Drug Manuals

Chapter 1: Antiarrhythmic drugs in ventricular tachyarrhythmias

Antiarrhythmic drugs and management of ventricular tachycardia, ventricular fibrillation

This manual presents recommendations for the management of ventricular tachyarrhythmias (VT, VF). It is primarily intended for use in an emergency setting. The manual includes the following sections (click to navigate to the section):

Classification of antiarrhythmic drugs.

Classification of ventricular tachyarrhythmias.

General principles for the management of VT/VF.

Antiarrhythmic agents: doses, indications, and contraindications.

Singh–Vaughan Williams classification of antiarrhythmic drugs

Antiarrhythmic drugs affect the function of cardiac ion channels. These agents are classified according to the Singh–Vaughan Williams classification (Table 1). Agents in bold text are commonly used to prevent or treat acute and subacute ventricular arrhythmias. The Singh-Vaughan Williams classification fails to clarify that the majority of these agents exert effects on multiple cardiac ion channels (Dan et al).

Table 1. Singh–Vaughan Williams classification of antiarrhythmic drugs

Class	Definition	Agents
Class IA	Na+ channel blocker with intermediate offset kinetics	Ajmaline, Cibenzoline, Disopyramide, Pilsicainide, Procainamide, Quinidine
Class IB	Na+ channel blocker with fast offset kinetics	Lidocaine, Mexiletine, Phenytoin
Class IC	Na+ channel blocker with slow offset kinetics	Flecainide, Propafenone
Class II	Beta-adrenergic Blockers (antagonists)	Atenolol, Carvedilol, Esmolol, Metoprolol, Nadolol, Propranolol
Class III	K+ channel blockers (prolongs action potential)	Amiodarone, Dronedarone, Dofetilide, Ibutilide, Sotalol
Class IV	Non-dihydropyridine L-type Ca2+ channel blockers	Diltiazem, Verapamil

Classification of ventricular tachycardia (VT)

Ventricular arrhythmia	Definition and classification
Ventricular tachycardia (VT)	Definition: ≥3 consecutive QRS complexes generated in the ventricles at >100 bpm (cycle length: <600 ms).Classification according to duration:– Sustained VT: VT >30 seconds, or VT <30 seconds terminated by therapy.– Non-sustained VT (NSVT): VT with ≥3 beats and spontaneous termination.Classification according to morphology:– Monomorphic VT: VT with constant QRS morphology.– Polymorphic VT: VT with beat-to-beat variations in QRS morphology.– Bidirectional VT: VT with alternating QRS axis. Occurs in CPVT (catecholaminergic polymorphic VT) or digitalis toxicity.
Torsade de pointes (TdP)	Definition: Polymorphic VT that results from long QT syndrome (LQTS).TdP occurs exclusively in individuals with LQTS (congenital or acquired). The VT is polymorphic with a gradual alteration in the QRS amplitude, often with twisting of the QRS complex around the isoelectric line. Most patients display QTc >500 ms during sinus rhythm. TdP is typically initiated by a long-short coupling sequence. Common scenarios leading to TdP: (1) sinus rate acceleration (tachycardia-dependent torsade, common in infants, often causes T-wave alternans); (2) heart rate deceleration (pause-dependent torsade, common in adults). In pause-dependent torsade de pointes, a sudden heart rate decrease (e.g due to sinus pause or post-VPC pause) results in augmentation of early afterdpolarization amplitude (typically seen with large T-wave amplitude), and QT prolongation.
Ventricular flutter	Monomorphic VT at a rate ~300 bpm (cycle length 200 ms).
Ventricular fibrillation	Irregular, rapid (>300 bpm) ventricular depolarizations, with very irregular waveforms (no visible QRS waveforms)
VT/VF storm (electrical storm)	≥3 episodes of sustained VT, VF, or appropriate shocks from an ICD within 24 h.

ECG showing polymorphic ventricular tachycardia degenerating into ventricular fibrillation. By Bagnall et al: BMC Medical Genetics 15 (2014): 99.

Polymorphic ventricular tachycardia degenerating into ventricular fibrillation.

ECG showing an episode of sinus rhythm (with multiple ventricular premature beats) spontaneously converting to Torsade de Pointes ventricular tachycardia. Notice how arterial blood pressure (ABP) drops at the onset of TdP. ECG by Nakstad et al (Scand J Trauma Resusc Emerg Med. 2010; 18: 7)

Bidirectional ventricular tachycardia. Source:

General principles

The risk of degeneration to ventricular fibrillation (VF) is substantially higher in polymorphic VT, as compared with monomorphic VT. Ongoing myocardial ischemia is the most common cause of polymorphic VT.

Always search for and correct reversible causes of ventricular arrhythmias. These should be treated simultaneously with the administration of antiarrhythmic agents. Acute decompensated heart failure, acute myocardial ischemia, electrolyte disturbances (hypokalemia, hypomagnesemia), etc, are such causes.

In the context of antiarrhythmic drugs, structural heart disease (SHD) is defined as ischemic heart disease, valvular heart disease, congenital heart disease, ventricular hypertrophy or myocardial disease. Structural heart disease confers a substantial risk of ventricular arrhythmias and a significant risk of proarrhythmic effects of antiarrhythmic drugs. While several antiarrhythmic drug classes are available for emergency treatment of VT/VF in these patients, long-term treatment is limited mostly to amiodarone, beta-blockers or sotalol. In patients with structural heart disease, only amiodarone and beta-blockers are considered safe (with regards to proarrhythmic effects) for long-term use without the implantation of an ICD.

Amiodarone is safe and effective in the presence of significant structural heart disease (including severely reduced ejection fraction), with the exception of patients with ventricular tachycardia or ventricular fibrillation caused by QT-prolongation (long QT-syndrome). Amiodarone is unlikely to induce hazardous QT-prolongation in patients with normal QT-interval; it may, however, induce lethal arrhythmias in patients with preexisting QT prolongation (congenital or acquired). Lidocaine is safe and effective in ventricular arrhythmias caused by QT prolongation (long QT syndrome).

It is important to distinguish polymorphic VT from torsade de pointes, since amiodarone (the most common first-line therapy) is contraindicated in torsade de pointes due to the fact that additional QT prolongation (induced by amiodarone) may cause degeneration into ventricular fibrillation and asystole. However, a polymorphic VT may exhibit the characteristic twisting of the points seen in torsade de pointes. A diagnosis of TdP should be made if a polymorphic VT occurs in a patient with a QTc interval >480 ms (QTc >500 ms in most patients).

Class III agents (amiodarone, dronedarone, dofetilide, ibutilide, sotalol) should be avoided in individuals at high risk of QT prolongation. QT prolongation >60 ms from baseline or QTc >500 ms, T-wave alternans, pronounced T–U wave distortion after a pause, and new ventricular ectopy are risk factors for torsade de pointes after the instigation of Class III agents (Dan et al).

Among the antiarrhythmic agents, only beta-blockers have been demonstrated to provide long-term protection for sudden cardiac arrest (SCA) and sudden cardiac death (SCD). Other antiarrhythmic drugs have failed to show efficacy in the prevention of SCD in randomized controlled trials. ICDs are effective for long-term prevention of SCD (Zipes et al, Priori et al). Beta-blockers are also effective in treating acute ventricular tachycardia, irrespective of type.

If antiarrhythmic agents fail to treat monomorphic VT, catheter ablation should be considered as an effective alternative (Tung et al).

Acute coronary angiography should be considered in all patients with ventricular arrhythmias potentially caused by myocardial ischemia. Coronary angiography should also be considered in the following scenarios:

New-onset ventricular arrhythmia in the absence of a clear (non-ischemic) cause.

In patients developing ventricular arrhythmias after recently undergoing a coronary intervention (stent thrombosis is highly likely in these scenarios).

Administration of prophylactic lidocaine upon return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA) is associated with less recurrent VF/VT arrest. Thus, lidocaine may be used as prophylaxis after OHCA. Whether the same holds true for amiodarone remains unknown (Kudenchuck et al).

Non-sustained ventricular tachycardia (NSVT)

Patients without structural heart disease:

First-line therapy: beta-blockers or verapamil are usually effective.

Second-line therapy: amiodarone or sotalol.

Patients with structural heart disease:

First-line therapy: beta-blockers, verapamil and amiodarone.

Sotalol may be given to patients with moderate structural heart disease, including ischemic heart disease. Consider implantation of an ICD if sotalol is required for prophylaxis.

Class IC drugs (flecainide, propafenone) are only used in the absence of ischemia, previous myocardial infarction, and structural myocardial disease.

Sustained ventricular tachycardia

First-line therapy: beta-blockers, amiodarone, lidocaine, procainamide.

Second-line therapy: Sotalol.

Idiopathic ventricular tachycardia

Idiopathic ventricular tachycardia is defined as ventricular tachycardia in the absence of structural heart disease, genetic forms of ventricular tachycardia, including channelopathies. These arrhythmias mostly originate in the right ventricular outflow tract (RVOT), the left ventricular fascicular system (LVFS) or the mitral annulus.

First-line therapy: Beta-blockers are usually effective to treat idiopathic VT. Beta-blockers should be titrated to maximally tolerated dose.

Second-line therapy: Class IV agents (verapamil).

Third-line therapy: amiodarone, sotalol, flecainide, mexiletine, or propafenone are available as third-line alternatives.

Catheter ablation should be considered if beta-blockers fail.

Ventricular tachycardia in structural heart disease

First-line therapy: Beta-blockers.

Second-line therapy: Beta-blockers are frequently insufficient and may therefore require combination therapy with amiodarone.

Third-line therapy: Monotherapy with sotalol.

Monotherapy with beta-blocker is inferior to monotherapy with sotalol or combination therapy with amiodarone and beta-blocker (Connolly et al).

