EPINEPHRINE

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CARDIOVASCULAR PHARMACOLOGY Prof.Alsaeed
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Objectives

• Pharmacology 1
• Pharmacology 2

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PHARMACOLOGY 1

• DRUGS AFFECTING
• CO
• HR
• PVR

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PHARMACOLOGY 1

• VASOPRESSORS USED TO TREATE CARDIAC ARREST
• ADRENERGIC VASOPRESSOR
• EPINEPHERINE
• NON- ADRENERGIC VASOPRESSOR
• VASOPRESSIN
• INOTROPIC AND VASOPRESSOR AGENTS USED TO SUPPORT
  CIRCULATION
• ADRENERGIC AGONISTS
• NON- ADRENERGIC AGONISTS
• (VASOPRESSIN)

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• 3-INODILATORS
• PHOSPHODIESTRASE INHIBITORS
• INAMRINONE
• MILRINONE
• CARDIAC GLYCOSIDES
• DIGOXIN
• 4-VASODILATORS ß BLOCKERS
• VASODILATORS
• NITROGLYCERINE
• SODIUM NITROPRUSSIDE
• ß BLOCKERS
• PROPRANOLOL
• METOPRELOL
• ATENOLOL
• ESMOLOL
• LABETALOL

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PHARMACOLOGY 2

• AGENTS FOR CONTROL OF RateRhythm

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ADRENERGIC RECEPTORS
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EPINEPHRINE
Mechanism of Action

• Systemic vascular resistance
• Systemic arterial pressure
• Heart rate
• Contractile state
• Myocardial oxygen requirement
• Improved cerebral and myocardial blood flow from
  vasoconstriction and increased perfusion pressure

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EPINEPHRINE
Indications
Cardiac Arrest

• Ventricular fibrillation
• Asystole
• EMD (consider noncardiac causes)

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EPINEPHRINE

• Indications
• Symptomatic bradycardia after other
  measures(atropine,dopamine ,transcutaneouse
  pacing) have failed (Class IIb)
• Sever hypotension
• Anaphylaxis

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EPINEPHRINE
Dosage

• In cardiac arrest
• 1 mg (10 mL 110,000 solution)
• IV push every 3 to 5 minutes.
• If this fails, higher doses of epinephrine (up to
  0.2 mg/kg) are acceptable but not recommended
  (there is growing evidence that it may be
  harmful).
• Precautions
• Be aware of increased MVO2
• can precipitate myocardial ischemia
• Avoid mixing with alkaline solutions
• Can induce myocardial ectopy

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VASOPRESSIN

• Mechanism of action
• Is a non-adrenergic peripheral vasoconstrictor
  by directly stimulating smooth muscle V1
  receptors without increase of myocardial oxygen
  consumption because it has no B-adrenergic
  activity
• Indications
• Alternative pressor to epinephrine for the
  treatment of shock-Refractory VF in adults
• A systole or pulseless electrical activity
• Refractory cardiac arrest after treatment with
  epinephrine
• Septic shock and sepsis syndrome

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VASOPRESSIN

• Dose
• Shock-Refractory VF/pulseless VT
• 40 U IV, single dose, 1 time only
• As a Class Indeterminate action, it is acceptable
  to resume epinephrine
• 1 mg IV push every 3 to 5 minutes if there was
  no response in 5 to 10 minutes to a single IV
  dose of vasopressin.
• Precautions
• Skin pallor
• Nausea
• Intestinal cramps
• Bronchial constriction
• Uterine contractions in women

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NOREPINEPHRINE
Indications (temporarily only)

• Cardiogenic shock
• Absence of peripheral vasoconstriction with
  hypotension
• Dosage
• 16µg/mL, bitartrate IV in 5 dextrose in water
• Initial Infusion
• 0.5-2µg/min titrate (2-12µg/min)

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NOREPINEPHRINE
Precautions

• Hypovolemia
• Arrhythmias
• Extravasation
• Excessive elevations of BP

Monitor BP, ECG and venous site
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DOPAMINE
Mechanisms of Action

• Precursor of epinephrine
• Alpha- and beta- receptor stimulator
• Dopaminergic receptor stimulator
• Low dose
• Dilates renal and mesenteric vessels
• Venoconstricts
• Arterial resistance may vary
• High dose
• Alpha effects dominate
• Arterial and venous constriction including
  renal and mesenteric vessels

