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57 views48 pagesPharmac
Questions pepper
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© © All Rights Reserved
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/ 48
Pharmacology of Drugs Acting on CVS (Chapter 1) 15
<=
CHAPTER Pharmacology of Drugs
1 Polit: mol meh cd
PIR PM Gt cath ea
1.1.1. Introduction
Cardiovascular system comprises of the heart and
tructure of Blood vessels. that transports oxygen, nutrients, heat, and other
substances throughout the body,
n_ extensively branched
Cantiac or heart muscles are involuntary. striated muscles found in the hear and
jis walls, especially in the myocardium (the muscle tissue forming a thick
eadle layer amid the outer epicardium and the inner endocardium). For
oxygen and nutrients, and removing waste products such as carbon
cardiac muscle cells depend on the available blood and electrical
delivering
dioxide, the
supply
The myocardial tissue is made up of contracting cells and conducting cells.
heart involves the contracting cells. The
The pumping action of the
conducting tissues of the heart include SA node (acts as the pacemaker), AV
node, and His-Purkinje system. Various parts of the conducting tsstie exhibit
Gutomaticity. Cardiac muscles being specialised tissues have_ distinct
propertiesof:
Excitability: It is the ability of cardiac cells to depolarise in ©
stimulus.
response to a
Itis the ability of myocardium to contract and pump blood out
2) Contractilit
of the heart.
3) Antomaticity: It is the ability of cardiac cells to generale electrical impulses
spontaneously
1.1.2. Hemodynamics
dy of the dynamic behaviour of blood is termed hemodynamics.
nL
Ga are generated in the various parts of heart (cardiovascular pressures)
hen blood flows from one chamber to-another, w hen valves open and close, and
‘when the myocardium contracts and relaxes Catheters are used
monitor these pressures by_placing-their-tips-in-the. atria, pulmonary artery. oF
mig arteries; these are called the hemodynamic lines,
1 to measure-and
Hemodynamic lines have multiple uses
1) They allow the sampling of venou
frequently,
and arterial blood without having to stick
nces tO
2) They help in monitoring different waveforms, thus providing.
Patient’s status. pressures, and_analysis of
yy .in-shock, cardiag
rect ao TE ing therap! _
sures helps in_ planning. and assesses a
failure fluid overload or deficit, and other conditions) 1
When a heart fail
1.1.3. Electrophysiology of Heart i requirements, a cor
A vmbrane. It has a resting oe ee
e cardiac cell is a polarised
i out
<80 to -90mV, and a high Na” ion concentration OF b :
jon concentration inside the membrane, Upon ‘excitation, depolarisation occurs as] CHF is caused due
te call embsane permeability to No" jons increases, the nepatiy of resting) 1) Narrowing of
potential is lost, and a positive current is generated inside the cell. The} 2) Any congenita
Pharacterstics of action potential rely on the type of the cell-myocardial | 3) Endocarditis (
coaraentle cell, or pacemaker, or potential pacemaker cell. There are five phases: eee
‘ofthe action potential of cardiac cells (figure 1.1): » Caan
1) Phase 0: In this phase, rapid >) Aye
depolarisation of the cell membrane a nae
is observed as the sodium ions é :
rapidly enter the cell through sodium —_, 6) Past history ¢
channels. This phase is followed by heart attack ar
re-polarisation.
2) Phase 1: In this short and initial
phase, rapid re-polarisation is
observed as the potassium ions move
out of the cell
side the membrane and K*
_Some common sy
1) Fatigue,
3) Shortness of br
1.2.2. las
3) Phase 2: This. prolonged plateau The foffowing dn
phase is observed as the calcium pss 1) Drugs with Pe
Gong enter the cell slowly.through the Fes: Faas of Gunlac tion Foie i) Cardiac!
alles Phase 0 Indicates R: Phases
calcium, channels. ‘This, phase..of .t-3tedecte Reecawate wn ii) Bipyridi
Reteerercnisisssrctentonly inthe Greamioeeudesacameneee a” 4
ton poten tring Distole iii) B-Adren
4) Phase 3: This phase is the second peri i ae
: riod of -polarisati a rihas
eaten Sea ity bortke cell: pers Cee i) Diuretic
5) Phase 4: This is the restiny ine
: 1g phase as the resting membrane i De
i ter - : -
established when the potassium ions return into the cell acct celvun a it) Cae
calcium ions move out of it. sodium and iv) Vasodil
The cells do not depolarise in res
The cells do ponse to another impulse dur
and 2; and this is called the absolute refractory period, The cell detracts inl CG
response 10 powerful impulse during the phases 3 and 4; and this eedlcg en, | Gee eee wine giyeeat
relative refractory period. : 27 a ude
The heart rate and stroke volume are used for determini
eZ j
siroke volume depends on the preload (which ee output The
afterload, and contractility, The load on the heart due to the blood ealune
volume
reaching the left ventricle is called preload; while the resis
ventricular ejection, ie, the Cotal peripheral resistance is a left ology-t1
nonary,
ysis of
cardiac
atial of
and K*
curs as
resting
I. The
cardial
phases
as the
| is re.