Polymorphic ventricular tachycardia and fibrillation in structural heart disease with normal QT interval

First-line therapy: Beta-blockers, amiodarone (150–300 mg i.v. bolus over 10 minutes), or lidocaine (1 mg/kg i.v bolus over 5 minutes). Immediate coronary angiography is indicated when ischemia is a likely cause.

Additional therapies:

Amiodarone or lidocaine.

Deep sedation and mechanical ventilation

Catheter ablation

Neuraxial modulation (Tung et al).

Catecholaminergic polymorphic VT (CPVT) typically responds to beta-blockers. Flecainide can be considered if beta-blockers fail. An ICD must be considered if beta-blockers fail.

Brugada syndrome causes polymorphic VT that responds to quinidine and isoproterenol.

Polymorphic ventricular tachycardia in patients with QT prolongation

Polymorphic ventricular tachycardia occurring during QT prolongation, with the characteristic twisting of the points, is referred to as torsade de pointes (TdP). The risk of degeneration into ventricular fibrillation and cardiac arrest is high. Torsade de pointes is treated as follows:

Magnesium sulfate 2 g i.v, regardless of serum magnesium level. Magnesium injections may be repeated and an infusion should be started.

Replenish serum potassium to levels around 4.5 to 5.0 mmol/L.

Torsade de pointes occurring during bradycardia or long pauses can be counteracted by increasing the heart rate (>70 beats per minute [bpm]):

If the patient has a pacemaker, increase the pacing rate.

In hte absence of a pacemaker, start infusion isoproterenol.

Temporary pacing may be required until isopreterenol can be started.

Lidocaine 1 mg/kg i.v should be considered in all patients with torsade de pointes.

Ventricular arrhythmias in acute coronary syndromes (unstable angina, NSTEMI, STEMI)

The use of beta-blockers in acute coronary syndromes is still debated. Early studies suggested that beta-blockers may limit infarct size and prevent sudden cardiac death (Braunwald et al). Beta-blockers are considered safe in the early phase of acute coronary syndromes (in the absence of acute heart failure), and are likely to reduce the incidence of ventricular arrhythmias (VT, VF) and cardiac arrest. Short-acting beta-blockers can be initiated early (within 48 hours).

Beta-blockers are efficient for the treatment of monomorphic and polymorphic VT.

Revascularization is very important to prevent recurrent ventricular arrhythmias (VT, VF) and sudden cardiac death.

Amiodarone should be considered if beta-blockers and revascularization are insufficient to eliminate the arrhythmias.

Lidocaine is as effective as amiodarone and should be preferred in patients with hypotension (amiodarone may aggravate hypotension and cause cardiogenic shock).

Left ventricular dysfunction

Beta-blockers reduce the risk of sudden cardiac arrest in individuals with heart failure (Packer et al).

Randomized trials have demonstrated that an ICD increases survival in patients with heart failure. Amiodarone is the first-line therapy only if an ICD is not available.

Optimizing heart failure therapy with evidence based drugs (beta-blockers, ARNI, ACEi/ARB, MRA, SGLT2-inhibitors) is presumably the most effective mean for reducing the incdience of ventricular arrhythmias.

Antiarrhythmic drug therapy in inherited arrhythmopathies and channelopathies

Ventricular arrhythmias in arrhythmogenic cardiomyopathies and channelopathies are mostly treated with antiarrhythmic agents.

ARVC (Arrhythmogenic Right Ventricular Cardiomoypathy): ARVC typically causes monomorphic VT. These arrhythmias can be controlled with amiodarone or sotalol.

HCM (Hypertrophic Cardiomoypathy): HCM typically causes atrial fibrillation, atrial flutter and ventricular fibrillation (VF). Ventricular fibrillation is managed with amiodarone.

LQTS (Long QT Syndrome): Several beta-blockers are highly effective; e.g propranolol, nadolol, metoprolol, and bisoprolol. Mexiletine, flecainide, and ranolazine are used in LQT3 syndrome.

Brugada syndrome: ventricular arrhythmias (polymorphic VT) are prevented and treated with quinidine. Acute therapy includes infusion of isoproterenol. An ICD may be warranted.

CPVT (Catecholaminergic polymorphic VT): beta-blockade (preferably nadolol) is first-line therapy and flecainide can be added.

Early repolarization syndrome, short-QT syndrome: quinidine is the first-line therapy.

Treatment of proarrhythmic effects: arrhythmias caused by antiarrhythmic agents

Risk factors: high drug dose, combination therapy with multiple antiarrhythmics, structural heart disease (ischemic heart disease, heart failure, etc), female sex, advanced age, renal failure, liver failure. Antiarrhythmic drugs may unmask underlying genetic arrhythmias (e.g flecainide and Brugada syndrome).

Monitor the heart rhythm, QRS duration and QTc interval when starting antiarrhythmic therapy (compare several 12-lead ECGs before and after administration of the drug). For Class III agents, QT prolongation >60 ms from baseline or QTc >500 ms, T-wave alternans, pronounced T–U wave distortion after a pause, and new ventricular ectopy are risk factors for torsade de pointes (Dan et al). Class IA agents (ajmaline, cibenzoline, disopyramide, pilsicainide, procainamide, quinidine) and Class III agents (amiodarone, dronedarone, dofetilide, ibutilide, sotalol) are most likely to cause torsade de pointes.

Flecainide, propafenone, mexiletine, disopyramide and quinidine are contraindicated in patients with a history of myocardial infarction.

Amiodarone rarely causes TdP.

Digitalis may cause most bradyarrhythmias and tachyarrhythmias, including VT.

Management

Discontinue the offending agent.

Search for and correct ongoing myocardial ischemia, hypokalaemia, hypomagnesemia, bradycardia, QT prolongation.

Treatment of drug-induced TdP:

Magnesium sulfate 2 g i.v, regardless of serum magnesium level. Magnesium injections may be repeated and an infusion should be started.

Replenish serum potassium to levels around 4.5 to 5.0 mmol/L.

Torsade de pointes occurring during bradycardia or long pauses can be counteracted by increasing the heart rate (>70 beats per minute [bpm]):

If the patient has a pacemaker, increase the pacing rate.

In hte absence of a pacemaker, start infusion isoproterenol.

Temporary pacing may be required until isopreterenol can be started.

Lidocaine 1 mg/kg i.v should be considered in all patients with torsade de pointes.

Treatment of arrhythmias caused by class I agents:

First-line therapy: beta-blockers or calcium antagonists (IV) to control ventricular rate. Infusion of sodium bicarbonate may terminate the VT.

Treatment of arrhythmias caused by flecainide:

First-line therapy: beta-blockers.

Arrhythmias due to digitalis toxicity:Administer potassium, aim for high-normal potassium (4.5–5.0 mEq/L).

Administer beta-blockers, lidocaine and/or digitalis-specific antibodies.

Isoproterenol infusion or cardiac pacing is effective when digitalis causes bradyarrhythmias.

Drug manual

Class III antiarrhythmic drugs

Amiodarone

Drug	Amiodarone
Brand names	Nexterone, Pacerone, Cordarone
Indications	Ventricular tachycardia (VT)Ventricular fibrillation (VF)Premature ventricular beats (PVB)Atrial tachyarrhythmias (atrial fibrillation)Cardiopulmonary resuscitation (CPR)
Mechanism of action	Amiodarone is a class III antiarrhythmic agent and prolongs phase 3 of the cardiac action potential.
Receptor targets	INa, ICa, IKr, IK1, IKs, Ito, Beta receptor, Alpha receptor, nuclear T3 receptor
ECG effects	Sinus rate slowedPR prolongedQRS prolongedQTc prolongedAV nodal refractoriness increased
Delivery	IV, PO
Dose	VF/pulseless VT (cardiac arrest): 300 mg IV bolus in 20 ml glucose. May be repeated.Stable VT: 150 mg bolus over 10 minutes, then 1 mg/min over 6 hours, then 0.5 mg/min over 18 hours. The maintenance dose is 0.5 mg/min IV.Daily infusion dose: 1200 mg per 24 hours.Switch to oral regime when ventricular arrhythmias are controlled: 400 mg every 8 to 12 hours for 1–2 weeks, then 300–400 mg daily. If possible, use 200 mg daily PO dose for long-term use. Acquire thyroid function studies if long-term therapy may be needed.
T1/2	Amiodarone has a very long half-life (26-107 days) and persists in the body for months.
Contraindications	Pre-excitation (WPW syndrome)Long QT syndrome (congenital or acquired)
Adverse effects	Cardiac: Bradycardia. Hypotension. Thyreotoxic (hypothyreosis). QT prolongation (torsade de pointes, TdP). AV blocks. Amiodarone may slow VT rate below the programmed ICD detection rate. Amiodarone increases DFT (defibrillation threshold).Other: Corneal microdeposits, thyroid abnormalities, ataxia, nausea, emesis, constipation, photosensitivity, skin discoloration, ataxia, dizziness, peripheral neuropathy, tremor, hepatitis, cirrhosis, pulmonary fibrosis or pneumonitis.
Comparison	Amiodarone resulted in substantially higher rates of survival to hospital admission in a randomized trial comparing amiodarone to lidocaine for shock-resistant out-of-hospital ventricular fibrillation (Dorian et al, NEJM, 2002).

Sotalol

Drug	Sotalol
Brand names	Betapace, Sorine, Sotylize, Sotacor
Indications	VT (ventricular tachycardia)PVC (premature ventricular complexes)VF (ventricular fibrillation)
Mechanism of action	Class III antiarrhythmic agent with beta blocking activity.
Receptor targets	IKr, Beta 1 and 2 receptor
ECG effects	Sinus rate slowedQTc prolongedAV nodal refractoriness increased
Delivery	IV, PO
Dose	IV: 75 mg every 12 hPO: 40–120 mg every 12 h. May increase dose every third day to a maximum of 320 mg/d
T1/2	12 h
Adverse effects	Cardiac: Bradycardia, hypotension, HF, syncope, TdP Other: Fatigue, dizziness, weakness, dyspnea, bronchitis, depression, nausea, diarrheaSotalol decreases defibrillatory threshold.

