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Cardio Block > Treatment of Angina > Flashcards

Treatment of Angina Flashcards

0
Q

What is angina?

A

lack of sufficient oxygen (ischemia) to the heart causes pain

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1
Q

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

A

Nitrates
BBs
CCBs (Dihydropyridine and Non-Dihydropyridine)
Ranazoline

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2
Q

Why does angina happen?

A

Coronary artery obstruction limits blood supply to part of the myocardium

  • atherosclerosis and thrombosis blocks blood flow (unstable angina)
  • vasospasm blocks blood flow (variant or Prinzmetal’s angina)
  • coronary circulation can meet oxygen demands of myocardium at rest, but not when heart work increased by exercise (exertional angina) due to atherosclerosis
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3
Q

Myocardial oxygen demand is a function of…

A

Heart work (DEMAND) determined by: HR, contractility, wall tension (afterload)

O2 SUPPLY determined by: coronary vascular resistance, perfusion pressure, collateral blood flow, HR and mechanics

Therapies can either DECREASE demand or INCREASE supply of oxygen. Ideal therapies will do both!

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4
Q

Unstable (pre-infarction, crescendo) angina

A

Recurrent angina associated with minimal exertion
Prolonged and frequent pain
Thought to be d/t fissuring of atherosclerotic plaques and subsequent platelet aggregation
HIGH CORRELATION WITH MI

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5
Q

Exertional (exercise-induced) angina or “Angina of Effort”

A

Usually d/t fixed coronary vascular obstruction (surgical revascularization or angioplasty may be beneficial)

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6
Q

Variant (vasospastic, Prinzmetal’s) angina

A

Direct result of reduction in coronary blood flow d/t vasospasm, not an increase in myocardial oxygen demand
Normal coronary angiograms
Excellent prognosis

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7
Q

What are the approaches for treating angina?

A
  1. Increase coronary blood flow
  2. Reduce myocardial oxygen consumption (mvo2)
  3. Prevent platelet deposition/aggregation (aspirin and statins)
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8
Q

You can reduce myocardial oxygen consumption (mvo2) by…

A

NEGATIVE CHRONOTROPIC EFFECT (HR)
NEGATIVE INOTROPIC EFFECT (myocardial contractility)
Decreased ventricular workload (wall stress) via reduced preload (venodilation) and reduced afterload (vasodilation)

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9
Q

When does perfusion of the heart occur?

A

DIASTOLE!

During diastole the blood vessels that go down into the myocardium OPEN, but during systole these vessels get squeezed and essentially no blood can flow to these deeper areas.

Any therapy that reduces contractility will reduce the amount of squeezing on these blood vessels during systole and any therapy that reduces HR will increase the amount of time the heart spends during diastole and thus increase supply of blood to mnyocardium.

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10
Q

Explain the cellular mechanism of nitrate action

A

Nitrovasodilators undergo denitration in blood stream to release NO which activates GC and elevates intracellular cGMP producing relaxing of vascular (and other) smooth muscle and produces venodilation and coronary vasodilation (endogenous NO produced by nitric oxide synthase)

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11
Q

What is the most important vasorelaxant pathway we have?

A

Endogenous NO production by nitric oxide synthase.

Note that this pathway is also one that decreases with age

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12
Q

What are the cardiovascular effects of nitrates?

A

VENODILATION RESULTS IN DECREASED PRELOAD***
- decreased pressure during diastole in ventricles of heart
- reduced wall stress and mvo2
- subendocardial blood flow is increased
CORONARY VASODILATION
- redistribution of blood flow to areas of ischemia
- selective dilation of epicardial and collateral coronary vessels
- prevents or reverses coronary vasospasm

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13
Q

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

A

BP: unchanged or slight decrease
HR: unchanged or slight increase
Pulmonary vascular resistance decreased
Cardiac Output reduced (slight)

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14
Q

What is one important DDI with nitrates?

A

Sildenifil (Viagra) and other Type V PDE inhibitors, increase cGMP by preventing metabolism, potential for augmented cGMP response to nitrates, profound hypotension, myocardial ischemia.

ABSOLUTE CONTRAINDICATION

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15
Q

What are the adverse effects of nitrates?

