Pharmacology of inotropes and vasopressors - KSS Deanery

Pharmacology of inotropesand vasopressors

Curriculum3.3 Recognises and manages the patient with circulatory failure4.4 Uses fluids and vasoactive / inotropic drugs to support thecirculationPR_BK_41 Drugs and the sympathetic nervous system: adrenergicreceptors and molecular mechanisms of action: Indications forpharmacological use of naturally occurring catecholamines andsynthetic analogues.PR_BK_43 Cardiovascular system: general: drug effects on theheart [inotropy and chronotropy] and on the circulation: arterial andvenous effects; systemic and pulmonary effectsPR_BK_44 Inotropes and pressors: Classification; site of action.Synthetic inotropes compared with adrenalinePB_BK_38 Cardiac muscle contraction

Definitions Inotrope: increases cardiac output byincreasing velocity and force of myocardialcontraction Vasopressor: causes contraction of arteriolarand venous smooth muscle Inodilator: increases cardiac output by acombination of inotropic and vasodilator effects

Mechanisms of drug action Sympathomimeticsα-agonistsβ-agonistsDopamine agonists (D 1 -like, D 2 -like)Phosphodiesterase inhibitors (PDE 3) OthersVasopressin (V 1 )LevosimendanCardiac glycosides

α-agonistsα 1 receptors: vascular smooth muscle contraction

β-agonistsβ 1 (β 2 ) Inotropy ( force) Chronotropy ( rate) Dromotropy (conduction)β 2 Vasodilatation

Phosphodiesterase 3 inhibitors Heart and vascularsmooth muscle Inodilators Lusitropic (improveddiastolic relaxation)

Vasopressin (AVP, ADH) Hypothalamic nonapeptidehormone , released fromposterior pituitary V 1 receptor agonist - potentarterial vasoconstrictor V 2 receptors in renal collectingduct – water reabsorption

Levosimendan Calcium sensitiser - ↑ sensitivity of contractileproteins to Ca 2+ without ↑ intracellular Ca 2+ Inotropic and chronotropic effects Independent of adrenoceptors and cAMP Vasodilator: opens ATP-sensitive K + channels onvascular smooth muscle

Cardiac glycosides: digoxinInhibits Na + /K + pump in myocardial cell membrane→ intracellular Na +→ intracellular Ca 2+ (Na + :Ca 2+ exchanger)→ force of contraction

Synthetic CatecholaminesIsoprenalineDobutamineDopexamine

Agentβ 1effects β 2effects α effects DA effectsInotropyChronotropyDromotropyVasodilatation Vasoconstriction Renal/ mesentericvasodilatationNatriuresisNoradrenaline ++ + ++++ -Adrenaline β effects predominate at low dose, α at high dose -DopamineDA effects at low dose, β at moderate dose and α at high doseDobutamine +++ ++ + -Dopexamine + ++ - +Isoprenaline ++++ ++++ - -

Benefits and side-effectsβ1Increased cardiac outputTachycardia, arrhythmia, ↑ myocardial O 2 consumption,myocardial ischaemiaβ2Vasodilatation, ↑ cardiac output, ↓ myocardial O 2 consumptionHypotensionα↑ systolic and diastolic blood pressureMay decrease renal, mesenteric and skin blood flow.↑ cardiac afterload and myocardial oxygen demand.

Adrenaline(epinephrine) Potent β-agonist < 0.1 µg/kg/min Potent α 1 -agonist > 0.1 µg/kg/min → vasoconstriction Renal and mesenteric vasoconstriction → ischaemia andrenal failure Metabolic - hyperglycaemia and hyperlactaemia Cardiac toxicity with prolonged, high dosage

AdrenalineAnaphylaxis blocks mediator release reverses bronchospasm and vasodilatation 50-100 µg (0.5-1ml of 1:10,000) IV 0.5 to 1mg (0.5-1ml of 1:1,000) IMCardiac arrest vasoconstriction → diversion of blood to essential organs diastolic pressure and coronary flow increased 1mg IV, every 3-5 minutes of resuscitation

AdrenalineCardiogenic shock increased cardiac output Arrhythmogenic ↑ afterload & myocardial O 2 demand second-line treatmentSeptic shock restores MAP and cardiac output ischaemia of intestinal mucosa, lactic acidosis,hyperglycaemia ↑ renal vascular resistance → reduced RBF 2 nd -line agent

