VASOPRESSORS AND INOTROPES

AMER ALJUNDI, PHARM D

Shock States and Vasoactive Agents

Disclosures

§ The author does not have financial or personal

relationships with entities that may have a direct or

indirect interest in the subject matter of this

presentation

Objectives

§ Define shock and list important physiological parameters for different types of shock states

§ Apply vasoactive drug fundamentals on

hemodynamic equations

§ Explain the differences between inoconstrictors, inodilators, and pure vasoconstrictors in terms of

hemodynamic effects and adverse effects

§ Recognize reasons for refractory shock and proper selection of vasoactive agents

Shock

§ Circulatory failure that can lead tissue hypoperfusionand inadequate O2 delivery to maintain cellular metabolism

§ Hypotension is the most common clinical manifestation of shock syndromes

§ Hypotension is due toú Low systemic vascular resistance (SVR) &/orú Insufficient cardiac output (CO)

Shock Progression

Hemodynamic Mechanisms

§ Hemodynamic Equations1. BP= CO X SVR2. CO= HR X SV

Preload Afterload Inotropy

+ +_

BP = blood pressure, CO = cardiac ouput,SVR = systemic vascular resistance,HR = heart rate, SV = stroke volume, MAP = mean arterial pressure, CVP = central venous pressure

3. CO X SVR = 80 (MAP-CVP)

Types of Shock

Cold shock

Inadequate CO

Compensatory ↑SVR

Cool extremities, weak distal pulses

Cardiogenic or Obstructive Shock

Warm shock

Vasodilation (↓SVR)

Compensatory ↑CO

Warm extremities, palpable pulses

Distributive (septic) Shock

Adrenoceptor types, locations, and physiological responses

Receptor Type Primary location (s) Response when stimulated

α1 Arteries, arterioles, veins Vasonstriction (↑SVR)

β1 Heart ↑ heart rate (chronotropy) ↑ force of contraction (inotropy)

β2 Skeletal muscle blood vessels Coronary arteries

Vasodilation (↓SVR)Vasodilation

Vasopressin (V) V1: VesselsV2: RenalV3: Pituitary gland

Vasoconstriction (↑SVR)Fluid retentionCortisol release

Pharmacologic and Hemodynamic Effects of Vasoactive Agents

Medication Heartβ1

Vasculatureα1

Vasculatureβ2

CO SVR HR

Dopamine (> 4 mcg/kg/min)

0 to 3+ 0 to 2+ 0 to 1+ ↑ ↑ ↑↑

Dobutamine 4+ + 2+ ↑↑ ↔↓ ↑

Epinephrine 4+ 2+ (HD 4+)

+ ↑↑ ↓↑

↑↑

Milrinone * 4+ “like” 0 3+ “like” ↑↑ ↓↓ ↑

Norepinephrine 2+ 4+ 0/+ ↑↓ ↑↑ ↑

Phenylephrine 0 4+ 0 ↓ ↑ ↔↓

Vasopressin ° 0 4+ “like” 0 ↓ ↑ ↔↓

Scale: 0= no agonist activity, 4+= very potent agonist* Milrinone does not bind to β or α receptors, it acts via phosphodiesterase-3 inhibition° Vasopressin does not bind to β or α receptors, it acts via V receptor agonismHD: high dose

Pharmacologic and Hemodynamic Effects of Vasoactive Agents

Medication Heartβ1

Vasculatureα1

Vasculatureβ2

CO SVR HR

Dopamine (> 4 mcg/kg/min)

0 to 3+ 0 to 2+ 0 to 1+ ↑ ↑ ↑↑

Dobutamine 4+ + 2+ ↑↑ ↓ ↑Epinephrine 4+ 2+

(HD 4+)+ ↑↑ ↓

↑↑↑

Milrinone * 4+ “like” 0 3+ “like” ↑↑ ↓↓ ↑Norepinephrine 2+ 4+ 0/+ ↑↓ ↑↑ ↑Phenylephrine 0 4+ 0 ↓ ↑ ↓Vasopressin ° 0 4+ “like” 0 ↓ ↑ ↓

