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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5265_Библиотеки_им_академика_М_И_Перельмана.pdf
Drugs Acting on Cardiovascular System 217
IUPAC Name: (2-butyl-1-benzofuran-3-yl)-[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl] methanone
Properties: Amiodarone occurs as crystalline powder. Its melting point is 156°C. It is soluble in
chloroform, methanol, ethanol, benzene, tetrahydrofuran, acetonitrile and petroleum ether. It is
sparingly soluble in isopropanol; and slightly soluble in acetone, dioxane and carbon tetrachloride.
Uses:
➢ Amiodarone can be used for both supraventricular and ventricular tachycardia including
atrial flutter.
➢ It is used in refractory AV (atrioventricular) nodal.
➢ It is also used in AV re-entrant tachycardia (commonly referred to as SVT).
➢ It is used in ventricular fibrillation.
Mechanism of Action: Amiodarone works by blocking potassium rectifier currents responsible
for the repolarization of the heart during phase 3 of the cardiac action potential. By blocking of
potassium channel, it results in increased action potential duration and a prolonged effective
refractory period in cardiac myocytes.
Dosage Forms and Strengths:
➢ Injectable Solution: 50 mg/mL, 150 mg/100 mL (Nexterone), 360 mg/200 mL
(Nexterone)
➢ Tablet: 100 mg, 200 mg and 400 mg
Storage: Amiodarone should be stored at room temperature and protected from light and
excessive heat. Light protection is not necessary upon administration.
7.2 ANTI-HYPERTENSIVE AGENTS
Blood pressure is a measure of the force of blood pushing against the walls of the arteries. At
every heartbeats, it pumps blood into the arteries. The ideal blood pressure is considered to be
between 90/60 mmHg and 120/80 mmHg. Blood pressure is measured in millimetres of mercury
(mmHg). Blood pressure is highest when heartbeats and pumps the blood out. This is called
systolic pressure. The pressure, when heart rests between beats, is known as diastolic pressure.
218 Text Book of Pharmaceutical Chemistry
➢ Systolic pressure (Top number): Systolic pressure, or the upper number, measures the
pressure within the arteries when the heartbeats.
➢ Diastolic pressure (Bottom number) – Diastolic pressure or the lower number measures
the pressure in the arteries between the heartbeats.
Blood Pressure Category
Systolic Blood Pressure
Diastolic Blood Pressure
Normal
less than 120
less than 80
Pre-hypertension
121-139
80-89
Stage 1 hypertension (mild)
140-159
90-99
Stage II hypertension (moderate)
160-179
100-109
Stage III (severe)
180-209
110-119
Stage IV (very severe)
>210
>120
Hypertension (high blood pressure) is defined as a physiologic condition wherever there is
an increase in the arterial blood pressure above normal. Normal B.P. is 120/80 mmHg. A person
is hypertensive when B.P. is higher than 140/90 mmHg. Hypertension is divided into two types:
1. Primary or essential hypertension: It is the most common type of high blood pressure.
In this type of primary hypertension, the causes are unknown. The various factors that
contribute to elevate B.P. are dietary intake of more sodium and less potassium. In some
cases, primary hypertension may be hereditary. Advancement of age and decreased
vascular synthesis of nitric oxide is useful in vasodilation.
2. Secondary or malignant hypertension: In this type of hypertension, causes can be
identified. It may be due to renal disease, chronic glomerular nephritis, adrenal disease,
pheochromocytoma (tumour on adrenal medulla), thyroid problem, muscular disorders
and encephalitis (inflammation of the brain).
Classification of Antihypertensive Drugs
1. Angiotensin II Subtype I (AT1) Receptor Antagonists: Losartan, Candesartan, Irbesartan,
Valsartan, Telmisartan.
2. Renin Synthesis Inhibitor: Aliskiren.
3. Sympatholytic Drugs:
(a) Centrally acting agents: Clonidine, Methyldopa, Guanabenz, Guanfacine.
(b) β-adrenergic blockers: Propranolol, Metoprolol, Atenolol.
(c) α-adrenoreceptor antagonists: Prazosin, Terazosin, Phentolamine, Doxazosine.
