Dr masoudnia

CARDIOVASCULAR

PHARMACOLOGY

degree of myocardial depression: difficult to establish

alterations in: systemic hemodynamics pulmonary hemodynamics ANS complicate LVSfunction

The difference myocardial depression by VA :independent of ANS Activity

Isovolumic and ejection phase measurement indices of ventricular contractility

Ha=en > iso=des=sevo

MYOCARDIAL CONTRACTILITY

• ↓myocardial contractility actility .• negative inotropic actions

exacerbated : ca↓, calcium (Ca2+) C.B., ß1-Chanel

blocker

reversed : Ca2+, cardiac PDE i fraction III , ß1-agonists, Ca2+ c. agonists, myofilament Ca2+ sensitizers.

Unique cardiovascular stimulation: rapid increase in inspired DES.

transient ↑ in myocardial contractility (augmentation of sympathetic nervous system tone.)

contractility by ISO>HAL at identical MAC.(20%)

The differential on myocardial contractility :

maintained during ↑ or ↓ inotropic state by vasoactive drugs.

DES=ISO in systemic & coronary hemodynamic

effects Iso= des= sevo ↓contractile

in normal ventricular myocardium.

The effects of VA on myocardial contractility in animal models or patients with LVdysfunction have been less extensively studied

Halothane : myocardial depression in

ischemic heart > normal

V.A:1. contractile dysfunction(HOCM) : sensitive to the negative inotropic effects ( in vivo=?)2. not more negative inotropic in myocardium of

DM.

VA–induced declines in contractile function were well tolerated and did not precipitate frank systolic dysfunction in myocardial ischemia or infarction.

important beneficial effects on mechanical function during myocardial ischemia and reperfusion injury.

EFFECT ON ISCHEMIA

1. ↓ experimental myocardial infarct size

2. preserved metabolic &structural integrity in regional ischemia & reperfusion.

3. functional recovery of stunned myocardium

4. ↑ indices LVDF in coronary artery occlusion.

ISO : decrease preload and afterload in IHD

offset the direct negative inotropic effects

maintenance of CO by optimizing the Starling operating range of the heart or by improving LV diastolic function.

Cellular Mechanisms of Myocardial Depression

↓in intracellular Ca2+ homeostasis in cardiac myocyte.

1. dose-related inhibition of the transsarcolemmal Ca2+ transient by L- and T-type Ca2+ channels.

A. ↓avaibility Ca2+ for contractile activation,B. ↓ release of Ca2+ from the sarcoplasmic

reticulum C. ↓ ca2+ stored in the SR

2. inhibiting Na+-Ca2+ exchange ↓ intracellular Ca2+ independent of the

voltage-dependent Ca2+ channel in vitro. ( important in neonatal )

3.↓myofilament Ca2+ sensitivity.(minore role)

4. ↓tension in skinned cardiac myofibrils. 5.↓myofibrillar ATPase

activity(ISO,SEVO,DES)

DIFFERENT BETWEEN HAL & ISO

ISO< HA.: ↓ in the intracellular Ca2+ transientR.

In contrast to ISO1. HAL: stimulate release of Ca2+ from the

SR directly activate ryanodine-sensitive SR Ca2+ release channels,

thereby reducing SR Ca2+ storage.

2. Halothane: nonspecific leakage of Ca2+ from the

SR, → ↓ca accumulation.

1,2 important mechanisms : ↓the intracellular Ca2+ transient

&myocardial contractility

hal> iso, des, or sevo. (in identical mac)

ISO & SEVO: inhibit Ca2+ transport from the cell

through sarcolemmalCa2+ (ATPase), offsets in SR ↓ca2+ stores.

↓ peak intracellular Ca2+ exaggerated ↓ in myofilament Ca2+

sensitivity in hypertrophied heart.

abnormalities in Ca2+ homeostasis characteristic failing myocardium and VA will decrease↓ in contractile function by additive or synergistic effects on Ca2+ metabolism under these conditions.

DIASTOLIC FUNCTION

The timing, rate, and extent of LV filling include:

1. rate and degree of myocardial relaxation,

2. the intrinsic mechanical properties LV 3. external constraints4. structure and function LA5. pulmonary venous circulation 6. mitral valve

HF: may result from primary diastolic dysF in the absence of or before alterations in LVSF, including IHD, pressure- or volume-overload hypertrophy, HOCM & restrictive disease processes.

