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PHRM 825 > Sympathomimetics > Flashcards

Sympathomimetics Flashcards

1
Q

sympathetic neurotransmitters: adrenergic

A

norepinephrine (noradrenaline)
epinephrine (adrenaline)
-the only difference between these is that epinephrine has a methyl group off of the N

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2
Q

derivatives of tryptophan

A

serotonin

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3
Q

derivatives of tyrosine

A

norepinephrine, epinephrine, dopamine

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4
Q

monoamines

A

contain one amino group connected to aromatic ring by two-carbon chain
-serotonin, dopamine, norepinephrine, epinephrine, (histamine)

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5
Q

catecholamines

A

monoamine with catechol group (benzyne with two hydroxyl groups), derivatives of tyrosine
-dopamine, norepinephrine, epinephrine

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6
Q

norepinephrine neurotransmission

A
  1. tyr transported into noradrenergic ending/varicosity by Na+ dependent carrier
  2. tyr converted to dopa by tyrosine hydroxylase, converted to dopamine by dopa decarboxylase
  3. dopamine transported to vesicle by vesicular monoamine transporter (VMAT)
    -same carrier transports NE
  4. dopamine converted to NE in vesicle by dopamine-b-hydroxylase
  5. release of transmitter occurs when action potential opens voltage-sensitive Ca2+ channels and increases intracellular Ca2+, fusion of vesicles with surface membrane causes expulsion of NE
  6. NE binds to adrenergic receptors on postsynaptic cell
  7. NE binds to regulatory receptors present on presynaptic terminal
  8. NE diffuses out of cleft/reuptaken into cytoplasm of terminal by NET where it’s metabolized by MAO and transported by VMAT into vesicles
  9. NE can diffuse away from synaptic cleft to other cells, degraded by COMT
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7
Q

where does dopamine become norepinephrine?

A

presynaptic vesicle

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8
Q

where does norepinephrine become epinephrine?

A

adrenal medulla

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9
Q

metabolic enzymes: COMT

A

catechol-O-methyltransferase
-highest activity in liver, important for metabolism of circulating and administer catecholamines
-at nerve terminals

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10
Q

metabolic enzymes: MAO

A

monoamine oxidase
-surface membrane protein of mitochondria
-high concentrations in nerve terminals, liver, kidney, gut

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11
Q

primary ANS receptors

A

adrenoceptors
-alpha: a1, a2
-beta: b1, b2, b3

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12
Q

direct acting adrenergic receptor agonists

A

levophed: norepinephrine
adrenalin: epinephrine

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13
Q

stereochemistry for catecholamines

A

have a specific spatial orientation for binding to a receptor

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14
Q

adrenergic receptors: a1 (Gq)

A

vasoconstriction (innervated)
pupillary dilation
ejaculation
inhibition of micturition
GI inhibition

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15
Q

adrenergic receptors: a2 (Gi)

A

vasoconstriction (uninnervated)
prejunctional inhibition of NE release
in CNS: decrease CV SNS input

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16
Q

adrenergic receptors: b1 (Gs)

A

cardiac stimulation (innervated)
secretion of renin

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17
Q

adrenergic receptors: b2 (Gs)

A

cardiac stimulation (uninnervated, minor)
bronchodilation
uterine relaxation
GI inhibition
vasodilation (uninnervated)

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18
Q

binding preference for epinephrine

A

b1, b2 > a1, a2

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19
Q

binding preference for norepinephrine

A

a1, a2, b1

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20
Q

NE receptors and CV effects

A

activates a and b1 receptors, little affinity for b2
-a1 agonist: vasoconstriction leading to rise in BP
-b1 agonist: cardiac stimulation by increase in force and conduction

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21
Q

E receptors and CV effects

A

activates a and b receptors
-a1 agonist: vasoconstriction leading to rise in BP
-b1 agonist: cardiac stimulation by increasing force, rate, and conduction
-b2 agonist: vasodilation leading to lower BP and bronchodilation
–target for allergy attacks to open airways

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22
Q

D receptors and CV effects

A

lower doses
-d1 agonist: vasodilation in renal, mesenteric, and coronary arteries, increase blood flow
-b1 agonist: cardiac stimulation by increasing force, rate, and conduction
high doses
-a1 agonist: vasoconstriction leading to rise in BP