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DOPAMINE
Indications

• Cardiogenic shock
• Hemodynamically significant hypotension
• Congestive heart failure with other agents
• Dosage
• Intravenous only
• Initial infusion rate 2µg/kg/min
• Increase infusion rate according to BP, urine
  flow response, and clinical response
• Adjust infusion rate as needed

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DOPAMINE
Precautions

• Excessive vasoconstriction
• Fall in BP
• Arrhythmias
• Nausea and vomiting
• Extravasation
• Monoamine oxidase inhibitors
• Pheochromocytoma

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DOBUTAMINE
Mechanisms of Action

• Direct beta-adrenergic stimulator
• Potent inotropic effect but less chronotropic
• Renal and mesenteric flow follows cardiac output
• Myocardial work is balanced by increases in
  coronary flow at clinical doses
• Indications
• Congestive heart failure
• Cardiogenic shock
• Hemodynamically significant hypotension

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DOBUTAMINE
Dosage

• Initial infusion rate 0.5µg/kg/min IV
• Usual infusion rate 2.5-20.0 µg/kg/min IV
• Titrated to not increase heart rate gt 10
• Precautions
• Tachycardia
• Arrhythmias
• Caution in coronary artery disease

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ISOPROTERENOL
Mechanisms of Action

• Pure beta-adrenergic stimulator (beta-1 and
  beta-2)
• Potent inotropic effect
• Potent chronotropic effect
• Increases cardiac output
• Increases myocardial oxygen consumption
• Vasodilation diastolic and mean BP may fall but
  systolic pressure maintained or increased due to
  increased cardiac output

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ISOPROTERENOL
Indications

• Hemodynamically significant atropine-refractory
  bradycardia
• Pacemaker better as soon as possible
• Contraindicated during cardiac arrest
• Dosage
• 2-10 µg/min
• Titrate to increase heart rate to 60/min

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ISOPROTERENOL
Precautions

• Excessive tachycardia
• Arrhythmias
• Increased myocardial oxygen consumption
• Exacerbate digitalis intoxication
• Hypokalemia

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AMRINONE
Mechanisms of Action

• Potent inotropic effect
• Independent of adrenergic effects
• Indications
• Severe refractory heart failure
• Septic shock
• Dosage
• Loading 0.75 mg/kg over 2-3 min
• Titrate to effect (2-20µg/kg/min

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AMRINONE
Precautions

• May induce or worsen ischemia
• Thrombocytopenia
• Allergic (sulphonamides)

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NITROPRUSSIDE
Mechanisms of Action

• Arterial vasodilation
• Venous vasodilation
• Enhanced systolic emptying
• Increased cardiac output
• Decreased LVEDP and pulmonary congestion
• Decreased myocardial oxygen consumption
• Indications
• Hypertensive crisis
• Congestive heart failure

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NITROPRUSSIDE
Dosage

• Heart failure dose 0.5µg/kg/min and titrate
• Average dose 0.5-8.0 µg/kg/min
• Higher doses may be required for hypertension

IV should be wrapped with aluminum foil
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NITROPRUSSIDE
Precautions - Hemodynamic Monitoring Essential

• Imbalance between coronary supply and demand
• Possible coronary steal
• Right-to-left shunting
• Thiocyanate toxicity
• Cyanide intoxication
• Hypotension
• Apprehension, restlessness
• Chest and abdominal pains
• Palpitations
• Dizziness
• Muscle twitching

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NITROGLYCERIN
Mechanisms of Action

• Increased supply theory
• Coronary artery vasodilation
• Collateral blood flow
• Decreases spasm
• Decreased work theory
• Venodilation decreases venous return
• Decreased ventricular volume-less work
• Arterial dilation if filling pressure is high
• Smooth muscle relaxation

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NITROGLYCERIN
Indications

• Sublingual
• Angina pectoris
• Myocardial infarction
• Intravenous
• Unstable angina pectoris
• Acute myocardial infarction
• Congestive heart failure

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NITROGLYCERIN
Dosage

• Sublingual
• 0.3 or 0.4 mg sublingual may be repeated twice at
  3-5 minute intervals
• Intravenous
• Continuous infusions starting at 10-20 µg/min and
  increase by 5-10 µg/min every 5-10
• minutes until desired response is obtained or
  bolus of 50 µg followed by an infusion

