L6 Flashcards
What is the rate limiting step in NE synthesis?
Tyrosine –> DOPA
Tyrosine hydroxylase
What enzyme converts DOPA –> dopamine?
DOPA decarboxylase
What enzyme converts dopamine –> NE?
Dopamine beta hydroxylase
What transporter brings dopamine into vesicles in the adrenergic nerve terminal?
VMAT2
H+ counter transport
Which drug can be used to deplete NE by inhibiting VMAT2?
Reserpine
When enzyme converts NE –> E? In what organ?
PNMT inside vesicles
Adrenal medulla
What is the mechanism of NE feedback inhibition?
Alpha 2 auto-receptors on the pre-synaptic side
What is the primary mechanism for NE inactivation?
NET reuptake into pre-synapse
What is the secondary mechanism for NE inactivation?
Facilitated diffusion out of cleft by OCT3 into the post-synaptic side
How does cocaine work at adrenergic nerve terminals?
Inhibits NET
Increases NE time in synapse
What are the 3 ways NE adrenergic receptors can be regulated on the post-synaptic membrane?
- Desensitization (sec)
- Phos the receptor, uncouple action from ligand binding - Sequestration (mins) = aggregation, internalization
- Down regulation (hrs) via less mRNA
If the receptor is G protein independent, what is the mechanism by which it will be regulated?
B arrestin = signaling molecule to inactivate
If the receptor is G protein dep, what is the mechanism by which it will be regulated?
B arrestin = chaperone for INTERNALIZATION
Does MAO or COMT metabolize NE in the pre-synaptic neuron?
MAO
Does MAO or COMT metabolize NE in the post-synaptic neuron?
COMT
Describe the sympathetic nerve metabolism of NE/E
- NE/E + MAO –> DHPG
- COMT –> MHPG
- MHPG reduced = glycol
MHPG oxidized (liver) = VMA
Describe the adrenergic nerve metabolism of NE/E
- N/E + COMT –> normet/met
- MAO –> MHPG
- MHPG reduced = glycol
MHPG oxidized (liver) = VMA
What is elevated plasma free (unconj) metanephrines diagnostic of?
Pheochromocytoma
Catecholamine secreting paraganliomas
Or pt is on drugs that release or inhibit reuptake of NE
A1 agonist
Phenylephrine
A2 agonist
Clonidine
B1 agonist
Dobutamine
B2 agonist
Albuterol
B3 agonist
Mirabegron
3 effects of A1 agonist
- Smooth muscle contraction - vascular, iris, GU
- Secretion - salivary & sweat glands
- K+ release from liver
4 effects of A2 agonist
- ↓NE @ nerve term
- Contract vasc smooth muscle
- ↓ insulin secretion
- Platelet aggregation
4 effects of B1 agonist
- ↑HR
- ↑contractility
- ↑conduction velocity
- ↑renin from kidney
4 effects of B2 agonists
- Dilate BVs in skeletal muscle & liver
- ↑glucose & K in skeletal muscle
- ↑glucose @ liver
- Mast cell stablization
2 effect of B3 agonists
- Relax bladder
2. Lypolysis
What is the difference between B1 & 2 receptors with NE/E?
B1: E=NE agonism
B2: E > NE
Are catecholamines hydrophobic or philic - explain effects.
Hydrophobic - poor penetration
- Injector topical
Do catecholamines have long or short half lives?
SHORT
What is NE’s receptor selectivity?
A1, 2
B1; 3
What is E’s receptor selectivity?
A1, 2
B1, 2
What is isoproterenol’s receptor selectivity?
= 100% beta agonist
B1, 2, 3 only
What is dopamine’s receptor selectivity?
B1 - need ↑[ ]
D1 - dilate renal & GI vascular beds, ↑NA excretion at kidneys
What is dobutamine’s receptor selectivity?
B1 only
What is the main adrenergic receptor in the heart?
B1
Some B2
NO ALPHA
What happens if E + SA node?
Epi + beta receptor - AC --> cAMP --> PKA ↑HR and contractility - Faster depol & repol due to ↑PKA - Faster pacemaker potential due to ↑cAMP ↑freq of impulses
What is a downside of using B agonists in the heart?
↑risk arrhythmia
↑risk cardiac arrest due to VFib
What do A1 & 2 receptors do to vascular smooth muscle: cuteanous, mesenteric, renal, muscle, liver?
Vasoconstrict
What is the baroreceptor reflex in context of slow NE infusion?
+ NE
A1 vasocontrict –> ↑TPR –> ↑BP
B1 at heart means you’d expect ↑HR… but vagal reflex dominates so ↑BP overrides to ↓HR
ACh acts on muscarinic receptors
What happens with slow E infusion?
B2 - vasodilation in skeletal muscle ↓TPR --> ↓DBP ↑CO --> ↑SBP Not dramatic enough rise BP to warrant vagal response - ↑HR & BP at same time (EXERCISE)
What happens with slow isoproterenol infusion?
B effects only
Dilation –> ↓DBP
↑HR & CO but overall BP ↓s even if systolic increases slightly due to CO
Why use E for cardiac arrest?
Peripheral vasoconstriction - ↑coronary perfusion
Why use E for anaphylatic shock?
↑CO
↑BP (alpha)
Bronchodilate (alpha & B2)
Stabilize mast cells (B2)
Why use NE or E for mucosal decongestion?
Alpha - vasocontrict to ↓swelling and secretions
Why use NE or E for hypotension?
Vasopressor short term
Why use DO during acute heart failure?
Selectively B1 -↑CO
Adverse effects E/NE
MI
Arrythmia
Hypoxia
Necrosis at IV sites