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23
Q

direct acting adrenergic receptor agonists: NE

A

potent a and b1 receptor agonist
substrate for MAO and COMT: both metabolize NE quickly
parenteral administration
used as a pressor
sodium bisulfite used in preparations to prevent oxidation

24
Q

direct acting adrenergic receptor agonists: E

A

potent a, b1, and b2 receptor agonist
substrate for MAO and COMT
parenteral administration
sodium bisulfite used in preparations to prevent oxidation
available as many salts: hydrochloride, nitrate, bitartrate
uses: anaphylaxis, in combination with local anesthetics

25
epinephrine
action: -low concen.: effects at b1 and b2 predominate -high concen.: effects at a1 predominate clinical use: Tx of acute anaphylaxis and cardiac arrest, adjunct with local anesthetics problems: not orally active due to COMT and MAO breakdown in liver (first pass metabolism), can produce unwanted effects through broad activation of adrenergic receptors
26
epinephrine and hypoglycemia
increase blood glucose levels -b2: glycogenolysis, gluconeogenesis -a2: inhibits insulin secretion
27
D1 agonist dopamine
action: -renal D1-receptor agonist, renal vessel dilation -direct and indirect b1-agonist, a1-agonist (high dose): sympathomimetic activity -cardio stimulate and systemic vasoconstrictor outside the kidney clinical use: shock, acute congestive heart failure -MUST BE GIVEN IV: can't withstand metabolism selective D1 agonist fenoldopam: severe hypertension in hospitalized patients
28
adrenergic receptor subtypes: a1
signal via Gq pathway -metabolize Ca2+ from intracellular stores, activate PKC -found on vascular smooth muscle, genitourinary smooth muscle, intestinal smooth muscle, heart, liver mediates vasoconstriction clinically manipulated for... -agonist: nasal decongestion, vascular failure in shock and supraventricular tachycardia -antagonist: hypertension, benign prostatic hyperplasia, pheochromocytoma drugs: phenylephrine, oxymetazoline
29
direct a1 agonist: phenylephrine
clinical use: nasal decongestant, mydriasis without cycloplegia, pressor, vasoconstrictor in regional anesthesia admin: parenteral, oral, local substrate for MAO problems: few (not very effective decongestant) differences from epi -missing OH group
30
SAR: NE
R1: H R2: H receptor selectivity: a MAO: more affinity
31
SAR: E
R1: -CH3 R2: H receptor selectivity: a, b1 MAO: slightly less affinity
32
SAR: isoproterenol
R1: -CH(CH3)2 R2: H receptor selectivity: b1, b2 MAO: less affinity
33
SAR: n-tert-butylnorepinephrine
R1: -C(CH3)3 R2: H receptor selectivity: b2 MAO: minimal
34
catechol ring modifications for selectivity: catechol
isoproterenol b selectivity
35
catechol ring modifications for selectivity: resorcinol
metaproterenol b2 selectivity (no COMT)
36
catechol ring modifications for selectivity: meta-hydroxymethyl
albuterol b2 selectivity (no COMT)
37
catechol ring modifications for selectivity: only meta-OH
phenylephrine a1 selectivity
38
direct acting adrenergic receptor agonists: a1 receptor agonists, 2-aralkylimidazolines
partial agonists at a receptors administered locally/topically to promote vasoconstriction basic nature of imidazoline ring causes compounds to exist in ionized form at physiologic pH -cation is resonance stabilized allowing the + charge to be spread over the entire 3 atom system: imidazolines are more basic tachyphylaxis/desensitization uses: nasal and ophthalmic decongestants drugs: naphazoline, tetrahydrozoline, oxymetazoline
39
adrenergic receptor subtypes: b1, b2, b3
signal through Gs -activate adenylyl cyclase -increase cAMP -increase cAMP-dependent protein kinase activity -results in phosphorylation of ion channels and other proteins
40
b1 receptors
found in... -heart: increase force of contraction, HR, conduction velocity in AV node -kidney: increase renin release clinically manipulated for... -agonist: shock, congestive heart failure -antagonist: hypertension, angina, arrhythmias, congestive heart failure
41
b2 receptors
found in... -smooth muscle: relaxation, especially bronchial -vasodilation clinically manipulated for... -agonist: asthma, premature labor -antagonist: glaucoma
