Cardiovascular Pharmacology

Manuel Otero Lopez

Department of Anaesthe>cs
Hôpital Avicenne, Bobigny, France
Conflict of interest declaration
WHAT DECLARATION
Grants/research support/P.I. Nothing to declare
Employee Nothing to declare

Consulta:on fees Nothing to declare

Honoraria Nothing to declare

Speakers bureau Nothing to declare

Company sponsored Nothing to declare

Stock shareholder Nothing to declare

Spouse/partner Nothing to declare
Scien:fic Advisory Board Nothing to declare

Other Nothing to declare

www.esahq.org
The Cardiovascular system

Ø One heart : two pumps

perfectly coordinated.
Intrinsic property of the
myocardium (The Starling
law, 1915)
Ø A high pressure system :
Systemic circula:on
Ø A low pressure system :
Pulmonary circula:on

www.esahq.org
The Autonomic Nervous System: Key points

u  Regula:on of the ac:vity of the

internal organs, including :
myocardial contrac:on, vascular
tone, and adrenaline secre:on
by the adrenal medulla.
u  Ac:vity of the autonomic
nervous system is involuntary.
u  Divided into two divisions:
Ø  Parasympathe?c
Ø  Sympathe?c

www.esahq.org

Eye miosis
near vision
Salivary glands Secre:on é

Heart heart rate ê
conduc:on velocity ê
contrac:on ê
Lungs bronchial constric:on é


Pancreas insulin é


Intes:ne
The parasympathe:c
nervous system
Morgan & Mikhail’s,
Bladder CLINICAL ANESTHESIOLOGY, 5° ed.

www.esahq.org
Eye α1 mydriasis
β Far vision (Ciliary muscle relax.)
Salivary α1 Secre:on é
Glands β2

Heart β1 heart rate é
conduc:on velocity é
contrac:lity é
Lungs α1 Bronchoconstric:on
β2 Bonchodilata:on

Pancreas α1 insulin secre:on ê
β2 insulin secre:on é
Upper GI tract α1, β2
Liver α1, β2
Gallbladder β3
Abdominal α1 Tone é
vessels β2 Tone ê The sympathe:c
Bladder α1, β2 nervous system
Morgan & Mikhail’s,
CLINICAL ANESTHESIOLOGY, 5°ed.


www.esahq.org
The Autonomic Nervous System

www.esahq.org
Responses elicited by s?mula?on of sympathe?c and parasympathe?c nerves

www.esahq.org
 Programme

v  Adrenergic agonists
v  Hypotensive drugs in the Opera:ng theatre and ICU
v  An:arrhythmic drugs
v  Periopera:ve management of chronic hypertension
treatment
v  Pulmonary hypertension treatment

www.esahq.org
Adrenergic agonists

Preganglionic & postganglionic

receptors of the sympathe?c
nervous system

www.esahq.org
Adrenergic agonists

The synthesis of endogenous

catecholamines

Morgan & Mikhail’s,

CLINICAL ANESTHESIOLOGY, 5 ed.

www.esahq.org
Adrenergic agonists

Morgan & Mikhail’s,

CLINICAL ANESTHESIOLOGY, 5 ed.

www.esahq.org
Mode of action of catecholamines

www.esahq.org
 Adrenaline / epinephrine

ü Synthesized in the adrenal medulla

ü S:mula:on of β1 receptors increased cardiac output and
myocardial oxygen consump:on (chronotrope + and
inotrope +)
ü Increased coronary blow. “Metabolic changes produced by
increased work” overshadow the α effect in the coronary
vessels
ü Increased systolic blood pressure with a less marked
increased in diastolic blood pressure

ü Bronchial smooth muscle dilata:on

www.esahq.org
 Adrenaline / epinephrine
Uses :
ü Fundamental for the treatment of anaphylaxis.
ü Fundamental in cardiopulmonary resuscita?on.
ü To counteract cardiac dysfunc:on (le` and/or right) a`er
CEC in cardiac surgery.
ü As inotropic agent in severe cardiac failure / hypotension.
Other uses :
ü Mixed to local anaesthe:cs to reduced bleeding and
decreased systemic absorp:on.
ü Bronchospasm. Severe croup in children (nebulizers).

