Inotropes & Vasopressors presentation (1).pptx

Inotropes

1. Inotropes & Vasopressors Moderator: Dr.Keshav Dev Jagar (Associate Professor) Presented by: Dr. Vara Manthan Shailesh

2. Vasopressors are a powerful class of drugs that induce vasoconstriction and thereby elevate mean arterial pressure (MAP). Vasopressors differ from Inotropes, which increase cardiac contractility; however, many drugs have both vasopressor and inotropic effects. Although many vasopressors have been used since the 1940s, few controlled clinical trials have directly compared these agents or documented improved outcomes due to their use .

3. CATECHOLAMINES Catecholamines are drugs that promote blood flow and blood pressure by stimulating adrenergic receptors. Despite differences in adrenergic receptor activation and physiological responses, no catecholamine drug has proven superior to the others for improving clinical outcomes.

4.   Dobutamine : Dobutamine is primarily a strong β1-receptor agonist, but also has weak β2- receptor agonist activity. Ratio of (β1:β2 = 3:1) The β1-receptor stimulation produces an increase in heart rate and stroke volume, while the β2-receptor stimulation produces peripheral vasodilatation . Because the increase in stroke volume is accompanied by a decrease in systemic vascular resistance, the blood pressure is usually unchanged or slightly increased . Increased urine output is due to increase in cardiac output & has no renal vasodilator effect. It comes in 12.5mg /50 mg / ml ampoule of dobutamine hydrochloride. It also comes in a conc. Of 250mg /20 ml vial and 500mg /40 ml vial solution(12.5 mg /ml).

5.  The cardiac stimulation produced by dobutamine is often accompanied by an increase in cardiac work and myocardial O2 consumption & perfusion . These effects can be deleterious in heart failure because cardiac work and myocardial energy needs are already heightened in the failing myocardium . Reduces left ventricular end diastolic pressure ,systemic vascular resistance. Dobutamine has been used to augment cardiac output in patients with decompensated heart failure due to systolic dysfunction . However , the unfavorable effects of dobutamine on myocardial energetics has created a preference for other inodilators in decompensated heart failure . Dobutamine remains the preferred inotropic agent for the treatment of myocardial depression associated with septic shock but it usually must be combined with a vasoconstrictor agent (e.g., norepinephrine) to raise the blood pressure . Uses: myocardial infarction ,cardiogenic shock, post cardiac surgery & in patients for cadiac stress testing in whom exercise testing cannot be done.

6. Dosing Regimen Dobutamine is started at an infusion rate of 3–5 μg/kg/min (without a loading dose), and this can be increased in increments of 3–5 μg/kg/min, if necessary, to achieve the desired effect . The usual dose range is 2 - 10 μg/kg/min . Dose as high as 200 μg /kg/min . have been used safely. Therapy should be driven by hemodynamic end-points, and not by pre-selected dose rates . At a dose above 5 μg/kg/min levo-dobutamine also exerts weak α1 action. Usually given with 5% dextrose / NS to avoid inactivation by alkaline solution. Adverse Effects Dobutamine produces only mild increases in heart rate (5-15 beats/min) in most patients, but it occasionally causes significant tachycardia (rate increases > 30 beats/min) , which can be deleterious in patients with coronary artery disease. Like all positive inotropic agents, dobutamine is contraindicated in patients with hypertrophic cardiomyopathy, cardiac tamponade, aortic stenosis, mitral stenosis, allergy.

7. Dopamine: Dopamine is an endogenous naturally occurring catecholamine that serves as a precursor to norepinephrine. When given as an exogenous drug, dopamine produces a variety of dose-dependent effects, as described. Actions: At low infusion rates (≤ 3 μg /kg/min), dopamine selectively activates dopamine-specific receptors in the renal and splanchnic circulations, which increases blood flow in these regions . Low-dose dopamine also directly affects renal tubular epithelial cells, causing an increase in both urinary ( natriuresis ) and urine output that are independent of the changes in renal blood flow . The renal effects of low-dose dopamine are minimal or absent in patients with acute renal failure .

