anti-anginal drugs Flashcards
Name 3 pathophysiologies of angina pectoris
- progressive occlusion by atherosclerotic plaque
- unstable plaque (evolving clot)
- vasospam
where does the actual pain come from with angina pectoris
- secondary to metabolite spill from HYPOXIC cells (especially adenosine leakage), which stimulates pain fibers
angina occurs when oxygen _____ exceeds oxygen ____
demand; supply
what is the main pharmacological goal of relieving angina
- decreasing myocardial oxygen demand, or increasing oxygen supply (less commonly)
What is the role of autoregulation of coronary blood flow?-
- limits ability to increase O2 supply
Name the two determinants of oxygen supply
- patency of blood vessels
2. length of diastole
Name the three determinants of oxygen demand
- heart rate
- contractile force
- ventricular wall stress
What two components are a part of ventricular wall stress? define them
- preload: amount of stretch of ventricular wall prior to systole… determined by LV end diastolic pressure and volume
- with more stretch you get more of a contractile force –> more meatbolism that requires more oxygen consumption and demand
- afterload: force districuted in ventricular wall during systole; determined by the peripheral vascular resistance
- with more afterload, you need to do more work, so you have increased oxygen consumptoin and demand
what receptor in the body, when stimulated, increases contractility how about heart rate?
- Beta 1 adrenergic for both
What is the relationship between heart rate and the length of systole? diastole?
- no relationship between heart rate and systole; heart rate is inversely related to length of diastole
what treatment do you use to decrease ventricular wall stress?
- Organic nitrates, calcium channel blockers, ranolazine
what treatment do you use to decrease cardiac contractility
beta blockers, some calcium channel blockers, ranolazine
what treatment do you use to increse O2 supply in heart
- anti-platelet agents (aspirin, clopidogrel, integrin blockers)
- Thrombolytics (streptokinase, tPA)
what do you use to reduce oxygen demand of heart via decreasing HR
- beta blockers
what is the another name for organic nitrates
- nitrovasodilators
Name three common organic nitrates and their MOA
- glyceryl trinitrate (NTG)
- Isosorbide mononitrate
- isosorbide dinitrate
NO donors to give vasodilation
What is the net effect of nitrovasodilators
- reduction of intracellular calcium and other effects – causes smooth muscle releaxation
What enzyme must be present to activate nitrovasodilators? what happens for activation
- ALDH-2; activation occurs when NO is released from the compound
how does tolerance work with nitrovasodilators
- suicide inhibition of ALDH-2; inhibits itself with bioactivation
Give pathway of NTG
- ALDH-2 activation of the nitrovasodilators to release NO
- NO acts on smooth muscle guanylyl cyclase to form cGMP
- cGMP activates cGMP dependent protein kinase which will decrease intracellular calcium levels
what is target of ED drugs
- PDE… keep out conversion of cGMP to GMP (keep cGMP high
what has greater enzymatic bioactivaiton capacity, veins or arterioles?
- VEINS; so we see preferential dilation of venous circulation and conduit arteries compared to arterioles
Describe mechanism of therapeutic effect in terms of supply and demand
- reduces venous return so we reduce preload, reduce ventricular wall stress, and decrease myocardial oxygen DEMAND
supply: dilates conduit/collaterals to help with supply benefit, and also inhibits platelet aggreation to help with unstable angina
How is nTG generally given? what is the difference in adminitsration and duration of effect
- sublingual administration – rapid onset and short duration
- transdermal: prlongs onset and duration of action
describe bioavailability and absorption of GTN… what nitrovasodilator is not subject to first pass meatabolism
- very high hepatic first pass metabolism
- Isosorbide mononitrate is not subject to first pass metabolism
Is tolerance present with nitrovasodilators? what is it dependent on and how long does it act?
- develops with all nitrates; dose dependent, but disaapperas in 24 hr after stopping the drug
What is the reason for adverse effects of nitrovasodialtors
excessive vasodilation and FALL in blood pressure
- orthostatic hypotension
- reflex sympathetic drive
- dizziness
- headache
*** cross potentiation (SYNERGISTIC EFFECT) of action with PDE-5 inhibitors like viagra…. to cause PROFOUND VASODILATION and visual disturbances
what is the reflex sympathetic drive?
- tachycardia nad increased cardiac contractile force which actually creates more work and increases myocardial oxygen demand
what types of channels do calcium channel blockers do and what is the result?
- block L type (slow) calcium channels
- reduce influx of extracellular calcium into vascular and cardiac muscle
what is preference of location of action for ca channel blockers
- preferentially on arteriolar vasodilators v veins
calcium channel blockers have mostly an effect on ______ with littel effect on ______
- afterload
- preload
what two triggers exist for L type calcium channel activity in cardiac muscle cells
- depolarization
2. beta-1 adrenergic receptors
what is the effect of L-type blockade at cardiomycotes
- reduces inotropy AND chronotropy
what two triggers exist for L type calcium channel activity in vascular smooth muscle cells
- vasoconstrictors (like angiotensin)
2. myogenic phenomena (like stress)
what is the effect of L-type blockade at vascular SMC
- relaxation
2. vasodilation
what is the difference in efficacy of verapamil, diltiazem, and nifedipine at peripheral vasoconstriciton?
- ALL EQUAL
what is the difference in efficacy of verapamil, diltiazem, and nifedipine for:
cardiac contractility
heart rate
AV conduction
spectrum
verapamil gives more block in av conduction, cardiac contractility, and heart rate
diltiazem is in the middle
nifedipine gives less block
Give adverse effects of calcium channel blockers
- vasodilation evokes sympathetic reflex
- verampamil and diltiazem can SYNERGIZE with beta blockers to produce excessive bradycardia, av block, inotropic depression
how to block the sympathetic reflex
- use beta 2 receptor antagonists OR
2. use non-dihydropyridine calcium channel blockers (verapamil and diltiazem
What is a contradication with using dihydropyridine calcium channel blockers?
- angina (higher risk of sudden death)
What is the goal of using beta 1 antagonists
- reduce major detemrinatns of myocardial oxygen DEMAND ( heart rate and contractility)\
THUS
increasing diastolic interval and allowing increased time for endocardial perfusion
what are the main choices for beta 1 antagonists
- non selective like propanolol
2. beta 1 selective (metoprolol)
adverse effects of blocking beta 1 receptors
- can exacerbate herat failure
- can synergistically act with non-DHP ccb to dpress contractility and HR and produce AV block
- withidrawwal can precipitate tachy, angina, and arrythimas
What is target of ranolazine?
- targets the late sodium current
give pathophys of ischemia in relation to late sodium current
- ischemia impairs na channgel inactiation, leading to higher intracellular na in the late phase of na action potnetion, leading to calcium overload, resulting in mechanical dysfunciton , electrical instability, and higher O2 demand
Ranolazine’s anti-anginal effects are independent of what?
- reductions in BP/HR
Ranolazine is useful for what condition? what is it not useful for?
- chronic angina
- acute coronary syndrome
what are adverse effects of ranolazine?
- prolongs QT
What are the 4 antiplatelet agents we can use to increase O2 supply? why do we use them?
- aspirin (prevents TXA2 synthesis)
- clopidogrel (P2Y12 receptor antagonist– no ADP activation so you can’t get platelet activation)
- integrillin (integrin block)
- reopro (integrin block)
USED for prophylaxis against clotting
side effects of The antiplatelet?
Bleeding!!
Why is nifedipine unique in where it works?
when would we see contraindications of nifedipine
- it’s a CCB that helps with vasodilation, but doesn’t act on L-type channels in the haert
short acting formulations CONTRAINDICATED in Coronary artery disease
