Vasoactve drugs
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1) Vasoactive drugs include vasopressors, ionotropes, and other drugs that act on vascular smooth muscle and cardiac muscle. 2) Norepinephrine is the first-line vasopressor for treating septic shock as it increases cardiac index and blood pressure while preserving organ perfusion. Dopamine can also be used but has greater risks. 3) Ionotropes like dobutamine are used to increase cardiac contractility in conditions with low cardiac output such as cardiogenic or hypodynamic septic shock.
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Vasoactve drugs
- 2. OVERVIEW • Basic physiological principles • Classification and basic pharmacology of Vasoactive drugs • Common indications of their use • Evidence based medicine
- 3. Vasoactive drugs Vasopressors Ionotropes Increase the force of contraction of myocardial muscle Positive ionotropism Stimulates smooth muscle contraction of the capillaries & arteries Vasoconstriction Rise in Mean Blood Pressure Improved tissue perfusion and oxygenation
- 4. BASIC PHYSIOLOGY MAP = CO x SVR ~ 1 r4 HR x SV PRELOAD CONTRACTILITY AFTERLOAD
- 5. VASOPRESSORS ↑MAP = CO x↑SVR ~ 1 ↓r4 HR x SV PRELOAD CONTRACTILITY AFTERLOAD NORADRENALINE VASOPRESSIN
- 6. IONOTROPES ↑MAP = ↑ CO xSVR ~ 1 r4 HR x ↑ SV PRELOAD ↑ CONTRACTILITY AFTERLOAD DOPAMINE DOBUTAMINE ADRENALINE
- 7. Vasoactive Receptors • ALPHA (α1 , α2) • BETA ( β1, β2, β3 ) • VASOPRESSIN (V1 , V2) • PHOSPHODIESTERASE ( PDE III) • DOPAMINERGIC (D1, D2 ,D3, D4, D5) ADRENOCEPTORS
- 8. RECEPTOR LOCATION ACTION on stimulation α1 • Vascular smooth muscle • Myocardium • Vasoconstriction • Arrythmia α2 • CNS •Vascular smooth muscle • Platelets • Reduced central sympathetic flow •Vasoconstriction • Platelet aggregation β1 • Myocardium • + ve Ionotropism • + ve Chronotropism β2 • Bronchi • Blood vessels • Bronchodilation • Vasodilation
- 9. RECEPTOR LOCATION ACTION on stimulation V1 Vascular smooth muscle • SKELETAL • MESENTRIC • CORONARY • Vasoconstriction PDE- III • Myocardium •Vascular smooth muscle • + ve Ionotropism • + ve Chronotropism •Vasodilatation IONODILATION D1 Vascular smooth muscle • RENAL • MESENTRIC • CORONARY • Vasodilatation
- 10. Vasoactive drugs in practice VASOPRESSORS/ PRESSORS – DIRECT ACTING SYMPATHOMIMETIC INDIRECT ACTING SYMPATHOMIMETIC MIXED ACTING SYMPATHOMIMETI C OTHERS NOR ADRENALINE ADRENALINE @ high doses PHENYLEPHRINE ISOPRENALINE METARAMINOL EPHEDRINE MEPHENTERMINE VASOPRESSIN DOPAMINE @ VERY HIGH DOSES
- 11. IONOTROPES – Sympathomimetic drugs - • Dobutamine •Adrenaline @ low dose • Dopamine @ mod doses Other mechanism of action – 1. PHOSPHODIESTERASE III INHIBITOR ( Ionodilators ) • Amrinone, Milrinone 2. CARDIAC GLYCOSIDES • Digoxin 3. MYOFILAMENT CALCIUM SENSITISERS • Levosimendan, pibomendan, sulmazole 4. GLUCAGON, CALCIUM
- 12. DRUG DOSE α1 β1 β2 CO SVR MAP HR ADRENALINE @ Low dose @ High dose 0.1-0.5 µg/kg/ min 0.5-1 µg/kg/ Min ++ +++ +++ ++ ++ ++ ↑↑ ↔↑ ↓ ↑↑ ↑ ( SBP > DBP) ↑↑ ↑ ↑ NORAD 0.5- 30 µg/min +++ ++ 0 ↔↑ ↑↑ ↑↑ ( SBP ~ DBP) ↓ PHENYL EPHRINE 40–180 μg/min +++ 0 0 ↔↑ ↑↑ ↑↑ ( SBP ~ DBP) ↓↓ ISOPRENALINE 2–10 μg/min 0 +++ +++ ↑ ↓ ↓ ( SBP >>>DBP↓↓ ) ↑ ↑
- 13. DRUG α1 β1 β2 D1 EFFECTS DOPAMINE 0.5 – 2 µg/kg/min 2- 5 µg/kg/min 5-10 µg/kg/min 10-20 µg/kg/min 0 0 + ++ + + ++ ++ 0 0 0 0 ++ ++ ++ ++ RENAL, MESENTRIC VASODIL CO ↔↑, VASODILATION CO ↑ SVR ↑↑↑ MAP↑ (SBP> DBP) HR ↔ DOBUTAMINE 2.5–20 μg/kg/min 0 +++ ++ 0 CO ↑ SVR ↓ MAP ↔↑ HR ↔
- 14. VASOPRESSIN- • V1 receptor stimulation • ↑ SVR • ↑MAP PHOSPHODIESTERASE III INHIBITORs (Ionodilators ) – Amrinone, Milrinone Enoximone , Piroximone (highly selective) • ↑↑CO • ↓SVR • ↓↔ MAP
- 15. DIGOXIN (↑ intracellular Ca++) – • ↑CO • ↓SVR • ↔ ↑MAP • ↔ HR MYOFILAMENT CALCIUM SENSITISERS Levosimendan, Pimobendan, Sulmazole Enhance response of myofilament contractile element to Ca without altering availability of this ion • ↑CO • ↓SVR • ↑MAP • ↔ HR
- 16. Adrenaline 1) DOC for cardiovascular resuscitation 1mg every 3 min (Ionotropy + chronotropy + pressor action ) 2) DOC for anaphylaxis 0.5 mg bolus f/b 1-10 µg/min infusion 0.5 mg bolus i.m. repeated every 5 min (Mostly ‘coz of bronchodilator action)
- 17. 3) Second-line agent in the management of septic shock Reasons being considered second to Noradrenaline – 1) Splanchnic and renal vasoconstriction at high doses 2) Lactic acidosis 3) Increased myocardial O2 demand and potential for inducing myocardial ischemia 4) Tachyarrhythmias However these observations not found to be significant in following trials -
