1. Dr SHASHANK CHAUHAN

2. Definitions
Inotrope
 Increases cardiac contractility
Vasopressor
 Induces vasoconstriction elevation of mean arterial
pressure

3. Use of inotropes & vasopressors
 To support the failing heart
 To support the failing peripheral vasculature
 To correct hypotension during anaesthesia (general or
regional)

4. Physiology
Sympathetic Nervous System
 Post synaptic NT = NA
 Exceptions: sweat glands (Ach, muscarinic) and adrenal
medulla (Ach, nicotinic)
 Adrenergic receptors on post synaptic membrane
 Catecholamines= adrenergic agonists
 Adrenergic receptors
 G-protein coupled receptors, 7 transmembrane alpha segments
 Alpha and Beta receptors
 Structure-activity relationship of adrenergic drugs

5. Clinical Effects of Adrenergic
Receptors
Alpha1
 Vasoconstriction
 Gut smooth muscle relaxation
 Increased saliva secretion
 Hepatic glycogenolysis
Alpha2
 Inhibit NA & Ach release
 Stimulate platelet aggregation

6. Beta1
 Chronotropy
 Inotropy
 Gut smooth muscle relaxation
 Lipolysis
Beta2
 Vasodilatation
 Bronchiole dilatation
 Visceral smooth muscle relaxation
 Hepatic glycogenolysis
 Muscle tremor

7. Drug and Receptor Interactions
Drug Alpha1 Alpha2 Beta1 Beta2 Dopamine
Epinephrine ++ ++ +++ +++ 0
Norepinephrine +++ +++ ++ + 0
Dopamine 0 ++ ++ +++
+
Dopexamine 0 0 + +++ ++
Phenylephrine ++ 0 0 0 0

9. Alpha receptors
post synaptic cardiac alpha1 receptors:
- stimulation causes significant increase in contractility without an
increase in rate
- not mediated by cAMP
- effect more pronounced at low heart rates
- slower onset and longer duration than beta1 receptor mediated
response
- presynaptic alpha2
receptors in heart and vasculature appear to be
activated by norepinephrine released by sympathetic nerve itself and
mediate negative feedback inhibition of further norepinephrine
release
post synaptic alpha1 and alpha2
receptors in peripheral vessels mediate
vasoconstriction

10. Beta receptors
post synaptic beta1 receptors are predominant
adrenergic receptors in heart. Stimulation causes
increased rate and force of cardiac contraction.
Mediated by cAMP
post synaptic beta2 receptors in vasculature mediate
vasodilatation

11. Dopamine receptors
peripheral DA1 receptors mediate renal, coronary and
mesenteric arterial vasodilatation and a natriuretic
response
DA2receptors: presynaptic receptors found on nerve
endings, inhibit norepinephrine release from
sympathetic nerve endings, inhibit prolactin release
and may reduce vomiting
stimulation of either DA1 or DA2
receptors suppresses peristalsis and may
precipitate ileus

12. Epinephrine
Pharmacokinetics
Admin: IV/IM/infiltration
Elimination: mostly degraded by conjugation with glycuronic
and sulphuric acids and excreted in the urine. Smaller part
is oxidised by amine oxidase and inactivated by o-methyl-
transferase
Pharmacodynamics
- stimulates alpha1 and both beta1 and beta2 receptors.
Effects are mediated by stimulation of adenyl cyclase
resulting in an increase in cAMP
- beta2 receptors more sensitive to epinephrine than alpha1

13. CVS
- positive inotrope and chronotrope ( mediated by all 3 receptors)
- - increases incidence of dysrhythmias by increasing irritability of automatic
- conducting system
- - constricts vessels of skin, mucosa, subcutaneous tissues, splanchnic area,
- kidneys (alpha effects)
- - vessels of muscle and liver are dilated at physiological doses (beta effect)
- but are constricted at higher doses.
- - cerebral and pulmonary arteries are constricted
- - may precipitate angina in patients with IHD
- - CVS effects reduced by acidosis
- - at low doses causes: increased cardiac output, slight reduction in SVR,
- increase in effective circulating volume and increased venous return. Net
- result: systolic BP rises but diastolic falls
- - higher doses: rise in SVR, decreased cardiac output and rise in both systolic
- and diastolic BP

14. Renal
RBF and urine output reduced
RS
- bronchial tone decreased
- depth of respiration slightly increased
- irregular breathing sometimes seen
- decreases mucosal blood flow; results in reduced mucosal
oedema and bronchial secretions
GI tract
- muscle of gut relaxed, pyloric and ileocolic sphincters
constricted: leads to ileus
- intestinal secretion inhibited
- spleen contracts and empties its cells into the circulation