Beta-blockers

Metoprolol

Drug	Metoprolol
Brand names	Dutoprol, Kapspargo, Lopressor, Lopressor Hct, Toprol, Toprol XL, Seloken
Indications	VT (ventricular tachycardia)PVC (premature ventricular complexes)
Mechanism of action	Lowers blood pressure, reduces heart rate, myocardial oxygen consumption and myocardial contractility. Blocks proarrhythmic sympathetic activity.
Receptor targets	Beta 1 adrenergic receptor blocker.
ECG effects	Sinus rate slowedAV nodal refractoriness increased
Delivery	IV or PO
Dose	IV (emergency): 5 mg every 5 min up to 15 mg.PO (stable patients): 25–200 mg daily of extended release.
T1/2	3–4 h (immediate release).8 hours (extended release).
Adverse effects	Cardiac: Bradycardia, hypotension, AV-block.Other: Dizziness, fatigue, diarrhea, depression, dyspnea.

Nadolol

Drug	Nadolol
Brand names	Corgard
Indications	VT (ventricular tachycardia)PVC (premature ventricular complexes)LQTS (Long QT Syndrome)CPVT (Catecholaminergic Polymorphic VT)
Mechanism of action	Beta 1 and 2 adrenergic blocker. Lowers blood pressure, reduces heart rate, myocardial oxygen consumption and myocardial contractility. Blocks proarrhythmic sympathetic activity.
Receptor targets	Beta 1 and 2 receptors
ECG effects	Sinus rate slowedAV nodal refractoriness increased
Delivery	IV, PO
Dose	PO: 40–320 mg daily
T1/2	20–24 h
Adverse effects	Cardiac: Bradycardia, hypotension, HF, AV-block.Other: Edema, dizziness, cold extremities, bronchospasm.

Esmolol

Drug	Esmolol
Brand names	Brevibloc
Indications	VT (ventricular tachycardia)
Mechanism of action	Beta 1 adrenergic blocker. Lowers blood pressure, reduces heart rate, myocardial oxygen consumption and myocardial contractility. Blocks proarrhythmic sympathetic activity.
Molecular targets	Beta 1 receptors
ECG effects	Sinus rate slowedAV nodal refractoriness increased
Delivery	IV, PO
Dose	IV: 0.5 mg/kg bolus, then 0.05 mg/kg/min infusion.
T1/2	9 minutes
Adverse effects	Bradycardia, hypotension, heart failure, AV-block. Dizziness, nausea.

Bisoprolol

Drug	Bisoprolol
Brand names	Ziac, Zebeta, Emconcor, Bisomyl
Indications	VT (ventricular tachycardia)PVC (premature ventricular complexes)
Mechanism of action	Beta 1 adrenergic blocker. Lowers blood pressure, reduces heart rate, myocardial oxygen consumption and myocardial contractility. Blocks proarrhythmic sympathetic activity.
Molecular targets	Beta 1 receptors
ECG effects	Sinus rate slowedAV nodal refractoriness increased
Delivery	IV, PO
Dose	PO: 2.5–10 mg once daily
T1/2	9–12 h
Adverse effects	Cardiac: Chest pain, bradycardia, AV-block.Other: Fatigue, insomnia, diarrhea

Carvedilol

Drug	Carvedilol
Brand names	Coreg
Indications	VT (ventricular tachycardia)PVC (premature ventricular complexes)LQTS (Long QT Syndrome)
Mechanism of action	Blocks beta 1 and beta 2 adrenergic receptors, and alpha adrenergic receptors. Lowers blood pressure, reduces contractility and blocks the proarrhythmic sympathetic activity.
Molecular targets	Beta 1, beta 2 receptors, alpha receptor.
ECG effects	Sinus rate slowedAV nodal refractoriness increased
Delivery	IV, PO
Dose	PO: 3.125–25 mg every 12 h
T1/2	7–10 h
Adverse effects	Cardiac: Bradycardia, hypotension, AV-block.Other: Edema, syncope, hyperglycemia, dizziness, fatigue, diarrhea

Propranolol

Drug	Propranolol
Brand names	Hemangeol, Hemangiol, Inderal, Innopran
Indications	VT (ventricular tachycardia)PVC (premature ventricular complexes)LQTS (Long QT Syndrome)
Mechanism of action	Blocks beta 1, beta 2 and alpha adrenergic receptors. Lowers blood pressure, reduces contractility and blocks proarrhythmic sympathetic activity. Blocks cardiac sodium channels.
Molecular targets	Beta 1 and 2 receptors, INa
ECG effects	Sinus rate slowedAV nodal refractoriness increased
Delivery	IV, PO
Dose	IV: 1–3 mg q 5 min to a total of 5 mgPO, immediate release: 10–40 mg q 6 hPO, extended release: 60–160 mg q 12 h
T1/2	Immediate release: 3–6 hExtended release: 8–10 h
Adverse effects	Cardiac: Bradycardia, hypotension, heart failure, AV-block.Other: Sleep disorder, dizziness, nightmares, hyperglycemia, diarrhea, bronchospasm.

Acebutolol

Drug	Acebutolol
Brand names	Sectral
Indications	VT (ventricular tachycardia)PVC (premature ventricular complexes)
Mechanism of action	Beta 1 receptor antagonist. Mild intrinsic sympathomimetic activity.
Molecular targets	Beta 1 and 2 receptors, Alpha receptor.
ECG effects	Sinus rate slowed AV nodal refractoriness increased
Delivery	IV, PO
Dose	PO: 200–1200 mg daily or up to 600 mg bid.
T1/2	Active metabolite: 8–13 h. Prolonged in renal impairment.Metabolised in liver. Excreted in feces (60%) and urine (40%).
Adverse effects	Cardiac: Bradycardia, hypotension, HF, AV-blocks.Other: Dizziness, fatigue, anxiety, impotence, hyper/ hypoesthesia

Class IC agents

Lidocaine

Drug	Lidocaine
Synonyms	Lidocaína, Lidocaina, Lidocaine, Lidocainum, Lignocaine
Brand names	Xylocard
Indications	Any VT (ventricular tachycardia), including torsade de pointes (long QT syndrome).Digitalis induced VT.Ventricular fibrillation (VF).
Mechanism of action	Class I-B antiarrhythmic.
Receptor targets	INa
ECG effects	QTc can slightly shorten
Effects	Potent terminator of ventricular arrhythmias.
Delivery	IV
Dose	Loading dose: 1-1.5 mg/kg IV bolus over 2-3 min.Infusion dose: 2 to 4 mg/min.Additional boluses may be given: 0.5 mg/kg repeated every 5-10 minutes.Max cumulative dose: 3 mg/kg
Adverse effects	Lidocaine toxicity: drowsiness; disorientation, paresthesia, twitching, seizures. Toxicity is managed by decreasing dose by 50% (same bolus then infusion 1 mg/min).Cardiac: Bradycardia, hemodynamic collapse, AVB, sinus arrest.Other: Delirium, psychosis, seizure, nausea, tinnitus, dyspnea, bronchospasm

Mexilitine

Drug	Mexilitine
Indications	VT (ventricular tachycardia)PVC (premature ventricular complexes)VT in long QT syndrome (LQT3)Ventricular fibrillation (VF)
Molecular targets	INa
ECG effects	QTc can slightly shorten
T1/2	10–14 h. Metabolized in liver. Excreted in urine.
Delivery	IV
Dose	PO: 150–300 mg q 8 h or q 12 h
Adverse effects	Cardiac: heart failure, AV-blocks.Other: Lightheaded, tremor, ataxia, paresthesias, nausea, blood dyscrasias

Class IC agents

Flecainide

Drug	Flecainide
Brand names	Tambocor
Indications	VT (ventricular tachycardia)PVC (premature ventricular complexes), in the absence of structural heart disease.(CPVT)
Receptor targets	INa, IKr, IKur
ECG effects	PR prolongedQRS prolonged
Delivery	IV, PO
Dose	PO: 50–200 mg q 12 h.
T1/2	7–22 h Metab: H Excr: U
Adverse effects	Cardiac: Sinus node dysfunction, AVB, drug-induced Brugada syndrome, monomorphic VT in patients with a myocardial scar, exacerbation of HFrEF. Flecainide causes increased defibrillation threshold.Other: Dizziness, tremor, vision disturbance, dyspnea, nausea

Propafenone

Drug	Propafenone
Brand names	Rythmol
Indications	VT (ventricular tachycardia)PVC (premature ventricular complexes), in the absence of structural heart disease.
Mechanism of action	Propafenone inhibits sodium channels (INa) to restrict the entry of sodium into cardiac cells, resulting in reduced excitation.
Molecular target	INa, IKr, IKur, Beta receptor, Alpha receptor
ECG effects	PR prolonged QRS prolonged; increased DFT
T1/2	Extensive metabolizers: 2–10 h.Poor metabolizers: 10–32 h.Metabolized in liver. Excreted in urine.
Delivery	IV
Dose	PO:Immediate release: 150–300 mg q 8 hExtended release: 225-425 mg q 12 h
Adverse effects	Cardiac: HF, AVB, drug-induced Brugada syndromeOther: Dizziness, fatigue, nausea, diarrhea, xerostomia, tremor, blurred vision

Class IV agents (Calcium channel blockers)

