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Inotropes & Vasopressors

Also see vasopressin

Receptor pharmacology

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 rates
  - slower onset and longer duration than beta₁ receptor mediated response
• presynaptic alpha₂ 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 alpha₁ and alpha₂ receptors in peripheral vessels mediate vasoconstriction

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
• DA₂ receptors: 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

Dopamine

Immediate precursor of norepinephrine and epinephrine

Pharmacodynamics

Dose dependent effects:

• <5 mcg/kg/min predominantly stimulates DA₁ and DA₂ receptors in renal, mesenteric and coronary beds causing vasodilatation
• 5-10 mcg/kg/min: beta₂ 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 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. These effects may be due, in part to the powerful beta₂ 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 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 (alpha₁ 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 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

CVS

- positive inotrope and chronotrope (NB. mediated by all 3 receptors not just beta₁)
- 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 beta₂ receptors
- 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

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 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 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:

• 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 beta₂ 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

©Charles Gomersall, February, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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