7. Inotropes and Vasopressors

7/29/2019 7. Inotropes and Vasopressors

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Vasopressors andInotropes

Dr. E. McIntosh

November 2011


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Inotropes Vs. Vasopressors

V


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Inotropes

Drugs that affect the

force of contraction of

myocardial muscle

Positive or negative

Term inotropegenerally used to

describe positive

effect


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Vasopressor

Drugs that stimulatessmooth musclecontraction of thecapillaries & arteries

Causevasoconstriction & a

consequent rise inblood pressure


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NOT cause a positive

inotropic effect?

1 2 3 4 5 6

9% 9%

30%

26%

4%

22%

1. Adrenaline

2. Calcium

3. Digoxin

4. Enoximone

5. Nifedipine

6.

Glucagon


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Main Goal

Tissue perfusion &oxygenation


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Inadequate tissue perfusion to meet the

tissue demands

a result of inadequate blood flow and/orinadequate oxygen delivery.

Usually associated with hypotension


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Physiology of Shock

High or

Normal

Function

MaldistributedBlood Flow

Decreased SVR

Compensated

Deminished

Tissue

Perfusion

LowCardiac

Output

Reduced

Systolic Finction

Uncompensated

Myocardial

Dysfunction

Myocardial

Damage

ReducedVentricular

Filling

Pericardial

Tamponade

ReducedPreload

Hemmorrhage

Septic

(Distributive)

Cardiogenic Obstructive Hypovolemic

SHOC


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Physiological Principles

MAP = CO x SVR

CO = HR x SV

Preload Contractility Afterload

~ 1

r4


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Basic principles -

Vasopressors

MAP = CO x SVR

CO = HR x SV


~ 1

r4


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Basic principles - Inotropes

MAP = CO x SVR

CO = HR x SV



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Mixed action drugs


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Use of inotropes &

vasopressors


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Sympathomimetics

Sympathetic nervous system


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Sympathomimetics

Drugs that stimulate adrenergic receptors

G-protein coupled receptors

G - ProteinActivation of

intermediate

messenger


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Which adrenoceptor mediates

cardiac muscle contraction?

1 2 3 4

12% 12%

65%

12%

1. 1

2. 2

3. 1

4. 2


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Which adrenoceptor mediates

vascular smooth muscle

contraction?

1 2 3 4

58%

38%

4%

0%

1. 1

2. 2

3. 1

4. 2


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Main classes of Adrenoceptor

receptors

1 Located in vascular smooth muscle

Mediate vasoconstriction

2 Located throughout the CNS, platelets

Mediate sedation, analgesia & platelet aggregation


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receptors

1 Located in vascular smooth muscle

Mediate vasoconstriction

2 Located throughout the CNS, platelets

Mediate sedation, analgesia & platelet aggregation


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Differences between 1 and 2

Alpha-1 Alpha-2

Location Post junctional Prejunctional

Function Stimulatory GU,

Vasoconstriction, gland

secretion, Gut relaxation,

Glycogenolysis

Inhibition of transmitter

release, vasoconstriction,

decreased central symp.

Outflow, platelet

aggregation

Agonist Phenylephrine, Methoxamine Clonidine

Antagonist Prazosin Yohimbine


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1 adenoceptor

Clinical effects

Eye -- Mydriasis

Arterioles Constriction

Uterus -- Contraction

Skin -- Sweat Platelet - Aggregation

Male ejaculation

Hyperkalaemia

Bladder Sphincter Contraction 2 adrenoceptors on nerve endings mediate negative

feedback which inhibits noradrenaline release


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receptors

1 Located in the heart

Mediate increased contractility & HR

2 Located mainly in the smooth muscle of bronchi

Mediate bronchodilatation


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receptors

1 Located in the heart

Mediate increased contractility & HR

2 Located mainly in the smooth muscle of bronchi

Mediate bronchodilatation

Located in blood vessels

Dilatation of coronary vessels

Dilatation of arteries supplying skeletal muscle


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1 Adrenoceptor

G - Protein Adenyl cyclase

ATP cAMP

Increased heart

muscle

contractility

Adrenaline


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Differences between 1, 2 and 3

