Cardiac Physiology & Antiarrhythmics

Definitions

• Antiarrhythmics are categorized using the Vaughan Williams classification system, based on their mechanism of action.
• Arrhythmias or dysrhythmias refer to irregular heartbeats.
• The atrioventricular (AV) node connects atrial and ventricular depolarization.
• The Bohr effect relates to carbon dioxide's role in facilitating oxygen release from hemoglobin.
• Cardiac output (CO) measures the volume of blood pumped by the heart per unit of time.
• Catecholamines are endogenous substances that stimulate an excitatory response at nerve endings when released into the bloodstream.
• A chronotropic agent influences the heart's contraction rate.
• Diastolic blood pressure (DBP) is the lowest blood pressure just before ventricular ejection.
• A dromotropic agent affects the conduction of electrical impulses, with a positive dromotropic agent enhancing conduction to the heart.
• An inotropic agent influences the strength of muscular contraction.
• Mean arterial pressure (MAP) is the average pressure driving blood into tissues throughout the cardiac cycle.
• Phosphodiesterase is an enzyme that breaks down cyclic adenosine 3′,5′-monophosphate (cAMP).
• Sudden cardiac death (SCD) involves ventricular fibrillation, pulseless ventricular tachycardia, pulseless electrical activity, or asystole, leading to death.
• Systolic blood pressure (SBP) is the peak pressure during ventricular ejection.
• Tachycardia is an abnormally rapid heartbeat, usually exceeding 100 beats/min in adults.
• A vasodilator causes blood vessels to dilate.
• Vasopressors cause contraction of capillaries and arteries.

Factors Affecting Blood Pressure

• Systolic blood pressure (SBP) and diastolic blood pressure (DBP) are factors
• Mean arterial pressure (MAP) drives blood into tissues during the cardiac cycle.
• MAP is calculated as [2(DBP) + SBP]/3 or as CO × SVR, where CO is cardiac output and SVR is systemic vascular resistance.
• Cardiac output (CO) measures the blood volume leaving the heart per contraction per unit of time.
• CO is calculated as HR × SV, where HR is heart rate and SV is stroke volume.
• MAP = HR × SV × SVR is the summary equation.
• Pulmonary artery catheters help monitor patient response to vasoactive therapy and identify the cause of hypotension.
• Fluids are typically the first treatment for hypotensive episodes.

Agents Used in Shock Management

• Catecholamines like Norepinephrine, Isoproterenol, Dopamine, Phenylephrine, and Vasopressin
• Inotropic agents like Dobutamine, phosphodiesterase inhibitors and cardiac glycosides are used.

Catecholamines: Norepinephrine and Epinephrine

• Norepinephrine (Levophed) and epinephrine (Adrenalin) are endogenous catecholamines secreted by the adrenal medulla.
• Both cause vasoconstriction and tachycardia.

Isoproterenol (Isuprel)

• Isoproterenol is a synthetic catecholamine which treats symptomatic bradycardia or torsades de pointes.
• It is a β-Receptor agonist.
• β1 exerts inotropic and chronotropic effects, while β2 relaxes smooth muscles in bronchi, skeletal muscle, vasculature, and the GI tract.
• Its use is limited due to heart rate effects.

Dopamine (Inotropin)

• Dopamine is an endogenous catecholamine, a precursor to norepinephrine.
• Vasopressor dose ranges from 5 to 20 μg/kg/min.
• It stimulates β-receptors, producing chronotropic and inotropic effects, which increases afterload and myocardial O2 demand.
• Tachyarrhythmias, ectopic beat, palpitations, and decreased perfusion are adverse effects.

Phenylephrine (Neo-Synephrine)

• Phenylephrine is a purely α-agonist.
• It induces vasoconstriction in most vascular beds.
• It Elevates SBP by increasing total peripheral resistance.
• Aortic vasoconstriction may cause reflex bradycardia.
• It has no significant respiratory effects.

Vasopressin (Pitressin)

• Vasopressin has vasopressive and water retention effects; it is also known as antidiuretic hormone.
• Dose: 0.04 unit/min.
• It may decrease splanchnic blood flow.
• It's not a good first choice and should not be used as a lone agent, according to the Society of Critical Care Medicine 2008 practice guidelines.

Inotropic Agents: Dobutamine (Dobutrex)

• Dobutamine is for short-term treatment of heart failure due to depressed contractility.
• It is a synthetic catecholamine related to dopamine, but is not metabolized to norepinephrine and does not stimulate dopamine receptors.
• The (R)-Isomer causes positive inotropic and chronotropic effects, as well as vasodilatory effects.
• Adverse effects include tachyphylaxis, tachycardia, hypotension, and increased myocardial O2 demand.

Phosphodiesterase Inhibitors: Inamrinone (Inocor) and Milrinone (Primacor)

• These are inotropic vasodilator agents.
• They inhibit intracellular phosphodiesterase.
• Milrinone has a shorter half-life than Inamrinone.
• Initial bolus of Milrinone is 50 μg/kg over 10 minutes.
• Infusion of Milrinone is 0.375 to 0.75 μg/kg/min.
• The dose is adjusted in patients with severe cardiac failure or renal impairment.

