1. Pharmacology RHPT-365 Chapter 4: CardioVascular Pharmacology
By Majid Ahmad Ganaie M. Pharm., Ph.D. Assistant Professor Department of Pharmacology E mail:

2. Heart & Blood Circulation
Blood leaves each of the ventricles via a single artery, the pulmonary trunk from the right ventricle, and the aorta from
the left ventricle. Blood enters the right atrium via two large veins, the superior vena cava and inferior vena cava; it enters the left atrium via four pulmonary veins.

3. Path of blood flow through the entire cardiovascular system

4. Drugs Acting on the Cardiovascular System
Anti-hypertensive drugs  for treatment of hypertension (high blood pressure)
Anti-arrhythmic drugs  for treatment of arrhythmia
Anti-anginal drugs  for treatment of angina
Cardiotonic drugs (e.g., digoxin)  for treatment of heart failure

5. Antihypertensive drugs, Hypertension - Introduction
Hypertension is a condition that afflicts almost 1 billion people worldwide and is a leading cause of morbidity and mortality.
More than 20% of Americans are hypertensive, and one-third of these Americans are not even aware they are hypertensive. Therefore, this disease is sometimes called the "silent killer"
SBP: systolic blood pressure
DBP: diastolic blood pressure
When the left ventricle ejects blood into the aorta, the aortic pressure rises. The maximal aortic pressure following ejection is termed the systolic blood pressure (SBP)
As the left ventricle is relaxing and refilling, the pressure in the aorta falls. The lowest pressure in the aorta, which occurs just before the ventricle ejects blood into the aorta, is termed the diastolic blood pressure (DBP)
Hypertension may defined as an abnormal elevation of either SBP or DBP
*Arterial pressures less than 90/60 mmHg are considered hypotension, and therefore not normal
Stroke: sudden diminution or loss of consciousness, sensation, and voluntary motion caused by rupture or obstruction (as by a clot) of a blood vessel of the brain —called also apoplexy, brain attack, cerebrovascular accident

6. Antihypertensive drugs, Hypertension - Introduction
Causes of Hypertension: The are two basic types of hypertension:
Primary (essential) hypertension: The majority of patients (90-95%) have essential hypertension, which is a form with no identifiable underlying cause.
This form of hypertension is commonly treated with drugs in addition to lifestyle changes (e.g., exercise, proper nutrition, weight reduction, stress reduction).
Secondary hypertension: A smaller number of patients (5-10%) have secondary hypertension that is caused by an identifiable underlying condition such as renal artery disease, thyroid disease, primary hyperaldosteronism, pregnancy, etc.
Patients with secondary hypertension are best treated by controlling or removing the underlying disease or pathology, although they may still require antihypertensive drugs
Some causes of secondary hypertension:
Renal artery stenosis
Chronic renal disease
Primary hyperaldosteronism
Stress
Hyper- or hypothyroidism
Pheochromocytoma
Pre-eclampsia
Stroke: sudden diminution or loss of consciousness, sensation, and voluntary motion caused by rupture or obstruction (as by a clot) of a blood vessel of the brain —called also apoplexy, brain attack, cerebrovascular accident

7. Cardiac Output X Peripheral Resistance
Antihypertensive drugs, Introduction
Blood Pressure =
Cardiac Output X Peripheral Resistance
Each time the heart beats, a volume of blood (stroke volume “SV”) is ejected.
This stroke volume (SV), times the number of beats per minute (heart rate “HR”), equals the cardiac output (CO); i.e., CO = SV x HR
Thus cardiac output is the volume of blood being pumped by the heart, in particular by a ventricle in a minute.
Stroke volume is expressed in ml/beat and heart rate in beats/minute. Therefore, cardiac output is in ml/minute
Peripheral resistance (PR) refers to the resistance to blood flow offered by all of the systemic vasculature, excluding the pulmonary vasculature.
Mechanisms that cause vasoconstriction increase PR, and those mechanisms that cause vasodilatation decrease PR.
Therefore, patients with primary hypertension are generally treated with drugs that:
reduce blood volume (which reduces central venous pressure and cardiac output)
reduce peripheral resistance, or
reduce cardiac output by depressing heart rate and stroke volume
Stroke: sudden diminution or loss of consciousness, sensation, and voluntary motion caused by rupture or obstruction (as by a clot) of a blood vessel of the brain —called also apoplexy, brain attack, cerebrovascular accident