www.esahq.org
 Noradrenaline / norepinephrine

ü It’s endogenous postganglionic neurotransmiaer for the

sympathe:c nervous system.
ü Its effects are mainly mediated by s:mula:on of α1
receptors.
ü It acts also on β1 receptors. Β2 receptors are 10 to 50
:mes less sensi:ve to noradrenaline than adrenaline.
ü Noradrenaline increases myocardial contrac:lity and
produces peripheral vasoconstric:on. Systolic and
diastolic pressures rise. Decreases renal and splanchnic
blood flow and increases myocardial oxygen requirement.

www.esahq.org
 Noradrenaline / norepinephrine
•  Use :
ü Indicated in the treatment of refractory hypotension,
par:cularly when is due to sepsis or neurogenic shock

www.esahq.org
 Dopamine

ü Endogenous catecholamine as an intermediate compound

during noradrenaline synthesis.
ü “Complex pharmacological ac:ons:
ü At 1-2 μgr/kg/min => S:mula:on of D1 receptors. Renal
blood flow and urinary output are increased. “No
beneficial effect on renal func:on”.
ü At 3-10 μgr/kg/min => β1 s:mula:on => Increases
myocardial contrac:lity, heart rate and systolic blood
pressure.
ü At 10-20 μgr/kg/min => α1 s:mula:on is predominant
=> increased in peripheral vascular resistance.


www.esahq.org
 Dopamine
ü Uses : O`en use a an inotrope and various hypotensive
states including sep:c shock.

www.esahq.org
 Dobutamine
ü Synthe:c catecholamine (developed in
the seven:es).
ü Racemic mixture of 2 stereoisomers.
ü Plasma half-life of 2-3 min.
ü Predominant β1 adrenergic agonist. Also β2 agonist. Very weak
α1 agonist effect. So dobutamine Increases cardiac contrac:lity
and produces moderate vasodilata:on.
ü Inotrope agent of choice for pa:ents with conges:ve heart
failure, par:cularly if peripheral vascular resistances are raised.
ü Associated with noradrenaline in many ICU scenarios.
ü  However increases myocardial oxygen consump:on => uses for
“Stress tes:ng” / echocardiography.

www.esahq.org
 Ephedrine
ü Principe ac:ve of a tradi:onal chinese
drug “Ma Huang”. Naturally occurring in
Ephedra vulgaris.
ü Direct and indirect sympathomime:c ac:vity. Half-life 3-6 hrs.
² Direct => α1 and β2 receptors s:mula:on
² Indirect => Displaces noradrenaline from its storage granules;
and inhibits metabolism of noradrenaline by mitochondrial
MAO => Tachyphylaxis.
Phenylephrine
ü Synthe:c selec:ve α1 agonist.
ü Peripheral vasoconstric:on with rise in systemic blood pressure.
Reflex bradycardia. Short dura:on of ac:on 15 min.
ü Small IV bolus of 50-100 μg (in children: 5-10 μg/kg)
www.esahq.org
 Milrinone
ü  Selec:ve inhibitor of type III
phosphodiesterase (PDE3). 1988.
ü  Present in the myocardium, smooth
muscle and platelets.
ü  Increases cardiac contrac:lity, reduces
ventricular filling pressure and produces a
decrease in systemic and pulmonary
vascular resistance.
ü  Vasodilata:on also occurs in the coronary
artery bed.
ü  Can produce thrombocytopenia. Less than
with amrinone.
ü  Dose: 0,75 – 0,75 μg/kg/min. Bolus
loading dose (?) of 50 μg/kg.
ü  Frequently used in combina:on with
noradrenaline Novembre 21, 1991

www.esahq.org
 Levosimendan
ü Levosimendan is a new Ca2+-sensi?zing inotropic agent. Acts by
binding to cardiac troponin C. A new class of inotropic agents,
which have not the disadvantages of classic inotropic agents as
they are not associated with an increased risk of arrhythmias.
ü Levosimendan produces vasodila:on through the opening of ATP-
sensi:ve K+ channels in smooth muscle.
ü Loading dose of 6-12 microgram/kg infused over 10 minutes
followed by a con:nuous infusion of 0,05-0,2 μg/kg/min. The
recommended dura:on of infusion is 24 hrs.

