Amlodipine

S Isomer
Amlodipine is drug used to treat high blood pressure (hypertension), some types
of angina and other conditions caused by coronary artery disease. Amlodipine is a
calcium channel blocker that works by changing the movement of calcium in the
heart and blood vessel cells. This widens the blood vessels which increases the
blood and oxygen supply to the heart and also lowers blood pressure.
Prepared by
Fadhl AbdulQader & Hadi abdulqader & Hamza Al-
Hakimi & Awad Al-Hajaji & Ali Mosfer
➢Introduction
Calcium channel blockers are among the first-line drugs for treatment of
hypertension (HTN). S-amlodipine (S-AM), an S-enantiomer of amlodipine, is
available in India and in other countries like China, Korea, Russia, Ukraine, and
Nepal. Being clinically researched for nearly two decades, we performed in-
depth review of S-AM. This review discusses clinical evidence from total 42
studies (26 randomized controlled trials, 14 observational studies, and 2 meta-
analyses) corroborating over 7400 patients treated with S-AM. Efficacy and
safety of S-AM in HTN in comparison to racemic amlodipine, used as
monotherapy and in combination with other antihypertensives, efficacy in
angina, and pleiotropic benefits with S-AM, are discussed in this review.

➢History
Pfizer's patent protection on Norvasc lasted until 2007; total patent expiration
occurred later in 2007. A number of generic versions are available. In the
United Kingdom, tablets of amlodipine from different suppliers may contain
different salts. The strength of the tablets is expressed in terms of amlodipine
base, i.e., without the salts. Tablets containing different salts are therefore
considered interchangeable. Fixed-dose combination of amlodipine and
perindopril, an angiotensin converting enzyme inhibitor are also available.
The medical form comes as besylate, mesylate or maleate.

➢Pharmacoeconomic
Objectives: To review the pharmacoeconomic impact of the use of amlodipine
in coronary artery disease (CAD) patients.

Methods: A review of the available outcome trials evaluating the clinical

effectiveness of amlodipine in hypertensive patients or in patients with CAD or
diabetic nephropathy was carried out to identify pharmacoeconomic studies
that quantified the economic impact of using amlodipine instead of another
treatment.

Results: A combined analysis of two trials comparing angiotensin receptor

blockers (ARBs) with a calcium channel blocker amlodipine suggested that
amlodipine provided more protection against stroke and myocardial infarction
 than ARBs. In addition, in keeping with previous meta-analyses, calcium
channel blockade with amlodipine also prevented more stroke than
angiotensin-converting enzyme inhibitors and old drug classes.
Pharmacoeconomic analysis conducted in the US and Europe demonstrated
that the use of amlodipine resulted in fewer hospitalizations and the need for
fewer invasive surgical procedures in the short and long term and at a modest
incremental cost. The use of amlodipine resulted in improved clinical outcomes
as well as slight savings in cost.

Conclusions: Amlodipine is not only cost effective, but predicted to be cost

saving when compared with usual care, warranting its consideration as an
agent of choice in patients with CAD.

Resource:
/https://pubmed.ncbi.nlm.nih.gov/19450066

➢Pharmacokinetic
1 General pharmacodynamic effects

Amlodipine has a strong affinity for cell membranes, modulating calcium influx
by inhibiting selected membrane calcium channels. This drug's unique binding
properties allow for its long-acting action and less frequent dosing regimen.

2 Hemodynamic effects

After the administration of therapeutic doses of amlodipine to patients

diagnosed with hypertension, amlodipine causes vasodilation, which results in
a reduction of supine and standing blood pressure. During these blood
pressure reductions, there are no clinically significant changes in heart rate or
plasma catecholamine levels with long-term use. Acute intravenous
administration of amlodipine reduces arterial blood pressure and increases
heart rate in patients with chronic stable angina, however, chronic oral
administration of amlodipine in clinical studies did not cause clinically
significant alterations in heart rate or blood pressures in patients diagnosed
with angina and normal blood pressure. With long-term, once daily oral
administration, antihypertensive effectiveness is maintained for at least 24
hours.

~ 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. Experimental studies imply that amlodipine binds
to both dihydropyridine and no dihydropyridine 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.

~ Metabolism
Amlodipine is heavily (approximately 90%) converted to inactive metabolites
via hepatic breakdown with 10% of the parent compound and 60% of the
metabolites found excreted in the urine. Ex vivo studies have shown that about
93% of the circulating drug is bound to plasma proteins in hypertensive
patients. Characteristics that add to amlodipine's unique pharmacologic profile
include nearly complete absorption, late-peak plasma concentrations, high
bioavailability, and slow hepatic breakdown.

~ Absorption
Amlodipine 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.

