Ivabradine

drugbox
IUPAC_name = ("S")-3-(3-(((3,4-dimethoxybicyclo(4.2.0) octa-1,3,5-trien-7-yl)methyl)methylamino) propyl)-1,3,4,5-tetrahydro- 7,8-dimethoxy-2"H"-3-benzazepin-2-one

---

width = 158
CAS_number = 155974-00-8
ATC_prefix = C01
ATC_suffix = EB17
PubChem = 132999
DrugBank =
C = 27 | H = 36 | N = 2 | O = 5
molecular_weight = 468.585 g/mol
bioavailability = 40%
metabolism = Hepatic (first-pass) >50%, CYP3A4-mediated
protein_bound = 70%
elimination_half-life = 2 hours
excretion = Renal and fecal
licence_EU = Procoralan
pregnancy_AU = D
legal_UK = POM
routes_of_administration = Oral

Ivabradine (INN) (pronEng|ɪˈvæbrədin) is a novel medication used for the symptomatic management of stable angina pectoris. It is marketed under the trade name Procoralan (Servier) or, such as in Italy, Corlentor (Servier), and was also known as S-16257 during its development. Ivabradine acts by reducing the heart rate in a mechanism different from beta blockers and calcium channel blockers, two commonly prescribed antianginal drugs. It is classified as a "cardiotonic agent".

Mode of action

Ivabradine acts on the I_"f" ("f" is for "funny", so called because it had unusual properties compared with other current systems known at the time of its discovery) ion current, which is highly expressed in the sinoatrial node. I_"f" is a mixed Na⁺–K⁺ inward current activated by hyperpolarization and modulated by the autonomic nervous system. It is one of the most important ionic currents for regulating pacemaker activity in the sinoatrial (SA) node. Ivabradine selectively inhibits the pacemaker I_"f" current in a dose-dependent manner. Blocking this channel reduces cardiac pacemaker activity, slowing the heart rate and allowing more time for blood to flow to the myocardium. [cite journal |author=Thollon C, Cambarrat C, Vian J, Prost JF, Peglion JL, Vilaine JP |title=Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49 |journal=Br. J. Pharmacol. |volume=112 |issue=1 |pages=37–42 |year=1994 |pmid=8032660 |doi=] [cite journal |author=Sulfi S, Timmis AD |title=Ivabradine -- the first selective sinus node I(f) channel inhibitor in the treatment of stable angina |journal=Int. J. Clin. Pract. |volume=60 |issue=2 |pages=222–8 |year=2006 |pmid=16451297 |doi=10.1111/j.1742-1241.2006.00817.x | url=http://www.pubmedcentral.gov/articlerender.fcgi?pubmedid=16451297]

Uses

Ivabradine was approved by the European Medicines Agency in 2005. It is indicated for the symptomatic treatment of stable angina pectoris in patients with normal sinus rhythm, who have a contraindication to or intolerance to beta blockers. It has been shown to be non-inferior to the beta-blocker atenolol for this indicationcite journal |author=Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K |title=Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina |journal=Eur. Heart J. |volume=26 |issue=23 |pages=2529–36 |year=2005 |pmid=16214830 |doi=10.1093/eurheartj/ehi586] and amlodipine.

Apart from angina, it is also being used off-label in the treatment of inappropriate sinus tachycardia. [cite journal |author=Yusuf S, Camm AJ |title=Sinus tachyarrhythmias and the specific bradycardic agents: a marriage made in heaven? |journal=J. Cardiovasc. Pharmacol. Ther. |volume=8 |issue=2 |pages=89–105 |year=2003 |pmid=12808482 |doi=]

Dosage

A dose of 5 mg twice daily is recommended initially; after 1 month, it is recommended to increase to 7.5 mg twice daily to get the optimal efficacy linked to heart rate reduction. Given limited experience in the elderly, the manufacturer recommends a starting dose of 2.5 mgcite web |url=http://www.servier.com/pro/cardiologie/procoralan/procoralan.asp |title=Servier, procolaran product description for healthcare professionals |accessdate=2007-10-14 |format= |work=] .

Adverse effects

14.5% of all patients taking ivabradine experience luminous phenomena (by patients described as sensations of enhanced brightness in a fully maintained visual field). This is probably due to blockage of I _"h" ion channels in the retina which are very similar to cardiac I_"f". These symptoms are mild, transient, fully reversible and non-severe. In clinical studies about 1% of all patients had to discontinue the drug because of these sensations, which occurred on average 40 days after commencement of the drug.

Bradycardia (unusually slow heart rate) occurs at 2% and 5% for doses of 7.5 and 10 mg respectively (compared to 4.3% in atenonol). 2.6-4.8% reported headaches. Other common adverse drug reactions (1–10% of patients) include first-degree AV block, ventricular extrasystoles, dizziness and/or blurred vision. [cite journal | author = Anonymous | title = New medicines: Procoralan | url = http://www.pjonline.com/Editorial/20060204/products/p131products.html | journal = Pharmaceutical Journal | year = 2006 | volume = 276 | issue = 7386 | pages=131 }]

Contraindications

Ivabradine is contraindicated in sick sinus syndrome, and cannot be used concominantly with inhibitors of CYP3A4 such as azole antifungals (such as ketoconazole), macrolide antibiotics, nefazodone and the anti-HIV drugs nelfinavir and ritonavir.

Clinical Trials

* "Reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater." [cite journal | author = Kim Fox, Ian Ford, P Gabriel Steg, Michal Tendera, Prof Roberto Ferrari | title = Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction: a randomised, double-blind, placebo-controlled trial | url = http://www.thelancet.com/journals/lancet/article/PIIS0140673608611708/abstract | journal = The Lancet | year = 2008 | issue = 372 | pages = 807-816 | doi = DOI:10.1016/S0140-6736(08)61170-8 }]

References

External links

* [http://www.procoralan.com/ Official site]
* [http://www.servier.com/ Manufacturer´s web site]
* [http://www.procoralan.co.uk/ Procoralan UK]
* Źródło: "http://pl.wikipedia.org/wiki/Iwabradyna"