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CV Module Pharm > Rx of Angina > Flashcards

Rx of Angina Flashcards

1
Q

What are the four classes of drugs used in the treatment of angina?

A
  1. Nitrates
  2. BBs
  3. CCBs
  4. Ranolazine
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2
Q

What general mechanism gives rise to angina?

A

An imbalance of myocardial O2 demand and myocardial O2 supply.

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3
Q

What are the three types of Angina?

A
  1. Unstable Angina
  2. Variant (vasospastic, Prinzmetal’s) Angina
  3. Exertion Angina (exercise-induced, stable)
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4
Q

What are the characteristics of Unstable Angina?

A
  1. Recurrent angina associated with minimal exertion
  2. Prolonged and frequent pain
  3. Due to fissuring of atherosclerotic plaques and subsequent platelet aggregations (thrombosis)
  4. High correlation with MI→very dangerous
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5
Q

What are the characteristics of Variant Angina?

A
  1. It’s a direct result of reduction in coronary blood flow due to vasospasm, not an increase in myocardial O2 demand.
  2. It’s associated with normal coronary angiograms (rarely catches the vasospastic event in action).
  3. Excellent prognosis b/c it can be well controlled.
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6
Q

What causes extertional angina? What can help it?

A

Usually due to fixed coronary vascular obstruction (surgical revascularization or angioplasty may be beneficial)

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7
Q

What are the three general approaches to the treatment of angina? Which way is most effective?

A
  1. Increase coronary blood flow.
  2. Reduce myocardial O2 demand/consumption.
  3. Prevent platelet aggregation/deposition.
    Reducing myocardial O2 consumption/ demand is the most effective.
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8
Q

What are the 3 ways to reduce myocardial O2 consumption?

A
  1. Negative Chronotropic effect (reduce HR)
  2. Negative Inotropic effect (reduce contractility)
  3. Decreased ventricular workload (wall stress)→a) Reduced preload (venodilation) b)reduced afterload (vasodilation)
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9
Q

During what part of the cardiac cycle does perfusion of the heart occur?

A

Diastole

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10
Q

How do chronotropy (HR) and inotropy (contractility) relate to supply/perfusion of the heart? Why?

A

As chronotropy and Inotropy decrease, Supply/perfusion to the heart increases. This is because, during diastole, the blood vessels are open and can easily supply the deep myocytes that bear most of the work of contractility. But, during systole, the muscle the squeezes/compresses the vessels, pinching off supply and decreasing supply during systole.
So, by reducing HR (chronotropy) so we can spend more time in diastole than systole, you increase the blood supply to the heart.
By decreasing inotropy (chronotropy) you have less profound squeezing of arteries. So decreasing/inotropy reduced demand and increases supply.

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11
Q

What are nitrates?

A

They are a class of various compounds that have NO2 groups. They release NO, causing vasodilation and venodilation (decreased afterload and preload)

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12
Q

What is the cellular mechanism of anti-anginal effect of nitrates?

A
  1. They get into the blood and release nitric oxide (NO).
  2. In, VSM cells, NO activates guanylyl cyclase (GC), which increases production of cGMP, the most potent sm m relaxing agent.
  3. cGMP activates Protein Kinase G.
  4. PKG acts on contractile proteins to cause profound relaxation→BOTH venodilation (reduced preload) and vasodilation (reduced afterload).
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13
Q

What is the endogenous vasodilatory pathway? What is a drug that acts a substrate in this pathway?

A

Endothelial cells have eNOS, which produces NO which acts the same as when released from nitrates.
Vasomyne acts as a substrate for NOS.

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14
Q

What is endothelial dysfunction? In what type of people is it common in?

A

Endothelial dysfunction occurs when eNOS is defective, which is common in the elderly (and in pathologic states).

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15
Q

Can pt’s with endothelial dysfunction respond to nitrates

A

Yes, there eNOS is defective so they cannot produce NO on endogenously, but they can still respond to nitrates.

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16
Q

What are the two main antianginal effects of nitrates on an organ system level?

A
  1. Venodilation results in DECREASED PRELOAD (reduced demand)
  2. Coronary Vasodilation (increased supply)
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17
Q

How does the venodilation caused by nitrates help Rx angina?