A

HYPOTENSION - seen with higher doses of nitrates; results from arterial vasodilation. Decreased BP may trigger reflex sympathetic stimulation of the heart (tachy, increased contractility) and decrease coronary perfusion, which can worsen angina! Also, dizziness, orthostatic hypotension, and syncope in patients who are sensitive to reductions in prelaod (i.e. volume depletion, valvular heart disease, hypertrophic cardiomyopathy)
HEADACHE - d/t vasodilation of meningeal arteries (vasomotor headache).
DRUG RASH - seen with long acting nitrates, cutaneous nitrates

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16
Q

Continuous nitrate exposure leads to…

A

TOLERANCE and loss of efficacy!! Clinically significant in high dose oral, transdermal, or IV administration of nitrates

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17
Q

What are some mechanisms of tolerance to nitrates?

A

Volume expansion - reverses the effect of nitrate vasodilation
Neurohumoral activation
Depletion of tissue cysteine stores***

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18
Q

What is the recommended action to prevent tolerance to nitrates?

A

8-12 hour “nitrate free” interval each day, usually at night but in some individuals during the day
ISOSORBIDE MONONITRATE - eccentric dosing schedule (8AM-3PM)
IV NITROGLYCERIN - titrate dose upward as needed to maintain effect
24h PATCH - remove at night

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19
Q

How does depletion of cysteine stores contribute to nitrate tolerance?

A

Cysteine is needed in the processing of nitrates to release NO into the body (acts on s-nitrosothio to produce NO). With prolonged and higher dose therapy, the cysteine stores can be depleted.

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20
Q

What happens with abrupt cessation of nitrates?

A 
ANGINAL REBOUND (e.g. coronary vasospasm)
DO NOT suddenly interrupt IV nitroglycerin in unstable angina, overlap with transdermal or oral form.
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21
Q

List the three classes of CCBs and the drugs within each class

A

Dihydropyridine: Nifedipine, Amlodipine, Felodipine, Nicardipine, Isradipine

Phenylalkylamines: Verapamil

Benzothiazepines: Diltiazem

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22
Q

What are the uses of CCBs

A

Angina
HTN
Treatment of supraventricular arrhythmias (atrial flutter, AFib, paroxysmal SVT)

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23
Q

Describe the physiology of calcium

A

Intracellular Ca2+ induces contraction of muscle cells and is regulated by numerous different pumps, channels and exchangers.

  • Cardiac: binding to troponin C reduces inhibition of actin-myosin cross-bridges
  • Smooth muscle: binding to calmodulin activates MLCK, which phosphorylates myosin and triggers contraction
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24
Q

Describe the type of channels that CCBs act on

A

L-type Ca2+ channels, which are voltage-dependent channels with large conductance and slow inactivation. Widespread expression of these channels in the CV system.

Note: other types of Ca2+ channels and other proteins that regulate Ca2+ homeostatis are insensitive to CCBs. This is how CCBs affect CV function without significant side effects in other systems.

25
Q

Describe the role of calcium in cardiac and vascular muscle

A

Vascular smooth muscle relies on Ca2+ influx through L-type Ca2+ channels for contraction (graded, Ca2+ dependent contraction that is slow and sustained).

Cardiac cells rely on L-type Ca2+ channels for contraction and for the upstroke of the AP in slow response cells.

26
Q

What type of calcium channels mediate NT release in neurons?

A

N-type and P-type

THESE CHANNELS ARE INSENSITIVE TO CCBs!!!!

27
Q

MOA of CCBs

A
  1. Increase the time that Ca2+ channels are closed
    reduce the magnitude of the Ca2+ currant (all)
    slow the recovery of the channel (verapamil, diltiazem)
  2. Induce relaxation of the arterial smooth muscle but not much effect on venous smooth muscle. Results in significant reduction in afterload but not in preload.
  3. Reduce cardiac inotropy, slow AV conduction and slow pacemaker firing (non-DHPs)
28
Q

Describe the effects of Non-dihydropyridine Ca2+ channel blockers

A

Verapamil > Diltiazem
Direct effects predominate to reduce heart work (demand): decreased HR, decreased myocardial contractility, slowed AV/SA conduction
Prevents or reverses vasospasm (coronary vasodilation)
EFFECTIVE ALONE IN TREATING ANGINA, DO NOT COMBINE WITH BB!

