Inotropes & Vasopressors Also see vasopressin Receptor pharmacology Agent Alpha 1 Alpha 2 Beta 1 Beta 2 Dopamine Dobutamine + + ++++ ++ 0 Dopamine ++/+++ ? ++++ ++ ++++ Epinephrine ++++ ++++ ++++ +++ 0 Norepinephrine +++ +++ +++ +/++ 0 Alpha receptors post synaptic cardiac alpha 1 receptors:

- stimulation causes significant increase in contractility without an increase in rate

- not mediated by cAMP

- effect more pronounced at low heart rates

- slower onset and longer duration than beta 1 receptor mediated response

receptors: - stimulation causes significant increase in contractility without an increase in rate - not mediated by cAMP - effect more pronounced at low heart rates - slower onset and longer duration than beta receptor mediated response presynaptic alpha 2 receptors in heart and vasculature appear to be activated by norepinephrine released by sympathetic nerve itself and mediate negative feedback inhibition of further norepinephrine release

receptors in heart and vasculature appear to be activated by norepinephrine released by sympathetic nerve itself and mediate negative feedback inhibition of further norepinephrine release post synaptic alpha 1 and alpha 2 receptors in peripheral vessels mediate vasoconstriction Beta receptors post synaptic beta 1 receptors are predominant adrenergic receptors in heart. Stimulation causes increased rate and force of cardiac contraction. Mediated by cAMP

receptors are predominant adrenergic receptors in heart. Stimulation causes increased rate and force of cardiac contraction. Mediated by cAMP post synaptic beta 2 receptors in vasculature mediate vasodilatation Dopamine receptors peripheral DA 1 receptors mediate renal, coronary and mesenteric arterial vasodilatation and a natriuretic response

receptors mediate renal, coronary and mesenteric arterial vasodilatation and a natriuretic response DA 2 receptors: presynaptic receptors found on nerve endings, inhibit norepinephrine release from sympathetic nerve endings, inhibit prolactin release and may reduce vomiting

receptors: presynaptic receptors found on nerve endings, inhibit norepinephrine release from sympathetic nerve endings, inhibit prolactin release and may reduce vomiting stimulation of either DA 1 or DA 2 receptors suppresses peristalsis and may precipitate ileus Dopamine Immediate precursor of norepinephrine and epinephrine Pharmacodynamics Dose dependent effects: <5 mcg/kg/min predominantly stimulates DA 1 and DA 2 receptors in renal, mesenteric and coronary beds causing vasodilatation

and DA receptors in renal, mesenteric and coronary beds causing vasodilatation 5-10 mcg/kg/min: beta 2 effects predominate. Increases cardiac contractility and HR

effects predominate. Increases cardiac contractility and HR >10 mcg/kg/min: alpha effects predominate causing arterial vasoconstriction and increased 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 Dopexamine Synthetic catecholamine structurally related to dopamine Pharmacokinetics 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 beta 1 adrenoreceptors, DA1 and DA2 dopaminergic receptors

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. These effects may be due, in part to the powerful beta 2 effects of dopexamine, causing vasodilatation in skeletal muscle beds and resulting in a much greater degree of general vasodilatation 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 - thrombocytopaenia Caution - patients with hyperglycaemia and hypokalaemia in view of beta-adrenergic activity. Dobutamine Possesses the same basic structure as dopamine but has a bulky ring substitution on the terminal amino group. Synthetic catecholamine Physical properties - supplied in lyophilized form which should be reconstituted with 10 ml of water or 5% dextrose

- compatible with 5% dextrose, N/saline and D/saline but, like dopamine is rapidly inactivated under alkaline conditions

- stable for 24 hrs after reconstitution. May turn slightly pink during this time but this is not associated with a change in potency

- racemic preparation Pharmacodynamics - strong +ve inotropy due to beta 1 agonist effects and alpha 1 agonism

- mild +ve chronotropy due (+) isomer effect on beta receptors

- weaker alpha receptor blockade and beta 2 stimulation, produced by (+) isomer and alpha 1 agonism produced by (-) isomer

- overall peripheral effect should be an increase in blood flow to skeletal muscle (beta 2 agonism) and some reduction in skin blood flow (alpha 1 agonism 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 Pharmacokinetics Admin: slow IVI. Has little direct peripheral vascular effect and does not stimulate norepinephrine release. Skin necrosis due to extravasation is therefore rare and dobutamine can be given via a peripheral line. However the risks of loss of the line in a inotrope dependent patient warrants the use of a central line. Onset of action within 2 min and maximal effect associated with a given infusion rate occurs approximately 10 min after starting the infusion

Elim: metabolized by COMT to inactive metabolites which are excreted in the urine. t1/2 2.3 min Toxicity - side effects similar to other catecholamines but are relatively uncommon

- tachycardia and tachyarrhythmias less frequent than with dopamine

- enhances AV conduction and may precipitate AF in predisposed patients Epinephrine Pharmacokinetics Admin: IV/IM/infiltration Elim: 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-transferase Pharmacodynamics - stimulates alpha 1 and both beta 1 and beta 2 receptors. Effects are mediated by stimulation of adenyl cyclase resulting in an increase in cAMP

- beta2 receptors more sensitive to epinephrine than alpha1 CVS - positive inotrope and chronotrope (NB. mediated by all 3 receptors not just beta 1 )