8. Antihypertensive drugs, Classes, the most important ones
Diuretics
Angiotensin Converting Enzyme Inhibitors (ACE inhibitors)
Angiotensin Receptor blockers
Renin Inhibitors
Calcium Channel Blockers
Potassium Channel openers
a1-adrenoceptor antagonists (a1-blockers)
Beta Blockers
a2-adrenoceptor agonists
Peripheral Vasodilators
Stroke: sudden diminution or loss of consciousness, sensation, and voluntary motion caused by rupture or obstruction (as by a clot) of a blood vessel of the brain —called also apoplexy, brain attack, cerebrovascular accident

9. Antihypertensive drugs, Classes, the most important ones
Diuretics:
Mechanism of action.
Diuretics act on the kidney to enhance sodium and water excretion  urine output by the kidney (i.e., promote diuresis)  blood volume
Reducing blood volume not only reduces central venous pressure, but even more importantly, reduces cardiac output
Examples: chlorothiazide, furosemide, amiloride
ACE inhibitors
Mechanism of action.
Dilate arteries and veins by blocking formation of angiotensin II (AII, a vasoconstrictor)  vasodilatation, thus reduces arterial pressure, preload and afterload on the heart
Promote renal excretion of sodium and water. This reduces blood volume, venous pressure and arterial pressure
Examples: captopril, enalapril
This is accomplished by altering how the kidney handles sodium. If the kidney excretes more sodium, then water excretion will also increase.
Most diuretics produce diuresis by inhibiting the re-absorption of sodium at different segments of the renal tubular system.

10. Antihypertensive drugs, Classes, the most important ones
Angiotensin Receptor blockers (ARBs)
Mechanism of action:
ARBs are receptor antagonists that block type 1 angiotensin II receptors on bloods vessels and other tissues such as the heart
These drugs have similar effects to ACE inhibitors and are used for the same indications (hypertension, heart failure)
Examples: losartan, valsartan
Renin Inhibitors
Mechanism of action:
Renin inhibitors produce vasodilation by inhibiting the activity of renin, which is responsible for stimulating angiotensin II formation
These drugs have similar effects to ACE inhibitors and ARBs and are used for the same indications (hypertension, heart failure)
Example: aliskiren
This is accomplished by altering how the kidney handles sodium. If the kidney excretes more sodium, then water excretion will also increase.
Most diuretics produce diuresis by inhibiting the re-absorption of sodium at different segments of the renal tubular system.

11. Membrane Potential
An electrical potential difference, or membrane potential, can be recorded across the plasma membrane of living cells
The potential of unstimulated muscle and nerve cells, or resting potential, amounts to – 50 to – 100mV (cell interior is negative)
A resting potential is caused by a slightly unbalanced distribution of ions between the intracellular fluid and extracellular fluid
anionic proteins and phosphates present in high concentrations in the cytosol are virtually unable to leave the cell
All living cells have a (resting) membrane potential, but only excitable cells such as nerve and muscle cells are able to greatly change the ion conductance of their membrane in response to a stimulus, as in an action potential

