What are the catecholamines?
How are endogenous catecholamines made and what is the rate-limiting step?
Tyrosine + Tyrosine Hydroxylase (RLS) to make DOPA
DOPA + Da Decarboxylase to make Da that is taken up into storage vesicles
DA + Da-beta-Hydroxylase to make NE
How is DA taken up into vesicles? What inhibits this mechanism?
Vesicular monoamine transporter VMAT2 exchanges monoamines for protons
need acidic vesicles so need proton pump of V-ATPase
RESERPINE depletes NE from storage Vesicles as a selective VMAT2 blocker
Where and How is Epinephrine made?
Adrenal Medulla Chromaffin cells express enzyme PNMT to methylate cytosolic NE to Epi and then both can accumulate into storage vesicles for release
How is NE signaling inactivated or turned off?
Primarily through REUPTAKE via the NE -Transporter (NET) into terminal that released it
Secondarily signal ends via fascilitated diffusion into tissues with polyspecific Organic Cation Transporter (OCT3)
Where does Cocaine act in the peripheral nervous system?
Cocaine inhibits NET - NE Transporter and so potentiates sympathetic activity by allowing excess NE at nerve terminal (acts on Da transporter in the CNS for effects)
What are mechanisms of Adrenergic Receptor Regulation?
Desensitization (seconds) via PKA phosphorylation of intracellular tail
Sequestration (minutes) via aggregation of receptors and internalization
Down-regulation (hours) with decreased mRNA
Beta-Arrestin with Ligand Bias for desensitization and acts as a chaperone to mediate internalization into clathrin-coated pits into endosome where receptors can be recycled or degraded
What are the enzymes that degrade NE/Epi and where are they found?
Monoamine Oxidase - MAO - pre-synaptic and mitochondrial - found in BBB, GI tract, Liver
Catechol-O-Methyl-Transferase (COMT) - found in most tissues EXCEPT pre-synaptically - found in adrenal medulla
Adrenal-Medullary Pathway for breakdown of Ne/Epi?
COMT inactivates and makes the "metas" in the adrenal medulla and then they leak out
MAO acts on the Metas to make MHPG MHPG gets oxidated in the liver to VMA and excreted in urine
Sympathoneuronal Pathway for breakdown of Ne/Epi?
NE from nerve terminals made into DHPG by MAO
DHPG circulates and turned into MHPG by COMT
MHPG oxidized to VMA in the liver and excreted in urine
Alpha 1 Receptor Agonists
Tissues and Responses
Agonists: = EPINEPHRINE > NE >> Iso = Phenylephrine
Antagonists = Prazosin
Tissues and Responses
- SM of vasculature, Iris, GU and activation = contraction
- Salivary and Sweat Glands and activation = secretions
-Liver and activation = K+ Secretion from liver
What is Isopreterol significance?
Synthetic Adrenergic agonist that's only really effective at Beta-receptors!
Alpha 2 Receptor Agonists Antagonists Tissues and Responses
Agonist:s: = Epinephrine > NE >> Isopreterol = Clonidine Antagonists = Yohimbine Tissues and Responses - Vascular SM contraction - Pancreatic Beta cells = decreased insulin secretion - Platelets = aggregation - Nerve Terminals acts as an Autoreceptor and lowers NE release
Beta 1 Receptor Agonists Antagonists Tissues and Responses
Agonists: = Iso > Epi = Ne = Dobutamine
Antagonists = Metoprolol and Atenolol Tissues and Responses - Heart - Activation increases HR, Force, and CV - JG cells in Kidney and activation increases Renin release
Beta 2 Receptor Agonists Antagonists Tissues and Responses
Agonists: = Iso> Epi >>>>>> Ne - Albuterol
Antagonists - none Tissues and Responses - Smooth Muscle of vasculature, Pulmonary and Uterine and activation leads to relaxation - Skeletal Muscle and activation leads to increase Glucose and K+ uptake and tremors -Liver and activation increases glucose from liver - Mast cells to decrease granule release
Beta 3 Receptor Agonists Antagonists Tissues and Responses
Agonists: = Iso = NE > Epi = Mirabegron Antagonists = none Tissues and Responses - Adipose Tissue activation leads to thermogeneration and lypolysis - Urinary bladder activation leads to relaxation of bladder
Which beta receptor is NE a weak agonist on ?