Diltiazem

Drug	Diltiazem
Synonyms	Diltiazemum
Brand names	Cardizem, Cartia, Matzim, Taztia, Tiadylt, Tiazac
Indications	VT specifically RVOT, idiopathic LVT
Mechanism of action	Diltiazem inhibits the calcium influx into cardiac and vascular smooth muscle during depolarization. Compared to dihydropyridine drugs, such as nifedipine, that preferentially act on vascular smooth muscle and verapamil that directly acts on the heart muscle, diltiazem displays an intermediate specificity to target both the cardiac and vascular smooth muscle. Diltiazem is used as an antihypertensive, antiarrhythmic, and as an antianginal agent.
Molecular targets	INa, IKr, IKur
ECG effects	Sinus rate slowedPR prolongedAV nodal conduction slowed
Delivery	IV, PO
Dose	IV: 5–10 mg every 15–30 min.Extended release, PO: 120–360 mg/day.
T1/2	Injection 2–5 h.Immediate release 4.5 hExtended release 12 hSevere hepatic impairment 14–16 h.Metabolized in liver. Excreted in urine.
Adverse effects	Cardiac: Hypotension, edema, heart failure, AV-blocks, bradycardia, exacerbation of HFrEF.Other: Headache, rash, constipation

Verapamil

Drug	Verapamil
Synonyms	Iproveratril, Vérapamil, Verapamilo, Verapamilum
Brand names	Calan, Isoptin, Isoptin Retard, Tarka, Verelan
Indications	VT (specifically RVOT, verapamilsensitive idiopathic LVT)
Mechanism of action	Verapamil is an L-type calcium channel blocker with antiarrhythmic, antianginal, and antihypertensive effect. Verapamil has a negative inotropic effect and should be avoided in HCM and severe HFrEF. L-type calcium channels are expressed in vascular smooth muscle (affecting vascular resistance) and myocardial tissue (affecting contractility). Verapamil lowers systemic vascular resistance and thus blood pressure. Verapamil also increases the refractory period in the AV node, thereby reducing AV nodal conduction.
Receptor targets	Cardiac L-type calcium channels.
ECG effects	Sinus rate slowed PR prolonged AV nodal conduction slowed
Delivery	IV, PO
Dose	IV: 2.5–5 mg q 15–30 min Sustained release PO: 240–480 mg/d
T1/2	3–7 hMetaoblized in liver. Excreted in urine.
Adverse effects	Cardiac: Hypotension, edema, HF, AVB, bradycardia, exacerbation of HFrEFOther: Headache, rash, gingival hyperplasia, constipation, dyspepsia

Class IA agents

Procainamide

Drug	Procainamide
Synonyms	Procainamida, Procainamide, Procaïnamide, Procainamidum
Brand names	Procan
Indications	VT (ventricular tachycardia), including digitalis induced VT.VF (Ventricular fibrillation)
Receptor targets	INa, IKr
Effects	Procainamide is a sodium channel blocker.
Delivery	IV
Dose	IV, loading dose: 10–17 mg/kg at 20–50 mg/minMaintenance dose: 1–4 mg/minPO (SR preparation): 500–1250 mg q 6 h
T1/2	2–5 h.Prolonged in renal dysfunction.
Adverse effects	Cardiac: TdP; AVB, hypotension and exacerbation of HFrEFOther: Lupus symptoms, diarrhea, nausea, blood dyscrasias

Other agents

Magnesium

Drug	Magnesium
Indications	VF (ventricular fibrillation)VT (ventricular tachycardia)Should be used in most patients with long QT syndrome (LQTS) with ventricular arrhythmias.
Mechanism of action	Electrolyte with antiarrhythmic effects, regardless of blood magnesium levels.
Effects	Membrane stabilization.
Delivery	IV
Dose	20 mmol IV over 20 min, then 20 mmol every 20 hour.

Bretylium

Drug	Bretylium
Brand names	VF (ventricular fibrillation)VT (ventricular tachycardia)
Mechanism of action	Bretylium inhibits the release of norepinephrine. Bretylium is used for the prophylaxis and therapy of ventricular fibrillation (VF) and ventricular tachycardia (VT).
Effects	Bretylium blocks the release of noradrenaline from the peripheral sympathetic nervous system by inhibiting voltage-gated K+ channels and, possibly, the Na-K-ATPase.
Delivery	IV
Dose	Injection (undiluted): 5 mg/kg by rapid injection; if arrhythmia persists, may increase dose to 10 mg/kg and repeat as necessary.Infusion (diluted): 1-2 mg/min; alternatively, 5-10 mg/kg IV over at least 8 min repeated every 6 hour.

References

Schleifer JW, Sorajja D, Shen W. Advances in the pharmacologic treatment of ventricular arrhythmias. Expert Opin Pharmacother 2015;16:2637–51.

Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Com. Europace 2006;8:746–837.

Priori SG, Blomstro ̈ m-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Europace 2015;17:1601–87.

Tung R, Vaseghi M, Frankel DS, Vergara P, Di Biase L, Nagashima K et al. Freedom from recurrent ventricular tachycardia after catheter ablation is associated with improved survival in patients with structural heart disease: an International VT Ablation Center Collaborative Group Study. Heart Rhythm 2015;12:1997–2007.

Connolly SJ, Dorian P, Roberts RS, Gent M, Bailin S, Fain ES et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA 2006;295:165–71.

Kudenchuk PJ, Newell C, White L, Fahrenbruch C, Rea T, Eisenberg M. Prophylactic lidocaine for post resuscitation care of patients with out-ofhospital ventricular fibrillation cardiac arrest. Resuscitation 2013;84:1512–8.

Eugene Braunwald, Robert A Kloner.. Intravenous Beta-Blockade for Limiting Myocardial Infarct Size: Rejuvenation of a Concept. J Am Coll Cardiol. 2016 May 10;67(18):2105-2107.

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Chapter 2: Inotropes and Vasopressors: Doses, indications, contraindications and effects

Inotropes and vasopressors

Vasopressors induce vasoconstriction and increase mean arterial pressure (MAP). Inotropes increase cardiac contractile force (contractility). Several endogenous and synthetic agents exist and are frequently combined to achieve the desired hemodynamic outcome. Most agents exhibit both vasopressor and inotropic effects (Figure 1). Below follows a drug manual for use in the CCU (coronary care unit), ICU (intensive care unit) or ER (emergency room). Careful electrocardiographic and hemodynamic monitoring with ECG, central vein catheter and intra-arterial catheter (A-line) is warranted.

Overview of vasopressors and inotropes

Inotropes and vasopressors.

Table 1. Drug manual for inotropes and vasopressors

Drug	Indications	Dose	α1 effect	β1 effect	β2 effect	D1/D2 effect	Result	Side Effects
Dopamine – low dose	Rarely used	Low dose: 0.5-3.0 μg/kg/min	+	+	+	+++++	Low dose dopamine stimulates D1 receptors and induces vasodilation in coronary, renal, cerebral and mesenteric vessels.	Few
Dopamine – medium dose	Cardiogenic shockVasodilatory shockHeart failure (HF), acuteHeart failure (HF), chronicBradycardia (second-line alternative)	Medium dose: 3.0-10.0 μg/kg/min.	+	++++	+	+++++	Medium dose dopamine activates β1, releases norepinephrine and thus increases contractility, chronotropy and mild increase in SVR.	Ventricular arrhythmiasMyocardial ischemia Tissue ischemia (high doses or extravasation)
Dopamine – high dose	Cardiogenic shockVasodilatory shockHeart failure (HF), acuteHeart failure (HF), chronicBradycardia (second-line alternative)	High dose: 10.0-20.0 μg/kg/min.	++++	++++	++	+++++	Hig dose dopamine additionally induces α1 stimulation and thus vasoconstruction and pronounced increase in SVR.	As medium dose, and additionally severe hypertension (caution if patient on nonselective beta-blockers).
Dobutamine	Cardiogenic shockBradycardia (second-line therapy)Stress testing (due to induced increase in myocardial O2 consumption)	Regular: 2.0–20 μg/kg/minMax: 40 μg/kg/min	+	+++++	+++	0	Potent inotrope with slight chronotropic effect. Doses <5 μg/kg/min induces mild vasodailation. Doses >5 μg/kg/min induces vasoconstriction, which dominates at dosease >15 μg/kg/min.	TachycardiaIncreased ventricular rate in AFVentricular arrhythmias Cardiac ischemia Hypertension (in patients on nonselective β-blocker)Tolerance after a few days
Norepinephrine	Shock (any)Hypotension (any)	0.01–3.0 μg/kg/minSafe for peripheral use	+++++	+++	++	0	Potent vasoconstrictor with mild inotropic effect. Increases systolic pressure, diastolic pressure and pulse pressure with minimal effect on CO. Minimal chronotropic effect. Increases coronary blood flow.	Atrial or ventricular arrhythmias BradycardiaPeripheral (digital) ischemiaHypertension (especially nonselective β-blocker patients)Prolonged use may be cardiotoxic.
Epinephrine	Shock (any)Cardiac arrestBronchospasmAnaphylaxisBradycardia (second-line alternative)	Infusion: 0.01 to 0.10 μg/kg/minBolus: 1 mg IV every 3 to 5 min (max 0.2 mg/kg) IM: (1:1000): 0.1 to 0.5 mg (max 1 mg)Safe for peripheral use	+++++	++++	+++	N/A	Beta-effect more pronounced at low doses. Alpha-effect pronounced at higher doses. Coronary flow enhanced.Pulm vasoconstriction.Increased pulmonary blood flow.	Ventricular arrhythmias Severe hypertension resulting in cerebrovascular hemorrhage Cardiac ischemia Sudden cardiac deathProlonged use may be cardiotoxic.
Isoproterenol	Bradycardia (first-line therapy)Bradycardia causing torsade de pointesBrugada syndrome	2.0–10.0 μg/minSafe for peripheral use	0	+++++	+++++	0	Powerful chronotropic and inotropic effect. Potent systemic vasodilation. Mild pulmonary vasodilation. No effect on CO.	Ventricular arrhythmias Cardiac ischemia Hypertension Hypotension
Phenylephrine	Typically used as emergency bolus to correct acute hypotension.Hypotension (any)Used to increase MAP during hypotension in aortic stenosis.Used to decrease LVOT gradient in HCMUsed to correct hypotension caused by the simultaneous ingestion of sildenafil and nitrates	Bolus: 0.1 to 0.5 mg IV every 10 to 15 minInfusion: 0.4 to 9.1 μg/kg/minSafe for peripheral use	+++++	0	0	N/A	Immediate and pronounced increase in MAP.	Reflex bradycardia Hypertension (especially with nonselective β-blockers)Severe peripheral and visceral vasoconstriction Tissue necrosis with extravasation
Milrinone (Phosphodiesterase Inhibitor)	Heart failure, acuteHeart failure, decompensated chronic.	Bolus: 50 μg/kg bolus over 10 to 30 minInfusion: 0.375 to 0.75 μg/kg/min.	0	0	0	0	PDI (Phosphodiesterase Inhibitor).Potent inotrope.Induces vasodialtion.Results in reduced preload, afterload and SVR.	Ventricular arrhythmias HypotensionMyocardial ischemiaTorsade des pointesAccumulates in renal failure (dose adjustment necessary)
Amrinone	Heart failure, acuteHeart failure, decompensated chronic	Bolus: 0.75 mg/kg over 2 to 3 min Infusion: 5 to 10 μg · kg−1 · min−1	0	0	0	0	PDI (Phosphodiesterase Inhibitor). Rarely used due to side effects.	Arrhythmias, enhanced AV conductionHypotension Thrombocytopenia Hepatotoxic
Vasopressin	Shock (any)Cardiac arrest	Infusion: 0.01–0.1 U/min (common fixed dose 0.04 U/min)Bolus (IV): 40 U	0	0	0	0	Vasopressin stimulates V1 receptors (vascular smooth muscle) and V2 (renal). V1 stimulation induces vasoconstriction, and V2 increases renal water reabsorption. Vasopressin increases SVR with no significant effect on CO. Vasopressin potentiates the vascular effect of norepinephrine.	Arrhythmias Hypertension Decreased CO (at doses >0.4 U/min) Cardiac ischemia Severe peripheral vasoconstriction causing ischemia (especially skin) Splanchnic vasoconstriction
Levosimendan	Heart failure, decompensated chronic	Loading dose: 12–24 μg/kg over 10 min Infusion: 0.05–0.2 μg/kg/min	0	0	0	0	Levosimendan is a calcium sensitizer that enhances ventricular contractility and induces peripheral arteriolar and venous vasodilation.	Enhanced AV conductionHypotension

