Vasopressors and Inotropes

Dr. E. McIntosh November 2011

Objectives

Define the terms Inotrope & vasopressor

Discuss basic physiological principles

Discuss drug classification

Sympathomimetics Other

Describe some clinical uses

Inotropes Vs. Vasopressors

Inotropes

Drugs that affect the force of contraction of myocardial muscle

Positive or negative
Term inotrope generally used to describe positive effect

Vasopressor

Drugs that stimulates smooth muscle contraction of the capillaries & arteries Cause vasoconstriction & a consequent rise in blood pressure

Which of these drugs does NOT cause a positive inotropic effect?

1.

2.
3. 4. 5. 6.

Adrenaline Calcium Digoxin Enoximone Nifedipine Glucagon

30% 26% 22%

9%

9% 4%

Main Goal

Tissue perfusion & oxygenation

Inadequate tissue perfusion to meet the tissue demands

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

Usually associated with hypotension

Physiology of Shock
Septic (Distributive )
Decreased SVR

Cardiogenic

Obstructive

Hypovolemic

Myocardial Dysfunction

Myocardial Damage

Pericardial Tamponade Reduced Ventricular Filling

Hemmorrhage

Maldistributed Blood Flow

Compensated

Uncompensated

Reduced Preload

Reduced Systolic Finction Low Cardiac Output Deminished Tissue Perfusion

High or Normal Function

SHOC

Physiological Principles

MAP = CO x SVR
~ 1

CO = HR x SV

r4

Preload Contractility Afterload

Basic principles Vasopressors

MAP = CO x SVR
~ 1

CO = HR x SV

r4

Preload Contractility Afterload

Basic principles - Inotropes

MAP = CO x SVR
CO = HR x SV
Preload Contractility Afterload

Mixed action drugs

Use of inotropes & vasopressors

Drug Classification
(Mechanism of Action)

Sympathomimetics

Naturally occurring Synthetic

Other inotropes

cAMP dependent cAMP independent

Other vasopressors

Sympathomimetics

Sympathetic nervous system

Sympathomimetics

Drugs that stimulate adrenergic receptors

G-protein coupled receptors

G - Protein

Activation of intermediate messenger

Which adrenoceptor mediates cardiac muscle contraction?

1.

2.
3. 4.

1 2 1 2

65%

12%

12%

12%

Which adrenoceptor mediates vascular smooth muscle contraction? 58%

1. 2. 3. 4.

1 2 1 2
4% 0%
1 2 3

38%

Main classes of Adrenoceptor

receptors

Located in vascular smooth muscle Mediate vasoconstriction

Located throughout the CNS, platelets Mediate sedation, analgesia & platelet aggregation

Main classes of Adrenoceptor

receptors

Located in vascular smooth muscle Mediate vasoconstriction

Located throughout the CNS, platelets Mediate sedation, analgesia & platelet aggregation

Differences between 1 and 2

Alpha-1
Location Function Post junctional Stimulatory GU, Vasoconstriction, gland secretion, Gut relaxation, Glycogenolysis Phenylephrine, Methoxamine

Alpha-2
Prejunctional Inhibition of transmitter release, vasoconstriction, decreased central symp. Outflow, platelet aggregation Clonidine

Agonist

Antagonist

Prazosin

Yohimbine

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

Main classes of Adrenoceptor

receptors

Located in the heart Mediate increased contractility & HR

Located mainly in the smooth muscle of bronchi Mediate bronchodilatation

Main classes of Adrenoceptor

receptors

Located in the heart Mediate increased contractility & HR

Located mainly in the smooth muscle of bronchi

Mediate bronchodilatation Dilatation of coronary vessels Dilatation of arteries supplying skeletal muscle

Located in blood vessels

1 Adrenoceptor
Adrenaline

G - Protein

Adenyl cyclase

ATP

cAMP

Increased heart muscle contractility

Differences between 1, 2 and 3

Beta-1
Location Heart and JG cells

Beta-2
Bronchi, uterus, Blood vessels, urinary tract, eye Salbutamol Alpha-methyl propranolol

Beta-3
Adipose tissue -

Agonist Antagonist

Dobutamine Metoprolol, Atenolol

Action on NA

Moderate

Weak

Strong

2 Adrenoceptor Clinical Effects

Bronchi -- Relaxation Arterioles -- Dilatation Uterus Relaxation Skeletal Muscle - Tremor Hypokalaemia Hepatic Glycogenolysis

Dopamine receptors

D1-receptors are post synaptic receptors located in blood vessels and CNS D2-receptors are presynaptic present in CNS, ganglia, renal cortex

Sympathomimetics

Naturally occuring

Synthetic

Epinephrine Norepinephrine Dopamine

Dobutamine Dopexamine Phenylephrine Metaraminol Ephedrine

Classification (Chemical Structure)