- 18. EVIDENCE BASED MEDICINE (EBM) 1) Anane et al ( Lancet, 2007 ) - no difference ADR Vs NA ± DOBUTAMINE 28 day mortality – 40 vs 34 % 90 day mortality - 52 vs 50 % 2) Myburgh et al ( Intensive care medicine, 2008 ) ADR Vs NA with use of other drugs in either group Primary outcome – assess time to achieve MAP of 65 (35.1 vs 40 hours) Secondary outcome - 28 day and 90 day mortality – same But Adrenaline group had significant but transient lactic acidosis, tachyarrythmias and insulin requirements in both the studies.
- 19. NOR ADRENALINE 1) First line drug in hyperdynamic septic shock (0.5- 30 µg/min) (↑ C I , ↓ SVR, ↓ MAP ) PROS - 1) ↑ MAP – Better end organ perfusion 2) Efferent > afferent glomerular arteriolar constriction - imroved glomerular filtration 3) Potency > Dopamine 4) Preservation of Splanchnic circulation > Adrenaline 5) Cardiac index > Vasopressin CONS - 1) Need very high dose (10 -30 µg/min ) due to alpha 1 receptor downregulation in sepsis 2) Consequent damage due to vasoconstriction
- 20. EBM 1)Martin et al ( Chest 1993) DOPA vs NA Goal – maintain MAP > 80 or SVR > 1100 dyne or both 5 – improved with DOPA 15 – improved with NA 11 - who didn’t improve with high dose DOPA did improve with NA 2) Martin et al ( Critical care med 2000) High-dose DOPA vs NA Use of norepinephrine was associated with improved survival 3) Bellomo R et al ( Critical care med 2001) NA improves renal blood flow and urine output
- 21. 2) Can be used in spinal shock 3) Cautious use in cardiogenic shock Contraindicated in hypovolemic shock Costlier than dopamine and adrenaline PHENYLEPHRINE Used primarily in situations where severe vasodilatation has led to Hypotension -> shock Eg- Anesthesia-induced hypotension Utility of PNP in hyperdynamic septic shock is debatable Limited trials available till date to support its use
- 22. EBM – use of PNP in septic shock 1) Gregory et al ( Critical Care Med 1991) very small sample size Addition of phenylephrine to dobutamine or dopamine increased mean arterial pressure, systemic vascular resistance & urine output without a change in heart rate 2) Krejci V et al (Crit Care Med- 2006) Compared to epinephrine and norepinephrine, phenylephrine is less likely to decrease microcirculatory blood flow in the splanchnic circulation Advantage of it being useful in situations where other vasopressors cant be used due to tachycardia/ tachyarrythmias
- 23. Isoproterenol Temporary treatment of hemodynamically significant bradycardia unresponsive to atropine till more definitive treatment with an external or transvenous pacemaker is made available Temporary chronotropic and ionotropic support post cardiac transplantation. Due to risk of - Tachycardia/ tachyarrythmias Increased myocardial O2 demand and ischemia not used routinely as an vasoactive drug
- 24. DOPAMINE 1) Hyperdynamic septic shock (when excessive vasodilation is the primary pathology) DOPA @ Mod to high doses cause increase CI > SVR NA preferred over it. May use as an add on to NA 2) Hypodynamic septic shock May be useful 3) Acute decompensated heart failure and hypotension In combination with venodilators, dobutamine
- 25. EBM 1) Sakr et al ( Crit Care Med 2006) (SOAP study – Sepsis Outcome in critically ill Patients ) Dopamine was associated with increased mortality 2) Provoa Et al (Crit Care Med. 2009) SACiUCI trial – portugese population study 28Day mortality NA a/w 3.5 x increase mortality , p= <0.001 Dopamine a/w 0.7x lower mortality, p=0.049
- 26. 3) Daniel de Backer et al ( NEJM 2010) Dopamine Vs NA in shock ( collective) with goal to maintain MAP allowing addition of other drugs to either group 28 day mortality- Overall – same ( 52.5 vs 48.5 %) Septic shock- same Hypovolemic shock- same Cardiogenic shock - more with Dopamine Arrythmic events – More with DOPA group (24.1 vs 12.4 %)
- 27. 4) Ruokonen E et al ( Crit Care Med 1993) DOPA vs NA Former was associated with splanchnic oxygen shunting Splanchnic O2 delivery >>>>> O2 extraction 5) Marik PE et al (JAMA 1994) DOPA vs NA Former was associated with worser intragastic pH values 6) ANZICS (Lancet 2000) DOPA vs PLACEBO No renoprotective effect at lower doses in early renal dysfunction as thought earlier.