Beta-1 Beta-2 Beta-3

Location Heart and JG cells Bronchi, uterus,

Blood vessels,

urinary tract, eye

Adipose

tissue

Agonist Dobutamine Salbutamol -

Antagonist Metoprolol, Atenolol Alpha-methyl

propranolol

-

Action on

NA

Moderate Weak Strong


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2 Adrenoceptor Clinical Effects

Bronchi -- Relaxation

Arterioles -- Dilatation

Uterus Relaxation Skeletal Muscle - Tremor

Hypokalaemia

Hepatic Glycogenolysis


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Dopamine receptors

D1-receptors are post synaptic receptors

located in blood vessels and CNS

D2-receptors are presynaptic present in CNS,

ganglia, renal cortex


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Sympathomimetics

Naturally occuring

Epinephrine

Norepinephrine

Dopamine

Synthetic

Dobutamine

Dopexamine

Phenylephrine

Metaraminol

Ephedrine


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Classification

(Chemical Structure)

Catecholamines:

Natural:Adrenaline, Noradrenaline, Dopamine

Synthetic: Isoprenaline, Dobutamine

Non-Catecholamines: Ephedrine, Amphetamines, Phenylepherine, Methoxamine,

Mephentermine

Also called sympathomimetic amines as most of

them contain an intact or partiallysubstituted amino(NH2) group


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Catecholamines:

Compounds containing

a catechol nucleus

(Benzene ring with 2

adjacent OH groups)and an amine

containing side chain

Non-catecholamines

lack hydroxyl (OH)

group


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Biosynthesis of

CatecholaminesPhenylalanine

PH

Rate limiting Enzyme

5-HT, alpha Methyldopa

Alpha-methyl-p-

tyrosine


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Metabolism of CAs

Mono Amine Oxidase (MAO) Intracellular bound to mitochondrial membrane

Present in NA terminals and liver/ intestine

MAO inhibitors are used as antidepressants Catechol-o-methyl-transferase (COMT)

Neuronal and non-neuronal tissue

Acts on catecholamines and byproducts

VMA levels are diagnostic for tumours


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Metabolism of CAs

(Homovanillic acid) (Vanillylmandelic acid)


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Adrenaline as prototype

Potent stimulant of alpha and beta receptors

Complex actions on target organs


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Blood Pressure

Most potent vasopressor known Both systolic andDiastolic BP rise

Has a characteristic effect on BP

Rapid rise to a peak: Direct myocardial stimulation

+ve inotropic Increased heart rate

+ve chronotropic

Vasoconstriction which leads to increased peripheralresistance

Reflex Bradycardia


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Blood Vessels

Seen mainly in the smaller vessels -arterioles

Decreased blood flow to skin and mucus

membranesalpha 1 effect Increased blood flow to skeletal muscles-

(Beta-2 effect) counterbalanced by avasoconstrictor effect of alpha receptors

If alpha receptors are blocked there is noopposing effect and this leads to fall of BP


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Heart

Powerful Cardiac stimulant

Acts on beta-1 receptors in myocardium,pacemaker cells and conducting tissue Heart rate increases Rhythm is altered

Cardiac systole is shorter and more powerful

Cardiac output is enhanced

Oxygen consumption is increased

Cardiac efficiency is markedly decreased


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Actions of Adrenaline

Respiratory:

Powerful bronchodilator

Relaxes bronchial smooth muscle Beta-2 mediated effect

Physiological antagonist to mediators ofbronchoconstriction e.g. Histamine

Smooth Muscles:

Effects on vascular smooth muscle are important

GIT and Urinary tract smooth muscle are relaxed butare clinically unimportant

In the pregnant uterus there is inhibition of tone andcontractions


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Metabolic effects

Increases concentration of glucose and lactic

acid

Calorigenesis (-2 and-3)

Inhibits insulin secretion (-2)