Receptors of catecholamines

Alpha-1 adrenergic receptors: expressed in vascular smooth muscle cells, activation leads to vasoconstriction and increased SVR.

Beta-1 adrenergic receptors: expressed in the myocardium; excitation results in increased contractile force (contractility) and increased chronicity.

Beta-2 adrenergic receptors: expressed in the vascular smooth musle cells and leads to vasodilation.

D1 and D2 (Dopamine receptors): Excitation of D1 and D2 dopaminergic receptors in the kidney and splanchnic vasculature induces renal and mesenteric vasodilation.

NB: Rapid blood pressure alterations may induce reflexive autonomic responses that affect the final hemodynamic result.

Dobutamine is a synthetic catecholamine.

References

Overgaard, Dzavik et al. Inotropes and Vasopressors: Review of Physiology and Clinical Use in Cardiovascular Disease. Circulation 2011.

Jentzer et al. Pharmacotherapy Update on the Use of Vasopressors and Inotropes in the Intensive Care Unit. J Cardiovasc Pharmacol Therap (2014).

Müllner M, Urbanek B, Havel C, et al. Vasopressors for shock. Cochrane Database Syst Rev 2004

Ballieu P, Besharatian Y, Ansari S. Safety and Feasibility of Phenylephrine Administration Through a Peripheral Intravenous Catheter in a Neurocritical Care Unit. J Intensive Care Med 2021; 36:101.

Lherm T, Troché G, Rossignol M, et al. Renal effects of low-dose dopamine in patients with sepsis syndrome or septic shock treated with catecholamines. Intensive Care Med 1996; 22:213.

Unverferth DA, Blanford M, Kates RE, Leier CV. Tolerance to dobutamine after a 72 hour continuous infusion. Am J Med 1980; 69:262.

Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med 1995; 333:1025.

Gregory JS, Bonfiglio MF, Dasta JF, et al. Experience with phenylephrine as a component of the pharmacologic support of septic shock. Crit Care Med 1991; 19:1395.

De Backer D, Creteur J, Silva E, Vincent JL. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best? Crit Care Med 2003; 31:1659.

MacGregor DA, Smith TE, Prielipp RC, et al. Pharmacokinetics of dopamine in healthy male subjects. Anesthesiology 2000; 92:338.

Löllgen H, Drexler H. Use of inotropes in the critical care setting. Crit Care Med 1990; 18:S56.

Steel, A, Bihari, D . Choice of catecholamine: does it matter? Curr Opin Crit Care 2000; 6:347.

Hannemann L, Reinhart K, Grenzer O, et al. Comparison of dopamine to dobutamine and norepinephrine for oxygen delivery and uptake in septic shock. Crit Care Med 1995; 23:1962.

Al-Hesayen A, Azevedo ER, Newton GE, Parker JD. The effects of dobutamine on cardiac sympathetic activity in patients with congestive heart failure. J Am Coll Cardiol 2002; 39:1269.

De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010; 362:779.

Mutlu GM, Factor P. Role of vasopressin in the management of septic shock. Intensive Care Med 2004; 30:1276.

Sharshar T, Blanchard A, Paillard M, et al. Circulating vasopressin levels in septic shock. Crit Care Med 2003; 31:1752.

Tsuneyoshi I, Yamada H, Kakihana Y, et al. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med 2001; 29:487.

Dünser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation 2003; 107:2313.

Kill C, Wranze E, Wulf H. Successful treatment of severe anaphylactic shock with vasopressin. Two case reports. Int Arch Allergy Immunol 2004; 134:260.

Schummer C, Wirsing M, Schummer W. The pivotal role of vasopressin in refractory anaphylactic shock. Anesth Analg 2008; 107:620.

McIntyre WF, Um KJ, Alhazzani W, et al. Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With Atrial Fibrillation in Patients With Distributive Shock: A Systematic Review and Meta-analysis. JAMA 2018; 319:1889.

Albanèse J, Leone M, Delmas A, Martin C. Terlipressin or norepinephrine in hyperdynamic septic shock: a prospective, randomized study. Crit Care Med 2005; 33:1897.

Kam PC, Williams S, Yoong FF. Vasopressin and terlipressin: pharmacology and its clinical relevance. Anaesthesia 2004; 59:993.

O’Brien A, Clapp L, Singer M. Terlipressin for norepinephrine-resistant septic shock. Lancet 2002; 359:1209.

Leone M, Albanèse J, Delmas A, et al. Terlipressin in catecholamine-resistant septic shock patients. Shock 2004; 22:314.

Rodríguez-Núñez A, Fernández-Sanmartín M, Martinón-Torres F, et al. Terlipressin for catecholamine-resistant septic shock in children. Intensive Care Med 2004; 30:477.

Morelli A, Rocco M, Conti G, et al. Effects of terlipressin on systemic and regional haemodynamics in catecholamine-treated hyperkinetic septic shock. Intensive Care Med 2004; 30:597.

Polito A, Parisini E, Ricci Z, et al. Vasopressin for treatment of vasodilatory shock: an ESICM systematic review and meta-analysis. Intensive Care Med 2012; 38:9.

Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA 2016; 316:509.

Malay MB, Ashton JL, Dahl K, et al. Heterogeneity of the vasoconstrictor effect of vasopressin in septic shock. Crit Care Med 2004; 32:1327.

Kahn JM, Kress JP, Hall JB. Skin necrosis after extravasation of low-dose vasopressin administered for septic shock. Crit Care Med 2002; 30:1899.

Leather HA, Segers P, Berends N, et al. Effects of vasopressin on right ventricular function in an experimental model of acute pulmonary hypertension. Crit Care Med 2002; 30:2548.

Dünser MW, Mayr AJ, Tür A, et al. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med 2003; 31:1394.

Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877.

Jeon K, Song JU, Chung CR, et al. Incidence of hypotension according to the discontinuation order of vasopressors in the management of septic shock: a prospective randomized trial (DOVSS). Crit Care 2018; 22:131.

Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med 2021; 49:e1063.

Landoni G, Lomivorotov VV, Alvaro G, et al. Levosimendan for Hemodynamic Support after Cardiac Surgery. N Engl J Med 2017.

Mehta RH, Leimberger JD, van Diepen S, et al. Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery. N Engl J Med 2017.

Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med 2017; 377:419.

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Chapter 3: Levosimendan (Simdax, Simendan) in acute heart failure

Key points

Levosimendan alleviates heart failure symptoms, increases cardiac output, and lowers pulmonary artery pressure without increasing myocardial oxygen consumption. The inotropic effect of levosimendan is not affected by the concurrent use of beta-blockers. The vasodilating effect reduces preload and afterload, further reducing myocardial workload.

Levosimendan is used in severe acute or chronic heart failure.

Consider urgent angiography in patients with unknown etiology for acute severe heart failure.

A recent echocardiographic examination should be available or performed urgently to evaluate ventricular and valvular function.

Levosimendan drug is generally well-tolerated. Severe adverse effects are less common.

Levosimendan may be administered simultaneously with milrinone. The drugs can also be given sequentially.

Hypotension can be counteracted with simultaneous administration of norepinephrine.

All patients with severe acute heart failure who receive levosimendan should be monitored invasively (e.g. arterial line, PiCCO, central venous catheter).

