Inotropes
& Vasopressors
Also see vasopressin
Receptor pharmacology
Agent |
Alpha1 |
Alpha2 |
Beta1 |
Beta2 |
Dopamine |
Dobutamine |
+ |
+ |
++++ |
++ |
0 |
Dopamine |
++/+++ |
? |
++++ |
++ |
++++ |
Epinephrine |
++++ |
++++ |
++++ |
+++ |
0 |
Norepinephrine |
+++ |
+++ |
+++ |
+/++ |
0 |
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
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
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.
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
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
- 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:
|
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
- 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
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
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
- 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
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
|