CARDIOVASCULAR

PHARMACOLOGY

Ana Sharmaine S. Uera, MD

DR PJGMRMC
Anesthesiology Department
1st Year Resident
CHOLINERGIC DRUGS
CHOLINERGIC AGONISTS
CHOLINERGIC DRUGS
CHOLINESTERASE INHIBITORS
MUSCARINIC ANTAGONISTS
MUSCARINIC ANTAGONIST
TOXICITY
CATECHOLAMINES
EPINEPHRINE
• activating a1, b1, and b2 adrenoceptors
• useful for the treatment of acute LV failure
• enhances cardiac output and oxygen
delivery without causing deleterious
increases in heart rate in septic,
hypotensive patients.
• limited use because of development of
atrial or ventricular arrhythmias.
NOREPINEPHRINE
• activates both a1 and b1 adrenoceptors similar to
epinephrine, but exerts few if effects on the β2
adrenoceptor.
• enhances myocardial contractility while simultaneously
causing arterial vasoconstriction.
• norepinephrine does not usually increase heart rate
because elevated blood pressure stimulates
baroreceptor-mediated reflexes
• for tx of refractory hypotension and vasoplegic syndrome
• associated w/ ventricular and supraventricular
arrhythmias
DOPAMINE
• biochemical precursor of norepinephrine
• Low doses (typically below 3 μg/kg/min) of dopamine selectively
increase renal and splanchnic blood flow via activation of DA1
receptors and also reduce norepinephrine release from autonomic
nervous system ganglia and adrenergic neurons through a DA2
receptor–mediated mechanism.
• Moderate doses (3 to 8 μg/kg/min) of dopamine activate both α1
and β1 adrenoceptors,
• High doses (in excess of 10 μg/kg/min) almost exclusively act on
α1 adrenoceptors to increase arterial pressure through arteriolar
vasoconstriction.
• often used for inotropic support in patients with acute LV
dysfunction.
• increases myocardial O2 consumption and may worsen myocardial
ischemia in the presence of hemodynamically significant coronary
stenoses.
DOPAMINE
• often markedly increases heart rate by direct
chronotropic effects resulting from β1
adrenoceptor stimulation
• may cause “demand” myocardial ischemia in
patients with flow-limiting coronary stenoses
• useful inotropic drug to enhance cardiac output
in cardiac surgery patients with pre-existing
pulmonary hypertension
DOBUTAMINE
• synthetic catecholamine w/ +/- stereoisomers
• stimulate b adrenoceptors
• dobutamine causes potent β adrenoceptor stimulation,
but exerts little or no effect on α1 adrenoceptors when
administered at infusion rates <5 μg/kg/min.
• increase cardiac output in the presence or absence of
LV dysfunction.
• negative isomer dobutamine begins to stimulate the α1
adrenoceptor at infusion rates >5 μg/kg/min
ISOPROTERENOL
• nonselective b adrenoceptor agonist synthetic
catecholamine that exerts almost no activity at α
adrenoceptors.
• used for “pharmacologic pacing” because it
causes sustained increases in heart rate in
patients with symptomatic bradyarrhythmias or
AV conduction block
• also used during cardiac transplantation to
increase heart rate and augment myocardial
contractility in the deneverated donor heart.
SELECTIVE B2-ADRENOCEPTOR
AGONISTS
• include metaproterenol, albuterol, salmeterol, and
fenoterol, are currently in clinical use for treatment of
asthma and chronic obstructive pulmonary disease
• stimulate β2- adrenoceptors in bronchial smooth muscle
to produce bronchodilation, reduce airway resistance,
and improve obstructive symptoms.
• Reductions in histamine and leukotriene release from
pulmonary mast cells, and improvements in mucociliary
function
FENOLDOPAM
• an intravenous selective DA1-receptor agonist
that does not exert activity at α- or β-
adrenoceptors.
• dilates mesenteric, splenic, and renal arterioles,
increases renal blood flow, decreases renal
vascular resistance, reduces systemic vascular
resistance, improves creatinine clearance, and
promotes both natriuretic and diuretic effects
• protecting the kidney against radiographic
contrast-induced nephropathy, presumably by
virtue of enhanced renal blood flow;
FENOLDOPAM
• IV has a rapid onset of action as an
antihypertensive medication.
• drug undergoes hepatic metabolism and is
excreted in the urine.
• elimination half-life approximately 5
minutes.
• MC SE include hypotension, tachycardia,
flushing, dizziness, headache,
tachycardia, and nausea.
SYMPATHOMIMETICS
EPHEDRINE
• exerts direct and indirect actions on adrenoceptors.
• Transport of ephedrine into α1 and β1 adrenoceptor presynaptic
terminals displaces norepinephrine from the synaptic vesicles.
• NE is then released to activate the corresponding postsynaptic
receptors to cause arterial and venous vasoconstriction and
increased myocardial contractility, respectively. (indirect effect)
• directly stimulates b2 adrenoceptors, thereby limiting increases in
arterial pressure resulting from α1 adrenoceptor activation
• tachyphylaxis to the hemodynamic effects of ephedrine occurs with
repetitive administration of the drug because presynaptic
norepinephrine stores are rapidly depleted.
• often used as an intravenous bolus to treat acute hypotension
accompanied by decreases in heart rate.
PHENYLEPHRINE
• almost exclusively stimulates a1 adrenoceptors to
produce vasoconstriction, while exerting little or no effect
on adrenoceptors except when large doses are
administered.
• constricts venous capacitance vessels and causes
cutaneous, skeletal muscle, splanchnic, and renal
vasoconstriction to increase preload and afterload
• Intravenous boluses or infusions of phenylephrine are
most often used intraoperatively for short-term treatment
of hypotension resulting from vasodilation.
• not arrhythmogenic
A1 ADRENOCEPTOR ANTAGONISTS