m and
ases 1
rise in
led the
ut. The
eturn),
lume
Jeft
pharmacology of Drugs Acting on CVS (Chapter 1)
eect me ee a
eS
1.2.1, Introduction
When @ heart fails to pump blood in a
estive
ntity sufficient to fulfil the body
art Failure (CHF) occurs, which is
requirements, @ condition of C
also known as a Heart Failure (HF).
CHF is caused due to:
J) Narrowing of the arteries supplying blood to the heart muscles,
Any congenital heart defects
3) Endocarditis (infection in heart valves) or myocarditis (infection of heart
muscles)
Cantiomyopathy (disease of the heart muscles)
5) Any long-term heart valve disease (due to past rheumatic fever or other
causes) and high blood pressure, and
6) Past history of the patient who has suffered from myocardial infarction or
heart attack and the injured tissue obstructs the normal functioning of heart.
Some common symptoms of CHF are
1) Fatigue 2) Swelling or oedema,
3) Shortness of breath, and 4) Increased urination.
12.2. Classification
The foffowing drugs are employed in the treatment of CHF
1) Drugs with Positive Inotropic Effects
i) Cardiac Glycosides: Digoxin, Digitoxin, and Ouabain.
ii) Bipyridines/Phosphodiesterase Inhibitor:
iii) Adrenergic Agonists: Dobutamine and Dopamine.
Amrinone and Milrinone.
2) Drugs without Positive Inotropic E
i) Diuretics: Thiazides, Furosemide,
ii) Angiotensin Antagonists: ACE inhibitors and Losartan,
iii) B-Adrenergic Antagonists: Bisoprolol, Carvedilol, and Metoprolol
iv) Vasodilators: Nitrates and Hydralazine
nd Spironolactone.
1.2.3. Cardiac Glycosides
c glycosides are derived-from plant derivatives and are steroidal in mature,
coside is-a sugar-containing compouiid in Which one of the hydroxyl groups
of the sugar molecule is replaced with another compound. )
Digoxin, digitoxin, and ouabain are the common ide:
5 bain o xd cardiac glycosides.
Ofien, the term di ‘otal lds axall
igitalis refers to the complete group of eardiae-glycosides
the drugs in this group exert the same effects on the hearts TREY rater oly i
ipid_solubility, bind
rapidity, degree of absorpi stein _b
Pathway, and excretion. ae 1.2)
vent follows (figure
a a ae
polite ‘since digitalis incre
digitalis can
mechanism of action of ‘i
Hr als exerts poste rca
citation -contraction cot io.
Scare antec
a Or ae Myocardial cell
on 7
me
Ca + Troponin —»
Actin + Myosin —»
Actomyosin >
Myocardial contraction
nzyme N“/K*-AT
Mechanism of Digitalis Action. Bi
Ml K to low out along the concentration
hg the Na’ out and drawing the K” in:
of Ca” from Sarcoplasmic
iating myocardial contraction,
* Digitalis acts on the
Figure 1.2: Cella
ee
Reticulum (SR); e) Ca™+ troponin i
2) It inhibits the membrane bound Na‘/K*-ATPase transport system (sodium
Pump), resulting in increase of inracellilar Na* fone ony ye of intracellular
K* ions
Na" ions accumulate inside the cell, it activates a Na®/Ca* c; m
Cae tic protein carrier) within the membrane The activation of
Na:/Ca"‘carrier system results in an increase ip the influx of Ca** ions Three
Na” ions are exchanged for each Ca?" ion thereby generating an electrogenié
Potential By this exchanger. 7
4) Normally, the concentration of Ca™ ions around the myofilaments is lowered by
ihe Ca ion pump in the Satcoplasmic Reticulum (SR), The energy for diving
this pump is obtained by ATP hydrolysis carried out by Na'/K~ATPase.