www.esahq.org
Morgan & Mikhail’s,
CLINICAL ANESTHESIOLOGY, 5° ed.

www.esahq.org
Morgan & Mikhail’s,
CLINICAL ANESTHESIOLOGY, 5° ed.

www.esahq.org
 Dopexamine
ü Analogue of dopamine. Potent β2 agonist. D1 and D2 agonist. No
α and β1 ac:vity. Dose range : 0,5 – 6 μg/kg/min
Fenoldopam
ü Selec:ve D1 agonist ac:vity. But liale or no ac:on α1, β or D2.
Potent hypotensive effects and increases renal blood flow. USA.
Vasodilator. Half-life 5 min.
Digoxin ??
ü Increases myocardial contrac:on and reduced atrioventricular
conduc:on.
ü Inhibi:on of membrane Na+/K+ ATPase => Increases intracellular
Ca++.
ü Uses since 1785. Large volume of distribu:on. Half-life 36 hrs.

www.esahq.org
Hypotensive drugs in the operating
theatre and in ICU

www.esahq.org
 Urapidil
ü Urapidil is a peripheral postsynap:c alpha 1-adrenoceptor
antagonist with central agonis:c ac:on at serotonin 5-HT1A
receptors.
ü Absorp?on: Rapidly absorbed. Bioavailability: 70-80%.
ü Metabolism: Extensively metabolised in liver, mainly by
hydroxyla:on. Elimina:on half-life: 4.7 hr (oral) and 2.7 hr
(IV).

www.esahq.org
 Nicardipine
ü Dihydropyridine calcium channel blocker.
ü Arterial selec:ve vasodilator. Have liale effects on cardiac
conduc:on and ventricular contrac:lity
ü Currently used for periopera:ve control of hypertension.

Clevidipine

ü Rapidly metabolised by plasma esterases.
ü Biological half-life 1 min.
ü Formulated as a lipid emulsion in 20% soybean oil.

www.esahq.org
 Nitrovasodilators:
1) Sodium nitroprusside (SNP)
ü Potent vasodilator, ac:ng mainly on arteries,
but also on veins. Cardiac output is maintained.
Reduces myocardial O2 consump:on whist
increasing coronary flow. Compensatory
tachycardia should be an:cipated.
ü  Releases NO (endothelium derived relaxing factor), which ac:vates
guanylyl cyclase, enzyme responsible for the synthesis of cGMP.
ü  Ac:ve within 30 sec. Plasma half-life 2 min. Dose: 0,5-1,5 μg/kg/min,
increased to a max of 8 μg/kg/min (maximal total dose : 1mg/kg over
2-3 hrs). Solu:ons require protec:on from light.
ü  Possible rebound hypertension following withdrawal :Renin/
angiotensin ì & catecholamine levels ì

www.esahq.org
 Nitrovasodilators:
1) Sodium nitroprusside (SNP)
ü SNP is broken down within the red blood cells where it receives
an electron from the Fe++ of oxyhemoglobin to produce finally 5
cyanide ions.
ü Possibility of acute cyanide toxicity/poisoning => (treatment:
Sodium thiosulfate, sodium nitrate, hydroxocobalamin).
2) Nitroglycerin / Glyceryl trinitrate (GTN)
ü Relaxes vascular smooth. Venous dilata:on more important.
Mechanism of ac:on similar to SNP. Reduces myocardial oxygen
demand and increases myocardial oxygen supply.
ü Boluses of 50-100 μg. IV infusion 0,2-0,5 μg/kg/min. Effects last
5-10 min. Tolerance.
3) Isosorbide dinitrate
ü Similar, but longer dura:on than GTN. Does not contain
addi:ves like propylene glycol.
ü IV infusion 2-10 mg/hr