(d) α + β-adrenergic blockers: Labetalol, Carvedilol.
(e) Ganglion blocking agents: Trimethaphen.
(f) Adrenergic neuron blocking agents: Guanethidine, Reserpine, Guanadrel.
Drugs Acting on Cardiovascular System 219
4. Calcium Channel Blockers: Verapamil, Diltiazam, Nifedipine, Felodipine, Amlodipine,
Lacidipine.
5. Vasodilator Drugs:
(a) Arterial vasodilators: Hydralazine
(b) Venous dilators: Nitroprusside
6. Potassium Channel Openers: Minoxidil, Diazoxide.
7. Diuretics:
(a) Thiazide diuretics: Hydrochlorothiazide, Chlorthalidone, Indapamide,
Bendroflumethiazide.
(b) High ceiling: Furosemide, Torsemide, Etharynic Acid.
(c) K
+
sparing: Spironolactone, Amiloride.
7.2.1 Propranolol
Generic Name: Propranolol
Brand Names: Hemangeol, Hemangiol, Inderal, Innopran
Chemistry and Structure:
Propranolol is a propanolamine derivative substituted by a propan-2-ylamino group at
position 1 and a naphthalen-1-yloxy group at position 3. It is a racemic mixture and the active
form is the S(–)-isomer of propranolol. With the exception of inhibition of the conversion of
thyroxine to triiodothyronine, it is unlikely that any additional ancillary properties possessed by
R(+)-propranolol, in comparison with the racemic mixture, will give rise to different therapeutic
effects. The S(–)-enantiomer has approximately 100 times the binding affinity for beta adrenergic
receptors.
IUPAC Name: 1-naphthalen-1-yloxy-3-(propan-2-ylamino) propan-2-ol
Properties: Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble
in water and ethanol. It is slightly soluble in chloroform and practically insoluble in ether. It is a
racemic mixture of dextrorotary and levorotary forms.
Mechanism of Action: Propranolol is a non-selective beta receptor antagonist. Blocking of beta-
adrenergic receptors leads to vasoconstriction, inhibition of angiogenic factors like vascular
endothelial growth factor (VEGF) and basic growth factor of fibroblasts (bFGF), induction of
apoptosis of endothelial cells, as well as down regulation of the renin-angiotensin-aldosterone
system.
220 Text Book of Pharmaceutical Chemistry
Uses: Propranolol has been used for the therapy of myocardial infarction, arrhythmia, angina
pectoris, hypertension, hyperthyroidism, migraine, pheochromocytoma and anxiety.
Dosage Forms: Intravenous solution (1 mg/mL); oral capsule, extended release (120 mg; 160
mg; 60 mg; 80 mg); oral liquid (4.28 mg/mL); oral solution (20 mg/5 mL; 40 mg/5 mL); oral
tablet (10 mg; 20 mg; 40 mg; 60 mg; 80 mg).
➢ Hypertension:
Oral administration: Initial dose of 40 mg twice daily, may be increased at weekly
intervals to a maintenance dose of 160 to 260 mg daily. (0Some patients require 320 mg
daily.
Intravenous administration: The optimal dose is 1 to 3 mg (inject slowly: 1 mg/minute
maximum). The total dose should not exceed 5 to 10 mg.
➢ Migraine: 80 mg/day PO divided q6-8hr initially may be increased by 20-40 mg/day
every 3-4 weeks; not to exceed 160-240 mg/day divided q6-8hr.
➢ Angina: 80-320 mg/day PO divided q6-12hr.
Storage Conditions: It should be stored in well-closed containers, protect from light. Store it
at controlled room temperature (20°C to 25°C).
Officials:
➢ Propranolol Hydrochloride, I.P.
➢ Propranolol Hydrochloride Injection, I.P.
➢ Propranolol Hydrochloride Tablet, I.P.