Scale: 0= no agonist activity, 4+= very potent agonist* Milrinone does not bind to β or α receptors, it acts via phosphodiesterase-3 inhibition° Vasopressin does not bind to β or α receptors, it acts via V receptor agonismHD: high dose

Pharmacologic and Hemodynamic Effects of Vasoactive Agents

Medication Heartβ1

Vasculatureα1

Vasculatureβ2

CO SVR HR

Dopamine (> 4 mcg/kg/min)

0 to 3+ 0 to 2+ 0 to 1+ ↑ ↑ ↑↑

Dobutamine 4+ + 2+ ↑↑ ↓ ↑Epinephrine 4+ 2+

(HD 4+)+ ↑↑ ↓

↑↑↑

Milrinone * 4+ “like” 0 3+ “like” ↑↑ ↓↓ ↑Norepinephrine 2+ 4+ 0/+ ↑↓ ↑↑ ↑Phenylephrine 0 4+ 0 ↓ ↑ ↓Vasopressin ° 0 4+ “like” 0 ↓ ↑ ↓

Scale: 0= no agonist activity, 4+= very potent agonist* Milrinone does not bind to β or α receptors, it acts via phosphodiesterase-3 inhibition° Vasopressin does not bind to β or α receptors, it acts via V receptor agonismHD: high dose

Pharmacologic and Hemodynamic Effects of Vasoactive Agents

Medication Heartβ1

Vasculatureα1

Vasculatureβ2

CO SVR HR

Dopamine (> 4 mcg/kg/min)

0 to 3+ 0 to 2+ 0 to 1+ ↑ ↑ ↑↑

Dobutamine 4+ + 2+ ↑↑ ↓ ↑Epinephrine 4+ 2+

(HD 4+)+ ↑↑ ↓

↑↑↑

Milrinone * 4+ “like” 0 3+ “like” ↑↑ ↓↓ ↑Norepinephrine 2+ 4+ 0/+ ↑↓ ↑↑ ↑Phenylephrine 0 4+ 0 ↓ ↑ ↓Vasopressin ° 0 4+ “like” 0 ↓ ↑ ↓

Scale: 0= no agonist activity, 4+= very potent agonist* Milrinone does not bind to β or α receptors, it acts via phosphodiesterase-3 inhibition° Vasopressin does not bind to β or α receptors, it acts via V receptor agonismHD: high dose

Pharmacologic and Hemodynamic Effects of Vasoactive Agents

Medication Heartβ1

Vasculatureα1

Vasculatureβ2

CO SVR HR

Dopamine (> 4 mcg/kg/min)

0 to 3+ 0 to 2+ 0 to 1+ ↑ ↑ ↑↑

Dobutamine 4+ + 2+ ↑↑ ↓ ↑Epinephrine 4+ 2+

(HD 4+)+ ↑↑ ↓

↑↑↑

Milrinone * 4+ “like” 0 3+ “like” ↑↑ ↓↓ ↑Norepinephrine 2+ 4+ 0/+ ↑↓ ↑↑ ↑Phenylephrine 0 4+ 0 ↓ ↑ ↓Vasopressin ° 0 4+ “like” 0 ↓ ↑ ↓

Scale: 0= no agonist activity, 4+= very potent agonist* Milrinone does not bind to β or α receptors, it acts via phosphodiesterase-3 inhibition° Vasopressin does not bind to β or α receptors, it acts via V receptor agonismHD: high dose

Pharmacologic and Hemodynamic Effects of Vasoactive Agents

Medication Heartβ1

Vasculatureα1

Vasculatureβ2

CO SVR HR

Dopamine (> 4 mcg/kg/min)

0 to 3+ 0 to 2+ 0 to 1+ ↑ ↑ ↑↑

Dobutamine 4+ + 2+ ↑↑ ↓ ↑Epinephrine 4+ 2+

(HD 4+)+ ↑↑ ↓

↑↑↑

Milrinone * 4+ “like” 0 3+ “like” ↑↑ ↓↓ ↑Norepinephrine 2+ 4+ 0/+ ↑↓ ↑↑ ↑Phenylephrine 0 4+ 0 ↓ ↑ ↓Vasopressin ° 0 4+ “like” 0 ↓ ↑ ↓

