NITHIYA

Vasoactive 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

Receptor Physiology› Main categories of adrenergic receptors relevant to vasopressor activity:– Alpha-1adrenergic receptor– Beta-1, Beta-2 adrenergic receptors– Dopamine receptors – Vasopressin receptors

ALPHA 1 (A1):

A1 receptors are in vascular smooth muscle & also in the myocardium, which mediate positive inotropic and negative chronotropic effects.

Stimulation of A1 receptors leads to vasoconstriction.

ALPHA 2 (A2):- A2 receptors are located in large blood vessels.

Stimulation of A2 receptors mediates arterial and venous vasoconstriction.

BETA 1 (B1):-

Beta 1 receptors increase heart rate and myocardial contractility.

BETA 2 (B2):-

Beta 2 receptors enhance vasodilation; relax bronchial, uterine and gastrointestinal smooth muscle

 

DOPAMINERGIC: Related to the effect of dopamine.

Dopaminergic receptors

› D1-5

› D1 like-D1 and D5

› Excitatory-increase cAMP formatoin and PIP2 hydrolysis

› D2 like-D2-D4

› Inhibitory

› Overall effect-vasodilation-reduced SVR

VASOPRESSIN RECEPTORS

1

MECHANISM OF ACTION

Vascular Smooth Muscle

› Calcium dependent effects– Agents that increase intracellular cAMP increase

intracellular calcium requirements for contraction, thus encouraging smooth muscle relaxation and vasodilation

Vascular Smooth Muscle

› Calcium independent effects– G protein mediated activation of phospholipase C

results in breakdown of phosphatidylinositol bisphosphate into IP3 and DAG.

– IP3 releases calcium from the sarcoplasmic reticulum initiating contraction and DAG activates protein kinase C with phosphorylation of intracellular proteins

SYNTHESIS OF NORADRENALNE

› DIRECT AND INDIRECT ACTING

› DIRECT-adrenaline and noradrenaline

› INDIRECT-dopamine,dobutamine

CLASSIFICATION

CATECHOLAMINES-Camp dependent signalling

Adrenaline,noradrenaline,dopamine,dobutamine

PDEIII inhibitors=milrinone,amrinone

Calcium sensitisers-levosimendan

MECHANISM OF ACTION

INDIVIDUAL AGENTS

› Catecolamines : dopamine, dobutamine,

adrenaline, noradrenaline

› PDE inibitors: milrinone, amrinone

› Vasoconstrictors –Vasopressin,phenylephrine

› Vasodilators -SNP, NTG

Effects of Agents› Pressors: increase systemic vascular resistance and

increase blood pressure

› Inotropes: affect myocardial contractility and enhance stroke volume

› Chronotropic Agents: affect heart rate

› Lusotropic Agents: improve relaxation during diastole and decrease EDP in the ventricles

› Dromotropic Agents: Affects conduction speed through AV node; increases heart rate

› Bathmotropic Agents: affect degree of excitability

Epinephrine› Both an alpha- and beta-adrenergic agent

– Low-dose infusion (0.05-0.3 mic/kg/min)= β activation› Increase HR, contractility, decrease SVR

– Higher doses(05-1mic/kg/min) = activation› Increased SVR and MAP› Increased myocardial O2 demand

Epinephrine› Indications for its use as a continuous infusion are:– low cardiac output state

› beta effects will improve cardiac function› alpha effects may increase afterload and decrease cardiac

output

– septic shock› useful for both inotropy and vasoconstriction

Epinephrine› Adverse effects include:

– Anxiety, tremors,palpitations– Tachycardia and tachyarrhythmias– Increased myocardial oxygen requirements and

potential to cause ischemia– Decreased splanchnic and hepatic circulation

(elevation of AST and ALT)– Anti-Insulin effects: lactic acidosis, hyperglycemia

Norepinephrine

› An epinephrine precursor that acts primarily on receptors

› Used primarily for alpha agonist effect - increases SVR without significantly increasing C.O.