EFFECT OF VA ON DIASTOLIC DYS

1.↑ LV isovolumic relaxation in vivo.

decrease in early LV filling but not affect LV chamber stiffness.

2.CBF is highest during isovolumic relaxation

delays in relaxation:↓ coronary flow

in early diastole.

Prolongation of LV relaxation as a result of depression of myocardial contractility,

not due to direct negative lusitropic effect.

Lusitropy is myocardial relaxation. The increase in cytosolic calcium of

cardiomyocytes via increased uptake leads to increased myocardial contractility (positive inotropic effect), but the myocardial relaxation, or lusitropy, decreases.

with catecholamine-induced calcium uptake into the sarcoplasmic reticulum, which increases lusitropy.

3.↓ rate & extent of early LV filling +

4. negative inotropic effects 5. ↓ LV filling associated with atrial

systole.

VA.

not exacerbate the preexisting diastolic dysfunction

Due to: ↓ LV preload not due to direct positive lusitropic

effects.

iso-induced improvement LV isovolumic relaxation & maintenance of CO in the presence of LVdys despite ↓contractility.

patients with severe IHD or CHF tolerate ISO or HAL without acute hemodynamic decompensation

In failing myocardium: ↑dependence of LV relaxation on

afterload ↓ afterload : LV systolic performance ,↓ impedance to

LV ejection,& rate of LV relaxation ↑ in LV diastolic filling &compliance. LV isovolumic relaxation in failing

myocardium dependent of negative inotropic effect.

Left Ventricular–Arterial Coupling and Mechanical Efficiency

The elastances of the contracting lv (Ees)

the elastances arterial vasculature (Ea) The ratio of Ees to Ea : coupling between the LV & the arterial

circulation

useful technique for assessment of the actions of drugs(V.A) on LV-arterial matching .IN VIVO

LV-arterial coupling maintained in anesthesia because:

declines in LV afterload may balance reductions in myocardial contractility.

iso at 2 MAC ↓ Ees/Ea Because vasodilating unable to

compensate for the greater declinesin contractility.

Des sev, and iso: maintained optimum LV-arterial

coupling and mechanical efficiency as evaluated by Ees/Ea at low anesthetic concentrations (<0.9 MAC) by declines in myocardial contractility and LVafterload

Halothane (<1.0 MAC) but not isoflurane also reduced the ratio of oscillatory to mean hydraulic power , which indicates that ↓ LV mechanical efficiency as well.

LEFT VENTRICLE AFTERLOAD

LV afterload= the mechanical properties of the

arterial vasculature opposing LVejection

SVR=the ratio of MAP to CO, used of LV afterload.

SVR inadequately describes LV afterload1. ignores the mechanical characteristics

of the blood and arterial walls,2. fails to account for the frequency-

dependent, phasic nature of arterial blood pressure and blood flow

3. not consider the potential effects of arterial wave reflection.

SVR cannot be used reliably to quantify changes in LV afterload produced by drugs, V.A. or cardiovascular disease

electrical three-element Windkessel model of the arterial circulation that describes characteristic aortic impedance (Zc), total arterial compliance (C), and total arterial resistance (R).

Zc aortic resistance to LV ejection, C compliance of the aorta R combined resistance of the

remaining arterial vasculature.

iso :decreases in R consistent with effects on SVR

ISO ,HAL: ↑ in C and Zc ↓MAP. the major difference between ISO,HAL on LV

afterload : R,( arteriolar resistance vessels), not to C or Zc, mechanical characteristics of the aorta.

sevo,des: ↓ R in (more potent peripheral vasodilator.)

the inverse relationship between C and MAP remains unchanged by VA, unlike arterial vasodilator sNP or propofol.

VA do not fundamentally affect aortic mechanical characteristics.

VA ↓arterial pressure but did not affect C and Zc in the presence of LV dysfunction.

Iso not reduce R in the presence of DCM in contrast of normal LV performance.

VA not beneficial actions on LV afterload in the presence of heart failure.

RIGHT VENTRICULAR FUNCTION

The crescent-shaped RV is composed of

embryologically distinct inflow and outflow tracts that differ in their structure and response to ANS.

True isovolumic relaxation does not occur in the RV.

