Anti-Anginal Drugs DSA Flashcards

1
Q

1) Organic Nitrates

A

a) Nitroglycerin
b) Isosorbide dinitrate
c) Isosorbide mononitrate

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2
Q

2) Calcium Channel Blockers (CCBs)

A

a) Dihydropyridines (DHPs)
i) Amlodipine
ii) Felodipine
iii) Nicardipine
iv) Many others…

b) Non-dihydropyridines
i) Diltiazem
ii) Verapamil

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3
Q

3) β-Adrenergic Antagonists (β-Blockers)

A

a) Atenolol
b) Metoprolol
c) Propranolol
d) Timolol
e) Many others…

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4
Q

Angina pectoris

A

chest pain that occurs during myocardial ischemia. It is primarily caused by an imbalance between the O2 requirement of the heart and O2 supplied by the coronaries. This imbalance is most often due to coronary artery disease (CAD), resulting in atheromatous obstruction of large coronary vessels. The two main treatment strategies are: (1) to decrease O2 demand, and/or (2) to increase O2 delivery. Both strategies are important components in the treatment of unstable angina. Nitrates are first-line agents for immediate relief of angina. Calcium channel blockers (especially verapamil, diltiazem, and amlodipine) and beta blockers are useful for long-term prophylaxis of chronic stable angina. The table below summarizes the hemodynamic mechanisms by which the major classes of anti-anginal agents reduce O2 demand and/or increase O2 delivery.

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5
Q

ORGANIC NITRATES prototype and MOA

A

i) Prototype: Nitroglycerin
ii) Other agents: isosorbide dinitrate, isosorbide mononitrate
iii) MOA: Release of nitric oxide via enzymatic metabolism, which binds to and activates soluble guanylyl cyclase leading to increased cGMP

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6
Q

ORGANIC NITRATES pharmacodynamics

A

(1) Nitrates dilate veins, arteries, and coronary arteries by relaxing smooth muscle (veins are more sensitive due to increased bioavailability); virtually no direct effect on cardiac or skeletal muscle
(2) Primary antiischemic effect is to decrease myocardial O2 demand by producing systemic vasodilation (more so than coronary vasodilation)
(3) Systemic vasodilation increases venous capacitance; decreases ventricular preload; reduces left ventricular wall stress; and pulmonary vascular pressures and heart size are reduced
(4) In the absence of heart failure, cardiac output is reduced
(5) Compensatory reflex mechanisms: tachycardia, increased cardiac contractility, salt and water retention
(6) Decreases platelet aggregation (due to NO stimulation of guanylate cyclase in platelets and resultant increase in platelet cGMP)

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7
Q

organic nitrates pharmacokinetics

A

(1) High first-pass effect results in low bioavailability; sublingual route of administration is typically used to avoid first-pass
(2) Therapeutic blood levels are reached within minutes and last 15-30 minutes
(3) Oral, transdermal, and buccal preparations are available when longer duration of action is needed
(4) Tolerance may occur following continuous exposure, especially with nitroglycerin; a nitrate-free period of at least 8 hours between doses is required to prevent tolerance

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8
Q

organic nitrates CIs

A

(1) Common: orthostatic hypotension, syncope, throbbing headache
(2) Mechanisms of tolerance are incompletely understood, but may include:
(a) Diminished release of NO due to reduced bioactivation
(b) Reduced availability of sulfhydryl donors
(c) Increased generation of oxygen free radicals
(d) Compensatory responses contributing to the development of tolerance: activation of the sympathetic nervous system (tachycardia & increased cardiac contractility) and activation of the renin-angiontensin-aldosterone system (retention of salt and water & vasoconstriction)
(3) Glaucoma was previously thought to be a contraindication, but it has been shown that nitrates can be used safely in the presence of intraocular pressure
(4) Contraindicated if intracranial pressure is elevated
(5) Transdermal patches should be removed before the use of external defibrillators

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9
Q

organic nitrates DDIs

A

Synergistic hypotension with phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil); severe hypotension and a few MIs have been reported in men taking both drugs; use of nitrates and PDE5 inhibitors should be separated by at least 6 hours