12. Action Potential
Definition: an action potential (also known as a nerve impulse) is a pulse-like wave of voltage that passes on through an axon or along a muscle fiber that influences other neurons or induces muscle contraction
During depolarization:
Opening of sodium channels and influx of sodium ions is usually associated with cell stimulation
During repolarization:
Inactivation of sodium channels and repolarizing efflux of potassium ions is usually associated with cell inhibition
Depolarization
Repolarization
The normal ratio of ion concentrations across the membrane is maintained by the continual action of the sodium–potassium pump, which transports three sodium ions out of the cell and two potassium ions in
Cathode Ray Oscilloscope (CRO)
The few ions that do cross are pumped out again by the continual action of the sodium–potassium pump, which, with other ion transporters, maintains the normal ratio of ion concentrations across the membrane
The action potential stops at the end of the neuron, but usually causes the secretion of neurotransmitters at the synapses that are found there
These neurotransmitters bind to receptors on adjacent cells

13. Cardiac Action Potential
The cardiac action potential differs from the neuronal action potential by having an extended plateau, in which the membrane is held at a high voltage for a few hundred milliseconds prior to being repolarized by the potassium current as usual
This plateau is due to the action of slower Ca2+ channels opening even after the Na2+ channels have inactivated
The cardiac action potential plays an important role in coordinating the contraction of the heart
The cardiac cells of the sinoatrial node provide the pacemaker potential that synchronizes the heart
The action potentials of those cells propagate to and through the atrioventricular node (AV node), then from the AV node travel through the bundle of His and thence to the Purkinje fibers.
Phases of a cardiac action potential
The sharp rise in voltage ("0") corresponds to the influx of sodium ions, whereas the two decays ("1" and "3", respectively) correspond to the sodium-channel inactivation and the repolarizing efflux of potassium ions
The characteristic plateau ("2") results from the opening of voltage-sensitive calcium channels
Action potentials in cardiac muscle are of much longer duration than those in skeletal muscle (!p. 59 A) because gK temporarily
decreases and gCa increases for 200 to 500ms after rapid inactivation of Na+ channels. This allows the slow influx of Ca2+, causing the action potential to reach a plateau. As a result, the refractory period does not end until a contraction has almost subsided (!p. 59 A). Therefore, tetanus cannot be evoked in cardiac muscle.
This plateau is due to the action of slower Ca2+ channels opening and holding the membrane voltage near their equilibrium potential even after the Na2+ channels have inactivated
منظم القلب Pacemaker:

14. Cardiac Action Potential
The cardiac action potential differs from the neuronal action potential by having an extended plateau, in which the membrane is held at a high voltage for a few hundred milliseconds prior to being repolarized by the potassium current as usual
This plateau is due to the action of slower Ca2+ channels opening even after the Na2+ channels have inactivated
The cardiac action potential plays an important role in coordinating the contraction of the heart
The cardiac cells of the sinoatrial node provide the pacemaker potential that synchronizes the heart
The action potentials of those cells propagate to and through the atrioventricular node (AV node), then from the AV node travel through the bundle of His and thence to the Purkinje fibers
Cardiac Cycle
The resting heart rate is 60–80 beats per minute. A cardiac cycle (!A) therefore takes roughly 1 s. It can be divided into four distinct
phases: (I) contraction phase and (II) ejection phase, both occurring in systole; (III) relaxation phase and filling phase (IV), both occurring in
diastole. At the end of phase IV, the atria contract (phase IVc). Electrical excitation of the atria and ventricles precedes their contraction.

15. Antihypertensive drugs, Classes, the most important ones
Diuretics
Angiotensin Converting Enzyme Inhibitors (ACE inhibitors)
Angiotensin Receptor blockers
Renin Inhibitors
Calcium Channel Blockers
Potassium Channel openers
a1-adrenoceptor antagonists (a1-blockers)
Beta Blockers
a2-adrenoceptor agonists
Peripheral Vasodilators
Stroke: sudden diminution or loss of consciousness, sensation, and voluntary motion caused by rupture or obstruction (as by a clot) of a blood vessel of the brain —called also apoplexy, brain attack, cerebrovascular accident

