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82 Cards in this Set
- Front
- Back
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5 stages of catecholamine neurochemistry
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synthethis
storage release receptor interaction termination |
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rate limiting step in synthesis of all catecholamins
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tyrosine hydroxylated to DOPA by tyrosine hydroxylase (TH), a ferro-enzyme requiring tetrahydrobiopterin
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Why won't adding more tyrosine increase dopamine levels?
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1. conversion is the rate limiting step
2. tyrosin doesn't cross blood brain barrier (BBB) easily |
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How is DOPA converted to dopamine?
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decarboxylated by l-aromatic amino acid decarboxylase (enzyme requires pyridoxal phosphate)
dopamine then stored in synaptic vesicles in neurons or chromaffin granules in adrenal medulla |
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How is dopamine converted to norepinephrine?
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OH added to beta carbon of dopamine (catalyzed by dopamine beta-hydroxylase: DbetaH)
takes place inside vesicles |
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How is norepinephrine converted to epinephrine?
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PNMT transfers methyl group from S-adenosyl-methionine to nitrogen of norepi to from EPI
takes place in cytosol |
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stress response
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glucocorticoids (synthesized in adrenal cortex) and EPI (synthesized in adrenal medulla) are released
glucocorticoids carried to chromaffin cells where they induce transcription of TH, DbetaH, and PNMT |
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catecholamine synthesis steps
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tyrosine-->DOPA (rate limiting step
DOPA-->dopamine dopamine-->NE NE-->EPI |
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catecholamine alternative synthesis
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tyrosine-->tyramine
tyramine-->octopamine octopamine-->NE-->EPI |
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dopamine storage
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transported into synaptic vesicles through 2 pumps:
1. proton ATPase (proton translocase) 2. vesicular monoamine transporter (VMAT) |
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pump that concentrates H+ w/in vesicles
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proton ATPase pump
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protein antiporter that exchanges 2H+ for each dopamine
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VMAT pump
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benefits of catecholamines CAs) complexing w/ ATP
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1. decrease osmotic pressure
2. prevent back diffusion 3. ATP=cotransmitter CAs complexed w/ ATP in 4:1 ratio |
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other compounds found in vescicles
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ascorbic acid (antioxidant), neuropeptied Y, enkephalins, chromogranins
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catecholamine release
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action potential leads to influx of Ca and fusion of vesicles w/ terminal membrane, releasing entire vesicle contents
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alpha-1 receptors
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postsynaptic
G-protein coupled to PLC-IP3-->releases Ca from sarcoplasmic reticulum (SR)-->contracts smooth muscle and increases inotrophy (contraction force) |
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alpha-1 receptor subtypes
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alpha-1A, a1B and a1D
only a1A is targeted-blocked by tamsulosin (flomax); used to treat benign prostatic hypertrophy |
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receptors that inhibit adenylyl cyclase that then decreases cAMP
located both presynaptically (autoreceptors) and postsynaptically (contract smooth muscle) |
alpha2
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alpha-2 subtypes
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a2A, a2B, a2C
not Rx targets |
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beta receptors
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classified as B1, B2, and B3
act through G proteins to stimulate adenylyl cyclase-->increase cAMP-->activateds protein kinases |
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B receptor in heart and cortex
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beta-1
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B receptor in smooth muscle, skeletal muscle, liver, cerebellum
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beta-2
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B receptor found in adipose tissue
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beta-3 (stimulate lipolysis)
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termination mechanisms
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reuptake
diffusion metabolism |
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2 active transport processes of reuptake
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1. high affinity uptake from synapse by NE transporter (NET)-cotransports Na, transports CAs against 1:10,000 concentration gradient
2. from cytoplasm into vesicles by VMAT (Mg dependent process) |
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uptaken by extarneuronal transporter (ENT), a low affinity mechanism that takes CAs into muscles and glands
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diffusion
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metabolosim
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monoamide oxidase (MAO)-located in outer mitochondrial membrane of neurons and glia
catechol-O-methyltransferase (COMT)-located in cytosol (liver) |
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2 forms of MAO
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MAO-A: brain and gut, metabolizes NE, EPI, 5-HT
MAO-B: human bain, metabolizes dopamine |
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2 different mechanisms (MAO and COMT), same result
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forms MOPEG and VMA
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MAO pathway
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1. NE and EPI deaminated to aldehyde
2. aldehyde converted to glycol or acid (depending on interaction w/ aldehyde reductase or aldehyde dehydrogenase) 3. glycol and acid are reacted w/ COMT which transfers CH3 from S-adenosyl-methionine to #3 OH group on catechol ring to form MOPEG and VMA |
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COMT pathway
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1. NE and EPI form normetanephrine and metanephrine
2. acted on by MAO to from MOPGAL 3. MOPGAL contverted to MOPEG or VMA (depending on aldehyde reductase or aldehyde dehydrogenase reaction) |
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3 general rules of thumb regarding Rx effects on vasculature
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1. alpha contracts, beta relaxes
2. beta more sensitive (low concentrations) 3. when alpha/beta stimulated together, alpha predominates |
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catecholamines as Rx
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1. epinephrine (IV)-mixed a/B activity; low, high doses
2. norepinephrine (IV)-mostly a activity 3. dopamine (IV)-low, medium, high concentrations |
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low dose epi
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stimulate beta receptors (due to sensitivity)
net effect: increases flow to skeletal muscles, increases heart rate, and cardiac output w/ little change in blood presssure |
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Why doesn't blood pressure drop in low dose epi?
