Antihypertensives II

Calcium Channel Blockers

Nifedipine
• Nifedipine, is a first generation dihydropyridine L-
type calcium channel blocker.
• Nifedipine was developed first in 1972.
• Since nifedipine's development, second and third
generation dihydropyridines have been developed
with slower onsets and longer durations of action.
• The most popular of the third generation
dihydropyridines is amlodipine.
 Nifedipine
Indication
• Nifedipine capsules are indicated to treat
vasospastic angina and chronic stable angina.
• Extended release tablets are indicated to treat
vasospastic angina, chronic stable angina, and
hypertension.
 Nifedipine
Pharmacodynamics
• Nifedipine is an inhibitor of L-type voltage gated
calcium channels that reduces blood pressure and
increases oxygen supply to the heart.
• Immediate release nifedipine's duration of action
requires dosing 3 times daily.
• Nifedipine dosing is generally 10-120mg daily.
• Patients should be counselled regarding the risk of
excessive hypotension, angina, and myocardial
infarction.
 Nifedipine
Mechanism of action
• Nifedipine blocks voltage gated L-type calcium
channels in vascular smooth muscle and myocardial
cells.
• This blockage prevents the entry of calcium ions into
cells during depolarization, reducing peripheral
arterial vascular resistance and dilating coronary
arteries.
• These actions reduce blood pressure and increase
the supply of oxygen to the heart, alleviating angina.
 Calcium Channel Blockers
Amlodipine
• Amlodipine, initially approved in 1987, is a popular
antihypertensive drug belonging to the group of
drugs called dihydropyridine calcium channel
blockers.
• Due to their selectivity for the peripheral blood
vessels, dihydropyridine calcium channel blockers
are associated with a lower incidence of myocardial
depression and cardiac conduction abnormalities
than other calcium channel blockers.
 Amlodipine
• Amlodipine is commonly used in the
treatment of high blood pressure and angina.
Amlodipine has antioxidant properties and an
ability to enhance the production of nitric
oxide (NO), an important vasodilator that
decreases blood pressure.
• The option for single daily dosing of
amlodipine is an attractive feature of this
drug.
 Amlodipine
Mechanism of action on blood pressure
• Amlodipine is considered a peripheral arterial
vasodilator that exerts its action directly on vascular
smooth muscle to lead to a reduction in peripheral
vascular resistance, causing a decrease in blood
pressure.
• Amlodipine is a dihydropyridine calcium antagonist
(calcium ion antagonist or slow-channel blocker)
that inhibits the influx of calcium ions into both
vascular smooth muscle and cardiac muscle.
 Amlodipine
• Experimental studies imply that amlodipine binds to both
dihydropyridine and nondihydropyridine binding sites, located
on cell membranes.
• The contraction of cardiac muscle and vascular smooth muscle
are dependent on the movement of extracellular calcium ions
into these cells by specific ion channels.
• Amlodipine blocks calcium ion influx across cell membranes
with selectivity.
• A stronger effect of amlodipine is exerted on vascular smooth
muscle cells than on cardiac muscle cells.
• Direct actions of amlodipine on vascular smooth muscle result
in reduced blood pressure.
 Amlodipine
Mechanism of action in angina
- It is likely twofold:
• Amlodipine has a dilating effect on peripheral
arterioles, reducing the total peripheral resistance
(afterload) against which the cardiac muscle
functions.
• Since the heart rate remains stable during
amlodipine administration, the reduced work of the
heart reduces both myocardial energy use and
oxygen requirements.
 Amlodipine
• Dilatation of the main coronary arteries and
coronary arterioles, both in healthy and
ischemic areas, is another possible mechanism
of amlodipine reduction of blood pressure.
• The dilatation causes an increase in
myocardial oxygen delivery in patients
experiencing coronary artery spasm
(Prinzmetal's or variant angina) and reduces
coronary vasoconstriction caused by smoking.
 Amlodipine
Absorption
• Amlodipine is absorbed slowly and almost completely
from the gastrointestinal tract.
• Peak plasma concentrations are achieved 6-12 hours
after oral administration.
• The estimated bioavailability of amlodipine is 64-90%.
• Steady-state plasma amlodipine levels are achieved
after 7-8 days of consecutive daily dosing.
• Absorption is not affected by food.
• Dose: 5-10mg daily
 Calcium Channel Blockers
Verapamil
• Verapamil is a phenylalkylamine calcium channel blocker used in the
treatment of high blood pressure, heart arrhythmias, and angina,
and was the first calcium channel antagonist to be introduced into
therapy in the early 1960s.
• It is a member of the non-dihydropyridine class of calcium channel
blockers, which includes drugs like diltiazem and flunarizine, but is
chemically unrelated to other cardioactive medications.
• Verapamil is administered as a racemic mixture containing equal
amounts of the S- and R-enantiomer, each of which is
pharmacologically distinct - the S-enantiomer carries approximately
20-fold greater potency than the R-enantiomer, but is metabolized
at a higher rate.
 Verapamil