www.esahq.org
 Labetalol
ü  α1, β1 and β2 blocker agent. Selec:ve for α1 receptors, but not for β
receptors, with some intrinsic sympathomime:c ac:vity. Ra:o alpha:beta
effects is 1:3 when orally and 1:7 when given IV.
ü  Dose IV 2-10 mg boluses. Infusion: 2,5-30 μg/kg/min.
ü  When given IV acts in 5 min. Mean dura:on of ac:on 50 min.
ü  Elimina:on half-life > 5 hrs.
ü  If given orally, first-pass metabolism +++

Esmolol
ü  Cardioselec:ve β1 antagonist with no (or liale)
intrinsic sympathomime:c ac:vity.
ü  Hydrolysed by esterases. Elimina:on half-life of 9
min.
ü  Dose periopera:ve: 0,5-1 mg/kg, followed by
50-300 μg/kg/min infusion.

www.esahq.org
Antiarrhythmic drugs

« The hospital at 4 am », Douglas Manry

www.esahq.org
 Antiarrhythmic drugs

ü The use of an:arrhythmic drugs has diminished because

some clinical trials have show increased mortality in several
clinical situa:ons, and the advanced technological therapies
such as pacing, abla:on and implantable defibrillators.

ü The most frequent an:arrhythmic drug used nowadays is

amiodarone.

ü Paroxysmal supraventricular tachycardia can be treated by

nodal-blocking agents (adenosine); and new episodes
prevented by abla:on with radiofrequency

www.esahq.org
The Vaughan-Williams and Singh classification

ü Introduced in 1970.
ü Classifica:on of an:arrhythmic agents in 4
classes, according to their effects on the
ventricular ac:on poten:al.
ü A fi`h class has been suggested for a number of
miscellaneous agents that they do not fit into
the 4 classes : adenosine, cardiac glycosides,
magnesium.

www.esahq.org
 Purkinje fibre action potential

Pharmacotherapy A Pathophysiologic Approach,

8th ed. J.T. DiPiro, et all, Mc Graw Hill

www.esahq.org
 The Vaughan-Williams and Singh classification

ü Class I : Reduces Na+ entry (slowing phase O depolariza:on)

Ia : Slow rate of depolariza:on and prolong ac:on
poten:al : quinidine, procainamide.
Ib : Slow rate of depolariza:on in ischaemic cells, shorten
ac:on poten:al: lignocaine, phenytoin.
Ic : Do no affect the dura:on of the ac:on poten:al :
flecainide.
ü Class II : β blockers
ü Class III : Prolong phase 3 repolariza:on : amiodarone, sotalol,
bretylium.
ü Class IV : Calcium channels blockers

www.esahq.org
The Vaughan-Williams and Singh classification

www.esahq.org
 Antiarrhythmic drugs

q Amiodarone
ü Par:al antagonist of α and β agonists. In addi:on decreases the delayed slow
outward K+ current.
ü Mainly used in arrhythmias associated with anomalous conduc:ng pathways.
In can be use in other supraventricular and ventricular arrhythmias.
ü Toxicity/Side effects: Affects thyroid func:on and can cause hypothyroidism.
Develop corneal micro deposits. Pulmonary fibrosis. Peripheral neuropathy.
Hepatotoxicity.
ü Variable bioavailability a`er oral ad. (22-86%). Large VD. Elimina:on half life
+/- 28 days. Extensively metabolised in the liver. Modifica:on of the dose is
not require in renal failure. Not removed by dialysis.
ü IV or PO. If given IV beaer by a central catheter (the drug carrier is highly
irritant)
ü Contra-indicated in porphyria.

