Chapter 13

Catecholamines:
-epinephrine, norepi, dopamine, dobutamine, isoproterenol – all activate b1 adrenoreceptors
on sarcomere membrane of atrial/ventricular myocytes
 Positive chronotropy (HR), dromotropic (conduction velocity), inotropic (contractility),
lusitropic (relaxation)
 Stimulate G1 protein  activate adenylyl cyclase  accelerate cAMP formation from
ATP.
 More Ca for contraction, higher efficacy, higher removal of Ca
-Tissue specific distribution of alpha/beta receptors
-dopamine – selective for dopa 1, 2 receptors, at larger doses affect b1, a1 R
-a1 – regulators of arteries, arterioles, veins; norepi acts to inc SVR, reduce venous capacitance,
through artery, venous vasoconstriction. Via G1 inhibitory protein  inc Ca release in
SR/calmodulin  inc intracellular Ca, vascular smooth m contraction. Cutaneous BV.
-b2 – skeletal muscle; arteriolar vasodilation via adenylyl cycase mediating signal.
-all catecholamines cause inc in myocardial O2 consupmtion  acute MI

Epinephrine:
-a1, b1, b2 receptors
-b1 – inc chronotropic, inotropic. Enhance rate/extent myocardial relaxation (greater LV filling
in diastole). Inc CO, O2 delivery – good for LV dysfunction.
-initial tachy can be attenuated by baroreceptor mediated reflexes.
-clinical use limited – can cause atrial/ventricular arrhythmias. Inc conduction velocity, reduces
refractory period in AV node, his bundle, purkinje fibers, ventricular muscle.  afib, aflutter,
vfib, vtachy
-a1 – vasoconstriction of arteriolar vascular smooth m in cutaneous, splanchnic, renal
perfusion.
-b2 adrenoreceptor – skeletal muscle; vasodilation. (First activated at low doses >a1).
-inc in myocardial o2 demand result from inc HR, contractility, preload, afterload  coronary
vasodilation  inc blood flow
-causes greater inc in SCR, arterial pressure after admin of nonselective beta blocker
(propranolol) b/c it doesn’t oppose a1 induced vasoconstriction anymore. However pos
chronotropic/inotropic effect of catecholamine lessened b/c b1 blockade too.
 Basically effect  similar to pure a1 agonist phenylephrine in presence of b1/b2
blockade

Norepinephrine:
-from SNS postganglionic neuron; activates a1, b1 (not b2); enhance myocardial contractility
and arterial vasoconstriction  inc arterial P, SVR; CO not affected (phenylephrine would dec
CO b/c lack b1)
-elevated BP  baroreceptor mediated reflexes  no inc HR
-inc stroke volume, inc BP, cardiac index, urine output in pt with sepsis/refractory hypoTN, can
tx vasoplegic syndrome (hypotensive state, low SVR)
-Norepi can cause arrhythmias, less than epi
-dec hepatic, skeletal muscle, splanchnic, renal blood flow during norepi via a1 R activation
when BP is normal/modestly reduced. If pt hypotensive, then blood flow to these organs inc.

Dopamine:
-precursor to norepi
-low dose: DA1 R – inc renal/splanchnic blood flow, DA2 R – reduce norepi from ANS
ganglia/adrenergic neurons  reduced arterial pressure
-moderate doses can act a1, b1 R, high dose only act on a1 (inc arterial P through arteriolar
vasoconstriction). But high doses cont to activate DA1 and maintain renal blood flow/UO.
-acute inotropic support in pts with LV dysfunction (b1)
-can cause greater inc in HR Than epi in cardiac sx pts
-inc myocardial O2 consumption, worsen ischemia in presents of hemodynamically significant
coronary stenosis

Dobutamine:
-b1, b2 receptors – enhances myocardial contractility, reduces arterial vasomotor tone
-inc CO in presence or absence of LV dysfunction  can therefore improve renal perfusion
-inc HR from b1 stimulation (higher than epi in pts after CABG). Inc O2 consumption – demand
myocardial ischemia in pts with flow limiting coronary stenosis.
-used in stress test
-in failing heart – can favor reduced myocardial O2 consumption (b2 R activation decreases LV
preload and afterload, aka LV end diastolic and end systolic wall stress)
-inc mortality in HF – no longer recommended for inotropic use in this state

Isoproterenol:
-b1, b2
-sustained inc in HR in pts with bradyarrhythmias or AV conduction block – but better to use
pacing
-limited clinical use
-inc myocardial o2 consumption  myocardial ischemia, subendocardial necrosis
-b2 R arteriolar vasodilation in skeletal muscle, dilates renal/splanchnic circulations  reduce
SVR. Dec diastolic/MAP but maintain systolic BP.

