DR RIYAS ADR S M C S I ,KARAKONAM

Vasopressors and Inotropic Agents

Objectives

Understand the vasopressor and inotropic agent receptor physiology

Understand appropriate clinical application of vasopressors and inotropic agents

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.

Vasopressors are indicated for a decrease of >30 mmHg from baseline systolic blood pressure or MAP <60 mmHg, when either condition results in end-organ dysfunction secondary to hypoperfusion.

Receptor Physiology

Main categories of adrenergic receptors relevant to vasopressor activity: Alpha-1adrenergic receptor Beta-1, Beta-2 adrenergic receptors Dopamine receptors

Receptor Physiology

Receptor   Location EffectAlpha-1 Adrenergic  

Vascular wall Vasoconstriction

    HeartIncrease duration of contraction without

     increased chronotropy

Beta Adrenergic Beta-1 Heart↑Inotropy and chronotropy

  Beta-2Blood vessels Vasodilation

Dopamine   Renal Vasodilation

   

Splanchnic (mesenteric)  

    Coronary      Cerebral  

 Subtype   Vasoconstriction

PHARMACOLOGICAL ACTIONS

Cardiac effectsPositive chronotropic effect

An action that increases heart ratePositive dromotropic effect

An action that speeds conduction of electrical impulses (↑ conduction velocity through AV node)

Positive inotropic effect An action that increases the force of contraction of

cardiac muscle

Cardiac effects of epinephrine

Cardiac output is determined by heart rate and stroke volume

Epi→ β1receptors at SA node→↑HR

Epi→ β1receptors on ventricular myocytes→

↑ force of contraction

CO = HR x SV

vascular smooth muscle

In blood vessels supplying skin, mucous membranes, viscera and kidneys, vascular smooth muscle has almost exclusively alpha1-adrenergic receptors

Also biphasic response

α1

α1+β1 effect

β2 effect (at low doses) Mainly α -

action

β Blocker β2 effect

α Blocker

EE

(A)

(B)

Biphasic Response

vascular smooth muscle

In blood vessels supplying skeletal muscle, vascular smooth muscle has both alpha1 and beta2 adrenergic receptors

α1

β2

α1 stimulation β2 stimulation

Effects of epinephrine on blood vessel caliber

Blood vessels to skin, mucous membranes, viscera and kidneys

Stimulation of α1-adrenergic receptors causes constriction of vascular smooth muscle

α1

Effects of epinephrine on blood vessel caliber: skeletal muscle

At low plasma concentrations of Epi, β2 effect predominates→ vasodilation

At high plasma concentrations of Epi, α1 effect predominates→ vasoconstriction

α1

β2

Effects of Epi on arterial blood pressure

Arterial BP = CO x PVR

Epinephrine: ↑ COLow doses ↓ PVR (arteriolar dilation

in skeletal muscle)High doses ↑PVR

Effects of epinephrine on airways

Epi→β2-adrenergic

receptors on airway

smooth muscle→

rapid, powerful

relaxation→

bronchodilation

Effects of epinephrine in the eye Epi at α1-

adrenergic receptors on radial smooth muscle → contraction→ mydriasis

Epi at B2-adrenergic receptors→ relaxation of ciliary muscle

α1

β2

OTHER SYSTEMS

GIT: Peristalsis is reduced, sphincters are contracted.

Bladder : Detrusors relaxed, trigone contractedSplenic capsule : Contracts (alpha action), RBCs are

poured Skeletal muscle : Neuromuscular transmission is

facilitated. (Tremors due to beta 2 actions)CNS: Restlessness , tremors , fall in BP and

bradycardiaMetabolic : Hyperglycemia, lipolysis

Mnemonic for therapeutic uses of adrenaline ABCDEG

A- Anaphylactic shockB- Bronchial asthmaC- Cardiac arrestD- Delay absorption of local anestheticsE- Epistaxis, Elevate BPG- GlaucomaOthers : Reduce nasal congestion, Induces

mydriasis

Epinephrine (contd..)

