Cardiovascular Pharmacology Global Overview/Review Topics discussed: Autonomic Nervous System and Blood Pressure Control eNotes: Cardiovascular Pharmacology
Antihypertensive Drugs Drugs for Angina
ACE Inhibitors Calcium Channel Blockers Prepared and presented by: Marc Imhotep Cray, M.D.
Adrenergic Blockers Cardiac Glycosides
Blood Pressure
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Blood Pressure(2)
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Autonomic Nervous System and Blood Pressure Control • 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)
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Neural Control of the CVS: Autonomic Nervous System Higher Centers Vasomotor Center
Carotid Sinus Brain Stem
Parasympathetic (Vagus) ď ˘-Adrenoceptor
Spinal Cord
Sympathetic ď Ą-Adrenoceptor Arteriole
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Baroreceptor Reflexes in BP Control
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ď‚Ż BP
Parasympathetic
Sympathetic
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Baroreceptor Reflexes in BP Control 2
1
BP
Carotid sinus senses BP
Parasympathetic
Sympathetic
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Baroreceptor Reflexes 1 BP in BP Control Vasomotor Center responds with Symp. NS activity 3 and Parasymp. activity
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Carotid sinus senses BP
Parasympathetic
Sympathetic
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Baroreceptor Reflexes in BP Control 3
Vasomotor Center responds with Symp. NS activity and Parasymp. activity
1
2
BP
Carotid sinus senses BP
Parasympathetic
4
Sympathetic
Heart rate and contractility
4 PVR 9
Baroreceptor Reflexes in BP Control Vasomotor Centre responds with Symp. NS activity 3 and Parasymp. activity
2
1
BP
Carotid sinus senses BP
Parasympathetic
4
Sympathetic
Heart rate and contractility
4 PVR
5
BP 10
Blood Pressure Control: Control of Stroke Volume •
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)
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Stroke volume (SV) • Stroke volume (SV) is volume of blood pumped by right/left ventricle of heart in one contraction • Specifically, it is volume of blood ejected from ventricles during systole Calculation Its value is obtained by subtracting end-systolic volume (ESV) from end-diastolic volume (EDV) for a given ventricle: SV = EDV − ESV In 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.
• SV is not all of blood contained in left ventricle • Normally, only about twothirds of blood in ventricle is put out with each beat • What blood is actually pumped from left ventricle is stroke volume and it, together with heart rate, determines the cardiac output 12
Blood Pressure Control: Control of Stroke Volume Factors Determining Stroke Volume • Contractility – sympathetic activity increases contractility
• End-diastolic volume – Determined by venous filling pressure (distensible ventricle) 13
Blood Pressure Control:
Stroke Volume
Control of Stroke Volume Venous filling pressure and stroke volume • The Frank-Starling relationship Output increases with increased filling pressure
Overdistended, output falls
End diastolic volume (filling pressure) 14
Blood Pressure Control: Control of Stroke Volume What determines venous filling pressure? • Blood volume, mostly contained in a distensible venous circulation!
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Blood Pressure Control: Renin-Angiotensin • 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)
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Renin-Angiotensin System Liver
SENSOR IN KIDNEY
Angiotensin Precursor (Circulating) Renin (Circulating) Angiotensin I OUTCOMES
Angiotensin II Vasoconstriction Na+ Retention K+ Excretion
Aldosterone from adrenal cortex
AT1 Receptor 17
BP Control Mechanisms Summary 18
Antihypertensive Drugs
See Antihypertensive Agents
Antihypertensive Drug Strategies • Reduce cardiac output – -adrenergic blockers – Ca2+ Channel blockers
• Dilate resistance vessels – Ca2+ Channel blockers – Renin-angiotensin system blockers – 1 adrenoceptor blockers – Nitrates**
• Reduce vascular volume – diuretics 20
Calcium Channel Blocking Drugs Calcium-channel blockers (CCBs)
(Also have uses in treating cardiac rhythm disturbances & angina)
Membrane Ca2+ Channels • • • •
All cells, voltage or ligand-gated, several types [Ca2+]e 2.5mM [Ca2+]i 100nM (maintained by Na+/Ca2+ antiport) [Ca2+]i Signaling Actin-myosin interaction Myocardial membrane depolarization (Phase 2) 22
Effect of Ca2+ Influx: Muscle Contraction Ca2+ Channel
Ca2+
Plasma Membrane “Trigger”
Sarcoplasmic Reticulum
Ca2+
Ca2+
contraction (myocardial or vascular)
Actin & Myosin 23
Ca2+ Channel Blockers • Cardioselective – verapamil • Non-selective – diltiazem
• Vascular selective – dihydropyridines • nifedipine • felodipine • amlodipine
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Ca2+ 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 25
ď ˘1 Adrenoceptor Antagonists Beta-adrenoceptor antagonists (beta-blockers)
Cardiac 1 Adrenoceptor Stimulation • Heart rate • contractility blood pressure heart work