7.2.2 Captopril
Generic Name: Captopril
Brand Name: Capoten
Captopril is a sulfhydryl-containing analog of proline with antihypertensive activity and
potential antineoplastic activity. It is L-proline derivative in which L-proline is substituted on
nitrogen with a (2S)-2-methyl-3-sulfanylpropanoyl group. It has the following structure:
IUPAC Name: (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl] pyrrolidine-2-carboxylic acid
Properties: Captopril occurs as a white to off-white crystalline powder that may have a slight
sulfurous odor. It is soluble in water, methanol and ethanol; and sparingly soluble
in chloroform and ethyl acetate.
Drugs Acting on Cardiovascular System 221
Mechanism of Action: Captopril inhibits the conversion of angiotensin I to angiotensin II and
prevents the degradation of vasodilatory prostaglandins, thereby inhibiting vasoconstriction and
promoting systemic vasodilation.
Uses:
➢ Captopril is used for the treatment of hypertension.
➢ It is used for the treatment of congestive heart failure.
➢ It is used in left ventricular dysfunction after myocardial infarction and diabetic
nephropathy.
➢ It may be used alone or in combination with other medications.
Storage: Do not store above 30°C (86°F). Keep bottles tightly closed (protect from moisture).
Dosage Forms:
➢ Hypertension:
Initial: 25 mg orally every 8-12 hours, increase gradually based on response (may start
lower in some patients).
Maintenance: 25-150 mg orally every 8-12 hours, 450 mg/day maximum.
➢ Congestive Heart Failure:
Target therapy: 50 mg every 8 hours, 450 mg/day maximum
Officials:
➢ Captopril, I.P.
➢ Captopril Tablet, I.P.
7.2.3 Ramipril
Brand Name: Altace
Generic Name: Ramipril
Ramipril is a prodrug and a class of non-sulfhydryl containing angiotensin-converting
enzyme (ACE) inhibitors. It is used alone or in combination with other medications to treat high
blood pressure.
Structure and Chemistry: Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid
derivative. Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl angiotensin-
converting enzyme inhibitor. Ramipril is converted to Ramiprilat by hepatic cleavage of the ester
group. Molecular weight of Ramipril is 416.5. The structural formula for Ramipril is:
222 Text Book of Pharmaceutical Chemistry
Uses:
➢ Ramipril is used for the treatment of hypertension to lower blood pressure by reducing or
relaxing blood vessels.
➢ It is also used to lower blood pressure and to reduce the risk of stroke, heart attack and
increase survival in heart failure patients after a heart attack.
Properties: It occurs as a white, crystalline substance. It is sparingly soluble in water, freely
soluble in methanol, and soluble in polar organic solvents and buffered aqueous solutions. It melts
between 105°C and 112°C.
Mechanism of Action: Ramipril and Ramiprilat inhibit angiotensin-converting enzyme (ACE).
Ramipril is converted in the liver by de-esterification into its active form Ramiprilat, which
inhibits ACE, thereby blocking the conversion of angiotensin I to angiotensin II. This inhibits the
vasoconstrictive actions of angiotensin II and leads to vasodilatation.
Dosage Forms:
➢ Hypertension:
Initial (not on diuretic): 2.5 mg orally once a day
Initial (with diuretic): 1.25 mg orally once a day
Maintenance: 2.5-20 mg/day orally qday or divided q12hr
➢ Heart Failure:
Initial: 2.5 mg q12 hr; may titrate to 5 mg orally once a day; decrease to 1.25 mg q12hr if
hypotension occurs; monitor for > 2 hours after initial dose and reduce concomitant
diuretic if hypotension occurs.
Maintenance: After 1 week, increase dose (if tolerated) to target dose of 5 mg q12hr.
Storage: Store the medicine in a closed container at room temperature, away from heat, moisture
and direct light. Keep from freezing. It should be stored at 20°C to 25°C. Keep container tightly
closed in a dry and well-ventilated place.
7.2.4 Methyldopate Hydrochloride
Generic Name: Methyldopate hydrochloride injection, solution
Brand Name: Methyldopate HCl
Drugs Acting on Cardiovascular System 223
Methyldopate Hydrochloride is the hydrochloride salt form of methyldopa, a phenylalanine
derivate and aromatic amino acid decarboxylase inhibitor. It has a role as an alpha-adrenergic
agonist and an antihypertensive agent. It is more soluble and stable in solution than methyldopa,
and is the preferred form for intravenous use.