However, digitalis inhibits this enzyme-and-hence less chergy is-available for
diving. the Ca ion pump, Thus, the supply of Ca ions from SR around the
myofilaments increases, which in turn SStvales the contractile machinery,
5) The binding Of digitalis to sodium Pump is inhibited by the K* ions Present in
the serum. Hence, conditi hypokalaemia faciies apes
digitalis. On the other hand condi vperkttethe_action of
ia induce 28. Of byperkalacaaa can_decrease
cardiac toxicity, Amhythmia nduced by digitalis, ie hee cr
8F hypercalcaemia or hypo emg is "teased by conditions
1.2.3.2. Pharmacokinetics
Route of administration of digitalis ig cither 9, i
7 +f OF intraye is
Suitable for administration by subcutaneous or TT Tits 4
absorption from these sites is not reliable fd may bring abo cote a
tenderness, swelling, and abscess, imi Pharmacology of Drugs Acting on CVS (Chapter 1) 19
Digitalis does not bind selectively to the myocardium-when-administered through
these sites. Digitalis is a cumulat _a prolonged half-life and the
duration of its action ranges from days to weeks. The prolonged plasma half-
life of digitoxin is due fo its enterohepatic circulation. ci
1.2.3.3. Pharmacological
Cardiac glycosides have the capability of increasing the myocardial contraction force,
which is the most significant property of these drugs. Other than this, they have
several extra-cardiac effects on vascular smooth muscles, kidneys, gut and the CNS:
ns on Heart
i) Admi ion in small doses causes an increase in the vagal tone by
sensitisation of baroreceptors and/or activity of the afferent nerves. As a
result, sinus activity decreases which leads to decrease in conductivity,
prolongation of refractory period of the AV node, decrease in atrial
refractory period, and bradycardia.
ii) Contractility of the myocardium increases by a direct positive
inotropic action of digitalis on the heart. Thus, the failing heart contracts
even more forcefully, which results in increased cardiac output, complete
ventricular emptying,
size. Systole lasts for a shorter duration, giving more time for ventricular
filling and rest to the heart
and decreased diastolic pressure and ventricular
iii) With the increase in contractility of heart, the oxygen consumption in the
myocardium increases. On the other hand, decrease in the heart rate and
ventricular size decreases oxygen requirements of the heart. Hence, the
general effect of digitalis is an improved ventricular performance of
the failing heart without any significant increase in energy requirement
iv) When administered in comparatively small therapeutic doses, digitalis
improves. the—abil tation of the myocardium. and. the
conduction velocity. However, its administration in high doses causes an
increased automaticity and decreases the refractory period of the atria
and the ventricles, resulting in extra-systoles, pulsus bigeminus, and
ventricular fibrillation.
¥) Digitalis slows the conduction velocity in the AV node and His-Purkinje
gystem, regardless of the dose administered. This is achieved by an
increase in the refractory period by both vagal as well as the extra-vagal
actions of digitalis. Low-doses-are characterised by-a predominance of
vagal-effeets. As the dose sed, direct depressant action on the
AVnodeis-seen.
vi) Digitalis does not act directly to influence. the coronary flow. The
enhanced coronary circulation_is.a secondary. effect of the increased
) Erythromycin, omeprazole, and tetracycline increase the bioavailability of
ents, digoxin
8) Propranolol, verapamil, diltiazem, and disopyramide oppose the positive
notropic action of digitalis and may add to the depression of A-V conduction.
©) Phenobarbitone accelerates the metabolism of digitoxin, thus, reducing its
plasma half-life.
heart 10) Administration of succinylcholine by the patients on digitalis therapy causes
by arrhythmias.
1.2.3.7. Contraindications
Cardiac glycosides are contraindicated in the following conditions
talis is contraindicated in hypokalaemia as its binding to Na"K*-ATPase
is increased, thus increasing digitalis toxicity
2) Itis contraindicated in elderly and in patients having severe renal or hepatic
disease.
3) It is contraindicated in myocardial infarction as severe arrhythmias may
develop.
4) It is contraindicated in thyrotoxicosis as the patient's responsiveness
dex decreases, and arrhythmias may also develop.
rt a 5) It is contraindicated in ventricular tachycardia as it may precipitate
ents ventricular fibrillation
v 6) It is contraindicated in Wolff-Parkinson-White Syndrome as it may result
lude in ventricular failure.
ie to 7) Administration of digitalis in patients with a partial A-V block may convert
The it into a complete A-V block.
tan 8) Digoxin is contraindicated in myxoedema as its elimination rate decreases,
oca, thus, cumulative toxicity of digitalis may be seen.
