Med Chem - Shock Flashcards
shock is defined as
an inadequate organ and peripheral tissue perfusion
what are the categories of shock
hypovolemic
neurogenic
cardiogenic shock
restrictive - vasodilatory/distributive - septic
anaphylactic
what kind of shock involves blood loss due to hemorrhage or fluid loss due to uncontrolled diarrhea/dehydration or losing plasma after serious burns
hypovolemic
hypovolemic shock ____ cardiac output
decreases
spinal cord injury leads to
neurogenic shock
what kind of shock is characterized by sudden loss of sympathetic nerve activity
neurogenic shock
during neurogenic shock the equilibrium shifts towards parasympathetic tone leading to the relaxation of blood vessels, hypotension, bradycardia, hypoxia leading to
multiple organ failure
what kind of shock is caused by severe impairment of myocardial performance that results in reduced cardiac output, hypotension and end organ hypoperfusion
cardiogenic shock
cardiogenic shock ___ inotropy and ____ chronotropy
decreases, decreases
inotropy is
the force of heart muscle contraction
chronotropy is
heart rate
septic shock is cause by
infection
what kind of shock involves massive vasodilation - hypotension and inadequate peripheral perfusion
septic
a severe allergic response with decreased blood flow to the brain leading to fainting is known as
anaphylactic shock
the treatment of shock patients involves the administration of
endogenous catecholamines
vasopressor agents
exogenous catecholamines
what are the endogenous catecholamines
EPI and NE and DA
vasopressin is a ___ agent
vasopressor
what are the exogenous catecholamines
dobutamine and phenylephrine
vasopressors ___ BP
increase
inotropes ___ cardiac output
increase
what are the inotropes
dopamine, dobutamine, milrinone
what are the vasopressors that are adrenergic agonists
EPI NE DA
what are the vasopressors that are GPCR agonists
vasopressin V1 V2
what activates AT1 receptor and is an agonist
Angiotensin II
AT1 receptor agonist acts by
vasoconstriction and increased BP
NE is a
endogenous NT in the sympathetic nervous system
adrenergic agonists are structurally related to
nE
how do epi and ne differ
R group is H in NE and CH3 in EPI
catecholamines are ___ molecules with good solubility in body fluids
polar
___ is a circulatory hormone
epi
where is epi released from
the chromaffin cells in the adrenal medulla
what is the rate limiting step of epi and norepi synthesis
tyrosine hydroxylase
T or F Tyrosine hydroxylase is controlled by feedback inhibition by NE and EPI
T
EPI that is formed is stored in
granules until released
what primarily terminates the activity of NE and EPI
primarily by the reuptake into the presynaptic terminal followed by metabolism
other than reuptake, NE and EPI are terminated by metabolism by
COMT and MAO
what does COMT stand for
catechol o methyl transferase
what does MAO stand for
monoamine oxidase
where does MAO occur
mitochondria
COMT regioselectively methylates the ___ of catecholamines
meta OH
MAO acts on the primary amines of catecholamines by
oxidative deamination
T or F compounds that are resistant to even just one of the metabolic enzymes of EPI and NE have a longer duration of action and greater oral availability
T
what is the end metabolite of NE
vanillylmandelic acid VMA
4 hydroxy 3 methoxy mandelic acid
which catecholamine is most potent at alpha adenoceptors
NE EPI ISO
which catecholamines are most potent at beta adrenoceptors
ISO EPI NE
what are the three mechanisms of actions of adrenergic agonists
direct acting
indirect acting
mixed acting
direct acting adrenergic agonists have the
same affinity and intrinsic activity as the endogenous agonists NE and EPI
the indirect acting adrenergic agonists work by
stimulate release of NE from presynaptic terminals
inhibit reuptake of released NE into presynaptic terminals
inhibits the metabolic degradation of NE by MAO
the amino N of catecholamines must be
primary or secondary and separated by 2C from a substituted phenyl ring
if the amino N on catecholamines are ter or quaternary amines then they are
inactive
if R1 of catecholamines are H or CH3 then they
maintain affinity for both alpha and beta receptors, nonselective
if R1 of catcholamines are CHCH32 - isopropyl then
potent selectivty for beta receptors