8. At moderate infusion rates (3 – 10 μg /kg/min), dopamine stimulates β1&2- receptors in the heart and peripheral circulation, producing an increase in myocardial contractility and heart rate, along with peripheral vasodilatation. At high infusion rates (>10 µg/kg/min), it produces a dose-dependent activation of stimulates α1 receptors, in the systemic and pulmonary circulations, resulting in progressive pulmonary and systemic vasoconstriction. Apart from acting directly on receptors it also releases nor epinephrine. so dopamin has got both direct & indirect actions as sympathomimetic. Clinical Uses: Dopamine can be used to manage patients with cardiogenic shock and septic shock, although other measures are favored in these conditions (i.e., mechanical assist devices are preferred for cardiogenic shock, and norepinephrine is preferred for septic shock ). Low-dose dopamine is NOT recommended as a therapy for acute renal failure.

9. Dosing Regimen Dopamine is usually started at a rate of 3 – 5 μg /kg/min (without a loading dose), and the infusion rate is increased in increments of 3 – 5 μg /kg/min to achieve the desired effect . The usual dose range is 3 – 10 μg /kg/min for increasing cardiac output, and 10 – 20 μg /kg/min for increasing blood pressure. Dopamine infusions should be delivered into large, central veins, because extravasation of the drug through peripheral veins can produce extensive tissue necrosis. Adverse Effects: Sinus tachycardia and atrial fibrillation are reported in 25% of patients receiving dopamine infusions . Other adverse effects of dopamine include: increased intraocular pressure , splanchnic hypo perfusion, and delayed gastric emptying, which could predispose to aspiration pneumonia.

10. EXTRAVASATION OF VASOPRESSORS : The risk of tissue necrosis from extravasation of dopamine is a concern with all vasopressor (vasoconstrictor)drug infusions, and eliminating this risk is the reason that large, central veins are recommended for all vasopressor drug infusions . If dopamine or any other vasopressor drug escapes from a peripheral vein into the surrounding tissues, the tendency for ischemic tissue necrosis can be reduced by injecting phentolamine (an α-receptor antagonist) into the involved area . The recommended injectate is a solution containing 5 – 10 mg phentolamine in 15 mL of isotonic saline.

11. Epinephrine: Epinephrine is an endogenous catecholamine that is released by the adrenal medulla in response to physiological stress . It is the most potent natural β-agonist. Actions: Epinephrine stimulates both α-adrenergic and β-adrenergic receptors (β1 and β2 subtypes), and produces dose-dependent increases in heart rate, stroke volume, and blood pressure . Epinephrine is a more potent β1- receptor agonist than dopamine, and produces a greater increase in stroke volume and heart rate than comparable doses of dopamine.

12. The α-receptor stimulation produces a nonuniform peripheral vasoconstriction, with the most prominent effects in the subcutaneous, renal, and splanchnic circulations . Epinephrine also has several metabolic effects, including lipolysis, increased glycolysis, and increased lactate production (from β-receptor activation), and hyperglycemia from α-receptor-mediated inhibition of insulin secretion. Clinical Uses: Epinephrine plays an important role in the resuscitation of cardiac arrest and it is the drug of choice for hemodynamic support in anaphylactic shock . Epinephrine is also used for hemodynamic support in the early postoperative period following cardiopulmonary bypass surgery . Although epinephrine is as effective as other catecholamines in septic shock concerns about side effects have limited its popularity in septic shock.

13. Dosing Regimen: The dosing regimens for epinephrine in cardiac arrest is 1 mg IV every 3–5 minutes . Vasopressor effect can increase coronary perfusion pressure, but cardiac stimulation is counter productive . Dosing for anaphylactic shock is : Epinephrine infusions are not preceded by a loading dose. The initial infusion rate is usually 1 – 35 μg /min (or 0.02 μg /kg/min), and the rate is then increased in increments of 1 – 2 μg /min to achieve the desired effect . The usual dose range for augmenting cardiac output or correcting hypotension is 5 – 15 μg /min.

14. Adverse Effects: Epinephrine creates a greater risk of unwanted cardiac stimulation (which can be deleterious in patients with coronary artery disease) than the other catecholamine drugs . Other adverse effects include hyperglycemia, increased metabolic rate, and splanchnic hypo perfusion (which can damage the mucosal barrier in the bowel ). Epinephrine infusions are accompanied by an increase in serum lactate levels but this is not an adverse effect because it reflects an increased rate of glycolysis (not tissue hypoxia), and the lactate can be used as an alternative fuel source.