The hemodynamic effects persist for 7–10 days after the end of infusion.

Refer to Table 2 for a comparison between levosimendan, milrinone and dobutamine.

Mechanisms of action

Levosimendan exhibits both inotropic and vasodilatory effects. The drug exerts its effects through three pharmacological mechanisms: (1) augmentation of myocardial contractility via calcium sensitization of troponin C; (2) vasodilatory actions; and (3) modulation of sarcolemmal and mitochondrial potassium-ATP channels. Levosimendan alleviates heart failure symptoms, increases cardiac output, and lowers pulmonary artery pressure without increasing myocardial oxygen consumption. The inotropic effect of levosimendan is not affected by the concurrent use of beta-blockers. The vasodilating effect reduces preload and afterload, further reducing myocardial workload.1

The pharmacokinetic profile of levosimendan is modulated by the presence of an active metabolite, which exerts sustained hemodynamic effects for up to 2 weeks. The peak vasodilatory effect is observed between 2-4 days following the infusion. This delayed onset is attributable to its active metabolite, which reaches maximum plasma concentration approximately 48 hours after the infusion has been completed. Furthermore, the blood pressure-lowering effect persists for a duration of 3 to 4 days post-infusion, thereby providing extended therapeutic benefits.2

Infusion of levosimendan can be repeated at 2-6 weeks intervals, or more frequently, as individually appropriate.3

Important study: Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock (N Engl J Med 2021; 385:516-525) In a randomized, double-blind study involving 192 patients with cardiogenic shock, researchers compared the effectiveness of milrinone and dobutamine. The primary composite outcome included in-hospital mortality, resuscitated cardiac arrest, cardiac transplantation or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack or stroke, and initiation of renal replacement therapy. The study found no significant differences between the two treatment groups with respect to either the primary or secondary outcomes. Primary outcome events occurred in 49% of patients in the milrinone group and 54% in the dobutamine group, with a relative risk of 0.90 (95% CI: 0.69 to 1.19; P=0.47). The study suggests that in cardiogenic shock, milrinone and dobutamine offer comparable therapeutic efficacy and safety profiles, and thus the selection between them may be guided by individual patient needs rather than by a distinct advantage of one drug over the other. Mathew et al. Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock. N Engl J Med 2021; 385:516-525

Indications

Severe left ventricular failure, acute or chronic.

Severe biventricular failure, acute or chronic.

Severe left ventricular failure post-myocardial infarction.

Low cardiac output states or cardiogenic shock post cardiac surgery or percutaneous coronary or valvular interventions.

Cardiogenic shock refractory to high doses of dobutamine (>5 µg/kg/min for >24 h).

Adverse effects

5% of normotensive patients develop hypotension.

Premature ventricular beats and short bursts of ventricular tachycardia (VT) are common, particularly when levosimendan is administered at doses exceeding the recommendations.

QT interval prolongation, particularly at doses exceeding the recommendations.

High doses may cause a drop in hemoglobin concentration.

Hypokalemia is common, particularly at higher doses.

Should severe adverse events occur, a decrease in the infusion rate or discontinuation of the infusion may be warranted.

Contraindications

Hypersensitivity to levosimendan

Severe hypotension (consider initiating norepinephrine infusion in order to continue levosimendan).

Severe tachycardia.

Severe outflow obstruction (e.g. aortic stenosis, mitral stenosis, LVOT obstruction).

History of torsade de pointes (TdP).

Renal failure (eGFR <30 ml/min) is a relative contraindication. Levosimendan is considered in urgent scenarios, or when renal failure is a direct consequence of heart failure.

Hepatic failure is a relative contraindication.

Caution

Hypotension or risk of hypotension.

Rapid atrial fibrillation or sinus tachycardia.

Ventricular arrhythmias.

Hepatic or renal failure may result in elevated plasma concentrations of levosimdenan.

Correction of potassium levels (particularly hypokalemia) is warranted before administration of levosimendan.

Anemia may be exacerbated by levosimendan, which may aggravate myocardial ischemia.

Monitoring

ECG monitoring is required in all patients receiving levosimendan.

ST segment monitoring should be used in suspicion of ongoing myocardial ischemia.

An arterial line for invasive blood pressure monitoring is recommended for all patients receiving levosimendan due to acute heart failure.

Consider a central venous catheter to measure central venous pressure (CVP) or establish a PiCCO for advanced hemodynamic monitoring.

Dosage and administration

A loading dose is not required.

Levosimendan should be administered over 24 hours. Longer infusions are unlikely to further improve hemodynamic status.

No dose adjustment is required in mild to moderate renal failure or during RRT (renal replacement therapy).

Hemodynamic responses should be evaluated 30 to 60 minutes following the initiation of the infusion. The starting dosage is set at 0.1 µg/kg/min. If the initial assessment indicates that the dose is excessively high, it can be reduced to 0.05 µg/kg/min. The dosage may be increased to 0.2 µg/kg/min if required.

Route: Central route is preferred but a large dedicated peripheral line is accepted.

Administration

One vial of levosimendan is adequate for treatment in the majority of cases. Patients >90 kg (>200 lbs) may require a second vial in order to complete the 24 hour infusion.

Vials: Levosimendan 2.5 mg/ml in 5 ml vials (12.5 mg per vial).

Dilution: 5 ml levosimendan is added to 245 ml glucose 5%; resulting in a concentration of 0.05 mg/ml.

Table 1. Infusion rate for levosimendan 0.05 mg/ml

Body weight (kg / lbs)	0.05 µg/kg/min	0.1 µg/kg/min	0.2 µg/kg/min
	Reduced dose	Normal dose	Increased dose
40 kg / 90 lbs	2 ml/h	5 ml/h	10 ml/h
50 kg / 110 lbs	3 ml/h	6 ml/h	12 ml/h
60 kg / 132 lbs	4 ml/h	7 ml/h	14 ml/h
70 kg / 155 lbs	4 ml/h	8 ml/h	17 ml/h
80 kg / 180 lbs	5 ml/h	10 ml/h	19 ml/h
90 kg / 200 lbs	5 ml/h	11 ml/h	22 ml/h
100 kg / 220 lbs	6 ml/h	12 ml/h	24 ml/h
110 kg / 240 lbs	7 ml/h	13 ml/h	26 ml/h
120 kg / 260 lbs	7 ml/h	14 ml/h	29 ml/h

Table 2. Comparison of levosimendan, dobutamine and milrinone.

	Levosimendan	Dobutamine	Milrinone
Mechanism	Calcium sensitizer	Beta-1 adrenergic agonist	Phosphodiesterase 3 inhibitor
Effect on intracellular calcium level	None	Increased calcium level	Increased calcium level
Inotrope	Yes	Yes	Yes
Vasodilator	Yes:– Coronary– Systemic– Pulmonary	– Mild systemic vasodilation	Yes:– Pulmonary– Systemic
Myocardial oxygen consumption	Not affected.	Increased.	Not affected.
Arrhythmogenic potential	Rare (less than dobutamine). May be due to QT prolongation.	Less than milrinone. Ventricular and supraventricular arrhythmias.	Ventricular and supraventricular arrhythmias are common (>10%).
Hemodynamic effects	Increased contractility, lower preload, lower afterload, blood-pressure lowering.	Increases cardiac output by increased contractility and (to some extent) heart rate.	Increases cardiac output by improving myocardial contractility and inducing vasodilation.
Compatilibity with beta-blockers	Yes.	Yes, but effects may be attenuated when used alongside beta-blockers.	Yes.
Adverse effects	Headache. Hypotension. Premature ventricular beats, QT prolongation, hypokalemia, hemoglobin drop.	Increased heart rate, arrhythmias, increased myocardial oxygen consumption. Hypertension.	Headache. Hypotension. Ventricular arrhythmias. Thrombocytopenia
Drug interactions	None significant	None significant	Few significant

References

Follath F et al. Dose ranging study and safety with iv levosimendan in low output heart failure:Experience in three pilot studies and outline of the levosimendan infusion versus dobutamine (LIDO)trial. Am J Cardiol 1999; 83: 211 – 251.

Summary of product characteristics, Simdax, Orion Pharma. Last updated 03/10/2016 accessed viawww.simdax.com on 26/04/2018

Injectable Medicines Guide Levosimendan monograph accessed via http://www.injguide.nhs.uk26/04/2018

(none)

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Chapter 4: Hypertensive emergency (crisis)

This drug manual is provided for use in patients with hypertensive emergency (also referred to as hypertensive crisis or malignant hypertension). Hypertensive emergency is defined as significantly elevated blood pressure (systolic pressure ≥180 mmHg and/or diastolic pressure ≥120 mmHg) with concurrent signs of acute organ damage or failure. Any of the drugs listed below may be used to treat hypertensive emergencies. The desired time to action, contraindications and risk of adverse effects should guide the choice of agent.

Calcium channel blockers (CCB)

Clevidipine

Drug	Clevidipine
Brand names	Cleviprex ®
Indications	Hypertension and hypertensive emergency.Treatment of postoperative hypertension.
Mechanism of action	Ultra-short acting calcium channel blocker (CCB).Half-life: 5 minutes. Rapidly inactivated by esterases.
Effects	• Clevidipine is a dihydropyridine L-type calcium channel blocker. Clevidipine is highly selective for vascular smooth muscle cells and has little or no effect on myocardial contractility or conduction. Clevidipine reduces mean arterial blood pressure (MAP) by decreasing systemic vascular resistance (SVR). Clevidipine does not reduce cardiac filling pressure (pre-load), since it has no effects on the venous capacitance vessels. Hence, Clevidipine reduces blood pressure without affecting cardiac filling pressures.• Clevidipine is more effective than nitroglycerin, nitroprusside, and nicardipine in hypertensive emergencies.
Time to onset of action	2-4 minutes
Duration of action	5-15 minutes
Delivery	IV (infusion).
Dose	Initial dose: 1-2 mg/h iv.Increase as necessary. Rapid titration is possible.Maximum dose: 21 mg/h iv.Common therapeutic dose: 4-6 mg/h.Clevidipine is administered in lipid emulsion (containing soy, egg), of which the maximum dose per 24 hours is 1000 mL.
Adverse effects	Headache. Nausea. Fever. Atrial fibrillation. Worsening of heart failure.
Caution	• Used cautiously in patients with acute heart failure.• Clevidipine can cause reflex tachycardia.• Contraindicated in severe aortic stenosis due to risk of hypotension.