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vessels not involved in sympathetic response constrict
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How does EPI stimulate lipolysis?
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B2/B3 receptors activate hormone sensitive lipase that hydrolyzes triacelglycerols to free fatty acids and glycerol
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high dose EPI
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massive vasoconstriction via alpha-1 (alpha predominates at high dose)
net effect: increased cardiac output (CO)/ blood pressure (BP) w/out stressing heart |
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Why does HR only slightly increase in high dose EPI?
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baroreflex
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What happens to coronary blood flow in high dose epi?
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increases to to local production of adenosine (vasodilator)
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EPI uses (rapid onset but short duration of action; available IV, SC, inhalation)
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alpha-hemostatic; vasopressor in shock; vasoconstrictor in local anesthetics
beta-bronchodilator |
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EPI side effects
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CNS-anxiety, tension, headaches, tremors
PNS-increase BP-->increase risk of cerebral hemorrhage, cause fluid backup in lungs-->pulmonary edema increases chronotropic effect and risk of arrhythmia caution if hyperthyroid-have more B1 receptors (susceptible to hypertensive crisis) |
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norepinephrine (IV)
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mostly alpha activity
HR and CO-inotropic (baroreflex overrides beta-1) coronary blood flow increases due to alpha-2 stimulation-->increases NO (vasodilator) |
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norepi use
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shock or any hypotensive state
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norepi caution
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watch for decrease in renal blood flow
hyperthyroid (some beta activity) |
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low dose (<2) dopamine (DA)-IV
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stimulate DA D1 receptors in renal vasculature
stimulate D2 receptors on NE to decrease NE release-->vasodilatory effects net effect: increase renal blood flow problem: doesn't increase survival-obsolete |
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medium (2-10) DA concentrations (IV)
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stimulate renal D1 and cardiac B1 receptors
net effect: increases blood flow, BP, and CO problem: greater incidence of adverse events (arrhythmias) compared to NE |
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high (>10) DA concentrations
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stimulate renal D1, cardiac B1 and a1/a2 receptors
vasoconsriction, decreased renal blood flow use-shock caution-monitor renal function |
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DA side effects
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nausea (area of postrema contains chemoreceptors linked to nausea response-doesn't have BBB there), arrhythmias
few CNS side effects (can't cross BBB) |
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alpha agonists
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phenylephrine
metaraminol midodrine clonidine apraclonidine |
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phenylephrine
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alpha-1 nasal spray for cough/cold
sometimes added to local anesthetics (vasoconstriction-minimizes systemic absorption of local anesthetic) side effects-headaches from hypertension |
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metaraminol
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mainly alpha-1 agonist for shock/hypotension
icreases BP |
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midodrine
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prodrug-metabolized to desglymidodrine (a1 agonist)
used for orthostatic hypotension and urinary incontinence |
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clonidine (transdermal patch) overview
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centrally acting a2 agonist; inhibits sympathetic outflow from CV control centers in brain
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clonidine MOA
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1. opens postsynaptic K channels-->K efflex-->hyperpolarization
2. inhibits presynaptic Ca channels-->decreases NE release net effect: decreases peripheral resistance, HR, and CO, increases PNS tone (due to decreased sympathetic tone) |
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clonidine uses
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antihypertensive-can cause Na/H2O retention (can be given w/diuretic)
withdrawal from drugs and EtOH epidural for caner pts who don't respond to opioids tourette's ADHD anxiety and panic attacks menopausal flushing |
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clonodine side effects
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1. dry mouth
2. sedation 3. sexual dysfunction (inhibits ejaculation) 4. constipation a. decreases GI secretions (alpha-2) b. inhibits ACh release-->relaxes smooth muscle-->increases absorption (a1/2) caution-dicontinue slowly to avoid rebound sympathetic activity |
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apraclonidine (eye topical)
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alpha-2 agonist
use-glaucoma (decreases production of aqueous humor) |
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miscellaneous alpha agonists
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oxymetazoline
psuedoephedrine |
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stereoisomer of ephedrine used as decongestant