Decreases uptake of glucose by peripheral

tissue

Simulates glycogenolysis - Beta effect

Increases free fatty acid concentration in

blood


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ADME

Ineffective orally

Absorbed slowly from subcutaneous tissue

Faster from IM site Inhalation is locally effective

Not usually given IV

Rapidly inactivated in Liver by MAO andCOMT


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Adrenaline Clinical uses

Injectable preparations are available indilutions 1:1000, 1:10000 and 1:100000

Used in:

Anaphylactic shock (0.3 0.5mg sc) Cardiac arrest (1mg iv PRN)

Second line agent in septic shock

IV Infusion 0.01 0.12 mcg/kg/min

Prolong action of local anaesthetics


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ADRs

Tachycardia

Hypertension

Decreased renal blood flow Restlessness, Throbbing headache, Tremor,

Palpitations

Cerebral hemorrhage, cardiac arrhythmias


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Clinical

Question: A Nurse was injecting a dose of penicillin

to a patient in Medicine ward without prior skin test

and patient suddenly developed immediate

hypersensitivity reactions. What would you do? Answer: As the patient has developed Anaphylactic

reaction, the only way to resuscitate the patient is

injection of Adrenaline

0.5 mg (0.5 ml of 1:1000) IM and repeat after 5-10 minutes Antihistaminics: Chlorpheniramine 10 20 mg IM or IV

Hydrocortisone 100 200 mg


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Noradrenaline

Neurotransmitter released from

postganglionic adrenergic nerve endings

(80%)

Orally ineffective and poor SC absorption

IV administered

Metabolized by MAO, COMT

Short duration of action


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Actions and uses

Agonist at 1, 2 and 1 Adrenergic receptors

Equipotent on 1, but No effect on 2

Increases systolic, diastolic B.P, mean pressure, pulse pressureand stroke volume

Total peripheral resistance (TPR) increases due to

vasoconstriction Decreases blood flow to kidney, liver and skeletal muscles

Increases coronary blood flow

Uses: Injection Noradrenaline bitartrate slow IV infusion at therate of 2-4mg/ minute used as a vasopressor agent in treatment

of septic shock and other hypotensive states in order to raise B.P


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Noradrenaline - ADRs

Anxiety, palpitation, respiratory difficulty

Rise of B.P, headache

Extravasations causes necrosis, gangrene Contracts gravid uterus

Severe hypertension, violent headache,

photophobia, anginal pain, pallor and

sweating in hyperthyroid and hypertensive

patients


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Dopamine

Endogenous catecholamine

Immediate metabolic precursor of

Noradrenalin

Central neurotransmitter

Ineffective orally, IV use only

Short T 1/2 (3-5minutes) given as

continuous infusion


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Dopamine

Agonists at dopaminergic D1, D2receptors

Agonist at adrenergic 1 and 1


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Dopamine

In small doses 2-5g/kg/minute, it stimulates

D1-receptors in renal, mesenteric and

coronary vessels leading to vasodilatation

Renal vsoconstriction occurs in CVS shock due tosympathetic overctivity

Increases renal blood flow, GFR an causes

natriuresis


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Dopamine

Moderate dose (5-10 g/kg/minute), stimulates 1-receptors in heart producing positive inotropic andmoderate chronotropic actions

Releases Noradrenaline from nerves by 1-stimulation

Does not change TPR and HR

Great Clinical benefit in CVS shock and CCF

High dose (10-30 g/kg/minute), stimulates vascularadrenergic 1-receptors vasoconstriction anddecreased renal blood flow


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Dopamine

Adverse effects

Tachycardia

Arrhythmias

Excessive vasoconstriction (higher doses)

Decreased splanchnic, renal blood flow

Decreased cardiac output


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Dobutamine (Dobutrex)

Not a vasopressor but rather an inotrope thatcauses vasodilation.

Predominant beta-1 receptor effect increases

inotropy and chronotropy and reduces LV fillingpressures.

