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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)