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.