› Used in cases of low SVR and hypotension such as profound “warm shock” with a normal or high C.O. state- usually in combination with dopamine or epinephrine

› Infusion rates titrated between 0.05 to 1 mcg/kg/min

Norepinephrine› Differs from epinephrine in that the vasoconstriction outweighs any increase in cardiac output.– i.e. norepinephrine usually increases blood

pressure and SVR, often without increasing cardiac output.

Norepinephrine

› Adverse Effects:– Similar to those of Epinephrine– Can compromise perfusion in extremities – More profound effect on splanchnic circulation and

myocardial oxygen consumption

Dopamine› Intermediate product in the enzymatic pathway leading to the production of norepinephrine; thus, it indirectly acts by releasing norepinephrine.

› Directly has , and dopaminergic actions which are dose-dependent.

› Indications are based on the adrenergic actions desired.

Dopamine

› renal perfusion 2-5 mcg/kg/min (dopaminergic effects) by sensitivity of vascular smooth muscle to intracellular calcium (? Effects on UOP)

› C.O. in Cardiogenic or Distributive Shock 5-10mcg/kg/min ( adrenergic effects)

› Post-resuscitation stabilization in patients with hypotension (with fluid therapy) 10-20mcg/kg/min ( adrenergic effects) peripheral vasoconstriction, SVR, PVR, HR, and BP

Low dose dopamine in renal failure

ADVERSE EFFECTS

› Extravasation

› Tachyphylaxis

› Immunosuppression and endocrine disturbances

› Increased myocardial o2 demand

› Tachycardia and arrhythmia

Dobutamine

› Synthetic catecholamine with 1 inotropic effect (increases stroke volume) and 2

peripheral vasodilation (decreases afterload)

› Positive chronotropic effect 1 (increases HR)

› Some lusitropic effect

› Overall, improves Cardiac Output by above beta-agonist acitivity

Dobutamine

› Used in low C.O. states and CHF e.g. myocarditis, cardiomyopathy

› In combination with Epi/Norepi in profound shock states to improve Cardiac Output and provide some peripheral vasodilatation

Studies

› Martin: Norepi in Septic Shock– 97 patients in septic shock– Dopamine started at 5mcg/kg/min, titrated to

15mcg/kg/min– If hypotension persisted:

› DA increased to 25mcg/kg/min OR› NE added at 0.5mcg/kg/min

Martin et al

› Patients receiving NE had best survival rate on all days of hospital stay (p<0.001)

› Mortality strongly associated with high lactate and low urine output

› “NE was associated with a highly significant decrease in hospital mortality. The data contradict the notion that norepinephrine potentiates end organ hypoperfusion through excessive vasoconstriction

Studies

› De Backer: Norepi v Dopamine in Shock.

– Multicenter study, 1679 patients– DA with 52.5% mortality– NE with 48.5% mortality (p=0.10)– More arrhythmic events with DA (207v102)

DeBacker et al

› Included Septic (62.2%), Cardiogenic (16.7%), and Hypovolemic (15.7%) shock.

› More patients in DA group required 2nd pressor

› Subgroup: DA in cardiogenic shock increased mortality significantly (p=0.03)

› Conclusion: “This study raised serious concern about the safety of Dopamine”

RECEPTORS

Milrinone/Amrinone› Belong to class of agents “Bipyridines”

› Non-receptor mediated activity based on selective inhibition of Phosphodiesterase Type III enzyme resulting in cAMP accumulation in myocardium

› cAMP increases force of contraction and rate and extent of relaxation of myocardium

› Inotropic, vasodilator and lusitropic effect

› Advantage over catecholamines: – Independent action from -receptor activation,

particularly when these receptors are downregulated (CHF and chronic catecholamine use)

Milrinone› Increases CO by improving contractility, decreased SVR, PVR, lusotropic effect; decreased preload due to vasodilatation

› Unique in beneficial effects on RV function

› Protein binding: 70%

› Half-life is 2.3 hours

› Elimination: primarily renally excreted

› Load with 50 mcg/kg over 30 mins followed by 0.25 to 0.75 mcg/kg/min

› No increase in myocardial O2 requirement

Vasopressin

› a peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure

› possesses antidiuretic and vasopressor properties

› deficiency of this hormone results in diabetes insipidus

Vasopressin

› Administration– interacts with two types of receptors

› V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction

› V2 receptors are found on renal tubule cells and mediate antidiuresis through increased water permeability and water resorption in the collecting tubules

› Newer drug to ACLS for resuscitation

› Use in refractory septic shock with low SVRI in pediatrics?

