Pharmacology of Inotropes and Vasopressors - KSS of Inotropes...receptors and molecular mechanisms...

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Transcript of Pharmacology of Inotropes and Vasopressors - KSS of Inotropes...receptors and molecular mechanisms...

  • Pharmacology of inotropesand 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-agonistsDopamine agonists (D1-like, D2-like)Phosphodiesterase inhibitors (PDE 3)

    OthersVasopressin (V1)LevosimendanCardiac glycosides

  • -agonists1 receptors: vascular smooth muscle contraction

  • -agonists

    1 (2)

    Inotropy ( force)

    Chronotropy ( rate)

    Dromotropy ( conduction)

    2 Vasodilatation

  • Phosphodiesterase 3 inhibitors

    Heart and vascular smooth muscle


    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


    Substitutions on ethylamine group

    sympathomimetic activity

    Dopamine, adrenaline, noradrenaline

    are naturally occurring

  • Synthetic Catecholamines




  • Agent

    1 effects 2 effects effects DA effects




    Vasodilatation Vasoconstriction Renal/ mesenteric



    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


    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


    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


    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


    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


    Dose-dependent tachycardia

    ? Beneficial effects on inflammation, splanchnic circulation and renal function

  • Isoprenaline


    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

    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



    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


    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


    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


    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: PreloadAfterload


  • Management of shock

    Optimise LV preload

    Fluid challenge

    Monitor: Clinical signsCVPPAOP (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 vasopress