REVIEW OF VASOPRESSORS IN ICU, REVIEW FROM BASICS

1. VASOPRESSORS IN ICU
Dr Abhinov K
MBBS DNB FNB

2. OVERVIEW
• INTRODUCTION AND DEFINITION
• HISTORY
• PHYSIOLOGY-RECEPTOR DISTRIBUTION
• CLASSIFICATION OF DRUGS
• BIOCHEMISTRY- SYNTHESIS OF ENDOGENOUS CATECHOLAMINES
• PHARMACOLOGY
• LAND MARK TRIALS

3. INTRODUCTION
• VASOPRESSOR- Vasopressors are a powerful class of drugs that
induce vasoconstriction and elevate MAP.
• INOTROPES- Drugs which alter cardiac contractility
• CHRONOTROPE- CHRONO-TIME- changes in heart rate
• DROMOTROPIC – (GREEK-drómos-RUNNING)- CONDUCTION
• BATHMOTROPIC- (GREEK-Bathmos- threshhold )EXCITABILITY
• LUSITROPIC- (GREEK-LUSIS-LYSIS)-RELAXATION

4. 4
MAP = CO*SVR
CO = HR*SV

5. HISTORY
• 1893, Dr. George Oliver, a physician from Harrowgate,
England, USING HIS SON AS his research subject and
used sheep adrenal glandular extract on him. He
observed the vasoconstrictive effects after ingesting
this extract.
• In 1900, Japanese chemist Jokichi Takamine, A pure
crystalline form of the active adrenaline was
successfully isolated from adrenal medulla.
• In 1906, adrenaline became the first hormone to be
synthesized de novo by Friederich Stolz and Fritz
Flacher.

6. ANATOMY & PHYSIOLOGY OF SNS

7. ADRENERGIC RECEPTOR DISTRIBUTION
• There are 2 classes of adrenergic receptors-
alpha (α) and beta (β). Furthermore, there are
at least 2 subtypes of receptors in each class:
α1, α2, β1 and β2. All of these receptors are
linked to G proteins and second messenger
systems which carry out the intracellular
effects.

8. • α1 – Mostly post synaptic, present in smooth
muscles through out the body. Activation
leads to vasoconstriction, spincters to
contract. Most important cvs effect is increase
in peripheral vascular resistance, increase in
afterload, increase in MAP
• α2 - mostly presynaptic, central α2 receptor
stimulation causes anxiolysis and sedation

9. • β1 - mostly located in cardiac muscle, postsynaptic, have
+ve chronotropic, inotropic and dromotropic effect.
• β2 – Primarily postsynaptic on smooth and gland cells.
Relaxes smooth muscles.
• β3 - located in gall bladder, brain and adipose tissue. Play
role in thermogenesis and lipolysis of brown fat.
• Dopaminergic receptors- D1 and D2 Dopamine receptors
are present in the renal, splanchnic (mesenteric), coronary,
and cerebral vascular beds; stimulation of these receptors
leads to vasodilation. A second subtype of dopamine
receptors causes vasoconstriction by inducing
norepinephrine release.

13. CLASSIFICATION
SYMPATHOMIMETICS
CATECHOLAMINES
SYNTHETIC
ENDOGENOUS
NON
CATECHOLAMINES

14. SYMPATHOMIMETICS
DIRECT ACTING
PHEYNYLEPHRINE
METHOXAMINE
INDIRECT ACTING MEPHENTERAMINE.

15. CLASSIFICATION OF
SYMPATHOMIMETICS
BASED ON SYNTHESIS
• Natural- epinephrine, nor epinephrine,
dopamine
• Synthetic- isoproterenol, dobutamine
BASED ON ACTIVITY AT RECEPTOR
• Direct acting- Phenylephrine.
• Indirect acting-mephenteramine.
• Mixed acting- Ephedrine.

18. Dopamine
Description and Pharmacology
• The function of doapmine as neurotransmitter was first
discovered in 1958 by ARVID CARLSSON
• It was named dopamine because it was a monoamine
and its synthetic precursor was 3,4
dihydroxyphenylalanine.
• It is endogenous catecholamine that serve as a
neurotransmitter and precursor of norepinephrine
synthesis.
• When given exogenously it activates variety of
receptors in a dose dependent manner and regulates
cardiac, vascular and endocrine functions.