Adverse effects of epinephrine

Hypertensive crisis Dysrhythmias Angina pectoris Necrosis following extravasation

Hyperglycemia

Dose(ng/kg/min

Receptor SVR

10-30 Beta May decrease

30-50 Beta,alpha variable

>150 Alpha and beta increased

NE

Primary physiological postganglionicsympathetic

Actions alpha 1&2 adrenergic action and beta agonist

HR Variable

Contractility Increased

CO Increasde or decreased

BP increased

SVR Increased

PVR increased

advantage

Redistibutiob of bloodDirect adrenergic agonistElicit intense alpha one and two adrenergic

agonism

disadvantage

Reduce organ perfusionMIPulmonary vasoconstrictionArrhythmiasSkin necrosis

Septic shockVasoplegia after CPBCondition in which SVR rise needed with

cardiac stimulation

Use through central line only

Dose 15-30ng/kg/min iv 30-300ng/kg/minMinimize duration of useWatch for oliguria and metabolic acidosisCan use along with vasodilators to counter

act alpha stimulationRVF—FOR stimulatinf Left atriumplus

inhaled nitric oxide

Dopamine (DA)

Dopaminergic neurons in brain, enteric

nervous system and kidney

Dopaminergic receptors in brain, mesenteric

and renal vascular beds

Dopamine

Moderate doses DA:Stimulate DA receptors in

mesenteric and renal vascular beds → vasodilation

Stimulate β1 receptors in heart → ↑HR and ↑force of contraction

High doses DA:Stimulate α1 receptors →

vasoconstriction

Receptor activation

1-3 mcg/kg/min DA Increaesed renal and mesentric blood flow

3-10mcg/kg/min beta1+beta 2+dopa Increases HR,CO,contractilityDecreses SVR

>10 alpha Increases SVR,decreases renal blood flow,increases HR,

advantages

At low dose renal blood flow increasesBP response easy to titrate

disadvantage

Indirect action get deminishedSkin necrosisPulmonary vasoconstrictionTachycardia and arrythmiaMVO2 increases ,MI can occur if coronory

flow doesn’t increase

Therapeutic uses

Shock (moderate doses)↑ blood flow to kidney and

mesentery↑ cardiac output

Refractory congestive heart failureModerate doses ↑ cardiac output

without ↑PVR

administration

Cental line onlyCorrect hypovolemia before useAt 5-10mcg/kg/min the response is not

adequate add epinephrine or milrinone

Synthetic Catecholamines: Dobutamine

It’s a derivative of DA but not a D1 or D2 receptor agonist

Stimulates β1- and β2-adrenergic receptors, but at therapeutic doses, β1-effects predominate

Increases force of contraction more than increases heart rate

↑CO = ↑HR x ↑ ↑ SV

Heart rate Increased

Contractility Increased

CO Increased

BP Increased

SVR Decresed

LVEDP Decreased

PVR Decreased

LAP Decreased

advantages

After load reduction—improve LV &RV fnRenal blood flow may increase

disavantages

Tachycardia and arrhythmiasTachyphylaxis more than 72hrsCoronary steal Nonselective vasodilatorMild hypokalemia

Dobutamine: Therapeutic uses

Cardiogenic ShockMICardiac surgery Refractory congestive heart failure

Administration…through i/v central line only

Clinical uses

Dose…2-20mcg/kg/minIncreases CO with lesser increment in MVO2

and higher coronary blood flowBeta blocked patients SVR may incease

Major toxic effects of catecholamines

All are potentially arrhythmogenic Epi and isoproterenol more arrhythmogenic than

dopamine and dobutamineSome can cause hypertensionEpinephrine, in particular, can cause CNS

effects – fear, anxiety, restlessnessDobutamine can cause vomiting and

seizures in cats – must be used at very low doses

Adverse effects

CNS: Restlessness Palpitation Anxiety, tremors

CVS: Increase BP….cerebral haemmorrhage Ventricular tachycardia, fibrillation May precipitate angina or AMI

