Inotropes & Vasopressors

Inotropes & VasopressorsDr SHASHANK CHAUHAN

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DefinitionsInotropeIncreases cardiac contractility

VasopressorInduces vasoconstriction elevation of mean arterial pressure

Use of inotropes & vasopressorsTo support the failing heart

To support the failing peripheral vasculature

To correct hypotension during anaesthesia (general or regional)

PhysiologySympathetic Nervous SystemPost synaptic NT = NA Exceptions: sweat glands (Ach, muscarinic) and adrenal medulla (Ach, nicotinic)Adrenergic receptors on post synaptic membrane

Catecholamines= adrenergic agonists

Adrenergic receptorsG-protein coupled receptors, 7 transmembrane alpha segmentsAlpha and Beta receptors

Structure-activity relationship of adrenergic drugs

Clinical Effects of Adrenergic ReceptorsAlpha1VasoconstrictionGut smooth muscle relaxationIncreased saliva secretionHepatic glycogenolysis

Alpha2Inhibit NA & Ach releaseStimulate platelet aggregation

Beta1ChronotropyInotropyGut smooth muscle relaxationLipolysis

Beta2VasodilatationBronchiole dilatationVisceral smooth muscle relaxationHepatic glycogenolysisMuscle tremor

Drug and Receptor InteractionsDrugAlpha1Alpha2Beta1Beta2Dopamine

Epinephrine++++++++++0

Norepinephrine

+++++++++0

Dopamine+0+++++++

Dopexamine00++++++

Phenylephrine++0000

Alpha receptors post synaptic cardiac alpha1 receptors:- stimulation causes significant increase in contractility without an increase in rate- not mediated by cAMP- effect more pronounced at low heart ratesslower onset and longer duration than beta1 receptor mediated responsepresynaptic alpha2receptors in heart and vasculature appear to beactivated by norepinephrine released by sympathetic nerve itself andmediate negative feedback inhibition of further norepinephrine release post synaptic alpha1 and alpha2receptors in peripheral vessels mediatevasoconstriction

Beta receptors post synaptic beta1 receptors are predominant adrenergic receptors in heart. Stimulation causes increased rate and force of cardiac contraction. Mediated by cAMP post synaptic beta2 receptors in vasculature mediate vasodilatation

Dopamine receptors peripheral DA1 receptors mediate renal, coronary and mesenteric arterial vasodilatation and a natriuretic response DA2receptors: presynaptic receptors found on nerve endings, inhibit norepinephrine release from sympathetic nerve endings, inhibit prolactin release and may reduce vomiting stimulation of either DA1 or DA2 receptors suppresses peristalsis and may precipitate ileus

EpinephrinePharmacokineticsAdmin: IV/IM/infiltrationElimination: mostly degraded by conjugation with glycuronic and sulphuric acids and excreted in the urine. Smaller part is oxidised by amine oxidase and inactivated by o-methyl-transferasePharmacodynamics- 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 alpha1

CVSpositive inotrope and chronotrope ( mediated by all 3 receptors)- increases incidence of dysrhythmias by increasing irritability of automaticconducting system- constricts vessels of skin, mucosa, subcutaneous tissues, splanchnic area,kidneys (alpha effects)- vessels of muscle and liver are dilated at physiological doses (beta effect)but are constricted at higher doses.- cerebral and pulmonary arteries are constricted- may precipitate angina in patients with IHD- CVS effects reduced by acidosis- at low doses causes: increased cardiac output, slight reduction in SVR,increase in effective circulating volume and increased venous return. Netresult: systolic BP rises but diastolic falls- higher doses: rise in SVR, decreased cardiac output and rise in both systolicand diastolic BP

RenalRBF and urine output reducedRS- bronchial tone decreased- depth of respiration slightly increased- irregular breathing sometimes seen- decreases mucosal blood flow; results in reduced mucosal oedema and bronchial secretionsGI tract- muscle of gut relaxed, pyloric and ileocolic sphincters constricted: leads to ileus- intestinal secretion inhibited- spleen contracts and empties its cells into the circulation

Metabolic- beta stimulation causes increased insulin and glucagon secretion, alpha decreased. Overall epinephrine has anti-insulin effect.- increased blood glucose due to increased mobilization of glycogen.- rise in metabolic rate. Initial rise is independent of liver and is probably due to cutaneous vasoconstriction, causing a rise in body temperature, or increased muscle activity or both. Later, smaller rise is probably due to increased oxidation of lactose by liver- increased lipolysis, muscle catabolism. Results in increased serum cholesterol, phospholipids and LDL- plasma K rises initially due to increased release from liver. Followed by aprolonged fall due to entry into skeletal muscle cells, mediated by beta2receptors- net result is an increase in O2 consumption- may result in lactic acidosis

