3. Introduction
The Kidney
• The kidney is a structurally complex organ that has evolved a
number of important functions:
– Excretion of the waste products of metabolism
– Regulation of body water and salt
– Maintenance of appropriate acid balance, and
– Secretion of a variety of hormones and autocoids
• The functional unit of kidney is the nephron
• The increased excretion of water and electrolytes by the kidneys
is dependent on three different processes
– Glomerular filtration
– Tubular reabsorption (active and passive) and
– Tubular secretion
3
4. Anatomical sites along the Nephron
• There are four major anatomical sites along the nephron that are responsible
for Na+ reabsorption & other ions.
– Determined by the chemical structure of the diuretics, site(s) of action of the
agents, patient’s salt intake & amount of extracellular fluid present
Site 1: The convoluted & straight portions of the Proximal Tubule
– Responsible for the reabsorption of
• 65-70% of the filtered loads of Na+, Cl-, Ca2+ & water
• 80-90% of the filtered loads of HCO3
- & phosphate
• 100% of the filtered loads of glucose, amino acids, protein, &
vitamin
Site 2: The thick ascending Limb of Henle’s Loop
– 20-25% of Na+& Cl- are reabsorbed via cotransport system (Na+/K+/2Cl-)
Site 3:The Distal Convoluted Tubule
– 5-10% of all sodium is reabsorbed
Site 4: The Collecting Tubule & the cortical Collecting Tubule
– 2-3% of all sodium is reabsorbed in exchange for H+ & K+
4
6. Diuretics
• Diuretics are defined as chemicals that increases the rate of urine
formation
– Are drugs inducing a state of increased urine flow rate
– Are drugs that promote the output of urine excreted by the kidneys
– Causes increase in urine volume due to increased osmotic pressure in
lumen of renal tubule
– Causes concomitant decrease in extracellular volume (blood volume)
– May enhance the rate of urine formation by either of the two following
phenomena
• Increasing glomerular filtration and
• Depressing tubular reabsorption
– Result: Removal of electrolytes (Na+ & Cl-) and water from the
body without affecting protein, vitamin, glucose, or amino acid
reabsorption
7
7. Diuretics cont.
A diuretic usually possesses some combination of Natriuretic,
chloruretic, saturetic, kaliuretic, bicarbonaturetic, and calciuretic
properties, depending on whether it enhances the renal excretion of
Na+, Cl-, NaCl, K+, HCO3
-, and Ca2+, respectively
The primary action of most diuretics is inhibition of renal ion
transporters
Decrease the reabsorption of Na+ at one or more of the
major anatomical sites along the nephron
As a result, Na+ & other ions, such as Cl-, enter the urine
in greater than normal amounts along with water
Which is carried passively to maintain osmotic
equilibrium
Diuretics, thus, increase the volume of urine and often change its
pH as well as the ionic composition of the urine and blood
8
8. Diuretics cont.
These pharmacological properties have led to the use of
diuretics in the treatment of edematous conditions resulting
from a variety of causes (e.g. congestive heart failure,
nephrotic syndrome, & chronic liver disease) & in the
management of hypertension
Diuretic drugs also are useful as the sole agent or as adjunct
therapy in the treatment of a wide range of clinical conditions
including hypercalcemia, diabetes insipidus, acute mountain
sickness, primary hyperaldosteronism, and glaucoma
The primary target organ for diuretics is the kidney
9
9. Types of diuretics and Sites of Action
• Based on the mechanism of action; diuretics can be classified into:
– Carbonic anhydrase inhibitors (in proximal tubule)
– Loop or High-Ceiling diuretics (in ascending limb of loop)
– Thiazide & Thiazide-like diuretics (in distal convoluted
tubule)
– Potassium-sparing diuretics (in collecting tubule)
– Osmotic agents (in proximal tubule, descending loop of Henle)
– Aquaretics (ADH-antagonists)
10
13. Mechanism of Action of CAIs:
• The enzyme CA helps to make H+ ions
available for exchange with Na+ & water in
the proximal tubules
• CAIs block the action of CA, thus
preventing the exchange of H+ ions with Na+
and water
• Inhibition of CA reduces H+ ion
concentration in renal tubules
• As a result, there is increased excretion of
HCO3
-, Na+, water, and K+ and
Reabsorption of water is decreased and
urine volume is increased
• Example includes Acetazolamide (Diamox),
Methazolamide, Dichlorphenamide
Carbonic Anhydrase Inhibitors (CAIs)
14
14. Structure-Activity Relationships (SARs)
• In 1937, Southworth observed that sulphanilamide
– Not only had antibacterial activity
– But also produced systemic acidosis and an alkaline urine
(HCO3-excretion)