15. Norepinephrine: Norepinephrine is an endogenous catecholamine that normally functions as an excitatory neurotransmitter . When used as an exogenous drug, norepinephrine functions as a vasopressor. Actions : The principal action of norepinephrine is α-receptor-mediated peripheral vasoconstriction. However , the adrenergic response to norepinephrine is altered in patients with septic shock . For example, norepinephrine infusions are usually accompanied by a decrease in renal blood flow but in patients with septic shock, renal blood flow is increased by norepinephrine infusions .

16. Similar alterations may also occur with splanchnic blood flow (i.e., normally reduced, but not in septic shock) Norepinephrine is also a weak β1-receptor agonist, but the effects of norepinephrine on stroke volume and heart rate can be comparable to dopamine (a more potent β1-receptor agonist) in patients with septic Shock. Clinical Uses: Norepinephrine is the preferred catecholamine for circulatory support in patients with septic shock . Instead , norepinephrine is favored in septic shock because it has fewer adverse effects than dopamine or epinephrine. Useful for increasing vascular tone in patients with distributive shock.

17.  Dosing Regimen Norepinephrine infusions are usually started at a rate of 8 2-35 μg /min , and the dose rate is then titrated upward or downward to maintain a mean blood pressure of at least 65 mm Hg . The effective dose rate in septic shock varies widely in individual patients, but is usually below 40 μg /min . Hypotension that is refractory to norepinephrine usually prompts the addition of dopamine or vasopressin, but there is no evidence that this practice improves outcomes. Adverse Effects: Adverse effects of norepinephrine include local tissue necrosis from drug extravasation, and intense systemic vasoconstriction with organ dysfunction when high dose rates are required . However , whenever high doses of a vasoconstrictor drug are required to correct hypotension, it is difficult to distinguish between adverse drug effects and adverse effects of the circulatory shock.

18.   Phenylephrine Phenylephrine is a potent vasoconstrictor and synthetic non catecholamine. stimulates α1-adrenergic receptors by a direct effect, indirect acting by ability to evoke release of noradrenaline. Actions: Phenylephrine in a pure α-receptor agonist that produces widespread vasoconstriction. alpha -1 > alpha -2 No/minimal effect on beta receptors. The consequences of this vasoconstriction can include bradycardia, a decrease in cardiac stroke output (usually in patients with cardiac dysfunction), and hypoperfusion of the kidneys and bowel.

19. Clinical Uses: The principal use of phenylephrine is for the reversal of severe hypotension produced by spinal anesthesia . Phenylephrine is not recommended for hemodynamic support in septic shock, although a clinical study comparing phenylephrine and norepinephrine for the early management of septic shock showed no differences in hemodynamic effects or clinical outcomes with the use of either drug . Apart from that specific indications would be in patient with Aortic stenosis where cardiac output is fixed. To maintain mean arterial pressure and as it has only alpha 1 effect so no tachycardia. In patients with HOCM phenylephrine is agent of choice maintain MAP.

20. Dosing Regimen: Phenylephrine can be given as intermittent IV doses. 50-200 mcg IV bolus. continuous infusion (20-100 µg per minute) in adults to maintain normal blood pressure during surgery. Adverse Effects: The principal adverse effects of phenylephrine are Bradycardia , low car- diac output, and renal hypoperfusion .

21. EPHEDRINE: Has direct action on beta & alpha receptors & indirectly stimulates secretion of norepinephrine leading to vasoconstriction & increasing MAP. Commonly used as bolous agent (5-10 mg bolus doses max 50mg) in Anaesthetic induced Hypotension. Once you give one to two doses of ephedrine to maintain BP. In later stages Tachyphylaxis is seen with subsequent doses. Also crosses blood brain barrier and causes confusion. Previously it was preferred agent in parturients who have post spinal hypotension but studies have shown umbilical cord blood P h was lower with ephedrine when compared to phenylephrine. So chance of fetal acidosis was more. So phenylephrine is much better compared to ephedrine. Excreted in breast milk so decision to breastfeed during therapy should be made considering risk of infant exposure.

22. Vasopressin aka Antidiuretic hormone (ADH ): is an osmoregulatory hormone that is also called vasopressin because it produces vasoconstriction .   Actions: The vasoconstrictor effects of vasopressin are mediated by specialized vasopressin (V1) receptors located on vascular smooth muscle . Vasoconstriction is most prominent in skin, skeletal muscle, and splanchnic circulations . Exogenous vasopressin does not increase blood pressure in healthy volunteers, but it can produce significant increases in blood pressure in patients with hypotension caused by peripheral vasodilatation .

