Drugs used in Chronic IHD Flashcards

1
Q

What are the two approaches to treat angina pectoris?

A

1) Reduce O2 demand by decreasing cardiac work.

2) Increase oxygen supply by increasing blood flow through coronary arteries.

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2
Q

What are ways to increase coronary blood flow?

A

1) Surgical or non-surgical revascularization approaches

2) Vasodilators

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3
Q

What type of angina are vasodilators useful for? Not useful for?

A

Useful - Vasospastic (Prinzmetal) angina.

Not useful for atherosclerotic (classic) angina.

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4
Q

What is the significance of coronary steal phenomenon?

A

Explains why vasodilators are not useful in atherosclerotic angina. Arteriolar dilation (i.e. Dipyridamole) of normal vessels diverts blood away from ischemic/stenotic areas.

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5
Q

What are the determinants of myocardial oxygen demand that are used to reduce O2 demands of heart in tx of angina?

A

HR, contractility, preload, afterload

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6
Q

What are three nitrovasodilators?

A

1) Nitroglycerin
2) Isosorbide dinitrate
3) Isosorbide mononitrate

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7
Q

Where is there high nitrate reductase activity?

What else is special about nitrate reductase activity?

A

Liver - first pass metabolism.

Nitrate reductase activity is saturable.

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8
Q

What is EDRF?

A

Nitric Oxide: Endothelium-Derived Relaxing Factor - released by ACh when endothelium is PRESENT. NO] relaxes smooth muscle of blood vessels.

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9
Q

What does endothelial NOS produce? And what is the ultimate result?

A

Produces endogenous NO, resulting in vasorelaxation (of vascular smooth muscle).

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10
Q

What acts as an extracellular NO donor?

A

An organic nitrate (i.e. Nitroglycerin) that gets metabolically activated to NO.

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11
Q

What physiologically results from NO inside a vascular smooth muscle cell?

A

NO activates GC, which turns GTP to cGMP, which then activates PKG, which then causes:
1) hyperpolarization of cell and reduced Ca entry (opens K channel) AND 2) smooth muscle relaxation

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12
Q

Sensitivity of vasculature to nitrate-induced vasodilation.

A

veins > large arteries > small arteries and arterioles

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13
Q

What two things does nitrate-induced relaxation of vascular smooth muscle result in?
What change in coronary blood flow in atherosclerotic angina?

A

Dilation of veins (major)
Dilation of arteries (needs higher concentration of nitrates). No significant increase in coronary blood flow to ischemic area in atherosclerotic angina.

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14
Q

What effects do nitrates have in angina of effort/atherosclerotic angina (2)?

A

1) Decreased preload/volume heart has to pump, therefore deceased O2 demand.

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15
Q

What effects do nitrates have in vasospastic angina (2)?

A

1) Relaxation of coronary artery vascular smooth muscle, relieving coronary artery spasm

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16
Q

Clinical use: short v. long acting nitrovasodilators.

What is the duration of short v. long?

A

Short acting used to relieve angina attack (10-90min)

Long acting used to prevent attacks (3-10hrs)

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17
Q

Which nitrovasodilators are short acting? Long acting? Formulation?

A

BOTH:
1) Nitroglycerin - short (subL, spray shortest duration) and long (oral, ointment, patch)
2) Isosorbide dinitrate - short (subL, spray) and long (oral)
ONLY LONG:
3) Isosorbide mononitrate - long (oral longest duration)

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18
Q

How is NO depleted in tissue?

A

Increased generation of superoxide radicals deplete tissues of NO.

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19
Q

What occurs in development of nitrate tolerance (4)?

A

Depletion of thiol compounds, increased oxygen radical generation, REFLEX ACTIVATION of SNS (tachycardia, decreased coronary blood), retention of salt and water

20
Q

What are the ADVERSE EFFECTS of nitrates?

A

1) HA (meningeal vasodilation)
2) Orthostatic hypotension
3) Increased sympathetic discharge*

21
Q

What are the adverse effects of increased sympathetic discharge due to nitrates (and tolerance)?

A

Tachycardia, increased cardiac contractility, Increased renal salt and water reabsorption.

22
Q

What is the major class of drug interaction with nitrates (3 drugs) and what is this class used for? What two adverse effects can occur?

A

Drugs used for ED - sildenafil, vardenafil, tadalafil.

(1) Severe cGMP increased and a dramatic drop in BP and (2) acute MIs have been reported.

23
Q

What two classes of CCBs are used in angina, and what drugs in each class?