16. Antihypertensive drugs, Classes, the most important ones
Calcium Channel Blockers (CCBs):
Mechanism of action.
These drugs bind to calcium channels located on the vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular nodes).
These channels are responsible for regulating the influx of calcium into muscle cells, which in turn stimulates smooth muscle contraction and cardiac myocyte contraction.
In cardiac nodal tissue, calcium channels play an important role in pacemaker currents and in phase 0 of the action potentials. Therefore, by blocking calcium entry into the cell, CCBs cause vascular smooth muscle relaxation (vasodilation), decreased myocardial force generation, decreased heart rate, and decreased conduction velocity within the heart, particularly at the atrioventricular node.
Examples: nifedipine, verapamil
Mechanism of action.
Potassium-channel openers are drugs that activate (open) K+-channels in vascular smooth muscle. Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium.
With less calcium available to combine with calmodulin, there is less activation of myosin light chain kinase and phosphorylation of myosin light chains. This leads to relaxation and vasodilation
This promotes K+ efflux and the cell hyperpolarizes, thereby preventing voltage-operated Ca2+ channels (VOCs) from
opening

17. Antihypertensive drugs, Classes, the most important ones
Potassium Channel openers:
Mechanism of action.
These are drugs that activate (open) ATP-sensitive K+-channels in vascular smooth muscle. Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium, leadings to muscle relaxation and vasodilation, decreasing systemic vascular resistance and lowering blood pressure.
Examples: Nicorandil, minoxidil sulphate
a1-adrenoceptor antagonists (a1-blockers)
Mechanism of action.
These drugs block the effect of sympathetic nerves on blood vessels by binding to a-adrenoceptors located on the vascular smooth muscle. Most of these drugs acts as competitive antagonists to the binding of norepinephrine to the smooth muscle receptors
a--blockers dilate both arteries and veins because both vessel types are innervated by sympathetic adrenergic nerves; however, the vasodilator effect is more pronounced in the arterial resistance vessels. Thus they decrease systemic vascular resistance and lower blood pressure.
Examples: prazosin, doxazosin
Mechanism of action.
Potassium-channel openers are drugs that activate (open) K+-channels in vascular smooth muscle. Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium.
With less calcium available to combine with calmodulin, there is less activation of myosin light chain kinase and phosphorylation of myosin light chains. This leads to relaxation and vasodilation
This promotes K+ efflux and the cell hyperpolarizes, thereby preventing voltage-operated Ca2+ channels (VOCs) from
opening

18. Antihypertensive drugs, Classes, the most important ones
b-blockers :
Mechanism of action.
Beta-blockers are drugs that bind to b-adrenoceptors and thereby block the binding of norepinephrine and epinephrine to these receptors. This inhibits normal sympathetic effects that act through these receptors. Thus, drugs decrease heart rate, conduction velocity and force of contraction
The first generation of b-blockers were non-selective, meaning that they blocked both b1 and b2 adrenoceptors. Second generation b-blockers (b1-blockers) are more cardioselective in that they are relatively selective for b1 adrenoceptors.
Examples:
For non-selective b blockers: propranolol
For selective b1 blockers: atenolol
a2-adrenoceptor agonists (centrally acting sympatholytics)
Mechanism of action.
Centrally acting sympatholytics block sympathetic activity by binding to and activating a2-adrenoceptors  inhibition of NE release. This reduces sympathetic outflow to the heart thereby decreasing cardiac output by decreasing heart rate and contractility
Reduced sympathetic output to the blood vessels decreases sympathetic vascular tone, which causes vasodilation and reduced systemic vascular resistance, which decreases arterial pressure
Examples: clonidine
Mechanism of action.
Potassium-channel openers are drugs that activate (open) K+-channels in vascular smooth muscle. Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium.
With less calcium available to combine with calmodulin, there is less activation of myosin light chain kinase and phosphorylation of myosin light chains. This leads to relaxation and vasodilation
This promotes K+ efflux and the cell hyperpolarizes, thereby preventing voltage-operated Ca2+ channels (VOCs) from
opening