• Carbonic anhydrase (CA) inhibitors are derived from the
sulphonamide antibacterials
• All inhibit carbonic anhydrase activity
• Importantly, they have no antibacterial activity
• SAR studies involving the simple heterocyclic sulfonamides
yielded the prototypic CAI, acetazolamide
16
15. Structure-Activity Relationships cont.
• Sulfonamide group (-SO2NH2) is essential for its activity
• Substitution on the sulphamoyl (-SO2NH2) group gives
inactive compounds
– Some potent CA inhibitors have an aromatic group
(phenyl ) or heterocycle attached to sulphamoyl group
• Substitution of a methyl group on one of acetazolamide’s
ring nitrogens yields methazolamide
• The moiety to which the sulphonyl group is attached must
possess aromatic character
17
16. SARs cont.
In addition, within a given series of heterocyclic sulfonamides, the
derivatives with the highest lipid/water partition coefficients and
the lowest pK values have the greatest CA -inhibitory and
diuretic activities
The SAR studies involving the meta-disulfamoylbenzenes revealed
that the parent 1,3-disulfamoylbenzene lacked diuretic activity,
but key substitutions led to compounds with diuretic activity
The first commercially available analogue, dichlorphenamide is
similar to acetazolamide in its CA-inhibitory activity, but it is also a
chloruretic agent
18
19. SARs cont.
Chloraminophenamide was shown to possess less CA
inhibitory activity but greater chloruretic activity when
given by the intravenous route
Poor diuretic activity following the oral administration
of chloraminophenamide precluded its marketing
21
20. Loop or High-Ceiling Diuretics
The diuretics in this class have extremely diverse
chemical structures
Used to control blood pressure in the treatment of
hypertension
Although brief mention is made of the organomercurial
diuretics, primary attention is focused on the agents
with clinical utility: for example,
Furosemide (a 5-sulfamoyl-2-aminobenzoic acid or Anthranilic
acid derivative),
Bumetanide (a 5-sulfamoyl-3-aminobenzoic acid or metanilic
acid derivative),
Torsemide (a 4-amino-3-pyridinesulfonylurea), and
Ethacrynic acid (a phenoxyacetic acid derivative)
22
21. Organomercurials
The organomercurials were the mainstay of diuretic
therapy from 1920 to the early 1950s
They elicit diuresis by inhibiting Na+ reabsorption at
site 2, and they block the subsequent exchange of Na+ for
K+ at site 4
Thus, they are Natriuretic and chloruretic and minimally
kaliuretic
Although these properties are true attributes for any class
of diuretics, the organomercurials have a number of
limitations
First, when given orally they cannot be relied on to elicit
diuresis because of poor and erratic absorption
23
22. Organomercurials cont.
Second, after parenteral administration there is a 1 to 2 hour lag
in the onset of diuresis
Third, their ability to trigger a diuretic response depends on the
acid-base status of the individual (i.e., they are ineffective
when the urine is alkaline)
Fourth, they are cardio- and nephro-toxic
The organomercurials became obsolete with the introduction of the
Thiazides and thiazide-like diuretics, furosemide,
bumetanide, and ethacrynic acid
All of the latter agents are
Orally effective,
Equally effective in both acidotic and alkalotic conditions,
Capable of inducing relatively rapid diuresis when given
parenterally, and
Relatively nontoxic
24
23. Loop or High-Ceiling diuretics
26
Mechanism of Action
• They inhibit reabsorption of Na+ by
inhibiting the Na+/K+/2Cl- symport
in the luminal membrane of the thick
ascending limb of loop of Henle
• Increase renal PGs, resulting in the
dilation of blood vessels and
reduced peripheral vascular
resistance
• They also have direct effects on
vasculature including increase in renal
blood flow, and increase in systemic
venous capacitance
Furosemide
24. 5-sulfamoyl-2-and 3-aminobenzoic acid derivatives
• This includes Bumetanide (a 5-sulfamoyl-3-aminobenzoic acid or metanilic acid
derivative) and Furosemide (a 5-sulfamoyl-2-aminobenzoic acid or Anthranilic
acid derivative)
• Structure-Activity Relationships (SARs)
• The development of the loop diuretics is an outgrowth of the research involving the
thiazide and thiazide-like diuretics
• There are important structural requirements that are common to the 5-sulfamoyl-2-
aminobenzoic acid derivatives and the 5-sulfamoyl-3-aminobenzoic acid derivatives
• The substituent at the 1-position must be acidic
– The carboxyl group provides optimal diuretic activity, but other groups, such
as a tetrazole, may impart respectable diuretic activity
28
25. Structure-Activity Relationships cont.
• A sulfamoyl group in the 5-position is a prerequisite for optimal high-ceiling
diuretic activity
• The "activating" group (-X) in the 4-position can be Cl-, or CF3 as was the case
with the thiazides and thiazide-like diuretics, or better yet, a phenoxy, alkoxy,
aniline, benzyl or benzoyl group
– Interestingly, substitution of one of the latter five functional groups for the
Cl- or CF3 group in the thiazides or thiazide-like diuretics decreases their
diuretic activity
29
27. Structure-Activity Relationships of Ethacrynic acid
• Designed to mimic mercurial diuretics
• Increased activity when a electron withdrawing
group (i.e. Cl-) is placed ortho to the unsaturated
ketone (active site for sulfhydryl reactivity)
• Ortho and meta positions substituted with chlorine
– Produce most active compound
31
28. Thiazide and Thiazide-like Diuretics
Thiazides are also called benzothiadiazides
Used mainly to control blood pressure in the treatment of hypertension
Thiazides are sulfonamide derivatives
32
29. Thiazide and Thiazide-like Diuretics cont.
• There are some diuretics having similar pharmacological actions
as thiazides but have different structures from thiazides-called
Thiazide-like diuretics
• All the drugs are actively secreted into the tubule and act in the
distal tubule
33
30. Mechanism of Action
• Thiazides inhibit a Na+/Cl–
symport in the luminal membrane of
the epithelial cells in the distal
convoluted tubule
• Thus, thiazides inhibit NaCl
reabsorption in the distal convoluted
tubule
• They enhance Ca++ reabsorption in
the distal convoluted tubule by
inhibiting Na+ entry and thus
enhancing the activity of Na+/Ca++
exchanger in the basolateral
membrane of epithelial cells
• Dilate the arterioles by direct
relaxation
– Thiazides are usually preferred for
the treatment of hypertension
34
Thiazide and Thiazide-like Diuretics cont.
31. Structure-Activity Relationships of thiazides
• The thiazide diuretics are weakly acidic with a benzothiazine-1,1-dioxide nucleus
• H atom at 2-N is the most acidic due to the electron-withdrawing effects of the
neighbouring sulfone group
• Sulfonamide group that is substituted at C-7 provides an additional point of
acidity in the molecule but is less acidic than 2-N proton
– These acidic protons make possible the formation of a water-soluble sodium salt that
can be used for I.V. administration
– A free sulfonamide group at position 7 is essential for diuretic activity
– Replacement or removal of the sulfonamide group at position 7 yield compounds
with little or no diuretic activity
• An electron-withdrawing group is essential at position 6 for diuretic activity
– Little diuretic activity is seen with a H atom at position 6, but compounds with a chloro
or trifluoromethyl substituent are highly active
36
32. Structure-Activity Relationships of thiazides cont.
• Replacement of Cl at position 6 by CF3 does not change potency but alters
duration of action due to its more lipid-solubility
• When electron-donating groups (e.g. –OCH3 or CH3) are placed at position 6,
the diuretic activity markedly reduced
• The diuretic potency is enhanced by substitution with lipophilic group at
position 3
– Haloalkyl, aralkyl, or thioether substitution increases lipid solubility and hence, has
longer duration of action
• Alkyl substitution on the 2-N position also decreases the polarity & increases the
duration of diuretic action
• Saturation of thiadiazine ring to give 3, 4-dihydro derivative produces a
diuretics that is 10-fold more active than the unsaturated derivatives
37
33. Potassium-sparing Diuretics
• The adrenal cortex secretes a potent mineralocorticoid
called aldosterone, which promotes salt and water
retention and potassium and hydrogen ion excretion.
