PHARM CARDIAC

In what medication class should you avoid abrupt discontinuation because they can precipitate exacerbation of angina, myocardial infarction, or ventricle arrhythmia?

Beta-blockers

Cardioselective receptors

Beta-1 receptors

What are the effects related primarily to beta-1 blockade?

• Decreased heart rate (neg chronotropic)

• Decreased contractility (neg inotropic)

• Decrease myocardial oxygen demand

• Anti-arrhythmic effects

What are effects of the beta-2 blockade?

Bronchoconstriction

What are the nonselective beta-blockers?

• Propranolol

• Nadolol

• Pindolol

• Sotalol

• Timolol

• Carvedilol

• Labetalol

What are the cardioselective beta blockers?

• Metoprolol

• Atenolol

• Nebivolol

• Bisoprolol

• Acebutolol

• Betaxolol

• Esmolol

What medications?:

• Cardioselective

• Low doses → cardioselectively → minimize bronchoconstriction

• Metoprolol

• Atenolol

What is metoprolol available as?

• Metoprolol tartrate → regulate release formulation (IV and PO)

• Metoprolol succinate → extended release formulation (PO)

What is atenolol available as?

• PO tablets

• Boxed warning: avoid abrupt cessation

What medication?:

• Selective beta-1 blocker

• Controls BP or heart rhythm in critically ill patients or those undergoing surgical or diagnostic procedures

• Only available IV

Esmolol

What medication?:

• Selective beta-1 blocker

• Also increases release of nitric oxide from endothelial cells → causes vasodilation

Nebivolol

What are the uses of selective beta-1 blockers?

• Hypertensive patients with pulmonary impairment

• Chronic stable angina

• Bisoprolol and metoprolol → chronic heart failure

What medications?:

• ISA (intrinsic sympathomimetic activity)

  • Able to stimulate beta-receptor they bind to; inhibit stimulation by more potent endogenous catecholamine (epi and NE)

• Designed to decrease side effects and improve tolerability

• Acebutolol

• Pindolol

What medications?:

• Side effects:

  • Bronchoconstriction (nonselective)

  • Bradycardia

  • Arrhythmias

  • Lethargy

  • Disturbance in glucose metabolism

  • Fatigue

  • Insomnia

  • Sexual dysfunction

  • Hypotension

Beta-blockers

What are the beta-blockers with partial agonist activity?

• Acebutolol

• Pindolol

What are the beta-blockers at both alpha and beta receptors?

• Labetalol

• Carvedilol

What medications?:

• Beta-blocking and vasodilating effects

• Nonselective beta-blockers with alpha-1 blocking action

• Reduce BP by causing peripheral vasodilation

• Labetalol

• Carvedilol

What beta-blocker also lowers lipid peroxidation and vascular wall thickening which is useful in heart failure?

Carvedilol

What are the uses of labetalol and carvedilol?

• HTN

• Heart failure

Adverse effects of labetalol and carvedilol?

• Orthostatic hypotension (alpha-1 blockage)

• Dizziness

What are the effects of beta-blockers in MI?

• Reduce myocardial oxygen demand

• Reduce ventricular arrhythmias

• Reduce mortality rates after MI

What medications?:

• Prevent calcium from entering cells of heart and arteries → decreases BP

• Relaxation of blood vessels → vasodilation

• Reduce heart rate, contractility (negative inotropes), and oxygen requirements

Calcium channel blockers

What medications?:

• Bind to L-type channels in cardiac myocytes, cardiac nodal tissues, vascular smooth muscle cells → dec. calcium entry into these cells

• Reduces automaticity (neg. chronotropic effect)

• Dec. myocardial contractility (negative inotropic effects)

• Decrease atrioventricular node conduction velocity (negative dromotropic effect)

• Smooth muscle relaxation → system vasodilation

• Decrease cardiac afterload → decrease in blood pressure (effective in HTN)

Calcium channel blockers

What are the dihydropyridines?

• Nifedipine- PO

• Amlodipine- PO

• Felodipine- PO

• Isradipine- PO

• Nicardipine- PO/IV

• Nisoldipine- PO

• Clevidipine- IV

What are the nondihydropyridines?