CNS- CNS stimulation usually very modest- pupillary dilatation- elevates pain threshold- at high doses: anxiety, restlessness from mild cerebral stimulation, throbbing headache, vertigo

Norepinephrine- alpha and beta1 agonist with no clinically significant beta2 effects- equipotent with epinephrine as a beta1 agonist but less potent an alpha agonist in most tissues- used for refractory hypotension- may result in no change or slight decrease in cardiac output and oxygen delivery due to increased afterload- 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. However in some patients may CO by stroke volume. 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.

Comparison of effects of infusion of epinephrine and norepinephrineEpinephrineNorepinephrineHeart rate+-Stroke volume++++Cardiac output+++0/-Arrhythmias++++++++Coronary blood flow++++Systolic BP++++++MAP+++Diastolic BP+/0/-++TPR-/+++Cerebral blood flow++0/-Muscle blood flow+++0/-Renal blood flow--Oxygen demand++0/-Blood glucose+++0/-

NB 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 pressureLittle effect on PAWP. Mean PA pressure unchanged or slightly .Clinical usein doses of 0.01-2 m g/kg/min reliably and predictably improves haemodynamic variables to normal or supranormal values in the majority of septic patientseffect on oxygen transport variables cannot be determined from current data

Dopamine

Immediate precursor of norepinephrine and epinephrine Pharmacodynamics Dose dependent effects: 10 m g/kg/min: a effects predominate arterial vasoconstriction and -BP Pharmacokinetics Marked variability in clearance in the critically ill. As a result plasma concentrations cannot be predicted from infusion rates

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-effects on splanchnic perfusion unclear-increases urine output without increasing creatinine clearance in a number of settings.-Low dose dopamine does not prevent renal failure in critically ill patients

DopexamineSynthetic catecholamine structurally related to dopaminePharmacokinetics-Admin: IV infusion-Distribution: extensive tissue distribution. Drug acts as a substrate for extra-neuronal catecholamine uptake mechanism (uptake 2).-Elimination: short t1/2 of 7 mins (11 mins in patients with low cardiac output). Extensively metabolised in the liver. Both metabolites and parent drug excreted in urine and faeces.Pharmacodynamics-marked intrinsic agonist activity at beta2 receptors-lesser agonist activity at beta1 adrenoreceptors, DA1 and DA2 dopaminergic receptors inhibits neuronal catecholamine uptake by uptake 2-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.-probably not as effective as dopamine at increasing renal blood flow, but causes a substantially greater increase in cardiac index.

Adverse effects-nausea and vomiting most common adverse effect. Respond well to dosage reduction.-tachycardia may precipitate angina in patients with ischaemic heart disease.-said not to have arrhythmogenic potential but is associated with ventricular ectopics.-tremor-reversible reductions in neutrophil and platelet counts.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- thrombocytopaeniaCaution- patients with hyperglycaemia and hypokalaemia in view of beta-adrenergic activity.

DobutaminePossesses the same basic structure as dopamine but has a bulky ring substitution on the terminal amino group.Synthetic catecholaminePhysical properties- supplied in lyophilized form which should be reconstituted with 10 ml ofwater or 5% dextrose- compatible with 5% dextrose, N/saline and D/saline but, like dopamine israpidly inactivated under alkaline conditions- stable for 24 hrs after reconstitution. May turn slightly pink during this timebut this is not associated with a change in potency- racemic preparation

Pharmacodynamics- strong +ve inotropy due to beta1 agonist effects and alpha1 agonism- mild +ve chronotropy due (+) isomer effect on beta receptors- weaker alpha receptor blockade and beta2 stimulation, produced by (+) isomer and alpha1 agonism produced by (-) isomer- overall peripheral effect should be an increase in blood flow to skeletal muscle (beta2 agonism) and some reduction in skin blood flow (alpha1agonism balanced by some alpha blockade). These effects are weak compared to the myocardial effects- 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. Dose required to produce toxic effects seems to be increased equivalently