if R1 of catecholamines is CCH33 - arylalkyl then confer
optimal beta affinity with some beta 2 selectivity but NO ALPHA RECEPTOR ACTIVITY
when are catecholamines sensitive to MAO mediated metabolism and why
when R2 has two alpha hydrogens
because MAO requires an absolute 2 hydrogens on the alpha carbon
R3 of catecholamines must be in ___ configuration to effectively H bond with Asn293
R
what must R3 be in catecholamines and why
OH
with catechol to yield direct adrenergic action at both alpha and beta receptors
the R4 and R5 side groups of catecholamines are attached to
catechol
if only one group of R4/5 is present with OH then it is preferred to be ___ to retain ___
R5 at 4, beta 2 activity
if in a catecholamine the phenyl group has no OH substituent then it may be
acting directly or indirectly
epinephrine is susceptable to ____ which is the removable of -ch3
n dealkylation
T or F epinephrine can penetrate the BBB
F, too polar to penetrate BBB, no CNS activity
NE is more or less polar than EPI
more
-CH3 of EPI makes it more lipophillic
NE is a less potent ____ than EPI
inotrope
___ is a pure vasoconstrictor
NE
when is NE preferred and why
settings in which heart rate stimulation is undesirable , minimal chronotropic effects
which pathway is generally desirable to treat shock patients mostly
alpha 1 stimulation
alpha 1 receptor stimulation leads to
vasoconstriction - contraction of vascular smooth muscle
beta 2 receptor stimulation leads to
vasodilation - relaxation of smooth muscle
_____ is a key regulator of cardiac contractility
phospholamban
alpha 1 signaling is ___ linked
Gq linked
alpha 2 signaling is ___ linked
Gi linked (inhibition)
alpha 2 signaling results in
reduction of camp
alpha 1 signaling results in
release of calcium and activation of calcium dependent pk
beta 2 signaling is linked to
Gs linked
beta 2 signaling leads to
increase in camp
epinephrine is CI in patients with
narrow angle glaucoma
precaution in pregnancy
phenylephrine is a powerful vasoconstrictor due to
its lack of affinity for beta adrenergic receptors
Ar-OF on 5 position instead of preferred 4
phenylephrine is more or less polar than EPI NE
less polar
because phenylephrine is less polar than EPI and NE it has a ___ half life
longer half life , duration of action
vasopressin is released from
posterior lobe of the pituitary fland
vasopressin is a ____ hormone
nonapeptide - 9 aa
there is ____ intramolecular disulfide bond between Cys1/6 in vasopressin
one
the effects of vasopressin are that it
regulates water reabsorption in the renal tubule
vasopressin is also known as
ADH antidiuretic hormone
what is the mechanism of action of vasopressin
V1 - gq and V2- gs receptor agonists
what are the primary actions of vasopressin
vasoconstriction and increased blood volume due to fluid reabsorption in the kidneys
overall increased arerial pressure
dobutamine stimulates beta ___ receptor
1
dobutamine does not cause the release of
endogenous NE
dobutamine stimulates beta 1 receptors of the heart to
increase myocardial contractility and stroke volume resulting in increased cardiac output
milrinone is a
dihydrobipyridine
which drug is a PDEIII inhibitor
milrinone
what is the mechanism of action of milrinone
inhbits camp breakdown
increases PKA
inhibits MLCK which causes myosin light chains to contract leadign to no contract but relaxation
PDE III inhibition of milrinone prevents ___ which leads to vasodilation
cAMP hydrolysis
milrinone is a ___ inotrope and vasodilator
positive
milrinone acts by inhibiting PDE III which mimicks beta ___ activation
beta 1
when is milrinone active
R2 - CH3
R3 = H
R5 = CN NH or BR all retain activity
milrinone is inactive when
R2 = H
RH = CH3
and R5 is just H
for milrinone to be active the torsion angle must be
greater than 0 degrees
the renin angiotensin aldosterone system is ___ in septic shock which leads to impaired angiotensin II
altered
angiotensin II is a ____ peptide
octapeptide
what is the therapeutic use of angiotensin II
it is used to increase blood pressure in patients with hypotension
how is angiotensin II metabolized
by ACE 2 and aminopeptidase into heptapeptide
what is the half life of AG II in the circulation vs the tissues
about 30 seconds in circulation
abot 15-30 minutes in tisses
AG II is used to increase
aldosterone and ADH secretion
