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INOTROPES AND VASOPRESSORS
PADRAIG HEADLEY ST7
OBJECTIVES
•

Review physiology of cardiac contraction and inotropy

•

Classify inotropes

•

Discuss their mechanism of action

•

Overview of vasopressors

•

Choosing the right one????

•

The future??
Positive inotropes increase the force of contraction of the
myocardium
The smallest unit functional unit of the myocardium is the
actin-myosin unit
Cross bridge cycle
•Ca binds troponin C and alters tropomysin uncovering actin for binding
•ATP attaches to myosin head and causes rotation and breakdown to ADP and binding to
actin
•On attachment to actin --- further rotation and displacement ADP --produces force (on
time) --- detaches and enters non force state (off time).
•This process cycles
The extent of the force produced per unit time depends on the amount of crossbridges activated. This depends on:
a) the amount of Ca available

b) its affinity to troponin C
c) cross bridge function and co-operativity

European Heart Journal (2011) 32, 1838–1845 doi:10.1093/eurheartj/ehr026

Removal of calcium is
also an active process
HOW DOES THE HEART CONTROL IT'S FORCE OF
CONTRACTION PHYSIOLOGICALLY??
•

Length dependant activation of cross bridges :- the frank
starling mechanism -- improves co-operativity and therefore
most energy efficient means

•

Frequency dependant activation - in normal hearts increase
in heart rate will result in increased intracellular calcium,
defective in disease states and other factors involved -energy dependant

•

Catecholamine mediated activation
Positive
inotropy

Increased work,
imbalances in
supply and
demand, risk of
arrhythmia and
ischaemia

It's increasingly recognised that the economics of these processes may mean that
some inotropes may work without increasing energy requirements.
Both contraction and relaxation are active processes reflecting types of heart
dysfunction - systolic and diastolic
INOTROPES
CLASSIFICATION
BETA ADRENORECEPTORS

β-1 adrenergic

β-2 adrenergic
CATECHOLAMINES
• Natural or synthetic
• Most commonly used agents act on multiple receptors in a
dose-dependent manner

• Have multisystem effects also - central, respiratory, endocrine,
immune
Natural catecholamines
ADRENALINE
• Potent β-1, moderate α-1 & β-2
• Low dose – chronotrope and inotrope
• Increased CO, decreased SVR, variable MAP

• High dose – α effect increases
• Increased CO, increased SVR
DOPAMINE
• Dose range dependent effects:
• 1 – 2 μg/kg/min dopamine-1 receptors in the renal, mesenteric, cerebral, and
coronary beds, resulting in selective vasodilation

• 5 -10 μg/kg/min β-1 stimulation – increased SV, variable effect on HR
• >10 μg/kg/min adrenergic stimulation – vasoconstriction & increased SVR
DOBUTAMINE
• Synthetic derivative of isoprenaline
• Overall an inotrope with vasodilatory properties
• Predominantly β-1 - inotropy, chronotropy, decreased LV filling pressure
• Minimal α and β-2 – overall vasodilation
Inotropes and Vasopressors
PHOSPHODIESTERASE INHIBITORS
• Selective or non selective
• PDE3 inhibitors - Inotropic and vasodilatory
• Mainly in impaired cardiac function and medically refractory heart failure
• Limitations in sepsis due to vasodilatation
Inotropes and Vasopressors
LEVOSIMENDAN
•

Inodilator

•

Enhances sensitivity of troponin C to Ca without increase in intracellular Ca

•

Only acts in presence of high Ca therefore does not affect relaxation phase

•

Opening of ATP K channels causes vasodilation and reduced afterload

•

Overload cardiac output is augmented with improved diastolic relaxation without
an increase in workload

•

In vitro PDE III inhibitor ? In vivo effect

•

Long half life due to active metabolites

•

Given as loading dose followed by 24hr infusion, effects last up to 9 days
OTHERS

Glucagon

Insulin
VASOPRESSORS
ALPHA ADRENORECEPTORS
ADRENALINE
• Potent β-1, moderate α-1 & β-2
• Low dose – chronotrope and inotrope
• Increased CO, decreased SVR, variable MAP