A

It decreases preload:

  1. Decreased P during diastole in ventricles
  2. Reduced wall stress and MvO2 (myocardial O2 demand)
  3. Subendocardial blood flow is increased (decreased squeezing)
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18
Q

How does Coronary vasodilation caused by nitrates aid in the Rx of angina?

A
  1. Redistribution of blood flow to areas of ischemia thru selective dilatation of epicardial and collateral coronary vessels.
  2. This prevents or reverses coronary vasospasm
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19
Q

What are the overall effects on hemodynamics of nitrates at usual antianginal doses?

A
  1. BP: unchanged or slight decrease (b/c nitrates are short-lived)
  2. HR: unchanged or slight increase (barorec reflex to vasodilation)
  3. Decreased Pulmonary vascular resistance
  4. Cardiac output reduced (slight)
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20
Q

What are the four preparations/routes of administration of nitrates?

A
  1. Mucosal: Sublingual and Sprays; this allows good absorption and some selective delivery to coronary and pulmonary vasculatures.
  2. Transdermal (patches and pastes)
  3. IV
  4. Oral (not as common as 1 and 2)
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21
Q

Why is it recommended to remove transdermal nitrate patches at night?

A

to prevent nitrate tolerance

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22
Q

What are the adverse effects of Nitrates?

A
  1. Hypotension
  2. Dizziness, orthostatic hypotension, syncope
  3. Headaches
  4. Drug rash
  5. Drug interaction
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23
Q

When is hypotension seen more commonly seen as an adverse effect of nitrates? Why? How can this hypotension paradoxically worsen angina pectoris?

A

It is seen with HIGHER DOSES of nitrates due to extreme arterial vasodilation.
Decreased BP may trigger barorec reflex sympathetic stimulation of the heart (tachycardia, increased contractility) and decrease coronary perfusion, which may paradoxically worsen angina pectoris.

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24
Q

In what patients are dizziness, orthostatic hypotension, and syncope seen as an adverse effect of nitrates?

A

Pt’s who are sensitive to reductions in preload, such as those with volume depletion, valvular heart disease, or hypertrophic cardiomyopathy.

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25
Q

Why can nitrates cause headache? How do you deal with this?

A

Due to dilation of meningeal arteries (vasomotor headache); these are transient b/c tolerance develops.
Give aspirin/acetominophen; may require reduced dose of nitrates

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26
Q

With what type of nitrates is drug rash seen?

A

long-acting oral nitrates or cutaneous (patch) nitrates

27
Q

What is the adverse drug interaction that is an absolute contraindication for nitrates?

A

Sildenafil (viagra/cialis) and other Type V PDE inhibitors (erectile dysfunction) increase cGMP by preventing its breakdown/metabolism, with the potential for augmented cGMP response to nitrates, resulting in PROFOUND hypotension and myocardial ISCHEMIA.
ABSOLUTE CONTRAINDICATION.

28
Q

What is effective oral administration of nitrates difficult?

A

They are rapidly absorbed, but they are rapidly METABOLIZED by the hepatic enzyme system Glutathione-Organic Nitrate Reductase. This EXTENSIVE FIRST PASS HEPATIC METABOLISM makes effective oral administration difficult.

29
Q

How can this extensive first pass metabolism by the liver on nitrates be avoided?

A
  1. BYPASS PORTAL CIRCULATION: sublingual, buccal, transdermal, or IV
  2. Alter structure to slow metabolism (such as isosorbide dinitrate with steric hindrance of catalysis of NO2 groups)
  3. Prodrugs: active metabolites with longer half-lives
  4. Force Zero-order kinetics (give a slow release nitrate with a rapid nitrate)
  5. Administer extended release formulations (in doses sufficient to force zeroorder kinetics)
30
Q

What is the problem with continuous nitrate exposure? Does this mean?

A

TOLERANCE (loss of efficacy). Frequently repeated or continuous exposure to high doses of nitrates leads to attenuation (reduction) of their biological effects.

31
Q

Tolerance to nitrates is clinically significant in what forms of administration?

A

High dose oral, transdermal, or IV

32
Q

What is the recommended action to avoid tolerance to nitrates?

A

8-12 hr “nitrate-free” interval each day; usually at night. Remove 24hr patch at night before bed. Give the pt a spray/sublingual form to only use as needed. When giving IV nitroglycerin, titrate the dose up to maintain effect.

33
Q

What are the mechanisms of nitrate tolerance?