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Cardiac 1 Adrenoceptor Blockade • Heart rate • contractility blood pressure heart work
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Cardiac 1 Adrenoceptor Blockers • Metoprolol • Atenolol
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Cardiac 1 Adrenoceptor Blockers: Clinical Uses • Antiarrhythmic (slows some abnormal fast rhythms) • Antihypertensive • Antiangina: via reduced heart work
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Blockade of Renin-AngiotensinAldosterone System (RAAS) 1. Angiotensin converting enzyme (ACE) inhibitors 2. Angiotensin II receptor (AT1) antagonists
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Renin-angiotensin system Liver
Renal Blood Flow Na+ load
Angiotensin Precursor Renin Angiotensin I Angiotensin Converting Enzyme Angiotensin II
Vasoconstriction Na+ Retention K+ Excretion
Aldosterone
AT1 Receptor
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Angiotensin Converting Enzyme (ACE) Inhibitors • Captopril • Enalapril • anything else ending in -pril – (lisinopril, trandolapril, fosinopril, perindopril, quinapril, etc)
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AT1 Blockers (ARB’s) • Candesartan, • irbesartan, • others ending in -sartan
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ACE-Inhibitors & AT1 Blockers: Clinical Uses • reduced vascular resistance • aldosterone salt & H2O retention
Uses • Antihypertensive • Heart failure 35
ď Ą1 Adrenoceptor Blockers Alpha-adrenoceptor antagonists (alpha-blockers)
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Neural Control of Circulation: Autonomic NS Higher Centers Vasomotor Center
Carotid Sinus Brain Stem
Parasympathetic (Vagus) ď ˘-Adrenoceptor
Spinal Cord
Sympathetic ď Ą1-Adrenoceptor 37
1 Adrenoceptor Blockers • Peripheral vasodilator vascular resistance • Agents: – Prazosin
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Volume Reduction • Reduces cardiac filling pressure (LVEDV/P) • Thus reduces stroke volume and cardiac output • Independent vascular relaxation with long term use
See Diuretics eNotes 39
Clinical 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 BP 40
Drug Treatment of Angina Antianginal Agents
What is Angina and Why Does it Happen? • 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 demands of myocardium at rest, but not when heart work increased by exercise, etc. – Ischemia (O2 deficiency) causes pain: “angina”
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Determinants of Heart Work •
Heart work determined by: 1. Heart rate 2. Cardiac contractility 3. Peripheral resistance See: Antihypertensive Agents Physiological Factors Influencing Arterial Pressure for full discussion
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Drug Treatment of Angina: Limiting Heart Work • Reduce heart rate and contractility – adrenoceptor blockers – Ca2+ channel blockers (verapamil and diltiazem)
• Dilate resistance vessels – Ca2+ channel blockers (nifedipine, felodipine, amlodipine) – Nitrates 44
Nitrates • Glyceryl trinitrate (GTN)
• Isosorbide (di)nitrate
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GTN
Vascular Smooth Muscle Cell R-SH
OrganicNitrate
NO2
-
R-SH
NO
Nitrosothiols (R-SNO)
Ester Reductase
+ See : Nitrates, Digoxin and Calcium Channel Blockers Dr. Paul Forrest Royal Prince Alfred Hospital
cGMP RELAXATION
Guanylate Cyclase
GTP
Protein Kinase G
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Nitric Oxide and Vasodilation After receptor stimulation, Larginine-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 Therapy ROBERT J. LUNN, M.D. http://www.mayoclinicproceedings.com/inside. asp?ref=7003sc
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Use 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 chest pain (angina) that happens during exercise when there is coronary artery obstruction. • Not used for managing chronic high blood pressure 48
Digitalis purpurea (Foxglove) Cardiostimulatory
Medicines 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/Digitalis 49
Cardiac Glycosides: Digoxin
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Digoxin Mechanism of Action Na+/K+ ATPase
Outside
Na+ Ca2+
Na+
Na+
Inside K+
Channels
K+
Pump
Ca2+ Exchanger
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Digoxin blocks Na+/K+ ATP’ase P
P
Mg2+ ATP’ase
K+
Mg2+ ATP’ase Dig
less efficient Na+/K+ exchange diminished Na+ gradient diminished K+ gradient 52
Digoxin increases intracellular Ca2+ Na+
K+
Pump
Na+
Ca2+ Exchanger
diminished Na+ gradient ď‚Ž ď‚ intracellular Ca2+
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Effect of [Ca2+]i Na+/Ca2+ antiporter Na+/K+ ATP’ase
+ + K NaNa + + Ca2+ K
Na+
Ca2+ channel
Ca2+ “Trigger”
Sarcoplasmic Reticulum
Ca2+
Ca2+
contractility Actin & Myosin 54
Digoxin Effects on Rhythm Therapeutic • Vagus nerve activity – Slower heart rate – Slower AV conduction
Toxic • Various abnormal rhythms 55
Uses of Digoxin • Atrial fast arrhythmias: slows rate • Heart Failure: increases contractile strength
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Reference Resource
Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Cairo CW, Simon JB, Golan DE. (Eds.); LLW 2012
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