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

MethoxaminePharmacodynamics- direct and indirect effects- alpha agonist and beta blocker- primary effect is peripheral vasoconstriction resulting in rise in systolic anddiastolic 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 fallsIndications and dosage- hypotensive states due to excessive vasodilatation eg spinal or epiduralblock- 5-10 mg IV acts within 2 mins. Effect persists for about 20 mins. Dose can betitrated against effect in 2 mg bolusesContra-indications- patients on MAOIshistory of hypertensionToxicity- excessive rise in BP; may precipitate myocardial ischaemia- vomiting, headache, desire to micturate, significant reduction in HR- treat with IV alpha blocker (eg phentolamine)

Phenylephrine- similar effects to norepinephrine but probably even shorter acting- direct acting- potent alpha and weak beta agonistcauses 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- largely replaced by catecholamines

EphedrineNaturally occurring amine with both direct and indirect (stimulatesnorepinephrine release from postganglionic sympathetic nerve endings)sympathomimetic effects.Pharmacodynamics- both alpha and beta agonist effects- haemodynamic effects are similar to epinephrine but it has a longer duration of action and is active when administered orally- increased cardiac contractility and heart rate and thus cardiac output- peripheral vasoconstriction is balanced by vasodilation with little overall change in SVR- rise in arterial BP - systolic > diastolic- may increase cardiac irritability- relaxes bronchial and other smooth muscle, but less effective than epinephrinereduces uterine muscle activity - side effects similar to epinephrine Admin: PO/IV Elimination: not broken down by MAO. Excreted unchanged by kidney

Phosphodiesterase III Inhibitors (I)Inhibit PDE III isoenzyme increase intracellular cAMP + cGMP in myocardial & sm. muscle cells

cAMP phosphorylates cellular protein kinases Myocardium: Ca2+ influx more Ca2+ for contraction & improved Ca2+ reuptake improved relaxationSm. Muscle: relaxation & 20 vasodilatation

Clinical effectsIncreased cardiac contractility without increasing myocardial oxygen consumptionDecreased preload and afterload Minimal chronotropic effect

Phosphodiesterase III Inhibitors (II)Clinical uses:Short term treatment for acute on chronic severe CCFSynergistic effect with beta agonistsRole in cardiopulmonary bypass

EnoximoneYellow, effect for 4-6 hoursLoading dose then infusionMonitor for hypotensionHepatic metabolism, renal excretion

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Levosimendan Calcium sensitizer

ActionStabilises interaction between Ca2+ & Troponin C by binding Troponin C in Ca2+ dependent mannerK+-ATP channel opener (PDE III inhibit effect in vitro)

Clinical effectsIncreased cardiac contractility no increase in myocardial oxygen demandVasodilatation resulting in decreased preload & afterloadNot proarrythmogenic

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Vasoactive drugs for shock statesShock stateFirst-tier agentsSecond-tier agentsAnaphylactic shockEpinephrine, 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 (515 mg/minNorepinephrine infused at 0.11 mg/kg/min (0.530 mg/min)Cardiogenic shock, left ventricularSBP 70, norepinephrine infused at 0.11 mg/kg/min (0.530 mg/min)SBP 7090, dopamine infused at 15 mg/kg/minSBP O90, dobutamine infused at 220 mg/kg/minAmrinone, 0.75 mg/kg loading dose, then 510 mg/kg/min(not recommended post-MI)Milrinone, 50 mg/kg loading dose, then 510 mg/kg/min(not recommended post-MI)Cardiogenic shock, pulmonaryembolismDobutamine infused at 5 mg/kg/minNorepinephrine infused at 0.11 mg/kg/minPhenylephrine infused at 1020 mg/kg/minHemorrhagic shockVolume resuscitationDopamine infused at 515 mg/kg/min as a temporizing adjunct

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Neurogenic shockDopamine infused at 515 mg/kg/minNorpinephrine infused at 0.11 mg/kg/minPhenylephrine infused at 1020 mg/kg/min

Septic shockNorepinephrine infused at 0.11 mg/kg/minDobutamine infused at 5 mg/kg/minDopamine infused at 515 mg/kg/minEpinephrine infused at 0.02 mg/kg/min

Toxic drug overdose with shockNorepinephrine infused at 0.11 mg/kg/minPhenylephrine infused at 1020 mg/kg/minGlucagon given as a 5-mg IV bolus, thenas a 15 mg/h infusionCalcium salts: calcium gluconate, 0.6 mL/kg bolus,then a 0.61.5 mL/kg/h infusionInsulin started at 0.1 units/kg/h IV and titratedto a goal of 1 unit/kg/h

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Smaller combined doses of inotropes and vasopressors may be advantageous over 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, and it may be particularly useful in settings of catecholamine hyposensitivity and after prolonged critical illness.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