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pseudoephedrine
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oxymetazoline (ophthalmic solution)
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MOA: alpha-2 agonist
side effects-hypotension (if it gets into brain, can inhibit sympathetic outflow), palpitations (baroreflex for hypotension) |
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alpha antagonists
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phenoxybenzamine
phentolamine metyrosine prazosin all except phenoxybenzamine are competetive antagonists net effect: relax arteriolar resistance vessels-->reflex tachycardia-->increase CO |
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phenoxybenzamine (oral) overview
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covalently binds a1/a2-irreversible, long acting (1-2 days), must synthesize new receptors
blocking a2 sympathetics innervating heart can stimulate NE release-->increase CO |
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phenoxybenzamine uses
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1. pheochrmocytoma-tumor of adrenal medulla-->excessive secretion of CAs (sympathetic effects)
2. EPI reversal (reverses alpha receptor effects) 3. prostate and bladder obstruction (blocks alpha-1 to relax sphincters |
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phenoxybenzamine side effects
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postural hypotension (blocked alpha-1 can't constrict vessels
tachycardia-baroreflex due to hypotension |
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phentolamine (IV)
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competetive (reversible) inhibitor of a1 receptors (effects similar to phenoxybenzamine but shorter acting-4 hours)
uses-short term control of hypertensize states side effects-similar to phenoxybenzamine |
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metyrosine
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not alpha antagonist but used to treat pheochromocytoma
MOA-inhibits TH |
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prazosin
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a1 selective
blocks a1 in arterioles and veins-->decreases peripheral resistance and venous return *no reflex tachycarida or increased CO if Na/H20 retention, add diuretic short half life (dose 2-3 x/day) use-antihypertensive |
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1st dose phenomenon
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caused by prazosin-characterized by postural hypotension and syncope
1. 30-90 minutes after 1st dose 2. after rapid dose increase 3. adding another hypotensive Rx mechanism-delayed compensatory tachycardia (give 1st dose at bedtime) |
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Beta agonists
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isoproterenol
dobutamine albuterol pirbuterol salmeterol |
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isoproterenol (IV)
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massive vasodilation (B2)
+ inotropy/chronotropy (B1) Net: increase HR and CO w/ slight decreased BP Use-cardiac stimulant for bradycardia or heart block (B1) |
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dobutamine
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racemic mixture
+ racemate is beta-1/beta-2 agonist - racemate is an alpha-1 agonist both racemates contribute to + inotropy and increased CO advantage vs isoproterenol-smaller effect on HR use-cardiac decompensation |
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albuterol
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selective beta-2 agonist for oral/inhalation (adding nubulized Mg increases bronchodilation in kids)
mechanism-antagonizes Ca caution: can delay labor |
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pirbuterol
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selective B2 agonist for inhalation only
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salmeterol (inhalation)
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longest acting (12 hours)
not for acute attacks due to long onset FDA warning-increases risk of asthma attack and death |
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inhibit release of histamine and other mediators of inflammation that contribute to bronchospasms
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beta agonists
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decrease HR, contractility, BP, CO, O2 demand (B-1 effecgts)
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beta antagonists
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beta antagonist caution
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asthma, bronchospasms-bronchioles need to be dilated for easier breathing
diabetes-beta blockers + insulin = very low blood sugar levels |
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cardinal CV sign of hypoglycemia
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tachycardia-occurs due to sympathetic signals
Beta antagonists block tachycardia effect (so monitor closely) |
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propranolol
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equal B1/B2 affinity
higher doses have membrane stabilizing/quinidine-like local anesthetic effect (from blocking Na channels) uses-arrhythmias; MI; hypertension, etc. |
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nadolol
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equal B1/B2 affinity
no membrane stabilizing activity long acting (20-24 hours) uses-hypertension, angina |
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beta-1 blockers
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1. atenolol
2. metoprolol use-hypertension, angina, MI *discontinue B blocker use slowly |
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beta blocker adverse effects
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bradycardia (life threatening)
fatigue (decreased K in muscles, increased K in plasma--> hyperkalemia) increased plasmid lipids (triglycerides, LDL, VLDL, free cholesterol) decrease in HDL |