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NITROGLYCERIN
Precautions

• Headache
• Hypotension
• Syncope
• Methemoglobinemia
• Hypoxemia
• Bradycardia

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BETA BLOCKERS-PROPRANOLOL METOPROLOL
Mechanisms of Action

• Beta-adrenergic receptor blockade
• Competitive with adrenergic stimulants
• Action depends on level of adrenergic influence
• Antiarrhythmia effect (quinidine effect)
• Indications
• Recurrent VT/VF
• Refractory PSVT
• Post infarction protection

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BETA BLOCKERS-PROPRANOLOL METOPROLOL
Dosage - Propranolol

• 1.0-3.0 mg slow IV dose every 5 min
• Do not exceed 0.1 mg/kg every 5 min

- Metoprolol

• 5 mg IV every 5 min to 15 mg

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BETA BLOCKERS-PROPRANOLOL METOPROLOL
Precautions

• Cardiac failure
• Bradycardias or AV block
• Asthma or bronchospastic disease

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Anti-arrhythmic drugs
PHARMACOLOGY 2
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PROCAINAMIDE
Mechanisms of Action

• Suppresses ventricular ectopy
• Elevates VF threshold
• Indications
• Usually used when lidocaine has not controlled
• ventricular arrhythmias
• Ventricular premature complexes
• Recurrent ventricular tachycardia

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PROCAINAMIDE
Dosage

• 100 mg over 5 min (20 mg/min) until one of the
  following
• Arrhythmia suppressed
• Hypotension
• QRS complex widened by 50 of original width
• Total of 1 gm administered

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PROCAINAMIDE
Infusion Dosage

• 1-4 mg/min
• Reduce in presence of renal failure
• Monitor blood levels in renal failure and with
  infusions
• gt 3 mg/min or gt 24 hr
• Precautions
• Monitor systemic pressure for hypotension
• Observe ECG for increased PR and QT intervals,
  QRS
• widening and heart block

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LIDOCAINE
Mechanisms of Action

• Suppresses ventricular ectopy
• Elevates VF threshold
• Indications
• Shock-Refractory VF/pulseless VT
• Ventricular premature complexes especially in
• ischemia/infarction
• Ventricular tachycardia
• Prophylactic administration

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LIDOCAINE
Dosage VF/VT

• 1-1.5 mg/kg IV push followed by 0.5-0.75mg/kg
  every 5-10 min as needed 3 mg/kg
• Use infusion of 2-4 mg/min after termination of
  arrhythmia
• Dosage PVCs
• 1 mg/kg followed by 0.5 mg/kg every 2-5 min as
• needed to 3 mg/kg
• Infusion Rate
• 2 mg/min after 1 mg/kg
• 3 mg/min after 2 mg/kg
• 4 mg/min after 3 mg/kg

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LIDOCAINE
Dosage Prophylaxis of VF

• 1.5 mg/kg followed by 0.5 mg/kg at 8-10 min
  intervals to a total of 2 mg/kg unless persistent
  ectopy
• Infusion at 2-4 mg/min

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LIDOCAINE
Precautions

• Clinical indication of toxicity usually
  CNS-related
• Muscle twitching
• Slurred speech
• Altered consciousness
• Decreased hearing
• Seizures

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LIDOCAINE
Reduced Dosage

• Decreased cardiac output (cardiogenic shock, CHF)
• Hepatic dysfunction
• Elderly patients (gt 70 yr)

In all of these, use one-half recommended bolus
and observe response
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Adenosine

• Not in Vaughan Williams class
• Purine nucleotide (activates adenosine receptors)
• Slows AV nodal conduction
• Acute Rx
• Termination of SVT/ diagnosis of VT
• Given IV only (rapid bolus)
• T1/2 lt 2seconds

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Adenosine- adverse effects

• Feeling of impending doom!
• Flushing, dyspnoea, chest pain, transient
  arrhythmias
• Contraindicated in asthma, heart block

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Verapamil

• Class IV (calcium channel blocker)
• Prolongs conduction and refractoriness in AV
  node, slows rate of conduction of SA node
• Acute Rx /prophylaxis
• Used IV/oral
• SUPRAVENTRICULAR NOT VENTRICULAR ARRHYTHMIAS
  (cardiovascular collapse)
• Do not use IV verapamil with ß- blocker (heart
  block)
• T1/2 6-8 hours

