IVMS-CV -Cardiovascular Pharmacology-Global Review

IVMS 2004-20081IVMSCardiovascular PharmacologyLectureTopics discussed:Antihypertensive DrugsDrugs for AnginaACE InhibitorsCalcium ChannelBlockers Adrenergic BlockersCardiac GlycosidesPrepared and Presented by: Marc Imhotep Cray, M.D.Companion:IVMS Heart and Circulation LectureAn Integrated Basic Medical Sciences Perspective and PresentationIVMS 2004-20082Click for reading: http://www.mfi.ku.dk/ppaulev/chapter6/chap_6.htmIVMS 2004-20083Blood PressureAntihypertensive DrugsAntihypertensiveAgentsIVMS 2004-20085Autonomic Nervous System and Blood Pressure ControlSee: IVMS Heart and Circulation Lecture•Cardiac Output (Output of Pump)–heart rate x stroke volume•Caliber of Arteries & Arterioles •(Flow Resistance)–Neural•sympathetic & parasympathetic NS –Hormonal•Renin-angiotensin-aldosterone system–Local transmitters•Nitric Oxide (NO)IVMS 2004-20086Spinal CordBrain StemCarotid SinusParasympathetic(Vagus)Sympathetic-Adrenoceptor-AdrenoceptorVasomotorCenterHigher CentersNeural Control of the CVS: The Autonomic Nervous SystemArterioleIVMS 2004-20087ParasympatheticSympatheticBaroreceptor Reflexes in BP ControlBP1IVMS 2004-20088Carotid sinussenses BPParasympatheticSympathetic2Baroreceptor Reflexes in BP ControlBP1IVMS 2004-20089Carotid sinussenses BPParasympatheticSympatheticVasomotor Center respondswith Symp. NS activityand Parasymp. activity23Baroreceptor Reflexes in BP ControlBP1IVMS 2004-200810Carotid sinussenses BPParasympatheticSympatheticPVRHeart rate and contractilityVasomotor Center respondswith Symp. NS activityand Parasymp. activity2344Baroreceptor Reflexes in BP ControlBP1IVMS 2004-200811Carotid sinussenses BPParasympatheticSympatheticPVRHeart rate and contractilityVasomotor Centre respondswith Symp. NS activityand Parasymp. activityBaroreceptor Reflexesin BP ControlBP23445BP1IVMS 2004-200812•Cardiac Output (Output of Pump)–heart rate x stroke volume•Caliber of Arteries & Arterioles (Flow Resistance)–Neural•sympathetic & parasympathetic NS –Hormonal•Renin-angiotensin-aldosterone system–Local transmitters•Nitric Oxide (NO)Blood Pressure Control:Control of Stroke VolumeIVMS 2004-200813Stroke volume (SV)•Stroke volume (SV) is the volume of blood pumped by the right/left ventricle of the heart in one contraction. •Specifically, it is the volume of blood ejected from ventricles during systole.•The stroke volume is not all of the blood contained in the left ventricle. •Normally, only about two-thirds of the blood in the ventricle is put out with each beat. What blood is actually pumped from the left ventricle is the stroke volume and it, together with the heart rate, determines the cardiac output.CalculationIts value is obtained by subtracting end-systolic volume(ESV) from end-diastolic volume(EDV) for a given ventricle:SV= EDV− ESVIn a healthy 70-kg man, the left ventricular EDV is 120 ml and the corresponding ESV is 50 ml, giving a stroke volume of 70 ml.IVMS 2004-200814Factors Determining Stroke Volume•Contractility–sympathetic activity increases contractility•End-diastolic volume–Determined by venous filling pressure (distensible ventricle) Blood Pressure Control: Control of Stroke VolumeIVMS 2004-200815Venous filling pressure andstroke volume•The Frank-Starling relationshipStroke VolumeEnd diastolic volume (filling pressure)Output increases with increased filling pressureOverdistended,output fallsBlood Pressure Control: Control of Stroke VolumeIVMS 2004-200816What determines venous filling pressure?