- increases incidence of dysrhythmias by increasing irritability of automatic conducting system

- constricts vessels of skin, mucosae, 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. Net result: systolic BP rises but diastolic falls

- higher doses: rise in SVR, decreased cardiac output and rise in both systolic and diastolic BP Renal RBF and urine output reduced RS - bronchial tone decreased

- depth of respiration slightly increased

- irregular breathing sometimes seen

- decreases mucosal blood flow; results in reduced mucosal oedema and bronchial secretions GI 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, phospholipid and LDL

- plasma K rises initially due to increased release from liver. Followed by a prolonged fall due to entry into skeletal muscle cells, mediated by beta 2 receptors

- net result is an increase in O 2 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 Clinical use infusion rates of 0.04-1 mcg/kg/min required to increase haemodynamic and oxygen transport variables to supranormal values in septic patients

in septic patients increases MAP predominantly by increased SV with more modest increase in heart rate and systemic vascular resistance (SVR). Dose response for SVR unpredictable. Decreases splanchnic blood flow and increases serum lactate.

Minimal effect on PA pressures Contraindications Relative - patients on MAOIs, tricyclics or receiving halothane, because of risk of VF

- hypertension

- hyperthyroidism Norepinephrine - alpha and beta 1 agonist with no clinically significant beta 2 effects

- equipotent with epinephrine as a beta 1 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 increase CO by increasing 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. Should be considered a temporary measure

Comparison of effects of infusion of epinephrine and norepinephrine: Epinephrine Norepinephrine Heart rate + - Stroke volume ++ ++ Cardiac output +++ 0/- Arrhythmias ++++ ++++ Coronary blood flow ++ ++ Systolic BP +++ +++ MAP + ++ Diastolic BP +/0/- ++ Mean PAP ++ ++ TPR -/+ ++ Cerebral blood flow ++ 0/- Muscle blood flow +++ 0/- Skin blood flow -- -- Renal blood flow - - Splanchnic blood flow - 0/- Oxygen demand ++ 0/+ Blood glucose +++ 0/+ Blood lactate +++ 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 pressure

Little effect on PAWP. Mean PA pressure unchanged or slightly � . Clinical use in doses of 0.01-2 mcg/kg/min reliably and predictably improves haemodynamic variables to normal or supranormal values in the majority of septic patients

effect on oxygen transport variables cannot be determined from current data 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

- in sepsis: patients with low CI (<2 l/min/m2) increase CI and HR without change in BP. In patients with normal CI may decrease BP due to beta 2 effects Ephedrine Naturally occurring amine with both direct and indirect (stimulates norepinephrine 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 epinephrine

- reduces uterine muscle activity

- ? little/no effect on renal blood flow, ? decrease

- side effects similar to epinephrine Pharmacokinetics Admin: PO/IV

Elim: not broken down by MAO. Excreted unchanged by kidney Metaraminol - direct and indirect effects

- alpha and beta agonist

- CVS effects similar to ephedrine except that overall peripheral resistance is increased and thus there is a greater increase in BP, especially diastolic BP 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 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 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) Phenylephrine - similar effects to norepinephrine but probably even shorter acting

- direct 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

- largely replaced by catecholamines Phosphodiesterase inhibitors - inhibit phosphodiesterase in cardiac tissue thereby increasing the level of intracellular cAMP (phosphodiesterase inactivates cAMP) and increasing intracellular calcium availability by causing increased calcium influx via slow channel. This increases rate and force of myocardial contraction

- cAMP also affects diastolic heart function through the regulation of phospholamban (regulatory subunit of the Ca pump of the sarcoplasmic reticulum. Enhances Ca re-sequestration rate and hence improves diastolic relaxation

- synergistic with beta agonists

- also relax vascular smooth muscle resulting in vasodilatation.

- myocardial oxygen consumption and heart rate are not significantly increased

- tolerance is not a feature

- ?? inhibit platelet aggregation

- ?? reduce post-ischaemic reperfusion injury Enoximone Pharmacology - belongs to imidazoline class of cardioactive drugs

- metabolised to an active metabolite which is excreted in the urine.

- elim half life is about 2 hours in normal subjects but about 7 hours in patients with cardiac failure (half life of dobutamine is 2-3 minutes) Clinical studies - vasodilator, weak inotrope and even weaker chronotrope.

- increases cardiac index and reduces ventricular filling pressure by about 50% in patients with CCF. However in hypotensive or volume depleted patients can reduce both cardiac index and blood pressure. Therefore unsuitable for patients with cardiogenic shock and should be used only where BP and PCWP can be monitored.

- inotropic effect may be potentiated by catecholamine such as dobutamine.

- no evidence that it increases long term survival in patients with CCF. Adverse effects - abnormal LFTs

- thrombocytopaenia Uncommon with short term IV use Main disadvantage is long half life so that dose titration takes longer and adverse haemodynamic effects persist for longer. Dose Loading: 0.5-1 mg/kg

Maintenance: 5-10 mcg/kg/min Further reading Rudis MI, Basha MA, Zarowitz BJ. Is it time to reposition vasopressors and inotropes in sepsis? Crit Care Med 1996; 24:525-537 Zaritsky AL. Catecholamines, inotropic medications, and vasopressor agents. In Chernow B. The pharmacologic approach to the critically ill patient. 1994. � Charles Gomersall December 1999