CONT,

The effects of V.A. on the function & contraction sequence of the RV inflow and outflow tracts have been incompletely studied

V.A. may alter RV contraction dynamics by adversely affecting cardiac ANS activity.

ISO: different effects on RV and LV afterload and hydraulic power generation that mediated by ANS.

HAL:↓contractile function ISO: different actions on RV and

LV contraction dynamics in vivo.

LEFT ATRIAL FUNCTION

3 major roles :

on LV filling& cardiovascular performance

1. a contractile chamber : empties immediately before the onset

of LV systole and establishes the final LV end-diastolic volume.

2. a reservoir : stores pulmonary venous return during

LV contraction and isovolumic relaxation after closure and before opening of the mitral valve.

3.a conduit : empties its contents into the lV down a

pressure gradient after the mitral valve opens and continues to passively transfer pulmonary venous blood flow during LV diastasis.

contraction, reservoir, and conduit functions facilitate the transition continuous flow through the pulmonary venous circulation and the intermittent filling of the Lv.

VA depressed the contractile of LA 1. ↓ in transsarcolemmal Ca2+ influx

through voltage-dependent Ca2+ channels

2. ↓ in Ca2+ availability from the SR similar to depression of LV

myocardium.

Des, sevo &iso at 1.2 MAC: ↓50% LA contractility & impaired LA

and LV relaxation similar.

equivalent alterations in contractility & relaxation in LA & LV by VA.

↓ LA inotropic & lusitropic state similar in the intact LA

LA reservoir function maintained MAC< 1.0

In higher MAC : delays in LA relaxation&↓ in LV systolic → ↓ reservoir function.

LA contribution to LV filling : passive during VA.

↓ability of LA to act as a reservoir for pulmonary venous by iso.(In lvdys)

↓ LA storage by ISO:↓ the quantity of blood transferred from the LA to the lV when the mitral valve opens.

VA can reduce early LV filling in the presence of preexisting LV dysfunction

Systemic Hemodynamics

negative chronotropic in vitro(↓SAN activity) HR : interaction of VA & baroreceptor .in VIVO Halothane not change HR (↓ baroreceptor ) ISO& DES:↑ HR (↓ arterial pressure.) ↑HR: in pediatric or by vagolytic drugs ↓HR: in neonates & geriatric or by opioids . VA reserver baroreceptor reflex than the

old VA

Rapid increase in the spired DES> 1MAC : transient ↑ in HR & arterial pressure (sympathetic nervous system).

The cardiovascular stimulation by rapid increase in DES or ISO:

activation of tracheopulmonary & systemic receptors

pretreatment by ß1-adrenoceptor antagonists, a2- adrenoceptor agonists, or opioids.

SEVO In contrast to ISO and DES:

not alter HR or cardiovascular stimulation in rapid ↑MAC.

↓ arterial BP & cardiovascular effect:1. H , EN:↓myocardial contractility and CO2. ISO, DES, &SEVO: ↓ LV afterload. ↓SVR,maintain

CO3. ISO,DES: preserve ANS regulation 4. ↓by surgical stimulation or nitrous oxide. 5. altered by the anesthesia duration 6. ↑ myocardial contractility &CO &↓ in LV preload &

afterload occur after several hours of constant MAC . Recovery from circulatory depression in H> ISO

&DES .

The systemic hemodynamic effect of VA in the peresence of LVDysfanction are similar but not identical

altered baroreceptor reflex activity, ß1-adrenoceptor downregulation, increases in central sympathetic nervous system activity, and withdrawal of parasympathetic nervous system tone associated with heart failure.

ISO& H :↓ LV end-diastolic pressure & ↓ MAP ↓PAP

↓ LV preload and myocardial contractility, by ISO or H in the presence of preexisting LV dysfunction ↓CO

↓PAP during ISO ( in CAD ,HF) venodilation (major hemodynamic

consequence of ISO) in HF

Volatile anesthesia and cardiac electrophysiology

Cardiac conduction

VA slow the rate of SA node discharge may be altered by vasoactive drugs or

ANS . Older VA and, to a lesser extent, iso : shorten the cardiac AP. and the

effective duration of the refractory period in normal Purkinje fibers, also prolong His-Purkinje and ventricular conduction times.