• Aldosterone exerts its biological effects through binding to
the mineralocorticoid receptor (MR), a nuclear
transcription factor
• A substance that antagonizes the effects of aldosterone
could conceivably be a good diuretic drug
• These drugs are also classified as mineralocorticoid
receptor antagonists
39
34. Potassium-sparing Diuretics cont.
Amiloride
Triamterene
40
Mechanism of Action
• Work in collecting ducts
• Interfere with sodium-potassium exchange
• Competitively bind to aldosterone receptors
• Block the reabsorption of sodium and water
usually induced by aldosterone
• Decreased Na+ reabsorption in the collecting
tubule with slightly increased natriuresis
– Natriuretic: substance that promotes the
renal excretion of Na+
• Decreased K+ secretion (excretion) into the
lumen of the collecting tubule
• Examples:
– Spironolactone (Aldactone); Eplerenone
– Triamterene (Dyrenium); Amiloride
(Midamor)
Spironolactone
35. Osmotic diuretics
44
• Are the agents that mobilize fluids by increasing the osmotic
pressure in tubules
• A number of simple, hydrophilic chemical substances that are
filtered through the glomerulus, such as mannitol and urea,
result in some degree of diuresis
– This is due to their ability to carry water with them into the
tubular fluid
Mechanism of Action
Osmotic diuretics are used to effect increased water excretion
rather than Na+ excretion, they are not useful for treating
conditions in which Na+ retention occurs
37. Introduction
Cardiovascular drugs generally exert their action on the heart or
blood vessels in a
Direct or indirect manner thereby affecting the distribution of
blood to certain specified portions of the circulatory system
Therefore, they essentially embrace a wide spectrum of drugs
which possess cardiovascular actions
The treatment and therapy of cardiovascular disease have
undergone dramatic changes since the 1950s
Data show that since 1968 and continuing through the 1990s, there
has been a noticeable decline in mortality from cardiovascular
disease
46
38. Introduction cont.
The bases for advances in the control of heart
disease have been
(a)A better understanding of the disease state
(b)The development of effective therapeutic agents
(c) Innovative medical intervention techniques to
treat problems of the cardiovascular system
47
39. Introduction cont.
The following class of drugs are used in the treatment
of angina, hypertension, heart failure, cardiac
arrhythmias, hyperlipidemia and disorders of
blood coagulation
Antianginal agents and vasodilators
Antihypertensive agents
Drugs used for treatment of congestive heart failure
(Cardiac glycosides and derivatives)
Antiarrythemic drugs
Antihyperlipidemic drugs
Coagulant and anticoagulants
48
41. Antianginal agents and vasodilators
What is angina ?
Angina literally means “chocking pain”
Angina pectoris or ischemic heart diseases
It is the chronic disease affecting the coronary arteries
Which supply oxygenated blood from the left ventricle to all
heart tissues including the ventricle themselves
Angina occurs when the blood supply to the heart is not able to
meet the metabolic demands of the heart for oxygen
Also refers to painful or uncomfortable sensation in the chest
That occurs when part of the heart does not receive sufficient
oxygen due to disease in the coronary artery
During this, the heart is said to be ischemic (oxygen deficient)
In healthy individuals when oxygen demand increases coronary
arterioles dilates and the resultant decrease in vascular resistance
allows blood flow to increase
50
43. Over view of pathophysiology of angina
Major cause of angina are:
Coronary artery disease (CAD)
Coronary artery spasm (CAS)
Coronary artery disease
Develops when one or more of the coronary arteries that
supply blood to the heart become narrowed that is due to
Build up of cholesterol & other substance in the wall of
artery affecting the blood flow to the heart
Due to the formation of cholesterol reach plaque,
narrowing and hardening of blood vessel occur and this
process called atherosclerosis
Atherosclerosis is deposition of fatty plaque in the wall
of artery
52
44. Over view of pathophysiology of angina cont.
CAD lead to development of two type of angina
Stable angina (classic angina pectoris, external angina )
Unstable angina
Stable angina
Result from a fixed obstruction of blood flow to the heart
Angina attack occur when the heart doing much work, during
Physical exercise, emotion or eating
When there is no enough supply of blood for fast pumping
heart
It is less serious & does not lead to heart attack in most cases
than unstable angina
53
45. Over view of pathophysiology of angina cont.
Unstable Angina
Caused by episodes of increased epicedial coronary artery
tone
Occurs due to sudden interruption of blood flow to the heart
Because of partial or complete blockade of the arteries
Result from rupture of plaque which triggers
thrombus formation
Can occur when a person is at
Resting, Sleep or Under physical exertion
Can be very dangerous as it may quickly progress into
Myocardial infarction (MI) & thus heart attack
MI-Destruction of heart tissue resulting from obstruction of the
blood supply to the heart muscle
54
46. Over view of pathophysiology of angina cont.
Variant angina pectoris (prinzmetal’s angina, vasospatic
angina)