Scale: 0= no agonist activity, 4+= very potent agonist* Milrinone does not bind to β or α receptors, it acts via phosphodiesterase-3 inhibition° Vasopressin does not bind to β or α receptors, it acts via V receptor agonismHD: high dose

Pharmacologic and Hemodynamic Effects of Vasoactive Agents

Medication Heartβ1

Vasculatureα1

Vasculatureβ2

CO SVR HR

Dopamine (> 4 mcg/kg/min)

0 to 3+ 0 to 2+ 0 to 1+ ↑ ↑ ↑↑

Dobutamine 4+ + 2+ ↑↑ ↓ ↑Epinephrine 4+ 2+

(HD 4+)+ ↑↑ ↓

↑↑↑

Milrinone * 4+ “like” 0 3+ “like” ↑↑ ↓↓ ↑Norepinephrine 2+ 4+ 0/+ ↑↓ ↑↑ ↑Phenylephrine 0 4+ 0 ↓ ↑ ↓Vasopressin ° 0 4+ “like” 0 ↓ ↑ ↓

Scale: 0= no agonist activity, 4+= very potent agonist* Milrinone does not bind to β or α receptors, it acts via phosphodiesterase-3 inhibition° Vasopressin does not bind to β or α receptors, it acts via V receptor agonismHD: high dose

Pharmacologic and Hemodynamic Effects of Vasoactive Agents

Medication Heartβ1

Vasculatureα1

Vasculatureβ2

CO SVR HR

Dopamine (> 4 mcg/kg/min)

0 to 3+ 0 to 2+ 0 to 1+ ↑ ↑ ↑↑

Dobutamine 4+ + 2+ ↑↑ ↓ ↑Epinephrine 4+ 2+

(HD 4+)+ ↑↑ ↓

↑↑↑

Milrinone * 4+ “like” 0 3+ “like” ↑↑ ↓↓ ↑Norepinephrine 2+ 4+ 0/+ ↑↓ ↑↑ ↑Phenylephrine 0 4+ 0 ↓ ↑ ↓Vasopressin ° 0 4+ “like” 0 ↓ ↑ ↓

Scale: 0= no agonist activity, 4+= very potent agonist* Milrinone does not bind to β or α receptors, it acts via phosphodiesterase-3 inhibition° Vasopressin does not bind to β or α receptors, it acts via V receptor agonismHD: high dose