1.2.3.8. Treatment of Digitalis Toxicity
The cases of digitalis toxicity can be treated in the following ways:
mia, 1) Withdrawal: Administration of digitalis should either be stopped or the dose
should be reduced based on the severity of toxicity. Use of potassium
depleting diuretics should be discontinued,
2) Potassium Repletion: KCl is administered by oral route (or by slow
in a dosage of 2gm in every 4 hours. During this time, ECG of the t
should be continuously monitored, However, in case of a Se ;
KCI should not be given. IE EI Drugs: Ventricular tachyarshythimias em be suppressed
I and. lignocaine since they have either: litle, OE SD fe
‘conduction. Phenytoin is ‘administered in a dose of 100mg if
every $ minutes till arrhythinia is treated,
Supraventricular and ventricular tachycat
wend by administering propranolol in dos
‘Sinus bradycardia and various degrees of AV block can
dia, without AV block, can
sages of 20-HOmg/day-
be controlled
atropine.
4) Advanced Cases of Life Threatening Digitalis Intoxieation: Such conditions | 1.2.6, Di
an be reversed by inserting a temporary cardiac pacemaker catheter, along with} Diuretics are co
specific antibody (digitalis immune fab) fragments. these agents are
1.2.6.1. Me
Bipyridine derivati: Duele ad
(PDE) inhibiting activity. These drugs are selective inhibitors of PDE-isoenzyme } ventricular pre-
MI, found in the cardiac en ale
blood vessels. 1
1.2.4.1. Mechanism of Action ———a
Bipyriines Increase the production of cAMP in the heart and blood vessels, and
Tea aX Positive inotropic action along with vasodilator activities. Increase | 1-28-2- The
Ones th ntecellular CAMP enable the availability of more intracellular Cg} Diuretics are us
ons, thus, a more positive inotropism may result. ae
1242. "Therapeutic Uses ae
utput is increased. The peripheral vascul e Dee
& decreased with no significant change in. heat Tae ned od an
ipynidines are used only for the treatment of heart fa cen a loos seems
lure or exacerbation of CCE.
B-Adrenergie Agonj.
ZOnists
The discovery of By-agonists has suffic, d
agonist with minimal positive chronowee jes Sees
| h for a positive inotropie
dobutamine being the most potential one resp **AYthmogenie potential wi
lese agents,
amongst th
1.2.5.1. Mechanism of Action
The radrenergic agonists increase the cardi
ventricular filling pressure and pre-load, Some rks, cu PU and decrease
With the use ofthese drugs. They increase the coma of ehyeardia is also se
of oxygen, Pharmacology of Drugs Acting on CVS (Chapter 1) 23
1.2.5.2. Therapeutic Uses
The f-adrenergic agonists have been limited to the management of acute heart
failure. They may occasionally be employed in the treatment of refractory
be CCF.
1.2.5.3. Adverse Effects
th | The P-adrenergic agonists may cause tachyphylaxis.
ns, 1.2.6. Diuretics
th Diuretics are commonly used in the management of CHF. Since the last 50 years,
these agents are favoured for CHF treatment.
1.2.6.1. Mechanism of Action
- Diuretics increase the excretion of salt and water. This in tum decreases the
3 yentricular pre-load and the cardiac size, improves pump function, and helps
relieve oedema. In CHF patients, aldosterone promotes fibrosis in the heart and
blood vessels. This effect of aldosterone is antagonised by spironolactone (an
aldosterone antagonist).
1.2.6.2. Therapeutic Uses
Diuretics are used in the management of all stages of CHF. Furosemide is a very
efficient diuretic in treating acute left ventricular failure (cardiac asthma).
1.2.6.3. Adverse Effects
The adverse effects of various classes of diuretics are:
ad 1) Loop Diuretics: Hypokalaemia is a common adverse effect. Patients on
long-term diuretics require potassium supplements and _ regular
monitoring. At high doses, hyponatraemia may occur, which needs
careful supervision in heart failure patients, Ototoxicity characterised
with tinnitus, vertigo and deafness also occurs at high doses of loop
diuretics. Therefore, intravenous administration of furosemide should not
ly be faster than 4mg/min.
2) Thiazide Diuretics: Due to potassium and sodium loss, the adverse effects
er | of thiazide diuretics are similar to those of loop diuretics. However, the
potassium loss is reduced when ACE inhibitors are simultaneously
prescribed. Diabetic patients need monitoring as diabetes may occur with
thiazide diuretics. Impotence as well as sensitivity may also develop due to
the presence of sulphonamide in the drugs.
‘ 3) Aldosterone Antagonists: Adverse effects include fibrosis, hypertrophy,
fi arthythmogenesis, and hyperkalaemia, which require regular monitoring
because of its potentially lethal effects in CHF patients due to renal
failure.