19. Anti-arrhythmic drugs
Generation & propagation of normal cardiac impulse 1
SA node 2
AV node
Bundle of Hiss 3
Right & left
bundle branch 4
Purkinje system
Na Ca Na Na K
K K Ca
Mechanisms of cardiac arrhythmias:
Abnormal impulse formation: From SA node or abnormal pacemaker
Abnormal impulse conduction: AV node, purkinje system or myocardium

20. Clinical aspects of cardiac arrhythmias
Incidence:
10 % patients in hospital have abnormal cardiac rhythm
Causes:
CVS or other diseases, drugs, electrolyte changes
Types:
Ectopic beats: atrial, AV-nodal or ventricular
Bradycardias: Sinus bradycardia, heart block (AV block)
Tachycardias: Sinus tachycardia
Atrial tachycardia, flutter & fibrillation
Ventricular tachycardia, flutter & fibrillation
Effects:  cardiac output &  tissue blood perfusion

21. Anti-arrhythmic drugs (Cont.)
Class I: Sodium Channel blockers
Further sub-divided into IA, IB & IC
Class II: Beta Blockers
Class III: Potassium Channel Blockers
Class IV: Calcium Channel Blockers
Class V: Miscellaneous

22. Class IA (Quinidine, procainamide)
Mechanism of action:
Block Na-channel in SA node & ventricles
↓ rate of rise of phase 0 in pacemaker cells
↑ effective refractory period (ERP) & QT interval
Prolong repolarization due to ↓ in K eflux
Prolonged
repolarization
Slow rise
of phase 0

23. Quinidine (Cont.) Other actions:
Anti-cholinergic (vagolytic effect), ↑ AV-conduction
This increases ventricular rate in atrial flutter
Propranolol or verapamil is added to reduce this effect
Uses:
Supra-ventricular & ventricular tachycardia (given oral & IV)
Adverse effects:
CVS: Bradycardia & cardiac depression
Quinidine syncope (a-blocking effect)
Thrombocytopenia (immune reaction)
GI: nausea, vomiting & diarrhea
Cinchonism: tinnitis, vertigo & headache
Drug interaction: ↑ toxicity of digoxin, due to ↓ renal excretion

24. Procainamide (Cont.) Use:
ventricular arrhythmia after MI (given oral & IV)
Adverse effects:
Hypotension
reversible systemic lupus erythematosis (SLE) like effects: skin rash, arthritis, pleuritis & pericarditis

25. Class IB (lidocaine & phenytoin)
Mechanism of action:
Block Na-channel, particularly in ischemic myocardium
less effect on rate of rise of phase 0
↓ effective refratory period (ERP) & QT interval
Less effect
on phase 0
Shortened
repolarization

26. Lidocaine (Cont.) Other properties:
Short half-life (20 minutes) given by IV infusion
Metabolized in liver (↑ toxicity with enzyme inhibitors)
Use:
Ventricular tachycardia in ischemic heart disease (MI)
Also used as local anesthetic (also named lignocaine)
Adverse effects:
Less cardiac depression
Confusion, dizziness, slurred speech & seizures

27. Class IC (flecainide & propafenone)
Mechanism of action:
Block Na-channel, in SA node & ventricles
Marked ↓ of rate of rise of phase 0 of action potential
No effect on effective refractory period (ERP) & QT
Minimal effect on the duration of action potenial
Marked effect
on phase 0
Minimal effect
on repolarization

28. Flecainide (Cont.) Uses: Paroxysmal supra-ventricular tachycardia
Premature ventricular contractions
Ventricular tachycardia
Reserved for resistant cases
(because of chances of cardiac depression)
Adverse effect:
Cardiac depression, prolonged PR & QRS interval
Nausea, dizziness & blurred vision

29. Class II (β-blockers-Propranolol & esmolol)
Mechanism of action:
Competitively block β receptors & inhibit the effect of catecholamines on cardiac β receptors
Propranolol also ↓ Na-channel like class I drugs
Decreased slope of phase 4 in SA node
Prolonged repolarization at AV node
Decreased slope of
phase 4 in SA node
Prolonged repolarization
at AV node