• clonidine and dexmedetomidine are commonly used by

anesthesiologists and pain medicine specialists for
sedation, anxiolysis, and analgesia.

• Clonidine binds to α2-adrenoceptors and inhibits

norepinephrine release from presynaptic postganglionic
sympathetic neurons.
• for the treatment of hypertension.
• blunts centrally mediated sympathetic nervous system
tone, decreases serum norepinephrine and
norepinephrine concentrations, and reduces activation of
the renin–angiotensin–aldosterone axis.
• does not affect baroreceptor mediated reflex control of
heart rate
DEXMEDETOMIDINE
• sevenfold more selective for the α2-
adrenoceptor (α2 to α1 ratio of 1,600:1) and has
a substantially shorter context-sensitive half-life
than clonidine.
• reduces anesthetic requirements during general,
neuraxial, and regional anesthesia;
• decreases heart rate, arterial pressure, and
plasma catecholamine concentrations;
attenuates intraoperative cardiovascular lability;
and does not cause clinically significant
respiratory depression.
DEXMEDETOMIDINE
• useful for functional neurosurgery;
neuroprotective effects against cerebral
ischemia and hypoxia;
• facilitates perioperative care of obese patients
with OSA and those undergoing bariatric surgery
because the drug provides analgesia, reduces
opioid requirements, and does not substantially
depress respiration
• hypothermia because the drug lowers the
threshold body temperature at which
compensatory thermoregulation mechanisms
are activated.
B ADRENOCEPTOR ANTAGONISTS
(B- BLOCKERS)

• first-line therapy for treatment of patients with

ST-segment elevation myocardial infarction in
the absence of cardiogenic shock,
hemodynamically significant bradyarrhythmias,
or reactive airway disease.
• reduce mortality and morbidity associated with
myocardial infarction in a number of large clinical
trials.
• effective for the treatment of essential
hypertension and also exert useful
antiarrhythmic effects
• reduce myocardial oxygen demand while
simultaneously increasing supply.
• inhibit platelet aggregation.
PROPRANOLOL
• “first generation” (nonselective) β-blocker
that competitively inhibits both β1- and β2-
adrenoceptors
• highly lipophilic, easily absorbed from the
stomach, and undergoes extensive first-
pass hepatic metabolism.
• used for treatment of hypertension and
symptomatic coronary artery disease.
relatively short half-life (approximately 4
hours)
METOPROLOL
• selective for β1-adrenoceptors but has no intrinsic
sympathetic or membrane stabilization activity.
• oral metoprolol is rapidly absorbed, undergoes first-pass
hepatic metabolism by cytochrome P450 2D6 that limits
its initial availability.
• half-life of 3 to 4 hours allows twice-per-day dosing in
patients with normal metabolism
• commonly used for treatment of hypertension, angina
pectoris, acute myocardial infarction and chronic heart
failure
ATENOLOL
• selective inhibitor of β1-adrenoceptors and does not
possess intrinsic sympathetic or membrane stabilization
activity.
• longer half-life (6 to 9 hours) than metoprolol that
facilitates a daily dosing regimen.
• not metabolized by liver, most excreted in its original
form by the kidney.
• dose of atenolol must be reduced in patients with
moderate to severe renal insufficiency.
• lack of first-pass hepatic metabolism reduces variability
in plasma atenolol
• used for the treatment of hypertension, coronary artery
disease, acute myocardial infarction, and heart failure.
ESMOLOL
• relatively selective b1 adrenoceptor blocker.
• contains an additional methylester group that facilitates
the drug’s rapid metabolism via hydrolysis by red blood
cell esterases, resulting in an elimination half-life of
approximately 9 minutes.
• useful for the treatment of acute tachycardia and
hypertension during surgery.
• attenuate the sympathetic nervous system response to
laryngoscopy, endotracheal intubation, or surgical
stimulation, particularly in patients with known or
suspected coronary artery disease who may be at risk of
myocardial ischemia.
ESMOLOL

