Anti anginal Agents Flashcards
β-Adrenergic Antagonists (β-Blockers)
Drug list
- Atenolol
- Metoprolol
- Propranolol
- Timolol
Organic Nitrates
Drug list
- Nitroglycerin
- Isosorbide dinitrate
- Isosorbide mononitrate
Calcium Channel Blockers (CCBs
Drug list
- Dihydropyridines(DHPs)
- Amlodipine
- Felodipine
- Nicardipine
- Many others…
- Non-dihydropyridines
- Diltiazem
- Verapamil
Angina Pectoris
- The primary symptom of ischemic heart disease
- Coronary artery disease is usually the underlying cause
chest pain from ischemia
Types of Angina
- Effort angina (aka classic angina)
- Variant angina (aka vasospastic or Prinzmetal’sangina)
- Unstable angina (aka acute coronary syndrome)
•Effort angina (aka classic angina)
- Myocardial O2requirement increases during exercise, but coronary blood flow does not increase proportionately
- Resulting ischemia usually, but not always, leads to pain
•Variant angina (aka vasospastic or Prinzmetal’sangina)
•O2delivery decreases as a result of reversible coronary vasospasm
•Unstable angina (aka acute coronary syndrome)
•Angina at rest or an increase in the severity, frequency, and duration of chest pain in patients with previously stable angina
Molecular Mechanisms of Anti-AnginalAgents in the Vasculature
•Increase cGMP
- Nitroglycerin (NTG), other nitrates and nitrites
* Potentiated by PDE inhibitors (ed drugs)
Molecular Mechanisms of Anti-AnginalAgents in the Vasculature
•Decrease intracellular Ca2+
•Calcium channel blockers
Molecular Mechanisms of Anti-AnginalAgents in the Heart
- Decrease intracellular Ca2+
- Calcium channel blockers (reduces heart rate)
* Verapamil > diltiazem > DHPs - Beta blockers (reduces contractility and heart rate)
- Calcium channel blockers (reduces heart rate)
•Physiologic effect: decrease rate and contractility in cardiac myocytes
Organic Nitrates
Prototype
nitroglycerin (NTG)
- Available in many different formulations:
- Sublingual tablet or spray
- Sustained release oral capsules
- Buccal tablets or gel
- Ointment
- Transdermal patch
Organic Nitrates
Other Agents
- Isosorbide dinitrate
- Isosorbide mononitrate
- Sublingual, oral, or sustained release tablets
they are extended release
Organic Nitrates: Pharmacodynamics
- MOA: metabolism releases NO
- Dilates both arterial and venous vessels—decreases TPR and venous return
- Decreases both preload & afterload
- Mainly relaxation of large veins decreases venous return decreases preload decreases O2demand (major effect), smaller in afterload
- Primary antiischemic effect is to decrease myocardial O2demand by producing systemic vasodilation (more so than coronary vasodilation)
- Prevents coronary vasospasm (dialate coronaries)
Nitrate Use in Angina
- First-line therapy for an acute anginalattack (typically sublingual administration, spray equally effective)
- Long-acting oral and transdermal formulations improve exercise tolerance and time to onset of angina
- Improve antianginal and antiischemiceffects of beta blockers and calcium channels blockers
- Long-term utility is limited by tolerance
Nitrate Tolerance
- Effectiveness diminishes significantly with continuous use
- Multiple mechanisms proposed
- Generally not a problem with sublingual nitroglycerin (drug is only in body for short time)
- Limits the usefulness of oral and transdermal nitroglycerin and oral isosorbide mono-and dinitrate
Prevention of Nitrate Tolerance
- Intermittent therapy with a nitrate-free interval of at least 8 hours may prevent tolerance (for q 24 hour period)
- Angina frequency and silent ischemia may increase during off-patch hours
Nitrates: Adverse Effects
•Common: orthostatic hypotension, syncope, throbbing headache, flushing
- Drug-drug interaction: synergistic hypotension with phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) (bc both increase cgmp)
- Can lead to myocardial infarction and death
β-Adrenoreceptor Antagonists
Non-selective
Non-ISA
Propranol
carvedilol (also blocks a1 and has vasodilating activity)
nadolol
timolol
β-Adrenoreceptor Antagonists
Non-selective
ISa
labetalol (also blocks a1 and has vasodilating activity)
carteolol
penbutolol
pindolol
β-Adrenoreceptor Antagonists
B1 selective (Cardioselective)
Non-isa
metoprolol atenolol esmolol bisoprolol betaxolol
β-Adrenoreceptor Antagonists
B1 selective (Cardioselective)
ISA
acebutolol
nebivolol (b3 agonist and has vasodilating activity)
Beta Blockers: Pharmacodynamics
- Reduce cardiac work (i.e., O2consumption) by decreasing heart rate and contractility
- Most are not vasodilators; no effect on O2supply
Beta Blocker Use in Angina
- Prototype: propranolol
- First-line therapy to reduce frequency of angina (i.e., prophylaxis) and improve exercise tolerance (for effort angina)
- Reduce O2requirement by reducing heart rate and contractility
- All types are equally effective in exertional angina; cardioselective(β1-selective) often preferred
- NOT effective in variant angina (caused by vasospasm, beta blocker with keep arteries from vasodilating so you exacerbate the problem)
Beta Blockers Stabilize Heart Rate
antagonists dampen physiologic agonists so their efficacy depends on how much agnoist is available, so beta blockers shine when you ahve more norepi in system,