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10
Q

organic nitrates clinical uses

A

Hypertensive emergencies, angina, heart failure

(1) Sublingual nitroglycerin tablets or spray are the treatment of choice for acute angina episodes or for prophylaxis of activities known to exacerbate exertional angina
(2) Chronic nitrate therapy improves exercise tolerance and time to onset of angina in patients with exertional angina, but must be dosed appropriately to prevent drug tolerance
(3) Coronary vasodilation is beneficial in patients with vasospastic angina

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11
Q

Beta blockers: Non-ISA, ISA, selective and non-selective

A

Non-Selective, Non ISA:
Propanalol and Carvedilol

Non-selective, ISA:
Labetalol

B1- selective Non-ISA
Metoprolol, Atenolol

B1 selective, ISA:
Acebutolol, nebivolol (not important)

ISA means Intrinsic Sympathomimetic Activity due to partial agonist action

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12
Q

beta blocker pharmacodynamics

A

(1) With the exception of carvedilol and nebivolol, beta blockers are not vasodilators
(2) Benefit in angina is due primarily to hemodynamic effects (decreased heart rate, blood pressure, and contractility reduce O2 requirements during both rest and exercise)
(3) Unfavorable effects (increased end-diastolic volume and increased ejection time, which tend to increase O2 demand) can be offset by concomitant nitrate use

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13
Q

beta blocker pharmacokinetics

A

(1) Except esmolol, all are available as oral preparations; carvedilol, metoprolol, and propranolol are available as extended-release tablets; atenolol, esmolol, labetalol, metoprolol, and propranolol are available as parenteral preparations
(2) A wide range of half-lives contributes to differences in dosing schemes
(3) Most exhibit low-to-moderate lipid solubility; exceptions are propranolol and penbutolol, which are quite lipophilic and readily cross the blood-brain barrier (see also Katzung Table 10-2)

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14
Q

beta blocker adverse effects/ CIs

A

(1) Asthma/COPD: Blockade of β2 receptors in bronchial smooth muscle may lead to an increase in airway resistance; no currently available β1-selective agents are specific enough to completely avoid β2 blockade; these agents should be avoided in asthmatics

(2) Diabetes: glycogenolysis is partially inhibited after β2 blockade; may mask signs of hypoglycemia and delays recovery from insulin-induced hypoglycemia; use with caution in insulin-dependent diabetics (benefits may outweigh risks in diabetics after MI)
(3) Most common side effects are bradycardia and fatigue; sexual dysfunction and depression sometimes occur
(4) Chronic use has been associated with unfavorable plasma lipid profiles (increased VLDL and reduced HDL)
(5) Sudden withdrawal may cause rebound hypertension, angina, and possibly MI; mechanism may involve upregulation of receptor synthesis

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15
Q

beta blocker DDIs

A

: Can cause heart block, especially if combined with the CCBs verapamil or diltiazem, which also slow conduction

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16
Q

beta blocker clinical uses

A

(1) Ischemic Heart Disease: beta blockers reduce the frequency of angina and improve exercise tolerance in many patients; all types appear to be equally effective in exertional angina, but timolol, metoprolol, and propranolol prolong survival after MI
(2) Beta blockers should not be used in patients with vasospastic or variant (Prinzmetal) angina; they are ineffective and may induce vasospasm due to unopposed alpha-receptor activity
(3) Hypertension: Metoprolol and atenolol are the most widely used; not commonly used for initial monotherapy in the absence of a specific indication
(4) Heart Failure: administration may worsen acute congestive heart failure; even in stable, compensated heart failure, cardiac decompensation may occur if cardiac output is dependent on sympathetic drive; but careful long-term use with gradual dose increases may prolong life; specifically, carvedilol, bisoprolol, and metoprolol reduce mortality by unknown mechanisms
(a) Agents with intrinsic sympathomimetic activity should not be given to patients with prior MI or heart failure in whom beta blockade improves survival
(5) Cardiac Arrythmias: beta blockers are often effective in the treatment of supraventricular and ventricular arrythmias
(6) Glaucoma: topical drops of timolol, betaxolol, carteolol, and others reduce intraocular pressure (agents with local anesthetic action are not used topically on the eye)
(7) Agents with partial β2-agonist activity (i.e., intrinsic sympathomimetic activity) may be advantageous in patients with bradyarrhythmias or peripheral vascular disease
(8) β1-selectivity may be advantageous in treating patients with comorbid asthma, diabetes, or peripheral vascular disease

