Inotropes and vasopressors

The term inotropic state is most commonly used in reference to various drugs that affect the strength of contraction of heart muscle (myocardial contractility). However, it can also refer to pathological conditions. For example, enlarged heart muscle (ventricular hypertrophy) can increase inotropic state, whereas dead heart muscle (myocardial infarction) can decrease it.

1. INOTROPES AND VASOPRESSOR USED IN ICU PRESENTED BY PANKAJ SINGH RANA NURSE PRACTITIONER 1 ST YEAR

2. Definitions Inotrope Increases cardiac contractility Vasopressor Induces vasoconstriction pressure elevation of mean arterial

3. Use of inotropes & vasopressors To support the failing heart To support the failing peripheral vasculature To correct hypotension during anaesthesia (general or regional)

4. Clinical Effects of Adrenergic Receptors Alpha 1 Vasoconstriction Gut smooth muscle relaxation Increased saliva secretion Hepatic glycogenolysis Alpha 2 Inhibit NA & Ach release Stimulate platelet aggregation

5. Beta 1 Chronotropy Inotropy Gut smooth muscle relaxation Lipolysis Beta 2 Vasodilatation Bronchiole dilatation Visceral smooth muscle relaxation Hepatic glycogenolysis Muscle tremor

6. Dopamine receptors 1. Peripheral DA1 receptors mediate renal, coronary and mesenteric arterial vasodilatation and a natriuretic response 2. DA2receptors : presynaptic receptors found on nerve endings, inhibit norepinephrine release from sympathetic nerve endings, inhibit prolactin release and may reduce vomiting stimulation vasoconstriction

7. Drug and Receptor Interactions

8. EPINEPHRINE Pharmacokinetics Admin: IV / IM Elimination: mostly degraded by conjugation with glycuronic and sulphuric acids and excreted in the urine. Pharmacodynamics stimulates alpha1 and both beta1 and beta2 receptors. Effects are mediated by stimulation of adenyl cyclase resulting in an increase in cAMP beta2 receptors more sensitive to epinephrine than alpha 1

9. USES Hypotension- usual dose 1-70 mcg/min Cardiac arrest- 1-3 mg every 2-3 min during resuscitation Anaphylaxis - 0.3-1mg IM or Subcutaneous. Can be given IV in life threatening anaphylaxis ( dilute 1mg in 10ml of NS and give 1mg every 2-3 min. Children- 10 mcg/kg for cardiac arrest every 5 min if necessary, and subcutaneous in severe anaphylaxis or asthma repeated at 20 min to 4 hours.

10. NO R EPINEPHRINE alpha and beta1 agonist with no clinically significant beta2 effects used for refractory hypotension may result in no change or slight decrease in cardiac output and oxygen delivery due to increased afterload

11. In the non-septic patient produces vasoconstriction in all vascular beds, Including the renal circulation in septic patients increases BP and SVR, often without altering cardiac output. Often improves renal blood flow and urine output in these patients by increasing perfusion pressure without compromising cardiac output. May be useful in cardiogenic shock: increases coronary perfusion pressure.

12. norepinephrine has no effect on renal blood flow in patients with established acute renal failure and in hypotensive patients both epinephrine and norepinephrine may increase renal blood flow by increasing perfusion pressure clinical use in doses of 0.01-2 m c g/kg/min reliably and predictably improves hemodynamic variables to normal.

13. DOPAMINE Immediate precursor of norepinephrine and epinephrine Pharmacodynamics Dose dependent effects: <5 m g/kg/min predominantly stimulates DA1 and DA2 receptors in renal, mesenteric and coronary beds vasodilatation 5-10 m g/kg/min: b 2 effects predominate. cardiac contractility and HR >10 m g/kg/min: a effects predominate arterial vasoconstriction and -BP

14. Pharmacokinetics Marked variability in clearance in the critically ill. As a result plasma concentrations cannot be predicted from infusion rates

15. Clinical use variable effects due to variable clearance increases cardiac output (mainly due to increased stroke volume) with minimal effect on SVR in patients with septic shock increases pulmonary shunt fraction increases urine output without increasing creatinine clearance in a number of settings. Low dose dopamine does not prevent renal failure in critically ill patients

16. DOPEXAMINE marked intrinsic agonist activity at beta2 receptors net effect is reduction in afterload by pronounced arterial vasodilatation, increased renal perfusion by selective renal vasodilatation and mild direct and indirect positive inotropism . Also has positive chronotropic effect.