• Verapamil- PO/IV

• Diltiazem- PO/IV

What medications?:

• Affect calcium channels in blood and heart

• Do not cause reflex tachycardia

Nondihydropyridines

What medication?:

• ER and regular release formulations

• Effects on both cardiac and vascular smooth muscle cells

• Uses:

  • Angina

  • Supraventricular tachyarrhythmias

  • Migraines and cluster headaches

Verapamil

What medication?:

• ER and regular release formulations

• Effects on both cardiac and vascular smooth muscle

• Less negative inotropic effects

• Favorable AE profile

Diltiazem

What medications?:

• Greater affinity for vascular calcium channels than channels in the heart

• Can lead to reflex tachycardia

• HTN treatment

• Fewer interactions with other cardiovascular drugs

Dihydropyridines

What medications?:

• Uses:

  • Angina

  • A-fib → diltiazem, verapamil

Calcium channel blockers

What medication?:

• AE:

  • Dose dependent first-degree atrioventricular block

  • Dose dependent constipation

Verapamil

What medications?:

• Dose dependent constipation

• Avoid in hear failure

• Avoid in atrioventricular block

Verapamil and diltiazem

What medications?:

• Constipation

• Dizziness

• HA

• Fatigue

• Peripheral edema

• Gingival hyperplasia

• Reflex tachycardia

• Flushing d/t vasodilation

Dihydropyridines

What medications?:

• Decrease HR and contractility → reduces myocardial oxygen demand

Beta-blockers

What medications?:

• Reduce systemic vascular resistance (SVR)

• Improve coronary and myocardial blood flow

• Decrease myocardial contractility

Calcium channel blockers

What medications?:

• Venous dilation → decreases preload and oxygen demand by heart

Organic nitrates

What medications?:

• Reduces late sodium current → decreases intracellular sodium concentration and calcium overload → improves diastolic function

Sodium channel blockers

What medications prevent thrombus formation?

Antiplatelet medications

What medications?:

• Decrease oxygen demands → decreased HR, contractility, CO, BP

• Decrease myocardial oxygen demand during exertion and at rest

• Reduce both frequency and severity of angina attacks

• Avoid with ISA (pindolol, acebutolol)

• Taper dose to avoid rebound angina, MI, HTN

Beta-blockers

Hypoxia causes membrane depolarization which increases what during ischemia?

Calcium influx

What medications block calcium influx into cardiac and smooth muscle cells?

Calcium channel blockers

How do CCB’s reduce oxygen demand?

• Decreasing HR

• Decreasing contractility

• Decreasing afterload

How do CCB’s increase oxygen supply?

Vasodilation of coronary arteries

In effort-induced angina, CCB’s reduce vascular resistance which does what?

Decreases afterload

How do CCB’s work in vasospastic angina?

Relax coronary arteries

What medications?:

• Block L-type calcium channels in cardiac and vascular smooth muscle

• Decrease oxygen demand by:

  • Decrease HR

  • Decrease contractility

  • Decrease afterload

• Increase coronary blood flow

Calcium channel blockers

What medications?:

• Greater affinity for vascular calcium channels than channels in the heart → greater effect on vasodilation, less effect on heart function

Dihydropyridines

What medication?:

• Dihydropyridine

• Vasodilatory effect is useful in variant angina

Amlodipine

What medication?:

• Nondihydropyridine

• Slows AV conduction

• Lowers HR, contractility, BP, and oxygen demand

• CI in preexisting depressed cardiac function or AV conduction abnormalities

Verapamil

What medication?:

• Nondihydropyridine

• Slows AV conduction

• Decrease firing rate of sinus node pacemaker

• Coronary artery vasodilator

Diltiazem

What medication?:

• Most therapeutic effects caused by venodilation, especially at low doses

• Venodilation reduces preload

• Decreased preload → decreases force of contraction during systole and decreased work by heart

• Decreased work → decreased oxygen demand

• Dilate coronary vasculature → increases blood supply to cardiac muscle

Nitrates

What medications?:

• Onset of action varies

  • 1 minute for NTG

  • 30 minutes for isosorbide mononitrate

Nitrates

What medications?:

• Tablet or spray formulation

• DOC for prompt relief of angina attack caused by exercise or emotional stress

• One SL tablet at onset of angina, may repeat

Sublingual NTG

What nitrate?:

• Administered SL or via patch/ointment to avoid first pass metabolism

NTG

What nitrate?:

• Improved bioavailability and long DOA → stable against hepatic breakdown

Isosorbide mononitrate

What nitrate?:

• De-nitrated to two mononitrates

Isosorbide dinitrate

What formulations of nitrates are used for prolonged prophylaxis to decerase angina frequency?