Nicardipine

Drug	Nicardipine
Brand names	Cardene ®
Indications	Hypertension, hypertensive emergency/crisis.Pregnancy induced hypertension.Angina pectorisPrinzmetal’s angina
Mechanism of action	Nicardipine is a dihydropyridine calcium-channel blocker (CCB). Nicardipine inhibits the influx of extracellular calcium in the myocardial and peripheral vascular smooth muscle cell membranes, thus inhibiting the contraction of smooth muscle cells. As compared with nitroprusside, nicardipine induces relatively greater venodilation than arteriolar dilation.
Effects	Nicardipine causes dilation of the coronary and systemic arteries, decreases total peripheral resistance, decreases systemic blood pressure, and decreases afterload. Nicardipine has antianginal and antihypertensive effects.
Time to onset of action	5 to 15 minutes
Duration of action	1.5 to 5 hours
Delivery	IV
Dose	5–15 mg/hour IV infusion.Higher doses (up to 30 mg/hour) may be required in some patients.
Adverse effects	Tachycardia. Headache. Flushing. Edema. Dizziness.
Caution	Should be used cautiously in patients with myocardial ischemia and/or heart failure.

ACE-inhibitors

Enalaprilat

Enalaprilat is rarely used in hypertensive crisis due to its slow onset, prolonged duration of effect, and significant individual variations in its effect.

Drug	Enalaprilat
Brand names	Vasotec IV ®
Indications	Hypertension and hypertensive emergency.Acute left ventricular failure.
Mechanism of action	Enalaprilat is the active metabolite (ester) of enalapril, an angiotensin-converting enzyme (ACE) inhibitor. Enalaprilat lowers blood pressure by inhibiting ACE.
Effects	• The hypotensive effect of enalaprilat depends on plasma volume and plasma renin activity. Volume depletion and high plasma renin activity increase the effect of enalaprilat, and may cause severe hypotension.
Time to onset of action	15 to 30 minutes.
Peak effect	Within hours.
Duration of effect	8 to 24 hours
Delivery	IV
Dose	Initial dose: 1.25 mg iv.Increase as necessary.Maximum dose: 5 mg iv every six hours.
Adverse effects	Severe hypotension.
Contraindications	• Contraindicated in pregnancy, severe renal artery stenosis, severe hyperkalemia.• Avoid in acute heart failure and acute myocardial infarction.

Beta-blockers

Esmolol

Drug	Esmolol
Brand names	Brevibloc ®
Indications	Short-term control of ventricular rate (including perioperative tachycardia) and hypertension (including hypertensive emergency, perioperative hypertension).
Mechanism of action	• Relatively cardioselective (beta-1 receptor blocker) beta-blocker with ultra-short acting effect.• Half-life: 9 minutes.
Effects	• Esmolol is a beta-adrenergic receptor blocker.• Esmolol lowers blood pressure immediately (within 1 minute)• Esmolol may also be used to control supraventricular tachycardia (rate control).• Esmolol may be used to reduce myocardial ischemia in the CCU or ICU.
Time to onset of action	1 minute
Duration of action	20-30 minutes
Delivery	IV
Dose	Loading dose: 500 μg/kg bolus over 1 minute.Infusion start dose: 25–50 μg/kg/min.Maximum infusion dose: 300 μg/kg/min.Bolus doses of 300 μg/kg can be repeated during infusion.
Adverse effects	Flushing. Nausea. Bronchospasm. AV-block.
Caution	• Avoid in acute heart failure.• May cause bradycardia.

Labetalol

Drug	Labetalol
Brand names	Trandate ®
Indications	Mycoardial ischemia. Hypertension.Hypertensive emergency, including in pregnancy.Postoperative hypertension.
Mechanism of action	Combined beta-adrenergic and alpha-adrenergic blocker with rapid onset of action. Labetalol has less antihypertensive efficacy as compared with nicardipine. Labetalol is safe in patients with coronary artery disease since it does not increase heart rate, and reduces myocardial oxygen consumption.Time to onset of action: 5 minutes.
Effects	Lowers blood pressure, reduces heart rate, myocardial oxygen consumption and myocardial contractility.
Time to onset of action	5 to 10 minutes
Duration of action	2 to 4 hours
Delivery	IV
Dose	Can be given as repeated intravenous bolus injections or as a constant-dose infusion.Bolus regime:• 20 mg IV bolus over 2 minutes, followed by 20 to 80 mg every 10 minutes to a total dose of 300 mg.Infusion regime: • 0.5–2 mg/minute IV infusion.Higher doses are sometimes required.
Adverse effects	Vomiting. Dizziness. Nausea. Atrioventricular blocks (AV-blocks). Orthostatic hypotension. Paresthesias (scalp tingling). Bronchospasm.
Caution	• Avoided in hypertensive emergencies with left ventricular failure (due to negative inotropic effect).• Used cautiously in patients with asthma (due to risk of bronchospasm).• Used cautiously in bradycardia due to negative chronotropic effect.• In patients with pheochromocytoma, cocaine or methamphetamine overdose, prior treatment with alpha blockade is necessary before administering labetalol (risk of elevating blood pressure in these settings).

Metoprolol

Drug	Metoprolol
Brand names	Dutoprol ®, Kapspargo ®, Lopressor ®, Lopressor Hct ®, Toprol ®, Seloken ®
Indications	Mycoardial ischemia.Perioperative hypertension.
Mechanism of action	Beta-1 adrenergic blocker.
Effects	Lowers blood pressure, reduces heart rate, myocardial oxygen consumption and myocardial contractility. Less pronounced blood pressure lowering effect than esmolol and labetalol.
Time to onset of action	20 minutes
Duration of action	5 to 8 hours
Delivery	IV
Dose	1.25 to 5 mg IV followed by 2.5–15 mg IV every 3 to 6 hours.
Adverse effects	Vomiting. Dizziness. Nausea. Atrioventricular blocks (AV-blocks). Orthostatic hypotension. Paresthesias (scalp tingling). Bronchospasm.
Caution	• Avoided in hypertensive emergencies with acute heart failure.• Used cautiously in patients with asthma (due to risk of bronchospasm).• Used cautiously in bradycardia due to negative chronotropic effect.

Dopamin receptor agonists

Fenoldopam

Drug	Fenoldopam
Brand names	Corlopam ®
Indications	Short term management of hypertension, including hypertensive emergency.
Mechanism of action	• Systemic Dopamine-1 (D1) receptor agonist.• Lowers blood pressure while maintaining or increasing kidney perfusion.
Effects	Dopamine-1 receptor agonists lower systemic blood pressure and increase renal perfusion.
Time to onset of action	50 to 10 minutes
Duration of action	30 to 60 minutes
Delivery	IV
Dose	Initial infusion dose: 0.1 μg/kg/minute iv.Titrated at 15 minutes intervals.Maximum infusion dose: 1.6 μg/kg/minute
Adverse effects	Headache. Flushing. Tachycardia. Nausea. Hypokalemia. Increased intra-ocular pressure in patients with glaucoma.
Caution	Used cautiously in patients with glaucoma or increased intracranial pressure.

Alpha-agonists

Clonidine

Drug	Clonidine
Brand names	Catapresan ®, Catapres ®, Dixarit ®, Catapres-TTS ®, Catapres-TTS-1 ®, Duraclon ®, Kapvay ®
Indications	• Agitated delirium• Analgesia• Hypertension, hypertensive crisis/emergency
Mechanism of action	Clonidine is primarily a centrally acting alpha-2 agonist. Stimulation of alpha-2 adrenoceptors in the ventromedial and rostral-ventrolateral areas of the medulla result in the blood pressure lowering effect.
Effects	Potent blood pressure lowering effect.Pain relief.
Delivery	IV, IM, PO, transdermal
Dose	Injection IV:• 150 μg in 1 ml vial. Dilute with 10 ml of normal saline and give by slow injection over 5-10 minutes. Dilute immediately before use.PO:Alternatives: Dixarit 25 μg tablets. Catapress 150 μg tablets.Dose: 75 μg daily increased as required to up to 900 μg/day.Transdermal (one patch lasts for a week):• Catapress TTS-1 (0.1 mg/24hrs).• Catapress TTS-2 (0.2 mg/24hrs)• Catapress TTS-3 (0.3 mg/24hrs)Dosage in renal failure and renal replacement therapy: Dose as in normal renal function
Adverse effects	Excessive sedation. Confusion. Hallucinations. Hypotension. Bradycardia. AV-block. Constipation
Contra indications	Bradycardia.
Caution	• Clonidine may induce severe hypotension.• Clonidine is not recommended in most patients with severe cardiovascular disease or in those who are otherwise haemodynamically unstable. The benefit of its administration in these patients should be carefully balanced against the potential risks resulting from hypotension.• Withdrawal of clonidine may lead to rebound hypertension. Withdraw slowly.• Simultaneous use of tricyclic antidepressants reduces the effect of clonidine.• Clonidine increases the CNS-depressive effects of alcohol and sedatives.

Nitric oxide (NO) inducing drugs

Nitroglycerin

Patients using nitroglycerin regularly may have developed tolerance and require higher doses, alternatively nitroprusside to achieve desirable blood pressure lowring effect.

