VASOACTIVE DRUGS

Inotropes and vasopressors

Support of the cardiovascular system forms a cornerstone in the management of the critically
ill patient:

• Therapy is directed towards optimising cardiac output, organ blood flow andorgan
perfusion pressure. This in turn leads to improved oxygen delivery.

• The drugs used to achieve these goals work primarily on receptors found through-out
the cardiovascular system. Other agents act by inhibiting catecholamine metabolism.

Receptor physiology

Adrenoceptors form an integral part of the sympathetic nervous system. They Are acted upon
by noradrenaline released from nerve terminals, and by circulating adrenaline. The receptors
are divided into and subgroups:

● Alpha1 receptors are found primarily in blood vessels. Stimulation of these receptors

leads to contraction of vascular smooth muscle with subsequent vasoconstriction.

● Alpha2 receptors are located at pre-synaptic nerve terminals. They have a role in

negative feedback, stimulation inhibiting further noradrenaline release.

● Beta1 receptors are located in the heart and intestinal smooth muscle. Noradrenaline

and adrenaline are equipotent at these sites. Stimulation results in positive inotropy
and chronotropy. Intestinal smooth muscle is relaxed.

● Beta2 receptors are found in bronchial, uterine and vascular smooth muscle, and

stimulation results in muscle relaxation. This leads to bronchodilation and

vasodilation. Beta 2 receptors are more sensitive to adrenaline, suggesting they act
primarily as hormonal receptors.

● The normal heart contains both beta1 and beta2 receptors in a ratio of 3:1. This may

change to 3:2 in severe heart failure due to downregulation of beta1 receptors.

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Mechanism of action:

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 Receptors Location Action

● Adrenergic ● Smooth muscles ● Vasoconstriction

alpha1
● Vascular walls ● Increased force of heart

contraction
● Heart

● Adrenergic ● Central nervous ● Sedation

alpha2 system
● Analgesia
● Alveoles

● Vasodilation
● Pancreas

● Inhibition of insulin

release

● Adrenergic ● Cardiac muscle ● Increased force and rate

beta1 of heart contraction

● Sinus node

● AV junction

● Adrenergic ● Skeletal vascular ● Vasodilation

beta2
● Bronchial smooth ● Bronchodilation

muscles

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 ● Liver ● Hepatic glycogenolysis

● Cell membrane

● Dopamine ● Kidney ● Vasodilation

● Heart ● vasoconstriction by

inhibiting release of
● Cerebral vascular norepinephrine

beds

● Vasopressin ● Vascular smooth ● Vasoconstriction

muscles

Individual drugs

Adrenaline (epinephrine)

Adrenaline is the body’s natural sympathomimetic agent. It is active at all adrenoceptors and
an infusion will lead to an increase in cardiac output and blood pressure with an
accompanying tachycardia.

The use of adrenaline as a single agent is attractive but there are serious side

effects associated with its use:

• It has potent dysrhythmogenic effects. The increase in cardiac workload may

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result in myocardial ischaemia.

• In severe sepsis the use of adrenaline can reduce splanchnic blood flow.

Noradrenaline (Norepinephrine)

This compound is predominantly used for its effects at Alpha1 receptors where stimulation
results in vasoconstriction with a resultant increase in blood pressure. It also has activity at
Beta 1 receptors.

● Noradrenaline is usually the first-line vasopressor and is often used to counteract the

vasodilatory effects of sedation.

● The agent is widely used in the treatment of sepsis where vasodilation is a major

component of the disease process. However, there have been concerns regarding its
potentially detrimental effects on various regional circulations.

Dobutamine

Dobutamine is a synthetic drug acting mainly at Beta receptors although it does possess some
activity. It is a potent inotrope and is the agent of choice in cardiogenic shock.

• The increase in cardiac output secondary to increased stroke volume may be due to
improved ventricular compliance.

• Tachycardia may be troublesome.