42
b3 receptors
found in... -urinary bladder: relaxation, prevention of urination clinically manipulated for... -agonist: overactive bladder
43
direct acting b adrenergic receptor agonists
non-selective: isoproterenol mixed b1, a1: dobutamine b2 selective: terbutaline, metaproterenol, albuterol, salmeterol, ritodrine b3 selective: mirabegron
44
direct acting non selective b receptor agonists: isoproterenol
catechol: nonselective bronchodilation increased cardiac output metabolized by conjugation reactions (phase II) and COMT not sensitive to MAO admin: oral, parenteral, local (inhaled) uses: asthma, COPD, cardiostimulant
45
isoproterenol
action: -b1 and b2 receptor agonist -positive inotropic and chronotropic effects, thereby increasing CO -peripheral vessels: stimulation of b2 receptors results in vasodilation and reduced peripheral resistance (can cause BP to fall) clinical use -emergency to increase HR in patients with bradycardia or heart block before pacemaker implantation -systolic dysfunction and slow HR with high systemic vascular resistance (after cardiac surgery in patients with previous use of b-blockers) -asthma and COPD note: not routinely used, E and D more common
46
selectivity of adrenergic receptor agonists
phenylephrine has more selectivity for a1, low for all b epinephrine has next selectivity for a1, second for b1 and b2 NE has third selectivity for a1, third for b1 and b2 (100 fold difference with E) isoproterenol has least selectivity for a1, most for b1 and b2
47
direct acting selective b2 receptor agonists: metaproterenol, terbutaline
resorcinol derivatives bronchodilation, cardiac effects only at high doses not metabolized by MAO or COMT longer duration of action than isoproterenol admin: oral, parenteral, local (inhaled) uses: asthma, COPD -terbutaline used as tocolytic (prevent premature labor)
48
direct acting selective b2 receptor agonists: albuterol, salmeterol
meta hydroxymethyl derivatives bronchodilation, cardiac effects only at high doses not metabolized by MAO or COMT longer duration of action than isoproterenol admin: oral, local (inhaled) uses: asthma, COPD
49
direct long acting selective b2 receptor agonists: salmeterol, formoterol
bronchodilation not metabolized by MAO or COMT onset of action -salmeterol: 10-20 min -formoterol: <5 min longer duration of action admin: inhaled (metered dose inhaler and powder) uses: long-term asthma, COPD not recommended for acute Tx of asthma symptoms
50
b2 agonist: albuterol and terbutaline
action: b2 receptor agonist clinical use -asthma: albuterol and terbutaline -tocolytic: terbutaline (relax uterus during premature labor) problems: minor cardiac stimulation
51
direct acting mixed b1, a1 receptor agonists: dobutamine
dopamine derivative, available as racemic mix -+ enantiomer: potent b1 receptor agonist -- enantiomer: potent a1 receptor agonist, potency for b receptors reduced 10x -exerts much stronger inotropic than chronotropic effect metabolized by COMT and conjugation, not sensitive to MAO short half life (~2 min) admin: IV uses: acute heart failure, shock, laboratory "stress test"
52
direct acting b3 receptor agonists: mirabegron
approved July 2012 clinical use: overactive bladder problems: slow onset (8 weeks), hypertension
53
adrenergic receptor subtypes: a2
signals through Gi -inhibit adenylyl cyclase -activate certain K+ channels -inhibit neuronal Ca2+ channels found pre-synaptically and function as autoreceptors to inhibit sympathetic output -results in decreased transmitter release clinically manipulated for... -agonist: hypertension, pain, glaucoma
54
direct acting a2 adrenergic receptor agonists
clonidine methyldopa guanabenz guanfacine brimonidine apraclonidine tizanidine
55
direct acting a2 adrenergic receptor agonists: clonidine
(phenylimino)imidazolidine basicity of guanidine group (pKa = 13.6) is decreased (pKa = 8) because of attachment to dichlorophenyl ring activation of a2 receptors in CNS (decrease SNS activity) and presynapses
56

PHRM 825 (5 decks)

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