19. Synthesis of Dopamine

21. Pharmacodynamics
• At doses of 1 to 2 mcg/kg per minute, dopamine acts
predominantly on D1 receptors in the renal, mesenteric,
cerebral, and coronary beds, resulting in selective
vasodilation.
• At 5 to 10 mcg/kg per minute, dopamine also stimulates
beta-1 adrenergic receptors and increases cardiac output,
predominantly by increasing stroke volume with variable
effects on heart. It causes increase in HR, myocardial
contractility.
• At doses >10 mcg/kg per minute, the predominant effect of
dopamine is to stimulate alpha-adrenergic receptors and
produce vasoconstriction with an increased SVR

22. Clinical uses and indications.
• Dopamine is often used in situation where both
cardiac stimulation and peripheral
vasoconstriction is desired.
• It is used in cardiogenic shock.
• It is used to correct hypotension in septic shock-
2nd line agent, norepinephrine is the drug of
choice.
• Low dose dopamine for prevention of renal
failure-- no evidence– not recommended

23. Precautions-
• Patients on doapmine should be monitored
by continous ECG and ABP.
• Before starting infusion hypovolemia should
be excluded for the cause of hypotnesion.

24. Contraindications-
• Pt on MAO inhibitors
• On TCA agents
• Pheochromocytoma
• Uncontrolled tachyarrhythmia

25. Adverse effects of dopamine infusion-
• tachyarrhythmias
• Limb ischemia- if given through peripheral line
• Ocular- raised iop
• CNS- headache, anxiety
• Hyperglycemia- dopa causes inhibition of
insulin secretion.
• Pregnancy category c

27. Nor Adrenaline
• Hydroxylation of dopamine by dopamine beta
hydroxylase produces norepinephrine.
• Prefix nor- is derived from the german
abbreviation for “N ohne Radikal” (N is the
symbol for nitrogen, without radical) referring
to the absence of methyl functional group at
the nitrogen atom
• Norepinephrine is a catecholamine and
ethylamine

28. Pharmacology-
• Norepinephrine acts on both alpha-1 and beta-1
adrenergic receptors, thus producing potent
vasoconstriction as well as a modest increase in
cardiac output.
• A reflex bradycardia usually occurs in response to
the increased mean arterial pressure (MAP), such
that the mild chronotropic effect is canceled out
and the heart rate remains unchanged or even
decreases slightly.

30. INDICATIONS-
• First line therapy for mantainance of blood pressure
(after adequate fluid resuscitation) in septic shock.
Adverse Effects-
• HTN, Bradycardia,arrhythmias, palpitations
• Paleness, coldness in periphery, Ischemic injury due to
potent vasoconstrictor action .
• Anxiety, insomnia, confusion, headache, psychosis,
anorexia, nausea and vomiting.

31. Extravasation effect and management
• Extravasation of noradrenaline causes local
necrosis of tissues due to potent
vasoconstrictive effect.
• To prevent sloughing and necrosis in areas
which extravasation has taken place, the area
should be infiltrated as soon as possible with
10 -15ml of saline solution containing 5-10 mg
of phentolamine.

32. Drug interactions-
• MAO inhibitors
• Cardiac glycosides
• Thyroid hormones
• Ergot alkaloids
All of these agents potentiate
vasoconstrictive effects.

34. Epinephrine/adrenaline
Description and Pharmacology-
• Natural/endogenous catecholamine, direct acting
sympathomimetic.
Mechanism of Action-
• β activity at low doses and α activity at high doses
• Stimulation of β 1 receptors of myocardium causes-
increase in HR, contractility -> increase in CO
• At higher doses the alpha-adrenergic receptor effect
predominates, producing increased SVR in addition to
an increased CO.

35. Pharmacokinetics-
Onset- 1 min (iv and inhalation), 5-10 min (sc)
Duration- 1-3 min for iv
Metabolism- COMT and MAO mediated
Excretion- in urine

36. Indications
• Doc for anaphylaxis
• For resuscitation in cardiac arrest- ACLS- Ventricular
fibrillation / pulseless ventricular tachycardia after initial
shock have failed (after 2nd shock then after every 2-5
min). Asystole and PEA in initial cycle (and then every 2-5
min).
• Profound bradycardia after failure to respond to atropine
• For infiltration in operative field to reduce bleeding
• Acute severe asthma / bronchospasm / stridor
• cardiogenic shock
• septic shock- weak recommendation and low quality
evidence

37. Contraindications-
• Patient on MAOI
• Patient on anti arrythmic like procainamide and
quinidine.
Adverse Effects-
• Angina, arrythmias, palpitations.
• Anxiety, dizziness, flushing.
• Sweating, tachycardia.