• Dobutamine may improve renal function probably as a result of improved cardiac output.

• When compared to dopamine, dobutamine improves gastric mucosal perfusion in septic

patients. This may be beneficial during the establishment of enteral feeding.

Dopamine

Dopamine acts at alpha,Beta and dopaminergic receptors. At low doses ( 5 g/kg/min) the
dopaminergic effects predominate leading to improved renal blood flow. The beta and
alpha effects, seen at concentrations of 5–10 g/kg/min and 10 g/kg/min,respectively, allow
the drug to be used as an inotrope and a vasopressor. However, individual variation does not
allow for such easy prediction of effects at a given dose.

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Dopexamine

This is a relatively new drug with mainly Beta2 activity. It is a synthetic analogue of
dopamine and also demonstrates agonism at dopaminergic receptors:

• Dopexamine increases renal and splanchnic blood flow. Concerns over the effects of
dopamine have led to the use of dopexamine as an alternative.

• At doses of 1 g/kg/min dopexamine exhibits an inhibitory effect on prolactin release, similar

to that seen with dopamine.

Enoximone

Enoximone is a phosphodiesterase III inhibitor and acts to reduce the breakdown of cyclic
AMP. This leads to vasodilation and increased cardiac output (i.e it is an inodilator).The drug
also exhibits lusitropy – enhancing ventricular relaxation allows increased coronary blood
flow.Its use is limited due to the significant hypotension that can occur.

Milrinone

This phosphodiesterase inhibitor has similar properties to enoximone.Hypotension may be

worse with milrinone and its use is restricted to the treatment of severe cardiac failure.

Phenylephrine

This agent is a potent alpha1 agonist. It is used primarily in vasodilation unresponsive to

noradrenaline.

Vasopressin

Vasopressin is a naturally occurring compound, which is synthesised in the hypothalamus

and released from the posterior pituitary gland. It has both vasopressor and anti-diuretic
activity, mediated via vasopressin receptors (V1 and V2).

V2 receptors are located in the renal-collecting tubules and stimulation promotes water
reabsorption. V1 receptors are expressed in vascular smooth muscle and are responsible for
vasoconstriction.

General points for inotropes and vasopressors

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• Positive inotropes increase cardiac output. Mean arterial pressure (MAP) will usually
increase as a secondary effect.

• Vasoconstrictors will increase blood pressure.

• Fluid resuscitation should precede the start of cardiovascular support in the presence of
hypovolaemia. Starting therapy in a “dry” patient may have disastrous consequences.

• Severe metabolic derangements (e.g. hypophosphataemia), can impair cardiac function.

They should be sought for and corrected.

• Catecholamines may affect blood glucose control and frequent measurements should be
taken.

• Vasoactive drugs are rapidly acting with a short half-life. They are given by intravenous
infusion that allows easy titratability to desired end points.

Safe administration of inotropes and vasopressors

Small changes in the rate of infusions of these agents may produce a rapid response in

patients’ heart rate and blood pressure. In some ICU patients, the maintenance of blood

pressure is extremely dependant on the inotrope and vasopressor infusions and hence careful

titration and continuous monitoring is essential.

The above drugs must always be administered via a central venous catheter (CVC) (the only
exception being during an emergency situation).

Inotropes and vasopressors should never be purged or bolused. Purging results in

uneven doses of the drug being given to the patient and as a result the patient can have
huge changes in their haemodynamic parameters.

Inotropes and vasopressors need to be regulated by continuous infusion to maintain a

consistent dose delivery and haemodynamic control. Continuous monitoring of blood
pressure with arterial lines is necessary to help close monitoring and titration of therapy.

ICU patients commonly require multiple drug infusions together with intermittent drug
administration. These infusions and drugs need to be distributed amongst the available

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lumens according to safe administration, drug compatibility and the number of lumens
available.