Sympathomimetics:

Ephedrine:
-direct and indirect actions on a1, b1 R. Displaces norepi from synaptic vesicles. Then norepi
released to activate postsynaptic receptors  cause arterial/venous vasoconstriction, inc
myocardial contractility.
-directly agonist to b2 – limit inc in arterial P from a1. Resembles epi – dose related inc in HR,
CO, SVR.
-effects decrease with repetitive administration b/c norepi rapidly depleted (Tachyphylaxis).
This doesn’t happen with epi b/c epi acts directly on R.
-inc HR

Phenylephrine:
-stimulates a1 R to produce vasoconstriction DIRECTLY – produce CVS effects.
-constrict veins, cause cutaneous, skeletal m, splanchnic, renal vasoconstriction  dose related
inc in arterial pressure. Also dec in HR and CO.
-IV infusion/boluses intraop for short term treatment of hypotension resulting from
vasodilation
-reflex dec HR

Milrinone
-phophodiesterase – enzymes that hydrolyze and terminate intracellular actions of cAMP 
inactive metabolite.
-milrinone – bypyridine inhibitor of type III phosphodiesterase that preserves intracellular
cAMP by preventing 2nd messenger’s degradation. Inc systolic Ca+, Ca+ release from SR 
inotropic effect of b1 R.
-simultaneous inhibition of cAMP by milrinone = diastolic Ca removal from sarcoplasm 
myocardial relaxation.
-systemic/pulmonary arterial vasodilation mediated by cGMP in vascular smooth m.
-combination of pos inotropic effect with arterial vasodilation  inc CO, despite decline in
preload. Decline MAP. Dec pulm vascular resistance.
-inhibit platelet aggregation, blunts inflammatory cytokines response to cardiopulm bypass,
dilates epicardial coronary a  anti ischemic in CABG pts.

Vasopressin (ADH)
-posterior pituitary  regulates water absorption in kidney, potent hemodynamic effects
-V1 – cell membrane, vascular smooth muscle. Inc Ca concentration and contract vascular
smooth m cell. V2 on renal collecting ducts inc reabsorption of free water. V3 located in
pituitary.
-maintainence arterial P., esp in catecholamine refractory hypotension, vasodilatory shock,
sepsis, cardiac arrest
-used in ACLS for cardiac arrest from vfib, pulseless electrical activity, asystole

ANTI HTN Meds

Beta Blockers:
-anti ischemic effects, first line in pts with STEMI in absence of cardiogenic shock,
bradyarrhythmias, or reactive airway disease. Reduce mortality/morbidity in MI.
-treatment essential HTN, antiarrhythmic effects. Reduce HR, myocardial contractility, arterial
pressure (bind to b1, inhibit actions of circulating catecholamines and norepi release from
postganglionic SNS).
-dec in HR  prolong diastole, inc coronary blood flow to LV, enhance coronary collateral
perfusion to ischemic myocardium, improve O2 delivery to coronary microcirculation. These
reduce myocardial O2 demand and inc suppy.
-inhibit platelet aggregation.
Esmolol:
-beta 1 blocker, fast elimination half life
-useful for acute tachy and HTN during surgery; neg chronotropic/inotropic effects
-attenuate SNS response to laryngoscopy, endotracheal intubation, surgical stimulation
-rapid control of HR in pts with SVT (afib, atrial flutter)
-blunts SNS tachy/htn after seizure activity in ECT.
-can see hypotension since doesn’t affect b2 R

Labetolol:
-inhibit a1 and beta 1,2 R (alpha 1 to beta block of 1:7)
-arteriolar vasodilation  dec arterial P, reduce SVR (a1). Treat periop hypertension.
-partial b2 agonist – vasodilation
-b1 blocker – dec HR, myocardial contractility.
-stroke V and CO unchanged (action on a1 and beta).
-no reflex tachycardia. Helpful in tx of HTN in setting of MI. Can be used in type A aortic
dissection.
-long elimination half life: 6 hours

