Pharmacology of inotropes
and vasopressors
Curriculum
3.3 Recognises and manages the patient with circulatory failure
4.4 Uses fluids and vasoactive / inotropic drugs to support the
circulation
PR_BK_41 Drugs and the sympathetic nervous system: adrenergic
receptors and molecular mechanisms of action: Indications for
pharmacological use of naturally occurring catecholamines and
synthetic analogues.
PR_BK_43 Cardiovascular system: general: drug effects on the
heart [inotropy and chronotropy] and on the circulation: arterial and
venous effects; systemic and pulmonary effects
PR_BK_44 Inotropes and pressors: Classification; site of action.
Synthetic inotropes compared with adrenaline
PB_BK_38 Cardiac muscle contraction
Definitions
Inotrope: increases cardiac output by
increasing velocity and force of myocardial
contraction
Vasopressor: causes contraction of arteriolar
and venous smooth muscle
Inodilator: increases cardiac output by a
combination of inotropic and vasodilator effects
Mechanisms of drug action
Sympathomimetics
-agonists
-agonists
Dopamine agonists (D1-like, D2-like)
Phosphodiesterase inhibitors (PDE 3)
Others
Vasopressin (V1)
Levosimendan
Cardiac glycosides
-agonists
1 receptors: vascular smooth muscle contraction
-agonists
1 (2)
Inotropy ( force)
Chronotropy ( rate)
Dromotropy (
conduction)
2
Vasodilatation
Phosphodiesterase 3 inhibitors
Heart and vascular
smooth muscle
Inodilators
Lusitropic (improved
diastolic relaxation)
Vasopressin (AVP, ADH)
Hypothalamic nonapeptide
hormone , released from
posterior pituitary
V1 receptor agonist - potent
arterial vasoconstrictor
V2 receptors in renal collecting
duct water reabsorption
Levosimendan
Calcium sensitiser - sensitivity of contractile
proteins to Ca2+ without intracellular Ca2+
Inotropic and chronotropic effects
Independent of adrenoceptors and cAMP
Vasodilator: opens ATP-sensitive K+ channels on
vascular smooth muscle
Cardiac glycosides: digoxin
Inhibits Na+/K+ pump in myocardial cell membrane
intracellular Na+
intracellular Ca2+ (Na+:Ca2+ exchanger)
force of contraction
Drugs: Catecholamines
Aromatic ring + two adjacent
OH groups (catechol) + ethylamine
group
Substitutions on ethylamine group
sympathomimetic activity
Dopamine, adrenaline, noradrenaline
are naturally occurring
Synthetic Catecholamines
Isoprenaline
Dobutamine
Dopexamine
1 effects 2 effects effects DA effects
Agent
Inotropy Vasodilatation Vasoconstriction Renal/ mesenteric
Chronotropy vasodilatation
Dromotropy Natriuresis
Noradrenaline ++ + ++++ -
Adrenaline effects predominate at low dose, at high dose -
Dopamine DA effects at low dose, at moderate dose and at high dose
Dobutamine +++ ++ + -
Dopexamine + ++ - +
Isoprenaline ++++ ++++ - -
Pharmakokinetics of
catecholamines
t 1/2 1-2 minutes
Re-uptake into tissues Metabolism by MAO and
COMT
Steady-state plasma concentration in 5-10 min
Short half-life allows rapid titration
Benefits and side-effects
1 Increased cardiac output
Tachycardia, arrhythmia, myocardial O2 consumption,
myocardial ischaemia
2 Vasodilatation, cardiac output, myocardial O2 consumption
Hypotension
systolic and diastolic blood pressure
May decrease renal, mesenteric and skin blood flow.
cardiac afterload and myocardial oxygen demand.
Adrenaline
(epinephrine)
Potent -agonist < 0.1 g/kg/min
Potent 1-agonist > 0.1 g/kg/min vasoconstriction
Renal and mesenteric vasoconstriction ischaemia and
renal failure
Metabolic - hyperglycaemia and hyperlactaemia
Cardiac toxicity with prolonged, high dosage
Adrenaline
Anaphylaxis
blocks mediator release
reverses bronchospasm and vasodilatation
50-100 g (0.5-1ml of 1:10,000) IV
0.5 to 1mg (0.5-1ml of 1:1,000) IM
Cardiac arrest
vasoconstriction diversion of blood to essential organs
diastolic pressure and coronary flow increased
1mg IV, every 3-5 minutes of resuscitation
Adrenaline
Cardiogenic shock
increased cardiac output
Arrhythmogenic
afterload & myocardial O2 demand
second-line treatment
Septic shock
restores MAP and cardiac output
ischaemia of intestinal mucosa, lactic acidosis,
hyperglycaemia
renal vascular resistance reduced RBF
2nd-line agent
Noradrenaline
(norepinephrine)
1 > above 0.05g/kg/min
arterial constriction SBP and DBP
venous constriction venous return
reflex bradycardia
effect on cardiac output variable/ minimal
renal and mesenteric vasoconstriction (?)
