer 27

``` Orthostatic hypotension Diarrhoea Impaired Ejaculation Sodium and Water retention Nasal Stuffiness Upregulation of postsynaptic receptors ```

Question 28

What is the clinical indication of Guanethidine and Debrisoquine?

Answer 28

Hypertension | Limited use because of their side effects

Question 29

What is the mechanism of action of Bretylium?

Answer 29

``` Acts like Guanethidine in NE nerve terminals It blocks K+ channels on the heart (a class 3 anti-arrhythmic action) ```

Question 30

What is the clinical use of Bretylium?

Answer 30

Antiarrhythmic indication

Question 31

How is Bretylium administered?

Answer 31

IV in emergency during resuscitation from ventricular fibrillation after lidocaine and cardioversion

Question 32

What are the adverse effects of Bretylium?

Answer 32

``` Initial release of NE can lead to ventricular arrhythmias Sympatholytic action (e.g., orthostatic hypertension) ```

Question 33

What is the mechanism of action of reserpine?

Answer 33

Blocks the uptake of biogenic amines into the synaptic vesicles. they are not stored in the vesicles and thus broken down by MAO

Question 34

What are the theoretical indications of Reserpine?

Answer 34

Hypertension | Psychosis

Question 35

What are the main side effects of Reserpine?

Answer 35

``` Sympatholytic actions (diarrhoea, postural hypotension: NE depletion in the periphery) Mental depression (NE and serotonin depletion in the CNS) Parkinsons (dopamine depletion in the nigrostriatal system) ```

Question 36

What is the effect of alpha-methyl-tyrosine?

Answer 36

Blocks the tyrosine hydroxylase enzyme, no NE synthesis, decreased alpha and beta stimulation

Question 37

What are the clinical indications of alpha-methyl-tyrosine?

Answer 37

May act synergistically with phenoxybenzamene in the treatment of pheochromocytoma

Question 38

What is the mechanism of action of Tetrodotoxin, Saxitoxin and local aesthetics?

Answer 38

Blocks voltage sensitive Na+ channels

Question 39

What is the mechanism of action of w-Conotoxin?

Answer 39

Blocks calcium channels

Question 40

What is the action of 6-OH-dopamine?

Answer 40

Destroys the nerve terminal