• useful for rapid control of heart rate in

patients with supraventricular
tachyarrhythmias (e.g., atrial fibrillation,
atrial flutter).
• blunts the sympathetically mediated
tachycardia and hypertension that occur
shortly after the onset of seizure activity
during electroconvulsive therapy
• hypotension is more commonly observed
LABETALOL
• composed of four stereoisomers that inhibit a and b
adrenoceptors to varying degrees
• intravenous formulation of labetalol contains a ratio of α1 to
β adrenoceptor blockade of approximately 1:7.
• for tx of perioperative hypertension
• for controlling arterial pressure w/o producing tachycardia
in patients with hypertensive emergencies and acute
type A aortic dissection.
• attenuate the sympathetic nervous system response to
laryngoscopy and endotracheal intubation
• relatively long elimination half-life (approx 6 hours) limits its
use in this setting.
CARVEDILOL
• third-generation β-blocker that inhibits β1-, β2-,
and α1- adrenoceptors
• antioxidant and anti-inflammatory effects
• treatment of hypertension, stable angina
pectoris, acute myocardial infarction, heart
failure
• very lipophilic, is nearly entirely absorbed after
oral administration,undergoes extensive first-
pass hepatic oxidative metabolism via
cytochrome P450 2D6 with little or no
dependence on the kidney for elimination.
PHOSPHODIESTERASE INHIBITORS
• PDE III inhibitors increase cAMP concentration,
enhance protein kinase A activity, and
phosphorylate voltagedependent Ca2+
channels109 and phospholamban, the major
sarcoplasmic reticulum regulatory protein.
• PDE III inhibitors cause pronounced arterial and
venous vasodilation by blocking cGMP-
metabolism and facilitating the actions of this
second messenger in vascular smooth muscle.
MILRINONE
• Milrinone increases cardiac contractility by
inhibiting cardiac type III phosphodiesterase,
the enzyme responsible for the breakdown of
cyclic adenosine monophosphate.
• produce a positive inotropic effect independent
of the β1 adrenoceptor.
• decreases pulmonary vascular resistance, and
this action may be especially beneficial in
patients with pulmonary hypertension who are
undergoing cardiac surgery
LEVOSIMENDAN
• Myofilament Ca2+ sensitizers are positive inotropic, vasodilating
drugs that enhance myocardial contractility by increasing the Ca2+
sensitivity of the contractile apparatus
• used extensively in Europe for short-term treatment of heart failure
and for inotropic support in patients undergoing cardiac surgery
• binds to troponin C (TnC) and stabilizes the Ca2+-bound
conformation of the regulatory protein in a Ca2+-dependent manner.
• potent PDE III inhibitor that produces positive inotropic and lusitropic
effects and causes systemic, pulmonary, and coronary vasodilation.
• opens ATP-dependent K+ (KATP) channels and also produce the
additional benefit of myocardial protection against reversible and
irreversible ischemic injury.
DIGITALIS GLYCOSIDES
• naturally occurring substances found in several plant
species including “foxglove” (Digitalis purpurea).
• selectively bind to the α-subunit of the sarcolemmal Na+-
K+ ATPase on its extracellular surface and reversibly
inhibit the enzyme.
• tachyphylaxis does not occur
• "Treppe" rapid increase in heart rate causes a delay in
Na+-K+ ATPase activity, leading to a transient increase
in intracellular Na+ concentration and enhanced
contractile force mediated by favorable Na+-Ca2+
exchange.
VASOPRESSIN
• antidiuretic peptide hormone
• consist of three subtypes (V1, V2, and V3), all of
which are five subunit helical membrane proteins
coupled to G proteins
• indicated for the treatment of severe
hypotension after prolonged cardiopulmonary
bypass in patients who are otherwise
unresponsive to phenylephrine or
norepinephrine (vasoplegia).
• treatment of sepsis and cardiac arrest.
NITROVASODILATORS
• organic nitrates (e.g., nitroglycerin) and nitric oxide
(NO) donors (e.g., sodium nitroprusside)
• exogenous NO stimulates guanylate cyclase within
the vascular smooth muscle cell to convert
guanosine triphosphate to cGMP.
• stimulates Ca2+ reuptake
• stimulates potassium (K+) efflux from the cell by
activating the K+ channel.