1. H, en, and ISO: prolong atrioventricular conduction time and refractoriness.

2. the direct actions on SA node discharge bradycardia ,atrioventricular conduction

abnormalities. primary disturbances in atrioventricular

conduction leading to second- or third-degree AV block ,

probably do not occur with VA in the absence of conduction disease or drugs that directly prolong the atrioventricular conduction time.

arrhythmogenic or antiarrhythmogenic

cardioprotective against VF produced by coronary artery occlusion and reperfusion

Protective effects against ouabain-induced arrhythmias BY the older volatile agent.

antiarrhythmic effects by opposing subsidiary pacemaker activity in infarcted myocardium.

H ,to a lesser exent, ISO may be arrhythmogenic in Purkinje fibers in experimental myocardial infarction by facilitating reentrant activity or increasing temporal dispersion of refractory period recovery.

Inhibition of the slow Na+ current in false tendon fibers and induction of reentry of premature impulses into more refractory Purkinje fibers in the border zone of an ischemic area.

H,EN, ISO:↑ QTc . (torsades de point)

Epinephrine-Induced Arrhythmias

VA sensitize myocardium to the arrhythmogenic effects of EPI:

↓ threshold for both atrial and ventricular arrhythmias.

escalating doses of EPI produce PVC and sustained VT during H.

pretreatment with sodium thiopental,( effects on the AV node or the upper His bundle).

the pathogenesis of H- EPI–arrhythmias: a1- and ß-adrenoceptors Stimulation of the a1A-adrenoceptor in

the His-Purkinje transiently slows Purkinje fiber conduction.

mediated by phospholipase C and the intracellular second messenger inositol triphosphate.

The doses of EPI to produce ventricular arrhythmias during

DES = SEV < ISO and H

Hal-catecholamine sensitization promotes abnormal automaticity of the dominant and latent atrial pacemakers( produce PVC and arrhythmias originating from the His bundle).

Intact SA node:1. ↓the incidence EPI-HA ventricular scape 2. Protective against HIS bundle arrhythmias

Volatile Anesthetics and the Coronary Circulation

Coronary vascular effects in vitro

Direct vasodilation in vitro indirect: alter of (MVO2), including HR,

preload, afterload,& inotropic state, by these anesthetics cause coronary vasoconstriction via metabolic autoregulation.

CBF are affected by↓ in coronary perfusion pressure.

H>ISO coronary artery dilation at similar MAC

the combination of direct and indirect actions determines the net effect of VA on coronary vascular tone

Hal> ISO coronary artery dilation at similar MAC in isolated coronary arteries larger than 2000 μm. ( more suppression of the voltage-dependent Ca2+ current.)

In contrast, ISO: vasodilation of small (<900 μm) canine epicardial coronary arteries

Coronary Vascular Effects in Vivo

HALOTHANE ↓ MVO2 ,↓ CBF, maintenance or↑ CVR . ↑coronary sinus O2 tension &↓O2extraction

→ H is a relatively weak coronary vasodilator.

ISO: ↓ MVO2 &↓ O2 extraction, & direct coronary

vasodilation. & mild, transient ↑ in blood flow independent of changes in MVO2 and ANS

adenosine >ISO vasodilation in coronary micro vessels

Desflurane = isoflurane ↑O2 delivery to consumption , ↓O2

extraction. ↑CBF by DES( but not by ISO) : were attenuated by blockade of the

ANS ISO > DES direct coronary

vasodilatation SEVO not coronary vasodilation.

Coronary Vasodilator Reserve and Autoregulation

coronary vasodilator reserve= the ratio of peak CBF after brief

coronary artery occlusion (reactive hyperemia) to baseline flow.

Coronary vasodilator reserve ISO >H coronary vasodilator H>ISO ↓ MVO2 H > ISO

Dilation of coronary arteriolar resistance vessels altered pressure autoregulation of coronary .

ISO>HA alterations in autoregulation

VA impaired coronary autoregulation, but not as same as adenosine or dipyridamole

In contrast to VA, these drugs cause maximal coronary vasodilation and inhibit pressure autoregulation that CBF becomes directly dependent on coronary perfusion pressure.

Thus VA are weak coronary vasodilators.

Mechanisms of

Volatile Anesthetic–Induced Coronary Vasodilation

The coronary vasodilating of VA are probably not related to nitric oxide (NO).

direct coronary vasodilator by affecting

ca intera celluar and Inhibit G proteins linked to

phospholipase c ↓inositol triphosphat

ISO and H : coronary vasodilation by activation of

adenosine triphosphate (ATP)-sensitive potassium (KATP) channels.(GLYBURIDE)

coronary vasodilation by ISO: stimulation of A1(adenosine) receptors

(by ↓CVR)coupled to KATP channels.