Caused by CAS, which restricts blood flow to
myocardium
In contrast to classic angina whose symptoms occur at a
time of exertion
Variant angina can cause pain at any time, even
during rest and sleep
Oxygen delivery decrease as a result of reversible
coronary vasospasm
55
47. Determinants of cardiac oxygen demand & supply
Oxygen Demand
Determined by
Heart rate
Contractility
Afterload
Preload
Wall stress
Oxygen supply
Determined by
Myocardial blood flow
through dilation of
coronary arteries
56
48. Antianginal drugs
Antianginal drugs may relieve attacks of acute myocardial ischemia by
Increasing myocardial oxygen supply or
Decreasing myocardial oxygen demand or
both
The main goals of treatment in angina pectoris are to
Relieve the symptoms,
Slow the progression of disease, and
Reduce the possibility of future events, especially MI and premature death
Three groups of pharmacological agents have been shown to be
effective in reducing
Frequency, severity, or both of primary or secondary angina
These agents include the
Organic nitrates
-adrenoceptor antagonists and
Calcium channel blockers 57
49. Antianginal Drugs Cont.
• Organic nitrates and calcium channel
antagonists are indicated in spasmatic and
chronic stable angina, while β-adrenergic
antagonists are primarily for exertion-induced
angina
• Anti-anginal agents mainly alleviate the pain by
reducing the oxygen requirements of the
heart, thereby reducing anginal pain
58
50. Organic Nitrates
Organic nitrates are esters of simple organic alcohols or
polyols with nitric acid
This class was developed after the antianginal effect of amyl
nitrite (Ester of isoamyl alcohol with nitrous acid) was first
observed in 1857
Organic nitrates are also called nitrovasodilators
Five members of this class in clinical use includes:
Amyl nitrite (inhalant), nitroglycerin, Isosorbide dinitrate,
Erythrityl tetranitrate, and pentaerythritol tetranitrate
Two additional organic nitrates
Tenitramine and propatylnitrate are currently available
59
52. Organic nitrates cont.
• This class usually referred to as organic nitrates, because
all of these agents, except amyl nitrite, are nitrate esters
• The prototype of these agents is nitroglycerin
• With the exception of nitroglycerin, which is a liquid
having a high vapor pressure, these compounds are solid
at room temperature
• All organic nitrates are very lipid soluble
61
Nitroglycerin
53. Mechanism of action of Nitrates and nitrites
• They act by the formation of free radical nitric oxide
(NO), which interact with and activate guanylate cyclase,
an enzyme that produces cGMP
• Increase in the concentration of cGMP, in turn, activates
protein kinases that phosphorylate MLCK (myosin light
chain kinase)
– Thus, preventing the phosphorylation of myosin and
resulting in muscle relaxation
• Muscle relaxation, or vasodilation, results in
reduced workload for the heart, thus easing anginal
pain
62
57. -Adrenergic blocking agents
• The second major therapeutic approach to the
treatment of angina is the use of -Adrenergic
blocking agents
• Their use as antiaginal agent is limited to the
treatment of exertion-induced angina
• Propranolol is a prototype drug in this class, but
several newer agents have been approved for
clinical use
• Although these agents are used alone, they are
used in combination with nitrates, or Calcium-
channel blockers or both
66
58. Mechanism of action of β-Adrenergic Antagonist
• They decreases sympathetic stimulation of
the heart and thus reduces the heart rate and
decreases myocardial contractibility
• These effects in turn decrease the oxygen
requirements of the myocardium, both
during exercise and at rest
67
59. Calcium channel blockers
• The third major therapeutic approach to the treatment of
angina is the use of calcium channel blockers
• Three classes of calcium channel blockers are
approved for use in the prophylactic treatment of
angina
– The dihydropyridines
• E.g. Nifedipine, nicardipine, and amlodipine
– The benzothiazepine derivatives
• E.g. Diltiazem
– Aryl alkyl amine derivatives
• E.g. Verapamil
68
61. Mechanism of action of Calcium Channel Blockers
• These drugs acts by
–Selectively inhibiting Ca2+ influx into heart
muscle and
–Inhibit Ca2+ influx into vascular smooth
muscle
• It dilates the main coronary arterioles, and by
inhibiting coronary artery spasm
–They increase myocardial oxygen delivery in
patients with Prinzmetal’s angina (Variant
angina pectoris )
70
63. Introduction
• Hypertension or High Blood Pressure
– It is a pathological condition in which blood pressure is
persistently elevated (i.e. it stays high for a long period of
time)
• Blood Pressure
– A measurement of the pressure of the blood against the blood
vessel walls
– A measure of the force of the blood pushing against the walls
of the arteries (i.e. the blood vessels that carry blood from the
heart to the rest of the body)
• The persistent high blood pressure puts undue stress on the
heart, blood vessels and other organs
– Hypertension is a major public health problem of largely
unknown cause
72
64. Physiological concept of BP regulation and control
• Blood pressure (BP) is determined by the
– Amount of blood pumped by the heart
– Pumping power of the heart
– Condition of the heart valves and
– Size and condition of the arteries
• Many other factors can affect BP including the
– Volume of water in the body
– Salt content of the body
– Condition of the kidneys, nervous system
and the nature of blood vessels and
– Levels of various hormones in the body
73
65. Physiological concept of BP regulation and control cont.
• Systolic Blood Pressure (SBP)
– When the heart contracts to pump out blood, pressure is highest
• This measurement is called the systolic pressure
• Diastolic Blood Pressure (DBP)
– After pumping, the heart relaxes and pressure drops to its lowest point
just before new beat starts
• This measurement is called the diastolic pressure
• The measurement of an individual’s blood pressure is always
expressed as systolic pressure over diastolic pressure
– For example, normal BP for adults is considered to be in the
range of 120/80 mmHg
– Generally, BP above 140/90 mmHg is considered high for
adults, and
– BP under 90/60 mmHg is considered low for adults
74
68. Classification of Antihypertensive agents cont.
• Antihypertensives are those agents which are used to
reduce high blood pressure
• They are classified as:
(A) Adrenoceptor Blocking Agents
(B) Vasodilators
(C) Agents Acting on Renin-angiotensin system
(D) Diuretics
(E) 5-HT Antagonists
78
69. Classification of Antihypertensive agents cont.
(A) Adrenoceptor Blocking Agents
1) α-Adrenergic Antagonist
a) Piperazinylquinazoline derivatives: e.g. Prazosin, Terazosin
b) Imidazoline derivatives: e.g. Tolazoline, Phentolamine
79
70. Classification of Antihypertensive agents cont.
2) β-adrenoceptor antagonists: e.g. Propranolol,
Atenolol, Metoprolol
3) α, β-adrenoceptor antagonists: e.g. Labetalol
80
71. Classification of Antihypertensive agents cont.
4) Centrally Acting Agents: e.g. Methyldopa,
Clonidine, Guanabenz, Guanfacine
5) Agents Depleting Neurotransmitter Stores: e.g.