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Verapamil- adverse effects

• Heart failure
• Constipation
• Bradycardia
• Nausea

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Digoxin

• Not in Vaughan Williams class
• Cardiac glycoside (digitalis, foxglove)
• Act on Na/K-ATPase of cell membrane (inhibits
  Na/K pump, increases intracellular Na and
  calcium)/ increases vagal activity
• Increase cardiac contraction and slows AV
  conduction by increasing AV node refractory period

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Digoxin

• Atrial fibrillation or flutter (controls
  ventricular rate)
• Acute Rx/prophylaxis
• Oral/IV
• Loading and maintenance doses
• T1/2 36 hours
• Excreted by kidneys
• Narrow therapeutic index
• Therapeutic drug monitoring
• Reduce dose in elderly/renal impairment

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Digoxin adverse effects

• Arrhythmias, heart block, anorexia, nausea,
  diarrhoea, xanthopsia, gynaecomastia, confusion,
  agitation
• AE potentiated by hypokalaemia and
  hypomagnesaemia
• Overdose Digibind (digoxin binding antibody
  fragments), phenytoin for ventricular
  arrhythmias, pacing, atropine

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AMIODARONE
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Mechanism of action and properties
AMIODARONE

• Is a complex agent with multiple effects on
  Na,K,and Ca channels
• It prolong the refractory period and thus the QT
  interval on ECG
• Posses both alpha and beta adrenergic blocking
  properties

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AMIDARONE

• It is iodine-containing and has a very long
  half-life (26-127 days).
• Protein binding can displace digoxin or warfarin,
  so increasing their actions.
• Given intravenously, the anti-arrhythmic action
  occurs within a few hours given orally this may
  take 1-3 weeks.
• Amiodarone is the least negatively inotropic
  anti-arrhythmic with the exception of digoxin.

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Indications
AMIDARONE

• Shock-Refractory VF/ pulseless VT
• AF and Atrial flutter
• Stable narrow-complex tachycardia
• Stable monomorphic VT

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Dose of administration Cardiac arrest
AMIODARONE

• 300 mg IV push (diluted in 20 to 30 ml D5W)
• If VF/ pulseless VT recurs consider
  administration of 150 mg IV infusion in 3-5
  minutes
• An infusion of 1 mg/min for 6 hours can be given
  and then 0.5 mg/min (maximum cumulative dose of
  2.2 g IV per 24 hours
• Stable tachycardias, AF, and Atrial flutter
• Rapid infusion of 150 mg IV followed by 1mg/min
  for 6 hours and then 0.5mg/min for 18 hours
• The initial dose my be repeated after 10 minutes

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IV Amiodarone Dosing
Max 2.1g / 24 h
1,200
1,000
540 mg/18h
800
720 mg/24h
Total mg Dose
600
360 mg/6h
400
300 mg
200
150 mg/10min
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Cardiac Arrest
Perfusing Rhythm
Recurrences
Maintenance
Amiodarone I.V. should, whenever possible, be
administered through a CVL, and an in-line filter
should be used during administration.

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Side effects
AMIODARONE

• Hypotension and bradycardia
  
• Reversible corneal micro-deposits
  
• Metallic taste
  
• Alveolitis
  
• Slate grey discoloration of skin
  
• Arrhythmias (torsades)
• Hypothyroidism
  
• Ataxia
  
• Peripheral neuropathy
  
• Hepatitis
  
• Photosensitivity
  
• Hyperthyroidism

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MAGNESIUM

• Mechanism of action
• Magnesium is essential for the proper
  function
• of myocardial cells
• Indications
• Stable polymorphic VT with prolonged QT interval
  suggestive of torsades de pointes
• Persistent or recurrent VF/pulseless VT
  associated with a known hypomagnesemic stats
• Life-threatening ventricular arrhythmias caused
  by digitalis toxicity

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MAGNESIUM

• Dose
• Persistent VF/pulseless VT
• 1-2 g(2-4 ml of 50 solution) diluted in 10 ml
  of D5W
• IV push over 1 to 2 minutes
• Polymorphic VT (torsades de pointes)
• Initial dose of 1-2 g diluted in 50-100 ml of
  
