Intro to Adrenergics Flashcards
Where is the neurotransmitter dopamine used in the CNS?
Extrapyramidal system, mesolimbic (rewards system), mesocortical pathway (cognitive control to prefrontal cortex)
Where do sympathetic postganglionic fibers release dopamine? What are the receptors and what is the mechanism by which they conduct signal?
In renal and mesenteric vascular beds, D1 receptors, dilates them to decrease their resistance via Gs pathway (similar to beta-adrenergic receptors)
How is dopamine formed in the presynaptic nerve terminal?
Tyrosine is transported in, then hydroxylated by tyrosine hydroxylase to L-Dopa.
L-DOPA is decarboxylated by aromatic L-amino acid decarboxylase to dopamine (AAADC)
How is dopamine stored in the neuron following synthesis? What drug blocks this?
Transported into synaptic vesicles by Vesicular Monoamine Transporter (VMAT-2), which is nonselective for monoamines, including dopamine, NE, E, and serotonin (5-HT)
VMAT-2 is blocked by Reserpine -> causes a slow, prolonged depletion of catecholamines
How is dopamine made into epinephrine?
Dopamine is hydroxylated by dopamine-B-hydroxylase to Norepinephrine.
Only in adrenal medulla and brainstem neurons:
Norepinephrine is N-methylated by phenylethanolamine-N-methyltransferase (PNMT) to Epinephrine
How is NE co-released? What receptors do they bind? receptor type?
With other transmitters such as neuropeptide Y (NPY) and ATP
NPY -> binds Y receptors -> GPCR
ATP -> binds P2X (ion channels) or P2Y (GPCR)
Which transmitters can feedback presynaptically to inhibit activation? Which has a receptor for enhancement? What are the norepinephrine receptors?
All of them can (NPY, ATP, NE and even Dopamine)
Inhibitory receptor for NE - alpha-2 (Gi)
Stimulatory for NE - beta-2 (Gs)
What is the primary mechanism for termination of norepinephrine and dopamine effects in the synapse??
Reuptake via transporters
What are the transporters for dopamine / NE from the synapse, and what blocks this?
Na+-dependent transporters called NET or DAT (norepinephrine or dopamine transporter)
Blocked via SSRIs, SNRIs, tricyclic antidepressants, and COCAINE BABY!!!
What is the primary enzyme which metabolizes catecholamines in the sympathetic nerve ending? Where is it attached and which one is higher affinity for NE?
Monoamine oxidase - attached to outer surface of mitochondria, MAO-A has higher affinity for NE than MAO-B
Inhibitors will be used as antidepressants (monoamine oxidase inhibitors)
How is pheochromocytoma treated?
Methyltyrosine - inhibits tyrosine hydroxylase
What drugs are responsible for a relatively rapid, brief liberation of NE from the synaptic cleft to produce a sympathomimetic effect?
Tyramine, ephedrine, and amphetamine!
Thus, they stimulate non-vesicular catecholamine release!
What are the longterm biological effects of cocaine?
Since it blocks the reuptake via NET -> results in depletion of dopamine and norepinephrine in presynaptic storage vesicles
What is the byproduct of MAO digestion of NE, and why is this useful?
Produces VMA as byproduct, which can be detected in urine as diagnostic of pheochromocytoma
What is the rank order of affinity / potency for agonist action of E, NE, and isoproterenol for alpha receptors?
Epinephine > norepinephrine > isoproterenol
Just remember, epinephrine is always more potent than norepinephrine, and isoproterenol is an excellent beta-agonist
What are the subdivisions of the alpha receptor?
a1 -> higher affinity for phenylephrine
a2 -> higher affinity for clonidine
Each of these also have A, B, and C divisions present on different tissues
What GPCR pathway does alpha 1 use? alpha 2?
a1 -> Gq pathway, increasing Ca+2 stores
a2 -> Gi, typically presynaptic inhibitory of further norepinephrine release
What is the rank order of affinity / potency for agonist action of E, NE, and isoproterenol for beta receptors?
Isoproterenol > Epinephine > norepinephrine
Just remember, epinephrine is always more potent than norepinephrine, and isoproterenol is an excellent beta-agonist
How do beta1 and beta2 differ? Why is this relevant?
Beta2 has much higher affinity for epinephrine vs norepinephrine, whereas with beta1 they are about equal in affinity
Relevant because B2 is present on vasculature of skeletal muscle, which will make it particularly response to epinephrine produced by adrenal medulla
Where are beta3 receptors present and what are they used for?
Present on adipose tissue, increasing lipolysis
What signalling pathway do beta receptors use?
Gs (increased cAMP). Same pathway utilized by dopamine receptors (D1), opposite of alpha2
Where is the alpha1 receptor primarily present (review this table)?
Smooth muscle of vessels, serves to constrict blood vessels and raise blood pressure, including venous constriction to increase preload
What does the alpha-1 receptor do to the kidney? beta-1?
Alpha-1: Decreases renin release (negative feedback to too much high blood pressure)
Beta-1: Increases renin release
What is one major determinant of the blood pressure which keeps cardiac output up?
Venous return -> increased blood volume will also increase blood pressure
What does the alpha1 receptor do to the bladder and GI tract?
Bladder -> increases sphincter tone and urinary retention
GI tract -> sphincter contraction and decreased motility / tone
What does the alpha1 receptor do to the vas deferens?
Contraction, ejaculation
What receptor type is present on the iris to cause mydriasis? Same as piloerection receptor
alpha1
What do the alpha1 and beta2 receptor do to the liver?
Increased glycogenolysis, beta2 only: gluconeogenesis
Which receptors antagonize insulin release?
alpha2 and beta2
Alpha2 decreases insulin release
beta2 increases insulin release
What does alpha2 receptors do to aqueous humor production?
Decrease it (maybe helpful in glaucoma)
What do beta1 receptors do in heart and eye?
Heart: Increase heart rate and contractility + systolic pressure
Eye - ciliary body: increases aqueous humor production (opposite of alpha2)
What does beta2 do to diastolic blood pressure and why?
Decreases diastolic pressure by increasing vasodilation and reducing afterload
What does beta2 do to the bronchioles?
Bronchodilation
What does beta2 do to skeletal muscle?
Increases contractility, glycogenolysis, and K+ uptake
What controls the total peripheral resistance?
It is under both sympathetic control (via alpha1, beta2) and renin-angiotensin, aldosterone system (via angiotensin)
What are the two systems involved in baroreceptor blood pressure response?
- Vasomotor sensor - from baroreceptors present in aortic arch and carotid sinus
- Renal sensors - via renin system
How can a reflex tachycardia be blocked? What is this reflex in response to?
B1 antagonists
This reflex is in response to a drop in blood pressure
Reflex bradycardia can be blocked by muscarinic antagonists
What does aldosterone do?
Causes sodium and water retention in the kidney, a direct response to renin secretion as a result of a drop in mean blood pressure
What does beta-2 do to the uterus?
Causes it to relax -> lots of relaxation of smooth muscle
