Slide 1 : IVMS 2004-2008 1 IVMS Cardiovascular Pharmacology Lecture Topics discussed:
Antihypertensive Drugs
Drugs for Angina
ACE Inhibitors
Calcium Channel
Blockers
Adrenergic Blockers
Cardiac Glycosides Prepared and Presented by:
Marc Imhotep Cray, M.D. Companion:
IVMS Heart and Circulation Lecture
An Integrated Basic Medical Sciences
Perspective and Presentation
SEE IVMS- High Yield Autonomic Pharmacology Principles : SEE IVMS- High Yield Autonomic Pharmacology Principles IVMS 2004-2008 2
Slide 3 : IVMS 2004-2008 3 Click for reading: http://www.mfi.ku.dk/ppaulev/chapter6/chap_6.htm
Blood Pressure : IVMS 2004-2008 4 Blood Pressure
Antihypertensive Drugs : Antihypertensive Drugs Antihypertensive Agents
Autonomic Nervous System and Blood Pressure ControlSee: IVMS Heart and Circulation Lecture : IVMS 2004-2008 6 Autonomic 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)
Neural Control of the CVS: The Autonomic Nervous System : IVMS 2004-2008 7 Spinal Cord Brain Stem Carotid Sinus Parasympathetic
(Vagus) Sympathetic ?-Adrenoceptor ?-Adrenoceptor Vasomotor
Center Higher Centers Neural Control of the CVS: The Autonomic Nervous System Arteriole
Baroreceptor Reflexes in BP Control : IVMS 2004-2008 8 Parasympathetic Sympathetic Baroreceptor Reflexes in BP Control ? BP 1
Baroreceptor Reflexes in BP Control : IVMS 2004-2008 9 Carotid sinus
senses ? BP Parasympathetic Sympathetic 2 Baroreceptor Reflexes in BP Control ? BP 1
Baroreceptor Reflexes in BP Control : IVMS 2004-2008 10 Carotid sinus
senses ? BP Parasympathetic Sympathetic Vasomotor Center responds
with ? Symp. NS activity
and ? Parasymp. activity 2 3 Baroreceptor Reflexes in BP Control ? BP 1
Baroreceptor Reflexes in BP Control : IVMS 2004-2008 11 Carotid sinus
senses ? BP Parasympathetic Sympathetic ? PVR ? Heart rate
and contractility Vasomotor Center responds
with ? Symp. NS activity
and ? Parasymp. activity 2 3 4 4 Baroreceptor Reflexes in BP Control ? BP 1
Baroreceptor Reflexes in BP Control : IVMS 2004-2008 12 Carotid sinus
senses ? BP Parasympathetic Sympathetic ? PVR ? Heart rate
and contractility Vasomotor Centre responds
with ? Symp. NS activity
and ? Parasymp. activity Baroreceptor Reflexes in BP Control ? BP 2 3 4 4 5 ? BP 1
Blood Pressure Control: Control of Stroke Volume : IVMS 2004-2008 13 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 Volume
Stroke volume (SV) : IVMS 2004-2008 14 Stroke 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. 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.