Which beta receptor does NE = Epi agonism?
Which beta receptor is NE better agonist than Epi?
What does a solution that of catecholamines that is pinkish/brown mean?
Inactivated!! Catecholamines are very unstable and can be readily oxidized to colored products in presence of alkaline pH, heat and light
How are catecholamines administered and why?
Injection or topically NOT by mouth Very hydrophillic and so poor penetration of membranes
What receptors does NE act on?
A1, A2 B1, B3 NOT B2
What receptors does Epi act on?
A1, A2 B1, B2 Not B3
What receptors does Isoproteranol act on?
NOT alphas B1, 2, 3
What receptors does Dopamine act on?
Beta 1 MOSTLY on D1 in the sympathetic vasculature / capillary beds of kidney and mesentary Activation of D1 receptors in those vascular beds leads to relaxation and dilation
What receptors does Dobutamine act on?
What is the cellular effect of Epinephrine at the SA Node?
Beta-1 (and B2) activation increases the amplitude and rate of currents for: 1) L type calcium channels - slow inward current for upstroke of AP 2) K+ channels for repolarization and outward current to mediate RMP 3) If Current - funny cation channels turned on by hyperpolarization and bring cell back to trigger point for AP ALL MEDIATED BY cAMP!!! PLA phosphorylation of channels to activate currents
What is the clinical effect of Beta-AR activation in the heart?
Chronotropy - increased HR by pacemaker Automaticity - recruitment of latent pacemaker cells Increased conduction velocity and decreased Refractory Period Arrhythmogenicity increased!!! ionotropy - increased contractility BUT ALSO increased oxygen consumption Lusitropy - increased re-polarization and shortened systole
What happens with adrenergic stimulation in the vasculature?
Vasoconstriction with A1/A2 activation to increase TPR and get more blood back to heart
What are the effects on TPR, BP, and HR with low-dose IV infusion of NE in humans?
NE has little effect on Beta2 in heart but large effect on Beta1 - increased force of contraction!! Increase in BP from Beta-1 induces Vagal Reflex and Baroreceptor firing causes decreased HR and overrides Beta stimulation to the pacemaker Increased TPR and Increased Contractility = increased BP Vagal Response to decrease HR BP = CO x TPR
What are the effects on TPR, BP, and HR with low-dose IV infusion of Epi in humans?
Epi at low dose causes Beta-2 vasodilation in muscle and liver to over-ride alpha-mediated constriction so TPR down slightly Increased contractility in heart no sharp increase in BP and no vagal reflex so only see INCREASE in HR from beta activation **If increased dose of Epi get alpha-effects of vasculature and increased TPR
What are the effects on TPR, BP, and HR with low-dose IV infusion of Isopreterenol in humans?
Beta selective so no effects on Alpha receptors Vasodilation from beta receptors and decrase in TPR Increased HR bc MAP falls
When is Epinephrine indicated for use clinically?
Cardiac Arrest - push Epi every 3-5 minutes as peripheral vasoconstrictor to get blood back to heart and brain Anaphylactic shock - Epi pen to increase CO and BP and act on alpha receptors to stop secretions and open airways and act on beta2 in bronchioles to open airways and stabilize mast cell
When is Epi/NE used clinically?
Hypotension during surgery Mucosal congestion - alpha effect to reduce secretions Local anasthesia to constrict when giving NA channel blockers
When is Dopamine or Dobutamine used clinically?
Acute Heart Failure and Circulatory Shock Renal Dose Da to maintain urine production and renal vasodilation DO increases CO from BEta1 receptor activation so used to increase force of contraction in acute heart failure
What are the adverse effects of Epi and Ne use?
Increased Myocardial Oxygen demand leads to increased risk of angina and infarction Arrhythmias Decreased organ and tissue perfusion and hypoxia Extravasation at IV infusion site can lead to necrosis