Hyponatraemia and feminisation such as gynaecomastia are other adverse
effects. In patients having severe symptomatic systolic heart failure,
spironolactone is recommended along with ACE inhibitors. ™
1.2.7, Angiotensin Ant ;
‘The ACE inhibitors and angiotensin receptor blockers are included in thi
1.2.7.1. Mechanism of Action . A
Drugs which inhibit the activity of RAS either interfere with the biosynthesis
angiotensin I [Angiotensin Converting Enzyme (ACE) inhibitors]. or act
antagonists of angiotensin receptors {Angiotensin Receptor Blockers (ARBs)],
The production of angiotensin II from angiotensin I is inhibited by
inhibitors. These agents neutralise the raised peripheral vascular resistance
‘retention of sodium and water that resulted from angiotensin II and aldosterone,
1.27.2. Pharmacological Actions
‘The pharmacological actions of angiotensin antagonists are: 2) Moderate: Dia
1) Reduction in peripheral arterial resistance and after-load. Sci
2) Reduction in aldosterone secretion, thus decreasing the retention of salt ‘Symptoms of hype
‘Water. This causes venodilatation and reduces pre-load. 1) Chest pain,
%) Redaction in angiotensin concentration in the tissues, thus reduey 3) Earnoise orb
ansiotensin-induced tissue norepinephrine release 5) Nosebleed
4) Reduction in the long-term remodelling of heart and blood vessels. 7 ae aaa
1273. Therapeutic Uses (tpecaby for eppele
Angiotensin antagonists are indicated in all symptomatic and asymptomatid) “rps fet ishe
LV) dysfunction. ACE inhibitors (e.g,, enalap id ofeaaed ‘the
de diversity of actions and are considered to b 7%
nes ‘would result in orga
13.2. Classif
‘The antihypertensiv
1) Diureties
mpensation. Yet, it
Tithe treat
in Patients requiring Baa em OF i
been found in the cu e
1.2.9.
Vasodilators have an inditect benef
ees by hydralazine and ae the wi Aterolar aia
(caused by nitrates) decreases preload. These agents ie tot, Venodilatatig
Primary treatment. Use of hydralazine or isosorbiyn etl adjunctive ford
shown to decrease damage to the rem: on a long-term has
— FOU.
esis of
act as
a). |
ACE
and
one,
It and
ucing
matic
april
to be
adies
vhen
| any
rane-
ound
hese
| has
tion
tion
‘Pharmacology of Drugs Acting on CVS (Chapter 1) as
ANTI-HYPERTENSIVE DRUGS
1.3.1. Introduction
A condition in which the blood pressure of systemic artery increases beyond the
normal pressure is known as hypertension. Therefore to deliver blood to tissues,
the heart works harder to overcome the increased systemic pressure, This
increased systemic arterial pressure puts strain on the heart and other arteries,
thus resulting in high blood pressure
Based on the degree of severity, hypertension can be graded as:
1) Mild: Diastole up to 104mmHg,
2) Moderate: Diastole105-114mmHg, and
3) Severe: Diastole more than 11 5mmHg.
‘Symptoms of hypertension are
1) Chest pain, 2) Confusion,
3) Earnoise or buzzing (tinnitus), 4) Irregular heartbeat (arrhythmia),
5) Nosebleed (epistaxis), 6) Exhaustion (lethargy), and
7) Vision changes. yan
. Aaa
(erapy for hypertensive patients aims at reducin} {he increased blood pressut
This is accomplished by administration of drugs from different classes; treatment
is often given in the form of a combination of several agents. If left untreated, it
would result in organ damage, thus an increased risk for MI and stroke.
13.2. Classification
The antihypertensive agents are classified into the following classes
1) Diuretics
i) Thiazides: Hydrochlorothiazide, Chlorthalidone, and Indapamide.
ii) Loop Diuretics: Furosemide, Bumetanide, and Torsemide.
iii) K* Sparing Diuretics: Spironolactone, Amiloride, and Triamterene
2) Angiotensin Converting Enzyme Inhibitors: Captopril, Enalapril, Lisinopril,
Ramipril, Perindopril, Fosinopril, Trandolapril, Quinapril, and Benazepril.
3) Angiotensin II Receptor Antagonists: Losartan, Candesartan, Valsartan,
Eprosartan, and Irbesartan. z
4) Ganglion Blockers: Trimethaphan.