• improve hemodynamics and myocardial oxygen
supply–demand relations in patients with heart
failure.
NITROVASODILATORS
• decrease myocardial oxygen consumption.
• (pseudo-tolerance) accounts for the rebound
hypertension that may be observed after abrupt
discontinuation of nitrovasodilator therapy.
• drug holiday or N-acetylcysteine for reversing tolerance
• methemoglobinemia, interfere with platelet aggregation,
and produce heparin resistance.
• used with caution in patients receiving
phosphodiesterase type V inhibitors (e.g., sildenafil)
because NO-induced vasodilation is enhanced, and
profound hypotension, myocardial ischemia or infarction,
and death may result.
NITROGLYCERIN
• dilates venules to a greater degree than arterioles.
• At lower doses, venodilation without causing a
significant decrease in systemic vascular resistance.
• At higher doses, nitroglycerin dilates arterioles,
reducing LV afterload, causing more pronounced
decreases in arterial pressure, and stimulating greater
reflex tachycardia.
• direct coronary vasodilator (which increases supply) and
its systemic hemodynamic effects (which reduce
demand).
NITROGLYCERIN
• inhibits coronary vasospasm and dilates arterial
conduits used during CABG surgery
• decreases
• myocardial oxygen demand by reducing LV
preload and, to a lesser extent, afterload, thereby
producing corresponding reductions in LV end-
diastolic and end-systolic wall stress.
• very effective first-line drug for the treatment of
myocardial ischemia, caution should be exercised
when using nitroglycerin in patients with ischemia
who are also hypovolemic.
SODIUM NITROPRUSSIDE
• ultrashort-acting direct NO donor. It is a potent venous
and arterial vasodilator devoid of inotropic effects that
quickly reduces arterial pressure by decreasing LV
preload and afterload.
• first-line drug for the treatment of hypertensive
emergencies.
• useful for the treatment of cardiogenic shock because
arterial vasodilation improves forward flow by reducing
impedance to LV ejection, while venodilation decreases
LV filling pressures.
• relatively contraindicated in patients with acute
myocardial ischemia
SODIUM NITROPRUSSIDE
• Baroreceptor reflex–mediated tachycardia is
also more pronounced ; reflex tachycardia
dramatically increases heart rate and myocardial
oxygen consumption, thereby exacerbating
acute myocardial ischemia.
• metabolism produces cyanide, methemoglobin
and thiocyanate
• thiocyanate - accumulate in pts with renal
insufficiency and produce delirium or seizures
HYDRALAZINE
• direct vasodilator that reduces intracellular Ca2+
concentration in vascular smooth muscle, by activating
adenosine triphosphate– sensitive potassium channels.
• primary reduction in afterload stimulates baroreceptor
reflex–mediated tachycardia and increases cardiac
output.
• pronounced tachycardia may produce acute myocardial
ischemia
• pt w/ critical coronary stenoses
• commonly used for management of sustained
postoperative hypertension in the absence of
tachycardia.
CALCIUM CHANNEL BLOCKERS
• asymmetric biochemical pores consisting of at least four
subunits (α1, α2/Δ, and β with or without γ) that traverse
many biologic membranes.
• L-type Ca2+ channel is the predominant target of all
calcium channel antagonists in current clinical use
• produce vasodilation, direct negative chronotropic,
dromotropic, and
• inotropic effects and baroreceptor reflex–mediated
increases in heart rate
• All Ca2+ channel blockers produce greater relaxation of
arterial than venous vascular smooth muscle.
NICARDIPINE
• dihydropyridine Ca2+ channel antagonist that is highly
selective for vascular smooth muscle.
• profound vasodilator because of its pronounced inhibition
of Ca2+ influx in vascular smooth muscle.
• preferentially dilates arteriolar vessels
• does not substantially depress myocardial contractility
nor does it affect the rate of sinoatrial node firing.
• tachycardia less pronounced than sodium nitroprusside
• highly potent coronary vasodilator and is often used to
dilate arterial grafts during CABG surgery.
• treatment of sustained perioperative hypertension
NIFEDIPINE
• most often used for chronic treatment of
essential hypertension
