This document discusses vasoactive agents and their receptor physiology and clinical applications. It begins by outlining the objectives of understanding vasopressor and inotropic receptor physiology and appropriate clinical use. It then provides background on vasopressors, inotropes, and drugs that have both effects. The majority of the document then discusses the receptor physiology and mechanisms of action of various adrenergic, dopaminergic, and vasopressin receptors. It also covers individual drug classifications, effects, indications, and considerations for agents like epinephrine, norepinephrine, dopamine, dobutamine, milrinone, vasopressin, levosimendan, and vasodilators. Studies comparing agents

1. NITHIYA
Vasoactive agents

2. Objectives
› Understand the vasopressor and inotropic agent receptor
physiology
› Understand appropriate clinical application of vasopressors
and inotropic agents

3. Background
 Vasopressors are class of drugs that elevate Mean Arterial
Pressure (MAP) by inducing vasoconstriction.
 Inotropes increase cardiac contractility.
 Many drugs have both vasopressor and inotropic effecTS

4. Receptor Physiology
› Main categories of adrenergic receptors relevant to
vasopressor activity:
– Alpha-1adrenergic receptor
– Beta-1, Beta-2 adrenergic receptors
– Dopamine receptors
– Vasopressin receptors

5. ALPHA 1 (A1):
A1 receptors are in vascular smooth muscle & also in the myocardium, which
mediate positive inotropic and negative chronotropic effects.
Stimulation of A1 receptors leads to vasoconstriction.
ALPHA 2 (A2):-
A2 receptors are located in large blood vessels.
Stimulation of A2 receptors mediates arterial and venous vasoconstriction.

6. BETA 1 (B1):-
Beta 1 receptors increase heart rate and myocardial contractility.
BETA 2 (B2):-
Beta 2 receptors enhance vasodilation; relax bronchial, uterine and gastrointestinal smooth
muscle
DOPAMINERGIC: Related to the effect of dopamine.

7. Dopaminergic receptors
› D1-5
› D1 like-D1 and D5
› Excitatory-increase cAMP formatoin and PIP2
hydrolysis
› D2 like-D2-D4
› Inhibitory
› Overall effect-vasodilation-reduced SVR

8. VASOPRESSIN RECEPTORS

9. MECHANISM OF ACTION
1

10. Vascular Smooth Muscle
› Calcium dependent effects
– Agents that increase intracellular cAMP increase
intracellular calcium requirements for contraction, thus
encouraging smooth muscle relaxation and vasodilation

11. Vascular Smooth Muscle
› Calcium independent effects
– G protein mediated activation of phospholipase C results in
breakdown of phosphatidylinositol bisphosphate into IP3 and
DAG.
– IP3 releases calcium from the sarcoplasmic reticulum
initiating contraction and DAG activates protein kinase C
with phosphorylation of intracellular proteins

12. SYNTHESIS OF NORADRENALNE

13. CLASSIFICATION
› DIRECT AND INDIRECT ACTING
› DIRECT-adrenaline and noradrenaline
› INDIRECT-dopamine,dobutamine

14. MECHANISM OF ACTION
CATECHOLAMINES-Camp dependent signalling
Adrenaline,noradrenaline,dopamine,dobutamine
PDEIII inhibitors=milrinone,amrinone
Calcium sensitisers-levosimendan

15. INDIVIDUAL AGENTS
› Catecolamines : dopamine, dobutamine,
adrenaline, noradrenaline
› PDE inibitors: milrinone, amrinone
› Vasoconstrictors –Vasopressin,phenylephrine
› Vasodilators -SNP, NTG

16. Effects of Agents
› Pressors: increase systemic vascular resistance and
increase blood pressure
› Inotropes: affect myocardial contractility and
enhance stroke volume
› Chronotropic Agents: affect heart rate
› Lusotropic Agents: improve relaxation during diastole
and decrease EDP in the ventricles
› Dromotropic Agents: Affects conduction speed
through AV node; increases heart rate
› Bathmotropic Agents: affect degree of excitability

17. Epinephrine
› Both an alpha- and beta-adrenergic agent
– Low-dose infusion (0.05-0.3 mic/kg/min)= β activation
› Increase HR, contractility, decrease SVR
– Higher doses(05-1mic/kg/min) =  activation
› Increased SVR and MAP
› Increased myocardial O2 demand