high doses digital gangrene
myocyte apoptosis in prolonged infusion
Noradrenaline
Septic shock
first line vasopressor (Surviving Sepsis Campaign)
ensure adequate fluid resuscitation first
gastric mucosal and renal perfusion in
vasodilated, normovolaemic cases
Anaphylaxis
Second line agent, for resistant hypotension
Dopamine
Direct: , , DA agonist
Indirect: releases NA from sympathetic nerve terminals
2-5g/kg/min (DA) RBF, diuresis, natriuresis
5-10 g/kg/min () cardiac output
10-20 g/kg/min () vasoconstriction
Arrhythmogenic, hypoxic drive, delirium, vomiting,
immunosuppression
Vasopressor in septic shock
No evidence for renal protection
Dobutamine
Synthetic derivative of isoprenaline
-agonist (weak 1). 1 > 2.
2-20 g/kg/min inotropic + moderate HR
SVR unchanged or slightly reduced
Myocardial O2 demand increased (stress testing)
Dobutamine
Cardiogenic shock/ acute heart failure
first-line inotrope
cardiac output + reduced ventricular afterload
may cause hypotension
Septic shock (with CO)
noradrenaline + dobutamine as effective as
adrenaline, with fewer side-effects
Dopexamine
Synthetic analogue of dopamine
60x potency of dopamine at 2 receptors, 1/3
potency at DA receptors
No activity
Inodilator
Dose-dependent tachycardia
? Beneficial effects on inflammation, splanchnic
circulation and renal function
Isoprenaline
Synthetic
Potent, non-selective -agonist
Historical role in treatment of bradycardia and
heart block
Superseded by more effective agents with fewer
side effects (tachycardia, arrhythmia)
Non-catecholamine
sympathomimetic amines
Metaraminol, ephedrine,
phenylephrine
Lack 2nd hydroxyl group
on 1o aromatic ring.
Metaraminol
Metaraminol
and agonist, mainly vasoconstrictor
SBP and DBP
Reverses hypotension caused by GA/ spinal
anaesthesia
Vasoconstriction may transient bradycardia
Indirect -effects tachyphylaxis
0.5-1mg IV, repeated as necessary
Ephedrine and phenylephrine
Ephedrine
and
Vasopressor and inotrope in anaesthetic-induced hypotension
Useful for bradycardic, hypotensive patient
Uterine blood flow maintained - drug of choice in pregnancy
3-6mg IV, repeated as necessary. 25-50mg IM
Action partly indirect tachyphylaxis
Phenylephrine
Selective -agonist
Rapid onset of action , duration 5-10 minutes
Vasoconstrictor - IV bolus (0.1-0.5mg) or infusion.
Vasopressin
V1 agonist (and V2 receptors in renal collecting duct)
Potent vasoconstrictor
CPR: not shown to produce better results than adrenaline
Rescue therapy in septic shock resistant to NA. No mortality
benefit of low-dose AVP over NA (VASST trial)
GI ischaemia, ischaemic skin lesions, reduced CO
Phosphodiesterase inhibitors
Amrinone, milrinone, enoximone
CO, afterload, minimal effect on myocardial O2 demand
Lusitropic improved diastolic relaxation
Adrenoceptors not involved - no tachyphylaxis
Treatment of AHF with reduced cardiac output: little
evidence of long-term survival benefit
Low CO states following cardiomyotomy
Long t1/2 (milrinone 2 hours)
May cause hypotension
Levosimendan
Inodilator
Diastolic relaxation maintained
Beneficial effects on myocardial energy
balance
Effective in acute and chronic heart failure
Management of shock
Inotropes and vasopressors are used for the
treatment of circulatory failure
unresponsive to fluid therapy alone
Management of shock
ABC
Aim - adequate perfusion and oxygen delivery to tissues
DO2 = arterial oxygen content x cardiac output
DO2 = [SpO2 x Hb x 1.34] x CO
Management of shock
Optimise LV preload
Blood pressure = CO x SVR
CO = SV x HR
SV: Preload
Afterload
Contractility
Management of shock
Optimise LV preload
Fluid challenge
Monitor: Clinical signs
CVP
PAOP (Swan-Ganz)
Stroke volume variation (LiDCO)
Global end-diastolic volume (PiCCO)
Corrected flow time (ODM)
Management of shock
Optimise CO and BP
Low CO inotrope
Low SVR vasopressor
Mixed pathology combination
Management of shock
What are optimal cardiac output and BP?