Reserpine, Guanethidine, Guandrel Sulfate
6) Ganglionic Blocking Agents: e.g. Pentolinium,
Trimethaphan, Mecamylamine HCl
81
72. Classification of Antihypertensive agents cont.
(B) Vasodilators
1) Directly Acting Vasodilators
a) Arterial dilators
E.g. Hydralazine, Dihydralazine, Sodium
nitroprusside
b) Potassium Channel agonist
E.g. Minoxidil, Diazoxide
2) Calcium Channel Blockers
a) Aryl alkyl amines: e.g. Verapamil
b) Benzothiazepines: e.g. Diltiazem
c) Dihydropyridines: e.g. Nifedipine, Felodipine,
Amlodipine, Nimodipine
82
73. Classification of Antihypertensive agents cont.
(C) Agents Acting on Renin-angiotensin system
1) Angiotensin Converting Enzyme (ACE) Inhibitors
E.g. Captopril, Lisinopril, Enalapril
2) Angiotensin Receptor Antagonist
E.g. Losartan, Saralasin
(D) Diuretics
1) Thiazides: e.g. Hydrochlorothiazide
2) Loop Diuretics: e.g. Furosemide
3) Potassium Sparing Diuretics: e.g. Triamterene,
Spironolactone
(E) 5-HT Antagonists
– E.g. Ketanserine
83
76. Angiotensin converting enzyme (ACE), also called dipeptidyl
carboxypeptidase I, peptidase P, dipeptide hydrolase, peptidyl
dipeptidase, is a stereoselective drug target
Since currently approved ACE inhibitors act as either di- or tripeptide
substrate analogs, they must contain a stereochemistry that is
consistent with the L-amino acids present in the natural substrates
86
Structure-activity Relationships of ACE inhibitors
80. SAR of ACE inhibitors
• The N-ring must contain a carboxylic acid to mimic the C-
terminal carboxylate of ACE substrates
• Large hydrophobic heterocyclic rings in the ~N-ring
– Increase potency and alter pharmacokinetic parameters
• Groups A, B, or C can serve as zinc binding groups
• The sulfhydryl group shows superior binding to zinc (Phe in
carboxylate and phosphinic acid side chain compensates for
sulfhydryl group)
90
81. SAR of ACE inhibitors cont.
• Sulfhydryl-containing compounds
– Produce high incidence of skin rash and taste disturbances
– Can form disulfides, which may shorten duration of action
• Binding to zinc through either a
– Carboxylate or phosphinate mimics the peptide hydrolysis
transition state
• Esterification of the carboxylate or phosphinate
– Produces an orally bioavailable prodrug
91
82. SAR of ACE inhibitors cont.
• “X” is usually methyl to mimic the side chain of alanine within
the dicarboxylate series
• When “X” equals n-butylamine (lysine side chain)
– This produces a compound, which is orally active without
being a prodrug
• Optimum activity occurs when stereochemistry of inhibitor is
consistent with L-amino acid stereochemistry
92
83. SAR of angiotensin II antagonists
• All commercially available angiotensin II antagonists are analogs of
the following general structure:
– The "acidic group" is thought to mimic either the Tyr4 phenol
or the Asp1 carboxylate of angiotensin II
• Groups capable of such a role include the carboxylic acid (A),
a phenyl tetrazole (B), or a phenyl carboxylate (C)
– In the biphenyl series, the tetrazole and carboxylate groups must
be in the ortho position for optimal activity
• The tetrazole group is superior in terms of metabolic
stability, lipophilicity, and oral bioavailability
93
84. SAR of angiotensin II antagonists cont.
• The n-butyl group of the model compound provides hydrophobic
binding and most likely mimics the side chain of Ile5 of angiotensin
II
• As seen with candesartan and telmisartan, this n-butyl group can be
replaced with a substituted benzimidazole ring
94
85. SAR of angiotensin II antagonists cont.
• The imidazole ring or an isosteric equivalent, is required to mimic
the Histidine side chain of angiotensin II
• Substitution with a variety of R groups including a
– Carboxylic acid, methyl alcohol, ether, or an alkyl chain is
required to mimic the Phenylalanine of angiotensin II
95
86. SAR of calcium channel blockers
• The SAR depends on the structure1, 4-Dihydropyridine (DHP)
derivatives
• A substituted phenyl ring at the C4 position optimizes activity
– Heteroaromatic rings, such as pyridine, produce similar
therapeutic effects but are not used due to observed animal
toxicity
• C4 substitution with a small nonplanar alkyl or cycloalkyl group
decreases activity
• Phenyl ring substitution (X) is important for size and position
rather than for electronic nature
96
88. SAR of calcium channel blockers cont.
• Compounds with ortho or meta substitutions possess optimal
activity, while those which are unsubstituted or contain a para-
substitution show a significant decrease in activity
• Electron withdrawing ortho or meta-substituents or electron
donating groups demonstrated good activity
• The importance of the ortho and meta-substituents is to provide
sufficient bulk to "lock" the conformation of the 1, 4-DHP such
that the C4 aromatic ring is perpendicular to the 1, 4-
dihydropyridine ring
– This perpendicular conformation has been proposed to be
essential for the activity of the 1, 4-DHP
98
89. SAR of calcium channel blockers cont.
• The 1, 4-dihydropyridine ring is essential for activity
– Substitution at the N1 position or the use of oxidized (piperidine)
or reduced (pyridine) ring systems
• Greatly decreases or abolishes activity
• Ester groups at the C3 and C5 positions optimize activity
– Other electron withdrawing groups show decreased antagonist
activity and may even show agonist activity
99
90. SAR of calcium channel blockers cont.
• For example, the replacement of the C3 ester of
isradipine with a NO2 group produces a calcium channel
activator, or agonist
– Thus the term, calcium channel modulators, is a more
appropriate classification for the 1, 4-DHPs
100
91. SAR of calcium channel blockers cont.
• When the esters at C3 and C5 are nonidentical, the C4carbon becomes
chiral and stereoselectivity between the enantiomers is observed
• Additionally, there is evidence that the C3 and C5 positions of the
dihydropyridine ring are not equivalent positions
• Crystal structures of Nifedipine, a symmetrical 1, 4-DHP, have shown
that the C3 carbonyl is synplanar to the C2-C3 bond, but that the C5
carbonyl is antiplanar to the C5_C6 bond
• Asymmetrical compounds have shown enhanced selectivity for specific
blood vessels and are preferentially being developed
• Nifedipine, the first 1, 4-DHP to be marketed, is the only symmetrical
compound in this chemical class
101
92. SAR of calcium channel blockers cont.
• With the exception of amlodipine, all 1, 4-DHPs have C2 and C6-
methyl groups. The enhanced potency of amlodipine (vs.
Nifedipine) suggests that the 1, 4-DHP receptor can tolerate larger
substituents at this position and that enhanced activity can be
obtained by altering these groups
102
93. SAR of calcium channel blockers cont.
• With the exception of amlodipine, all 1, 4-DHPs have C2 and C6-
methyl groups. The enhanced potency of amlodipine (vs.