5) Adrenergic Drugs
i) Centrally Acting Drugs: Clonidine, Methyldopa, Guanabenz, and
Guanfacine.
ii) Adrenergic Neuron Blockers: Guanethidine and Reserpine.
iii) Sympatholytics (Adrenergic Receptor Blockers) 4
4) @ Blockers: Prazosin, Terazosin, Doxazosin, Phenoxybenzamine,
and Phentolamine. r
b) BBlockers: Propranolol, Atenolol, Esmolol, and Metoprolol.
©) a+B Blockers: Labetalol and Carvedilol. e -
0 Channel Blockers: Verapamil, Nifedipine,
Saati ‘Amlodipine, and Felodipine.
7) Vasodilators:
idi
i) Arteriolar Dilators: Hydralazine, Minox)
HN Arteriolar and Venular Dilators: Sodium nitroprus
il, and Diazoxide.
sside.
1.3.3. Diuretics om Bracediel
Drugs promoting urine output are known as eee Aiea deal y 4
kidneys and primarily increase the excretion vin
chloride (CT) or bicarbonates (HCO ; )] from the body:
: strokes, heart
The antihypertensive action of diuretics is that they promote the excretion g 2) Combate
sodium and water resulting in: fee dose reduces t
1) Decreased plasma volume — 4 cardiac output > inks 2) Dinca
2) Decreased body sodium — relaxation of vascular smoot iy” owed ape
Na’ ion depletion in the vascular smooth muscle) — PVR > J BP.
The amount of diuretic required will be reduced if the intake of dietary salt i
restricted, Some common drugs used as diuretics are: ,
1) Thiazides: These diuretics (e:g., hydrochlorothiazide and chlorthalidone) are] 6) Eplerenone d
the inexpensive first-line antihypertensive agents. They are commonly myocardial in
in hypertension treatment. the treatment
Loop Diuretics: These diuretics (e.g, furosemide, bumetanide, and] Loop diureties a
torsemide) are powerful diuretics but have low antihypertensive efficacy.| function. Loop d
They are used only in hypertensive patients having chronic renal failure o#| than 2.Smelal. In
congestive heart failure. They are included in the treatment of malignant} an acute vasodilat
hypertension and hypertension with hypervolemia (e.g, ren
insufficiency), 1333. Adv
Thiazide diureti
ficacy; however, they] "YPokalacmia,
correct the potassium loss eaused by thiazide and loop divretic hyper teaeaaae
used in combination with hydrochlorothiazide. their side effects
and sulphonamid
levels.
2) Loop Diuretics: These diuretics act atthe hs
ma ,
prevent the reabsorption of CI and Na* ions ge sScendin
action in comparison to thiazide diuretics is
fom hss loop of Henle
silition sa
agi ine. Their onset y on the
m (Na*),
etion of
(due to
alt is
one) are
ly used.
le, and
fficacy.
ilure or
lignant
renal
lactone,
er, they
hey are
jazide)
jazone)
odium-
e. This
| renin
y some
atment
enle to
nset of
‘pharmacology of Drugs Acting on CVS (Chapter 1) ”
43) Potassium-Sparing Diuretics: These diuretics decrease the excretion of
Mg” and K* ions, Amiloride and triamterene inhibit the Na/proton exchanger
in the distal and collecting tubules, ‘They block the epithelial sodium
transport channel. Spironolactone inhibits the Na/K exchanger affected by
aldosterone, as it is a potent non-selective aldosterone blocker which
interacts with androgen and progesterone receptors,
1.3.3.2. Therapeutic Uses
Diuretics are used in the treatment of the following conditions:
»
2)
3)
4)
3)
6
‘Thiazide or thiazide-like diuretics are effective in reducing the incidences of
strokes, heart failure, or total cardiovascular mortality
Combination of a thiazide diuretic and potassium-sparing diuretic in a fixed
dose reduces the potassium and magnesium wasting
Diuretics can be effectively used in obese, elderly, and diabetic patients. They
are used in patients with systolic heart failure and excess sodium intake,
Thiazide diuretics increase calcium level and decrease osteoporosis.
Spironolactone reduces mortality and morbidity in cases of advanced heart
failure
Eplerenone decreases cardiovascular mortality in patients who sustained a
myocardial infarction with left ventricular dysfunction. This drug is useful in
the treatment of resistant hypertension and diabetes mellitus.
Loop diuretics are ineffective in hypertensive patients having normal renal
fun
in, Loop diuretics are used in patients with serum creatinine level more
than 2.Smg/dl. Intravenous doses of furosemide in cases of heart failure produce
an acute vasodilator effect.