~ Route of elimination
Elimination from the plasma occurs in a biphasic with a terminal
elimination half-life of about 30–50 hours. Steady-state plasma
levels of amlodipine are reached after 7-8 days of consecutive
daily dosing. Amlodipine is 10% excreted as unchanged drug in the
urine. Amlodipine can be initiated at normal doses in patients
diagnosed with renal failure.
➢ Stereochemistry of Amlodipine s
Stereochemistry is now influencing most areas of pharmacotherapy. The chirality
that is inherent in the enzyme systems of living organisms' results in an
abundance of enantiopure organic molecules in the living world. In addition to the
optical properties first noticed by Pasteur, stereospecific interactions at
recognition sites result in differences in both biological and toxicological effects.
With chirality becoming so important in pharmacotherapy, the need to develop
chirally pure molecules has greatly increased. The pharmaceutical industry has
recognized and accepted the need for developing chirally pure molecules.
Research into new chemical entities that can interact specifically with enzyme
families may potentially lead to new therapies for complex disease processes.

The basis for the development of chirally pure drugs lies behind the fact that the
human body is chiroselective i.e., the body interacts with different isomers
differently. Besides, two-third of the molecules are chiral, so nature itself uses
chiral molecules, hence the best way to interact with nature for a positive
outcome would be to use chiral molecules. Often only one stereoisomer of a
racemate drug is able to affect the desired process so, when given as a
racemate; patients end up absorbing and metabolizing useless quantities of the
other stereoisomer of the drug. This unnecessary fraction is usually the one,
which causes adverse effects. Thus, purifying the active part of the drug gives a
better efficacy with reduction in side effects.

Calcium antagonists are a biochemically heterogeneous group of drugs that

share the property of blocking the entry of calcium into cells by voltage-operated
channels in cardiac and smooth muscle. They are useful in the management of
angina pectoris and hypertension. The drugs included in this class are
amlodipine, nifedipine, verapamil, diltiazem etc. Of all these drugs, amlodipine
has been shown to have a completely different pharmacokinetic profile.
Amlodipine has a long half-life and hence provides with an advantage of a once
daily dosing.1,2 It has a slow onset and a slow offset of antihypertensive action,
which avoids any sudden changes in blood pressure. Amlodipine, because of its
novel pharmacokinetics, offers practical advantages over the other calcium
antagonists in the long-term treatment of cardiovascular disease. But the use of
amlodipine has been associated with side effects such as headache, dizziness,
peripheral edema etc., with peripheral edema being the commonest reason for
the withdrawal of the drug in most of the patients.

Interestingly, amlodipine exhibits chirality, i.e., it exists as two isomers.2,3

Moreover, the receptor binding studies have shown that it the S (-) isomer of
amlodipine that has L-type calcium channel blocking activity. The R (-) isomer
exhibits a 1000-fold weaker calcium channel blocking activity. Thus, the
antihypertensive and antianginal activity of amlodipine can be attributed only to
S (-) amlodipine, whereas the R (-) isomer can be regarded as inactive. Since
racemic amlodipine contains R (+) and S (+) isomer in 1:1 ratio, purifying the
pharmacologically active S (-) isomer can reduce the dose of racemic
amlodipine to half.
Clinical studies conducted at four centres in India have shown that S (-)
amlodipine at half the dose i.e., 2.5 mg produces a similar blood pressure
lowering efficacy as that of racemic amlodipine 5 mg.4 Thus, S (-) amlodipine
reduces the dose of amlodipine to half. Studies have even shown that S (-)
amlodipine produces a significant reduction in the total serum cholesterol and
triglyceride levels in hyperlipidemic patients.

It is seen that the S (-) component is found to produce vasodilation by blocking the
calcium channels in the arterial circulation. This property contributes to its
antihypertensive effect. The R (+) isomer on the other hand produces venodilation
and is responsible for the side effects associated with racemic amlodipine.

In atherosclerosis it is seen that the smooth muscle cell membrane becomes

enriched with unesterified cholesterol. The membrane becomes thicker and
develops distinct cholesterol domains. These alterations increase the permeability
of smooth muscle cells to Ca++ ions, which further consolidates the
atherosclerothic plaque. Only the S (-) component of amlodipine has calcium
channel blocking activity, hence, it is S (-) amlodipine that has anti-atherosclerotic
activity. Since R (-) amlodipine has no calcium channel blocking activity, it has no
anti-atherosclerotic effect.