Patch or slow-release

Why should you take caution with patch or slow-release formulations of nitrates?

Tolerance develops with continual use

What medications?:

• AE:

  • HA

  • High doses → postural hypotension, facial flushing, tachycardia

  • Avoid using with phosphodiesterase type 5 inhibitors (sildenafil) → hypotension

  • Tolerance develops

Nitrates

Pathophysiology of sodium channel inactivation failure and ischemia

• Myocardial ischemia inhibits inactivation of cardiac sodium channels

• Increase in sodium influx and intracellular sodium concentration → increase in intracellular calcium → contributes to pathogenesis of abnormalities in ischemic heart

What medication?:

• Inhibits late phase sodium current

• Intracellular sodium reduced

• Calcium overload reduced

• Improves oxygen supply and demand

Ranolazine

What medication?:

• Antianginal effects less in women than men

• Extensive metabolism by 3A enzymes and 2D6

• Substrate of P glycoprotein

• Avoid with drugs that cause QT prolongation

Ranolazine

Rapid, temporary change in electrical potential across heart muscle cell membrane that triggers muscle contraction

Action potential

Time during which cardiac muscle cell cannot respond to new stimulus

Effective refractory period

Ability to spontaneously depolarize and generate an action potential

Automaticity

Refers to phenomenon where a drug’s effect is more pronounced at higher HR → efficacy of these agents increases as HR increases → more effective arrhythmia control during episodes of tachycardia

Use-dependence/state-dependence

What are the class 1 antiarrhythmics?

• Sodium channel blockers

• 1A

  • Diospyramide

  • Quinidine

  • Procainamide

• 1B

  • Lidocaine

  • Mexiletine

• 1C

  • Flecainide

  • Propafenone

What are the class 2 antiarrhythmics?

Beta-blockers

What are the class 3 antiarrhythmics?

• Potassium channel blockers

  • Amiodarone

  • Dronedarone

  • Sotalol

  • Dofetilide

  • Ibutilide

What are the class 4 antiarrhythmics?

• Calcium channel blockers

  • Verapamil

  • Diltiazem

What are the miscellaneous antiarrhythmics?

• Digoxin

• Adenosine

• Magnesium sulfate

• Ranolazine

What drives depolarization?

Sodium influx

What are the phases of cardiac repolarization?

• Phase 0: Rapid sodium influx through open fast sodium channels

• Phase 1: Transient potassium channels open and potassium efflux returns TMP to 0mV

• Phase 2: Influx of calcium through L-type channels is electrically balanced by potassium efflux through delayed rectifier potassium channels

• Phase 3: Calcium channels close but delayed rectifier potassium channels remain open and return TMP to -90mV

• Phase 4: Sodium, calcium channels closed, open potassium rectifier channels keep TMP stable at -90mV

What medications?:

• Modify impulse generation and conduction

• Also have proarrhythmic actions

• Inhibiting potassium channels widens action potential → prolongs QT interval

  • Torsades de pointes

Antiarrhythmics

What are the classifications of Class 1 antiarrhythmics?

• Sodium channel blockers

• 1A: prolongs action potential

• 1B: shortens action potential

• 1C: minimal effect on action potential duration

Where do class 1 antiarrthymics work?

Phase 0

Where do class 2 antiarrthymics (beta-blockers) work?

Phase 4

Where do class 3 (potassium channel blockers) work?

Phase 3

Where do class 4 (CCB’s) antiarrhythmics work?