Catecholamines:

Natural: Adrenaline, Noradrenaline, Dopamine Synthetic: Isoprenaline, Dobutamine Ephedrine, Amphetamines, Phenylepherine, Methoxamine, Mephentermine

Non-Catecholamines:

Also called sympathomimetic amines as most of them contain an intact or partially substituted amino (NH2) group

 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

Biosynthesis of Catecholamines
Phenylalanine
PH

Alpha-methyl-ptyrosine

Rate limiting Enzyme

5-HT, alpha Methyldopa

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

Metabolism of CAs

(Homovanillic acid)

(Vanillylmandelic acid)

Adrenaline as prototype

Potent stimulant of alpha and beta receptors Complex actions on target organs

Blood Pressure

Most potent vasopressor known Both systolic and Diastolic 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 peripheral resistance Reflex Bradycardia

Blood Vessels

Seen mainly in the smaller vessels arterioles Decreased blood flow to skin and mucus membranes alpha 1 effect Increased blood flow to skeletal muscles(Beta-2 effect) counterbalanced by a vasoconstrictor effect of alpha receptors If alpha receptors are blocked there is no opposing effect and this leads to fall of BP

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

Actions of Adrenaline
Respiratory: Powerful bronchodilator Relaxes bronchial smooth muscle Beta-2 mediated effect Physiological antagonist to mediators of bronchoconstriction e.g. Histamine Smooth Muscles: Effects on vascular smooth muscle are important GIT and Urinary tract smooth muscle are relaxed but are clinically unimportant In the pregnant uterus there is inhibition of tone and contractions

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

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 and COMT

Adrenaline Clinical uses

Injectable preparations are available in dilutions 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

ADRs

Tachycardia Hypertension Decreased renal blood flow Restlessness, Throbbing headache, Tremor, Palpitations Cerebral hemorrhage, cardiac arrhythmias

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

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

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 pressure and 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 the rate of 2-4mg/ minute used as a vasopressor agent in treatment of septic shock and other hypotensive states in order to raise B.P

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

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

Dopamine

Agonists at dopaminergic D1, D2 receptors Agonist at adrenergic 1 and 1

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 to sympathetic overctivity

Increases renal blood flow, GFR an causes natriuresis

Dopamine

Moderate dose (5-10 g/kg/minute), stimulates 1receptors in heart producing positive inotropic and moderate chronotropic actions Releases Noradrenaline from nerves by 1stimulation Does not change TPR and HR Great Clinical benefit in CVS shock and CCF High dose (10-30 g/kg/minute), stimulates vascular adrenergic 1-receptors vasoconstriction and decreased renal blood flow

Dopamine

Adverse effects

Tachycardia Arrhythmias Excessive vasoconstriction (higher doses)

Decreased splanchnic, renal blood flow Decreased cardiac output

Dobutamine (Dobutrex)

Not a vasopressor but rather an inotrope that causes vasodilation. Predominant beta-1 receptor effect increases inotropy and chronotropy and reduces LV filling pressures. Minimal alpha and beta-2 receptor effects result in 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.

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.

Isoproterenol (Isuprel) Drawbacks

Tachycardia Dysrhythmias Peripheral vasodilation Increased myocardial consumption

CPK indicating myocardial necrosis

Decreased coronary O2 delivery Splanchnic steal by skeletal muscle

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)

Phosphodiesterase Inhibitors

Amrinone and Milrinone Nonadrenergic drugs with inotropic and vasodilatory actions. Acts by inhibiting the breakdown 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.

Vasopressin

Acts like ADH; directly stimulates smooth muscle V1 receptors, resulting in vasoconstriction
Often used in the setting of DI or esophageal variceal bleeding. May be useful in the treatment of refractory septic shock, particularly as a second (add-on) pressor agent.

Vasopressin

Addition of vasopressin to norepinephrine was more effective in reversing late vasodilatory shock than norepinephrine alone. (1) Vasopressin did not reduce mortality compared to norepi. (2) Timely treatment, rather then specific agent is the decisive 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.

Alpha adrenergic agonists

Selective Alpha-1 Agonists:

Phenylepherine Methoxamine Metaraminol Mephentermine Clonidine -methyldopa Guanfacine, Guanabenz Ephederine, Phenylepherine, Xylometazoline, Oxymetazoline, Naphazoline an d Tetrahydrazoline

Selective Alpha-2 Agonists:

Nasal Decongestants:

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

Ephedrine

Plant alkaloid, indirect sympathomimetic

Stimulates release of noradrenaline from adrenergic nerve endings Increase BP and HR

Actions resembling adrenaline peripherally

Centrally Increased alertness, anxiety, insomnia, tremor and nausea 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