AMLODIPINE

By Hui Syuen Tan

Group A (Master of Pharmacy)

Dr. Amal Elkordy
University of Sunderland
Sunderland
5th November 2018
INTRODUCTION
Amlodipine, also known as Norvasc, is a dihydropyridine L-type calcium-channel blocker which helps to dilate
the arteries in the heart thus it is used mainly to lower blood pressure which treats coronary artery disease and
angina. What makes it distinct from other hypertensive lowering drugs is its long half-life, making it perfect to
be a one-a-day oral dose.

Diagram 1: Chemical Structure of Amlodipine

CHEMISTRY OF AMLODIPINE

Diagram 2: Chemical Structure of Amlodipine with labelled functional groups

Hydrophobic COOMe:
Stabilize the closed state of the
activation gate of L-type calcium
channels (Tikhonov and Zhorov, 2009)

Diagram 3: Chemical Structure of Amlodipine with circled of main effecting of functional group

There are four types of L-Type Calcium Channel(LTCC) which are Cav1.1, Cav1.2, Cav1.3, Cav1.4. Cav1.2 is
the main LTCC in arterial smooth muscles and heart ventricular muscles where it determines peripheral
vascular resistance and contractility respectively. (Streissnig, 2015, cited in Zhang et al 2007)

The hydrophobic COOMe blocks the activation gate of Cav1.2 by nearing the EEEE locus and stop a second
calcium ion from binding to the pore. Plus, having the ammonium group results in a prolonged duration of
action when compared to neutral or uncharged analogs(Tikhonov and Zhorov, 2009)

Diagram 3: Chemical Structure of Amlodipine with circled charged ammonium group

PHARMACODYNAMICS

Significant increase in heart rate is not observed whilst lowering the blood pressure when amlodipine is
administered unlike other drugs. It also has lesser “vasodilator” detrimental effects. (Johnston, 1999, p. 260)
Vascular smooth-muscle(VSM)cells depends heavily on the influx of extracellular calcium for contraction
because the intracellular calcium stores is significantly lesser when compared to myocardial cells. Therefore,
the contraction of VSM at the coronary arteries is a little dissimilar to skeletal and cardiac muscles. Amlodipine
are membrane-active drugs which reduces the entry of calcium into cells by blocking the LTCC hence results in
a greater effect on vascular wall contraction i.e. dilate coronary and peripheral arteries in doses which do not
adversely affect myocardial contraction or that have little, if any, effect on skeletal muscle. It is also less active
in veins than in arteries as there are much lesser smooth muscle cells present when compared to arteries. Since
calcium ions are required for smooth-muscle contractions, amlodipine can inhibit contractions in the
gastrointestinal tract but only to a small extent. However, there is no proof that amlodipine effects the endocrine
glands in clinical doses.(Frishman and Sonnenblick, 1998, p.75,78)

Amlodipine can result in a negative intropic effect by blocking the L-type calcium channel in certain cardiac
muscle cells (Robles, 2009, p.3) which results in decreased left ventricular contractility but only at the highest
dose used which is stated by Frishman and Sonnenblick(1998, p.77) and Messerli(1990, p.1022).
This is proven by the strong reflex beta-adrenergic response which enhances the performance of the ventricles
but “unlikely to play similar role in patients with severe congestive heart failure, in whom the baroreceptor
sensitivity is markedly attenuated”.(Frishman and Sonnenblick, 1998, p.75,78)

Patients with hypertension shows reduction in renal resistance compared to baseline values after daily
administration of amlodipine for 6 weeks with mean dose 8.8mg/day. The measured inulin clearance of the
patients concluded a reduction in systemic arterial pressure and an increase in glomerular filtration, and
measurements from para-aminohippurate shows effective renal plasma flow. After acute administration of
15mg of amlodipine, plasma renin activity increased a little but was not apparent after 6 weeks of amlodipine
therapy. (Messerli, 1990, p.1022, cited in Bauer JH, 1987)
PHARMACOKINETICS

Absorption:
Absorption of amlodipine after oral administration is complete as Messerli (1990, p.1023, cited in Beresford
AP et al, 1988) states, “the amounts of radiolabel excreted into urine(about60%) and feces(about25%) are the
same after oral and intravenous administration”. Messerli also mentioned that the rate of absorption and total
amount of drug uptake will not be influenced by food.

Distribution
High concentrations of the drug after administered are found in the lungs, kidneys, liver and adrenal glands
while low levels are seen in the amniotic fluid, brain and blood. The volume of distribution of amlodipine is
about 21L/kg. (Messerli, 1990, p.1023, cited in Faulkner et al 1986) The bioavailability is about 60%-65% and
it has more than 95% protein binding.(Frishman and Sonnenblick, 1998, p.81)
After about 6-12 hours, peak concentrations are achieved, showing the slow and steady absorption of drug.
Plus, the lengthy plasma half-life is 35-48 hours makes it satisfactory for once-a-day dosage regimen (Opie,
2013, p.86-88) Hence the statement, “The sustained duration of action of amlodipine, as well as its good
bioavailability, are properties that set it apart from other dihydropyridine calcium-channel blockers” by
Messerli (1990, p.1023) is compliant.

Metabolism and Elimination:

Messerli also said that amlodipine is substantially metabolized as “only 10% of the urinary radioactivity
consists of unchanged drug” and the leftover radioactivity is oxidized to the pyridine analogue by
cytochromeP3A4 (Chen ,2013) and distributed between nine inactive metabolites. Hence, age, severe hepatic
impairment and severe renal impairment will influence the pharmacokinetic profile leading to higher plasma
concentrations and longer half-lives.
SIDE EFFECT
The most common side effects are in table 1 below taken from Messerli (1990, p.1031).