133.3. Adverse Effects
Thiazide diuretics give rise to many metabolic effec
such as hypercaleaemia,
hypokalaemia, hypernatremia, hypomagnesaemia, —_hypercaleaemia,
hyperglycaemia, hyperlipidaemia, and hyperuricemia; however, in low doses,
their side effects are minimised. They may also cause gout, sexual dysfunction,
and sulphonamide-related skin eruptions (occasionally).
Loop diuretics produce quite intense metabolic imbalances like hypokalaemia
and hypocalcaemia, thus are not prescribed as
itial_monotherapy for
hypertension,
133.4. In
Some commonly used diuretics are discussed below:
)
2)
Hydrochlorothiazide: This prototype agent of thiazide diuretic reduces the
electrolyte reabsorption from the renal tubules, thus increases the excretion
of water and electrolytes (sodium, potassium, chloride, and magnesium). It is
used in several disorders like oedema, hypertension, diabetes insipidus, and
hypoparathyroidism.
Furosemide: Chemically, it is a benzoic-sulfonamide-furan compound: It has 2
fast onset of action and short duration of action. It is used in oedema associated Pharmacology.
yrotie syndrome),
in combination wit
J 1 disease (including nepl
ide either alone OF
tiver cirthosis, renal
i CHE, ‘
Si ii ean yer
oar anhyperensve ds *" 1 diuretic antagonises the aldosterong
Spironolactone: ‘This p ra
9 Sem
inte ce
in Converting Enzyme
sin Converting En
tb he action of ACE e1
he treatment of refractory oedema jn
or hepatic cirthosis.
yndron
rotic sy
(ACE) Inhibitors
sme. They competitively
TI occurring in the presence
1: levels of angiotensin T],
otensin TI increase plasm
3.4. Angiotens
i onversion of angiotensin I to ang l
cca erting enzyme. This results in lowe!
ort i a potent vasoconstric or, Lower levels of
Tenin activity and reduce aldosterone secretion.
|. Mechanism of Action t dae
tak Metin yn al ll
a eos Rana
Masel hich the Kidneys release in response to reduced renal blood circulatiow
Set ts in the plasma angiotensinogen to produce
pam rs nr converted ino angiotensin mainly in the lungs)
Angiotensin II causes vasoconstriction and also helps in sodium retention by
releasing aldosterone. Angiotensin II is converted to angiotensin TI in adrenal)
gland. Aldosterone release is stimulated by both angiotensin II and angiotensial
Il Angiotensin 1 is inactive in the cardiovascular system, while angiotensin Th
has some cardiovascular-renal actions. The angiotensin-converting enzyme is
mostly found in the lungs; however they are also found in kidneys, central
nervous system, and some other body tissues also
13.42, Therapeutic Uses
‘The ACE inhibitors have the following therapeutic uses:
0) Hypertension: They are the fist line drugs for the treatment of all grades of
ee Sf of patients respond to monotherapy with ACE
ton ay majority of the remaining respond to the combination of ACE
inkibitors ctics or B-bloc i
pee ih ie $s or P-blockers. The hypotensive effect of lower doses
Congestive Heart Failure (CH):
vasodilatation in CHF patients, and al
They do not produce any dire
volume and cardiac output
and water are lost duc
2)
yey cause arteriolar aswell as
also reduce both after-load and pre-load.
fe myocardial action, thus ane stroke
while reducing the heart rate. Accumulated salt
=
logy of Drugs Acting on CV
ari
jatent or overt ventricular
wfford survival benefit ove
ophylaxis in High Car
4) eeyeart failure or diabet
cardiovascular risk even
‘ventricular dysfunction.
piabetic Nephropathy:
») Gelays the end stage re
‘sibuminuria remains sta
untreated diabetic patient
6) Scleroderma Crisis: As
deterioration of renal fun
this condition and are lif
13.4.3. Adverse Effect
In most of the patients,
toxicities but some of the 1
dizziness, angioedema, loss
cough, hyperkalaemia, bloo«
Individual Dr
The commonly used ACE i
1) Captopril: It is a sul
abolishes the pressor a
angiotensin TI receptor
is responsible for the ¢
which regulates blood
Captopril administered
renovascular hyperten
‘cosides, diureties, a
heart failure, It impr
dysfunction following
Studies show that if
tolerated in most of
hypotension, hryperkal
fetopathic, headache,
Proteinuria, and acute
2) Enalapril: It is the s
into enalaprilat (a tr
orally due t0 poor
Enalaprilat is a poten
the conversion of ang
Enalaprilat is used ir
Congestive heart fail toeology of Drugs Acting on CVS (Chapter 1)
is continued
Jatent oF overt ventricular dysfunction (CHF), the therapy is continued’ 10
‘afford survival benefit over years,
fractory Ci ct -duce the risk
¢ Jaxis in High Cardiovascular Risk Subjects: They re i
Y oedema 4) Prophaifure of diabetes; thus, act as protective in subjects with a high
a Sinfiovascular risk even When there is no associated hypertension or left
= Ventricular dysfunction,
E) Inhibito ¢ Nephropathy: Prolonged therapy of ACE inhibitors prevents or
rs 5) Diabetic Nephropathy: 8
They Competitive, >” gelays the end stage renal disease in types 1 and II diabetic patients.