Factors Determining Stroke Volume : IVMS 2004-2008 15 Factors Determining Stroke Volume Contractility
? sympathetic activity increases contractility
End-diastolic volume
Determined by venous filling pressure (distensible ventricle) Blood Pressure Control:
Control of Stroke Volume
Venous filling pressure and stroke volume : IVMS 2004-2008 16 Venous filling pressure and stroke volume The Frank-Starling relationship Stroke Volume End diastolic volume (filling pressure) Output increases with increased filling pressure Overdistended,output falls Blood Pressure Control:
Control of Stroke Volume
What determines venous filling pressure? : IVMS 2004-2008 17 What determines venous filling pressure? Blood volume, mostly contained in a distensible venous circulation! Blood Pressure Control:
Control of Stroke Volume
Blood Pressure Control: Renin-Angiotensin : IVMS 2004-2008 18 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-Angiotensin
Slide 19 : IVMS 2004-2008 19 The Renin-Angiotensin System Renin
(Circulating) Liver Angiotensin Precursor
(Circulating) Angiotensin I AT1 Receptor Aldosterone from
adrenal cortex SENSOR IN
KIDNEY Vasoconstriction Na+ Retention
K+ Excretion Angiotensin II OUTCOMES
Antihypertensive Drug Strategies : IVMS 2004-2008 20 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
Calcium Channel Blocking Drugs : (Also have uses in treating cardiac rhythm disturbances & angina) Calcium Channel Blocking Drugs Calcium-channel blockers (CCBs)
Membrane Ca2+ Channels : IVMS 2004-2008 22 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)
Effect of Ca2+ Influx: Muscle Contraction : IVMS 2004-2008 23 Effect of Ca2+ Influx: Muscle Contraction Ca2+ Channel Sarcoplasmic
Reticulum Actin & Myosin Ca2+ Ca2+ “Trigger” ? contraction (myocardial or vascular) Plasma Membrane
Ca2+ Channel Blockers : IVMS 2004-2008 24 Ca2+ Channel Blockers Cardioselective
verapamil Vascular selective
dihydropyridines
nifedipine
felodipine
amlodipine Non-selective
diltiazem
Ca2+ Channel Blockers : IVMS 2004-2008 25 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
?1 Adrenoceptor Antagonists : ?1 Adrenoceptor Antagonists Beta-adrenoceptor antagonists (beta-blockers)
Cardiac ?1 Adrenoceptor Stimulation : IVMS 2004-2008 27 Cardiac ?1 Adrenoceptor Stimulation ? Heart rate
? contractility ?? blood pressure
?? heart work
Cardiac ?1 Adrenoceptor Blockade : IVMS 2004-2008 28 Cardiac ?1 Adrenoceptor Blockade ? Heart rate
? contractility ? ? blood pressure
? ? heart work
Cardiac ?1 Adrenoceptor Blockers : IVMS 2004-2008 29 Cardiac ?1 Adrenoceptor Blockers Metoprolol
Atenolol
Cardiac ?1 Adrenoceptor Blockers: Clinical Uses : IVMS 2004-2008 30 Cardiac ?1 Adrenoceptor Blockers: Clinical Uses Antiarrhythmic (slows some abnormal fast rhythms)
Antihypertensive
Antiangina: via reduced heart work
Blockade of Renin-Angiotensin-Aldosterone System : IVMS 2004-2008 31 Blockade of Renin-Angiotensin-Aldosterone System Angiotensin converting enzyme (ACE) inhibitors
Angiotensin II receptor (AT1) antagonists
Renin-angiotensin system : IVMS 2004-2008 32 Renin-angiotensin system Renin Liver Angiotensin Precursor Angiotensin I Angiotensin II Angiotensin Converting Enzyme AT1 Receptor Renal Blood Flow
Na+ load Aldosterone Vasoconstriction Na+ Retention
K+ Excretion
Angiotensin Converting Enzyme (ACE) Inhibitors : IVMS 2004-2008 33 Angiotensin Converting Enzyme (ACE) Inhibitors Captopril
Enalapril
anything else ending in -pril
(lisinopril, trandolapril, fosinopril, perindopril, quinapril, etc)
AT1 Blockers (ARB’s) : IVMS 2004-2008 34 AT1 Blockers (ARB’s) Candesartan,
irbesartan,
others ending in -sartan
ACE-Inhibitors & AT1 Blockers: Clinical Uses : IVMS 2004-2008 35 ACE-Inhibitors & AT1 Blockers: Clinical Uses ? reduced vascular resistance
? aldosterone ? ? salt & H2O retention Uses
Antihypertensive
Heart failure
?1 Adrenoceptor Blockers : IVMS 2004-2008 36 ?1 Adrenoceptor Blockers Alpha-adrenoceptor antagonists (alpha-blockers)
Neural Control of Circulation: Autonomic NS : IVMS 2004-2008 37 Neural Control of Circulation: Autonomic NS Spinal Cord Brain Stem Carotid Sinus Parasympathetic
(Vagus) Sympathetic ?1-Adrenoceptor ?-Adrenoceptor Vasomotor
Center Higher Centers
?1 Adrenoceptor Blockers : IVMS 2004-2008 38 ?1 Adrenoceptor Blockers Peripheral vasodilator ? ? vascular resistance
Agents:
Prazosin
Volume Reduction : IVMS 2004-2008 39 Volume Reduction See “Diuretics” lecture
Reduces cardiac filling pressure
Thus reduces stroke volume and cardiac output
Clinical Use of Antihypertensives : IVMS 2004-2008 40 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
Drug Treatment of Angina : Drug Treatment of Angina Antianginal
What is Angina and Why Does it Happen? : IVMS 2004-2008 42 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.
