Drugs for ACS and Stable Angina (Konorev) Flashcards
What are the 3 nitrates (nitrovasodilators) used in chronic IHD?
- Nitroglycerin
- Isosorbide dinitrate
- Isosorbide mononitrate
Increasing coronary blood flow using vasodilators is useful in treating what kind of angina?
Vasospastic (Prinzmetal) angina
Why is Dipyridamole not useful in atherosclerotic (classic) angina?
- “Coronary steal” phenomenon = redistribution of blood to non-ischemic areas
- No substantial increase in coronary blood flow into the ischemic area
Which nitrate is a poor substrate of nitrate reductase in the liver and therefore has higher bioavailability?
Isosorbide mononitrate
Describe the rationale behind using sublingual, buccal, and transdermal routes of administration of nitrates, as opposed to oral administration of these drugs
Undergo significant first-pass metabolism - high nitrate reductase activity in liver = oral bioavailability is LOW
What is the crucial for the activation of nitrates to release nitric oxide?
Reduced thiols (ADH2) –> release NO from nitrates
Describe the role of nitric oxide in maintaining vascular tone?
- Open K+ channel = hyperpolarization and reduced Ca2+ entry
- NO activates guanylate cyclase –> ↑ cGMP –> ↑PKG –> Myosin-LC dephosphorylation –> smooth m. relaxation
Describe sensitivity of different types of vessels towards vasodilatory activity of nitrates, from greatest effect to least
Veins > Large arteries > Small arteries and arterioles
Nitrates used in the treatment of angina have a major effect of causing dilation of veins, which leads to what 2 therapeutic effects?
- Increased venous capacitance
- Reduced ventricular preload –> ↓O2 demand
`Higher concentratins of nitrates are needed to dilate arteries, which will have what 2 effects?
``- May reduce afterload
- May dilate large epicardial coronary arteries
Nitrous oxide has effects beyond just vasodilation, describe some of the inhibitory effects.
- Inhibits platelet aggregation
- Inhibits monocyte adhesion
- Inhibits smooth m. proliferation
- Inhibits free radical formation
- Inhibits LDL oxidation
Variant (Prinzmetal) angina is characterized by episodes of what (i.e., leading mechanism of injury)?
Episodes of vasoconstriction of coronary ateries
Major overall effect of nitrates is a decrease in?
Myocardial O2 demand
The development of tolerance to Nitrates is associated with what 4 events?
- Depletion of thiol compounds
- ↑ generation of superoxide radicals
- Reflex activation of sympathetic NS –> Tachycardia, ↓ coronary blood supply
- Retention of Na+ and H2O
Increased generation of superoxide radical depletes tissues of what?
NO
What are short-acting formulations of nitrates used for clinically?
Via which route of administration?
- Used to relieve the angina attacks
- Sublingual spray
What are long-acting formulations of nitrates used for clinically?
Via which route of administration?
- Used to prevent attacks
- Oral, ointment, or patch
Nitroglycerin comes in 3 long-acting formulations, which can be administered via which routes?
- Oral
- Ointment
- Patch
What are 4 adverse effects associated with Nitrates?
- Headache
- Orthostatic hypotension
- Increased sympathetic discharge –> Tachycardia + ↑ contractility
- Increased renal Na+ and H2O reabsorption
Why are nitrates contraindicated if ICP is elevated?
Due to meningeal vasodilation
Which drug should nitrates not be used in combination with due to drug-drug interactions?
ED drugs –> Sildenafil, Vardenafil, Tadalafil
Combination of nitrates with drugs for ED (i.e., Sildenafil, Vardenafil, Tadalafil) cause what AE?
What serious AE has been reported?
- Severe ↑ in cGMP and a dramatic ↓ in BP
- Acute MI have been reported
What are the 3 non-cardioactive (dihydropyridines) calcium channel blockers used in angina?
1) Amlodipine
2) Nifedipine
3) Nicardipine
What are the 2 cardioactive calcium channel blockers used in angina?
- Diltiazem
- Verapamil
What are the anti-anginal mechanism of CCB’s in atherosclerotic (“classic”) angina?
- Dilation of peripheral arterioles
- ↓ PVR and afterload + ↓ BP (heart doesn’t have to work as hard)
Which non-cardioactive (dihydropyridine) is the longest-acting?
Amlodipine
Which group of CCB’s are more potent vasodilators?
Non-cardioactive (dihydropyridines)
Why is there less orthostatic hypotension as an AE when using CCB’s for angina?