29
Q

Describe how the different binding sites of CCBs results in differing pharamacological effects

A

Non-DHPs: use-dependent binding (target cardiac cells) –> bind to channels that are constantly opening and closing

DHPs: voltage-dependent binding (targets smooth muscle) –> tend to bind to channels that are at a certain voltage and will find channels that are in smooth muscle b/c voltage changes very slowly there

30
Q

Describe the effects of Dihydropyridine Ca2+ channel blockers

A

Nifedipine, Felodipine, etc.
Potent vasodilation, reduced mvo2 by reducing afterload
Coronary vasodilation (increased supply)
Reflex cardiac stimulation (HR, myocardial contractility can increase reflexively!)
AV node conduction unaffected
ONLY USE IN COMBINATION WITH BB (to modulate reflexive effects)

31
Q

Situations favoring use of DHPs in angina

A

In combination with BB for coronary vasodilation, reduced afterload
Sinus bradycardia, SA/AV block
Valvular insufficiency (aortic, mitral): reduces afterload

32
Q

Situations favoring use of N-DHPs in angina

A

Use in asthma/bronchospastic COPD (these pts. cant tolerate BBs)
Severe peripheral vascular disease with rest pain depression
Labile (variable glucose levels) insulin dependent diabetes

33
Q

What types of angina are CCBs used for

A

Highly effective agents for relief of symptoms in exertional and vasospastic angina.

34
Q

What is a source of concern with CCBs and what does it mean for the treatment of angina?

A

CCBs may inhibit apoptosis (affect cancer cell growth). Therefore, BBs considered drugs of FIRST CHOICE in angina. CCBs are reserved for use in patients unable to tolerate BB or as add-on therapy for angina uncontrolled by BB+nitrate

35
Q

Describe the PKs of CCBs

A

Rapid absorption from GI tract - extensive first-pass hepatic metabolism reduced bioavailability. Bolus effect results in reflex tachycardia, headache, coronary steal.

Effect terminated by hepatic metabolism - reduce dosage in hepatic disease; both metabolized by and inhibits CYP3A3 (verapamil > diltiazem)

Plasma T/2 short for most CCBs - exception is Isradipine and Felodipine. This led to the development of SR preparations of all other CCBs, which have lower side effects and improved safety.

36
Q

What are the adverse effects specific to DHPs

A

Excessive vasodilation: dizziness, hypotension, headache
GI irritation: nausea
Peripheral edema: precapillary arteriolar vasodilation
Paradoxical exacerbation of angina (CORONARY STEAL): less problematic with SR preparations that don’t have rapid onset. Coronary steal results when massive vasodilation occurs during an MI or anginal event, essentially stealing perfusion away from myocardium.

37
Q

What are the adverse effects specific to N-DHPs

A

Bradycardia, asystole, AV block (thus should never be combined with BB therapy, which also slows conduction through heart)

CHF (they have negative ionotropic effects)

Constipation (Verapamil)

38
Q

Do CCBs have any effect on pregnancy?

A

YES! Pregnancy category C (cross placenta and breast milk)

39
Q

What are some notable DDIs with CCBs

A

Verapamil (and to a lesser extent Diltiazem) are both metabolized by CYP3A4 and can inhibit CYP3A4.

  • Drugs that inhibit CYP3A4 will delay their metabolism (e.g. Cimetidine, erythromycin, grapefruit juice).
  • May increase plasma levels of drugs metabolized by CYP3A4 (Theophylline, statins, cyclosporine).
  • Rifampin and phenobarbital induce CYP3A4 and reduce verapamil
  • Verapamil reduces renal and non-renal clearance of digoxin
  • BB use with Verapamil or Diltiazem increases risk of SA/AV block
40
Q

Why use BBs in treatment of angina

A

Blunt HR and inotropic response to excercise
Reduce afterload (CNS)
Do not reduce preload (may paradoxically increase short term)
Do not prevent coronary vasospasm

41
Q

Explain the rationale for combining BB with other agents

A

BBs prevent reflex tachycardia and positive inotropic effect of nitrates and DHP CCBs.

Nitrates - reduces LVEDP, LV volume, dilates coronary arteries
DHP CCBs - prevent coronary vasospasm, reduce systemic vascular resistance

42
Q

Describe the spectrum of action of BBs in angina

A

Unstable angina - use with nitrates, ASA and heparin
Exertional angina - reduces HR, myocardial contractility
Vasospastic angina - INEFFECTIVE (b/c of their ability to block B2 receptors which can give vasodilatory responses)
Myocardial Infarction

43
Q

Describe the action of BBs in MI

A

Reduce chest pain, ST elevation, cardiac enzyme elevation
Reduced ventricular ectopy and ventricular fibrillation
Reduced reinfarction and ischemic episodes during hospitalization
Reduced mortality during 2-3y following MI

44
Q

What is the recommendation in treatment of MI/unstable angina with BBs

A

Give BB IV followed by PO therapy provided no CHF, hypotension, or sinus bradycardia/heart block.

