10/20/2017

In the ICU/CICU…

In CIPs: rapid changes of

hemodynamic

They need drugs that:

Rovina Ruslami, dr., SpPD, PhD Act rapidly (rapid onset)
Dept. of. Clinical Pharmacology
FKUP/RSHS Bandung Predicted potency 100% BA

Pharmacologic management of hemodynamic in critically ill patients

We need potent drugs that can
be given intravenously.
PK/PD of Vasopressors & inotropes
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Haemodynamics-CVS-ANS Adrenergic receptors

Changing metabolic O2
needs physiologic
changes
(mediated by endogenously
released catecholamine)
α-r, β-r, D-r

Distributed throughout the

body (≈ ANS function)

Distribution & proportion…

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Adrenergic Agonists Adrenergic Agonist

(definition and PK) (classification – chemical structure)

Drugs that mimic the effect of adrenergic ANS

A. Catecholamine
stimulations on its effectors
• Sympathomimetic amines contain 3,4-dihydroxibenzene
They are important group of th/ agents • Exp.: E (Adr), NE (N-adr), isoproterenol (ISP), D
can be used to maintain hemodynamic • Properties: High potency and rapid inactivation (short DOA)

MOA: bind to adrenergic-receptors B. Non-catecholamine

• Having substitution on their benzene ring
Classification… • Exp.: PE, Eph, Amph
• Properties: longer DOA

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Adrenergic Agonist PD of Adrenergic Agonists

(classification - MOA)

It has effect on: Effect:

a. Direct
• E, NE, PE • Cardiovascular system • Maintain hemodynamic
• Vascular smooth muscle (↑ C.O (and) BP)
b. Indirect • Nonvascular smooth muscle • Bronchial, eye, uterine, etc
• Amphetamine
• CNS • Stimulate brain

c. Mixed • Metabolic • Glucose and fat metabolism

• Ephedrine, dopamine • Potassium homeostasis
• Potassium homeostasis

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CVS – ANS – Adrenergic Agonists PK/PD of Adrenergic Agonist

Keep in mind α1 Vascular Arteriolar vasoconstrictor
Vasoconstriction:
↑ PVR, ↑ BP
that…
α α2
Presynaps of
NFB for release catecholamines
↓ release of insulin &
ANS neuron cathecolamines
Some drugs have > 1 actions:
• (+) chronotropic • ↑ HR
+/- inotropic effect β1 Heart • (+) inotropic • ↑ contractility
+/- contractility • alter conduction velocity • ↑ velocity AVNode
+/- chronotropic effect β
• vascular • vasodilator in skeletal muscle • vasodilatation: ↓ PVR
+/- HR β2
•bronchial • bronchodilator • bronchodilatation
Alter conduction velocity
renal &
Alter automaticity D D1 intestinal vasc.
beds
vasodilator −Renal BF

Alter vasc. smooth muscle tone

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Pathophysiology of CS

Vasopressors & Inotropes

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Vasopressors & Inotropes Factors affect the magnitude of

drug response
All of them are Adrenergic agonist Distribution & proportion of r-type present in various body tissue
Heart >> β1-r and in vascular >> α1-r
Mostly given iv-ly
Existence of reflex hemostatic mechanism
α1-r induction ↑BP vagal reflex ↓HR
They act direct/indirect on SNS
Down-regulation
Effect varies depends on: Prolong exposed by agonist adr << sensitivity of –r
Distribution and proportion of the –r in the body
Up-regulation
Affinity to the –r
Prolong exposed by antagonist adr >> sensitive of –r
Duration of action
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Synthesis & molecular of AA

Affinity of some drugs to adrenoceptor:

a. to α-r b. to β -r Tyrosine DOPA Dopamine Norepinephrine

ISP E NE NE E ISP Phenylephrine

Dobutamine Epinephrine

Amphetamine Ephedrine
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Effects of Adrenergic Agonist CVS Effect of Cathecolamine

CV function E NE ISP
SBP ++ +++ 0/+
DBP - ++ --
MAP +0- ++ --
TPR -- +++ ---
HR + - ++
Stroke output ++ + ++
C.O +++ -0 +++
Craig CR. Modern Pharmacology
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Choices:

Vasopressor Inotropic

NE/DP Dobu Let’s have a look some of them…

Epi, VE,
VSP
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NOREPINEPHRINE (NORADRENALINE) EPINEPHRINE (ADRENALINE)

α1,2 and β1 -r (α dominant) α1,2 and β1,2 -r (β dominant)

more to α-r vasoconstriction Vasodilatation (β effect) vasoconstriction (α effect)

↑C.O, ↑SBP, ↓ DBP
↑C.O, ↑SBP & DBP, HR↓ (vagal reflex due to ↑ BP) Other effects:
Pupil midriasis, sphincter int. VU contraction, ↑ BG
Indication:
Indication:
Septic shock (drip)
Septic shock (drip), Cardiac arrest (iv)
Not for asthma
Other: asthma, anaphylactic shock, etc.

SE: SE:
Ventr. arrhythmia, hypertension, tachycardia
↓ RBF

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DOPAMINE DOBUTAMINE
D >> β 1 >> α1 (D dominant) >> β1 and D (B dominant)

Precursor of Norepinephrine; also binds to As inotropic therapy if there is cardiac dysfunction

adrenoceptor (α and β1 -r) AND Does not precursor of Norepinephrine BUT only binds
specific with D-r (in renal) to adrenoceptor (β1-r) AND specific with D-r (in renal)
↑ RBF ↑C.O, ↑SBP vasoconstriction ↑ RBF ↑C.O, ↑SBP

Indication: Indication:
Cardiogenic, septic shock (drip) Cardiogenic shock (drip)
SE:
SE:
Atrial fibrillation
Ventr. arrhythmia, hypertension, tachycardia
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VASOPRESSIN VASOPRESSIN
(not an adrenergic drug) (not an adrenergic drug)

ADH synthesized in the hypothalamus stored in posterior

pituitary gland …it’s used as additional vasopressor in septic shock

CVS homeostasis One of vasopressor of choice for septic shock

Kidney: water resorption (BUT not as initial vasopressor)
Vasculature: smooth muscle tone
CNS: brainstem autonomic function Low dose of vasopressor:

It‘s released in response to stress 0.03 unit/min continuous infusion as add on NE

deficiency in prolonged vasodilatory shock
(severe sepsis)

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Norepinephrine versus dopamine, major adverse events 29

Thank you ….. Istirahat dulu….

Norepinephrine versus dopamine, cardiac arrhythmias

Vasopressors for the Treatment of Septic Shock: Systematic Review and Meta-Analysis, PLoS One. 2015; 10(8): e0129305.
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