18. Epinephrine
› Indications for its use as a continuous infusion are:
– low cardiac output state
› beta effects will improve cardiac function
› alpha effects may increase afterload and decrease cardiac output
– septic shock
› useful for both inotropy and vasoconstriction

19. Epinephrine
› Adverse effects include:
– Anxiety, tremors,palpitations
– Tachycardia and tachyarrhythmias
– Increased myocardial oxygen requirements and potential to
cause ischemia
– Decreased splanchnic and hepatic circulation (elevation of AST
and ALT)
– Anti-Insulin effects: lactic acidosis, hyperglycemia

20. Norepinephrine
› An epinephrine precursor that acts primarily on 
receptors
› Used primarily for alpha agonist effect - increases SVR
without significantly increasing C.O.
› Used in cases of low SVR and hypotension such as
profound “warm shock” with a normal or high C.O.
state- usually in combination with dopamine or
epinephrine
› Infusion rates titrated between 0.05 to 1 mcg/kg/min

21. Norepinephrine
› Differs from epinephrine in that the vasoconstriction
outweighs any increase in cardiac output.
– i.e. norepinephrine usually increases blood pressure and
SVR, often without increasing cardiac output.

22. Norepinephrine
› Adverse Effects:
– Similar to those of Epinephrine
– Can compromise perfusion in extremities
– More profound effect on splanchnic circulation and
myocardial oxygen consumption

23. Dopamine
› Intermediate product in the enzymatic pathway
leading to the production of norepinephrine; thus, it
indirectly acts by releasing norepinephrine.
› Directly has ,  and dopaminergic actions which are
dose-dependent.
› Indications are based on the adrenergic actions
desired.

24. Dopamine
›  renal perfusion 2-5 mcg/kg/min (dopaminergic
effects) by  sensitivity of vascular smooth muscle to
intracellular calcium (? Effects on UOP)
›  C.O. in Cardiogenic or Distributive Shock 5-
10mcg/kg/min ( adrenergic effects)
› Post-resuscitation stabilization in patients with
hypotension (with fluid therapy) 10-20mcg/kg/min (
adrenergic effects) peripheral vasoconstriction,  SVR,
PVR, HR, and BP

25. Low dose dopamine in renal failure

26. ADVERSE EFFECTS
› Extravasation
› Tachyphylaxis
› Immunosuppression and endocrine disturbances
› Increased myocardial o2 demand
› Tachycardia and arrhythmia

27. Dobutamine
› Synthetic catecholamine with 1 inotropic effect
(increases stroke volume) and 2 peripheral
vasodilation (decreases afterload)
› Positive chronotropic effect 1 (increases HR)
› Some lusitropic effect
› Overall, improves Cardiac Output by above beta-agonist
acitivity

28. Dobutamine
› Used in low C.O. states and CHF e.g. myocarditis,
cardiomyopathy
› In combination with Epi/Norepi in profound shock
states to improve Cardiac Output and provide some
peripheral vasodilatation

29. Studies
› Martin: Norepi in Septic Shock
– 97 patients in septic shock
– Dopamine started at 5mcg/kg/min, titrated to
15mcg/kg/min
– If hypotension persisted:
› DA increased to 25mcg/kg/min OR
› NE added at 0.5mcg/kg/min

30. Martin et al
› Patients receiving NE had best survival rate on all days
of hospital stay (p<0.001)
› Mortality strongly associated with high lactate and
low urine output
› “NE was associated with a highly significant
decrease in hospital mortality. The data contradict
the notion that norepinephrine potentiates end
organ hypoperfusion through excessive
vasoconstriction

31. Studies
› De Backer: Norepi v Dopamine in Shock.
– Multicenter study, 1679 patients
– DA with 52.5% mortality
– NE with 48.5% mortality (p=0.10)
– More arrhythmic events with DA (207v102)

32. DeBacker et al
› Included Septic (62.2%), Cardiogenic (16.7%), and
Hypovolemic (15.7%) shock.
› More patients in DA group required 2nd pressor
› Subgroup: DA in cardiogenic shock increased
mortality significantly (p=0.03)
› Conclusion: “This study raised serious concern about
the safety of Dopamine”

33. RECEPTORS

34. Milrinone/Amrinone
› Belong to class of agents “Bipyridines”
› Non-receptor mediated activity based on selective
inhibition of Phosphodiesterase Type III enzyme
resulting in cAMP accumulation in myocardium
› cAMP increases force of contraction and rate and
extent of relaxation of myocardium
› Inotropic, vasodilator and lusitropic effect
› Advantage over catecholamines:
– Independent action from -receptor activation, particularly
when these receptors are downregulated (CHF and chronic
catecholamine use)