45
Q

What is Ranolazine and when its use indicated?

A

Novel metabolic modulator that is indicated in chronic stable angina in combination with amlodapine, BB or nitrates. WILL NOT RELIEVE ANGINA ATTACKS.

46
Q

What is the MOA of Ranolazine?

A

UNKNOWN
Partial FA oxidase inhibitor, increasing glucose oxidation and efficiency of O2 utilization in the heart.
Late sodium current inhibitor
No effect on HR and BP

47
Q

Is there a benefit to the use of Ranolazine?

A

Not really…expensive adjunct therapy with marginal benefit.

In patients who are refractory to or not candidates for revascularization, Ranolazine may provide a modest benefit when added as an adjunct for patients with angina refractory to treatmetn with BBs, nitrates and amlodapine.

48
Q

What are adverse effects to use of Ranolazine?

A

Dizziness, headache, constipation, nausea (4-6%)
Small, reversible elevations seen in serum creatinine and BUN
Syncope and asthenia (<1%)

49
Q

What are contraindications to Ranolazine

A
  • pregnancy category C
  • concurrent use of CYP3A4 inhibitors (verapamil, diltiazem, cyclosporine, quinolone and macrolide ABXs, PIs, azole antifungals, grapefruit juice)
  • existing long QT or use of class Ia and III antiarrhythmics
  • use of tricyclic antidepressants, fluxetine, haldol, nefazodone, quetiapine, chlorpromazine, diprasidone
  • any hepatic impairment is contraindicated and caution should be used in midl renal impairment
50
Q

What is a VERY IMPORTANT EXAM WORTHY contraindication with Ranolazine?

A

Digoxin concentration increases 40-60% through p-glycoprotein inhibition with Ranolazine

51
Q

What is the drug regimen in preventing MI and CHD death in patients with angina?

A

1) BBs: reduce CHD events (nitrates do not, CCBs variable)
2) Aspirin: after unstable angina or MI, reduces reinfarction and CHD death, reduces stroke (warfarin has comparable effect but is costly and has higher morbidity). ALL PATIENTS WITH CHD SHOULD RECEIVE ASPRIN THERAPY UNLESS CONTRAINDICATED!
3) ACE-I: improve survival post-MI and LV dysfunction, reduces MI in high-risk patients.
4) Revascularization: coronary angioplasty, atherectomy, CABG

52
Q

What is other therapy that can be used in preventing MI and CHD death in patients with angina

A

Thrombolytics: reduction in mortality within first year following MI
LDL reduction with HMG-RI: reduces recurrent MI and may acutely stabilize coronary plaque
HDL raising/TG lowering (e.g. gemfibrozil and niacin): reduces recurrent MI/CHD death

53
Q

SUMMARY NITRATES

A 
Coronary vasodilation 
Reduced Preload (venous)
Reduced afterload (arterial)
54
Q

SUMMARY N-DHPs

A

Coronary vasodilation
Reduced HR
Decreased contractile force
Reduced afterload (arterial)

55
Q

SUMMARY DHPs

A 
Coronary vasodilation 
Reduced afterload (arterial)
56
Q

SUMMARY BBs

A

Reduced HR
Reduced contractile force
Reduced afterload (arterial)* - this is an indirect effect via reduced renin release and possibly decreased sympathetic outflow

57
Q

A patient is admitted with unstable angina and is hospitalized on a telemetry bed. You should administer…

A

Transdermal, nitroglycerin paste or IV nitroglycerin

58
Q

A patient is hospitalized with unstable angina and is transferred to CCU for recurrent chest pain

A

IV nitroglyerin

59
Q

The BEST choice of oral antihypertensive therapy in a patient with a history of Prinzmetal’s (variant) angina would be…

A

A N-DHP type calcium channel blocker

60
Q

The WORST choice of oral antihypertensive therapy in a patient with a history of Prinzmetal’s (variant) angina would be…

A

BB - b/c Prinzmetal’s angina is a vasospasm

Cardio Block (6 decks)

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