VASOPRESSIN LEVELS IN SHOCK

VASST

Levosimendan Calcium sensitiser

› Binds to troponin C and change configuration of tropomyosin and increases contractility

› Opens potassium channels-reduced SVR and coronary vasodilation

› Does not increase myocardial o2 demand

› SV/CO/HR increases

› Pulmonary arterial pressure and MAP decreases

› Atrial arrhythmias common

› Half life-1.5-2 hours

› Metabolite OR-1896 half life-70-80hours

Calcium Sensitisation by Levosimendan

› Enhanced contractility of myocardial cell by amplifying trigger for contraction with no change in total intracellular Ca2+

› Enhanced contractility of myocardial cell by amplifying trigger for contraction with no change in total intracellular Ca2+

Effects of Opening ATP-Sensitive Potassium Channels

›Reduces preload and afterload› Increased coronary blood flow

(Lilleberg et al. Eur Heart J. 1998;19:660-668.)

›Anti-ischemic effect (Kersten et al. Anesth Analg. 2000;90:5-11;Kaheinen et al. J Cardiovasc Pharmacol. 2001;37:367-374.)

Levosimendan

› Loading dose of 12mic/kg over 10 minutes f/b

› Continous infusion of 0.1-0.2 mic/kg/min

› TRIALS

› LIDO/CASINO/SURVIVE TRIALS

› Compared LM with dobutamine

› REVIVE and RUSSLAN TRIAL

› Compared LM with placebo

Istaroxime

› Ino lusitropy

› Short half life

Vasodilators

› Classified by site of action

› Venodilators: reduce preload - Nitroglycerin

› Arteriolar dilators: reduce afterload Minoxidil and Hydralazine

› Combined: act on both arterial and venous beds and reduce both pre- and afterload Sodium Nitroprusside

Nitroprusside› Vasodilator that acts directly on arterial and venous vascular smooth muscle.

› Indicated in hypertension and low cardiac output states with increased SVR.

› Also used in post-operative cardiac surgery to decrease afterload on an injured heart.

› Action is immediate; half-life is short; titratable action.

Nitroprusside› Toxicity is with cyanide, one of the metabolites of

the breakdown of nipride.

› Severe, unexplained metabolic acidosis might suggest cyanide toxicity.

› Dose starts at 0.5 mcg/kg/min and titrate to 5 mcg/kg/min to desired effect. May go higher (up to 10 mcg/kg/min) for short periods of time.

Nitroglycerine› Direct vasodilator as well, but the major effect is as a venodilator with lesser effect on arterioles.

› Not as effective as nitroprusside in lowering blood pressure.

› Another potential benefit is relaxation of the coronary arteries, thus improving myocardial regional blood flow and myocardial oxygen demand.

Nitroglycerine

› Used to improve myocardial perfusion following cardiac surgery

› Dose ranges from 0.5 to 8 mcg/kg/min. Typical dose is 2 mcg/kg/min for 24 to 48 hours post-operatively

› Methemoglobinemia is potential side effect

Classification Agent Physiologic response End result Examples

Inotrope ↑ cardiac contraction ↑ CO, BP unchanged or ↑

Dop, dobut, milrin, Adr, NA

Chronotrope ↑ HR ↑ CO , ↑ HR Isopren, dop, adr, dobut ( higher dose)

Vasopressor ↑ vascular tone, ↑ SVR& PVR ↑ BP, CO unchanged or ↓

Adr,, NA, vasopressin, dop ( higher dose)