15. Metabolic
- beta stimulation causes increased insulin and glucagon secretion, alpha
decreased. Overall epinephrine has anti-insulin effect.
- increased blood glucose due to increased mobilization of glycogen.
- rise in metabolic rate. Initial rise is independent of liver and is probably
due to cutaneous vasoconstriction, causing a rise in body temperature,
or increased muscle activity or both. Later, smaller rise is probably due
to increased oxidation of lactose by liver
- increased lipolysis, muscle catabolism. Results in increased serum
cholesterol, phospholipids and LDL
- plasma K rises initially due to increased release from liver. Followed by a
prolonged fall due to entry into skeletal muscle cells, mediated by beta2
receptors
- net result is an increase in O2 consumption
- may result in lactic acidosis

16. CNS
- CNS stimulation usually very modest
- pupillary dilatation
- elevates pain threshold
- at high doses: anxiety, restlessness from mild cerebral
stimulation, throbbing headache, vertigo

17. Norepinephrine
- alpha and beta1 agonist with no clinically significant beta2 effects
- equipotent with epinephrine as a beta1 agonist but less potent an alpha
agonist in most tissues
- used for refractory hypotension
- may result in no change or slight decrease in cardiac output and oxygen
delivery due to increased afterload
- in the non-septic patient produces vasoconstriction in all vascular beds,
including the renal circulation
- in septic patients increases BP and SVR, often without altering cardiac
output. However in some patients may Þ CO by stroke volume. Often
improves renal blood flow and urine output in these patients by
increasing perfusion pressure without compromising cardiac output
- may be useful in cardiogenic shock: increases coronary perfusion
pressure.

18. Comparison of effects of infusion of epinephrine and
norepinephrine
Epinephrine Norepinephrine
Heart rate + -
Stroke volume ++ ++
Cardiac output +++ 0/-
Arrhythmias ++++ ++++
Coronary blood flow ++ ++
Systolic BP +++ +++
MAP + ++
Diastolic BP +/0/- ++
TPR -/+ ++
Cerebral blood flow ++ 0/-
Muscle blood flow +++ 0/-
Renal blood flow - -
Oxygen demand ++ 0/-
Blood glucose +++ 0/-

19.  NB norepinephrine has no effect on renal blood flow
in patients with established acute renal failure and in
hypotensive patients both epinephrine and
norepinephrine may increase renal blood flow by
increasing perfusion pressure
 Little effect on PAWP. Mean PA pressure unchanged or
slightly .
Clinical use
 in doses of 0.01-2 m g/kg/min reliably and predictably
improves haemodynamic variables to normal or
supranormal values in the majority of septic patients
 effect on oxygen transport variables cannot be
determined from current data

20. Dopamine
Immediate precursor of norepinephrine and epinephrine
Pharmacodynamics
Dose dependent effects:
<5 m g/kg/min predominantly stimulates DA1 and DA2
receptors in renal,
mesenteric and coronary beds. Þ vasodilatation
5-10 m g/kg/min: b 2 effects predominate. Þ cardiac
contractility and HR
>10 m g/kg/min: a effects predominate Þ arterial
vasoconstriction and -BP
Pharmacokinetics
Marked variability in clearance in the critically ill. As a
result plasma concentrations cannot be predicted from
infusion rates

21. Clinical use
-variable effects due to variable clearance
-increases cardiac output (mainly due to increased
stroke volume) with minimal effect on SVR in patients
with septic shock
-increases pulmonary shunt fraction
-effects on splanchnic perfusion unclear
-increases urine output without increasing creatinine
clearance in a number of settings.
-Low dose dopamine does not prevent renal failure in
critically ill patients

22. Dopexamine
Synthetic catecholamine structurally related to dopamine
Pharmacokinetics
-Admin: IV infusion
-Distribution: extensive tissue distribution. Drug acts as a substrate for extra-neuronal
catecholamine uptake mechanism (uptake 2).
-Elimination: short t1/2 of 7 mins (11 mins in patients with low cardiac
output). Extensively metabolised in the liver. Both metabolites and
parent drug excreted in urine and faeces.
Pharmacodynamics
-marked intrinsic agonist activity at beta2 receptors
-lesser agonist activity at beta1 adrenoreceptors, DA1 and DA2
dopaminergic receptors inhibits neuronal catecholamine uptake by uptake 2
-net effect is reduction in afterload by pronounced arterial vasodilatation, increased renal
perfusion by selective renal vasodilatation and mild direct and indirect positive
inotropism. Also has positive chronotropic effect.
-probably not as effective as dopamine at increasing renal blood flow,
but causes a substantially greater increase in cardiac index.