Drug	Nitroglycerin
Brand names	Gonitro ®, Minitran ®, Mylan-nitro ®, Nitro-bid ®, Nitro-dur ®, Nitroject ®, Nitrolingual ®, Nitromist ®, Nitrostat ®, Rectiv ®, Trinipatch ®
Indications	Pulmonary edema, congestive heart failure.Angina pectoris.Hypertension, hypertensive crisis/emergency.Pulmonary hypertension.Blood pressure control.
Mechanism of action	Nitroglycerin provides nitric oxide (NO) that induces vasodilatation (of both arterioles and veins) via generation of cyclic GMP, which then activates calcium-sensitive potassium channels in the cell membrane. Nitroglycerin is similar in action and pharmacokinetics to nitroprusside, although the latter is more potent.
Effects	Antihypertensive.Antianginal.
Time to onset of action	2 to 5 minutes
Duration of action	5 to 10 minutes
Delivery	IV
Dose	Initial infusion dose: 5 μg/min.Increase by 5-10 μg/min every 5 min to desired blood pressure.Maximum dose: 100 μg/min.Time to onset of action: 2 to 5 minutesDuration of action: 5 to 10 minutes.
Adverse effects	Headache (cerebral vasodilation). Tachycardia (due to reflex sympathetic activation). Nausea. Vomiting. Flushing. Palpitations. Tolerance with prolonged use. Methemoglobinemia. Hypoxemia.
Caution	Proceed with caution in afterload-dependent conditions.

Nitroprusside

Drug	Nitroprusside
Brand names	Nipride ®, Nipride RTU ®, Nitropress ®.
Indications	Pulmonary edema, congestive heart failure.Angina pectoris.Hypertension, hypertensive crisis/emergency.Pulmonary hypertension.Blood pressure control.
Mechanism of action	Nitroprusside provides nitric oxide (NO) that induces vasodilatation of both arterioles and veins via generation of cyclic GMP, which then activates calcium-sensitive potassium channels in the cell membrane.Time to onset of action: 1 minute.Duration of action: <10 minutes.
Effects	Potent blood pressure lowering.Antianginal effect.Reduces afterload and preload.Effective in pulmonary edema.Can produce severe hypotension.
Time to onset of action	30 seconds to 1 minute
Duration of action	1 to 10 minutes
Delivery	IV
Dose	Infusion:Starting dose: 0.25 to 0.5 μg/kg/minute.Increased as necessary (increments of 0.5 μg/kg/min).Maximum dose: 8-10 μg/kg/minute.Common maximum dose: 3 μg/kg/minute.Maximum dose (10 μg/kg/minute) should never be used for mor than 10 minutes.Administer sodium thiosulfate (cyanide into thiocyanate) and terminate infusion of nitroprusside if cyanide toxicity is suspected.
Adverse effects	• Nausea. Vomiting. Agitation. Muscle spasm. Sweating. Flushing.• Prolonged high-dose use may cause thiocyanate and cyanide toxicity. Nitroprusside is metabolized to cyanide. Cyanid toxicity may be fatal (should be suspected if patient develops altered mental status and lactic acidosis). Fatal outcomes are rare. Renal failure increases risk of cyanide toxicity. Cyanide toxicity requires doses >2 μg/kg/minute. Use the lowest possible dose, avoiding prolonged use (<2-3 days), and monitor the patient closely to avoid cyanide toxicity.• Dose-dependent reduction in coronary and renal perfusion.• Dose-dependent elevation of intracranial pressure (ICP) and reduction in cerebral blood flow.
Caution	• Used cautiously in patients with high intracranial pressure or azotemia.• Should not be given to pregnant women.• Should not be given to patients with Leber optic atrophy.

Other drugs

Phentolamine

Drug	Phentolamine
Brand names	Oraverse ®, Rogitine ®
Indications	Hypertensive crisis.
Mechanism of action	Phentolamine is a non-selective alpha-adrenergic blocker. Phentolamine reduces blood pressure while increasing catecholamine activity.
Effects	Primarily causes afterload reduction.
Time to onset of action	1 to 2 minutes
Duration of action	10 to 30 minutes
Delivery	IV
Dose	Bolus injection:5 to 15 mg every 5 to 15 minutes as necessary.Continuous infusion:Start infusion at 0.1 mg/min and increase in increments of 0.1 mg.
Adverse effects	Tachycardia. Flushing. Headache. Nausea. Vomiting.
Caution	Rarely used unless patient has a confirmed diagnosis of pheochromocytomaTreatment of hypertension associated with pheochromocytoma; treatment of dermal necrosis after extravasation of drugs with á-adrenergic effects.

Hydralazine

Not preferred for hypertensive emergencies due to the high risk of reflex sympathetic stimulation.

Drug	Hydralazine
Brand names	Apresoline ®, Bidil ®
Mechanism of action	• Induces arteriolar vasodilation. No effect on venous circulation.• May cause reflex sympathetic stimulation (can be counteracted with simultaneous administration of beta-blockers).
Effects	Induces arteriolar vasodilation without effects on venous circulation. The reduction in systemic vascular resistance (SVR) is rapid and may cause reflex sympathetic stimulation, including tachycardia. May therefore induce or worsen angina pectoris. The rapid reduction of afterload is desired in conditions requiring afterload reduction.
Time to onset of action	10-30 minutes.
Duration of action	<4 hours.
Delivery	IV or IM.
Dose	Injections• IV: 10–40 mg every 4–6 hours• IM: 10–20 mg every 4–6 hours.Infusion• Afterload reduction: Start infusion at 1 mg/hour. Increase by 0.5 mg/hour every 20 min to desired blood pressure. Maximum infusion rate 5 mg/hour.• Antihypertensive treatment: Start infusion at 5 mg/hour. Increase by 2.5 mg/hour every 20 min to desired blood pressure. Maximum infusion rate 25 mg/hour.
Adverse effects	Tachycardia. Flushing. Headache. Angina pectoris.
Caution	Heart failure. Angina pectoris (ischemic heart disease).

References

Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Hypertension 2018; 71:e140-e144]. Hypertension 2018; 71:e13-e115.

Marik PE, Varon J. Hypertensive crises: Challenges and management. Chest 2007; 131:1949.

Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42:1206.

Varon J. Treatment of acute severe hypertension: Current and newer agents. Drugs 2008; 68:283.

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Chapter 5: Adenosine for tachyarrhythmias (AVNRT, AVRT, NCT)

Substance: Adenosine

Brand names: Adenocor

Mechanism of action

Adenosine works by slowing down the impulse transmission through the atrioventricular (AV) node, thereby interfering with the pathway that enables reentry tachyarrhythmias (AVNRT and AVRT). These arrhythmias rely on AV node transmission. By disrupting this transmission, the reentry- and hence, the arrhythmia- may be terminated. Generally, adenosine is considered safe for patients with narrow complex tachycardia (NCT).

Adenosine typically causes a short-lasting second- or third-degree AV block which may be unpleasant to the patient. This side effect lasts a few seconds. Case reports have indicated that the risk of high-degree AV block and ventricular arrhythmias is greater in patients on digoxin or verapamil, although this is not an established drug interaction.

The half-life of adenosine is 8 seconds. Adverse effects are therefore very brief.

Indications

Paroxysmal supraventricular tachycardia (PSVT), which includes forms that are caused by pre-excitation.

Myocardial perfusion scintigraphy.

Contraindications

Asthma and COPD. Adenosine has caused mild to moderate exacerbation of asthma symptoms. Adenosine should be used with caution in patients with obstructive lung disease or asthma.

Irregular wide complex tachycardia (absolute contraindication).

Irregular wide complex tachycardia is most often due to atrial fibrillation with wide QRS complexes due to bundle branch blocks or other conduction defects. However, in rare instances, it may be due to pre-excited atrial fibrillation (i.e. atrial fibrillation with impulses conducted via an accessory pathway [see Wolff-Parkinson-White Syndrome]); blocking AV node conduction may result in accelerated transmission of atrial impulses to the ventricles and thus ventricular fibrillation and cardiac arrest.

High-degree AV block (second-degree Mobitz type 2 AV block, third-degree AV block).

Sick sinus syndrome or symptomatic bradycardia in the absence of a pacemaker.

Hypersensitivity to adenosine.

Administration

Normal route: Peripheral intravenous (IV).

Alternative route: Central venous administration of adenosine is suitable in the intensive care unit or coronary care unit.

Adenosine injection must be administered quickly (1-2 seconds), followed immediately by a rapid saline flush (use a three-way tap system).

Compatible IV fluids: normal saline.

Storage: room temperature.

Dosage

Adults

Initial dose: 6 mg

Wait 60 seconds before attempting a second dose.

Second dose: 12 mg.

Wait 60 seconds before attempting a third dose.

Third dose: 12 or 16 mg.

Renal failure or renal replacement therapy

No dosage adjustment is required in renal failure or renal replacement therapy.

Pediatric patients

Body weight < 50 kg:

Initial dose: 0.05 to 0.1 mg/kg

Second dose: Increase the dose by 0.05 to 0.1 mg/kg.

Maximum single dose: 0.3 mg/kg

Body weight >50 kg:

Adult dosage.

Adverse effects

Adverse effects typically persist <10 seconds due to the short half-life of adenosine.

Anxiety

Chestpain.

Palpitations.

Headache

Hypotension.

Facial flushing.

Sweating.

Bronchospasm

Dyspnea

Nausea

Metallic taste

Tightness in throat

Lightheadedness, dizziness, tingling in arms, numbness, blurred vision, burning sensation.

Relevant reading

Diagnosis and management of narrow and wide complex tachycardia

References

Drug Bank

Zipes et al: Arrhythmology, Elsevier (2019).

Wellington ICU Drug Manual

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