Adequacy of tissue perfusion indicated by:
Urine output
Conscious state
Skin temperature
Serum lactate
Acid-base status
Cardiogenic shock
Optimise preload
Pump failure
Pure inotrope or inodilator
Avoid afterload/ myocardial O2 consumption
Avoid arrhythmia
In MI, inotropes may cause infarct expansion,
cytosolic Ca2+ and apoptosis
Cardiogenic shock/ AHF
Dobutamine
American College of Cardiology/ AHA recommendation for acute MI
with moderate hypotension
May cause hypotension and tachycardia - caution in profound shock
Combination with dopamine may limit side effects
Adrenaline
Low-dose infusion in profound shock
High dose afterload and myocardial O2 demand
Arrhythmia, promotes coronary thrombosis
Noradrenaline
Has been recommended for severe, refractory cardiogenic shock
Improves coronary perfusion ( DBP)
Antithrombotic effect
afterload and myocardial oxygen demand
Acute Heart Failure
Aim to CO, end-diastolic pressure, improve perfusion
and diuresis, allowing re-introduction of ACEIs, diuretics,
-blockers
Dobutamine but CHF associated with uncoupling of
adrenoceptors from intracellular transduction
resistance to treatment
Positive inotropes increase mortality in CHF
( intracellular Ca2+)
Acute Heart Failure
PDE3 inhibitors
CCF with cardiac output
Minimal effect on myocardial O2 demand
Hypotension and long t1/2
Similar outcomes to dobutamine
Levosimendan
CCF with cardiac output
No myocardial O2 demand
? Survival benefit compared with dobutamine
Septic shock
Vasopressor
Surviving Sepsis Campaign: 1st line noradrenaline or
vasopressin (alternative or in addition)
Adrenaline may intestinal ischaemia, lactic
acidosis, hyperglycaemia, reduced RBF
Dopamine in selected cases (no risk of arrhythmia,
low cardiac output)
Septic shock
Inotrope ( CO)
Dobutamine
Noradrenaline + dobutamine effective as
adrenaline in restoring CO and BP, but
less effect on lactate and GI perfusion
Septic shock
Other
Corticosteroids (SSC)
Dopexamine ?
Dopamine:
a) may produce ventricular arrhythmias T
b) increases mesenteric blood flow at high
doses T
c) crosses the blood-brain barrier F
d) is synthesised from L-dopa T
e) is inactivated in alkaline solution T
The following are precursors of
adrenaline:
a) Tyrosine T
b) Phenylalanine T
c) Dopamine T
d) Isoprenaline F
e) Noradrenaline T
Dopexamine:
a)causes arterial vasoconstriction F
b) is an agonist at dopaminergic D1 and D2
receptors T
c) increases the force of myocardial contraction T
d) increases renal blood flow T
e) causes arrhythmias T
Dobutamine:
a)is structurally similar to isoprenaline T
b) activates adenyl cyclase T
c) has a selective action on beta-1
adrenoreceptors F
d) has a half-life of 2 minutes T
e) increases the left ventricular end-diastolic
pressure F
Reading
Aung K, Htay T. Vasopressin for cardiac arrest: a systematic review
and meta-analysis. Arch. Int. Med. 2005; 165: 17-24.
Dellinger RP, Levy MM, Carlet JM et al for the Surviving Sepsis
Campaign Guidelines Committee. Surviving Sepsis Campaign:
International guidelines for management of severe sepsis and septic
shock; 2008. Crit Care Med 2008; 36(1):296-327.
Mullner M, Urbanek B, Havel C et al. Vasopressors for shock.
Cochrane Database of Systematic Reviews 2004 ; Issue 3. Art. No.
CD003709.DOI:10. 1002/14651858. CD003709.pub2.
Overgaard CB, Dzavik V. Inotropes and vasopressors: review of
physiologyand clinical use in cardiovascular medicine. Circulation
2008; 118:1047-56.
Resuscitation Council (UK). 2010 Resuscitation Guidelines.
Russell JA, Walley KR, Singer J et al. Vasopressin versus
Norepinephrine Infusion in Patients with Septic Shock. N Engl J Med
2008; 358:877-887.
Trials
Bellomo R, Chapman M, Finfer S et al; Australian and New Zealand Intensive
Care Society (ANZICS) Clinical Trials Group. Low-dose dopamine in patients with
early renal dysfunction: a placebo-controlled randomised trial. Lancet. 2000;
356: 21392143
Dunser MW, Mayr AJ, Ulmer H et al. Arginine vasopressin in advanced
vasodilatory shock: a prospective, randomized, controlled study. Circulation.
2003; 107: 23132319
Follath F, Cleland JG, Just H et al. Efficacy and safety of intravenous
levosimendan compared with dobutamine in severe low-output heart failure (the
LIDO study): a randomised double-blind trial. Lancet. 2002; 360: 196202.
Mebazaa A, Nieminen MS, Packer M et al. Levosimendan vs dobutamine for
patients with acute decompensated heart failure: the SURVIVE randomized trial.
JAMA. 2007; 297: 18831891.
Russell JA, Walley KR, Singer J et al. Vasopressin versus Norepinephrine Infusion
in Patients with Septic Shock. N Engl J Med 2008; 358:877-887.
