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Cardiovascular Active Medications
Dr. L. Al tmimi
Academic year 2012-2013
Introduction
Many drugs are used to manage the hemodynamic of patient before, during or even
after the operation. These drugs can be given through different way like orally,
intravenously, intramuscularly, rectally, or even subcutaneously. There are so many
groups of medications with different dosages, mechanism of action and also for
different indications. We should be very carefully when we prescribe or use any
medications because drugs error remains one of the most accidental injuries to the
patients especially critically ill patients.
Drug dose calculation
Unfortunately, not all the drugs are labeled in uniform manner. Conversion of units is
often necessary. A drug labeled Z% contains Z gram /dl; 10 x Z equals the number of
grams / liter which is the same as milligram/ milliliter. For example Manniltol 20%
solution contains 20 g/dl; that equals to 200 g/L or 200 mg/ml.
Concentrations given as ratios are converted as follows:
Epinephrine 1:1000 equal to 1 gram/1000 milliliter which is the same as 1
milligram/milliliter
Calculating infusion rate
Step 1: Dose rate µg/min for example Levophed in a dose of 0.1 µg/kg/min for
someone weighted 70 kg equal 7µg/min x 60 equals to 420µg/ hour dose rate.
Step 2: Calculate the concentration of the drug µg/ml. Levophed 8mg/40 ml Nacl
equal to 200µg/ml concentration.
Step 3: Volume infusion rate ml/hour: Divide the dose rate by the concentration,
(µg/h÷µg/ml = ml/h). So 420 µg/h Levophed divided by 200µg/ml concentration equal
to 2.1 ml/h Levophed the infusion rate for someone of 70 kg that needs Levophed in
a dose of 0.1µg/kg/min.
Drug-receptors interaction
Drug receptors are macromolecules that interact with a drug to mediate characteristic
intercellular changes
The study of the relationship between a drug’s dose, tissue concentration, and
elapsed time is called Pharmacokinetics (how a body affects a drug). While the study
of drug action, including toxic responses is called Pharmacodynamics (how a drug
affects a body).
Pharmacokinetics is defined by four parameters: absorption, distribution,
biotransformation and excretion.
Pharmacodynamics also inquires into mechanisms of action, drug interactions, and
structure-activity relationships.
A chronic decrease in receptors stimulation lead to increase in density or mass of the
receptors this is called (Up-regulation). Example patients who are on beta-blocker
for long period of time lead to increases of numbers of beta-adrenergic receptors.
While (Down-regulation) is caused by chronic increase in receptors stimulation (e.g.
chronic asthma patients on beta agonist) lead to decrease the number of the betadrenergic receptors.
Adrenergic receptors
These are G protein-coupled receptors, which are targets for catecholamine.
Adrenergic receptors are discussed in more details in my lecture for “Autonomic
Nervous System”
Adrenergic agonists
Catecholamines are called so because they contain a catechol or 3,4dihydroxyphenyl group (Fig.1). They are derived from the amino acid tyrosine. In
human the catecholamines are epinephrine (adrenaline), norepinephrine
(noradrenaline), and dopamine, all of them are derived from phenylalanine and
tyrosine.
Fig. 1catechol
Catecholamines have a half-life of a few minutes when circulating in the blood. They
can be degraded either by methylation by catechol-O-methyltransferases (COMT) or
by deamination by monoamine oxidases (MAO).
Sympathomimetic are drugs that produce sympathetic-like effect but lack the basic
structure of catecholamine example clonidine, which is a α2-receptors agonist that
does not have a catechol nucleus. All clinically useful catecholamines are
sympathomimetics, but not all sympathomimetics are catecholamines.
Adrenergic agonists can be simply classified according to their sensitivity to α or β
receptors, for example phenylephrine has a α1 agonist effect with very minimally
effect on β-adrenergic receptors, while isoproterenol activate only the β-adrenergic
receptors. Other medications like epinephrine, norepinephrine, dopamine, etc., can
stimulate both receptors.
Vasopressor medications
Vasopressor is a class of drugs that induce vasoconstriction and thereby elevate
mean arterial pressure (MAP). Below is a list of the most commonly using drugs with
an important vasopressor effect.
1. Phenylephrine
2. Vasopressin
3. Norepinephrine
4. Epinephrine in high doses
5. Dopamine in high doses
6. Ephedrine
1. Phenylephrine
Phenylephrine (Neosynephrine ®) is a mainly α1 agonist drugs with minimally effect
on β1 receptors. It causes vasoconstriction to the arterioles and to a lesser extent to
the venous. It has a short duration of action of less than 5 minutes. Its offset occurs
by rapid metabolism by MAO; there is no COMT metabolism. The main indication is
in hypotension due to decrease systemic vascular resistance during general or
locoregional anesthesia. It can be also used in cases of supraventricular tachycardia
(SVT) in the operation room, due to its reflex bradycardia effect. In addition to that,
Neosynephrine becomes frequently used in cases of Tetralogy of Fallot (TOF) when
patient desaturation occurs due to the right – left shunt through the ventricular
septum defect.