Another clinically revelant observation with S (-) amlodipine was that there were no
reported cases of any adverse event with the drug. No cases of peripheral edema
have been reported by any of the patients included in the trial. Our own multicenter
trial showed that S-amlodipine in equivalent inefficacy and tolerability compared to
amlodipine. Recent studies have shown that nitric oxide (NO) produced in the
peripheral blood vessels by different nitric oxide synthetase (NOS) isoforms
contributes to edema and development of hyperalgesia. The R (+) isomer of
amlodipine has been shown to release nitric oxide in a concentration-dependent
manner by kinin-mediated mechanisms. Since amlodipine has a peripheral action,
the release of nitric oxide by the R (+) isomer in the peripheral blood vessels may
lead to edema. On the other hand, the S (-) isomer has been shown to have no effect
on the nitric oxide release at any concentration.5 Thus, it is R (+) amlodipine that is
responsible for the development of peripheral edema, commonly associated with
racemic amlodipine. Hence, purifying S (-) amlodipine can reduce the incidences of
peripheral edema and other side effects.
References

- Webster J, Robb OJ, Jeffers TA, Scott AK, Pibrie JC, Towler HM. Once daily
amlodipine in the treatment of mild to moderate hypertension. Br J Clin Pharmacol
1987; 24:713-9.

- Pharmacotherapy of Hypotension. Ch. 26 Satoskar RS et al in Pharmacology and

Pharmacotherapeuties, Popular Prakashan. 386-417.

Comparison of the
averaged structures for (S)-
amlodipine and (R)-
amlodipine. Carbon atoms
are colored in yellow and
ribbon colored in green in
Ca v 1.2-(S)-amlodipine;
carbon atoms are colored in
purple, and ribbon colored
in gray in Ca v 1.2-(R)-
amlodipine.
 Why (S)-amlodipine is more efficacious than (R)-amlodipine?
Amlodipine has an interesting S-stereochemistry preference, indicating that
(S)-amlodipine may have tighter binding with Cav1.2 than (R)-amlodipine.
Stereochemistry is a critical factor that should be taken into account when
investigating stereoisomer–receptor interaction, and the changes in
stereochemistry might cause considerable change of binding potency. As
shown in Fig. 5, the bowsprit group of (S)-amlodipine points upward and then
approaches the Ca2+ion chelated by the acid residues of the selectivity filter,
while the bowsprit group of (R)-amlodipine points downward. In addition, the
port side group of (S)-amlodipine is closer to the selectivity filtering
comparison with that of (R)-amlodipine. These results are consistent with
previous studies that the antagonistic action of DHP derivatives is directly
associated with the Ca2+occupancyof the selectivity filter.24As shown in Table
2, the predicted binding free energy for (R)-amlodipine is weaker than that of
(S)-amlodipine byB16 kcal mol 1, which is consistent with the experimental
data.64The electrostatic interaction for (S)-amlodipine is obviously

➢ Uses, Side Effects, and Interactions

S Amlodipine Tablet is used to treat angina, high blood pressure and coronary
heart disease. It is recommended in case of heart failure if other medications
fail to work. S Amlodipine Tablet is the key ingredient of this medicine. It
increases the myocardial oxygen delivery in patients with vasospastic angina.

S Amlodipine Tablet belongs to the class of a calcium channel blocker that

inhibits calcium ion from entering the slow channels of vascular smooth muscle
and myocardium during depolarization. This leads to cause relaxation of
coronary vascular smooth muscle and coronary vasodilation.

The medicine should be taken as per the dosage on the prescription.

Overdosage of the drug can lead to complications. Depending on the effects
the drug has on a patient, the doctor may make variations to the dosage.

The medicine may not be safe to use during pregnancy or breastfeeding.

Dosage should be low for elderly people and for those with liver problems. If
you have heart problems then intake of S Amlodipine Tablet may increase your
health problems.
Side effect of Lev amlodipine:

1. Serious side effects of

Lev amlodipine
2. Other effects

Along with its needed effects, lev amlodipine may cause some unwanted
effects. Although not all of these side effects may occur, if they do occur, they
may need medical attention.

Check with your doctor immediately if any of the following side effects occur
while taking lev amlodipine:
Less common
• Dizziness
• fast, irregular, pounding, or racing heartbeat or pulse
• feeling of warmth
• redness of the face, neck, arms, and occasionally, upper chest
• Rare
• Chest pain
• cough
• difficulty with swallowing
• dizziness
• fainting
• hives, itching, rash
• increased sweating
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands…

S Amlodipine Tablet is used to treat angina, high blood pressure and coronary
heart disease. It is recommended in case of heart failure if other medications
fail to work. S Amlodipine Tablet is the key ingredient of this medicine. It
increases the myocardial oxygen delivery in patients with vasospastic angina.

S Amlodipine Tablet belongs to the class of a calcium channel blocker that

inhibits calcium ion from entering the slow channels of vascular smooth muscle
and myocardium during depolarization. This leads to cause relaxation of
coronary vascular smooth muscle and coronary vasodilation.
The medicine should be taken as per the dosage on the prescription.
Overdosage of the drug can lead to complications. Depending on the effects
the drug has on a patient, the doctor may make variations to the dosage.

The medicine may not be safe to use during pregnancy or breastfeeding.

Dosage should be low for elderly people and for those with liver problems. If
you have heart problems then intake of S Amlodipine Tablet may increase your
health problems.

Thank you