17
Q

Calcium Channel Blockers (list and subtypes)

A

i) Two major subclasses
(1) Dihydropyridines (DHPs)
(a) Prototypes: Nifedipine, Amlodipine
(b) MOA: Blocks L-type voltage-gated calcium channels in vasculature > cardiac channels
(2) Non-Dihydropyridines
(a) Prototypes: Verapamil, Diltiazem
(b) MOA: Nonselective block of vascular and cardiac L-type calcium channels

18
Q

CCBs Pharmacodynamics

A

(1) All CCBs block L-type calcium channels (voltage-gated), which are responsible for Ca++ flux into smooth muscle cells, cardiac myocytes, and SA and AV nodal cells in the heart
(2) All CCBs bind to L-type calcium channels, but DHPs and non-DHPs bind to different sites on the channel proteins; this leads to differences in effects on vascular versus cardiac tissue responses and different kinetics of action at the receptor
(3) Effects on smooth muscle: long-lasting relaxation; both DHP and non-DHP CCBs cause vasodilation at therapeutically relevant doses
(a) All CCBs cause vasodilation, which decreases peripheral resistance; arterioles are more sensitive than veins; orthostatic hypotension is not usually a problem; relaxation of arteriolar smooth muscle leads to decreased afterload and decreased O2 demand
(b) Verapamil exhibits a relatively smaller effect on vasodilation, possibly due to concomitant blockade of vascular smooth muscle potassium channels
(c) The DHPs may differ in their potency in different vascular beds
(d) Although less sensitive than vascular smooth muscle, bronchiolar, GI, and uterine smooth muscle also relax in response to calcium channel blockers
(4) Effects on cardiac muscle include reduced contractility throughout the heart and decreases in SA node pacemaker rate and AV node conduction velocity
(a) As noted above, non-DHPs exhibit more cardiac effects than DHPs; verapamil has the greatest negative inotropic action on the heart and diltiazem is more intermediate between verapamil and the dihydropyridines
(b) DHPs do have effects on cardiac muscle, but they block channels in smooth muscle at much lower concentrations; thus, cardiac effects are negligible at effective therapeutic concentrations

19
Q

CCBs Pharmacokinetics

A

iii) Pharmacokinetics
(1) All the CCBs are orally active, but have high first-pass metabolism; these drugs have a high degree of plasma protein binding, and are extensively metabolized; nifedipine, clevidipine, verapamil, and diltiazem are also used IV
(2) Amlodipine has a long elimination half-life (t1/2) of 35-50 hours; relative to t1/2 of 2-12 hours for most other CCBs; extended release preparations are available for many of the CCBs

20
Q

CCBs adverse effects/ CIs

A

(1) Generally, these drugs are well tolerated
(2) Dihydropyridines: excessive hypotension, dizziness, headache, peripheral edema, flushing, tachycardia, rash, and gingival hyperplasia have been reported
(a) Some studies reported increased risk of MI, stroke, or death in patients receiving short-acting nifedipine; also, reflex tachycardia may exacerbate ischemia; therefore short-acting DHPs should not be used for management of chronic HTN or angina
(3) Non-DHPs (verapamil > diltiazem) slow heart rate, can slow atrioventricular conduction, can cause heart block, and are contraindicated in patients also taking a beta blocker
(a) Dizziness, headache, peripheral edema, constipation (especially verapamil), heart failure, lupus-like rash with diltiazem, pulmonary edema, coughing, and wheezing are possible

21
Q

CCBs DDIs

A

(1) Verapamil may increase digoxin blood levels by inhibiting p-glycoprotein efflux transporters
(2) DHPs: Additive with other vasodilators
(3) Non-DHPs: Additive with other cardiac depressants and hypotensive drugs