23. Adverse effects
-nausea and vomiting most common adverse effect. Respond well to dosage
reduction.
-tachycardia may precipitate angina in patients with ischaemic heart disease.
-said not to have arrhythmogenic potential but is associated with
ventricular ectopics.
-tremor
-reversible reductions in neutrophil and platelet counts.
Dosage
for acute heart failure and haemodynamic support in patients following
cardiac surgery start at 0.5 mcg/kg/min and titrate upwards in
increments of 1 mcg/kg/min to a maximum of 6 mcg/kg/min.
Contraindications
- thrombocytopaenia
Caution
- patients with hyperglycaemia and hypokalaemia in view of beta-adrenergic
activity.

24. Dobutamine
Possesses the same basic structure as dopamine but has a
bulky ring substitution on the terminal amino group.
Synthetic catecholamine
Physical properties
- supplied in lyophilized form which should be reconstituted
with 10 ml of
water or 5% dextrose
- compatible with 5% dextrose, N/saline and D/saline but,
like dopamine is
rapidly inactivated under alkaline conditions
- stable for 24 hrs after reconstitution. May turn slightly pink
during this time
but this is not associated with a change in potency
- racemic preparation

25. Pharmacodynamics
- strong +ve inotropy due to beta1 agonist effects and alpha1 agonism
- mild +ve chronotropy due (+) isomer effect on beta receptors
- weaker alpha receptor blockade and beta2 stimulation, produced by (+)
isomer and alpha1 agonism produced by (-) isomer
- overall peripheral effect should be an increase in blood flow to skeletal
muscle (beta2 agonism) and some reduction in skin blood flow
(alpha1agonism balanced by some alpha blockade). These effects are
weak compared to the myocardial effects
- net effects are an increase in SV and CO. SVR may be unchanged or
moderately decreased and arterial pressure may thus rise, fall slightly or
remain unchanged
- at doses > 15 mcg/kg/min tachycardia and arrhythmias are more likely
- tolerance may be seen after 48-72 hrs, presumably due to down-
regulation of beta receptors. May necessitate an increase in dose. Dose
required to produce toxic effects seems to be increased equivalently

26. Isoproterenol
- powerful beta agonist with virtually no alpha effects
- lowers vascular resistance mainly in skeletal muscle but
also in renal and
mesenteric vascular beds.
- diastolic BP falls but with usual doses the increase in
cardiac output is
usually enough to maintain or raise mean BP
- positive inotrope and chronotrope
- renal blood flow is decreased in normotensive subjects
but is markedly
increased in patients with cardiogenic or septic shock
- PA pressures are unchanged

27. Methoxamine
Pharmacodynamics
- direct and indirect effects
- alpha agonist and beta blocker
- primary effect is peripheral vasoconstriction resulting in rise in systolic and
diastolic BP
- HR slows due to beta blocking effects and reflex slowing due to rise in BP
- no effect on cardiac contractility and so cardiac output falls
Indications and dosage
- hypotensive states due to excessive vasodilatation eg spinal or epidural
block
- 5-10 mg IV acts within 2 mins. Effect persists for about 20 mins. Dose can be
titrated against effect in 2 mg boluses
Contra-indications
- patients on MAOIs
- history of hypertension
Toxicity
- - excessive rise in BP; may precipitate myocardial ischaemia
- - vomiting, headache, desire to micturate, significant reduction in HR
- - treat with IV alpha blocker (eg phentolamine)

28. Phenylephrine
- similar effects to norepinephrine but probably even
shorter acting
- direct acting
- potent alpha and weak beta agonist
- causes peripheral vasoconstriction and thus a rise in
BP, especially diastolic
- often reflex reduction in heart rate
- only direct effect on heart is to slightly increase
myocardial irritability
- largely replaced by catecholamines

29. Ephedrine
Naturally occurring amine with both direct and indirect (stimulates
norepinephrine release from postganglionic sympathetic nerve endings)
sympathomimetic effects.
Pharmacodynamics
- both alpha and beta agonist effects
- haemodynamic effects are similar to epinephrine but it has a longer
duration of action and is active when administered orally
- increased cardiac contractility and heart rate and thus cardiac output
- peripheral vasoconstriction is balanced by vasodilation with little overall
change in SVR
- rise in arterial BP - systolic > diastolic
- may increase cardiac irritability
- relaxes bronchial and other smooth muscle, but less effective than
epinephrine
- reduces uterine muscle activity
- side effects similar to epinephrine
Admin: PO/IV
Elimination: not broken down by MAO. Excreted unchanged by kidney