Phase 2

What medications?:

• Block voltage-sensitive sodium channels in non-nodal tissue (myocytes of atria, ventricles, His-Purkinje system)

• Bind more rapidly to open or inactivated sodium channels (phase 0)

• “Use dependence” or “state dependence”

• Work more in tissues that are frequently depolarizing

  • B/c block cells that discharge at unusually high frequency, will not interfere with normal beating of heart

Class 1 antiarrhythmic

What medications?:

• Slow or block phase 0

  • Decrease slope of phase 0 → dec. in amplitude of action potential

  • Dec. velocity of action potential transmission in heart

• Have varying effects on phase 3 of action potential

• Affect atria, purkinje, ventricular tissues

Class 1 antiarrhythmic

What do class 1 antiarrhythmics have effect on?

• Phase 0

• Duration of action potential

• Effective refractory period

What are the class 1A antiarrhythmic medications?

• Disopyramide

• Quinidine

• Procainamide

What medications?:

• Block influx of sodium → slow or block phase 0

• Potassium channel effects:

  • Block potassium channels → decreases potassium efflux → slow repolarization

  • Causes increase in ERP and action potential duration → QT prolongation

• Prolong AP

• Increases ERP

Class 1A antiarrhythmics

What class 1 antiarrhythmic has alpha blocking and anticholinergic actions?

Quinidine

What class 1 antiarrhythmic has less anticholinergic activity?

Procainamide

What class 1 antiarrhythmic has more anticholinergic activity, greater negative inotropic effects, and peripheral vasoconstriction?

Disopyramide

What class 1 antiarrhythmics lack alpha blocking abilities?

• Procainamide

• Disopyramide

What class 1 antiarrhythmic is used in arrhythmias: atrial, AV junctional, and ventricular tachyarrhythmias?

Quinidine

What class 1 antiarrhythmic is only available for parenteral admin and is used in acute atrial and ventricular arrhythmias?

Procainamide

What class 1 antiarrhythmic is used for ventricular arrhythmias and rhythm control in atrial fibrillation (off label)?

Disopyramide

What medications?:

• AE:

  • Proarrhythmic

    • Prolong QT interval → torsades de pointes

  • Quinidine, disopyramide → caution with potent 3A4 inhibitors

  • Not used often d/t proarrhythmic and systemic toxicity

Class 1A antiarrhythmics

What medication?:

• AE

  • Highest proarrhythmic effects in its class

  • Large doses → induce symptoms of cinchonism (HA, tinnitus)

  • Inhibitors of 2D6 and P-glycoprotein

  • Boxed warning: increased mortality in treatment on non-threatening arrhythmias, inc. risk of structural heart disease

Quinidine

What medication?:

• AE:

  • Hypotension

  • Agranulocytosis, pancyropenia d/t bone marrow suppression → reversible drug-induced lupus (dose and duration-related)

  • Boxed warning: positive antinuclear antibody (ANA) test with or without symptoms of lupus erythematosus associated with prolonged use, proarrhythmic effects (restrict to life-threatening ventricular arrhythmias), blood dyscrasias

Procainamide

What medication?:

• AE:

  • Most anticholinergic AE

  • Boxed warning: Increased mortality in asymptomatic non-threatening ventricular arrhythmias with MI 6 days → 2 years prior; restrict use to life-threatening ventricular arrhythmias

Disopyramide

What medications?:

• General precautions/contraindications

  • Use caution or avoid in atherosclerotic heart disease or systolic heart failure

  • 2nd and 3rd degree heart block

  • Cardiogenic shock

  • Myasthenia gravias

  • Other meds that prolong QT interval (fluoroquinolone antibiotics)

Class 1A antiarrhythmics

What medications?:

• Lidocaine

• Mexiletine

• Rapid association and dissociation with sodium channels

• Treatment of ventricular arrhythmias

Class 1B antiarrhythmics

What medications?:

• Block sodium channels in phase 0

• Shorten phase 3 depolarization; dec. AP duration

• Shorten AP

• Normal or decreased ERP

• Little to no negative inotropic effects

Class 1B antiarrhythmics

What medications?:

• Post-myocardial infarction and other ventricular arrhythmias

• Digitalis-induced arrhythmias

Class 1B antiarrhythmics

What medication?:

• Class 1B

• IV administration

• Alternative to amiodarone for ventricular fibrillation or ventricular tachycardia

• Combination with amiodarone for VT storm

Lidocaine