• High dose – α effect increases
• Increased CO, increased SVR
DOPAMINE
• Dose range dependent effects:
• 1 – 2 μg/kg/min dopamine-1 receptors in the renal, mesenteric, cerebral, and
coronary beds, resulting in selective vasodilation

• 5 -10 μg/kg/min β-1 stimulation – increased SV, variable effect on HR
• >10 μg/kg/min adrenergic stimulation – vasoconstriction & increased SVR
NORADRENALINE
• α-1 & β-1
• Potent vasoconstriction, less pronounced increase in CO
• Reflex bradycardia
PHENYLEPHRINE
• Purely alpha-adrenergic agonist
• Increased afterload
•

CO usually actually maintained in patients without prior cardiac dysfunction

•

CO falls in patients with impaired ventricular function
VASOPRESSIN
•

Nanopeptide produced by hypothalamus & released by posterior pituitary.

•

3 receptors
•
•

V2 - aquaporins insertion in renal tubules, release vWF and factor VIII

•
•

V1 – G-protein coupled - vasoconstriction

V3 - anterior pituitary release of ACTH and endorphins

Synthetic derivatives - desmopressin (high V2 effect), terlipressin longer acting
WHICH INOTROPE /
VASOPRESSOR??
WHICH AGENT?
•

Depends on individual patient and type of shock

•

Potential Pitfalls and options
•

Knowing the patient's current cardiovascular status - ? more
cardiac output monitors

•

Recognising that things can change due to multiple factors
including the natural history of the underlying process eg
phases of sepsis, tachyphylaxis to adrenergic agents therefore choice of agent may need to change during course
of illness
SEPSIS
Inotropes and Vasopressors
• Vasopressin and Septic Shock Trial (VASST)
• 778 patients with septic shock randomly assigned to either low dose vasopressin (0.01 to
0.03 units per minute) norepinephrine (5 to 15 mcg per minute)
• similar 28-day and 90-day mortality rates, similar incidence of serious adverse events
•

Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM , Cook DJ, Presneill JJ, Ayers D, VASST Investigators.
Vasopressin ver sus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877
SEPSIS
• Annane et al, Lancet 2007; 370: 676–84, 330 patients with septic shock in French
ICU’s

• Titrated to maintain MAP at 70mmHg, Primary outcome 28 day mortality
CARDIOGENIC SHOCK
•

Little evidence to guide inotropic or vasopressor therapy. ESC guidelines suggest dobutamine
first line+/- noradrenaline if required to maintain perfusion pressures

•

Those that require these agents have a high mortality

•

Revascularisation if required is key

•

Inotropes and vasopressors may actually have a detrimental effect in longer term- everything
we know to improve outcome in heart failure works opposite in effect to these agents.

•

commonly used drugs may be less effective given changes in the myocardial cells due to the
disease state and also due to pretreatment with beta blockade - leading to theory that agents
such as PDEi may be more beneficial in these cases

•

However direct studies between PDEi and dobutamine are all small studies not showing any
difference in outcome
LEVOSIMENDAN
•

Little evidence base to date to direct critical care use

•

Biggest trials to date have been on Decompensated chronic
heart failure - REVIVE and SURVIVE - excluded shocked or
ventilated patients - use associated with reduction in BP
particularly with loading dose

•

Meta analysis suggested potential survival advantage compared
with dobutamine but not with placebo.... Is dobutamine actually
doing harm in these cases??
THE FUTURE???
Inotropes and Vasopressors
BETA BLOCKERS PLUS INOTROPES??
CONCLUSIONS
•

These are commonly used agents in critical care - has
appeared as viva topic in FFICM

•

Evidence base is limited to guide use of one agent over
another, choice should be based on individual patient
characteristics

•

Our understanding of basic science behind inotropy etc is
leading to novel agents / ideas
Inotropes and Vasopressors