Methyldopa is a prodrug and it is a structural analog of dopa. The antihypertensive action of
methyldopa seems to be attributed to its conversion into α-methynorepinephrine, which then
serves as the α
2
-adrenoceptor agonist in the medulla to decrease sympathetic outflow and
decreased blood pressure.
Chemistry and Structure: Methyldopate hydrochloride [levo-3-(3,4-dihydroxyphenyl)-2-
methylalanine, ethyl ester hydrochloride] is the ethyl ester of methyldopa. Its molecular weight is
275.73. It is more soluble and stable in solution than methyldopa and is the preferred form for
intravenous use. The molecular formula for methyldopate hydrochloride is C
12
H
17
NO
4
·HCl and
the structural formula is:
Nomenclature: ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)–2-methyl propanoate; hydrochloride
Properties: It occurs as white to yellowish white, fine powder, which may contain friable lumps,
odorless, almost tasteless. It is soluble in water, isopropanol and ethanol; practically insoluble in
common organic solvents; and soluble in dilute mineral acids.
Mechanism: The antihypertensive effect of methyldopa probably is due to its metabolism to
alpha-methyl-norepinephrine, which then lowers arterial pressure by stimulation of central
inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin
activity.
Uses: Methyldopa is indicated in the treatment of moderate to severe hypertension, including that
complicated by renal disease. It is an effective antihypertensive agent used in conjunction with a
diuretic.
Dosage and Administration:
➢ Adults: The usual adult dosage intravenously is 250 mg to 500 mg at six hours intervals
as required. The maximum recommended intravenous dose is 1 gram every six hours.
➢ Pediatric: The recommended daily dosage is 20 to 40 mg/kg of body weight in divided
doses every six hours. The maximum dosage is 65 mg/kg or 3 grams daily.
Precautions: Some person’s treatment with methyldopa experience clinical edema or weight gain
which may be controlled by use of a diuretic. Methyldopa should not be continued if edema
progresses or signs of heart failure appear.
224 Text Book of Pharmaceutical Chemistry
Storage Condition: Methyldopate HCl Injection, USP 250 mg/5 mL (50 mg/mL). Store at
controlled room temperature 15-30°C. Methyldopa oral suspension should be stored in tight,
light-resistant containers at a temperature less than 26°C and protected from freezing. Methyldopa
tablets should be stored in well-closed containers at a temperature less than 40°C, preferably at
15-30°C.
Officials:
➢ Methyldopa, I.P.
➢ Methyldopa Tablet, I.P.
7.2.5 Clonidine Hydrochloride
Brand Names: Catapres, Kapvay
Generic Name: Clonidine
Catapres (clonidine hydrochloride) is a centrally acting alpha-agonist hypotensive agent. It is
available as a patch, an oral tablet, and an oral extended-release tablet. For oral administration,
tablet is available in three dosage strengths: 0.1 mg, 0.2 mg and 0.3 mg. The 0.1 mg tablet is
equivalent to 0.087 mg of the free base.
Chemistry and Structure: Clonidine Hydrochloride is the hydrochloride salt form of clonidine,
an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-(2,6-
dichlorophenylamino)-2-imidazoline hydrochloride. The following is the structural formula:
IUPAC Name: N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine; hydrochloride
Properties: It occurs as an odorless, bitter, white, crystalline substance with melting point 305°C.
It is soluble in water and alcohol, and insoluble in water.
Uses:
➢ Clonidine hydrochloride and transdermal clonidine are used alone or in combination with
other classes of antihypertensive agents in the management of hypertension.
➢ Lowering high blood pressure help to prevent strokes, heart attacks and kidney problems.
➢ It works by relaxing blood vessels. So, blood can flow more easily.
➢ It is used as adjunctive therapy in combination with opiates in the management of severe
cancer pain that is not relieved by opiate analgesics alone.