Issues to consider in safe administration

● How ‘secure’ the lumen is, with the more distal lumens being the most secure (i.e.
drug delivery is less likely to be affected if the line migrates outwards). In general, the
most distal lumen should be reserved for emergency drug access and the second most
distal lumen reserved for vasoactive drugs.
● The use of double/multiple concentrations with inotropes and vasopressors is not
considered best practice. For patients on fluid restrictions, aim to optimize their fluid
management in other ways.
● The rate of administration of drugs on the same lumen (co-administration of a fast-
running drug can increase the delivery of a slow-running drug through the venturi
effect. This can result in unexpected cardiovascular changes if a drug is bolused
through a lumen through which a vasoactive drug is also being delivered).

Drug administration is also limited by drug compatibility. All lines should be monitored for
the formation of precipitates when more than one drug is delivered to a lumen.

The ongoing need for a central venous catheter should be reviewed daily and the central
venous catheter removed if it is no longer necessary.

USING THE CENTRAL VENOUS CATHETER FOR INOTROPES:

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The distal lumen

Opens at the catheter tip and is the most secure lumen.Reserved for central venous catheter
measurements, blood specimen collection and emergency drug administration.May be used
for intermittent drug administration if there is no other option.

Medial lumen

Second most distal lumen (opening 2 cm from the tip) and is the second most secure
lumen.Vasoactive drugs should be infused via this lumen (depending on compatibilities):

Adrenaline (epinephrine)

Dopamine

Dobutamine

Isoprenaline

Milrinone

Noradrenaline (norepinephrine)

Vasopressin (argipressin)

Proximal lumen

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If limited access, other infusions may run through this lumen provided they are physically
compatible and will not be bloused.Not appropriate for infusing vasopressors or inotropes
due to the risk for extravasation of drug into tissue.

Hypotensive agents

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• Occasionally it is necessary to lower a patient’s blood pressure (e.g. the obstetric patient
with pre-eclampsia).

• Acute uncontrolled hypertension requires rapidly acting agents to minimise end-organ

damage.

The commonest drugs in use are briefly outlined below.

Directly acting vasodilators

• Glyceryl trinitrate (GTN):

Predominantly causes venodilation resulting in reduced pre-load. Useful in patients with

myocardial ischaemia and ventricular failure. Given by intravenous (IV) infusion.

• Hydralazine:

Direct arteriodilator. Can be given orally or administered IV as a bolus or infusion. Mainly
used in the treatment of pregnancy-induced hypertension.

Sodium nitroprusside:

Arterio- and veno-dilator. Acts by stabilising smooth muscle membrane. Infusion leads to
compensatory tachycardia. May cause cyanide toxicity.

Adrenergic receptor antagonists

• Labetalol:

Acts at alpha1 and beta receptors, the latter predominating especially on intravenous
administration. Useful in obstetric hypertensive emergencies.

• Esmolol:

Rapidly acting, selective beta1 blocker. It has a short life (9 mins) making it eminently
suitable for IV infusion.

• Phentolamine:

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Competitive alpha blocker used in the treatment of hypertension associated with
phaeochromocytoma.

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Conclusion:

In conclusion, inotropes and vasopressors play an essential role in the supportive care of a
number of important cardiovascular disease processes.

A better understanding of the physiology and important adverse effects of these medications
should lead to directed clinical use, with realistic therapeutic goals.

References:

1) Ian McConachie, Handbook of ICU therapy, 2nd edition page no. 146-156.
2) K D Tripathi, Essentials of medical pharmacology, 7th edition.
3) David E.Golan,Ehrin J Armstrong: Principles of pharmacology, 4th edition
4) Saunders Nursing drug handbook 2019 edition
5) https://www.ncbi.nlm.nih.gov/books/NBK482411/
6) https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.107.728840
7) https://www.safercare.vic.gov.au
8) https://www.thecardiologyadvisor.com/home/decision-support-in-medicine/
cardiology/interventional-pharmacology-inotropes-and-vasopressors/

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