www.esahq.org
 Antiarrhythmic drugs
q Lignocaine Class IIb. (Also a local anaesthe:c agent)
ü First choice for ventricular dysrhythmias resistant to cardioversion. Decreases
normal and abnormal automa:city and decreases ac:on poten:al and
refractory period dura:on. The threshold for ventricular fibrilla:on is raised.
Effects enhanced by hypoxemia and acidosis. Par:cularly useful a`er
myocardial infarc:on or during cardiac surgery.
ü Metabolised in the liver (70%). Half-life 90-110 min. Rela:vely narrow
therapeu:c index
q Adenosine
ü Par:cularly affects SA automa:city. Acts by adenosine A1 receptors.
ü In supraventricular tachyarrhythmias. Incremental bolus doses of 3, 6 and 12
mg. Plasma half life 8-10 sec.
q Magnesium
ü Commonly used in torsade de pointes and ventricular tachycardia. Have been
used for supraventricular arrhythmias. Increases coronary blood flow.

www.esahq.org
 Perioperative management of
chronic hypertension treatment /agents

www.esahq.org
 Preoperative Management of
Cardiovascular Medications
ü An:hypertensive medica:ons: To con:nue on the day of the surgery for
all medica:ons, specially β-blockers.
Excep?on : ACEIs and ARBs (Stop if the indica:on is hypertension.
To con:nue if the indica:on is cardiac failure).
Diure:cs: usually stop (be careful of hypotension and hypoK+)
ü An:arrhythmic drugs Class 1 for Atrial fibrilla:on => Stop 24 h before
surgery

www.esahq.org
 Antimuscarinic agents
q Atropine
ü Has been used in anaesthesia for many years. Naturally
occurring levorotatory form, but the commercial mixture is
racemic
ü Most efficacious an:cholinergic agent to treat brady-
arrhythmias.
ü Use for premedica:on. Other uses : Local anaesthe:c
overdose , organophosphorus insec:cides poisoning.
q Hyoscine (scopolamine)
ü More potent an:sialagogue effect than atropine. Produces
more central nervous effects. Uses to prevent mo:on sickness
q Glycopyrronium
ü Synthe:c quaternary amine. Longer dura:on of ac:on than
atropine. Can not cross the blood brain barrier.

www.esahq.org
Management of Pulmonary hypertension

www.esahq.org
Management of Pulmonary
hypertension (PH)
ü Most common causes of PH in intensive care
pa:ents are le` heart diseases and hypoxemia. So
the treatment should be of the primary causes.
Some:mes the treatment could be specific, like
thrombolysis for pulmonary embolism.

ü Standard measures including: avoid hypoxemia and

acidosis, avoid ven:la:on perfusion mismatch,
reduce pulmonary vascular resistance

www.esahq.org
Management of Pulmonary hypertension
(PH)
q Nitric oxide (NO)
ü Ubiquitous naturally occurring gas.
ü It func:ons as a vasodilator and as a second messenger.
ü It has a great affinity for Hb (15.000 :mes that of CO)
ü Has a very short half life because is inac:vated by Hb.
ü Use by specific delivery systems

ü Has never been proven to decrease mortality.

ü Use frequently to improve RV func:on following cardiac surgery.
ü Dose : 5-20 ppm
q  Phosphodiesterase-5 inhibitors such as Sildenafil
q Inhaled prostacyclin such as Iloprost

www.esahq.org
Factors and drugs decreasing pulmonary
vascular resistance
Oxygen
Alkalosis
a-Adrenergic antagonists
β-Adrenergic agonists
Prostaglandins PGI2 and PGD2
Calcium channel blockers
ACE inhibitors
Acetylcholine
Aminophylline
Nitrates and nitrites
Nitric oxide
Sodium nitroprusside
Hydralazine, Diazoxide

www.esahq.org
Factors increasing pulmonary vascular
resistance

Hypoxia
Acidosis
a-Adrenergic agonists
β-Adrenergic antagonists
Protamine
Histamine
Serotonin
Angiotensin II
Thromboxane

www.esahq.org
Thank you for a]en?on Urueña, Valladolid, Spain
motero@doctors.org.uk

www.esahq.org