30. Phosphodiesterase III Inhibitors (I)
 Inhibit PDE III isoenzyme increase intracellular
cAMP + cGMP in myocardial & sm. muscle cells
 cAMP phosphorylates cellular protein kinases
 Myocardium: Ca2+ influx more Ca2+ for contraction &
improved Ca2+ reuptake improved relaxation
 Sm. Muscle: relaxation & 20 vasodilatation
 Clinical effects
1. Increased cardiac contractility without increasing
myocardial oxygen consumption
2. Decreased preload and afterload
3. Minimal chronotropic effect

31. Phosphodiesterase III Inhibitors (II)
 Clinical uses:
 Short term treatment for acute on chronic severe CCF
 Synergistic effect with beta agonists
 Role in cardiopulmonary bypass
Enoximone
 Yellow, effect for 4-6 hours
 Loading dose then infusion
 Monitor for hypotension
 Hepatic metabolism, renal excretion

33. Levosimendan
 Calcium sensitizer
 Action
 Stabilises interaction between Ca2+ & Troponin C by
binding Troponin C in Ca2+ dependent manner
 K+-ATP channel opener (PDE III inhibit effect in vitro)
 Clinical effects
 Increased cardiac contractility – no increase in
myocardial oxygen demand
 Vasodilatation resulting in decreased preload &
afterload
 Not proarrythmogenic

34. Vasoactive drugs for shock states
Shock state First-tier agents Second-tier agents
Anaphylactic shock Epinephrine, 1 mL of 1:10,000 Norepinephrine infused at 0.1–1
solution (100 mg),can be mg/kg/min (0.5–30 mg/min)
given as a slow IV push, then
as a 0.02 mg/kg/min infusion
(5–15 mg/min
Cardiogenic shock, SBP 70, norepinephrine Amrinone, 0.75 mg/kg loading
left ventricular infused at 0.1–1 mg/kg/min dose, then 5–10 mg/kg/min(not
(0.5–30 mg/min) recommended post-MI)
SBP 70–90, dopamine Milrinone, 50 mg/kg loading
infused at 15 mg/kg/min dose, then 5–10 mg/kg/min(not
SBP O90, dobutamine recommended post-MI)
infused at 2–20 mg/kg/min
Cardiogenic shock, Dobutamine infused at 5 Phenylephrine infused at 10–20
pulmonary mg/kg/min mg/kg/min
embolism Norepinephrine infused at
0.1–1 mg/kg/min
Hemorrhagic shock Volume resuscitation Dopamine infused at 5–15
mg/kg/min as a temporizing
adjunct

35. Neurogenic shock Dopamine infused at 5– Norpinephrine infused
15 mg/kg/min at 0.1–1 mg/kg/min
Phenylephrine infused
at 10–20 mg/kg/min
Septic shock Norepinephrine infused Dopamine infused at 5–15
at 0.1–1 mg/kg/min mg/kg/min
Dobutamine infused at 5 Epinephrine infused at
mg/kg/min 0.02 mg/kg/min
Toxic drug overdose with Norepinephrine infused Phenylephrine infused at
shock at 0.1–1 mg/kg/min 10–20 mg/kg/min
Glucagon given as a 5-mg
IV bolus, then
as a 1–5 mg/h infusion
Calcium salts: calcium
gluconate, 0.6 mL/kg
bolus,
then a 0.6–1.5 mL/kg/h
infusion
Insulin started at 0.1
units/kg/h IV and titrated
to a goal of 1 unit/kg/h

36. Conclusions and Recommendation
 Smaller combined doses of inotropes and vasopressors may be
advantageous over a single agent used at higher doses to avoid
dose-related adverse effects.
 The use of vasopressin at low to moderate doses may allow
catecholamine sparing, and it may be particularly useful in
settings of catecholamine hyposensitivity and after prolonged
critical illness.
 In cardiogenic shock complicating AMI, current guidelines
based on expert opinion recommend dopamine or dobutamine
as first-line agents with moderate hypotension (systolic blood
pressure 70 to 100 mm Hg) and norepinephrine as the preferred
therapy for severe hypotension (systolic blood pressure <70 mm
Hg).
Routine inotropic use is not recommended for end-stage HF.
When such use is essential, every effort should be made to either
reinstitute stable oral therapy as quickly as possible or use
destination therapy such as cardiac transplantation or LV assist
device support.

37. THANK YOU