35. Milrinone
› Increases CO by improving contractility, decreased
SVR, PVR, lusotropic effect; decreased preload due to
vasodilatation
› Unique in beneficial effects on RV function
› Protein binding: 70%
› Half-life is 2.3 hours
› Elimination: primarily renally excreted
› Load with 50 mcg/kg over 30 mins followed by 0.25 to
0.75 mcg/kg/min
› No increase in myocardial O2 requirement

36. Vasopressin
› a peptide hormone released by the posterior pituitary
in response to rising plasma tonicity or falling blood
pressure
› possesses antidiuretic and vasopressor properties
› deficiency of this hormone results in diabetes insipidus

37. Vasopressin
› Administration
– interacts with two types of receptors
› V1 receptors are found on vascular smooth muscle cells and mediate
vasoconstriction
› V2 receptors are found on renal tubule cells and mediate antidiuresis
through increased water permeability and water resorption in the
collecting tubules
› Newer drug to ACLS for resuscitation
› Use in refractory septic shock with low SVRI in
pediatrics?

38. VASOPRESSIN LEVELS IN SHOCK

39. VASST

40. Levosimendan
Calcium sensitiser
› Binds to troponin C and change configuration of tropomyosin
and increases contractility
› Opens potassium channels-reduced SVR and coronary
vasodilation
› Does not increase myocardial o2 demand
› SV/CO/HR increases
› Pulmonary arterial pressure and MAP decreases
› Atrial arrhythmias common
› Half life-1.5-2 hours
› Metabolite OR-1896 half life-70-80hours

41. Calcium Sensitisation by
Levosimendan
› Enhanced contractility of myocardial cell
by amplifying trigger for contraction with no
change in total intracellular Ca2+

42. Effects of Opening
ATP-Sensitive Potassium Channels
› Reduces preload and afterload
› Increased coronary blood flow
(Lilleberg et al. Eur Heart J. 1998;19:660-668.)
› Anti-ischemic effect
(Kersten et al. Anesth Analg.
2000;90:5-11;Kaheinen et al.
J Cardiovasc Pharmacol.
2001;37:367-374.)

43. Levosimendan
› Loading dose of 12mic/kg over 10 minutes f/b
› Continous infusion of 0.1-0.2 mic/kg/min
› TRIALS
› LIDO/CASINO/SURVIVE TRIALS
› Compared LM with dobutamine
› REVIVE and RUSSLAN TRIAL
› Compared LM with placebo

44. Istaroxime
› Ino lusitropy
› Short half life

45. Vasodilators
› Classified by site of action
› Venodilators: reduce preload - Nitroglycerin
› Arteriolar dilators: reduce afterload Minoxidil and
Hydralazine
› Combined: act on both arterial and venous beds and
reduce both pre- and afterload Sodium Nitroprusside

46. Nitroprusside
› Vasodilator that acts directly on arterial and venous
vascular smooth muscle.
› Indicated in hypertension and low cardiac output
states with increased SVR.
› Also used in post-operative cardiac surgery to
decrease afterload on an injured heart.
› Action is immediate; half-life is short; titratable action.

47. Nitroprusside
› Toxicity is with cyanide, one of the metabolites of the
breakdown of nipride.
› Severe, unexplained metabolic acidosis might
suggest cyanide toxicity.
› Dose starts at 0.5 mcg/kg/min and titrate to 5
mcg/kg/min to desired effect. May go higher (up to
10 mcg/kg/min) for short periods of time.

48. Nitroglycerine
› Direct vasodilator as well, but the major effect is as a
venodilator with lesser effect on arterioles.
› Not as effective as nitroprusside in lowering blood
pressure.
› Another potential benefit is relaxation of the coronary
arteries, thus improving myocardial regional blood flow
and myocardial oxygen demand.