Volatile Anesthetics and Ischemic Myocardium

Iso and hal1. ↓subendocardial blood flow and myocardial

lactate extraction, produced contractile dysfunction

2. caused electrocardiographic changes in the presence of coronary stenosis

3. declines in coronary perfusion pressure. Regional ischemia during iso- or hal-induced ↓

perfusion pressure was indicated by paradoxical systolic lengthening and postsystolic shortening.

Contractile dysfunction in the region distal to a critical coronary stenosis by iso> hal ( higher flow in the normal zone and lower flow in the ischemic zone.)

the coronary vasodilation by iso :redistribution of coronary blood flow away from ischemic myocardium if hypotension is allowed to occur (“coronary steal”).

these adverse effects of VA on ischemic myocardium were avoided if coronary perfusion pressure was restored.

treatment of hypotension with phenylephrine restored subendocardial blood flow.

Administration of phenylephrine to maintain arterial pressure constant increased subepicardial blood flow more than subendocardial flow.

Restoration of coronary perfusion pressure to baseline levels during iso increased coronary collateral blood flow and normalized myocardial oxygen tension in the ischemic zone.

These effects of volatile anesthetics were in stark contrast to those obtained with adenosine, a potent coronary vasodilator that produces coronary steal when arterial pressure is maintainedat control levels in models of multivessel coronary artery disease.

Volatile Anesthetic–Induced Myocardial Protection

Acute Preconditioning by Volatile Anesthetics

The controversy about volatile anesthetic–induced coronary vasodilation and coronary steal has detracted from substantial experimental evidence indicating that volatile anesthetics exert important protective effects during myocardial ischemia and reperfusion injury.

The older anesthetic halothane attenuated ST-segment changes caused by brief coronary artery occlusion and decreased ST-segment elevation to a greater extent than propranolol and sodium nitroprusside did despite producing similar hemodynamic effects.

Iso and des :beneficial actions on LV diastolic mechanics during acute regional myocardial ischemia.

Iso and sevo:↓myocardial reperfusion injury and improved functional recovery after global ischemia in isolated hearts.

VA also enhanced systolic functional recovery of postischemic-

reperfused (“stunned”) myocardium when these anesthetics were administered before brief periods of myocardial ischemia in vivo.

VA have been shown to attenuate the effect of oxygen-derived free radicals on development of LV pressure in isolated hearts.

Halothane also preserved contractile function and ultrastructural integrity during reperfusion after normothermic cardioplegic arrest.

administration of halothane or isoflurane before prolonged coronary artery occlusion and reperfusion reduces myocardial infarct size in vivo

Termed “anesthetic preconditioning,” this beneficial effect was found to persist despite

discontinuation of VA before coronary artery occlusion. This short-term memory phase was similar to that observed during ischemic preconditioning.

VA: effects on blood flow to and neutrophil

interaction with ischemic myocardium. VA produce coronary vasodilation: by1. activating KATP channels 2. affecting intracellular Ca2+ homeostasis Decreases in collateral blood flow after

coronary artery occlusion , to be less pronounced than declines in flow to normal myocardium in the presence of the older agent halothane.

↑ The ratio of myocardial O2 delivery to MVO2 in collateral-dependent myocardium by HA.

Halothane inhibited platelet thrombi formation via increases in platelet cyclic adenosine monophosphate concentration and thereby decreased cyclic variations in coronary blood flow associated with a critical coronary artery stenosis.

actions of VA on coronary perfusion and neutrophil function may be responsible for the protection against ischemia-reperfusion injury .

The effects of VA: ↓in the myocardial oxygen demand

required for active contraction along with concomitant preservation of energydependent vital cellular processes because VA cause direct negative inotropic, lusitropic, and chronotropic effects and decrease LV afterload.

Iso and hal: lower excessive intracellular Ca2+ during reperfusion

direct decline in the net transsarcolemmal Ca2+ transient resulting from partially inhibited Ca2+ channel activity

indirect reduction of oxygen-derived free radical formation

cardioprotection by volatile anesthetics occurs as a consequence of the activation of endogenous signal transduction pathways.