Anti-Anginal Drugs Flashcards
Classification of angina (0 to 4)
0 = asymptomatic 1 = angina with strenuous exercise 2= angina with moderate exertion 3 = angina with mild exertion (walking 1-2 level blocks at normal pace, climbing 1 flight of stairs) ---> prophylactics important at this stage 4 = angina at any level of physical exertion
Treatment rationale for angina pectoris
Increase oxygen delivery:
- coronary vasodilators
- anti-thrombotic drugs
Decrease oxygen demand:
- vasodilators (reduce preload and afterload)
- cardiac depressants (reduce HR and contractility)
Chronic stable ischemia is a demand ischemia
Unstable and Prinzmetal’s (variant) angina are supply ischemia
Nitrates MOA
Minic actions of endogenous NO
Direct vasodilatory action –> rapid reduction in myocardial oxygen demand and relief of symptoms
NO is primarily produced by vascular endothelial cells and functions as vasodilator, anti-thrombotic, anti-inflammatory –> due to NO-stimulated formation of cGMP
CVS actions of nitrates on systemic vasculature, heart and coronary arteries
Systemic vasculature:
- Vasodilation (venous > arterial)
- Decreased venous pressure
- Small effect of decreased arterial pressure
Cardiac:
- Reduce preload and afterload (decreases wall stress)
- Decrease O2 demand
Coronary
- Prevent and reduces vasospasm
- Vasodilation
- Improves subendocardial perfusion
- Increased O2 delivery
Clinical applications of different nitrates
Will see least effect on unstable angina but can be used for all types
Isosorbide mononitrate = orally for prophylaxis or all types of angina
Isosorbide dinitrate = orally for orally for prophylaxis or all types of angina and used to treat heart failure
IV nitroglycerin: unstable angina and acute HF
Nitroglycerin (sublingual or spray) = first-line therapy for treatment of acute anginal symptoms
Sodium nitroprusside
- Direct NO donor (immediate vasodilator)
- Used for severe hypertensive emergencies and severe HF in ICU/emergency settings
Nitrates PK
Nitroglycerin
- Undergoes significant first-pass metabolism therefore not given orally
- Fast acting: 2-5 min to onset on action
- Effects usually last 30 minutes
Isosorbide Mononitrate
- Longer onset of action and duration of action that nitroglycerin (therefore used for long-term prophylaxis)
- Takes over 1 hour to onset of action and nearly 100% oral bioavailability
Sodium Nitroprusside
- IV only
- Very short half life (3 minutes) –> needs continuous IV infusion
Nitrates AE and contraindications
Tolerance develops rapidly as vessels desensitise to vasodilation –> can be overcome by daily nitrate-free interval’ (10-12 hours)
Headache: cause cerebral vasodilation
High doses: postural hypotension, facial flushing, reflex tachycardia
Sodium nitroprusside AE:
- Cyanide intoxication, severe nausea, vomiting, headache
Contraindication:
Cannot use with sildenafil as they both increase cGMP in different ways and it can lead to severe hypotension
b-blockers used to treat angina (actions, clinical applications and contraindications)
Propanolol, metoprolol and atenolol
Reduce both HR and contractility
O2 demand decreased during exercise and at rest –> reduce frequency and severity of anginal attacks
Recommended in all patients (unless contraindicated) with stable angina who have had an acute coronary syndrome or who have left ventricular dysfunction
Contraindications:
- Variant angina: Do not want to block b2 mediated vasodilatory effects because in a patient that has intense vasoconstriction due to a vasospasm, don’t want to worsen it by causing more vasoconstriction (even with a b1 selective blocker, at some conc will still effect b2)
- Use with caution in patients COPD, asthma or peripheral vascular diseases
- Never discontinue abruptly - can cause rebound hypertension or angina
Ca2+ channel blockers used to treat angina MOA
Nifedipine, amlodipine, diltiazem and verapamil
Ca2+ is increased in ischemia due to hypoxia induced membrane depolarisation –> Ca2+ channel blockers improve anginal symptoms by:
- Coronary and peripheral vasodilation
- Reducing contractility which decreases O2 demand
Verapamil and diltiazem also slow AV conduction –> decrease HR, contractility, BP and O2 demand
Ca2+ channel blocker clinical applications
Used in combination with b-blockers when initial treatment is not as successful or as b-blocker substitute when b-blockers and contraindicated
Used in stable and unstable angina
b-blocker substitute in variant angina
Short acting dihydropryidines should be avoided unless combined with b-blockers (reflex tachycardia –> increases mortality)
Ranolazine MOA
Blocks Na+ current that facilitates Ca2+ entry via Na+/Ca2+ exchanger –> decreased intracellular Ca2+ –> reduces ventricular tension and decreases O2 demand
Also produces myocardial relaxation and may modify fatty acid oxidation
In angina, there is a decreased oxygen supply so there is decreased ATP which means that the Na+/K+ ATPase will not work properly –> this will increase intracellular Na+ –> flips the direction of Na+/Ca+ exchanger –> Will push Na+ out and Ca+ will come into the cell –> during an anginal attack, increase intracellular Ca+ will lead to more smooth muscle contraction and worsen the angina.
Ranolazine clinical application and AE
Last line for patients who have failed all other antianginal therapies
AE:
- Prolongs QT interval**
- Nausea
- Constipation
- Dizziness
Treatment of stable angina
Acute attacks: rest or nitroglycerin
Maintenance therapy
- Long acting nitrates or b-blockers
- Ca2+ channel blockers if b-blockers are not working or contraindicated
- Ranolazine - if all other drugs are unsuccessful
Treatment of unstable angina
Acute attacks: symptoms relieved by rest or nitroglycerin
Maintenance therapy: nitroglycerin or b-blockers
Treatment of variant angina
Symptoms respond to nitroglycerin and Ca2+ blockers (all are equally effective)
Do not give b-blockers
