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61 Cards in this Set
- Front
- Back
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What does tyrosine hydroxylase do?
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Rate limiting enzyme for the conversion of tyrosine to DOPA (precursor for dopamine)
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What two things regulate tyrosine hydroxylase?
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1) Phosphorylation
2) End-product feedback inhibition |
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What does dopamine beta-hydroxylase (DBH) do and where is it stored?
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- Rate limiting enzyme for the convertion of dopamine to norepinephrine
- Stored and takes place in adrenergic vesicles |
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What is the enzyme phenylethanolamine N-methyl-transferase (PNMT) responsible for and where does it occur?
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- Conversion of norepinephrine to epinephrine
- Occurs in chromaffin cells of adrenal medulla |
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What are the 3 ways in which the effects of norepinephrine are terminated?
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1) Reuptake (90%)
2) Diffusion away from cleft 3) Metabolism |
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What is the action of COMT (catchol-o-methyltransferase)?
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Enzyme that metabolizes epinephrine and norepinephrine into inactive form - terminates physiological action
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Why are COMT inhibitors given with L-DOPA therapy in Parkinson's?
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1) Carbidopa inhibits L-DOPA being converted to dopamine in periphery
2) This shifts pathway toward metabolization by COMT to inactive form 3) COMT inhibitor prevents the metabolization, leaving more L-DOPA to be transferred to the brain to be converted to dopamine |
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What does monoamine oxidase (MAO) do?
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Non-selective enzyme that breaks down phenylethylamines (epi, norepi, serotonin, dopamine)
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Where is MAO found and why?
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- Intestinal mucosa to breakdown phenylethylamines from intestinal bacteria and food
- Prevents these from getting into bloodstream and raising BP |
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What are the effects (good and bad) of MAO inhibitors?
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- Prevents breakdown of neurotransmitters (NE, serotonin) helping the mood
- Prevents breakdown of phenylethylamines in intestinal mucosa hurting BP, stroke, death |
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How do cocaine and tricyclic antidepressents produce their effects?
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- They are competitive antagonists of NE/serotonin transporter involved in reuptake
- Increase NE/serotonin activity by keeping more active NT in cleft |
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What is the historical significance of reserpine?
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First antihypertensive drug used worldwide
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What is the mechanism of reserpine?
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- Inhibits vesicular uptake of dopamine, reused NE, and other NTs
- Prevents dopamine from getting into vesicle and being converted to NE - Prevents reuse of NE reuptaken from cleft - Quickly depletes NE stores and lowers BP - Increases metabolization of catecholamines |
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How do alpha-2 adrenergic receptors work?
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- "Autoreceptors"
- Excess NE in cleft binds to it and provides negative feedback to prevent further release of NE |
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How do phenylethylamines produce sympathomimetic effects?
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- They are taken up by nonselective reuptake and transferred into vesicles
- This displaces NE to create "indirect" sympathomimetic action |
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What is indirect sympathomimetic action?
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Action due to release of NE
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What is direct sympathomimetic action?
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Action due to binding at adrenergic receptors
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How can selective MAO inhibitors prevent undesirable effects?
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- Tyramine is broken down by MAO-A and MAO-B in intestine
- MAO-A inhibition increases serotonin level while tyramine is broken down by B - MAO-B inhibition increases dopamine level while tyramine is broken down by A |
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What are MAO-A inhibitors used for?
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- Depression
- Prevents breakdown of serotonin |
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What are MAO-B inhibitors used for?
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- Parkinson's
- Prevents breakdown of dopamine |
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How do tyramine and amphetamine produce their effects?
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- They are good substrates for neuronal uptake
- These displace NE/serotonin from vesicle causing their release - "Indirect" sympathomimetic effects |
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What is the effect of norepinephrine on vascular smooth muscle?
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Constriction
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What is the effect of isoproterenol on vascular smooth muscle?
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Relaxation
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What is the effect of epinephrine on vascular smooth muscle?
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Constriction of relaxation
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What drugs have the most effect on alpha-adrenergic receptors?
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EPI > NE (Iso very little)
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What drugs have the most effect on beta-1-adrenergic receptors?
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Iso > EPI/NE
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What drugs have the most effect on beta-2-adrenergic receptors?
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Iso > EPI (NE very little)
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What is the cell signaling mechanism of beta receptors?
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Activate adenyl cyclase -- cAMP
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What is the cell signaling mechanism of alph-1 receptors?
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Activate phospholipase C -- Protein kinase C (PKC)
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What is the cell signaling mechanism of alpha-2 receptors?
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Activate Gi -- inhibits adenyl cyclase -- activates K channels
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How is desensitization of adrenergic receptors countered?
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Dephosphorylation to return to active state
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How is down regulation of adrenergic receptors countered?
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New receptor synthesis to return to active state (takes a long time)
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How does supersensitivity occur with beta-blockers (i.e. propranolol)?