•Blood volume, mostly contained in a distensible venous circulation!Blood Pressure Control: Control of Stroke VolumeIVMS 2004-200817•Cardiac Output (Output of Pump)–heart rate x stroke volume•Caliber of Arteries & Arterioles (Flow Resistance)–Neural•sympathetic & parasympathetic NS –Hormonal•Renin-angiotensin-aldosterone system–Local transmitters•Nitric Oxide (NO)Blood Pressure Control:Renin-AngiotensinIVMS 2004-200818The Renin-Angiotensin SystemRenin(Circulating)LiverAngiotensin Precursor(Circulating)Angiotensin IAT1ReceptorAldosterone fromadrenal cortexSENSOR INKIDNEYVasoconstrictionNa+RetentionK+ExcretionAngiotensin IIOUTCOMESIVMS 2004-200819Antihypertensive Drug Strategies•Reduce cardiac output–-adrenergic blockers–Ca2+Channel blockers•Dilate resistance vessels–Ca2+Channel blockers–Renin-angiotensin system blockers–1adrenoceptor blockers–Nitrates**•Reduce vascular volume–diuretics(Also have uses in treating cardiac rhythm disturbances & angina)Calcium Channel Blocking DrugsCalcium-channel blockers (CCBs)IVMS 2004-200821Membrane Ca2+Channels•All cells, voltage or ligand-gated, several types•[Ca2+]e2.5mM •[Ca2+]i100nM (maintained by Na+/Ca2+antiport)•[Ca2+]iSignalingActin-myosin interactionMyocardial membrane depolarization (Phase 2)IVMS 2004-200822Effect of Ca2+Influx:Muscle ContractionCa2+ChannelSarcoplasmicReticulumActin & MyosinCa2+Ca2+“Trigger”contraction (myocardial or vascular)Plasma MembraneCa2+IVMS 2004-200823Ca2+ Channel Blockers•Cardioselective–verapamil•Vascular selective–dihydropyridines•nifedipine•felodipine•amlodipine•Non-selective–diltiazemIVMS 2004-200824Ca2+ Channel Blockers•Myocardial selective:–Reduce cardiac contractility–Also reduce heart rate (action on heart rhythm)•BP, heart work•Vascular smooth muscle selective–Reduce vascular resistance •BP, heart work1Adrenoceptor AntagonistsBeta-adrenoceptor antagonists (beta-blockers)IVMS 2004-200826Cardiac 1AdrenoceptorStimulation•Heart rate•contractilityblood pressureheart workIVMS 2004-200827Cardiac 1Adrenoceptor Blockade•Heart rate•contractilityblood pressureheart workIVMS 2004-200828Cardiac 1 Adrenoceptor Blockers•Metoprolol•AtenololIVMS 2004-200829Cardiac 1 Adrenoceptor Blockers:Clinical Uses•Antiarrhythmic (slows some abnormal fast rhythms)•Antihypertensive•Antiangina: via reduced heart workIVMS 2004-200830Blockade of Renin-Angiotensin-Aldosterone System1.Angiotensin converting enzyme (ACE) inhibitors2.Angiotensin II receptor (AT1) antagonistsIVMS 2004-200831Renin-angiotensin systemReninLiverAngiotensin PrecursorAngiotensin IAngiotensin IIAngiotensin Converting EnzymeAT1ReceptorRenal Blood FlowNa+loadAldosteroneVasoconstrictionNa+RetentionK+ExcretionIVMS 2004-200832Angiotensin Converting Enzyme (ACE) Inhibitors•Captopril•Enalapril•anything else ending in -pril –(lisinopril, trandolapril, fosinopril, perindopril, quinapril, etc)IVMS 2004-200833AT1Blockers (ARB’s)•Candesartan,•irbesartan,•others ending in -sartanIVMS 2004-200834ACE-Inhibitors & AT1Blockers: Clinical Uses•reduced vascular resistance•aldosterone salt & H2O retentionUses•Antihypertensive•Heart failureIVMS 2004-2008351Adrenoceptor BlockersAlpha-adrenoceptor antagonists (alpha-blockers)IVMS 2004-200836Neural Control of Circulation: Autonomic NSSpinal CordBrain StemCarotid SinusParasympathetic(Vagus)Sympathetic1-Adrenoceptor-AdrenoceptorVasomotorCenterHigher CentersIVMS 2004-2008371Adrenoceptor Blockers•Peripheral vasodilator vascular resistance•Agents:–PrazosinIVMS 2004-200838Volume Reduction•See “Diuretics” lecture•Reduces cardiac filling pressure•Thus reduces stroke volume and cardiac outputIVMS 2004-200839Clinical Use of Antihypertensives•Consequences of chronic high blood pressure–heart failure–arterial disease•kidney failure•strokes•myocardial infarction (heart attack)•Aim of treatment–prevent consequences of high BPDrug Treatment of AnginaAntianginalIVMS 2004-200841•Oxygen demand depends on heart work•Coronary artery partial obstruction (due to atherosclerosis) limits blood supply to part of the myocardium•Coronary circulation can meet oxygen demandsof myocardium at rest, but not when heart work increased by exercise, etc.