• D5W over 5 to 60 minutes IV and a maintenance
  
• dose of 0.5-1 g /h IV
• Precautions
• Hypotension
• Use magnesium with caution if renal failure is
  present

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AHA Recommendations

• Class I

- definitely helpful, - excellent Level I
evidence

• Class IIa

- acceptable, probably helpful - good supportive
evidence

• Class IIb

- acceptable, possibly helpful - fair supportive
evidence

• Class III

- not indicated, may be harmful

• Class Indeterminate

- not recommended - insufficient data
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Tachyarrhythmic Agents
?-Blocker
Drug/Recommeded Use (Class)
Amiodarone
Ca-Blocker
Lidocaine
Magnesium
Procainamide
VF/Pulseless VT IIb
IND IND IIb
Wide-complex tachycardia IIb IIb
Stable VT IIb IIb IIa
PSVT (preserved cardiac function) IIa I
I IIa
PSVT (impaired cardiac function) IIb
Atrial fibrillation/flutter IIa I I
IIa (preserved cardiac function)
Atrial fibrillation/flutter IIb
IIb (impaired cardiac function)
Atrial fibrillation/flutter (WPW) IIb
III III IIb
Atrial fibrillation/flutter (impaired IIb ca
rdiac function plus WPW)
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Tachyarrhythmic Agents
?-Blocker
Drug/Recommeded Use (Class)
Amiodarone
Ca-Blocker
Lidocaine
Magnesium
Procainamide
VF/Pulseless VT IIb
IND IND IIb
Wide-complex tachycardia IIb IIb
Stable VT IIb IIb IIa
PSVT (preserved cardiac function) IIa I
I IIa
PSVT (impaired cardiac function) IIb
Atrial fibrillation/flutter IIa I I
IIa (preserved cardiac function)
Atrial fibrillation/flutter IIb
IIb (impaired cardiac function)
Atrial fibrillation/flutter (WPW) IIb
III III IIb
Atrial fibrillation/flutter (impaired IIb ca
rdiac function plus WPW)
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Tachyarrhythmic Agents
?-Blocker
Drug/Recommeded Use (Class)
Amiodarone
Ca-Blocker
Lidocaine
Magnesium
Procainamide
VF/Pulseless VT IIb
IND IND IIb
Wide-complex tachycardia IIb IIb
Stable VT IIb IIb IIa
PSVT (preserved cardiac function) IIa I
I IIa
PSVT (impaired cardiac function) IIb
Atrial fibrillation/flutter IIa I I
IIa (preserved cardiac function)
Atrial fibrillation/flutter IIb
IIb (impaired cardiac function)
Atrial fibrillation/flutter (WPW) IIb
III III IIb
Atrial fibrillation/flutter (impaired IIb ca
rdiac function plus WPW)
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Tachyarrhythmic Agents
?-Blocker
Drug/Recommeded Use (Class)
Amiodarone
Ca-Blocker
Lidocaine
Magnesium
Procainamide
VF/Pulseless VT IIb
IND IND IIb
Wide-complex tachycardia IIb IIb
Stable VT IIb IIb IIa
PSVT (preserved cardiac function) IIa I
I IIa
PSVT (impaired cardiac function) IIb
Atrial fibrillation/flutter IIa I I
IIa (preserved cardiac function)
Atrial fibrillation/flutter IIb
IIb (impaired cardiac function)
Atrial fibrillation/flutter (WPW) IIb
III III IIb
Atrial fibrillation/flutter (impaired IIb ca
rdiac function plus WPW)
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Tachyarrhythmic Agents
?-Blocker
Drug/Recommeded Use (Class)
Amiodarone
Ca-Blocker
Lidocaine
Magnesium
Procainamide
VF/Pulseless VT IIb
IND IND IIb
Wide-complex tachycardia IIb IIb
Stable VT IIb IIb IIa
PSVT (preserved cardiac function) IIa I
I IIa
PSVT (impaired cardiac function) IIb
Atrial fibrillation/flutter IIa I I
IIa (preserved cardiac function)
Atrial fibrillation/flutter IIb
IIb (impaired cardiac function)
Atrial fibrillation/flutter (WPW) IIb
III III IIb
Atrial fibrillation/flutter (impaired IIb ca
rdiac function plus WPW)
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Tachyarrhythmic Agents
?-Blocker
Drug/Recommeded Use (Class)
Amiodarone
Ca-Blocker
Lidocaine
Magnesium
Procainamide
VF/Pulseless VT IIb
IND IND IIb
Wide-complex tachycardia IIb IIb
Stable VT IIb IIb IIa
PSVT (preserved cardiac function) IIa I
I IIa
PSVT (impaired cardiac function) IIb
Atrial fibrillation/flutter IIa I I
IIa (preserved cardiac function)
Atrial fibrillation/flutter IIb
IIb (impaired cardiac function)
Atrial fibrillation/flutter (WPW) IIb
III III IIb
Atrial fibrillation/flutter (impaired IIb ca
rdiac function plus WPW)
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SODIUM BICARBONATE
Mechanisms of Action
Reacts with H ions, as in metabolic acidosis