A

1) Non-cardiactive (DHPs) - amlodipine, nifedipine, nicardipine.
2) Cardioactive (non-DHPs) - diltiazem, verapamil

24
Q

What two tissues have L-type calcium channels that CCBs interact with and what does intracellular calcium do?

A

Vascular smooth muscle (L-type) and Cardiac muscle (L-type). Calcium mediates smooth muscle contraction

25
Q

What do CCBs do for anti-angina (A, B)?

A

A. Decrease myocardial O2 demand (vasodilation of arterioles)
B. Increased blood supply - via dilation of coronary arteries (for VASOSPASTIC ANGINA only)

26
Q

How do CCBs decrease myocardial O2 demand (2)?

A

A:

(1) Dilation of peripheral arterioles (dec. afterload and PVR)
(2) Decreased cardiac contractility and HR (cardioactive DHPs)

27
Q

What type of angina can CCB-induced increased blood supply be used for (B)? What is it not used for?

A

B:
Vasospastic (Prinzmetal) angina - dilation of coronary arteries relieves local spasms. NOT used for atherosclerotic angina.

28
Q

Are DHPs or non-DHPs more potent vasodilators (of arterioles?

A

DHPs (non-cardioactive CCBs)

29
Q

MAJOR adverse effects of CCBs (4)

A

1) Cardioactive CCBs - cardiac depression, cardiace arrest, AcuteHF
2) Cardioactive CCBs - bradyarrhyth, AV block
3) Short active DHPs - vasodilation triggers reflex sympathetic activation
4) Nifedipine (immediate release) - increases risk of MI in people with HTN.

30
Q

What is better tolerated for tx of angina than Nifedipine, that will not increase risk of MI in patients with HTN?

A

Slow release and long acting DHPs.

31
Q

MINOR adverse effects of CCBs

A

Flushing, HA, anorexia, dizziness
Peripheral edema
Constipation

32
Q

What four beta-blockers are indicated in angina?

A

Propranolol
Nadolol
Metoprolol
Atenolol

33
Q

MOA of b-blockers in angina.

A

Decrease myocardial O2 demand: (1) Dec. HR leading to better perfusion and dec. O2 demand at rest+excercise. (2) Dec. contractility. (3) Dec. afterload

34
Q

Adverse effects of b-blockers

A

Reduced CO, Bronchoconstriction, Impaired liver glucose mobilization, Inc. VLDL/dec. HDL, Sedation and depression, Withdrawl.

35
Q

Contraindications of b-blockers

A

ASTHMA, PVD, Type1 DM on insulin, bradyarrhythmias, AV abnormalities, severe depression of cardiac function

36
Q

AE of admin of Nitrates alone for angina.

A

Reflex increase in HR and contractility.

37
Q

AE of Nitrates + b-blocker or CCBs for angina.

A

Increased end-diastolic volume and increased ejection time.

38
Q

Physiological action of Ranolazine

A

Inhibits late Na+ current in cardiomyocytes

39
Q

MOA of ranolazine in angina.

A

Normalizes the repolarization of myocytes and reduces mechanical dysfunction (it inhibits the Na+ current that is enhanced in ischemic myocardium, which results in Ca overload and repol abnormalities)

40
Q

What four things does ranolazine NOT affect?

A

HR, inotropic state of myocardium, coronary blood flow, peripheral hemodynamics.

41
Q

What is the clinical use of ranolazine? (When is it used and what does it do?

A

Use for stable angina that is refactory to standard meds.

It decreases angina episodes and improves excercise tolerance in people taking NITRATES, AMLODIPINE, OR ATENOLOL.

42
Q

Adverse effects of ranolazine.

A
QT prolongation (may trigger vent arrhythmias)
Constipation, nausea, dizziness, HA.
43
Q

What two types of drugs should not be used with ranolazine?

A

Do not use with CYP3A inhibitors (bc its metab by CYP3A4/5).
Do not use with drugs that prolong QT interval (Quinidine=antiarrhythmic or antipsychotic=thioridazine). Triggers vent arrhythmias.

44
Q

What CYP does ranolazine inhibit (and consequently, should not be used with what drugs)?

A

Inhibits CYP2D6, which increase half life of amitriptyline, fluoxetine, metoprolol, and opioid drugs

45
Q

What two things do nitrates alone increase?

A

Reflex increase in contractility

Reflex increase in HR

46
Q

What do BB or CCB alonge increase?

A

Increase EDV and Ejection time.

47
Q

Combined, what do nitrates and BB/CCB cause?

A

Decreased HR and Decreased arterial pressure.