23. This type of hypotension occurs in septic shock, anaphylactic shock, autonomic insufficiency, and the hypotension associated with spinal and general anesthesia . Other actions of vasopressin include enhanced water reabsorption in the distal renal tubules (mediated by V2 receptors), and stimulation of ACTH release by the anterior pituitary gland (mediated by V3 receptors ).

24. Clinical Uses : Vasopressin can be used in the following clinical situations : In the resuscitation of cardiac arrest, vasopressin can be given as a single IV dose (40 units) to replace the first or second dose of epinephrine . In cases of septic shock that are resistant, or refractory, to hemodynamic support with norepinephrine or dopamine, a vasopressin infusion can be used to raise the blood pressure and reduce the catecholamine requirement (catecholamine sparing effect) . Unfortunately, there is no survival benefit associated with the this practice. In cases of hemorrhage from esophageal or gastric varices, vasopressin infusions can be used to promote splanchnic vasoconstriction and reduce the rate of bleeding.

25. Dosing Regimen: The plasma half-life of exogenous vasopressin is 5 – 20 min , so vasopressin must be given by continuous infusion to produce prolonged effects . In septic shock, the recommended infusion rate is 0.01 – 0.04 units/min, and a rate of 0.03 units/min is most popular . Adverse Effects: Adverse effects are uncommon with infusion rates < 0.04 units/ hr . At higher infusion rates, unwanted effects can include consequences of excessive vasoconstriction (e.g., impaired renal and hepatic function ). along with excessive water retention and hyponatremia.

26.   Terlipressin : Terlipressin is a vasopressin analogue that has two advantages over vasopressin . First , it is a selective V1 receptor agonist, and does not produce side effects associated with stimulation of the other vasopressin receptors . Secondly , terlipressin has a much longer duration of action than vasopressin, and a single IV dose of 1 – 2 mg can raise the blood pressure for 5 hours . The long duration of action allows terlipressin to be given by intermittent IV dosing. Terlipressin is a potent splanchnic vasoconstrictor , and may prove valuable in the management of variceal bleeding . However , there is an increased risk of splanchnic ischemia with terlipressin , and ischemic effects cannot be reversed for 5 hours after the drug is administered

27. Levosimendan : It is a myofilament calcium sensitizer . It increases myocardial contractility without increasing myocardial ATP consumption, thereby improving contraction at low energy cost . It causes normal or improved diastolic relaxation and vasodilatation . It has been studied in acute decompensated heart failure, during and after cardiac surgery, and postmyocardial infarction . The IV loading dose is 6 to 12 µg/kg given over 10 minutes, followed by an infusion of 0.05 to 2 µg/kg/minute .

28. MILRINONE : Milrinone is a phosphodiesterase inhibitor that enhances myocardial contractility and relaxation via the same mechanism as dobutamine (i.e., cyclic AMP-mediated calcium influx into cardiac myocytes ). Milrinone has similar effects on cardiac performance as dobutamine , but is more likely to produce hypotension . Uses : management of acute LV dysfunction such as after cardiac surgery. Successful weaning of high-risk patients from CPB . Milrinone decreases pul.artery pressure more effectively than dobutamine . IV bolus of 50 µg/kg over 10 min f/b C ontinuous infusion of 0.375 to 0.75 µg/kg/min The maximum daily dose is 1.3 mg/kg/day .

29. Mephentermine : Mephentermine belongs to the class of adrenergic and dopaminergic cardiac stimulants excluding  cardiac glycosides . Used in the treatment of  heart failure . Mephentermine appears to act by indirect stimulation of β-adrenergic receptors causing the release of  norepinephrine  from its storage sites . AV conduction & refractory period of node is shortened,with increase in ventricular conduction velocity. It has a positive   inotropic  effect on the  myocardium . Its onset is 5 to–15 minutes with intramuscular dosing, and immediate with intravenous dosing .

30. Dose : 1) For maintainance of BP in Hypotensive states :30-45 mg IV bolus as single Dose . Repeat dose as needed , an iv infusion of 0.1% Mephentermine in 5% dextrose. 2) Hypotension secondary to spinal anaesthesia in obstetric patient: 15 mg iv as single dose ,repeat dose as needed.

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