Non-catecholamine direct-acting adrenergic agonists

Ephedrine Stimulates α1-, β1 and β2-adrenergic receptors

and ↑ NE release from noradrenergic fibersRepeated injections produce tachyphylaxis It is resistant MAO, orally Longer acting (4-6), cross BBB

Plant dervived

Sympathomimetic

EFFECTS

Heart rate Increased

Contractility Increased

CO Increased

BP Increased

SVR Slighltly incresed

Pre load increased

advantages

Easily titratedShort duration(i/m can prolong )TachyphylaxisSafe in pregnancyIdeal to correct sympathectomy induced

relative hypovolemiaAfter spinal or epidural

Dis advantage

Effect is decreased with NE stores get depleted

Malignant hypertion with MAO inhibiors

routes

i/v ,,,i/m,,,oral,,,s/cDose5-10mg i/v bolus,25-50mg i/m

phenylephrine

SyntheticActs on pre synaptic alpha 1 Vasoconstriction…mainly arteriolar Minimal venousMbmainly by MAO

effects

Heart rate Decreased

Contractility --

CO Nad or decreased

BP Increased

SVR Incresed

Pre load Minimal change

advantages

ShortIncreses perf press with low SVRWith hypotension increses CPPUseful in fixed out put lesions,CAD,TOF

disadvantages

Inceases PVRDecreases SV secon to decrese in after loadRarely may induce coronary artery spasm or

internal mammary,radial or gastro epiploiec

indication

Hypotension due to pheripheral vasodilatation

Temporay therapyR-L shunt SVT

dose

0.5-10mcg/kg/mini/v bolus1-10mcg/kg bolusFor TOF5-50mcg/kg

vasopressin

Endogenous ADHPheripheral vasoconstriction(v1)No action on betaMore constriction on skin,adipose,intestine

etc

advantage

Acts independently of adrenergicWhen phenylephrine or NE ineffetiveWithout producingSE increases coronary

perfussion after arrest

disadvantage

Decreses splanchnic circulationAdverse effects of severe constrictionDecreased platelet roductionLactic acidosis is common

uses

Alternative to epinephrine…>in countershock –refractory arrhythmias dose(40units i/v)

Septic shockVasoplegia after bypassIn drug interaction related hypotension such

as ACE or GA

milrinone

Powerful ionotrope,vasodilatory propertyIncreses

cAMPionotrophy,lusitrophy,chronotropy,dromotropy,increases automaticity

HR No change or slight increase

CO Increased

BP Variable

SVR & PVR Decreased

Preload Decreased

MVO2 Unchnaged or incresed

advantage

Favourable effect on myocardial oxygen supply and demand balance

No tachyphylaxisNo tachycardia or minimal

disadvantage

Arrhythmia

use

25-75 mcg/kg/min over 1-10 minMaintanance0.5mcg/kg/minAdminister before changing the patient from

pump

use

Low CO Increased LVEDPPulmonary hypotensionRV failureUse as a bridge in cadiac transplatation to

suppliment /potentiate beta receptors

Clinical Application

    1st Line Agent2nd Line Agent

Septic ShockNorepinephrine (Levophed) Vasopressin

   Phenylephrine (Neosynephrine)

Epinephrine (Adrenalin)

Heart Failure   Dopamine  Milrinone

    Dobutamine  Cardiogenic Shock  

Norepinephrine (Levophed)

    Dobutamine  Anaphylactic Shock   Epinephrine (Adrenalin) VasopressinNeurogenic Shock  

Phenylephrine (Neosynephrine)  

Hypotension

Anesthesia-induced

Phenylephrine (Neosynephrine)  vasopressin

 Following CABG Epinephrine (Adrenalin)