Lecture 20: antianginal drugs Flashcards
1
Q
Angina: Pfizz
A
Stable angina
- Lumen narrowed by plaque
- inappropriate vasconstriction
- Relative ischemia occurs when oxygen demand increases.
- Pain is usually associated with a predictable threshold of physical activity
Unstable angina
- plaque ruptured
- platelet aggregation
- unopposed vasoconstriction
- Clots often form in response to plaque rupture in atherosclerotic coronary arteries; however can also form because diseased coronary artery endothelium is unable to produce NO and prostacyclin that inhibit platelet aggregation and clot formation
Variant
- no overt plaques
- intensive vasospasms
- Enhanced sympathetic activity (eg, emotional stress) especially when coupled with a dysfunctional coronary vascular endothelium (reduced NO) can precipitate vasospastic angina
2
Q
Angina Rx rationale
A
Increase oxygen delivery
• Coronary vasodilators
• Anti-thrombotic drugs
Decrease oxygen demand
- Vasodilators (reduce afterload & preload)
- Cardiac depressants (reduce heart rate & contractility)
3
Q
Drugs used to treat angina
A
- Nitrates: isosorbinde dintrate, isosorbide mononitrate, nitro, sodium nitroprusside
- Beta-blockers: atenolol, metoprolol, propanolol
- CCB: Amlodipine, Felodipine, Diltiazem
- Na+ channel blockers: Ranolazine
4
Q
Nitrates
A
MOA
- Nitrates mimic the actions of endogenous NO
- Rapid reduction in myocardial O2 demand (systemic vasodilatation) & relief of symptoms
- In CV system, nitrous oxide (NO) is primarily produced by vascular endothelial cells
- NO functions (all involve NO-stimulated formation of cGMP) :
- Vasodilation
- Anti-thrombotic
- Anti-inflammatory
Uses
- Variant angina
- Stable & unstable angina
- IV nitroglycerin = unstable angina & acute heart failure • Nitroglycerin (sublingual or spray) = first-line therapy for treatment of acute anginal symptoms
- Isosorbide mononitrate = orally for prophylaxis (sustained release preps available)
Cardiovascular action
- Vasodilation (venous dilation > arterial dilation)
- Decreased venous pressure
- Decreased arterial pressure (small effect)
- Reduced preload & afterload (decreased wall stress)
- Decreased oxygen demand
Coronary
- Prevents/reverses vasospasm
- Vasodilation
- Improves subendocardial perfusion
- Increased oxygen delivery
Adverse
- Headache (cerebral vasodilation)
- High doses = postural hypotension, facial flushing, reflex
Contraindications: Sildenafil
5
Q
Nitroglycerin - PK
A
- Undergoes sig. first-pass metabolism taken sublingually, transdermally, buccal, IV)
- Fast-acting: 2-5 min to onset of action
- Effect usually lasts ~ 30 min
- Longer-acting (12-24 h) preparations are available (eg, transdermal patches)
6
Q
Isosorbide Mononitrate PK
A
- Longer onset of action & duration of action than nitroglycerin (more useful for long-term prophylaxis)
- Isosorbide mononitrate = >1 h (time to onset of action) & nearly 100 % oral bioavailability
- Metabolites have longer t1/2’s and significant activity
7
Q
Sodium nitroprusside
A
Direct NO donor = very effective, immediate vasodilator
Clinical Applications
- ICU & emergency settings
- Used to treat severe hypertensive emergencies &
severe heart failure
Pharmacokinetics
- IV only (t1/2 < 3min)
- Continuous infusion is required
Adverse
- Severe nausea
- Vomiting
- Headache etc
- High doses = cyanide intoxification (nitroprusside releases cyanide along with NO)
8
Q
Beta-blockers
A
Uses: Recommended in all patients (unless contraindicated) with stable angina who have had an ACS or who have left ventricular dysfunction
Contraindications
- Variant angina (treated by Ca2+ channel blockers or nitrates)/vasospastic angina; other types of angina still ok to use beta-blockers
- Use with caution in patients with obstructive airway disease or peripheral vascular disease and, initially at very low doses in patients with heart failure
- NEVER discontinue abruptly (can cause rebound hypertension or angina)
9
Q
CCB
A
MOA
- Ca2+ channel blockers improve angina symptoms by:
- Coronary & peripheral vasodilatation
- Reducing contractility
Uses
- Used in combination with Beta-blockers when initial treatment with Beta-blocker is not successful or, as a Beta - blocker substitute when Beta-blockers are contraindicated
- Relieve symptoms of variant angina
10
Q
Felodipine, Amlodipine
A
MOA
- Minimal effect on cardiac conduction or HR
- Short-acting dihydropyridines should be avoided unless combined with Beta-blocker (increased mortality)
11
Q
Verapamil
A
- Slows AV conduction directly -> decr HR, contractility, BP & O2 demand
- Has greater inotropic effects than dihydropyridines (weaker vasodilator)
Contraindications
- Preexisting depressed cardiac function or AV conduction abnormalities,
- Use with caution in patients taking digoxin (increases digoxin levels)
12
Q
Diltiazem
A
MOA
- Similar effects to verapamil (slow AV conduction)
- HR (lesser extent than verapamil) & BP
13
Q
Na+ channel blockers
A
- Ex. Ranolazine
- Only works for people who have excess intracell Na+ due to angina
- Uses: Option for patients who have failed all other antianginal therapies
- PK: metabolised by CYP3A4
14
Q
Stable Angina Rx
A
- Acute attacks: promptly relieved by rest or nitroglycerin • Maintenance therapy: long-acting nitrates & Beta- blockers are preferred
- Ca2+ channel blockers: when Beta-blockers are not successful or are contraindicated
- Ranolazine: when nitrates, Beta-blockers & Ca2+-blockers are unsuccessful
- Aspirin & aggressive cardiovascular risk reduction should be carried out in all patients
15
Q
Unstable Angina Rx
A
- The link between stable angina & MI. Chest pains occur more frequently & precipitated more easily.
- Symptoms relieved by rest or nitroglycerin
- In addition, therapy with nitroglycerin & Beta-blockers should be considered
17
Q
Effect of Anti-Angina Drugs
A