• HCO3- H ? H2CO3 ? CO2 H2O
• Indications
• Consider in cardiac arrest only after more
  definitive
• treatment
• Metabolic acidosis
• Dosage
• 1 mEq /kg initially, then no more than one-half
  this
• dose at 10 min intervals

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SODIUM BICARBONATE
Precautions

• Worsened mixed-venous (and intracellular)
  acidosis from CO2 formation and retention
• Hyperosmolality and hypernatremia
• Metabolic alkalosis
• Acute hypokalemia

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SODIUM BICARBONATE
Conclusions

• Clinically serious side effects, especially
  CO2 formation
• No definite evidence of benefit in arrest
• No basis for routine use
• Consider only after known beneficial therapy
• May be helpful in documented preexisting
  metabolic acidosis

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MORPHINE
Mechanisms of Action

• CNS Analgesic
• Hemodynamic
• Increased venous capacitance
• Decreased systemic vascular resistance
• Reduced myocardial oxygen needs
• Indications
• Acute myocardial infarction
• Acute pulmonary edema

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MORPHINE
Dosage

• Small (2-5 mg) intravenous increments titrated to
  desired analgesic or hemodynamic effect
• Precautions
• Depression of ventilation
• Systemic hypotension, especially in
• Volume-depleted patients
• Patients with increased systemic resistance

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CALCIUM CHLORIDE
Mechanisms of Action

• Increases cardiac contractile state
• Indications
• Acute hyperkalemia
• Hypocalcaemia
• Calcium channel blocker adverse effects
• No indication in cardiac arrest if any of above
  conditions present

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CALCIUM CHLORIDE
Dosage

• 2-4 mg/kg of 10 solution IV and repeated as
  needed at 10 min intervals
• Precautions
• Bradycardia with rapid injection
• Caution in digitalized patients
• Precipitates as carbonate salt in bicarbonate
  solution

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FUROSEMIDE
Indications

• Acute pulmonary edema
• Dosage
• 40 mg slowly IV
• Precautions
• Dehydration
• Hypovolemia
• Hypotension
• Hyperosmolality
• Hypokalemia

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ATROPINE
Mechanisms of Action
Parasympatholytic (vagolytic) action

• Accelerates rate of sinus node discharge
• Improves atrioventricular conduction
• May restore cardiac rhythm in a systole

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ATROPINE
Indications

• Bradycardia (sinus or AV nodal block) with
  hypotension or ventricular ectopy
• Ventricular a systole
  Dosage
  
  
• 0.5 mg IV every 5 min as needed in bradycardia
• For a systole use 1.0 mg IV and repeat in 5 min
  if needed
• Total maximum dose 3 mg (0.04 mg/kg)
• For endotracheal injection 1.0-2.0 mg diluted in
  10 mL water

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ATROPINE
Precautions

• Increased myocardial oxygen demand worsened
  ischemia
• Ventricular tachycardia or fibrillation

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OXYGEN
Impairment of Oxygenation During Cardiac Arrest

• Expired air 16 to 17 oxygen
• Low cardiac output
• Intrapulmonary right-to-left shunt
• Ventilation/perfusion mismatching
  
• Effects of Oxygen Administration
• Elevate Oxygen tension
• Increase oxygen content
• Improve tissue oxygenation

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OXYGEN
Indications

• Acute chest pain
• Suspected hypoxemia of any cause
• Cardiopulmonary arrest
• Precautions
• Toxicity
• Obstructive lung diseases

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