Nifedipine) suggests that the 1, 4-DHP receptor can tolerate larger
substituents at this position and that enhanced activity can be
obtained by altering these groups
103
94. Drugs used for treatment of congestive heart failure (Cardiac
glycosides and derivatives)
104
95. Drugs used for treatment of congestive heart failure (CHF)
• Congested cardiac failure is inability of the heart to pump blood
effectively at a rate that meets the needs of metabolizing tissues
• This is a direct result of a reduced contractility of the cardiac
muscles, especially those of the ventricles which causes a decrease in
cardiac output, increasing the blood volume of the heart (hence the term
“congested”)
• As a result, systemic blood pressure and renal blood flow are both
reduced, which often leads to the development of edema in the lower
extremities and the lung (pulmonary edema) as well as renal failure.
• A group of drugs known as the cardiac glycosides were found to reverse
most of these symptoms and complications
Cardiac glycosides
• They are an important class of naturally occurring drugs available to
treat CHF
• Classified into Cardenolides and Bufadenolides
105
96. Classification of Cardiac Glycosides
• Cardenolides, the cardiac glycosides of plant origin, possess
five membered ά-β-unsaturated lactone ring,
• Bufadenolides, derived from animal origin , possess a six
membered lactone ring with two conjugated double bonds
106
97. Mechanism of action
• Cardiac glycosides exert positive inotropic effect on
heart
• At the cellular level, digitalis inhibits membrane-
bound Na+/K+-activated adenosine triphosphatase
– This inhibition increases intracellular Na+
• This Na+ in turn exchanges with extracellular Ca2+,
thus increasing intracellular Ca2+ levels
• Inhibition of the enzyme also decreases outward
pumping of Na+
• The net effect is an increase in the Ca2+ pool
available for excitation-contraction coupling
107
98. congestive heart failure (CHF)
Chemistry of the cardiac Glycosides
• Cardiac glycosides and similar other glycosides are
composed of two portions
– The sugar and the non sugar (the aglycone)
Aglycone
• The aglycone portion of the cardiac glycosides is a
steroid nucleus with a unique set of fused rings,
which makes these agents easily distinguished from the
other steroids
• Rings A–B and C-D are cis fused, while rings B-C
have a trans configuration
– Such ring fusion gives the aglycone nucleus of cardiac
glycosides the characteristics “U shape”
108
99. congestive heart failure (CHF)cont.
• The steroid nucleus also caries, in most cases, two
angular methyl groups at C-10 and C–13
• Hydroxyl groups are located at C-3, the site of sugar
attachment, and at C-14
• The C-14 hydroxyl is normally unsubstituted
109
100. congestive heart failure (CHF) cont.
• However additional hydroxyl groups are located at C–12 and C-16,
the presence or absence of which distinguishes the important genins:
– Digitoxigenin, digoxigenin and gitoxigenin
• These additional hydroxyl groups have significant impact on the
partitioning and pharmacokinetics
• The lactone ring at C–17 is another major structural feature of the
cardiac aglycones
110
101. congestive heart failure (CHF) cont.
Sugars
• The hydroxyl group at C-3 of the aglycone portion is usually
conjugated to a monosaccharide or a polysaccharide with β-1,4
glucosidic linkages
• The number and identity of sugars vary from one glycoside to
another
• The most commonly found sugars in the cardiac glycosides
are D-glucose, D-digitoxose, D-rhamnose, and D- cymarose
– These sugars predominantly exist in cardiac glycosides in the β-
conformation
• In some cases, the sugar exists in the acetylated form
• The presence of an O-acetyl group on the sugar greatly affects
the lipophilic character and the pharmacokinetics of the
entire glycoside
111
103. congestive heart failure (CHF) cont.
Studies based primarily on cardiac toxicity testing data suggested
– The importance of steroid nucleolus
• The 14- β-hydroxyl and 17- unsaturated lactone for activity
– The 17-lactone ring is important for drug– receptor
interaction
113
104. – Using synthetic analogs, it was found that the unsaturation
in the lactone ring is important
• Saturated lactones analogs show diminished activity
– Lactones alone, when not attached with the steroid ring
system, show no Na+/ K+ ATP pump inhibitory activity
– 14–OH group is essential
114
congestive heart failure (CHF) cont.
105. Quiz
1. Explain classification and chemistry of Cardiac Glycosides
2. Describe SAR of ACE inhibitors and ARBs
3. What makes amlodipine different from other calcium channel
blocker structurally ?
115
106. Drugs for the treatment of cardiac arrhythmia
(antiarrhythmic drugs)
116
107. antiarrhythmic drugs
• Arrhythmia is an alteration in the normal sequence of electrical
impulse rhythm that leads to contraction of the myocardium.
• It is manifested as an abnormality in the rate, the site from which
the impulses originate, or in the condition through the
myocardium.
Causes of Arrhythmias
• Many factors influence the normal rhythm of electrical activity
in the heart.
• Arrhythmias may occur either due to
– Pacemaker cells fail to function properly or
– A blockage in the transmission through the Atrioventricular (AV) node
117
108. Classes of Antiarrhythmic Drugs
• Antiarrhythmic drugs can be
placed into four separate
classes, based on their
mechanism of action or
pattern of
electrophysiological effects
produced on heart tissue
– CLASS I. Membrane-
depressant Drugs
– CLASS II. -Adrenergic
Blocking Agents
– CLASS III. Repolarization
Prolongators
– CLASS IV. Calcium Channel
Blockers
118
109. Classes of Antiarrhythmic Drugs
• Anti-arrhythmic agents may also be classified
on the basis of their different pharmacological
actions as follows :
(a) membrane-stabilizing agents ;
(b) antisympathetic drugs ;
(c) prolonging cardiac action ; and
(d) interference with calcium conductance
119
110. Class I antiarrhythmic agents
• Class I antiarrhythmic agents are drugs that have membrane-
stabilizing properties (i.e., they shift membranes to more negative
potentials).
• Drugs in this class act on the fast Na+ channels and interfere with the
process by which the depolarizing charge is transferred across the
membrane.
• It is assumed that these drugs bind to the Na+ channel and block its
function, preventing Na+ conductance as long as the drug is bound.
• Quinidine and procainamide are the prototypical drugs in this class
• Class I antiarrhythmic drugs can be subdivided based on the relative
ease with which they dissociate from the Na+ ion channel as class IA,
class IB and class IC
120
111. Class I antiarrhythmic agents cont.
• Class IA antiarrhythmic agents:
– Quinidine, procainamide, and disopyramide are drugs that have an
intermediate rate of dissociation from Na+ channels.