Indication
• Verapamil is indicated in the treatment of
vasospastic (i.e. Prinzmetal's) angina, unstable
angina, and chronic stable angina.
• It is also indicated to treat hypertension, for the
prophylaxis of repetitive paroxysmal
supraventricular tachycardia, and in combination
with digoxin to control ventricular rate in
patients with atrial fibrillation or atrial flutter.
 Verapamil

• Given intravenously, it is indicated for the

treatment of various supraventricular
tachyarrhythmias, including rapid conversion
to sinus rhythm in patients with
supraventricular tachycardia and for
temporary control of ventricular rate in
patients with atrial fibrillation or atrial flutter.
• Verapamil is commonly used off-label for
prophylaxis of cluster headaches.
 Verapamil

Pharmacodynamics
• Verapamil is an L-type calcium channel blocker with
antiarrhythmic, antianginal, and antihypertensive activity.
• Immediate-release verapamil has a relatively short duration of
action, requiring dosing 3 to 4 times daily, but extended-release
formulations are available that allow for once-daily dosing.
• As verapamil is a negative inotropic medication (i.e. it decreases
the strength of myocardial contraction), it should not be used in
patients with severe left ventricular dysfunction or hypertrophic
cardiomyopathy as the decrease in contractility caused by
verapamil may increase the risk of exacerbating these pre-
existing conditions.
 Calcium Channel Blockers
Diltiazem
• Diltiazem is a benzothiazepine derivative with antihypertensive and
vasodilating properties.
• Approved in 1982, it is a member of the non-dihydropyridine
calcium channel blockers drug class.
• It works through various mechanisms of action, but it primarily
works by inhibiting the calcium influx into cardiac and vascular
smooth muscle during depolarization.
• Compared to dihydropyridine drugs, such as nifedipine, that
preferentially act on vascular smooth muscle and verapamil that
directly acts on the heart muscle, diltiazem displays an intermediate
specificity to target both the cardiac and vascular smooth muscle.
 Diltiazem
• Being a potent vasodilator, diltiazem is used clinically as an
antihypertensive, anti-arrhythmic, and as an anti-anginal agent for
the management of cardiovascular conditions such as
hypertension, chronic stable angina, atrial fibrillation, atrial flutter.
• Apart from its main FDA-approved indications, diltiazem has also
been used for numerous off-label indications, such as anal fissures
(in topical formulations), migraine prophylaxis, pulmonary
hypertension, and rest-related cramps in the lower extremities.
• Typically available in extended-release oral and intravenous
formulations, diltiazem is marketed under various brand names
with Cardizem and Tiazac being the most common ones.
 Calcium Channel Blockers
Nimodipine
• Nimodipine is a 1,4-dihydropyridine calcium
channel blocker. It acts primarily on vascular
smooth muscle cells by stabilizing voltage-gated L-
type calcium channels in their inactive
conformation.
• By inhibiting the influx of calcium in smooth muscle
cells, nimodipine prevents calcium-dependent
smooth muscle contraction and subsequent
vasoconstriction.
 Nimodipine
• Compared to other calcium channel blocking
agents, nimodipine exhibits greater effects on
cerebral circulation than on peripheral
circulation.
• Nimodipine is used to as an adjunct to
improve the neurologic outcome following
subarachnoid hemorrhage from ruptured
intracranial aneurysm.
 Nimodipine
Pharmacodynamics
• Nimodipine is indicated for the improvement
of neurological outcome by reducing the
incidence and severity of ischemic deficits in
patients with subarachnoid hemorrhage from
ruptured congenital aneurysms who are in
good neurological condition post-ictus.
 Nimodipine
• The contractile processes of smooth muscle cells are
dependent upon calcium ions, which enter these cells
during depolarization as slow ionic transmembrane
currents.
• Nimodipine inhibits calcium ion transfer into these cells
and thus inhibits contractions of vascular smooth
muscle.
• In animal experiments, nimodipine had a greater effect
on cerebral arteries than on arteries elsewhere in the
body perhaps because it is highly lipophilic, allowing it
to cross the blood brain barrier.
 ACE Inhibitors
Captopril
• Captopril is a potent, competitive inhibitor of
angiotensin-converting enzyme (ACE), the enzyme
responsible for the conversion of angiotensin I (ATI)
to angiotensin II (ATII).
• ATII regulates blood pressure and is a key
component of the renin-angiotensin-aldosterone
system (RAAS).
• Captopril may be used in the treatment of
hypertension.
 Captopril
Indication
• For the treatment of essential or renovascular
hypertension (usually administered with other drugs,
particularly thiazide diuretics).
• May be used to treat congestive heart failure in
combination with other drugs (e.g. cardiac glycosides,
diuretics, β-adrenergic blockers).
• May improve survival in patients with left ventricular
dysfunction following myocardial infarction.
• May be used to treat nephropathy, including diabetic
nephropathy.
 ACE Inhibitors
Enalapril
• Enalapril is a prodrug belonging to the angiotensin-
converting enzyme (ACE) inhibitor drug class that
works on the renin-angiotensin-aldosterone system,
which is responsible for the regulation of blood
pressure and fluid and electrolyte homeostasis.
• Enalapril is an orally-active and long-acting
nonsulphydryl antihypertensive agent that
suppresses the renin-angiotensin-aldosterone
system to lower blood pressure.
 Enalapril