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- Beta-blocker blocks NE receptors
- Receptors are upregulated - If blocker is stopped, NE release (within hours) hyperactivates upregulated receptors |
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What adrenergic receptors are found on the heart and what is their effect when activated?
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- Beta-1
- Increases heart rate (SA node) - Increases contractility and conduction velocity (atria and ventricles) |
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What is the effect of alpha-1 receptor activation on vascular smooth muscle?
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Constriction - found in skin/mucosa, kidney, abdominal viscera, veins
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What is the effect of beta-2 receptor activation on vascular smooth muscle?
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Relaxation - found in liver and skeletal muscle
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What is isoporterenol selective for?
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Beta-1 and beta-2 receptors
- B1 - increase HR, contractility - B2 - decreases peripheral resistence - Effect on BP depends |
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What is norepinephrine selective for?
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Alpha-1 and beta-1 receptors
- A1 - increases peripheral resistence - B1 - increases HR, contractility - Increases BP, ultimately decreases HR, contractility with baroreflex |
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What is epinephrine selective for?
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Alpha-1, beta-1, beta-2
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How is heart rate and contractility lowered with norepinephrine?
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- Main effect is to increase peripheral resistance and BP through activation of alpha-1 receptors
- Effect of beta-1 receptors is countered with baroreflex |
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What is the effect of beta-2 activation on bronchial smooth muscle?
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Relaxation - bronchodilatin increases air flow
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What is the effect of alpha-1 activation in the uterus?
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Contraction
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What is the effect of beta-2 activation in the uterus?
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Relaxation - slows labor
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What is the effect of alpha-1 activation in the eye?
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Contracts iris - pupil dilation
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What is the effect of beta-1 activation in the eye?
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Increases aqueous humor - blocked for glaucoma treatment
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What is the effect of beta-2 activation in mast cells?
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Inhibits granule release (histamine, leukotrienes, etc)
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What is the effect of alpha-1 and beta-1 activation in the liver?
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Glycogenolysis
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What is the effect of beta-1 activation in the kidney?
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Increased renin release
- Renin converts angiotensinogen (from liver) to angiotensin I - A1 is converted to A2 by ACE - A2 stimulates pituitary to release vasopressin (ADH) - A2 stimulates adrenal cortex to release aldosterone (Na retension) - A2 causes vasoconstriction, Na retension, water retension |
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What is the effect of alpha-2 activation on sympathetic nerve endings?
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Inhibits NE release - autoreceptor
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What is the effect of alpha-2 activation in the medulla?
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Inhibits efferent sympathetic outflow to peripheral vascular smooth muscle - antihypertensive effects
- Ex. clonidine |
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What is the effect of clonidine?
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- Activates alpha-2 receptors in medulla
- Inhibits efferent sympathetic outflow to peripheral vascular smooth muscle - Antihypertensive effects - Also used to treat addiction withdrawal |
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What is phenylephrine?
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- Alpha-1 agonist
- Used for hypotension - Used for mydriasis (dilating pupil) |
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What is responsible for bronchial smooth muscle contraction and secretion?
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Parasympathetic stimulation - M3 muscarinic receptors
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What is effect of albuterol?
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- Beta-2 selective agonist
- Fast acting (1-5 min onset, 2 - 6 hr duration) - Small increase in HR (side-effect) |
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What is effect of salmeterol?
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- Long-acting beta-2 selective partial agonist (possible factor in lack of long-term receptor desensitization)
- Another one is formoterol - Only used in conjunction with ICS (inhaled corticosteroids) |
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What are the 3 roles of epinephrine in acute allergic hypersensitivity reactions?
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1) Activates beta-2 receptors on mast cells - increases cAMP and inhibits degranulation
2) Activates beta-2 receptors in bronchial smooth muscle - prevents suffocation from glottic edema 3) Supports blood pressure |
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What are the three life-threatening events in acute allergic hypersensitivity reactions?
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1) Increase in vascular permeability (mast cell degranulation)
2) Vasodilation 3) Local edema |
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What is the effect and use of dobutamine?
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- Beta-1 agonist (mainly increases contractility but not HR)
- Used for acute heart failure - Short-term treatment of cardiac decompensation after surgery |
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What is the role of L-norephinephrine (Levophed) and phenylephrine in cirulatory shock?
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- Alpha-1 agonist vasopressors used when sympathetic nervous system has failed (however this usually isn't the problem)
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What is the role of dobutamine in circulatory shock?
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- Beta-1 agonist
- Increases cardiac output (maintly through contractility) without increasing peripheral resistance |
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What is the role of dopamine in circulatory shock?
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- Weak beta-1 agonist
- Increases cardiac output - **Results in vasodilation and increased perfusion of select tissues without decrease in BP (kidney, intestine, abdominal organs |