2. Vasopressin (Pitressin)
Pitressin is similar to a naturally occurring hormone present in the body, which is also
known as antidiuretic hormone (ADH) or vasopressin. In general, ADH has two main
effects in the body. Firstly, it acts on receptors in the kidney to retain water in the
body. Secondly, ADH causes vasoconstriction of blood vessels, thereby limiting
blood flow to a particular area of the body. It is used particularly in patient with
distributive shock due to hepatic failure, vasoplegic after cardio-pulmonary bypass, or
septic shock. It can be also used during reanimation in patient not respond to
epinephrine. Vasopressin thought to have a minimal effect on cardiac output.
Vasopressin increases systemic vascular resistance by binding to V1 receptors but,
experimentally, it leads to pulmonary vasodilatation, most likely as a result of
stimulation of endothelial nitric oxide release (Wallace AW et al. Effects of
vasopressin on pulmonary and systemic vascular mechanics. Am J Physiol 1989;
257: H1228–34.)
3. Norepinephrine (Levophed or noradrenaline)
Is a postganglionic sympathetic neurotransmitter that release from adrenal medulla
and the central nervous system (CNS) neurons. It has a direct effect α1, α2 & β1
adrenergic receptors and minimally or limited effect on β2 adrenergic receptors. As
other vasopressor drugs, noradrenaline is mostly used to restore the blood pressure
as in cases of septic shock, or in hypovolemic or hemorrhagic shock when the blood
is not yet ready, etc.
4. Epinephrine (adrenaline)
Epinephrine is a catecholamine that produced from the adrenal medulla. It is a
positive inotrope that in high dose may induce vasoconstriction. It stimulates both the
α and the β-adrenergic receptors. It cause increase in cardiac contractility, hart rate
while the systemic vascular resistance is variable, depending on the dosage. In
addition to it’s use in reanimation setting and as a potent inotropic in cardiac surgery
patients, epinephrine is the drug of choice in anaphylactic shock.
5. Ephedrine
Is a plant-derived alkaloid with sympathomimetic effects, widely used during
anesthesia to restore the systemic vascular resistance. It has a direct (α, β1, and β2
agonist) and indirect action, through stimulating noradrenaline release from the
neurons. It has a short duration of action (between 3-10 min) and can be safely used
in a pregnancy. Ephedrine may induce malignant hypertension when used with MAO
inhibitors (MAO is an enzyme that inactivates noradrenaline, dopamine and
serotonin). Offset of this drug through renal elimination. Ephedrine respond will be
diminished or ineffective when used in repeated doses, this is called Tachyphylaxis.
6. Dopamine (Dynatra)
Like epinephrine, has a mix inotropic and vasoconstrictor properties. It is a precursor
of noradrenaline. Has also direct and indirect mechanism of action. Its direct action
occurs through stimulation of α1, β1, β2-adrenergic receptors and DA1
(dopaminergic) receptors. While it’s indirect action arises from noradrenaline release
from neurons. In low dose dopamine lead to renal and mesenteric vasodilatation,
while moderate dose lead to stimulation of Dopaminergic and β1 receptors. In high
doses, works dopamine mainly as vasoconstrictor through stimulation of α1
receptors.
Inotropic agents
Inotropy means contraction of the heart muscles. This occurs when the actin and
myosin (proteins) interact to each other. This reaction will be prevented by the action
of two other proteins, troponin and tropomyocin. When intracellular calcium
concentration is increased, contraction of the myocardium will happen because
calcium has the ability to bind to troponin and this permits actin myosin interaction.
Different mechanisms regulate this intracellular calcium release like:
• Increasing in cAMP level that trigger additional calcium channel to open and
start muscles contraction. This effect can be obtained through sympathetic
stimulation or by using phosphodiesterase inhibitors, which prevents the
degradation of cAMP.
• Digitalis increases intracellular calcium through inhibition of Na+/K- ATPase.
• Increasing in intracellular cAMP by activation of a specific noradrenergic
receptor as in case of using glucagon
• Other mechanisms of action of inotropy like Ca+2 sensitizing agents; K+
channels inhibitor, etc. will not be reviewed in this lecture.
1. Isoproterenol (Isuprel)
Is a cAMP dependent inotropic that has a pure Beta agonist effect. Because of
tachycardia and decrease in peripheral resistance, made Isuprel as a poor inotropic
of choice. Isuprel used mostly in cases of bradycardia not responding to atropine or
in cases of 3rd degree AV block until a pacemaker can be placed. Isuprel also
decrease the pulmonary vascular resistance through stimulation of beta 2 receptors.
2. Dobutamine (Dobutrex)
Most frequently use inotropic drugs; it is also a cAMP dependent agent that mostly
given in a dose between 2 – 20 µ/kg/min. In clinical practice doses above 10
µ/kg/min will induce no beneficial effects and more side effects. Dobutamine may
induce slight decrease in peripheral vascular resistance due to beta2 activation.
Dobutamine is a good inotropic drug for patients with congestive heart failure and
ischemic heart disease because it decreases left ventricular filling pressure,
decrease peripheral vascular resistance and at the same time heart rate increases
are less marked than other Beta agonist medications.