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Inotropes and Vasopressors

  • 2. OBJECTIVES • Review physiology of cardiac contraction and inotropy • Classify inotropes • Discuss their mechanism of action • Overview of vasopressors • Choosing the right one???? • The future??
  • 3. Positive inotropes increase the force of contraction of the myocardium The smallest unit functional unit of the myocardium is the actin-myosin unit
  • 4. Cross bridge cycle •Ca binds troponin C and alters tropomysin uncovering actin for binding •ATP attaches to myosin head and causes rotation and breakdown to ADP and binding to actin •On attachment to actin --- further rotation and displacement ADP --produces force (on time) --- detaches and enters non force state (off time). •This process cycles
  • 5. The extent of the force produced per unit time depends on the amount of crossbridges activated. This depends on: a) the amount of Ca available b) its affinity to troponin C c) cross bridge function and co-operativity European Heart Journal (2011) 32, 1838–1845 doi:10.1093/eurheartj/ehr026 Removal of calcium is also an active process
  • 6. HOW DOES THE HEART CONTROL IT'S FORCE OF CONTRACTION PHYSIOLOGICALLY?? • Length dependant activation of cross bridges :- the frank starling mechanism -- improves co-operativity and therefore most energy efficient means • Frequency dependant activation - in normal hearts increase in heart rate will result in increased intracellular calcium, defective in disease states and other factors involved -energy dependant • Catecholamine mediated activation
  • 7. Positive inotropy Increased work, imbalances in supply and demand, risk of arrhythmia and ischaemia It's increasingly recognised that the economics of these processes may mean that some inotropes may work without increasing energy requirements. Both contraction and relaxation are active processes reflecting types of heart dysfunction - systolic and diastolic
  • 11. CATECHOLAMINES • Natural or synthetic • Most commonly used agents act on multiple receptors in a dose-dependent manner • Have multisystem effects also - central, respiratory, endocrine, immune
  • 13. ADRENALINE • Potent β-1, moderate α-1 & β-2 • Low dose – chronotrope and inotrope • Increased CO, decreased SVR, variable MAP • High dose – α effect increases • Increased CO, increased SVR
  • 14. DOPAMINE • Dose range dependent effects: • 1 – 2 μg/kg/min dopamine-1 receptors in the renal, mesenteric, cerebral, and coronary beds, resulting in selective vasodilation • 5 -10 μg/kg/min β-1 stimulation – increased SV, variable effect on HR • >10 μg/kg/min adrenergic stimulation – vasoconstriction & increased SVR
  • 15. DOBUTAMINE • Synthetic derivative of isoprenaline • Overall an inotrope with vasodilatory properties • Predominantly β-1 - inotropy, chronotropy, decreased LV filling pressure • Minimal α and β-2 – overall vasodilation
  • 17. PHOSPHODIESTERASE INHIBITORS • Selective or non selective • PDE3 inhibitors - Inotropic and vasodilatory • Mainly in impaired cardiac function and medically refractory heart failure • Limitations in sepsis due to vasodilatation
  • 19. LEVOSIMENDAN • Inodilator • Enhances sensitivity of troponin C to Ca without increase in intracellular Ca • Only acts in presence of high Ca therefore does not affect relaxation phase • Opening of ATP K channels causes vasodilation and reduced afterload • Overload cardiac output is augmented with improved diastolic relaxation without an increase in workload • In vitro PDE III inhibitor ? In vivo effect • Long half life due to active metabolites • Given as loading dose followed by 24hr infusion, effects last up to 9 days
  • 23. ADRENALINE • Potent β-1, moderate α-1 & β-2 • Low dose – chronotrope and inotrope • Increased CO, decreased SVR, variable MAP • High dose – α effect increases • Increased CO, increased SVR
  • 24. DOPAMINE • Dose range dependent effects: • 1 – 2 μg/kg/min dopamine-1 receptors in the renal, mesenteric, cerebral, and coronary beds, resulting in selective vasodilation • 5 -10 μg/kg/min β-1 stimulation – increased SV, variable effect on HR • >10 μg/kg/min adrenergic stimulation – vasoconstriction & increased SVR
  • 25. NORADRENALINE • α-1 & β-1 • Potent vasoconstriction, less pronounced increase in CO • Reflex bradycardia