- 28. Dobutamine 1) Acute and chronic decompensated heart failure (↑CO,↓SVR and PVR, ↓PCWP ) 2) Concomitant septic shock and depressed cardiac function - Hypodynamic septic shock @ 5 mics/kg /hr will cause ↑CO and improve (not restore) capillary perfusion 3) Doubtful utility in cardiogenic shock- may cause ↑ myocardial O2 demand - myocardial ischemia
- 29. Problems – • Down regulation of β receptors after 72 hrs use – tolerance may develop • Tachyarrytmias, myoischemia • Eosinophilic or hypersensitivity myocarditis with chronic use Ideal candidate – • Severly depressed LV function with low CO • Elevated LV filling pressure • Not associated with significant hypotension (MAP >70)
- 30. Vasopressin 1) Cathecolamine resistant septic shock/ refractory shock 2) Dose reduction of cathecolamines with concomitant use Rationale 1) Relative deficiency of vasopressin in septic shock 2) In hypoxia and acidosis though alpha adrenergic effects of other vasopressors is blunted, pressor effect of vasopressin seen. 3) Diuresis in shock < 24 hrs ( septic, cardiogenic ) shock at low doses as leads to NO and ANP release .
- 31. EBM 1) Russel JA et al ( Crit Care Med 2007) Vasopressin vs NA as monotherapy in septic shock 85% of those with vasopressin needed NA eventually to atttain desired MAP. None from NA group needed VASO 2) Russel JA et al ( NEJM 2008) VASST trial – Vasopressin And S eptic Shock Trial 778 patients with septic shock who were receiving a minimum of 5 μg per minute of norepinephrine to receive either 1) low-dose vasopressin (0.01 to 0.03 U per minute) or 2) norepinephrine (5 to 15 μg per minute) in addition to open-label vasopressors.
- 32. 28 days mortality rates – same Vasopressin Vs norepinephrine (35.4 Vs 39.3% ) Progression to renal failure – lesser with use of vaso Vasopressin Vs norepinephrine (20.8 Vs 38.6% ) 28 days mortality rates In patients with less severe sepsis Patients belonging to category R of RIFLE score Lesser with use of vasopressin – Vasopressin Vs norepinephrine (30.8 Vs 54.7% )
- 33. Other use of vasopressin – Treatment of cardiac arrest unresponsive to epinephrine and defibrillation EBM 1) Aung Ket al : Vasopressin as monotherapy for cardiac arrest.( Arch Intern Med, 2005) 2) Gueugniaud PY, et al Vasopressin and Epinephrine vs. Epinephrine alone in cardiopulmonary resuscitation( N Engl J Med 2008) No benefit in mortality alone or with epinephrine
- 34. PDE-III inhibitors (Milrinone – ionodilators) Used in acute decompensated heart failure Loading dose (50 μg per kg), followed by a continuous infusion @ 0.25 to 0.75 μg / kg/ min. Because it is a potent vasodilator, it should be avoided in the 1) patients with frank hypotension and is 2) contraindicated in patients with severe aortic stenosis.
- 35. Levosimendan Used in acute decompensated heart failure Mebazaa A, et al SURVIVE Trial (JAMA 2007) 1) Intravenous levosimendan showed no benefit compared to dobutamine in reducing all-cause mortality at 180 days (26% vs. 28% ) but 2) Increased the incidence of atrial fibrillation
- 36. Newer drugs • Methylene blue • Glucagon • Cortisol • Hydrocortisone • Levothyroxine • Dotrecognin -alfa
- 37. Shock PCWP CO SVR Preferred agent Hypovolemic / Low preload shock ↓ ↓ ↑ Fluids Cardiogenic shock ↑ ↓ ↑ Ionotropes (Dopa > dobut) Ionodilators Vasogenic /vasoplegic / Distributive shock •Hyperdynamic sepsis •Sepsis with depressed cardiac function •Anaesthetic induced ↑↔ ↔ ↔ ↑ ↓ ↔ ↓ ↓ ↔ N> D> A> V D>N + Dobut PNP, EPHEDRIN
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