Discussion of inotropes, indications, mechanism of action

1. Johnny Kenth – ST3 Anaesthesia,
Royal Blackburn Hospital

2. Inotropes
Definition:
An inotrope is an agent that alters force of contraction of cardiac muscle without
affecting the pre or after load. E.g. +ve inotropes  contractility
Classification
• Class 1  intracellular [ca], include:
• Ca ions
• Drugs  cAMP - adrenoagonists, PDIs, Glucagon
• Drugs affecting Na-K ATPase - digoxin
 Class 2  sensitivity actomyosin to Ca ions – Levosimendan
 Class 3 Metabolic / endocrinological – T3

3. Catecholamine Synthesis

5. Site of action
du Toit E et al. Heart 2001;86:81-87

6. Drug Alpha-1 Beta-1 Beta-2 Dopaminergic Predominant Clinical Effects
Phenylephrine *** 0 0 0 SVR ↑ ↑, CO ↔/↑
Noreadrenaline *** ** 0 0 SVR ↑ ↑, CO ↔/↑
Adrenaline *** *** ** 0
CO ↑ ↑, SVR ↓ (low dose)
SVR/↑ (higher dose)
Dopamine
(mcg/kg/min)
0.5 to 2 0 * 0 ** CO
5 to 10 * ** 0 ** CO ↑, SVR ↑
10 to 20 ** ** 0 ** SVR ↑ ↑
Dobutamine 0/* *** ** 0 CO ↑, SVR ↓
Isoproterenol 0 *** *** 0 CO ↑, SVR ↓
*** Very Strong Effect, ** Moderate effect, * Weak effect, 0 No effect.

7. Actions
Acts on 1, 2, + 1 receptors.
• CVS:  HR (chronotropic) + contractility (inotropic -force of contraction)
CO; also +ve dromotropic, bathmotropic & -ve lusitropic
SBP rises, but with low doses DBP may fall due to (2 vasodilation and
increased blood flow through skeletal muscle beds (2).
At higher doses = 1 mediated vasoconstrictor effects
• RS: Bronchial smooth muscle is relaxed 2 = bronchodilation
• Other: Adrenaline mobilises glucose from glycogen and raises blood
sugar. Pupillary dilation (mydriasis) occurs.
• Side effects Ventricular arrhythmias, hypertension. Care with halothane
anaesthesia as arrhythmias may occur
Adrenaline (Epinephrine)
Prepare the body for a "fight or flight" response.

8. Site of action
du Toit E et al. Heart 2001;86:81-87

9. • Noradrenaline
Acts mainly on 1 receptors with few effects on  receptors.
 BP by vasoconstriction. Less likely to cause tachycardia than
adrenaline.
Indications Septic shock where peripheral vasodilation may be causing
hypotension.
Cautions Acts by  afterload and therefore not appropriate for use in
patients in cardiogenic shock.  Blood supply to kidneys and peripheries
Dose - 0.01-1 mcg/kg/min
• Dopamine
Acts on D, 1, 2 and 1 receptors, depending on the dose administered.
Actions Dose dependent
1-2mcg/kg/min - acts on D receptors usually  UO
2-10mcg/kg/min - acts on  receptors   CO
>10mcg/kg/min - additional effects on 1 receptors  vasoconstrict.

10. • Dobutamine
Acts on 1 & 2, with minimal action on 1 receptors.
It  CO and  afterload (2 effects).
Indications Cardiogenic shock.
Dose 2-30mcg/kg/min
• Dopexamine
Acts on 2 and D receptors.
 CO and afterload.  blood supply to kidneys and ? + GI tract.
Dose 0.5-6mcg/kg/min
• Salbutamol
Acts on 2 receptors
Actions Relaxes bronchial smooth muscle i.e. bronchodilation;  HR
Indications Severe acute asthma.
Dose By infusion 5-20mcg/min. IV bolus 1- 5mcg/kg

11. Site of action
du Toit E et al. Heart 2001;86:81-87

12. • e.g. aminophylline, enoximone, milrinone
• Prevent breakdown of cAMP by enzyme phosphodiesterase: 
intracellular [Ca] in myocytes - augments catecholamines at 1 and 2
receptors.
• Actions: Inodilation, i.e.  rate and force of contraction, peripheral
vasodilation in skeletal muscle, bronchodilation.
Indications
• Aminophylline: asthma, cardiac failure.
• Enoximone: cardiac surgery - patients failing to respond to dobutamine
Phosphodiesterase inhibitors