Minimal alpha and beta-2 receptor effects resultin overall vasodilation, complemented by reflex

vasodilation to the increased CO. Net effect is increased CO, with decreased SVR

with or without a small reduction in BP.


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Dobutamine (Dobutrex)

Frequently used in severe, medically

refractory heart failure and cardiogenic

shock, especially with high or normal BP

Should not be routinely used in sepsis

because of the risk of hypotension.

Does not selectively vasodilate the renal

vascular bed.

I t l (I l)


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Isoproterenol (Isuprel)

Drawbacks

Tachycardia

Dysrhythmias

Peripheral vasodilation

Increased myocardial consumption CPK indicating myocardial necrosis

Decreased coronary O2 delivery

Splanchnic steal by skeletal muscle


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Isoproterenol (Isuprel)

Major indication

bradycardia

Pure beta Potent pulmonary/ bronchial vasodilator

Increased cardiac output

Widened pulse pressure

Increased flow to non-critical tissue beds(skeletal muscle)


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Phosphodiesterase Inhibitors

Amrinone and Milrinone

Nonadrenergic drugs with inotropic andvasodilatory actions.Acts by inhibiting thebreakdown of both cAMP and cGMP by the

phosphodiesterase (PDE3) enzyme. Effects are similar to dobutamine but with a

lower incidence of dysrhythmias.

Used to treat patients with impaired cardiac

function and medically refractory HF. Vasodilatory properties limit their use in

hypotensive patients.


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Vasopressin

Acts like ADH; directly stimulates smooth

muscle V1 receptors, resulting in

vasoconstriction

Often used in the setting of DI or esophagealvariceal bleeding.

May be useful in the treatment of refractory septic

shock, particularly as a second (add-on) pressor

agent.


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Vasopressin

Addition of vasopressin to norepinephrine was moreeffective in reversing late vasodilatory shock thannorepinephrine alone. (1)

Vasopressin did not reduce mortality compared to

norepi. (2)

Timely treatment, rather then specific agent is thedecisive factor. (3)

1. Arginine Vasopressin in Advanced Vasodilatory Shock, Circulation.

2003; 107: 23132319.

2. Vasopressin versus Norepinephrine Infusion in Patients with Septic

Shock, NEJM. 2008; 358:877-887.

3. Septic Shock Vasopressin, Norepinephrine, and Urgency, NEJM.

2008; 358;954-956.


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Alpha adrenergic agonists

Selective Alpha-1 Agonists: Phenylepherine

Methoxamine

Metaraminol

Mephentermine Selective Alpha-2 Agonists:

Clonidine

-methyldopa

Guanfacine, Guanabenz

Nasal Decongestants: Ephederine, Phenylepherine, Xylometazoline,

Oxymetazoline, Naphazoline an d Tetrahydrazoline


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Phenylepherine

Selective, synthetic and direct 1 agonist

Administered parenteraly & topically (eye, nose)

Long duration of action

Resistant to MAO and COMT

Peripheral vasoconstriction leads to rise in BP

Reflex bradycardia Produces mydriasis and nasal decongestion

Used in hypovolaemic shock as pressor agent

Sinusitis & Rhinitis as nasal decongestant

Mydriatic in the form of eye drops and lowers intraocular pressure

Does not cross BBB, so no CNS effects

Actions qualitatively similar to noradrenaline

ADRs: Photosensitivity, conjunctival hyperemia and hypersensitivity


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Ephedrine

Plant alkaloid, indirect sympathomimetic Stimulates release of noradrenaline from adrenergic nerve endings

Actions resembling adrenaline peripherally Increase BP and HR

Centrally Increased alertness, anxiety, insomnia, tremor andnausea in adults. Sleepiness in children

Effects appear slowly but lasts longer (t1/2-4h)

Tachyphylaxis on repeated dosing

Short term treatment of hypotension

Spinal anaesthesia, general anaesthesia, ICU Also used as bronchodilator, mydriatic, in heart block, mucosal

vasoconstriction

7. Inotropes and Vasopressors

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