4. Inotropes Flashcards
An inotrope
substance that affects the force of muscular contraction,
either positively or negatively.
By common usage, however,
the term ‘inotrope’ describes one of a range of drugs
which increase myocardial contractility.
Inotropes MOA
Most inotropes act via a final common pathway to increase the availability of calcium
within the myocyte
adenylyl cyclase leads to an increase in the
production of cAMP from ATP, which in turn activates protein kinase A. This
enzyme phosphorylates sites on the α1-subunits of calcium channels, leading to an
increase in open state probability, a rise in calcium flux and an increase in myocardial
contractile force.
Earlier steps
Earlier steps - lead to the activation of adenylyl cyclase
are considerably more complex than this final pathway,
there being at least 13 G protein-linked myocardial
cell membrane receptors.
β-adrenoceptors, 5-HT receptors, and histamine, prostaglandin
and vasoactive intestinal peptide receptors interact with Gs(stimulatory) proteins
to activate ACh.
Adenosine, ACh and somatostatin interact with Gi(inhibitory) proteins
to inhibit adenylyl cyclase activation, and α1-adrenoceptors and endothelin receptors
interact with Gq proteins to activate phospholipase C and thence protein kinases.
Ca
Calcium leads to the final increase in contractility,
almost all the inotropes in common use have actions that are cAMP dependent.
These include dobutamine, adrenaline, dopexamine, noradrenaline, dopamine, isoprenaline, enoximone, milrinone,
ephedrine and glucagon
Inflammatory response
Inflammatory response: inotropes also appear to modulate the cytokine response.
They inhibit secretion of TNF and alter the balance between pro-inflammatory
cytokines, particularly IL-6, and anti-inflammatory molecules such as IL-10.
Dobutamine
a synthetic catecholamine derivative of isoprenaline which
is predominantly a β1-adrenoceptor agonist
dose-dependent effects at β2- and α1-receptors.
It increases contractility, has minimal effects on heart rate and has little
direct effect on vascular tone
does not act at renal dopamine receptors, but may
increase urine output by improving circulatory performance
quoted dose range
is 2.5–10.0 μg kg−1 min−1, titrated against response, but much higher rates may be
needed in the critically ill.
Adrenaline
Exogenous and endogenous catecholamine,
which is both an α1-and β-agonist.
It causes an α1-mediated increase in the force and rate of myocardial
contraction, coupled with an
increase in stroke volume secondary to enhanced venous return
In low doses, β1-mediated vasodilatation is prominent,
but the BP rises because of the increase in cardiac output.
As the dose increases so both α- and β-effects are
seen, whereas at high doses α1-vasoconstriction predominates.
In the context of critical care,
adrenaline is given by intravenous infusion at a rate of 0.05–0.20 μg kg
Noradrenaline
Noradrenaline is another exogenous and endogenous catecholamine.
It is a powerful α1-agonist with weaker
β-effects which are most pronounced at low doses
(<0.05 μg kg−1 min−1).
Technically, it is more a vasopressor than a direct inotrope,
but it has become the first-line agent in many critical care units.
(Rises in SVR are associated
with increases in cardiac contractility.
This is the Anrep effect.)
Dopexamine
inodilator which increases myocardial contractility while decreasing SVR
dopamine analogue which also acts both at dopaminergic and
β2-adrenergic receptors. It has no effect at α-receptors.
Dopamine
is an endogenous precursor of noradrenaline,
which acts on dopaminergic DA1 and DA2 receptors
as well as at adrenoceptors
effects are dose-dependent:
at low doses (up to 5.0 μg kg−1 min−1)
it stimulates mainly dopamine receptors,
and it was believed that,
because this caused renal vasodilatation,
it conferred a renal protective effect
(There is no evidence for this purported benefit.)
At infusion rates of between 5 and 10 μg kg−1 min−1 it causes β1-mediated increases
in myocardial contractility and cardiac output
Isoprenaline
synthetic catecholamine with very potent β-adrenergic effects
(both β1 and β2),
but with no α-adrenergic activity
increase in myocardial contractility and heart rate.
It is the drug of choice for pharmacological treatment of complete heart block and for
overcoming overdose with β-blockers
Levosimendan
increases myocardial contractility by enhancing the sensitivity of
cardiac myocytes to calcium (it binds to cardiac troponin C
and reduces systemic vascular and coronary vascular resistance
(mediated via the opening of ATP sensitive K+ channels in vascular smooth muscle, both venous and arterial
does not increase intracellular free calcium and improves cardiac output
without increasing oxygen demand. Its elimination half-life is around 60 minutes
loading dose of
24 μg kg–1 followed by infusion at a rate of 0.1–0.2 μg kg min
Enoximone and milrinone
increase in cAMP
action of phosphodiesterase-III (PDE-III).
enzyme is responsible for the intracellular degradation of cAMP
drugs increase contractility while causing peripheral vasodilatation
dose of enoximone is 5–20 μg kg−1 min−1 after a loading dose of 90 μg k
these drugs can be useful if myocardial β-adrenoceptor downregulation
has occurred and the receptors have become desensitized
long-standing heart failure and prolonged exposure to
circulating catecholamines, but it can also occur acutely
Digoxin
is one of the cardiac glycosides
also acts ultimately via an increase in calcium in the sarcoplasmic reticulum
other inotropes, however, it inhibits Na+/K+ ATPase
increase in sodium concentration
reduces the inwardly directed
gradient across the cell membrane
One calcium ion is extruded from the cell in exchange for three sodium
ions. More calcium is therefore available for release from the sarcoplasmic reticulum
with each action potential
Glucagon
Glucagon exerts its positive inotropic effect via an increase in the synthesis of cAMP.
It is rarely used for this specific purpose, but more commonly in the emergency
treatment of hypoglycaemia. (It mobilizes hepatic glycogen.)
