Part 23: Vasodilators Flashcards
in vascular smooth muscle, the interaction between ___ and ___ causes contraction, resulting in vasoconstriction
myosin and actin
during membrane depolarization of vascular smooth muscle cells, large amounts of ____ ions come in through ____ channels
Ca; voltage gated Ca channels
Ca can also enter BV smooth muscle cells through the ___- exchanger where ___ is removed from the cytoplasm and ca enters
Na/Ca (NCX); Na
compared to the voltage-gated Ca channels, the NCX is a ____ (major/minor) contributor of Ca influx
minor
when might there be reduced removal of Na from the cells and entry of Ca by the NCX?
if the patient is taking a diuretic that depletes the body’s Na
when diuretics indirectly affect the NCX does it cause a vasodilator or vasoconstrictive effect?
vasodilator
the guanylyl cyclase pathway promotes vasodilation by increasing _____ of myosin, which releases the contractile stste of the smooth muscle cell
dephosphorylation
organic nitrates like ____ act in this pathway to cause vasodilation in patients with angina
nitroglycerin
what drug class does prazosin belong to?
alpha 1 adrenergic receptor antagonist (antihypertensive)
what is the MOA of alpha-1 antagonists like prazosin?
competes for binding to the A1 receptor and prevents endogenous action of NE secreted by sympathetic neurons and results in less Ca for contraction
activation of the alpha 1 receptor causes a _____coupled signalling cascade
Gq
a rise in intracellular Ca results in activation of mysoin ____
light chain kinase
while some Ca may come in by the NCX, most of the Ca enters through _____ channels
L-type voltage gated Ca channels
if we can block Ca channels, there will be less calcium ____ activation and a reduction in myosin _____ activity
calmodulin; light chain kinase
what are the 2 types of Ca channel blockers?
- dihydropyridine (DHP)
2. non-dihydropyridine
what class of drug does nifedipine belong to?
dihydropyridine type Ca channel blockers (vasodilator; antihypertensive)
what class of drug does diltiazem belong to?
non-dihydropyridine type Ca channel blocker (vasodilator; antihypertensive)
what is the clinical distinction between DHP and non-DHP Ca channel blockers?
DHPs are only effective in blocking Ca channels in smooth muscle cells, but not those in cardiac muscle cells, but non-DHP act in both
blocking Ca channels in cardiac muscle cells generally causes a _______ (increase/decrease) in the activity of these cells
decrease
why are non-DHPs like diltiaem not typically used?
they can block ca channels in the heart wich reduces activity of heart cells
what are some of the common ADRs of vasodilators?
orthostatic hypotension, dizziness, headaches, bradycardia, cardiac suppression, urinary incontinence
what is the severity of hypotension, dizziness and headaches ADRs of vasodilators?
usually not serious, typically resolves over time, but if it doesnt resolve some ptaintes may need dose adjustments
bradycardia & cardiac suppression as ADRs are typically seen with what types of vasodilators?
non-DHPs like diltiazem
urinary incontinence as an ADR is typically not severe and is typically caused by what class of vasodilators?
A1 andronergic blockers also acting in other smooth muscle like prazosin
t/f prozosin can be used for the treatment of urinary retnetion
t
t/f vasodilators alone are typically not enough to manage hypertension
t
when a drop in BP is sensed, the _____ nervous system is activated
sympathetic
stimulation of B____ receptors in cardiac tissues increases heart rate and contractility, and cardiac output, resulting in increased BP
1
why would it not make much sense to use nifedipine and prazosin togther?
they both act on smooth muscle to reduce contractility and it is typically better to choose agents that have differing MOAs
why would it not make sense to use an ACE inhibitor and ARB togther?
bc they act on the same pathway, and we typically want to diversify to get bettwer efficacy
what is angina?
a condition where narrowing of the coronary vessesl causes reduced blood flow and reduced O2
angina typically presents as ___
chest pain or pressure upon excretion of exercise
angina that worsens with exercise is called ___
effort angina
what is the main management for angina?
to balance out O2 supply and demand, which will help to reduce the symptoms ; lowering BP can also help
vasodilators increase O2 ____
supply
B blockers decrease O2 _____
demand
organic nitrates cause ____ to ____increase/decrease O2 supply
vasodilation; increase
what agents can be used to reduce cardiac output to reduce O2 demand?
B blockers and non-NHPs like diltiazem
organic nitrates act by increasing ____ in the vascular smooth muscle cells
nitric oxide
nitric oxide is normally produced by ____ cells surrounding vascular smooth muscle cells in BV
endothelial
when nitric oxide is made, it diffuses into the vascular smooth muscle cells where it increases the activity of ____, which promotes more ____
guanylase cyclase; cyclic GMP
cyclic GMP activates ____ that dephosphorylate myosin light chains, causing muscle relaxation
phosphatases
endogenously, nitric oxide has a very _____ (long/short) half life
short
due to its short t1/2, NO is not an effective therapeutic strategy on its own, but we can administer drugs that produce NO once they are inside these cells, these agents are called ____
nitric oxide donors
____ are one class of nitric oxide donors that can be used to achieve vasodilation in angina
organic nitrates
____ is one of the more familiar nitrate agents used clinically
nitroglycerin
nitroglycerin is metabolized in vascular smooth muscle cells by _____ and other enzymes to make NO
glutathione S-transferase
organic nitrates are readily metabolized in the ____, giving them _____ (high/low) oral bioavailability
liver; low
what are the typical administration routes of nitroglycerin?
parenteral: sublingual, transdermal are most common
sublingual nitroglycerin is for ______ (acute PRN or chronic prophylactic) use
acute PRN
transdermal nitroglycerin is for ______ (acute PRN or chronic prophylactic) use
chronic prophylactic
what type of nitroglycerin should a patient with effort angina take?
sublingual
what type of nitroglycerin should a patient with angina at rest take?
transdermal
nitrates cause a ______(reduced/increased) preload in the heart and _____ (reduces/increases) the after load
reduced;reduces
what is preload?
the filling pressure of the heart
what is after load?
the pressure the heart needs to pump against
dilation of ____ arteries reduces the after load
coronary
dilation of _____ reduces preload
veins
nitroglycerin increases O2 ____ and decreases O2 ____
supply; demand
when using nitrates, one of the ADRs (aside from orthostatic hypotension, headache, dizziness) is a compensatory increase in ______
heart rate (which can increase BP)
wrt to the ADR of compensatory tachycardia, which patients are more likely to require an additional antihypertensive to manage this?
those taking it chronically (usually goes away for PRN users)
_____ develops with continual nitrate exposure
tolerance
why does nitrate tolerance happen?
saturation of the metabolic pathways required to activate organic nitrate, causing less NO production and reduced vasodilation
is a patient has developed nitrate tolerance, will changing the dose restore the effect?
no
how can the development of nitrate tolerance be minimized?
have chronic use patients schedule a nitrate-free period , usually overnight for 8 hrs, which will promote restoration of the enzymes and substrates needed for the metabolic pathways in the morning
organic nitrates are dangerous when combined with what type of drug?
erectile dysfunction drugs like sildenafil
why is it dangerous to combine erectile dysfunction drugs like sildenafil with organic nitrates?
sildenafil inhibits the breakdown cyclic GMP by phosphodiesterase, which promotes vasodilation and blood flow to peripheral areas, when combined with nitrates, this causes a very large increase in cyclic GMP and a very large hypotensive effect that can be extremely dangerous and even fatal