Noradrenaline(norepinephrine) α 1 > β above 0.05µg/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

NoradrenalineSeptic shock first line vasopressor (Surviving Sepsis Campaign) ensure adequate fluid resuscitation first ↑ gastric mucosal and renal perfusion invasodilated, normovolaemic casesAnaphylaxis Second line agent, for resistant hypotension

DopamineDirect: α, β, DA agonistIndirect: releases NA from sympathetic nerve terminals2-5µg/kg/min (DA) → ↑ RBF, diuresis, natriuresis5-10 µg/kg/min (β) → ↑ cardiac output10-20 µg/kg/min (α) → vasoconstrictionArrhythmogenic, ↓ hypoxic drive, delirium, vomiting,immunosuppressionVasopressor in septic shockNo evidence for renal protection

Dobutamine Synthetic derivative of isoprenaline β-agonist (weak α 1 ). β 1 > β 2 . 2-20 µg/kg/min → inotropic + moderate ↑ HR SVR unchanged or slightly reduced Myocardial O 2 demand increased (stress testing)

DobutamineCardiogenic shock/ acute heart failure first-line inotrope ↑ cardiac output + reduced ventricular afterload may cause hypotensionSeptic shock (with ↓ CO) noradrenaline + dobutamine as effective asadrenaline, with fewer side-effects

Dopexamine Synthetic analogue of dopamine 60x potency of dopamine at β 2 receptors, 1/3potency at DA receptors No α activity Inodilator Dose-dependent tachycardia ? Beneficial effects on inflammation, splanchniccirculation and renal function

Isoprenaline Synthetic Potent, non-selective β-agonist Historical role in treatment of bradycardia andheart block Superseded by more effective agents with fewerside effects (tachycardia, arrhythmia)

Non-catecholaminesympathomimetic amines Metaraminol, ephedrine,phenylephrine Lack 2 nd hydroxyl groupon 1 o aromatic ring.Metaraminol

Metaraminol α and β agonist, mainly vasoconstrictor ↑ SBP and DBP Reverses hypotension caused by GA/ spinalanaesthesia Vasoconstriction may → transient bradycardia Indirect β-effects → tachyphylaxis 0.5-1mg IV, repeated as necessary

Ephedrine and phenylephrineEphedrineα and βVasopressor and inotrope in anaesthetic-induced hypotensionUseful for bradycardic, hypotensive patientUterine blood flow maintained - drug of choice in pregnancy3-6mg IV, repeated as necessary. 25-50mg IMAction partly indirect → tachyphylaxisPhenylephrineSelective α-agonistRapid onset of action , duration 5-10 minutesVasoconstrictor - IV bolus (0.1-0.5mg) or infusion.

Vasopressin V 1 agonist (and V 2 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 mortalitybenefit 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 O 2 demand Lusitropic – improved diastolic relaxation Adrenoceptors not involved - no tachyphylaxis Treatment of AHF with reduced cardiac output: littleevidence of long-term survival benefit Low CO states following cardiomyotomy Long t 1/2 (milrinone 2 hours) May cause hypotension

Levosimendan Inodilator Diastolic relaxation maintained Beneficial effects on myocardial energybalance Effective in acute and chronic heart failure

Management of shockInotropes and vasopressors are used for thetreatment of circulatory failureunresponsive to fluid therapy alone

Management of shockABCAim - adequate perfusion and oxygen delivery to tissuesDO 2 = arterial oxygen content x cardiac outputDO 2 = [SpO2 x Hb x 1.34] x CO

Management of shockOptimise LV preloadBlood pressure = CO x SVRCO = SV x HRSV: PreloadAfterloadContractility

Management of shockOptimise LV preloadFluid challengeMonitor:Clinical signsCVPPAOP (Swan-Ganz)Stroke volume variation (LiDCO)Global end-diastolic volume (PiCCO)Corrected flow time (ODM)

Management of shockOptimise CO and BP Low CO → inotrope Low SVR → vasopressor Mixed pathology → combination

Management of shockWhat 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 O 2 consumption Avoid arrhythmia In MI, inotropes may cause infarct expansion, ↑cytosolic Ca 2+ and apoptosis