17. Dosage for acute heart failure and haemodynamic support in patients following cardiac surgery start at 0.5 mcg/kg/min and titrate upwards in increments of 1 mcg/kg/min to a maximum of 6 mcg/kg/min . Contraindications T hrombocytopenia Caution patients with hyperglycaemia and hypokalaemia in view of beta-adrenergic activity.

18. DOBU T AMINE Possesses the same basic structure as dopamine but has a bulky ring substitution on the terminal amino group . Synthetic catecholamine

19. Pharmacodynamics S trong +ve inotropy due to beta1 agonist effects M ild +ve chronotropy O verall peripheral effect should be an increase in blood flow to skeletal muscle (beta2 agonism) and some reduction in skin blood. These effects are weak compared to the myocardial effects .

20. Net effects are an increase in SV and CO. SVR may be unchanged or moderately decreased and arterial pressure may thus rise, fall slightly or remain unchanged. At doses > 15 mcg/kg/min tachycardia and arrhythmias are more likely. Tolerance may be seen after 48-72 hrs, presumably due to down- regulation of beta receptors. May necessitate an increase in dose.

21. ISOPROTERENOL powerful beta agonist with virtually no alpha effects lowers vascular resistance mainly in skeletal muscle but also in renal and mesenteric vascular beds. diastolic BP falls but with usual doses the increase in cardiac output is usually enough to maintain or raise mean BP positive inotrope and chronotrope renal blood flow is decreased in normotensive subjects but is markedly increased in patients with cardiogenic or septic shock PA pressures are unchanged

22. METHOXAMINE Pharmacodynamics direct and indirect effects. alpha agonist and beta blocker. primary effect is peripheral vasoconstriction resulting in rise in systolic and diastolic BP. HR slows due to beta blocking effects and reflex slowing due to rise in BP. no effect on cardiac contractility and so cardiac output falls.

23. INDICATIONS AND DOSAGE hypotensive states due to excessive vasodilatation eg spinal or epidural block 5-10 mg IV acts within 2 mins . Effect persists for about 20 mins . Dose can be titrated against effect in 2 mg boluses

24. Contra-indications patients on MAOIs history of hypertension Toxicity excessive rise in BP; may precipitate myocardial ischaemia vomiting, headache, desire to micturate , significant reduction in HR treat with IV alpha blocker ( eg phentolamine )

25. PHENYLEPHRINE similar effects to norepinephrine but probably even shorter acting potent alpha and weak beta agonist causes peripheral vasoconstriction and thus a rise in BP, especially diastolic often reflex reduction in heart rate only direct effect on heart is to slightly increase myocardial irritability

26. Phosphodiesterase III Inhibitors (I) Inhibit PDE III isoenzyme increase intracellular cAMP + cGMP in myocardial & sm ooth muscle cells cAMP phosphorylates cellular protein kinases Myocardium : Ca 2+ influx more Ca 2+ for contraction & improved Ca 2+ reuptake improved relaxation Sm ooth Muscle : relaxation & 2 vasodilatation

27. Clinical effects Increased cardiac contractility without increasing myocardial oxygen consumption Decreased preload and afterload Minimal chronotropic effect

28. Phosphodiesterase III Inhibitors Clinical uses : Short term treatment for acute on chronic severe CCF Synergistic effect with beta agonists Role in cardiopulmonary bypass

29. Levosimendan Calcium sensitizer Action Stabilises interaction between Ca 2+ & Troponin C by binding Troponin C in Ca 2+ dependent manner . Clinical effects Increased cardiac contractility – no increase in myocardial oxygen demand Vasodilatation resulting in decreased preload & afterload Not proarrythmogenic

30. VASOPRESSIN Vasopressin, also named antidiuretic hormone (ADH), arginine vasopressin (AVP) or  argipressin . MOA I t increases the amount of solute-free water reabsorbed back into the circulation from the filtrate in the kidney tubules of the nephrons. AVP constricts arterioles, which increases peripheral vascular resistance and raises arterial blood pressure

