7. inotropes and vasopressors
TRANSCRIPT
-
7/29/2019 7. Inotropes and Vasopressors
1/63
Vasopressors andInotropes
Dr. E. McIntosh
November 2011
-
7/29/2019 7. Inotropes and Vasopressors
2/63
-
7/29/2019 7. Inotropes and Vasopressors
3/63
Inotropes Vs. Vasopressors
V
-
7/29/2019 7. Inotropes and Vasopressors
4/63
Inotropes
Drugs that affect the
force of contraction of
myocardial muscle
Positive or negative
Term inotropegenerally used to
describe positive
effect
-
7/29/2019 7. Inotropes and Vasopressors
5/63
Vasopressor
Drugs that stimulatessmooth musclecontraction of thecapillaries & arteries
Causevasoconstriction & a
consequent rise inblood pressure
-
7/29/2019 7. Inotropes and Vasopressors
6/63
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
-
7/29/2019 7. Inotropes and Vasopressors
7/63
Main Goal
Tissue perfusion &oxygenation
-
7/29/2019 7. Inotropes and Vasopressors
8/63
Inadequate tissue perfusion to meet the
tissue demands
a result of inadequate blood flow and/orinadequate oxygen delivery.
Usually associated with hypotension
-
7/29/2019 7. Inotropes and Vasopressors
9/63
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
-
7/29/2019 7. Inotropes and Vasopressors
10/63
Physiological Principles
MAP = CO x SVR
CO = HR x SV
Preload Contractility Afterload
~ 1
r4
-
7/29/2019 7. Inotropes and Vasopressors
11/63
Basic principles -
Vasopressors
MAP = CO x SVR
CO = HR x SV
Preload Contractility Afterload
~ 1
r4
-
7/29/2019 7. Inotropes and Vasopressors
12/63
Basic principles - Inotropes
MAP = CO x SVR
CO = HR x SV
Preload Contractility Afterload
-
7/29/2019 7. Inotropes and Vasopressors
13/63
Mixed action drugs
-
7/29/2019 7. Inotropes and Vasopressors
14/63
Use of inotropes &
vasopressors
-
7/29/2019 7. Inotropes and Vasopressors
15/63
-
7/29/2019 7. Inotropes and Vasopressors
16/63
Sympathomimetics
Sympathetic nervous system
-
7/29/2019 7. Inotropes and Vasopressors
17/63
Sympathomimetics
Drugs that stimulate adrenergic receptors
G-protein coupled receptors
G - ProteinActivation of
intermediate
messenger
-
7/29/2019 7. Inotropes and Vasopressors
18/63
Which adrenoceptor mediates
cardiac muscle contraction?
1 2 3 4
12% 12%
65%
12%
1. 1
2. 2
3. 1
4. 2
-
7/29/2019 7. Inotropes and Vasopressors
19/63
Which adrenoceptor mediates
vascular smooth muscle
contraction?
1 2 3 4
58%
38%
4%
0%
1. 1
2. 2
3. 1
4. 2
-
7/29/2019 7. Inotropes and Vasopressors
20/63
Main classes of Adrenoceptor
receptors
1 Located in vascular smooth muscle
Mediate vasoconstriction
2 Located throughout the CNS, platelets
Mediate sedation, analgesia & platelet aggregation
-
7/29/2019 7. Inotropes and Vasopressors
21/63
Main classes of Adrenoceptor
receptors
1 Located in vascular smooth muscle
Mediate vasoconstriction
2 Located throughout the CNS, platelets
Mediate sedation, analgesia & platelet aggregation
-
7/29/2019 7. Inotropes and Vasopressors
22/63
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
-
7/29/2019 7. Inotropes and Vasopressors
23/63
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
-
7/29/2019 7. Inotropes and Vasopressors
24/63
Main classes of Adrenoceptor
receptors
1 Located in the heart
Mediate increased contractility & HR
2 Located mainly in the smooth muscle of bronchi
Mediate bronchodilatation
-
7/29/2019 7. Inotropes and Vasopressors
25/63
Main classes of Adrenoceptor
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
-
7/29/2019 7. Inotropes and Vasopressors
26/63
1 Adrenoceptor
G - Protein Adenyl cyclase
ATP cAMP
Increased heart
muscle
contractility
Adrenaline
-
7/29/2019 7. Inotropes and Vasopressors
27/63
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
-
7/29/2019 7. Inotropes and Vasopressors
28/63
2 Adrenoceptor Clinical Effects
Bronchi -- Relaxation
Arterioles -- Dilatation
Uterus Relaxation Skeletal Muscle - Tremor
Hypokalaemia
Hepatic Glycogenolysis
-
7/29/2019 7. Inotropes and Vasopressors
29/63
Dopamine receptors
D1-receptors are post synaptic receptors
located in blood vessels and CNS
D2-receptors are presynaptic present in CNS,
ganglia, renal cortex
-