Classification of Vasoactive Agents

InoconstrictiorsNorepinephrine

Epinephrine

Dopamine

Pure Vasoconstrictors

Phenylephrine

Vasopressin

InodilatorsDobutamine

Milrinone

VasodilatorsNitroglycerin

Nitroprusside

Nesiritide

Direct Inotropic Effects

Yes No

Perip

hera

l Vas

cula

r Eff

ects

Vas

odila

tion

Vas

ocon

stric

tion

Vasopressors

Inotropes

Classification of Vasoactive Agents

InoconstrictiorsNorepinephrine

Epinephrine

Dopamine

Pure Vasoconstrictors

Phenylephrine

Vasopressin

Inodilators

Dobutamine

Milrinone

Vasodilators

Nitroglycerin

Nitroprusside

Nesiritide

Direct Inotropic Effects

Yes No

Perip

hera

l Vas

cula

r Eff

ects

Vas

odila

tion

Vas

ocon

stric

tion

Vasopressors

Inotropes

Classification of Vasoactive Agents

Inoconstrictiors

Norepinephrine

Epinephrine

Dopamine

Pure Vasoconstrictors

Phenylephrine

Vasopressin

InodilatorsDobutamine

Milrinone

Vasodilators

Nitroglycerin

Nitroprusside

Nesiritide

Direct Inotropic Effects

Yes No

Perip

hera

l Vas

cula

r Eff

ects

Vas

odila

tion

Vas

ocon

stric

tion

Vasopressors

Inotropes

Classification of Vasoactive Agents

Inoconstrictiors

Norepinephrine

Epinephrine

Dopamine

Pure Vasoconstrictors

Phenylephrine

Vasopressin

Inodilators

Dobutamine

Milrinone

Vasodilators

Nitroglycerin

Nitroprusside

Nesiritide

Direct Inotropic Effects

Yes No

Perip

hera

l Vas

cula

r Eff

ects

Vas

odila

tion

Vas

ocon

stric

tion

Vasopressors

Inotropes

Classification of Vasoactive Agents

Inoconstrictiors

Norepinephrine

Epinephrine

Dopamine

Pure Vasoconstrictors

Phenylephrine

Vasopressin

Inodilators

Dobutamine

Milrinone

VasodilatorsNitroglycerin

Nitroprusside

Nesiritide

Direct Inotropic Effects

Yes No

Perip

hera

l Vas

cula

r Eff

ects

Vas

odila

tion

Vas

ocon

stric

tion

Vasopressors

Inotropes

Inodilators

§ Dobutamine§ Milrinone

Inodilator- Dobutamine

MOA Pros Cons

Agonist β1, β2 • ↑ SV/CO & ↓ afterload

• In septic or cardiogenic shock and myocardial dysfunction

• PK: Short t1/2, not excreted renally

• ↓ MAP in vasodilatory shock

• Doses>10 mcg/kg/min minimal ↑ CO d/t ↑ HR

• Tachyphylaxis

• β-Blockers impair response

• Tachyarrythmia>milrinone

MOA: mechanism of action

Inodilators- Milrinone

MOA Pros Cons

PD3 inhibitor • ↑ SV/CO

• ↓both SVR & PVR

• In patients Rx β blockers

• Less tachycardia and arrhythmia vs. dobutamine

• PK: long t1/2, renal excretion

• NOT in septic shock d/tvasodilation > dobutamine

PD3: phosphodiesterase 3PVR: pulmonary vascular resistance

Inoconstrictors

§ Norepinephrine (NE)

§ Epinephrine (EPI)

§ Dopamine (DA)

Inoconstrictors- General Info

§ 1st line vasoactive agents for majority shock statesvNorepinephrine preferredvEpinephrine & dopamine can be added when ↑CO and/or

↑HR is required

Inoconstrictors

Place in Therapy Receptor Affinity

NE 1st line in different shock states α1>> β1>>>β2

EPI •1st line: anaphylactic shock•2nd line: other shock states

•LD (β1, β2): ↑ CO/HR, ↓ SVR (inotrope)•HD (β1, β2,α1): ↑ CO/HR, ↑ SVR (vasopressor)

DA Alternative for patients with low risk of tachyarrhythmia or bradycardia induced hypotension

Low dose < 4 mcg/kg/min• Renal dose• Renal vasodilation→ ?↑ urine output

Moderate dose 4 – 10 mcg/kg/min• Inotropic/chronotropic dose• Effects on CO peak ~8 mcg/kg/min d/t ↑ SVR

High dose: >10 mcg/kg/min• Vasopressor dose• MAP increases without further CO increase

LD: low dose; HD: high dose

Inoconstrictors

Place in Therapy Receptor Affinity

NE 1st line in different shock states α1>> β1>>>β2

EPI •1st line: anaphylactic shock•2nd line: other shock states

•LD (β1, β2): ↑CO/HR, ↓ SVR (inotrope)•HD (β1, β2,α1): ↑CO/HR, ↑ SVR (vasopressor)

DA Alternative for patients with low risk of tachyarrhythmia or bradycardia induced hypotension

Low dose < 4 mcg/kg/min• Renal dose• Renal vasodilation→ ?↑ urine output

Moderate dose 4 – 10 mcg/kg/min• Inotropic/chronotropic dose• Effects on CO peak ~8 mcg/kg/min d/t ↑ SVR

High dose: >10 mcg/kg/min• Vasopressor dose• MAP increases without further CO increase

LD: low dose; HD: high dose

Inoconstrictors

Place in Therapy Receptor Affinity

NE 1st line in different shock states α1>> β1>>>β2

EPI •1st line: anaphylactic shock•2nd line: other shock states

•LD (β1, β2): ↑CO/HR, ↓ SVR (inotrope)•HD (β1, β2,α1): ↑CO/HR, ↑ SVR (vasopressor)