Vasodilator ↓ arterial + venous tone, ↓ SVR & PVR

BP unchanged or ↓, CO ↑

SNP, NTG, milrinone

Inodilator ↑ cardiac contraction, ↓ SVR & PVR

↑ CO , , BP unchanged or ↑

Milrinone, dobut, levosimendan

Lusitrope diastolic relaxation of ventricles

↑ CO ( if diastolic dysfunction present)

milrinone

PRACTICAL CONSIDERATIONS

Central vs. Peripheral line› Jean-Damien, R et al. Central or peripheral catheters

for initial venous access of ICU patients– Patients randomized: peripheral (N=128) or central access

(N=135) › Included epinephrine/norepinephrine doses up ~0.4 mcg/kg/min (for 75 kg

patient); Dopamine/dobutamine doses up to 10 mcg/kg/min

– Less major complications with central rather than peripheral access (0.64 vs. 1.04, p<0.02)› Majority of complications in PIV group were inability to insert PIV

http://emcrit.org/podcasts/peripheral-vasopressors-extravasation/Ricard JD, et al. Central or peripheral catheters for initial venous access of ICU patients: a randomized controlled trial. Crit Care Med. 2013 Sep;41(9):2108-15

Extravasation

Drug Effect Mechanism(s) of tissue injury

Dobutamine Irritant; Rare reports of vesicant effects

Cytotoxicity, acidic pH

Dopamine, Epinephrine, Phenylephrine Norepinephrine, Vasopressin

Vesicants Vasoconstriction

Extravasation

› Phentolamine– Short-term alpha-adrenergic blocking activity– Administration →vasodilatation of vascular smooth

muscle– Infiltrate area of extravasation with phentolamine: 5 mg

diluted in 9 mL NS – Should see near immediate effects; otherwise consider

additional dose (Max = 10 mg)

Adverse Reactions

Epinephrine Norepinephrine Dopamine Dobutamine Vasopressin Phenylephrine

Tachycardia x High doses xArrhythmias x High doses x x (ventricular)Increased myocardial O2 demand x x x

Decreased perfusion to vital organs x x x (less) xNausea/vomiting x xMetabolic acidosis x x

Hypersensitivity

x (contains sulfites)

Extravasation x x x x x x

Resuscitation › Epinephrine vasoconstrictor effect Inotropy Sensitize myocardium to defibrillation attempts-no

evidence

› Adult studies Large dose of epinephrine versus standard dose Use of vasopressin in 0.4U/kg/dose after prolonged

arrests

Septic shock-surviving sepsis compaign

Myocarditis/heart failure

› Ideal inotrope Improves systolic and diastolic myocardial function Decreases systemic and peripheral vascular

resistance Without increasing myocardial o2 consumption Initial drugs-dobutamine,dopamine,milrinone,low

dose epinephrine

Post cardiac surgery

› LCOS

› Initially-dobutamine and low dose adrenaline

› PRIMACORP(prophylactic intravenous use of milrinone after cardiac operation in pediatrics)

› Levosimendan

› Vasopressin and norepinephrine

Post cardiac arrest syndrome

› Post cardiac brain injury

› Post cardiac myocardia dysfunction

› Systemic ischemia/reperfusion response

› Actual pathology

› Epinephrine,dopamine,dobutamine

› Vasopressin recently

Brain dead child

› To maintain perfusion to vital organs

› Dopamine –first line cardiovascular support

› Low dose vasopressin –first line pressor support

› Canadian guidelines

first line-low dose vasopressin

Second line-norepinephrine,epinephrine,phenylephrine

Preparations

› Rule of six

› 6*BW=amount(mg) in 100ml of solvent at 1ml/hr=1 microgram/kg/min

› Dopamine and dobutamine

› 6*BWmg in 25 ml NS at 1ml/hr=4mic/kg/min

› Adrenaline and noradrenaline

› 0.6 * BW in 50ml NS at 1ml/hr-0.2mic/kg/min

Vasoactive-inotrope score