3. Phosphodiesterase III inhibitors (PDE III inhibitors)
These agents are getting more interest in congenital and adult cardiac surgery. They
produce their inotropic effect through decreasing cyclic AMP degradation, this will
lead to increase cAMP concentration, which enhance calcium influx into the
myocardium and increase contraction. Inhibition of peripheral phosphodiesterase
lead to vasodilatation and slight decrease in blood pressure. These medications
could also induce decrease not only in systemic vascular resistance but also the
pulmonary vascular resistance will be decrease. An example of PDE III inhibitors is
Milirinone (Corotope). This medication is given in a bolus dose of 50 µ/kg followed by
continue infusion of 0.5µ/kg/min. dose should be decrease in patients with borderline
or decrease renal function. The therapeutic effect would be reach within one hour.
Another drug from this group is Enoximone (Perfan). Excessive dose of these
medications may induce arrhythmias, platelets dysfunction and decrease blood
pressure due to decrease in systemic vascular resistance.
4. Dopamine, adrenaline and ephedrine are already discussed under vasopressor
agents
5. Digoxin
It is an antiarrhythmic agent Class IV. Its inotropic effect is independent on cAMP.
Digitalis increases intracellular calcium through inhibition of Na+/K- ATPase. The
digitalis glycosides have a very narrow therapeutic index; therefore serum levels
should be monitored to account for inter-patient variability. Digoxin is excreted in
urine and does not distribute to fat. Digoxin is used in the treatment of congestive
heart failure and supraventricular arrhythmias. Adverse effects include cardiac
arrhythmias, anorexia, vomiting, diarrhea, headache, fatigue, drowsiness,
disorientation, delirium and blurred vision.
6. Calcium
It is well know that ionized serum calcium level below 0.5 mmoles/l is associated with
negative inotropic effect. Calcium is mostly used in cardiac surgery to overcome the
effects of cardioplegia and help weaning the patient from the heart lung machine. It
should be also used in cases of massive blood transfusion and in liver
transplantation. It should use in caution in patient with residual myocardial ischemia
because it increase the oxygen consumption of the heart and worse the condition.
Beside it may induce coronary artery spasm and pulmonary hypertension especially
if give to patients with normal serum calcium level. In addition to that calcium may
attenuate cardiac stimulating effect of β-agonists, but not of phosphodiesterase
inhibitors. The recommended intravenous dose in children is around 25 mg/kg slowly
over few minutes. While in adult the dose is 500 mg to 1 gram also should be given
intravenously and slowly.
Vasodilators drugs
Most vasodilator drugs have mixed arterial and venous dilator effect. These drugs
can be classified into
• Venodilators that lead to decrease preload.
• Arterial dilator that cause reduction in afterload.
• Mixed venoarterial dilator.
1. Isosorbide dinitrate (cedocard)
This drug is mainly a venodilator, with minimal effect on arterioles. It is frequently
use in ischemic heart disease to ensure relaxation of the coronary arteries, improving
myocardial regional blood flow and decreasing myocardial O2 demand. The usual
dose used in the operation room is 0.1-7 µ/kg/min. It has a short half-life 1-3 minute.
The main disadvantages of cedocard are: Tolerance in chronically used patient,
systemic blood pressure may decrease and cause reflex tachycardia that may worse
the condition and it may prevent hypoxic pulmonary vasoconstriction.
2. Inhaled Nitric Oxide (iNO)
Is a selective pulmonary vasodilator with minimal effect on systemic vascular
resistance. It has a great affinity to hemoglobin, Methemoglobinemia (metHb >5%)
can occurs in approximately 10% of newborns treated with iNO and resolves with
decreasing the iNO dose. iNO decrease intrapulmonary shunt and improves
ventilation/perfusion mismatching in cases of ARDS. Withdrawal of iNO may lead to
pulmonary hypertension.
3. Urapidil (Ebrantil)
It is an alfa1 antagonist and also a serotonin agonist. It causes reduction in systemic
as well as diastolic blood pressure. It is used in cases of hypertensive crises or in
cases of malignant or therapy resistance hypertension.
4. Clonidine (Catapressan)
Clonidine is an α2 receptors agonist that enjoys a remarkable spatial similarity to
norepinephrine that allows it to activate the receptor. Clonidine treats high blood
pressure by stimulating α2 receptors in the brain, which decreases cardiac output
and peripheral vascular resistance, lowering blood pressure. It has specificity
towards the presynaptic α2 receptors in the vasomotor center in the brainstem. This
binding decreases presynaptic calcium levels, and inhibits the release of NE. The net
effect is a decrease in sympathetic tone. [Shen, Howard (2008). Illustrated
Pharmacology Memory Cards: PharMnemonics. Minireview. pp. 12.ISBN 1-59541101-1.].
References
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Hensley F, Martin D. A practical approach to cardiac anesthesia. 2008.
Paul G. Barash. Clinical Anesthesia, 6th edition.
G Edward Morgan. Clinical Anesthesiology 2nd edition.