Cardiogenic shock/ AHFDobutamine American College of Cardiology/ AHA recommendation for acute MIwith moderate hypotension May cause hypotension and tachycardia - caution in profound shock Combination with dopamine may limit side effectsAdrenaline Low-dose infusion in profound shock High dose → ↑ afterload and myocardial O 2 demand Arrhythmia, promotes coronary thrombosisNoradrenaline 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 perfusionand diuresis, allowing re-introduction of ACEIs, diuretics,β-blockers Dobutamine – but CHF associated with uncoupling ofadrenoceptors from intracellular transduction →resistance to treatment Positive inotropes increase mortality in CHF(↑ intracellular Ca 2+ )

PDE3 inhibitorsAcute Heart Failure CCF with ↓ cardiac output Minimal effect on myocardial O 2 demand Hypotension and long t 1/2 Similar outcomes to dobutamineLevosimendan CCF with ↓ cardiac output No ↑ myocardial O 2 demand ? Survival benefit compared with dobutamine

Septic shockVasopressor Surviving Sepsis Campaign: 1 st line noradrenaline orvasopressin (alternative or in addition) Adrenaline may → intestinal ischaemia, lacticacidosis, hyperglycaemia, reduced RBF Dopamine in selected cases (no risk of arrhythmia,low cardiac output)

Septic shockInotrope (↓ CO) Dobutamine Noradrenaline + dobutamine effective asadrenaline in restoring CO and BP, butless effect on lactate and GI perfusion

Septic shockOther Corticosteroids (SSC) Dopexamine ?

Dopamine:a) may produce ventricular arrhythmiasb) increases mesenteric blood flow at highdosesc) crosses the blood-brain barrierd) is synthesised from L-dopae) is inactivated in alkaline solutionTTFTT

The following are precursors ofadrenaline:a) Tyrosineb) Phenylalaninec) Dopamined) Isoprenalinee) NoradrenalineTTTFT

Dopexamine:a)causes arterial vasoconstrictionb) is an agonist at dopaminergic D1 and D2receptorsc) increases the force of myocardial contractiond) increases renal blood flowe) causes arrhythmiasFTTTT

Dobutamine:a)is structurally similar to isoprenalineb) activates adenyl cyclasec) has a selective action on beta-1adrenoreceptorsd) has a half-life of 2 minutese) increases the left ventricular end-diastolicpressureTTFTF

ReadingAung K, Htay T. Vasopressin for cardiac arrest: a systematic reviewand meta-analysis. Arch. Int. Med. 2005; 165: 17-24.Dellinger RP, Levy MM, Carlet JM et al for the Surviving SepsisCampaign Guidelines Committee. Surviving Sepsis Campaign:International guidelines for management of severe sepsis and septicshock; 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 ofphysiologyand clinical use in cardiovascular medicine. Circulation2008; 118:1047-56.Resuscitation Council (UK). 2010 Resuscitation Guidelines.Russell JA, Walley KR, Singer J et al. Vasopressin versusNorepinephrine Infusion in Patients with Septic Shock. N Engl J Med2008; 358:877-887.

TrialsBellomo R, Chapman M, Finfer S et al; Australian and New Zealand IntensiveCare Society (ANZICS) Clinical Trials Group. Low-dose dopamine in patients withearly renal dysfunction: a placebo-controlled randomised trial. Lancet. 2000;356: 2139–2143Dunser MW, Mayr AJ, Ulmer H et al. Arginine vasopressin in advancedvasodilatory shock: a prospective, randomized, controlled study. Circulation.2003; 107: 2313–2319Follath F, Cleland JG, Just H et al. Efficacy and safety of intravenouslevosimendan compared with dobutamine in severe low-output heart failure (theLIDO study): a randomised double-blind trial. Lancet. 2002; 360: 196–202.Mebazaa A, Nieminen MS, Packer M et al. Levosimendan vs dobutamine forpatients with acute decompensated heart failure: the SURVIVE randomized trial.JAMA. 2007; 297: 1883–1891.Russell JA, Walley KR, Singer J et al. Vasopressin versus Norepinephrine Infusionin Patients with Septic Shock. N Engl J Med 2008; 358:877-887.