Arterioles are affected more than veins
Which CCB’s lead to ↓ cardiac contractility and HR?
Cardioactive CCB’s (diltiazem and verapamil)
Which CCB causes the greatest ↓ cardiac contractility, ↓ SA and AV node conduction?
Verapamil
What is the therapeutic action of CCB’s in variant angina?
Dilation of coronary arteries relieves local spasm
What are the major AE’s associated with cardioactive CCB’s?
- Cardiac depression, arrest, and acute heart failure
- Bradyarrhythmias, AV block
Adverse effects associated with the short-acting dihydropyridine CCB’s?
Vasodilation triggers relfex sympathetic activation
What is an AE of Nifedipine (immediate release) in pts w/ HTN?
Should use what type of dihydropyridine instead?
- ↑ risk of MI in pts w/ HTN
- Slow-release and long-acting (amlodipine) are better tolerated
What are some of the minor AE’s associated w/ CCB’s?
- Flushing, HA, anorexia, dizziness
- Peripheal edema
- Constipation
What are the 4 beta-blockers indicated in tx of angina?
- Propranolol
- Nadolol
- Metoprolol
- Atenolol
What is the major MOA of beta-blockers in tx of angina (i.e., HR, contractility, BP, O2 demand)?
- ↓ HR —> improved myocardial perfusion and ↓ O2 demand at rest and during exercise
- ↓ contractility
- ↓ BP leads to ↓ afterload
Withdrawl syndrome from beta-blockers is associated with what?
Sympathetic hyperresponsiveness
What are 5 AE’s associated with beta-blockers?
- ↓ cardiac output
- Bronchoconstriction
- Impaired liver glucose mobilization
- Produce unfavorable blood lipoprotein profile (↓ HDL and ↑ VLDL)
- Sedation, depression
Beta-blockers are contraindicated in pts with what 5 conditions?
- Asthma
- Peripheral vascular disease
- Type 1 diabetics on insulin
- Bradyarrhythmias and AV conduction abnormalities
- Severe depression of cardiac function
What are 2 potential undersirable effects of using nitrates alone for angina?
- Reflex ↑ in HR
- Reflex ↑ in contractility
What are 2 potential undesirable effects of using beta-blockers or CCB’s alone for treatment of angina?
- ↑ end-diastolic volume
- ↑ ejection time
What is the rational for using a combo of nitrates w/ beta-blockers or CCB’s for angina?
- ↓ HR (avoids reflex ↑ seen in nitrates)
- No effect or ↓ EDV (avoid ↑ associated w/ beta-blockers or CCB’s)
- No effect on contractility (avoid reflex ↑ seen in nitrates)
- No effect on ejection time (avoid ↑ seen w/ beta-blockers or CCB’s)
What is the MOA of Ranolazine?
Inhibits late Na+ current in cardiomyocytes
Ischemic myocardium is often partially in what state of polarization?
How do late Na+ channels contribute to this?
- Partially depolarized
- Late Na+ current is enhanced —> Ca2+ overload and repolarizaton abnormalities
What is the rationale for using Ranolazine for tx of angina based on its MOA?
Normalizes repolarization of cardiac myocytes and ↓ mechanical dysfunction
Ranolazine may reduce what 2 complications in the heart which contribute to angina?
- Reduce diastolic tension and compression of coronary vessels in diastole
- Reduce cardiac contractility and O2 demand
What is the effect of ranolazine on HR, coronary blood flow, and peripheral hemodynamics?
No effect
What are 2 indications for using Ranolazine for angina?
Especially in pts taking what medications?
- Stable angina which is refractory to standard meds
- ↓ angina episodes and improves exercise tolerance in pts taking nitrates or amlodipine, or atenolol
Which class of drugs are the first line for variant angina?
CCB’s
If CCBs are contraindicated (low BP, bradycardia, AV block) for tx of variant angina, what is used?
Long-acting (LA) nitrates
What are 4 approaches for tx of stable (atherosclerotic) angina?
- Lipid-lowering therapy
- Lifestyle modifications
- Immediate release nitrates (SL or spray)
- Antiplatelet therapy (aspirin)
If more than immediate release nitrates are needed for stable (atherosclerotic) angina what is the next in line?
Describe the progression of treatment if more drug is needed.
- Beta blocker or alternative (CCB or LA nitrate)
- Add CCB or BB (if not 1st drug)
- Consider triple therapy (BB + CCB + LA nitrate or ranolazine)
If pt with angina has low BP what 2 drugs can be used?
- LA nitrate (oral, ointment or patch)
or
- Ranolazine