Nitrovasodilators
-nitroglycerin, sodium nitroprusside
-NO – stimulate guanylate cyclase in vascular smooth m  cGMP  relaxation vascular smooth
m.
-NO stimulates Ca reuptake into SR by activating SR Ca ATPase through cGMP independent
mechanism.  relaxation
-stimulates K efflux by activating K channel  hyperpoarlziation  closes Ca channel 
relaxation
-improve hemodynamic and myocardial oxygen supply-demand in heart failure pts. Decline in
end diastolic V, P, systemic/pulmonary arterial P  dec myocardial O2 consumption and inc
supply by dilating coronary arteries. This enhances subendocardial perfusion.
-rebound hypertension after abrupt discontinuation of nitrovasodilator therapy.
-prolonged use of nitrates – methemoglobinemia, interfere with platelet aggregation, produce
heparin resistance
-use in caution with phosphodiesterase V inhibitors – sildenafil – profound hypotension,
MI/ischemia, death can result

Nitroglycerin:
-dilates venules > arterioles
-dec arterial P, CO; reflex baroreceptor inc in HR. Dec vascular resistance
-at high doses – reduce LV afterload, more dec in arterial P and greater reflex tachy.
-direct coronary vasodilator – inc myocardial O2 supply, reduce demand. Dilate epicardial
coronary a. Improve subendocardial perfusion.
-used in MI, but can be dangerous if patient is also hypovolemic  hypotension

Sodium Nitroprusside:
-ultrashort acting direct NO donor; potent venous/arterial vasodilator  reduces arterial
pressure by dec LV preload/afterload
-HTN emergency treatment!!!
-contraindicated in acute MI  abnl redistribution fo coronary blood flow away from ischemic
myocardium by causing coronary vasodilation
-more baroreceptor reflex mediated tachy, dramatically increases O2 consumption, HR
-metabolism produces cyanide – binds cytochrome C to inhibit aerobic metabolism  lactic
acidosis, also thiocyanate (produce neuro complications, renal insufficiency)

Hydralazine:
-direct vasodilator  reduces Ca concentration in vascular smooth m, activate K channels –
relaxation of small arteries/arterioles in cerebral, splanchnic, coronary, renal vascular beds.
Declines in SVR, arterial P.
-dec afterload  inc CO.
-baroreceptor tachycardia  can produce acute MI in critical coronary stenosis.
-used for postop HTN in absence of tachycardia.

Ca Channel Antagonists:
-L type Ca channel – taret of all calcium channel antagonists in current clinical use.
-1,4 dihydropyridines: nifedipine, nicardipine, clevidipine.
-benzothiazepineS: diltiazem
-phenylalkaylamines: verapamil
-diarylaminoproylamine ethers: bepridil
-vasodilation, direct neg chronotropic, dromotropic, inotropic effects; reflex inc in HR
-relaxation of arterial > venous smooth m. Reduces LV afterload while preserving preload.
-improve myocardial o2 supply through coronary arterial vasodilation, inhibiton coronary a
vasospasm
-diltiazem, verapamil – reduce myocardial o2 demand via depression of myocardial
contractility, dec in HR via SA node

Nicardipine:
-highly selective for vascular smooth muscle; similar to nifedipine but longer half life.
-vsodilator, inhibits Ca influx in vascular smooth m. Dilates arteriolar bv, dec arterial P.
-doesn’t depress myocardial contractility or affect SA node
-mild tachy reflex.
-coronary vasodilator – dilate arterial grafts in CABG.
-treatment of periop HTN but not acute transient HTN in operating room

Clevidipine:
-new, ultrashort acting dihydropyridine L type voltage gated Ca channel antagonist,2 min half
life
-effects less neg resting membrane potential in vascular smooth m. Lower potency in cardiac
myocytes in which resting membrane potentials more neg.
-highly selective – arterial vascular smooth m. No neg chronotropic/inotropic effects.
-tx HTN in pts with compromised LV fxn. Dose related arteriolar vasodilation, sparing venous.
Reduce SVR and arterial P. No change in LV preload.
-inc CO. Modest inc HR tachy.
-no accumulation in setting of organ dysfunction – hepatic, kidney dx