Ranolazine
اشراف الدكتور :اشرف العماري
عمل الطالب :حمزه جمال عبد الرحيم المقطري
Group:A
Summary
Ranolazine is an anti-anginal drug used for the treatment of chronic
angina
Background
Chronic angina is a common cardiovascular condition affecting
millions worldwide and causes significant disability while interfering
with daily activities.11 Ranolazine is a well-tolerated piperazine
derivative used for the management of this condition, offering relief
from uncomfortable and debilitating symptoms.17 With a mechanism
of action different from drugs used to treat the same condition,
ranolazine is a promising anti-anginal therapy. It was originally
approved by the FDA in 2006.15
Mechanism of action
Myocardial ischemia exerts effects on adenosine triphosphate flux,
leading to a decrease in the energy available for contraction and
relaxation of the heart muscle. Electrolyte balance of sodium and
potassium is necessary for maintaining normal cardiac contraction
and relaxation. Disruption of adequate sodium and potassium
electrolyte balance leads to excessively high concentrations of sodium
and calcium, which likely interferes with oxygen supply to the heart
muscle. This imbalance eventually leads to angina symptoms of chest
pain or pressure, nausea, and dizziness, among others.11,18
mechanism of action
The mechanism of action for ranolazine is not fully understood. At
therapeutic concentrations, it can inhibit the cardiac late sodium 205
current (INa), which may affect the electrolyte balance in the
myocardium, relieving angina symptoms. The clinical significance this
inhibition in the treatment of angina symptoms is not yet
confirmed.17
Ranolazine inhibits sodium and potassium ion channel currents.1 It
has been shown to exert weak activity on L-type calcium channels
making it a weak direct vasodilator and exerts minimal direct effects
on atrioventricular nodal conduction.2 Some additional mechanisms
have been elucidated. Ranolazine exerts antagonistic activity towards
Indication
Ranolazine is indicated for the treatment of chronic angina. It can be
used alone or in conjunction with nitrates, beta-blockers, angiotensin
receptor blockers, anti-platelet drugs, calcium channel blockers, lipid-
.lowering drugs, and ACE inhibitors
Ranolazine has also been used off-label for the treatment of certain
arrhythmias, including ventricular tachycardia, however, this use is
not strongly supported by scientific evidence. Ranolazine has also
been studied for the treatment of acute coronary syndrome,
microvascular coronary dysfunction, arrhythmia, and glycemic
.control, which are not yet approved indications
Pharmacodynamics
Ranolazine exerts both antianginal and ischemic effects independent from
lowering heart rate or blood pressure.9,17 It blocks IKr, the rapid portion of the
delayed rectifier potassium current, and prolongs the QTc interval in a dose-
dependent fashion. The Ikr is important for cardiac repolarization.17 Ranolazine
exerts its therapeutic effects without negative chronotropic, dromotropic, or
inotropic actions neither at rest, nor during exercise.1
Volume of distribution
The mean apparent volume of distribution of ranolazine is reported to
be 53.2 L16 and the average steady-state volume of distribution is
estimated to range from 85 to 180 L.6
Protein binding
Approximately 62% of the administered dose of ranolazine is bound
to plasma proteins.4,17 Ranolazine appears to have a higher binding
affinity for alpha-1 acid glycoprotein
Metabolism
Ranolazine is rapidly heavily metabolized in the liver an
gastrointestinal tract through the activity of the CYP3A4 enzyme with
minor contributions from CYP2D6.1,2,17 More than 40 ranolazine
metabolites have been found in plasma and more than 100
metabolites have been identified in the urine.4
Ranolazine and some of its metabolites are known to weakly inhibit
CYP3A4. However, the activity of the metabolites of ranolazine has
not been fully elucidated.16
Route of elimination
From the administered dose, about 3/4 of the dose is excreted
renally, while 1/4 of the dose is excreted in the feces. An estimated
5% of an ingested dose is excreted as unchanged drug.1,17
Half-life
The apparent terminal half-life of ranolazine is 7 hours
Clearance
The reported clearance rate of orally administered ranolazine is of 45
L/h when administered at a dose of 500 mg twice daily.6 The
clearance rate of ranolazine is dose-dependent and renal impairment
can increase ranolazine serum concentration by 40-50%
Toxicity
The reported LD50 of oral ranolazine in the rat is 980
mg/kg.MSDS High oral doses of ranolazine have led to dizziness,
nausea, and vomiting. These effects have been shown to be dose
related. High intravenous doses can cause diplopia, confusion,
paresthesia, in addition to syncope. In the case of an overdose,
provide supportive therapy accompanied by continuous ECG
monitoring for QT interval prolongation
Drug Interactions
Using this medicine with any of the following medicines is not
recommended. Your doctor may decide not to treat you with this
.medication or change some of the other medicines you take
Amitriptyline
Amoxapine
Amprenavir
Drug Interactions
Amitriptyline
Amoxapine
Amprenavir
Atazanavir
Bepridil
Carbamazepine
Cisapride
Clarithromycin
Precautions
If you will be taking this medicine for a long time, it is very important
that your doctor check you at regular visits for any problems or
unwanted effects that may be caused by this medicine. Blood tests
.may be needed to check for unwanted effects
Do not use ranolazine together with carbamazepine (Tegretol®),
clarithromycin (Biaxin®), nefazodone (Serzone®), phenobarbital,
phenytoin (Dilantin®), rifabutin (Mycobutin®), rifampin (Rifadin®,
Rimactane®), rifapentine (Priftin®), medicine to treat fungus
,infections (eg, itraconazole, ketoconazole, Nizoral®, Sporanox®)
Precautions
.Do not use this medicine to treat a sudden onset of chest pain
Contact your doctor right away if you have any changes to your heart
rhythm. You might feel dizzy or faint, or you might have a fast,
pounding, or uneven heartbeat. Make sure your doctor knows if you
.had a heart rhythm problem, such as QT prolongation
Check with your doctor right away if you have bloody urine, a
decrease in frequency or amount of urine, an increase in blood
pressure, increased thirst, loss of appetite, lower back or side pain,
nausea, swelling of the face, fingers, or lower legs, trouble breathing,
unusual tiredness or weakness, vomiting, or weight gain. These could
Side Effects
More common
Dizziness
Less common
Bloating or swelling of the face, arms, hands, lower legs, or feet
chest tightness
difficult or labored breathing
fast, irregular, pounding, or racing heartbeat or pulse
feeling of constant movement of self or surroundings
lightheadedness
rapid weight gain
Dosing
The amount of medicine that you take depends on the strength of
the medicine. Also, the number of doses you take each day, the time
allowed between doses, and the length of time you take the
medicine depend on the medical problem for which you are using the
.medicine
For oral dosage form (extended-release tablets or extended-release
:granules)
:For chronic angina