ing in the presengy ‘Albuminuria remains stable in patients on ACE inhibitor, but worsens in
of angiotensin untreated diabetic patients,
Increase plasms
6) Scleroderma Crisis: Angiotensin II mediates the marked rise in BP and
deterioration of renal function in scleroderma crisis. ACE inhibitors improve
this condition and are lifesaving
and as a result 1.34.3. _ Adverse Effects
uced. Renin is aq In most of the patients, ACE inhibitors do not produce any side effects or
blood circulation toxicities but some of the rarely occurring or dose related adverse effects are
}OgeN to produce . dizziness, angioedema, loss of taste, photosensitivity, severe hypotension, dry
inly in the lungs) ~ cough, hyperkalaemia, blood dyscrasias, and renal impairment.
ium retention by 1344. Individual Drugs
THT in adrenal, The commonly used ACE inhibitors are discussed below
and angiotensin 1) Captopril: It is a sulfhydryl-containing dipeptide substitute of proline. It
"angiotensin fl abolishes the pressor action of only angiotensin I, i.e., it does not block the
Beiptenzymedl angiotensin II receptors. It is a potent and competitive ACE inhibitor, which
Miifeys, conti is responsible for the conversion of angiotensin I to angiotensin II (an agent
4 Which regulates blood pressure and is a key component of the RAAS),
Captopril administered with thiazide diuretics is used for treating essential or
Tenovascular hypertension, In combination with other drugs (e.g.
glycosides, diuretics, and B-adrenergic blockers), it is used to treat congestive
of all grades of heart failure. It improves the survival in patients having left ventricular
EEpy with AGH dysfunction following myocardial infarction.
ination of ACE Studies show that if daily dose is kept below 150mg, captopril is well-
tof lower doses tolerated in most of the patients, but some mild adverse reactions like
hypotension, hyperkalaemia, cough, rashes, urticaria, angioedema, dyseeusia,
ee, wll fetopathic, headache, dizziness, nausea, bowel upset, granulocytopenia,
and pre-load Proteinuria, and acute renal failure, may occur.
ereasing s08@) 2) Enalapril: It is the second drug of this class which is a prodrug, converted
cumulated salt into enalaprilat (a tripeptide analogue). This converted form is not effective
d abolition eal due to poor absorption, thus is available as injectable preparation.
‘nalaprilat is a potent and competitive ACE blocker, which is responsible for
a iors il the conversion of angiotensin Ito angiotensin IL
and long-tef™ Enalaprilat is used in essential or
Tenovascular ion and symptomatic
congestive heart failure, either alo oa dc
ne or in combination with thiazide diuretics. 1 Angiotensin II Receptor Antagonists pal Oe
nT receptor antagonists [or ae ‘ia i a cd
Ty ntagonists/Sartans] act i
Se eeasaitowerons eyaern. ‘They are mainly used in the treatment
ypertension, diabetic nephropathy, and congestive heart failure.
1358.1. Mechanism of Action ,
inhibi Angiotensin System (RAS). The
The ARBs inhibit the final step of Reni anit ant rye 1 rece
this hormone and some of its effects th
to ACE inhibitors, ARBs cause
in I can also be produced b
promote atherosclerosis. In comparison
‘antagonism of angiotensin II, as angiotens
complete
non-ACE pathways (figure 1.3).
ARBs are preferred over ACE inhibitors
which causes dry cough.
because they do not increase brady!
1.352. Therapeutic Uses
“Angiotensin Il receptor antagonists have the following uses:
1) These agents are mainly used in the prevention of hypertension where the
patients intolerant to ACE inhibitor therapy. onic Sea
2) They are used in the treatment of heart failure in patients intolerant to ACE Femi
inhibitor therapy, particularly candesartan. The on-going studies show Se
ReeeTC rrr re typcrcasve'paucats win type Geel ©
and also delay the progression of diabetic nephropathy. ‘Trimethaphan is
(——— Arrtiotensinogen nna route t0
oeerae Benin Other substrates its rapid and short a
Blockade