DA Alternative for patients with low risk of tachyarrhythmia or bradycardia induced hypotension

Low dose < 4 mcg/kg/min• Renal dose• Renal vasodilation→ ?↑ urine output

Moderate dose 4 – 10 mcg/kg/min• Inotropic/chronotropic dose• Effects on CO peak ~8 mcg/kg/min d/t ↑ SVR

High dose: >10 mcg/kg/min• Vasopressor dose• MAP increases without further CO increase

LD: low dose; HD: high dose

Inoconstrictors

Place in Therapy Receptor Affinity

NE 1st line in different shock states α1>> β1>>>β2

EPI •1st line: anaphylactic shock•2nd line: other shock states

•LD (β1, β2): ↑CO/HR, ↓ SVR (inotrope)•HD (β1, β2,α1): ↑CO/HR, ↑ SVR (vasopressor)

DA Alternative for patients with low risk of tachyarrhythmia or bradycardia induced hypotension

Low dose < 4 mcg/kg/min• Renal dose• Renal vasodilation→ ?↑ urine output

Moderate dose 4 – 10 mcg/kg/min• Inotropic/chronotropic dose• Effects on CO peak ~8 mcg/kg/min d/t ↑ SVR

High dose: >10 mcg/kg/min• Vasopressor dose• MAP increases without further CO increase

LD: low dose; HD: high dose

Pure Vasoconstrictors

§ Phenylephrine§ Vasopressin

Pure Vasoconstrictors- General Info

§ 2nd line in most shock statesvMainly with uncontrolled tachycardiavVasodilatory/distributive shock when SVR is low and CO

is adequate

Pure Vasopressor Place in Therapy Pearl

Phenylephrine • Should not be used for cardiogenic shock

• Septic shock ifo NE triggers serious arrhythmias

• Add on in persistent hypotension /hypoperfusion with high CO

Good choice• Left ventricular outflow

tract obstructiono Severe aortic stenosiso Hypertrophic obstructive

cardiomyopathy

Vasopressin Good choice•During acidemia•RV failure d/t ↑PVR•Fixed dose

(0.03-0.04 U/min)

RV: right ventricle; PVR: pulmonary vascular resistance; SSC: surviving sepsis campaign

Positive Inotropy

Vasoconstriction

Vasodilation

Dobutamine Milrinone

Phenylephrine Vasopressin Norepinephrine HD epinephrine

HD dopamine LD epinephrine/dopamine

Management of Shock and Refractory Shock

IV fluids

MAP <65 mm Hg &/or SB< 90 mm Hg• UOP >0.5 ml/kg/hour• Normal or ↓ lactate• Near-normal venous O2

saturation

No

Yes

No

YesCVP<12 mm Hg

Norepinephrine (NE)

MAP >65 mm Hg on NE <1mcg/kg/min Refractory shock

HypovolemiaHypocortisolismAcidosisHypocalcemia

Reversible causes

+ epinephrineWarm/cold

Cold (low CO)Warm (low SVR) + dobutamine+ vasopressin(+ phenylephrine)

Adequate organ perfusion

corrected

Potential Adverse Effects of Vasoactive Agents

Agent Tachy-arrythmia

Peripheralvasoconstriction (digital ischemia)

Gut mucosalHypoperfusion

(increased lactate)

Increasedmyocardial O2 demand (MI)

Dobutamine ++++ +/- +++ ++

Dopamine ++++ + + ++

Epinephrine +++ + +++ ++

Norepinephrine + +++ +/- +

Phenylephrine +/- + + +/-

Vasopressin +/- +++ +++ ++

References

1. Jentzer JC, Coons JC, Link CB, et al. Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. J Cardiovasc Pharmacol Ther. 2015 May;20(3):249-60.

2. Moranville MP, Mieure KD, Santayana EM. Evaluation and management of shock States: hypovolemic, distributive, and cardiogenic shock. J Pharm Pract. 2011 Feb;24(1):44-60

THANK YOU