Ischaemia (O2 deficiency) causes pain: “angina” What is Angina and Why Does it Happen?
Determinants of Heart Work : IVMS 2004-2008 43 Determinants of Heart Work Heart work determined by:
Heart rate
Cardiac contractility
Peripheral resistance
See: Antihypertensive Agents
Physiological Factors Influencing Arterial Pressure for full discussion
Drug Treatment of Angina: Limiting Heart Work : IVMS 2004-2008 44 Reduce heart rate and contractility
? adrenoceptor blockers
Ca2+ channel blockers (verapamil and diltiazem)
Dilate resistance vessels
Ca2+ channel blockers (nifedipine, felodipine, amlodipine)
Nitrates Drug Treatment of Angina: Limiting Heart Work
Nitrates : IVMS 2004-2008 45 Nitrates Glyceryl trinitrate (GTN)
Isosorbide (di)nitrate
Slide 46 : IVMS 2004-2008 46 GTN NO2- OrganicNitrate
Ester Reductase R-SH R-SH NO Nitrosothiols (R-SNO) Guanylate Cyclase + GTP cGMP Protein Kinase G RELAXATION Vascular Smooth Muscle Cell See :
Nitrates, Digoxin and Calcium Channel Blockers
Dr. Paul Forrest
Royal Prince Alfred Hospital
Nitrous Oxide and Vasodilation : IVMS 2004-2008 47 Nitrous Oxide and Vasodilation After 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 Therapy
ROBERT J. LUNN, M.D.
From the Department of Anesthesiology, Mayo Clinic Rochester, Rochester, Minnesota.
http://www.mayoclinicproceedings.com/inside.asp?ref=7003sc
Use of Nitrates : IVMS 2004-2008 48 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 the chest pain (angina) that happens during exercise when there is coronary artery obstruction.
Not used for managing chronic high blood pressure
Digitalis purpurea (Foxglove)Cardiostimulatory : IVMS 2004-2008 49 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
Cardiac Glycosides: Digoxin : IVMS 2004-2008 50 Cardiac Glycosides: Digoxin
Digoxin Mechanism of Action : IVMS 2004-2008 51 Digoxin Mechanism of Action
Digoxin blocks Na+/K+ ATP’ase : IVMS 2004-2008 52 Digoxin blocks Na+/K+ ATP’ase ATP’ase Mg2+ K+ ATP’ase Mg2+ Dig ? less efficient Na+/K+ exchange
? diminished Na+ gradient
? diminished K+ gradient
Digoxin increases intracellular Ca2+ : IVMS 2004-2008 53 Digoxin increases intracellular Ca2+ diminished Na+ gradient ? ? intracellular Ca2+
Effect of ? [Ca2+]i : IVMS 2004-2008 54 Effect of ? [Ca2+]i Na+/K+ ATP’ase Ca2+ channel Sarcoplasmic
Reticulum Actin & Myosin Na+/Ca2+ antiporter ? ? contractility Na+ K+ Ca2+ Ca2+ “Trigger” Na+ Na+ K+ Ca2+
Digoxin Effects on Rhythm : IVMS 2004-2008 55 Digoxin Effects on Rhythm Therapeutic
? Vagus nerve activity
Slower heart rate
Slower AV conduction
Toxic
Various abnormal rhythms
Uses of Digoxin : IVMS 2004-2008 56 Uses of Digoxin Atrial fast arrhythmias: slows rate
Heart Failure: increases contractile strength
Slide 57 : IVMS 2004-2008 57 Companion:
IVMS Heart and Circulation Lecture
An Integrated Basic Medical Sciences
Perspective and Presentation
Reference resource for further study:
Cardiovascular Pharmacology Concepts