Cardiac Glycosides: Digoxin (Lanoxin)

• Digoxin is used for the management of chronic heart failure.
• It has an inotropic effect on the myocardium.
• It reversibly inhibits the Na+/K+-ATPase pump in cardiac muscle and inhibits the vagus nerve
• It generally has no hypotensive effects.
• It has a narrow therapeutic margin (0.5–2 ng/mL).
• Digitalis toxicity symptoms include nausea, vomiting, anorexia, and pain.
• It undergoes renal elimination.

Electrophysiology of the Myocardium

• The sinoatrial node (SA) initiates electrical activity, generating an action potential.
• This depolarizes the atria.
• The atrioventricular (AV) node links activity of the atria and ventricle.
• The potential travels to the bundle of His, bundle branches, and Purkinje fibers.

Electrophysiology of the Myocardium: Phases

• Phase 0 involves initial rapid depolarization of myocardial tissues, due to an abrupt transmembrane influx of sodium through "fast" sodium channels.
• Phase 1 involves the inactivation of fast sodium channels, coupled with the movement of K+ and Cl- ions, which leads to transient net outward current and the beginning of repolarization.
• Phase 2 is the "plateau" phase, maintained by the balance between calcium influx and potassium efflux.
• Phase 3 involves calcium channels closing, but the membrane remains permeable to potassium, resulting in cellular repolarization.
• Phase 4 occurs when the cell returns to its "resting" state. Resting membrane potential is reached through depolarization related to constant sodium influx balanced by decreasing efflux of potassium.

Electrophysiology of the Myocardium: Ablation and ICDs

• Ablation with radiofrequency current involves applying radiofrequency current to the part of the heart causing arrhythmia via a catheter.
• It is effective when atrial fibrillation (AF) is due to a single circuit.
• Success rate of normal sinus rhythm (NSR) is 30–90% over the next year.
• Implantable cardioverter-defibrillators (ICDs) are used to cardiovert, terminate ventricular tachycardia (VT), and pace bradycardia.
• ICDs are indicated for cardiac arrest secondary to VT or ventricular fibrillation (VF) that is not reversible/transient, spontaneous sustained VT, syncope due to VT/VF with no drug tolerance and nonsustained VT in coronary artery disease (CAD), myocardial infarction (MI), left ventricular (LV) dysfunction, and are generally used if drug therapy will not suffice.

Pharmacology of Antiarrhythmics

• Antiarrhythmics are classified according to mechanisms of action.

Class IA Antiarrhythmics

• Block fast Na channels in the atrium and block repolarizing K currents.
• Quinidine (Quinaglute) is efficacious in atrial fibrillation/flutter (AF/AFL).
• Initiate rate-controlling agent first.
• Use caution in patients with asthma, muscle weakness, or fever.
• Overdose can cause respiratory depression, vomiting, diarrhea, seizures, hypotension, syncope, and EKG changes.

Class IA Antiarrhythmics: Procainamide (Pronestyl)

• Indicated for the treatment of VT and torsades de pointes.
• Has proarrhythmic effects.
• May produce leukopenia and agranulocytosis.
• Adverse effects include lupus erythematosus-like syndrome.

Class IA Antiarrhythmics: Disopyramide (Norpace)

• Indicated for life-threatening VT and paroxysmal supraventricular tachycardia (PSVT).
• It should be initiated at the hospital.
• Has negative inotropic properties.
• Has anticholinergic side effects.
• Potassium should be corrected before initiation of therapy.

Class IB Antiarrhythmics

• Often used; has less proarrhythmic potential compared with class IA.
• Lidocaine (Xylocaine) is frequently used to treat ventricular arrhythmia (VA) during cardiac surgery or after MI.
• It is administered as an IV bolus followed by infusion.
• It is metabolized extensively in the liver.
• Metabolites formed are seizurogenic.
• Side effects include insomnia, drowsiness, ataxia, agitation, and dysarthria.
• Mexiletine (Mexitil) is available in oral formulation, for treatment of life-threatening VA and has anesthetic properties.
• Adverse effects: GI disturbances, tremors, lightheadedness, difficulty in coordination, dyspnea, and respiratory problems.
• Massive overdoses can cause coma and respiratory arrest.
• Tocainide (Tonocard) is an oral congener of lidocaine, used to treat VA, myotonic dystrophy, and trigeminal neuralgia.
• It carries a “black box warning” and may cause pulmonary edema, fibrosing alveolitis, pneumonitis, respiratory arrest and blood dyscrasias.

Class IC

• Generally not used due to high proarrhythmic potential, but may be used for supraventricular or ventricular arrhythmias.
• Flecainide (Tambocor) is indicated for prevention of paroxysmal AF/AFL, PSVT, and sustained VT and as a long half-life.
• Shown to contribute to excessive mortality and nonfatal cardiac arrest
• Clearance is affected by urinary pH, with acidic pH increases clearance; alkaline pH decreases clearance.
• "Pill in the pocket” approach has been shown to be successful.
• Propafenone (Rythmol) prevents PSVT and maintains NSR postcardioversion and is a first-line agent for recent onset AF.
• It is a nonselective β-blocker, so use caution with bronchospastic patients.