22
Q

CCBs Clinical Uses

A

(1) Hypertension: long-term outpatient therapy and HTN emergencies
(2) Angina
(a) All CCBs are effective in chronic stable angina (amlodipine and felodipine often preferred because they are long-acting and exhibit better side effect profiles)
(b) All CCBs are effective in variant (vasospastic) angina
(c) Immediate-release short-acting agents are contraindicated in unstable angina due to increased risk of adverse cardiac events; diltiazem is considered safe in non-STEMI

23
Q

Newer Antianginal drugs

A

i) Newer drugs include inhibitors of late inward sodium currents (e.g., ranolazine) and fatty acid oxidation inhibitors (e.g., pFOX inhibitors)
ii) Ranolazine
(1) MOA: reduces a late sodium current that facilitates calcium entry; resultant reduction in intracellular calcium reduces cardiac contractility and work
(2) Approved for use in patients with stable angina instead of beta blockers when beta blockers are contraindicated or poorly tolerated; also approved for use in combination with beta blockers when initial treatment with beta blockers is ineffective

24
Q

Anti anginal preventative therapies

A

i) Treatment strategies aimed at preventing cardiovascular events are important components of long-term therapy for stable angina
ii) Risk factors for CAD (smoking, hypertension, hyperlipidemia, obesity, & clinical depression) should be mitigated
iii) Regular aerobic exercise should be encouraged (it can result in a lower O2 requirement for a given workload, thereby improving exercise tolerance and reducing symptoms)
iv) Pharmacologic therapies shown to prevent MI and death:
(1) Anti-platelet drugs (aspirin, ADP receptor blockers)
(2) HMG-CoA reductase inhibitors (the –statins)
(3) ACE inhibitors (the –prils) and ARBs (the –sartans)
(4) Beta blockers (see above)

25
Q

Antiplatelet therapy

A

(1) Some experts recommend aspirin for all patients (unless contraindicated)
(2) A proton pump inhibitor (e.g., omeprazole) can be added if GI toxicity is a concern
(3) Clopidogrel is an alternative to aspirin

26
Q

Clinical Pharmacology

A

ii) Drug therapy of angina must address the underlying cause of coronary artery disease (CAD) in addition to the immediate symptoms of angina

27
Q

Management of chronic stable angina of effort

A

(1) Three primary drug classes are utilized: beta blockers, calcium channel blockers, & nitrates
(2) Nitrates are the mainstay of treatment for acute symptoms
(3) Drug of choice for long-term prophylaxis depends on individual response of patient; beta blockers are associated with better outcomes and symptomatic improvement versus CCBs; thus, cardioselective beta blockers are often recommended as initial first-line therapy
(4) CCBs and long-acting nitrates are recommended when beta blockers are contraindicated or poorly tolerated and in addition to beta blockers when angina persists with adequate beta blockade
(5) Combinations may be more effective than monotherapy (e.g., propranolol with amlodipine or nitrates with beta blocker or CCB); but caution, no non-DHPs with beta blockers
(6) Some patients may require therapy with all three drug groups

28
Q

Vasospastic Angina

A

(Variant/Atypical/Prinzmetal’s)

(1) CCBs or nitrates relieve vasospastic angina by preventing coronary artery spasm
(2) Beta blockers are not useful because they do not prevent vasospasm

29
Q

v) Unstable Angina & Acute Coronary Syndromes (ACS)

A

(1) complex and quite different than treatment of chronic stable angina;
(2) The principal pathophysiologic mechanism is often recurrent platelet-rich nonocclusive thrombus formation; aggressive ** antiplatelet therapy is therefore indicated (e.g., aspirin and clopidogrel); ** anticoagulants are also indicated in most patients
(3) Patients with STEMI often have complete occlusion of a coronary artery; reperfusion therapy with primary percutaneous coronary intervention (PCI) or ** fibrinolysis is a primary goal
(4) In these cases where stenting (PCI) is required, glycoprotein IIb/IIIa inhibitors such as ** abciximab can be beneficial
(5) *** Nitrates, beta blockers, lipid-lowering drugs, and ACE inhibitors should also be cons