30. Propranolol & esmolol (Cont.)
Uses:
Supraventricular tachycardia to control ventricular rate
Adverse effects:
Bradycardia, hypotension, broncho-constriction, muscle pain, fatigue & hypoglycemia, nightmares & depression
Esmolol:
Very short acting, given IV in ventricular arrhythmias during surgery

31. Class III (Amiodarone & sotalol)
Mechanism of action (amiodarone):
Block K-channels ( also blocks Na-channels)
Prolong re-polarization & action potential
Prolong effective refratory period (ERP)
Also possess some β adrenergic & Ca-channel blocking effects
Prolonged
repolarization

32. Amiodarone (Cont.) Uses: Supra-ventricular & ventricular tachycardias
IV for acute episode & oral for chronic recurrent arrhythmias
Adverse effects:
May cause bradycardia, AV-block & hypotension
Risk of induction of arrhythmias (torsade de pointes)
Pulmonary fibrosis, hepatic damage, photodermatitis
Blocks conversion of T4 to T3 (hypothyroidism)

33. Class IV (Verapamil & diltiazem)
Mechanism of action:
Block ‘L - type’ of Ca-channels in cardiac tissue
↓ inward Ca-current, in SA-node & AV-node
↓ conduction velocity & ↑ effective refractory period
Prolonged repolarization
Slow rise
of phase 0

34. Verapamil & diltiazem (Cont.)
Use:
Supra-ventricular tachycardia (to control ventricular rate)
Also used in angina and hypertension
Adverse effects:
Bradycardia, hypotension, edema, constipation
↑ plasma digoxin levels by ↓ in renal excretion

35. Miscellaneous anti-arrhythmic drugs
Adenosine
Mechanism of action:
Stimulates P-1 purinergic receptors & opens K channels
↓ conduction at SA node, atria & AV node
Also ↓ cAMP-induced Ca influx
Use:
Paroxysmal supra-ventricular tachycardia
Rapid onset (few seconds) & short half life (10-20 seconds)
Adverse effects:
Sinus bradycardia & AV block, initial rise & then fall in BP
Bronchoconstriction, headache, flushing & chest pain

36. Miscellaneous anti-arrhythmic drugs (Cont.)
Potassium:
Hypokalemia causes after depolarizations & ectopic beats
Hyperkalemia causes slow conduction & cardiac arrest
Correction of serum K levels controls these arrhythmias
For hypokalemia: K supplements; oral or IV
For hyperkalemia: Insulin with glucose & in severe cases hemodialysis
Magnesium:
Mg sulfate oral, IM or IV can be used for refractory ventricular tachycardia
Digoxin:
May be used in supraventricular tachycardia.

37. Ischemic Heart Disease
Angina pectoris
Chronic condition, episodic chest discomfort
Occurs during transient coronary ischemia
Myocardial infarction
Acute and complete occlusion of a coronary artery
Due to coronary thrombosis 37

38. increased demand for oxygen evoked by physical exertions
Angina- episodic chest pains as a result of transient coronary ischemia (as opposed to myocardial infarction which is acute and complete occlusion of a coronary artery .
angina (heavy weight or pressure or pain in the chest) occurs when blood (oxygen, nutrient) supply to the heart is limited as a result of :
disruption of coronary blood flow because of vasospasm or platelet aggregation
increased demand for oxygen evoked by physical exertions
a combination of both 38

39. ANGINA PECTORIS
Angina pectoris develops as a result of an imbalance between the oxygen supply and the oxygen demand of the myocardium. It is a symptom of myocardial ischemia. When the increase in coronary blood flow is unable to match the increased oxygen demand, angina develops. It has become apparent that spasm of the coronary arteries is important in the production of angina. 39

40. Vasospasm at rest or during sleep
If the frequency and severity increases- forerunner to a MI
If symptoms remains the same and angina occurs under similar circumstances 40