Class II

• Β-Blockers are used in management of hypertension and post-MI, but caution in bronchospastic patients.
• Can be IV and oral
• Propranolol (Inderal)
• Metoprolol (Lopressor), the only agent used in chronic heart failure
• Atenolol (Tenormin)
• Nadolol (Corgard)
• Esmolol (Brevibloc) IV only

Class III

• Amiodarone (Cordarone) is used for ventricular and supraventricular arrhythmias and may induce pulmonary toxicity.
• It may also cause life-threatening interactions with other prescription, herbal, or OTC medications.
• Dronedarone (Multaq), its chemical structure is like amiodarone, which reduces toxicities of the thyroid gland,.
• Reduces risk for hospitalization in patients with paroxysmal or persistent atrial fibrillation or flutter who are currently in NSR or pending cardioversion and is oral route only.
• It is contraindicated when use with potent CYP3A4 inhibitors and inducers.
• Amiodarone is considered more effective in management of chronic atrial fibrilation management
• Dofetilide (Tikosyn) is an oral formulation for maintenance of NSR after conversion, but ineffective in paroxysmal AF.
• Significant risk of VA, greatest among females, CHD, diminished renal function, doses exceeding 500 mg twice daily.
• Treatment must begin with inpatient monitoring and the prescriber and pharmacy must be TIPS (Tikosyn in Pharmacy System) participants.
• Sotalol (Betapace/Betapace AF) is an oral medication that prolongs action potential and relative refractory period.
• It is Used for ventricular and supraventricular arrhythmias, requires 3-day inpatient monitoring and caution when treating patients with restrictive airway disease.
• Ibutilide (Corvert) is an IV formulation, and is an alternative to electrical cardioversion.
• Indicated for rapid conversion of recent-onset AF/AFL, and no other class I or III medications within 4 hours!
• Patients should be adequately anticoagulated before administration.

Class IV

• Calcium channel blockers (CCBs) such as Verapamil (Isoptin) and diltiazem (Cardizem) are used in the management of supraventricular arrhythmias and ventricular rate control.
• They block Ca channels in AV node and are a good alternative to β-blockers, but not favorable in chronic heart failure.

Miscellaneous

• Digoxin (Lanoxin) has AV-blocking and vagotonic properties, prolongs relative refractory period.
• Not a first-line agent for AF, takes 2 hours to maximal effect and is less effective than β-blockers.
• Adenosine (Adenocard) is used to terminate SVT and has a 12-second half-life.
• Use a central or brachial line, hold arm up and flush immediately.
• Side effects: Bronchospasm, dyspnea, hyperpnea and cough.

Management and Pharmacotherapy of Advanced Cardiac Life Support

• Sudden cardiac death (SCD) is a leading cause of death in the United States.
• Includes VF, pulseless ventricular tachycardia (pVT), pulseless electrical activity (PEA), or asystole.
• Goals: Restore sinus rhythm, prevent further SCD episodes, prevent neurological damage.
• How? CPR and Minimize time to defibrillation
• Epinephrine is an Endogenous neurotransmitter, 1-mg dose of 10-mL solution that stimulates α1-receptors (Coronary and cerebral vasoconstriction).
• It also has β-adrenergic activity, which increases HR and impairs the delivery of O2 to the myocardium and CNS.
• Decreased affinity with metabolic acidosis.
• Vasopressin (Pitressin) is an Endogenous antidiuretic hormone and potent vasoconstrictor.
• 1× dose of 40 units, IV, and may substitute for first or second dose of epinephrine.
• Nonadrenergic, affinity not compromised in face of metabolic acidosis.
• Atropine (AtroPen) is a 1-mg IV push for asystole or PEA, given along with epinephrine or vasopressin.
• It blocks action of acetylcholine for a short-lived chronotropic effect.
• Maximum daily dose: 0.04 mg/kg.
• Adverse effects: Miosis, dry mouth, urinary retention, constipation.
• Sodium bicarbonate's Dose: 1 mEq/kg and has limited use.
• Use in a patient fails to respond to adequate ventilation, defibrillation, and compressions or is refractory to vasopressors, and to keep pH > 7.2.
• Will increase CO2 levels, so patient must be well ventilated.
• Magnesium sulfate is used for torsades de pointes.
• Dose: 1 to 2 g (may repeat after several minutes) and caution with renally impaired patients.
• Magnesium toxicity causes sweating, hypotension, hypothermia, reflex depression, CNS depression, respiratory paralysis, circulatory collapse and flaccid paralysis.

Alternative Administration Routes

• Intraosseous route is recommended for use in children and adults and used if IV access is too difficult to gain with infants, children, elderly and IV drug abusers.
• Needle should not remain for >3 or 4 hours.
• Endotracheal route is used when the intravenous route is not accessible.
• NAVEL (Naloxone, Atropine, Vasopressin, Epinephrine, Lidocaine)
• Double dose and dilute with 10 mL of normal saline (NS) or sterile saline H2O.
• Insert with catheter down the endotracheal tube (ETT) and follow with 5 to 10 rapid ventilations.