49. Nitroglycerine
› Used to improve myocardial perfusion following
cardiac surgery
› Dose ranges from 0.5 to 8 mcg/kg/min. Typical dose
is 2 mcg/kg/min for 24 to 48 hours post-operatively
› Methemoglobinemia is potential side effect

50. Classification
Agent Physiologic response End result Examples
Inotrope ↑ cardiac contraction ↑ CO, BP unchanged or
↑
Dop, dobut, milrin,
Adr, NA
Chronotrope ↑ HR ↑ CO , ↑ HR Isopren, dop, adr,
dobut ( higher dose)
Vasopressor ↑ vascular tone, ↑ SVR& PVR ↑ BP, CO unchanged or
↓
Adr,, NA, vasopressin,
dop ( higher dose)
Vasodilator ↓ arterial + venous tone, ↓ SVR &
PVR
BP unchanged or ↓, CO
↑
SNP, NTG, milrinone
Inodilator ↑ cardiac contraction,
↓ SVR & PVR
↑ CO , , BP unchanged
or ↑
Milrinone, dobut,
levosimendan
Lusitrope diastolic relaxation of
ventricles
↑ CO ( if diastolic
dysfunction present)
milrinone

51. PRACTICAL CONSIDERATIONS

52. Central vs. Peripheral line
› Jean-Damien, R et al. Central or peripheral catheters for initial
venous access of ICU patients
– Patients randomized: peripheral (N=128) or central access (N=135)
› Included epinephrine/norepinephrine doses up ~0.4 mcg/kg/min (for 75 kg patient);
Dopamine/dobutamine doses up to 10 mcg/kg/min
– Less major complications with central rather than peripheral access (0.64
vs. 1.04, p<0.02)
› Majority of complications in PIV group were inability to insert PIV
http://emcrit.org/podcasts/peripheral-vasopressors-extravasation/
Ricard JD, et al. Central or peripheral catheters for initial venous access of ICU patients: a randomized controlled trial. Crit Care Med. 2013 Sep;41(9):2108-15

53. Extravasation
Drug Effect Mechanism(s) of
tissue injury
Dobutamine Irritant; Rare reports of vesicant
effects
Cytotoxicity, acidic pH
Dopamine,
Epinephrine,
Phenylephrine
Norepinephrine,
Vasopressin
Vesicants Vasoconstriction

54. Extravasation
› Phentolamine
– Short-term alpha-adrenergic blocking activity
– Administration →vasodilatation of vascular smooth muscle
– Infiltrate area of extravasation with phentolamine: 5 mg diluted in 9
mL NS
– Should see near immediate effects; otherwise consider additional
dose (Max = 10 mg)

55. Adverse Reactions
Epinephrine Norepinephrine Dopamine Dobutamine Vasopressin Phenylephrine
Tachycardia x High doses x
Arrhythmias x High doses x x (ventricular)
Increased
myocardial O2
demand x x x
Decreased perfusion
to vital organs x x x (less) x
Nausea/vomiting x x
Metabolic acidosis x x
Hypersensitivity
x (contains
sulfites)
Extravasation x x x x x x

57. Resuscitation
› Epinephrine
 vasoconstrictor effect
 Inotropy
 Sensitize myocardium to defibrillation attempts-no
evidence
› Adult studies
 Large dose of epinephrine versus standard dose
 Use of vasopressin in 0.4U/kg/dose after prolonged
arrests

58. Septic shock-surviving sepsis compaign

59. Myocarditis/heart failure
› Ideal inotrope
 Improves systolic and diastolic myocardial function
 Decreases systemic and peripheral vascular
resistance
Without increasing myocardial o2 consumption
 Initial drugs-dobutamine,dopamine,milrinone,low
dose epinephrine

60. Post cardiac surgery
› LCOS
› Initially-dobutamine and low dose adrenaline
› PRIMACORP(prophylactic intravenous use of milrinone
after cardiac operation in pediatrics)
› Levosimendan
› Vasopressin and norepinephrine

61. Post cardiac arrest syndrome
› Post cardiac brain injury
› Post cardiac myocardia dysfunction
› Systemic ischemia/reperfusion response
› Actual pathology
› Epinephrine,dopamine,dobutamine
› Vasopressin recently

62. Brain dead child
› To maintain perfusion to vital organs
› Dopamine –first line cardiovascular support
› Low dose vasopressin –first line pressor support
› Canadian guidelines
first line-low dose vasopressin
Second line-norepinephrine,epinephrine,phenylephrine

63. Preparations
› Rule of six
› 6*BW=amount(mg) in 100ml of solvent at 1ml/hr=1
microgram/kg/min
› Dopamine and dobutamine
› 6*BWmg in 25 ml NS at 1ml/hr=4mic/kg/min
› Adrenaline and noradrenaline
› 0.6 * BW in 50ml NS at 1ml/hr-0.2mic/kg/min

64. Vasoactive-inotrope score