Lecture 9: Adrenergic agonists Flashcards
How do you call drugs that act directly on the adrenoceptor?
Sympathomimetics
How do you call drugs that block the action of the neurotransmitter at the adrenoceptor?
Sympatholytics
what is the primary neurotransmitter in adrenergic neurons?
Norepinephrine
Where can adrenergic receptors be found?
Pre-synaptically on the neuron
post-synaptically on the effector organ
If neuron 1 extends from spinal cord to ganglia and neuron 2 extends from ganglia to effector organ, which neuron is called “Pre-synaptic”? what’s the other called?
Neuron 2 is called Pre-synaptic. Neuron 1 is called Pre-ganglionic.
The synapse used as reference is the one between the neuron and effector organ, not the ganglia (which is a synapse).
From Tyrosine to NE, what are the intermediates?
Tyrosine –> DOPA –> Dopamine –> NE
What enzyme converts Tyrosine to DOPA?
Tyrosine hydroxylase 1
What enzyme converts DOPA to dopamine?
Dopa decarboxylase
What enzyme converts dopamine to NE?
Dopamine-β-hydroxylase
How is dopamine transported into synaptic vesicles? What is this system responsible for as well?
It’s transported by an Amine transporter system.
It’s also responsible for NE reuptake from the synapse (actively).
What system is responsible for NE reuptake from the synapse? What other function does it have in the neuron?
Amine transporter system.
It’s also responsible for dopamine transport into synaptic vesicles.
What molecule blocks the Amine transport system? give 2 functions of the system.
Molecule is reserpine (along with tricyclic antidepressants & cocaine)
System is responsible for transport of dopamine into vesicles and reuptake of NE from synapse.
The adrenal medulla’s main secreted element is…
Epinehrine (80%)
NE (20%)
What is Guanethidine? Where does it act?
It blocks the fusion of NE vesicles at synapses and keeps them in the neuron
What cellular pathways do adrenergic receptors use?
cAMP and phosphatidylinositol pathways.
Apart from diffusion and reuptake, how is NE metabolized at the level of the synapses?
It can be metabolized by post-synaptic cell membrane-associated Catechol-O-methyltransferase (COMT)
Once NE is taken back in the neuron, what’s its fate? (2)
- Stored for re-release
2. degraded by monoamine oxidase (MAO) present in neural mitochondria
what are the products of NE metabolism in urine? (3)
- Venillilmandelic acid
- metanephrine
- Normetanephrine
Rank these 3 drugs in order of potency on α receptors:
NE, E, Isoproterenol
most potent to least:
E > NE > Isoproterenol
Rank these 3 drugs in order of potency on β receptors:
NE, E, Isoproterenol
most potent to least:
Isoproterenol > E > NE
What do we know of the β3 receptor?
Not much except that it’s involved in lipolysis
Do β1 receptors have any affinity preference?
(between E/NE)?
no, they equally bind E and NE.
Do β2 receptors have any affinity preference?
(between E/NE)?
Yes, they have higher affinity to E (almost only).
Neurologically, where can we find α2 receptors?
- On the presynaptic/preganglial neuron itself where accumulated NE in the synapse binds to its mother-neuron and triggers an inhibitory cascade of the NE release.
- On presynaptic parasympathetic neurons: These can be reached by NE released by some nearby sympathetic nerve, toning it down. So Sympathetic is toning down nearby parasympathetic to be more potent.
When desensitization of receptors occurs, 3 mechanisms can be behind it, state them.
- Sequestration of receptors (their initial vesicles don’t fuse on plasma membrane)
- Down-regulation (destruction/decreased synthesis)
- Change in receptor making it unable to couple to G-protein.
What do catecholamines all have in common structurally?
3,4-dihydroxybenzene
What do catecholamines have in common functionally? (3)
- High potency
- Rapid inactivation (metabolized by COMT and MAO) (unlike non-catecholamines)
- Inability to reach CNS YET they can cause anxiety, tremor, headaches (unlike non-catecholamines)
What 2 techniques can indirect-acting agonists use?
- Block NE reuptake
2. cause the release of NE from adrenergic neurons
What do we mean by mixed-action agonists?
They can both stimulate adrenoceptors and affect the NE’s presence in the synapse.
How do direct-acting agonists work?
They directly bind adrenoceptors and cause depolarization (stimulation).
Which receptors does Epinephrine bind to?
Is it concentration dependent?
Epinephrine binds to β2 at low concentrations and α1 and high concentrations.
Also note that epinephrine is CONTINUOUSLY active on β1 receptors.
What is the usual adult dose give subQ?
0.3 - 0.5 mg
if given IV, taking good care to inject slowly, what is the dose of Epinephrine?
~0.25mg
what concentration ratio of Epinephrine is used for parenteral administration?
1:1000
At what concentration ratio can epinephrine start being fatal? why so?
1:100
Because of severe vasocinstriction and necrosis
How is Epinephrine used in anesthesia?
It can be injected subcutaneously to cause vasoconstriction and limit the spread of the anesthetics: We have longer duration for the same anesthetics dose.