7/29/2019 7. Inotropes and Vasopressors
30/63
Sympathomimetics
Naturally occuring
Epinephrine
Norepinephrine
Dopamine
Synthetic
Dobutamine
Dopexamine
Phenylephrine
Metaraminol
Ephedrine
-
7/29/2019 7. Inotropes and Vasopressors
31/63
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
-
7/29/2019 7. Inotropes and Vasopressors
32/63
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
-
7/29/2019 7. Inotropes and Vasopressors
33/63
Biosynthesis of
CatecholaminesPhenylalanine
PH
Rate limiting Enzyme
5-HT, alpha Methyldopa
Alpha-methyl-p-
tyrosine
-
7/29/2019 7. Inotropes and Vasopressors
34/63
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
-
7/29/2019 7. Inotropes and Vasopressors
35/63
Metabolism of CAs
(Homovanillic acid) (Vanillylmandelic acid)
-
7/29/2019 7. Inotropes and Vasopressors
36/63
Adrenaline as prototype
Potent stimulant of alpha and beta receptors
Complex actions on target organs
-
7/29/2019 7. Inotropes and Vasopressors
37/63
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
-
7/29/2019 7. Inotropes and Vasopressors
38/63
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
-
7/29/2019 7. Inotropes and Vasopressors
39/63
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
-
7/29/2019 7. Inotropes and Vasopressors
40/63
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
-
7/29/2019 7. Inotropes and Vasopressors
41/63
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
-
7/29/2019 7. Inotropes and Vasopressors
42/63
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
-
7/29/2019 7. Inotropes and Vasopressors
43/63
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
-
7/29/2019 7. Inotropes and Vasopressors
44/63
ADRs
Tachycardia
Hypertension
Decreased renal blood flow Restlessness, Throbbing headache, Tremor,
Palpitations
Cerebral hemorrhage, cardiac arrhythmias
-
7/29/2019 7. Inotropes and Vasopressors
45/63
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
-
7/29/2019 7. Inotropes and Vasopressors
46/63
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
-
7/29/2019 7. Inotropes and Vasopressors
47/63
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
-
7/29/2019 7. Inotropes and Vasopressors
48/63
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
-
7/29/2019 7. Inotropes and Vasopressors
49/63
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
-
7/29/2019 7. Inotropes and Vasopressors
50/63
Dopamine
Agonists at dopaminergic D1, D2receptors
Agonist at adrenergic 1 and 1
-
7/29/2019 7. Inotropes and Vasopressors
51/63
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
-
7/29/2019 7. Inotropes and Vasopressors
52/63
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
-
7/29/2019 7. Inotropes and Vasopressors
53/63
Dopamine
Adverse effects
Tachycardia
Arrhythmias
Excessive vasoconstriction (higher doses)
Decreased splanchnic, renal blood flow
Decreased cardiac output
-
7/29/2019 7. Inotropes and Vasopressors
54/63
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.
-
7/29/2019 7. Inotropes and Vasopressors
55/63
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)
-
7/29/2019 7. Inotropes and Vasopressors
56/63
Isoproterenol (Isuprel)
Drawbacks
Tachycardia
Dysrhythmias
Peripheral vasodilation
Increased myocardial consumption CPK indicating myocardial necrosis
Decreased coronary O2 delivery
Splanchnic steal by skeletal muscle
-
7/29/2019 7. Inotropes and Vasopressors
57/63
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)
-
7/29/2019 7. Inotropes and Vasopressors
58/63
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.
-
7/29/2019 7. Inotropes and Vasopressors
59/63
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.
-
7/29/2019 7. Inotropes and Vasopressors
60/63
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.
-
7/29/2019 7. Inotropes and Vasopressors
61/63
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
-
7/29/2019 7. Inotropes and Vasopressors
62/63
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
-
7/29/2019 7. Inotropes and Vasopressors
63/63
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