• Being a prodrug, enalapril is rapidly biotransformed into

its active metabolite, enalaprilat, which is responsible
for the pharmacological actions of enalapril.
• The active metabolite of enalapril competitively inhibits
the ACE to hinder the production of angiotensin II, a key
component of the renin-angiotensin-aldosterone
system that promotes vasoconstriction and renal
reabsorption of sodium ions in the kidneys.
• Ultimately, enalaprilat works to reduce blood pressure
and blood fluid volume.
 ACE Inhibitors
Lisinopril
• Lisinopril is an angiotensin converting enzyme
inhibitor (ACEI) used to treat hypertension, heart
failure, and myocardial infarction.
• Lisinopril and captopril are the only ACEIs that are
not prodrugs.
• It functions by inhibition of angiotensin converting
enzyme as well as the renin angiotensin aldosterone
system.
• Lisinopril was granted approval in December 1987
 Lisinopril

Pharmacodynamics
• Lisinopril is an angiotensin converting enzyme
inhibitor used to treat hypertension, heart failure,
and myocardial infarction.
• Lisinopril is not a prodrug, and functions by
inhibition of angiotensin converting enzyme as well
as the renin angiotensin aldosterone system.
• It has a wide therapeutic index and a long duration
of action as patients are generally given 10-80mg
daily.
 Lisinopril

Mechanism of action
• Angiotensin II constricts coronary blood
vessels and is positively inotropic, which under
normal circumstances, would increase
vascular resistance and oxygen consumption.
• This action can eventually lead to myocyte
hypertrophy and vascular smooth muscle cell
proliferation.
 Lisinopril

• Lisinopril is an angiotensin converting enzyme

inhibitor (ACEI), preventing the conversion of
angiotensin I to angiotensin II.
• This action prevents myocyte hypertrophy and
vascular smooth muscle cell proliferation seen in
untreated patients.
• Increased levels of bradykinin also exhibit
vasodilating effects for patients taking ACEIs.
• Lisinopril also inhibits renin's conversion of
angiotensin to angiotensin I
 Angiotensin II receptor blockers
• Angiotensin II receptor blockers (ARBs),
formally angiotensin II receptor type 1 (AT1)
antagonists, are a group of pharmaceuticals
that bind to and inhibit the angiotensin II
receptor type 1 (AT1) and thereby block the
arteriolar contraction and sodium retention
effects of renin–angiotensin system.
 Angiotensin II receptor blockers
• Their main uses are in the treatment of
hypertension (high blood pressure), diabetic
nephropathy (kidney damage due to diabetes)
and congestive heart failure.
• They selectively block the activation of the AT1
receptor, preventing the binding of
angiotensin II compared to ACE inhibitors.
 Angiotensin II receptor blockers
• ARBs and the similar-attributed ACE inhibitors
are both indicated as the first-line
antihypertensives in patients developing
hypertension along with left-sided heart
failure.
• However, ARBs appear to produce less
adverse effects compared to ACE inhibitors.
 Angiotensin II receptor blockers
• Angiotensin II receptor blockers are used
primarily for the treatment of hypertension
where the patient is intolerant of ACE inhibitor
therapy primarily because of persistent and/or
dry cough.
• They do not inhibit the breakdown of bradykinin
or other kinins, and are thus only rarely
associated with the persistent dry cough and/or
angioedema that limit ACE inhibitor therapy.
 Angiotensin II receptor blockers
• Azilsartan (Edarbi)
• Candesartan (Atacand)
• Eprosartan.
• Irbesartan (Avapro)
• Losartan (Cozaar)
• Olmesartan (Benicar)
• Telmisartan (Micardis)
• Valsartan (Diovan)
 Angiotensin II receptor blockers
• More recently, they have been used for the
treatment of heart failure in patients
intolerant of ACE inhibitor therapy, in
particular candesartan.
• Irbesartan and losartan have trial data
showing benefit in hypertensive patients with
type 2 diabetes, and may delay the
progression of diabetic nephropathy.