38. • VASOMOTOR REVERSAL OF DALE

39. Dilutions of adrenaline-
• Adrenaline 1:1000 (1mg) in 1mL ampoules
• 1:10000 prefilled 10 ml syringe
• 1:200000- 5mcg per ml in LA solutions.
• Pregnancy- category B

41. Dobutamine
Description and Pharmacology-
• Synthetic catecholamine, direct acting sympathomimetic.
• is not a vasopressor but rather is an inotrope that causes
vasodilation.
Mechanism of action-
• β1 >> β2.
• Increases HR ,contractility and decreases SVR.
• Decrease in svr is by β2 stimulation and baroreceptor
mediated in response to increase in SV.
• The net effect is increased CO, with decreased SVR with or
without a small reduction in blood pressure.

43. Indications-
• Mainly indicated in severe medically refractory
heart failure and cardiogenic shock.
• Sepsis- dobutamine in patients who show evidence of
persistent hypoperfusion despite adequate fluid loading
and the use of vasopressor agents (weak
recommendation, low quality of evidence).
Contraindications-
• Patient receiving MAOI, TCA
• Tachyarrhythmia
• Pheochromocytoma.

44. Adverse effects-
• Tachyarrhythmias
• Palpitations
• Nausea, headache
• Pregnancy- category B

45. PHENYLEPHRINE
• Phenylephrine has purely alpha-adrenergic agonist activity and
therefore results in vasoconstriction with minimal cardiac inotropy
or chronotropy. MAP is augmented by raising systemic vascular
resistance (SVR) . The drug is useful in the setting of hypotension
with an SVR <700 dynes x sec/cm5
• A potential disadvantage of phenylephrine is that it may decrease
stroke volume, so it is reserved for patients in whom epinephrine is
contraindicated due to arrhythmias or who have failed other
therapies.
• The drug is contraindicated if SVR >1200 dynes x sec/cm5.
Indications-
• Neurologic Disorders,
• Anesthesia Induced Hypotension.

46. Ephedrine
• Mixed acting sympathomimetic.
• It has both direct(alpha and beta1 adrenergic agonist)
and indirect effect via norepinephrine release. It leads
to increase in blood pressure, cardiac output, heart
rate and contractility.
• Indications-
• Hypotension due to anesthesia and regional blocks
• Used orally for bronchial asthma and coryza
• It also has antiemetic effect
• To treat diabetic neuropathic edema.

48. • Adverse effects-
• Tachycardia, arrhythmias
• Restlessness, confusion, insomnia, mild
euphoria, agitation.
• Headache, tremors, hyperglycemia.

49. VASOPRESSIN
• Also called as anti diuretic hormone, secreted
mainly by supraoptic and paraventricular nucleus
in small quantities. From here this hormone is
transported to posterior pituitary through the
nerve fibers of hypothalamo-hypophyseal tract,
by means of axonic flow.
• It acts in the body by means of V1 , V2 , V3, OTR
receptors.
• It causes pure vasoconstriction without
chronotropic or inotropic effect.

50. • V1 - receptors are found on vascular smooth
muscle of the systemic, splanchnic, renal, and
coronary circulations- activation causes VC
• V2 - receptors are predominantly located in the
distal tubule and collecting ducts of the kidney-
activation causes mobilisation of aquaporin
channels and absorption of free water.
• V3 - receptors are found mainly in the pituitary.
Activation aids in the release of ACTH

52. Indications-
• SSC suggest adding either vasopressin (up to 0.03 U/min)
(weak recommendation, moderate quality of evidence) to
norepinephrine with the intent of raising MAP to target, or
adding vasopressin (up to 0.03 U/min) (weak
recommendation, moderate quality of evidence) to decrease
norepinephrine dosage.
• Adjunct in GI bleed and esophageal varices.
• Central diabetes insipidus.

53. PHOSPHODIESTERASE INHIBITORS
• Milrinone is the most widely used drug of this
class
• It is also known as inodilator- i.e., inotropic
and vasodilatory effect.
• In many ways its effects are similar to
dobutamine but with lower incidence of
dysrhythmias.

55. Pharmacokinetics.
• Onset: 5-15 min (IV)
• Duration: 3-5 hr
Metabolism-
• Metabolized in liver (12%), mainly via glucuronidation
• Metabolites: Milrinone O-glucuronide (activity unknown)
Elimination
• Half-life: 2.5 hr
• Clearance: 2.3 mL/kg/min
• Excretion: Urine (95%; 83% as unchanged drug)
Dose reduction is advised as per creatinine clearance

56. • Indicated in congestive heart failure without
hypotension, 50 mcg/kg loading dose by IV
push over 10 minutes, then 0.375-0.75
mcg/kg/min IV

57. Adverse effects-
• Angina, headache, hypotension
• Abnormal liver function test results-serial LFT-
discontinue if deranged
• Anaphylaxis
• Atrial fibrillation
• Bronchospasm
• Hypokalemia

58. Calcium sensitizing agents
• Levosimendan and pimobendan are the calcium
sensitizing agents
LEVOSIMENDAN
• Levosimendan is a calcium sensitiser that can be
administered intravenously (IV) to patients with
acute decompensated congestive heart failure
(CHF). At therapeutic dosages levosimendan
enhances myocardial contractility without
increasing oxygen requirements, and causes
coronary and systemic vasodilation.