Table 1: Percentage Incidence of Side Effects of a Placebo-controlled Study of Amlodipine

Frishman and Sonnenblick (1998, p.88) also states, “edema is more common but headache and constipation are
less common. They also stated, “peripheral edema is most troublesome, occurring in approximately 10% of
patients at 10mg daily. In women there is more edema (15%) than in men (6%). Next significance are dizziness
(3%-4%) and flushing (2%-3%)”

COMMON SIDE EFFECTS UNCOMMON SIDE EFFECTS

• Constipation • Anxiety
• Diarrhoea • Chest Pain
• Drowsiness • Cough
• Gastrointestinal Discomfort • Depression
• Oedema • Dry mouth
• Vision Discomfort • Insomnia
• Tremor
• Urinary Disorder
Table 2: Common and Uncommon Side Effects of Amlodipine Extracted from BNF, 2018
HOW TO ADMINISTER AMLODIPINE TO
PATIENTS AND PATIENT COUNSELLING

Patients' medical history, consumption of other medications or nutritional supplements, and allergies towards
ingredients in amlodipine are reviewed before prescribing amlodipine (Amlodipine, 2017).
Extra caution must be taken when prescribing amlodipine as it has been confused with atenolol and nimodipine
(Amlodipine, 2018)

Pregnant women should refrain from amlodipine due to its reproductive toxicity, and it will also contaminate
mothers’ milk for breastfeeding.

The starting dose is a 5 mg amlodipine per day for adult hypertensive patients. Depending on patients’
response, dosage may be increased to maximum of 10 mg per day. Hypertensive patients aged 6 to 17 years are
recommended to start with 2.5mg per day. If blood pressure goal is not achieved after 4 weeks, then increase to
maximum of 5mg.

Children under 6 years should not be prescribed. Caution should be taken when increasing the dosage for the
elderly as their ability to metabolise the drug is slower. Patient’s blood pressure should be measured regularly
during medication to monitor the amount of amlodipine taken. Patients with liver complications should be
prescribed with a lower dose (2.5mg) to avoid possible side effects due to prolonged retention of drug within
the body. Some other side effects include headaches and dizziness. (Amlodipine 5mg tablets, 2018)
Amlodipine should not be administered to patients with cardiogenic shock, significant aortic stenosis or
unstable angina. (BNF, 2018, p. 156).

Tablets should only be swallowed with liquids. Struggles with swallowing can be resolved by dissolving it into
water then consuming it with foods like honey. An oral syringe or medicine spoon may be obtained from the
pharmacist to accurately measure liquid forms of the drug (Amlodipine for Hypertension, 2013).

Amlodipine should be consumed at the same time each day. Patients are allowed to continue taking the
medication only if the dose is missed within 12 hours of the assigned time. If not, they should skip the current
day’s dose and continue normally the next day without compensating missed doses. Patients should not
consume expired drugs and return it to pharmacists for disposal instead. Amlodipine must be stored at room
temperature and away from direct sunlight or heat. Also, ensure it is closed tightly within its original container.
(Amlodipine, Oral Tablets, 2018)
REFERENCING LIST
Tickhonov D. B. (2009) Structural Model for Dihydropyridine Binding to L-type Calcium Channels [Online]
Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707233/#B18(Accessed: 5th
November 2018)

Striessnig J. et al (2015) Pharmacology of L-type Calcium Channels: Novel Drugs for Old Targets? [Online]
Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384371/#r78 (Accessed: 5th
November 2018)

Messerli, F.H. (1990) Cardiovascular drug therapy. Philadelphia: WB Saunders Company.

Frishman, W. H. and Sonnenblick, E. H. (1998) Cardiovascular Pharmacotherapeutics. United States of

America: McGraw-Hill

Opie, L. H. and Gersh, B. J. (2013) Drugs for the Heart. Philadelphia :Elsevier Saunders

Chen, M. Z. (2013) Amlodipine Metabolism in Human Liver Microsomes and Roles of CYP3A4/5 in the
Dihydropyridine Dehydrogenation [Online] Available from:
http://dmd.aspetjournals.org/content/42/2/245 (Accessed: 4th November 2018)

Johnston, G.D. (1990) Fundamentals of Cardiovascular Pharmacology. England: John Wiley & Sons Ltd

Robles, Nicolás Roberto (2009) Calcium Channel Blockers and Renal Disease. New York: Nova Science
Publishers, Incorporated [Online] Available from:
https://ebookcentral.proquest.com/lib/sunderland/reader.action?docID=3018941&query
(Accessed: 21st of Cotober 2018)

Amlodipine (2017) [Online] Available from: https://www.nhs.uk/medicines/amlodipine/ (Accessed on: 3rd

November 2018)

Amlodipine (2018) [Online] Available from: https://bnf.nice.org.uk/drug/amlodipine.html (Accessed on: 3rd

November 2018)

Sandoz, a norvartis division, Amlodipine 5mg Tablets (2018) [Online] Available from:
https://www.medicines.org.uk/emc/product/4579/smpc#PHARMACEUTICAL_PARTS(Accessed: 3rd
November 2018)
BNF(2018). 76th Edition. England: BMJ Group

Amlodipine for Hypertension (2013) [Online] Available from:

https://www.medicinesforchildren.org.uk/amlodipine-hypertension-0 (Accessed: 3rd November 2018)

Amlodipine GH Tablets (2016) [Online] Available from:

https://www.nps.org.au/medical-info/medicine-finder/amlodipine-gh-tablets (Accessed on: 3rd
November 2018)

University of Illinois-Chicago, Drug Information Group, Amlodipine, Oral Tablet (2018) [Online] Available
from: https://www.healthline.com/health/amlodipine/oral-tablet#important-considerations(Accessed:
3rd November 2018)