Drugs Acting on Cardiovascular System 225
Dosage Forms and Strengths: Oral tablet (0.1 mg; 0.2 mg; 0.3 mg); oral tablet, extended release
(0.1 mg/12 hr)
➢ Hypertension (Immediate-release Tablets):
Initial dose: 0.1 mg orally 2 times a day (morning and bedtime).
Titration: Increments of 0.1 mg orally per day may be made at weekly intervals to
desired response.
Maintenance dose: 0.2 to 0.6 mg orally per day in divided doses.
Maximum dose: 2.4 mg orally per day in divided doses.
➢ Transdermal:
Initial dose: 0.1 mg/24 hr patch applied every 7 days.
Maintenance dose: If, after 1 to 2 weeks the desired reduction in blood pressure is not
achieved, increase the dosage by adding another 0.1 mg/24 hr patch or changing to a
larger system.
Maximum dose: Doses above two 0.3 mg/24 hr patches applied every 7 days is usually
not associated with additional efficacy
Mechanism of Action: It binds to and stimulates central alpha-2 adrenergic receptors, thereby
decreasing sympathetic outflow to the heart, kidneys and peripheral vasculature. The reduction in
sympathetic outflow leads to decreased peripheral vascular resistance, decreased blood pressure,
and decreased heart rate.
Storage: Clonidine hydrochloride tablets and injection should be stored in tight, light-resistant
containers at a controlled room temperature of 25°C, but may be exposed to temperatures ranging
from 15-30°C. Keep the medication away from light. Keep this drug away from areas where it
could get wet.
Officials:
➢ Clonidine Hydrochloride, I.P.
➢ Clonidine Hydrochloride Injection, I.P.
➢ Clonidine Hydrochloride Tablet, I.P.
7.2.6 Hydralazine Hydrochloride
Generic Name: Hydralazine
Brand Name: Apresoline
Hydralazine belongs to the hydrazinophthalazine class of drugs. It is the 1-hydrazino
derivative of phthalazine. Hydralazine hydrochloride is the hydrochloride salt of hydralazine,
with antihypertensive effects.
226 Text Book of Pharmaceutical Chemistry
IUPAC Name: Phthalazin-1-ylhydrazine; hydrochloride
Properties: Hydralazine hydrochloride occurs as a white to off-white, odorless crystalline
powder. It is soluble in water, slightly soluble in alcohol, and very slightly soluble in ether.
It melts at about 275°C, with decomposition, and has a molecular weight of 196.84.
Mechanism of Action: Hydralazine is a drug that lowers the blood pressure by vasoconstrictive
repression. It is a direct-acting smooth muscle relaxant and acts as a vasodilator primarily
in resistance arterioles, also known as the smooth muscle of the arterial bed. Vasodilators act to
decrease peripheral resistance, thereby lowering blood pressure.
Uses:
➢ Hydralazine is used to treat the symptoms of severe essential hypertension.
➢ It is used in chronic high blood pressure.
➢ It is used to treat congestive heart failure.
➢ It may be used alone or with other medications.
➢ Hydralazine is used intravenously when oral therapy cannot be given or when there is an
urgent need to lower blood pressure.
Dosage Form: Hydralazine hydrochloride USP is an antihypertensive, available as 10 mg, 25 mg,
50 mg and 100 mg tablets for oral administration.
➢ Hypertension:
Initial dose: 10 mg orally 4 times a day for 2-4 days; 25 mg orally daily for the first
week; increase to 50 mg orally 4 times a day.
Maintenance dose: Adjust dosage to the lowest effective levels.
➢ Congestive Heart Failure:
Initial dose: 10-25 mg orally q6-8hr; titrate dose q2-4weeks.
Maintenance dose: 225-300 mg/day orally divided q6-8hr.
Storage Conditions: Preparation of Hydralazine hydrochloride should be stored at a temperature
less than 40°C, preferably at 15°C to 30°C. Freezing of the injection should be avoided.
Hydralazine hydrochloride tablets should be stored in tight, light-resistant containers at a
controlled room temperature between 20°C to 25°C.
Officials:
➢ Hydralazine Hydrochloride, I.P.
➢ Hydralazine Hydrochloride Injection, I.P.