they lower and stabilize heart rate so it responds better
Beta Blockers Prolong Survival After MI
- Timolol, propranolol, and metoprolol have been specifically studied in large-scale clinical trials
- Use of other beta-blockers for this indication is less compelling
prevents irreversible damage
hesitant to use atenolol
propranolol can get to brain and causebc it is lipid soluble
depression sexual dysfunction
Beta Blockers & Systolic Heart Failure
additive benefit with ACEI and beta blockers in HF
Beta Blockers: Adverse Effects
•Most common: bradycardia and fatigue
- Relative contraindications
- Asthma/COPD (slective may be ok)
- Diabetes
- Variant angina
- Acute decompensated heart failure
•Can cause heart block, especially if combined with other negative inotropes (e.g., verapamil, diltiazem)
Beta Blocker
No Antagonist
full stimulation
Beta Blocker
without agonism
no stimulation without some sympatholytic ativity
Beta Blocker
with partial agonism
doesnt matter bc cell still gets some stimulation
Beta Blocker Withdrawal
hyperstimulation
Calcium Channel Blockers (CCBs)
All CCBs bind to L-type Ca++channels. But the two classes bind to different sites, resulting in different effects on vascular versus cardiac tissue. voltage gated
Non-dihydropyridines
- Prominent cardiac effects, but also act at vascular tissues
- Verapamil >Diltiazem
Dihydropyridines(DHPs)
- Predominantly arteriolar vasodilation effects
* Amlodipine, Clevidipine, Felodipine, Isradipine, Nicardipine,
Pharmacokinetic Properties of CCBs
- Good oral absorption but high 1stpass effect
- Amlodipine, felodipine, isradipineslowly absorbed, long t1/2is advantage (used as antianginals (first two))
- DHPs with long plasma half-lives preferred to minimize reflex cardiac effects; extended release preparations available (short acting could make worse)
Nifedipine, clevidipine, verapamil, and diltiazemsometimes used
IV
CCBs: Pharmacodynamics
- Relaxation of vascular smooth muscle causes peripheral vasodilation
- Arterioles are more sensitive than veins
- Reduce afterload and decrease O2demand
- Little effect on preload
- Also increase O2supply due to dilation of coronaries
reduce demand and increase supply
Calcium Channel Blocker Use in Angina
- Preferred agents: diltiazem, verapamil, amlodopine, or felodipine
- Added to or substituted for beta blockers in chronic stable angina
- Also effective in vasospastic angina
- Reduce O2requirement by reducing heart rate and contractility
- Increase O2delivery by vasodilation and reversal of vasospasm
no mortality reduction
Cardiovascular Effects of CCBs
Dihydropyridines
Vasodilation
(CoronaryFlow) - 5
Supressionof Cardiac Contractility -1
Supressionof Automaticity
(SA Node)-1
Supressionof Conduction
(AV Node)-0
Cardiovascular Effects of CCBs
non-Dihydropyridines
Vasodilation
(CoronaryFlow) - 3
Supressionof Cardiac Contractility - 2
Supressionof Automaticity
(SA Node) - 5
Supressionof Conduction
(AV Node) - 4
CCBs: Adverse Effects & Toxicity
- Generally very well tolerated
- Excessive vasodilation –dizziness, hypotension, headache, flushing, nausea; diminished by long-acting formulations and long half-life agents
- Constipation (esp., verapamil), peripheral edema, coughing, wheezing, pulmonary edema
Use of verapamil/diltiazemwith a b-blocker is
contraindicatedbecause of the potential for AV block
Verapamil/diltiazem should not be used in patients with
ventricular dysfunction, SA or AV nodal conduction defects and systolic BP
Short-acting dihydropyridinescan cause
reflex tachy
Are Calcium Channel Blockers Safe?
Short-acting Nifedipine
Proischemiceffect
+/-
Negative inotropic effect
+
Effects on rhythm
?
Marked hypotension
+
Reflex increase in sympathetic activity
+
Prohemorrhagiceffects
?
Are Calcium Channel Blockers Safe?
Long-acting CCBs
Proischemiceffect
-
Negative inotropic effect
+/-
Effects on rhythm
-
Marked hypotension
-
Reflex increase in sympathetic activity
-
Prohemorrhagiceffects
-
give long acting ccb for
angina
Ranolazine
- Relatively newer antianginal drug
- MOA: late sodium channel blocker
- Typically reserved for angina that is refractory to treatment with beta blockers, calcium channel blockers, and nitrates
- Used either in combination with beta blocker or as a substitute in patients who cannot receive beta blockers
Preventative Therapies
- Regular aerobic exercise
- Stress reduction
- Smoking cessation
- Weight control
- Blood pressure control
- Diabetes management
- Pharmacotherapies to prevent cardiovascular events
Angina Pharmacotherapies to prevent cardiovascular events
- Aspirin (or clopidogrel) (antiplatelet)
- HMG-CoA reductase inhibitors (the –statins)
- ACE inhibitors (the –prils) and ARBs (the –sartans) (prevent detrimental remodeling)
Clinical Pharmacology of Angina
- Three primary drug classes are utilized: beta blockers, calcium channel blockers, & nitrates
- Nitrates are the mainstay of treatment for acutesymptoms
- Cardioselectivebeta blockers are often recommended as initial first-line therapy for long-term prophylaxis
- Combinations may be more effective than monotherapy
- CCBs or nitrates relieve vasospastic angina by preventing coronary artery spasm