31. It has a very short half-life, between 16–24 minutes It is widely distributed throughout the body and remains in the extracellular fluid. It is degraded by the liver and excreted through the kidneys. Vasopressin infusions are also used as second line therapy for septic shock . Dose start 0.1 unit/hr to 2.4 unit/hr

32. USES Usually given in GI bleeding or esophageal variceal bleeding Also second pressor agent in refractory shock. More effective in late vasodilatory shock than vasopressin alone. Complication includes mesenteric ischemia, hyponatremia, pulmonary vasoconstriction and skin necrosis.

33. TERLIPRESSIN Vasopressin analogue Longer acting than vasopressin ( half life- 6hours) USES Shock associated with sepsis and other inflammation. Decrease cardiac output.

34. Treatment with terlipressin Loading dose- 20 µg/kg followed by Continuous infusion – 4-20 µg/kg/ hr

35. Vasoactive drugs for shock states Shock state First-tier agents Second-tier agents Anaphylactic shock Epinephrine, 1 mL of 1:10,000 solution (100 mg),can be given as a slow IV push, then as a 0.02 mg/kg/min infusion (5–15 mg/min Norepinephrine infused at 0.1–1 mg/kg/min (0.5–30 mg/min) Cardiogenic shock, left ventricular SBP 70, norepinephrine infused at 0.1–1 mg/kg/min (0.5–30 mg/min) SBP 70–90, dopamine infused at 15 mg/kg/min SBP O90, dobutamine infused at 2–20 mg/kg/min Amrinone, 0.75 mg/kg loading dose, then 5–10 mg/kg/min(not recommended post-MI) Milrinone, 50 mg/kg loading dose, then 5–10 mg/kg/min(not recommended post-MI) Cardiogenic shock, pulmonary embolism Dobutamine infused at 5 mg/kg/min Norepinephrine infused at 0.1–1 mg/kg/min Phenylephrine infused at 10–20 mg/kg/min Hemorrhagic shock Volume resuscitation Norepinephrine infused at 0.1–1 mg/kg/min (0.5–30 mg/min)

36. Neurogenic shock Dopamine infused at 5– 15 mg/kg/min Norpinephrine infused at 0.1–1 mg/kg/min Phenylephrine infused at 10–20 mg/kg/min Septic shock Norepinephrine infused at 0.1–1 mg/kg/min Dobutamine infused at 5 mg/kg/min Dopamine infused at 5–15 mg/kg/min Epinephrine infused at 0.02 mg/kg/min Toxic drug overdose with shock Norepinephrine infused at 0.1–1 mg/kg/min Phenylephrine infused at 10–20 mg/kg/min Glucagon given as a 5-mg IV bolus, then as a 1–5 mg/h infusion Calcium salts: calcium gluconate, 0.6 mL/kg bolus, then a 0.6–1.5 mL/kg/h infusion Insulin started at 0.1 units/kg/h IV and titrated to a goal of 1 unit/kg/h

37. Conclusions Inotropes and vasopressor are very essential in treatment of shock. Smaller combined doses of inotropes and vasopressors had benefit than a single agent used at higher doses to avoid dose-related adverse effects. The use of vasopressin at low to moderate doses may allow catecholamine sparing. In cardiogenic shock complicating AMI, current guidelines based on expert opinion recommend dopamine or dobutamine as first-line agents with moderate hypotension (systolic blood pressure 70 to 100 mm Hg) and norepinephrine as the preferred therapy for severe hypotension (systolic blood pressure <70 mm Hg) and effective in septic shock.

38. SUMMARY Understand appropriate clinical application of vasopressors and inotropic agents. In hyperdynamic septic shock, norepinephrine or phenylephrine is first-line agent. Vasopressin as second-line agent to reduce need for other pressors . In cardiogenic shock, norepinephrine is preferred initial agent. After establishing adequate perfusion, Dobutamine added. In anaphylactic shock, 1 st line agent is Epinephrine followed by Vasopressin as second line agent. Epinephrine is the 1 st line agent in hypotension after CABG.

39. thankyou