•Ischaemia(O2deficiency) causes pain: “angina”What is Angina and Why Does it Happen?IVMS 2004-200842Determinants of Heart Work•Heart work determined by:1.Heart rate2.Cardiac contractility3.Peripheral resistanceSee: Antihypertensive AgentsPhysiological Factors Influencing Arterial Pressure for full discussionIVMS 2004-200843•Reduce heart rate and contractility–adrenoceptor blockers–Ca2+channel blockers (verapamil and diltiazem)•Dilate resistance vessels–Ca2+channel blockers (nifedipine, felodipine, amlodipine)–NitratesDrug Treatment of Angina: Limiting Heart WorkIVMS 2004-200844Nitrates•Glyceryl trinitrate(GTN)•Isosorbide (di)nitrateIVMS 2004-200845GTNNO2-OrganicNitrateEster ReductaseR-SHR-SHNONitrosothiols (R-SNO)Guanylate Cyclase+GTPcGMPProtein Kinase GRELAXATIONVascular Smooth Muscle CellSee :Nitrates, Digoxin and Calcium Channel BlockersDr. Paul ForrestRoyal Prince Alfred HospitalIVMS 2004-200846Nitrous Oxide and VasodilationAfter receptor stimulation, L-arginine-dependent metabolic pathway produces nitric oxide (NO) or thiol derivative (R-NO). NO causes increase in cyclic guanosine monophosphate (cGMP), which causes relaxation of vascular smooth muscle.EDRF=endothelium-derived relaxing factor. From: Inhaled Nitric Oxide TherapyROBERT J. LUNN, M.D.From the Department of Anesthesiology, Mayo Clinic Rochester, Rochester, Minnesota.http://www.mayoclinicproceedings.com/inside.asp?ref=7003scIVMS 2004-200847Use of Nitrates•Very fast, short-lived vascular dilatation (Greater in venules than arterioles•lower vascular resistance means less heart work•less heart work means less need for coronary artery blood flow•therefore, nitrates help the chest pain (angina) that happens during exercise when there is coronary artery obstruction.•Not used for managing chronic high blood pressureIVMS 2004-200848Digitalis purpurea (Foxglove)CardiostimulatoryMedicines from foxgloves are called "Digitalin". The use of Digitalis purpurea extract containing cardiac glycosides for the treatment of heart conditions was first described in the English speaking medical literature by William Withering, in 1785. It is used to increase cardiac contractility (it is a positive inotrop) and as an antiarrhythmic agent to control the heart rate, particularly in the irregular (and often fast) atrial fibrillation. It is therefore often prescribed for patients in atrial fibrillation, especially if they have been diagnosed with heart failure. From: http://en.wikipedia.org/wiki/DigitalisIVMS 2004-200849Cardiac Glycosides:DigoxinIVMS 2004-200850Digoxin Mechanism of ActionOutsideInsideNa+K+Na+Ca2+Na+PumpExchangerChannelsCa2+K+Na+/K+ATPaseIVMS 2004-200851Digoxin blocks Na+/K+ATP’aseATP’asePMg2+K+ATP’asePMg2+Digless efficient Na+/K+ exchangediminished Na+gradientdiminished K+gradientIVMS 2004-200852Digoxin increasesintracellular Ca2+Na+K+Na+Ca2+PumpExchangerdiminished Na+gradient intracellular Ca2+IVMS 2004-200853Effect of [Ca2+]iNa+/K+ATP’aseCa2+channelSarcoplasmicReticulumActin & MyosinNa+/Ca2+antiportercontractilityNa+K+Ca2+Ca2+“Trigger”Na+Na+K+Ca2+Ca2+IVMS 2004-200854Digoxin Effects on RhythmTherapeutic•Vagus nerve activity–Slower heart rate–Slower AV conductionToxic•Various abnormal rhythmsIVMS 2004-200855Uses of Digoxin•Atrial fast arrhythmias: slows rate•Heart Failure: increases contractile strengthIVMS 2004-200856Companion:IVMS Heart and Circulation LectureAn Integrated Basic Medical Sciences Perspective and PresentationReference resource for further study:Cardiovascular Pharmacology Concepts