13. • Action : directly on 1 + 2 receptors,
indirectly on 1 receptors via NA release.
• Side effects May cause tachycardia and hypertension. Possible
arrhythmias if used with halothane. C/I MAOs, SNRI
• Indications Low blood pressure due to vasodilation e.g. following
spinal or epidural anaesthesia and drug overdoses. Better
vasopressor to use in pregnancy as it does not reduce placental blood
flow.
• Dose 3-10 mg boluses iv, repeat until effective. Maximum dose is
60mg.
• Length of action 5-15 minutes, repeated doses less effective (i.e. it
demonstrates tachyphylaxis)
EPHEDRINE

14. • Metaraminol
Acts directly on 1 receptors
also causes some noradrenaline and adrenaline release.
Actions  MAP and  CO.
Less likely to cause a reflex bradycardia than methoxamine or
phenylephrine.
Dose - 0.5 1mg boluses iv, 2-10mg s/c or im, by infusion at 1-20mg/hr.
• Phenylephrine
Acts directly on 1 receptors.
Action Hypertension and a reflex  HR.
Dose, 0.1-0.5mg iv, by infusion 0.1 – 1 mcg/kg/min
• Methoxamine
acts on 1 receptors.
Actions.  MAP + reflex  HR, and therefore it is good for hypotension
with tachycardia. Useful during spinal anaesthesia.
Side effects May produce bradycardia
Dose 2-4mg boluses IV.
Other pressors:

15.  Naturally occurring nonapetide hormone, produced in post
hypothamalamus by PVN SON, stored + released post pituitary.
 Acts on V1, V2, V3 and OTR - GPCR
 V1: receptors are found on vascular smooth muscle of the systemic,
splanchnic, renal, and coronary circulations  vasoconstriction (Gq)
 V2: predominantly located in the distal tubule and collecting ducts of
the kidney  aquaporin chn   water re-absorption
 Uses:
• Sepsis:  NA usage, VASST, as safe as NA, VANISH -
• Cardiac Arrest: ?  survival ( Krismer et al)
Asystole: ? survival to ED adm, + discharge. (Wenzel et), no
affect mortality.
VASOPRESSIN

16.  Direct: Inhibits cardiac Na-K ATPase:
•  Intracellular Na
•  Na / Ca exchange   intracellular Ca
•  Ca release from SR   actin-myosin cross linkage
•   contractile force
 Inirect: inhibits neuronal Na-K ATPase
•  Vagal activity
 PK
• Long T1/2 needs LD
• Renal clearence
Large VD
Digoxin

17. Clinical
Application
1st Line Agent 2nd Line Agent
Septic Shock Noradrenaline Adrenaline
Dopamine Vasopressin
Heart Failure Dopamine PDIs (Milrinone)
Dobutamine + Norad
Cardiogenic
Shock
Dobutamine
Levosimendan
+/- Norad SBP<80 PDIs
Anaphylactic
Shock Adrenaline Vasopressin
Neurogenic Shock Norad
Hypotension
Anesthesia-
induced
Ephedrine / Metaraminol /
Phenylephrine **Adrenaline
Following
CABG Epinephrine (Adrenalin)

18.  72 year-old woman with DM Type II, hypertension and Stage II
CKD, recurrent UTIs, is transferred from a MAU. Her vitals upon
arrival are as follows: Temp 39C, BP 70/45, Hr 140, RR 20, O2 Sat
95% 4L02 Lab findings: WCC 24, Cr 3.5, Lac 3.4, Positive Ur Dp,
CRP 241
 After adequate IVF resuscitation, pt continues to remain
hypotensive MAP 40-50s + tachycardic HR 110-130s. What is the
most appropriate 1st line vasopressor/inotropic agent?
A. Adrenaline
B. Dobutamine
C. Noreadrenaline
D. Dopamine

19.  64 year-old man with PMHx IHD; prev. MI and PCI (2004; drug-
eluting stents), ischemic cardiomyopathy (EF 30-35%) with ICD
(2007). ED 1/52 Hx progressively worsening SOB at rest,
orthopnea and bilateral lower extremity oedema, after running out of
all medications about 10 days ago.
 In ED, vitals: Temp 36.6 C, BP 88/48, Hr 75, RR 25, O2 Sat 91%
on RA. CXR reveals vascular congestion and bilateral pleural
effusion. Bedside ultrasound reveals significantly diminished EF.
 What is the most appropriate 1st line vasoactive agent?
A. Adrenaline
B. Dobutamine
C. Noreadrenaline
D. Dopamine

20.  76 year-old cachexic female with PMHx: COPD, HTN and
Osteoporosis was initially admitted under medics for acute exac
COPD. Had fall on ward # L-NOF.
 Underwent CNB-spinal anaesthesia. 15 mins post induction her
BP was 64/44, P108, RR18, SpO2 99% RA.
 What is the most appropriate 1st line vasopressor/inotropic
agent?
A. Adrenaline
B. Dobutamine
C. Dopexamine
D. Dopamine
E. Metaradine