  • 26. PHENYLEPHRINE • Purely alpha-adrenergic agonist • Increased afterload • CO usually actually maintained in patients without prior cardiac dysfunction • CO falls in patients with impaired ventricular function
  • 27. VASOPRESSIN • Nanopeptide produced by hypothalamus & released by posterior pituitary. • 3 receptors • • V2 - aquaporins insertion in renal tubules, release vWF and factor VIII • • V1 – G-protein coupled - vasoconstriction V3 - anterior pituitary release of ACTH and endorphins Synthetic derivatives - desmopressin (high V2 effect), terlipressin longer acting
  • 29. WHICH AGENT? • Depends on individual patient and type of shock • Potential Pitfalls and options • Knowing the patient's current cardiovascular status - ? more cardiac output monitors • Recognising that things can change due to multiple factors including the natural history of the underlying process eg phases of sepsis, tachyphylaxis to adrenergic agents therefore choice of agent may need to change during course of illness
  • 32. • Vasopressin and Septic Shock Trial (VASST) • 778 patients with septic shock randomly assigned to either low dose vasopressin (0.01 to 0.03 units per minute) norepinephrine (5 to 15 mcg per minute) • similar 28-day and 90-day mortality rates, similar incidence of serious adverse events • Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM , Cook DJ, Presneill JJ, Ayers D, VASST Investigators. Vasopressin ver sus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877
  • 34. • Annane et al, Lancet 2007; 370: 676–84, 330 patients with septic shock in French ICU’s • Titrated to maintain MAP at 70mmHg, Primary outcome 28 day mortality
  • 35. CARDIOGENIC SHOCK • Little evidence to guide inotropic or vasopressor therapy. ESC guidelines suggest dobutamine first line+/- noradrenaline if required to maintain perfusion pressures • Those that require these agents have a high mortality • Revascularisation if required is key • Inotropes and vasopressors may actually have a detrimental effect in longer term- everything we know to improve outcome in heart failure works opposite in effect to these agents. • commonly used drugs may be less effective given changes in the myocardial cells due to the disease state and also due to pretreatment with beta blockade - leading to theory that agents such as PDEi may be more beneficial in these cases • However direct studies between PDEi and dobutamine are all small studies not showing any difference in outcome
  • 36. LEVOSIMENDAN • Little evidence base to date to direct critical care use • Biggest trials to date have been on Decompensated chronic heart failure - REVIVE and SURVIVE - excluded shocked or ventilated patients - use associated with reduction in BP particularly with loading dose • Meta analysis suggested potential survival advantage compared with dobutamine but not with placebo.... Is dobutamine actually doing harm in these cases??
  • 39. BETA BLOCKERS PLUS INOTROPES??
  • 40. CONCLUSIONS • These are commonly used agents in critical care - has appeared as viva topic in FFICM • Evidence base is limited to guide use of one agent over another, choice should be based on individual patient characteristics • Our understanding of basic science behind inotropy etc is leading to novel agents / ideas

Hinweis der Redaktion

  1. Bit boring but an important topic Has appeared as FFICM viva
  2. Overview of the basic components of the actin myosin system
  3. Overview of the actin myosin function ATP binds to myosin head causing conformational change and metabolism to ADP Binds to actin at myosin binding sites - sliding occurs Release and process cycles Intracytosolic Calcium has and important role in binding to troponins on tropomysin and unwinding making myosin binding sites available
  4. Force of contraction is based on 3 factors Intracellular Ca concentration Voltage gated Ca channels in membrane and SR Reuptake is also and active process Sensitivity of tropC to available Ca Crossbridge optimisation
  5. The heart controls inotropy in states of stress by modifying the 3 previous factors Frank starling - Crossbridge optimisation Heart rate related to Ca levels Catecholamine induced
  6. All to a limit Work Filling time Diastolic coronary flow
  7. Inotropes can be classified based on how they affect these processes
  8. Trend towards increased survival however not significant