– They lengthen the refractory period of cardiac tissue to cause cessation of
arrhythmias
• Class IB antiarrhythmic agents:
– Include lidocaine, tocainide, and mexiletine
– Dissociate rapidly from the Na+ channels
• Thus, have the lowest potency as sodium channel blockers.
– They produce little, if any, change in action potential duration.
• Class IC antiarrhythmic agents:
– Include flecainide, encainide, lorcainide, and moricizine
– They are the most potent sodium channel-blocking agents of the class I
antiarrhythmic drugs
– They slowly dissociate from the Na+ channel, causing a slowing of the
conduction time of the impulse through the heart.
121
113. CLASS II: β-ADRENERGIC BLOCKING AGENTS
• β-Adrenergic blocking drugs cause membrane-
stabilizing or depressant effects on myocardial tissue
• Their antiarrhythmic properties, however, are
considered to be principally the result of inhibition of
adrenergic stimulation to the heart.
– Examples: Propranolol (the prototype drug in this class),
sotalol
123
114. CLASS III. REPOLARIZATION PROLONGATORS
• Drugs in this class cause several different electrophysiological
changes on myocardial tissue but share one common effect,
prolonging the action potential
– which increases the effective refractory period of the membrane action
potential without altering the phase of depolarization or the resting
membrane potential.
– Include bretylium (the prototype drug for this class), amiodarone,
ibutilide, and dofetilide
• Drugs in this class produce their effects by more than one
mechanism.
124
115. CLASS IV. CALCIUM CHANNEL BLOCKERS
• Not all Ca2+ channel blockers possess antiarrhythmic
activity, some members of this class of antiarrhythmic drugs
(verapamil, diltiazem) block the slow inward current of Ca2+
ions (voltage-sensitive channel) in cardiac fibers
– This slows down AV conduction and the sinus rate
• For example, the prototypical drug in this group, verapamil,
selectively blocks entry of Ca2+ into the myocardial cell.
• It acts on the slow-response fibers found in the sinus node
and the AV node, slowing conduction velocity and increasing
refractoriness in the AV node.
• These drugs are used in controlling atrial and paroxysmal
tachycardias
125
117. ANTIHYPERLIPIDEMIC AGENTS
• The major cause of death in the Western world today is
vascular disease, of which the most prevalent form is
atherosclerotic heart disease,
– which can be treated through medication or surgery.
• Hyperlipidemia is the most prevalent indicator for
susceptibility to atherosclerotic heart disease
– it is a term used to describe elevated plasma levels of lipids
that are usually in the form of lipoproteins.
• Hyperlipidemia may be caused by an underlying disease
involving the liver, kidney, pancreas, or thyroid, or it may not
be attributed to any recognizable disease.
• In recent years, lipids have been implicated in the development
of atherosclerosis in humans.
127
118. Introduction cont.
Atherosclerosis may be defined as degenerative changes in
the intima of medium and large arteries.
– This degeneration includes the accumulation of lipids,
complex carbohydrates, blood, and blood products and
– is accompanied by the formation of fibrous tissue and
calcium deposition on the intima of the blood vessels.
– These deposits or plaques decrease the lumen of the
artery, reduce its elasticity, and may create foci for
thrombi and subsequent occlusion of the blood vessel
128
119. Introduction cont.
Lipoprotein Classes
• Lipoproteins are macromolecules consisting of lipid substances
(cholesterol, triglycerides) non-covalently bound
with protein and carbohydrate.
• These combinations solubilize the lipids and prevent them from
forming insoluble aggregates in the plasma.
• They have a spherical shape and consist of a nonpolar core
surrounded by a monolayer of phospholipids whose polar groups
are oriented toward the lipid phase of the plasma.
– Included in the phospholipid monolayer are a small number of
cholesterol molecules and proteins termed apolipoproteins.
• The apolipoproteins appear to be able to solubilize lipids for
transport in an aqueous surrounding such as plasma.
129
120. Introduction cont.
• The various lipoproteins found in plasma can be separated by
ultracentrifugal techniques into
– Chylomicrons, very-low-density lipoprotein (VLDL),
intermediate-density lipoprotein (IDL), low-density lipoprotein
(LDL), and high-density lipoprotein (HDL).
– Chylomicrons contain 90% triglycerides by weight and
originate from exogenous fat from the diet.
• They are the least dense of the lipoproteins
• The VLDL is composed of about 60% triglycerides, 12%
cholesterol, and 18% phospholipids. It originates in the liver from
free fatty acids (FFAs).
– It is catabolized rapidly into IDL, which is degraded further into
LDL.
130
121. Introduction cont.
• The LDL consists of 50% cholesterol and 10%
triglycerides.
– This is the major cholesterol-carrying protein.
– In normal persons, this lipoprotein accounts for
about 65% of the plasma cholesterol and is of
major concern in hyperlipidemic disease states.
• The HDL is composed of 25% cholesterol and 50%
protein and accounts for about 17% of the total
cholesterol in plasma
131
122. Hyperlipoproteinemia
• Lipid disorders are related to problems of lipoprotein metabolism that create
conditions of hyperlipoproteinemia.
• The hyperlipoproteinemias have been classified into five types, each of
which is treated differently
Type I hyperlipoproteinemia: is caused by a decrease in the activity of
lipoprotein lipase, an enzyme that normally hydrolyzes the triglycerides present
in chylomicrons and clears the plasma of this lipoprotein fraction
– This type may be treated by decreasing the intake of dietary fat. There are
no drugs at present that can be used to counteract type I hyperlipidemia
effectively
Type II hyperlipoproteinemia: has been divided into types IIa & IIb
– Type IIa is characterized by elevated levels of LDL (β-lipoproteins) and
normal levels of triglycerides.
• It is very common and may be caused by disturbed catabolism of
LDL.
– Type IIb differs from type IIa, in that this hyperlipidemia has elevated
VLDL levels in addition to LDL levels.
132
123. Hyperlipoproteinemia cont.
Type III is a rare disorder characterized by a broad band
of β-lipoprotein.
– Like type II, it is also familial. Patients respond favorably to
diet and drug therapy.
Type IV hyperlipoproteinemia: levels of VLDL are elevated as
this type of lipoprotein is rich in triglycerides, plasma
triglyceride levels are elevated.
– The metabolic defect that causes type IV is still unknown; this
form of hyperlipidemia, however, responds to diet and drug
therapy.
Type V hyperlipoproteinemia: has high levels of chylomicrons
and VLDL, resulting in high levels of plasma triglycerides.