• relatively selective arterial vasodilator that does
not substantially affect venous vasomotor tone
• frequently used in patients with coronary artery
disease, most often in combination with a β1-
adrenoceptor antagonist to abolish baroreceptor
reflex-mediated tachycardia
• provide arterial vasodilation in patients with
Raynaud’s
CLEVIDIPINE
• ultrashort-acting dihydropyridine L-type voltagegated
Ca2+ channel antagonist with a plasma half-life of
approximately 2 minutes after intravenous
administration.
• exerts pronounced effects at the less negative resting
membrane potentials typically observed in vascular
smooth muscle cells, but demonstrates lower potency in
cardiac myocytes in which resting membrane potentials
are substantially more negative highly selective for
arterial vascular smooth muscle
• useful for the treatment of hypertension in patients with
compromised LV function.
• not associated with tachyphylaxis and rebound
hypertension
NIMODIPINE
• more lipophilic and more easily crosses
the blood–brain barrier than other drugs in
this class of Ca2+ channel blockers
• exerts more cerebral arterial vasodilation
than other dihydropyridines.
• treatment of cerebral vasospasm after
aneurysmal subarachnoid hemorrhage
• reduce cerebral arteriolar resistance and
enhance blood flow through pia mater
collateral vessels
DILTIAZEM
• only benzothiazepine Ca2+ channel blocker in current
clinical use
• produces arterial vasodilation and decreases arterial
pressure
• exerts potent negative chronotropic and dromotropic effects
on SA node automaticity and AV node conduction
• useful alternative medication fo patients with hypertension
and symptomatic coronary artery disease in clinical
situations in which β-adrenoceptor antagonists may be
relatively contraindicated (e.g., asthma, chronic obstructive
pulmonary disease).
• effective for ventricular rate control in pts with chronic atrial
fibrillation, atrial flutter, or SVT
VERAPAMIL
• phenylalkylamine Ca2+ channel blocker verapamil
produces less arterial vasodilation, but exerts more potent
effects on automaticity, conduction, and myocardial
contractility than the dihydropyridines.
• verapamil has the potential to markedly worsen pre-
existing LV systolic dysfunction in patients with heart
failure because of the Ca2+ channel blocker’s myocardial
depressant effects.
• coronary vasodilator and decreases myocardial oxygen
consumption as a result of its hemodynamic effects.
• may be effective for the treatment of angina pectoris and
myocardial infarction in patients who may be unable to
tolerate β1-adrenoceptor antagonists
ANGIOTENSIN-CONVERTING
ENZYME INHIBITORS
ACE INHIBITORS
• very effective in the treatment of LV systolic
dysfunction with or without heart failure
• well-documented salutary effects in patients with
acute myocardial infarction, especially those with
diabetes mellitus and hypertension
• exert renal protective effects in diabetic patients
and
• mitigate the progression of renal dysfunction in
other forms of nephropathy
• SE: Dry cough due to Bradykinin
ACE INHIBITORS
• may also cause hyperkalemia in patients with chronic
kidney injury and in those with normal renal function who
are treated with K+- sparing diuretics (e.g.,
spironolactone, triamterene) or K+ supplements.
• blunt the hypokalemic effects of thiazide and loop
diuretics.
• Acute renal failure, reversible neutropenia, fetal
teratogenicity, and dermatitis are other adverse effects of
ACE inhibitors.
• Angioedema - rare complication
 ANGIOTENSIN RECEPTOR
BLOCKERS
• inhibit the AT1 receptor with high affinity and thereby
markedly attenuate the cardiovascular, endocrine, and
renal effects of angiotensin II.
• All ARBs are potent antihypertensive medications that
more effectively inhibit the actions of angiotensin II at
AT1 receptors than do ACE inhibitors.
• ARBs are most often used in patients with heart failure
who are unable to tolerate the side effects of ACE
inhibitors
• ARBs provide renal protection in patients with diabetes
mellitus, reduce risk of stroke
• exert fetal toxicity and may cause hyperkalemia in
patients treated with K+-sparing diuretics or those with
renal insufficiency similar to ACE inhibitors.
THANK YOU!