A

There are several potential mechanisms:

  1. Reflex volume expansion
  2. Reflex neurohumoral activation
  3. Depletion of tissue cysteine stores (required from release of NO from nitrates)
34
Q

Why is it important to not suddenly interrupt IV nitroglycerin (NG) in unstable angina? What should you do instead?

A

Coronary vasospasm has been observed following abrupt cessation of nitrates in Rx of unstable angina. This is called ANGINAL REBOUND. So, instead, transition with overlap with transdermal or oral form.

35
Q

What are the two classes of CCBs? What do they act on and where?

A
  1. DHP (the diPINEs)
  2. Non-DHP→Verapamil and Diltiazem
    They both act to inhibit L-type Ca2+ Channels which are expressed thruout the vasculature in VSM cells, in cardiac myocytes, pacemaker cells, and SA/AV nodal cells, where they play a very important role in regulating the excitability of these cells.
36
Q

If DHPs and non-DHPs act on the same type of receptor, how do they give such different effects?

A

Due to different electrical dynamics and use states of the LtCCs in cardiac vs. VSM, non-DHPs target LtCCs in cardiac cells, while DHPs target LtCCs in smooth muscle.

37
Q

Why do non-DHPs (verapamil and diltiazem) target cardiac cells?

A

Non-DHPs exhibit USE-DEPENDENT BINDING. They block the channels by binding to sites inside the LtCCs, which requires the channels to be in an open state. In cardiac tissue, there is very rapid depol and repol, so there is rapic cycling of open active and closed states. In the active state, there is increased opportunity for these drugs to come in and block the channels. In contrast, in the vasculature, there is very slow depol and repol.

38
Q

Why do DHPs (diPINEs such as nifedipine) target LtCCs in VSM?

A

DHPs exhibit VOLTAGE-DEPENDENT BINDING. They don’t require the channel to be open in order to bind and block, but they do require a certain voltage. They are more likely to bind channels at their voltage preference, and VSM cells spend a lot more time at this voltage setting.

39
Q

What type of effects are seen with the non-DHP CCBs verapamil and diltiazem?

A

Their direct effects predominate→CARDIOSELECTIVE effects.

But, they still act in the vasculature as well.

40
Q

a) What are the effects of verapamil and diltiazem on the heart? b) How is this effective in the Rx of angina?

A

a) Decreased HR, decreased myocardial contractility, slowed AV nodal conduction.
b) They reduce myocardial O2 demand (MvO2) by reducing HR, contractility, and afterload. They also prevent or reverse vasospasm via coronary vasodilation.

41
Q

What are the predominant types of effects seen with DHP CCBs, such as nifedipine and felodipine?

A

More potent vasodilators, but potent vasodilatory effects=reflex cardiac stimulation. Direct and indirect effects are balanced.

42
Q

What are the net effects of treatment of DHP CCBs on HR, contractility, and AV node conduction?

A

HR, contractility usually unchanged (direct=indirect reflex) and may increase (reflex). AV node conduction is unaffected.

43
Q

What is the primary mechanism of antianginal effect of DHPs?

A

a) peripheral vasodilation reduces afterload (reduced myocardial O2 demand)
b) Coronary vasodilation increases O2 supply and reduces vasospasm

44
Q

Summary: How do the effects of DHP CCBs on arterial vasodilation, inotropy, and chronotropy compare to those of verapamil/diltiazem?

A

DHPs: greatly increased arterial vasodilation, no negative inotropic or chronotropic effect.
V/D: increased arterial vasodilation (less than DHPs though), and negative inotropic effect and negative chronotropic effect.

45
Q

What are the adverse effects of DHPs?

A
  1. Excessive vasodilation→dizziness, hypotension, headache
  2. GI irritation→nausea
  3. Peripheral edema (precapillary arterioloar vasodilation)→avoid in pt’s who already have edema
  4. Paradoxical exacerbation of angina→CORONARY STEAL
46
Q

What is coronary steal caused by DHPs?

A

If a patient has limited perfusion, esp if the pt is arrhythmic and/or undergoing MI and doesn’t have a normal heart rhythm, and you cause massive peripheral vasodilation, skel m beds will steal away the limited perfusion pressure that’s keeping the the brain and the heart perfused.

47
Q

Why should you not use a DHP alone in the Rx of angina? What should you combine it with?