– The biochemical defect of type V hyperlipoproteinemia is not
understood.
– Clearance of dietary fat is impaired, and reduction of dietary
fat is indicated along with drug therapy
133
125. ANTIHYPERLIPIDEMIC AGENTS cont.
• The following drugs are used to treat hyperlipidemic conditions
include:
– Clofibrate, Gemfibrozil, Fenofibrate, Probucol, Nicotinic acid, 3-
pyridinecarboxylic acid (Niacin), Sitosterol, Colesevelam,
Dextrothyroxine, Cholestyramine, Colestipol, and Ezetimibe
• Clofibrate: the drug of choice in the treatment of type III
hyperlipoproteinemias and may also be useful, to a lesser extent, in
types IIb and IV hyperlipoproteinemias.
– It is not effective in types I and IIa
– It can lower plasma concentrations of both triglycerides and
cholesterol, but it has a more consistent clinical effect on
triglycerides.
135
126. ANTIHYPERLIPIDEMIC AGENTS cont.
• Clofibrate also affects lipoprotein plasma levels by enhancing
removal of triglycerides from the circulation and causes reduction of
VLDL by stimulating lipoprotein lipase to increase the catabolism of
this lipoprotein to LDL
– It also regulates cholesterol synthesis in the liver by inhibiting
microsomal reduction of 3-hydroxy-3-methylglutaryl-CoA (HMG-
CoA), catalyzed by HMG-CoA reductase
• Gemfibrozil is a congener of clofibrate that was used first in the
treatment of hyperlipoproteinemia in the mid-1970s.
– Its mechanism of action and use is similar to clofibrate.
– It reduces plasma levels of VLDL triglycerides and stimulates
clearance of VLDL from plasma.
– It has little effect on cholesterol plasma levels but does cause an
increase of HDL
136
127. ANTIHYPERLIPIDEMIC AGENTS cont.
• Fenofibrate has structural features represented in
clofibrate.
– The primary difference involves the second
aromatic ring.
– This imparts a greater lipophilic character than
exists in clofibrate, resulting in a much more potent
hypocholesterolemic and triglyceride-lowering
agent.
– This structural modification results in a lower dose
requirement than with clofibrate or gemfibrozil.
137
128. ANTIHYPERLIPIDEMIC AGENTS cont.
• Probucol molecule has two tertiary butylphenol groups linked by a
dithiopropylidene bridge, giving it a high lipophilic character with
strong antioxidant properties.
– In humans, it causes reduction of both liver and serum
cholesterol levels, but it does not alter plasma triglycerides
– It reduces LDL and (to a lesser extent) HDL levels by a unique
mechanism that is still not clearly delineated.
– The reduction of HDL may be due to the ability to inhibit the
synthesis of apoprotein A-1, a major protein component of
HDL.
– It is effective at reducing levels of LDL and is used in
hyperlipoproteinemias characterized by elevated LDL levels
138
129. ANTIHYPERLIPIDEMIC AGENTS cont.
• Nicotinic acid, 3-pyridinecarboxylic acid (Niacin): is effective in the
treatment of all types of hyperlipoproteinemia except type I, at
doses above those given as a vitamin supplement
– The drug reduces VLDL synthesis and subsequently, its plasma
products, IDL and LDL.
– Plasma triglyceride levels are reduced due to the decreased
VLDL production.
– Cholesterol levels are lowered, in turn, because of the decreased
rate of LDL formation from VLDL
– Its hypolipidemic effects may be caused by its ability to inhibit
lipolysis (i.e., prevent the release of FFAs and glycerol from fatty
tissues).
139
130. HMG-CoA Reductase Inhibitors
• HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) Reductase
Inhibitors
• Drugs in this class of hypolipidemic agents inhibit the
enzyme HMG-CoA reductase
– Responsible for the conversion of HMG-CoA to mevalonate in
the synthetic pathway for the synthesis of cholesterol.
• HMG-CoA reductase is the rate-limiting catalyst for the
irreversible conversion of HMG-CoA to mevalonic acid in the
synthesis of cholesterol.
140
131. HMG-CoA Reductase Inhibitors cont.
141
• When cholesterol is available in sufficient amounts for body needs, the
enzyme activity of HMG-CoA reductase is suppressed
– Elevated plasma cholesterol levels have been correlated with an
increase in cardiovascular disease.
– Of the plasma lipoproteins, the LDL fraction contains the most
cholesterol.
– It is generally accepted that total plasma cholesterol is lowered most
effectively by reducing LDL levels
• HMG-CoA reductase inhibitors contribute to this by directly blocking the
active site of the enzyme.
• This action has a two-fold effect on cholesterol plasma levels; it
causes a decrease in de novo cholesterol synthesis and an increase in
hepatic LDL receptors.
• These HMG-CoA reductase inhibitors are effective hypocholesteremic
agents in patients with familial hypercholesteremia
132. HMG-CoA Reductase Inhibitors cont.
• Lovastatin, simvastatin (is an analog of lovastatin), and
pravastatin (is the most rapid acting of the three HMG-CoA
reductase inhibitor drugs, reaching a peak concentration in about
1 hour), compose the list of approved HMG-CoA reductase
inhibitors for the treatment of hyperlipidemia in patients.
• The three drugs have structures similar to the substrate, HMG-
CoA, of the enzyme HMG-CoA reductase.
• Lovastatin (is a potent inhibitor of HMG-CoA) and simvastatin
are lactones and prodrugs, activated by hydrolysis in the liver to
their respective β-hydroxy acids.
• Pravastatin, in contrast, is administered as the sodium salt of the
β-hydroxy acid
142
133. HMG-CoA Reductase Inhibitors cont.
• Fluvastatin is very similar to pravastatin
• Atorvastatin also possesses the heptanoic acid side
chain, which is critical for inhibition of HMG-CoA
reductase.
– Although the side chain is less lipophilic than the lactone
form, the high amount of lipophilic substitution causes this
agent to have a slightly higher level of CNS penetration than
pravastatin, resulting in a slight increase in CNS side effects.
143
Editor's Notes
preload is the end diastolic pressure that stretches the right or left ventricle of the heart to its greatest geometric dimensions under variable physiologic demand
Afterload is the tension or stress developed in the wall of the left ventricle during ejection.
Myosins are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility.
The sarcoendoplasmic reticulum (SR) calcium transport ATPase (SERCA)