59. • Mechanism of Action-
1. This agent sensitizes troponin C to calcium in a manner dependent
on the calcium concentration, thereby increasing the effects of
calcium on cardiac myofilaments during systole and improving
contraction at low energy cost. During diastole, sensitization is
diminished due to a plunge in calcium concentration level which
does not cause a deterioration of diastolic relaxation.
2. levosimendan also opens ATP-dependent potassium (K) channels
in myocytes and vascular smooth muscle cells, which results in
vasodilatation . This reduces preload and afterload, and increases
coronary and other organ blood flow.
3. During the acute exacerbation of heart failure levosimendan
exerts its cardio protective effect by activation of ATP-dependent
K (KATP) channels which inhibit mitochondrial apoptotic pathway .

61. Other effects of levosimendan
• Antiinflammatory effect
• Decreases the level of matrix
metalloprotienases- play an important role in
the left ventricular remodeling in chronic
heart failure, hence levosimendan may show
pleiotropic effects that may affect myocardial
remodeling .

62. INDICATIONS-
• Heart failure following acute myocardial
infraction.
• Cardiogenic shock not associated with severe
hypotension
• Has role in post cardiac surgery pts.

63. Pharmacokinetics-
• Levosimendan has an elimination half-life of 1 hour.
• The half-lives of its two circulating metabolites, OR-1855
and its acetylated form OR-1896, range between 70 and 80
hours .
• These metabolites reach their maximum serum
concentration 2 days after completion of a 24-hour
intravenous levosimendan infusion
• Since the OR-1896 metabolite is hemodynamically active,
with properties similar to those of levosimendan, the
hemodynamic effects of levosimendan should theoretically
persist for at least 7–10 days following the intravenous
infusion.

64. Dosage-
• Initial bolus-6-12 mcg/kg followed by 0.05 to 0.2 mcg/kg/min as
continous infusion.
• Peak effects are observed within 10 to 30 min of infusion, duration
of action of levosimendan is about 75-78 hrs to 1 week due to
active metabolites.
• No dose adjustments required for renal or hepatic impairement
Adverse Effects
• Headache , hypotension, dizziness, and nausea.
• Among laboratory parameters, slight decreases of red blood cell
count, hematocrit, and hemoglobin (10%), and, particularly in
higher doses group, a slight decrease of serum K levels have been
reported.

67. VASST TRIAL-NEJM 2008
• Among patients with septic shock on a catecholamine
vasopressor, does addition of low-dose vasopressin reduce all-
cause mortality at 28 days when compared to addition of
norepinephrine?
• It is multicentered, randomized, double blinded study which
concluded there was no significant difference between the
vasopressin and norepinephrine groups in the 28-day
mortality rate (35.4% and 39.3%, respectively; P=0.26) or in
90-day mortality (43.9% and 49.6%, respectively; P=0.11).
There were no significant differences in the overall rates of
serious adverse events (10.3% and 10.5%, respectively;
P=1.00).

68. SOAP II TRIAL-NEJM 2010
• Among patients with shock, how does
dopamine compare to norepinephrine in
decreasing mortality?
• Multicenter, double-blinded, parallel-group,
randomized controlled trial, The trial included
1679 patients, of whom 858 were assigned to
dopamine and 821 to norepinephrine. The
baseline characteristics of the groups were
similar.

69. • NO difference in 28 day mortality- primary outcome
• Secondary outcome-icu death, inpatient mortality, 6
month, 12 months mortality- no difference between two
groups.
• More arrhythmic events in patients among dopamine
group
• A subgroup analysis showed that dopamine, as compared
with norepinephrine, was associated with an increased rate
of death at 28 days among the 280 patients with
cardiogenic shock but not among the 1044 patients with
septic shock or the 263 with hypovolemic shock (P=0.03 for
cardiogenic shock, P=0.19 for septic shock, and P=0.84 for
hypovolemic shock, in Kaplan–Meier analyses).

70. Angiotensin II
• Angiotensin II — Preliminary trials have
reported an adequate vasopressor effect when
synthetic angiotensin II is exogenously
administered for vasodilatory shock (eg, septic
shock) .
• There was no change in mortality or organ failure
scores when compared to other vasopressors.
• Angiotensin II resulted in less background
vasopressor use and higher heart rates but did
not result in life-threatening tachyarrhythmias.