A

The reflex cardiac stimulation can be a problem in pt’s with angina, so to attenuate this, you give them with a BB.
DONT COMBINE BBs WITH NON-DHP CCBs!!!

48
Q

What are the adverse effects of verapamil and diltiazem?

A
  1. Bradycardia, asystole, AV block
  2. Contraindicated in congestive HF
  3. Constipation (esp w/ verapamil)
49
Q

What is a common contraindication of all CCBs?

A

Pregnancy and Breast-feeding. They are all category C teratogens, and they can cross the placenta and breast milk

50
Q

CCBs are highly effective agents for the relief of symptoms in what?

A

Exertional or vasospastic angina

51
Q

What is the clinical use of CCBs in the Rx of angina?

A

BB’s are considered the drug of choice for angina. So, CCBs are reserved for use in pt’s who cannot tolerate BBs or have a contraindication for BBs or they are used as an add-on therapy for angina uncontrolled by BB+nitrate.

52
Q

What is the mechanism of antianginal effect by BBs?

A
  1. They blunt/decrease HR and inotropic response to EXERCISE.
  2. They reduce afterload (CNS effects, so only the lipophilic ones).
  3. They DO NOT reduce preload (may paradoxically increase in the short-term).
  4. They do not prevent coronary vasospasm (ineffective in vasospastic angina)
53
Q

What drugs are BBs commonly used in combination with?

A
  1. Nitrates→reduces LVEDP, LV volume (preload), dilates coronary arteries
  2. DHP CCBs→prevent coronary vasospasm, reduces systemic vascular effect
54
Q

Why are combinations of BBs with either DHPs or nitrates particularly effective?

A

BBs reflex reflex tachycardia and positive inotropic effect of nitrates and DHPs, making these combinations particularly effective.

55
Q

What is the spectrum of action of BB’s in the Rx of angina?

A
  1. Effective in Unstable Angina with nitrates and thrombolytics (heparin, ASA)
  2. Very effective in Exertional Angina as it reduces HR and contractility which normally increase in response to exercise.
  3. Ineffective in Vasospastic Angina b/c it doesnt prevent coronary vasospasm.
  4. They are also very effective with MI’s.
56
Q

What are situations favoring the use of DHP CCBs in angina?

A
  1. In combination with BBs for coronary vasodilation, reduced afterload.
  2. If the pt has sinus bradycardia or SA/AV block b/c they dont really affect HR or AV conduction.
  3. Valvular insufficiency: reduces afterload
57
Q

What are situations favoring the use of the non-DHP CCBs verapamil and diltiazem?

A

They are good for use whenever the pt has a contraindication for BBs, which are listed here:

  1. Asthma/bronchospastic COPD
  2. Severe peripheral vascular disease
  3. Depression
  4. Labile (variable glucose levels) insulin-dependent diabetes b/c they can mask the signs of hypoglycemic episodes
58
Q

What is Ranolazine?

A

A novel metabolic inhibitor/modulator

59
Q

What are the mechanism of action and effects of Ranolazine? Does it effect HR or BP?

A

It mech of action is unknown.

  1. It is a partial fatty acid oxidase inhibitor, increasing glucose oxidation and efficiency of O2 utilization in the heart.
  2. It is a late Na+ current inhibitor
  3. No effect on HR and BP (it has no real hemodynamic effects)
60
Q

What are the indications for Ranolazine use in the Rx of angina?

A

Chronic stable angina in combination with amlodipine (DHP), BBs, or nitrates.
It will not relieve acute angina attacks.

61
Q

What are the problems with Ranolazine?

A

Its a teratogen. It’s very expesnsive for only minor benefit, so we really only use it as an add on when other stuff is not working.

62
Q

What are the adverse reactions of Ranolazine?

A
  1. Dizziness, headache, constipation, nausea
  2. Small, reversible elevations in SrCr and BUN
  3. Syncope and asthenia (rare)
63
Q

What are contraindications for Ranolazine use?

A
  1. Concurrent use of CYP3A4 inhibitors
  2. Existing Long QT syndrome or use of class IA or III antiarrhythmics
  3. Use of tricyclic antidepressants, etc.
64
Q

What drug’s concentrations are affected by concurrent use with Ranolazine? Why?

A

Digoxin concentrations increase 40-60% due to its p-glycoprotein inhibition.

CV Module Pharm (13 decks)

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