41. Drugs used in Angina pectoris:
Organic nitrates
e.g. Nitro-glycerine, isosorbide Dinitrate, etc.
Beta adrenergic blocking agents
e.g. Propranolol, Atenolol, etc.
Calcium channel blocking agents
e.g. Verapamil, nifedipine, etc.
Miscellaneous drugs
e.g. Aspirin, Heparin, Dipyridamole. 41

42. Drugs employed: Antianginal drugs : Typical Variant MI
Stable Unstable
Organic nitrite and nitrates
Ca2+-channel blockers to
- adrenergic Antagonists
Aspirin
Fibrinolytic drugs
Antianginal drugs :
-O2 increase supply and/or lower demand
Myocardial O2 supply: Coronary blood flow, regional flow distribution
Myocarial O2 –demand: amount of energy required to support the work of the heart
Cardiac work influenced by: heart rate, heart contractility, myocardial wall tension 42

43. Mechanism of Action: 43

44. Vasodilators- organic compounds containing ONO or ONO2 (prodrugs) all release NO upon interacting with serum components.
these are converted intracellularly to nitrite ions and then No (Nitric oxide) which in turn activate guanylate cyclase that lead to increase the cyclic GMP and to dephosphorylation of the myosin light chain which result in relaxation of vascular smooth muscle.

45. HEART FAILURE
Congestive heart failure occurs when there is an inability of the heart to maintain a cardiac out put sufficient to meet the requirements of the metabolising tissues.
Heart failure is usually caused by one of the following:
Ischaemic heart disease,
Hypertension,
Heart muscle disorders, and
Valvular heart disease.
Drug management aims to provide symptomatic relief for the patient while also preventing further deterioration in cardiac function 45

46. The Vicious Cycle of Heart Failure
CARDIAC INJURY
Pump failure
Vasoconstriction
Na+ H2O retention
Neurohormonal Activation
Renin Angiotensin, Aldosterone system
Sympathetic Nervous system
Others e.g. Natriuetic peptides

47. Background of Heart Failure:
Normal cardiac output needed to adequately perfuse peripheral organs
Provide O2, nutrients, etc
Remove CO2, metabolic wastes, etc
Maintain fluid flow from capillaries into interstitium and back into venous system  if flow reduced or pressure increased in venous system  build up of interstitial fluid = edema
Because CO is a function of
Heart Rate – determined by pacemaker cells in the sinoatrial node
Stroke volume – determined by fill rate and contractile force
Atrial/ventricular/valvular coordination
Any negative change on above can lead to inadequate perfusion and development of the syndrome of heart failure 47

48. Drugs used to treat Heart Failure:
A. Drugs with positive inotropic effect:-
Drugs with positive inotropic effect increase the force of contraction of the heart muscle. These include:
Cardiac glycosides, e.g. digoxin and digitoxin
Bipyridine derivatives e.g. amrinone, milrinone.
Sympathomimetics e.g. dobutamine, dopamine
Methylxanthines e.g. aminophylline
B. Drugs without positive inotropic effect.
These include:
Diuretics, e.g. hydrochlorothiazide, furosemide
Vasodilators, e.g. hydralazine, sodium nitroprusside
Angiotensin converting enzyme inhibitors e.g. captopril, enalapril 48

50. Digoxin: Mechanism of Action
Na-K ATPase
Na-Ca Exchange
Na+ K+
Na+
Ca++
Myofilaments K+
Na+
Ca++
Contractility
Digoxin: Mechanism of Action
Digoxin inhibits the Na+/K+ ATPase, which causes an increase in intracellular sodium concentration. This leads to accumulation of intracellular calcium in the heart via Na+/Ca++ exchange. Increased intracellular calcium promotes calcium release by the sarcoplasmic reticulum. Increased calcium binds troponin-C, leading to increased contractility.
Digoxin also increases vagal activity to the heart, resulting in reduced chronotropy (heart rate) and dromotropy (conduction velocity).

51. THANK YOU
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