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| Protein binding | 78 |
| Eliminationhalf-life | 14.3 +/-3.7 |
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| Chemical and physical data | |
| Formula | C22H27ClN2O |
| Molar mass | 370.92 g·mol−1 |
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Lorcainide (Lorcainide hydrochloride) is a Class 1cantiarrhythmic agent that is used to help restore normal heart rhythm and conduction in patients withpremature ventricular contractions,ventricular tachycardiac[1] andWolff–Parkinson–White syndrome.[2] Lorcainide was developed byJanssen Pharmaceutica (Belgium) in 1968 under the commercial name Remivox and is designated by code numbers R-15889 or Ro 13-1042/001.[3] It has a half-life of 8.9 +- 2.3 hrs which may be prolonged to 66 hrs in people with cardiac disease.[2]
Cardiac dysrhythmia is a heart rate disorder that manifests as an altered cardiac rhythm. It results from either abnormalpacemaker activity or a disturbance in impulse propagation, or both.[4] Arrhythmias can be caused by various conditions includingischemia,hypoxia, pH disruptions, B adrenergic activation, drug interactions or the presence of diseased tissue.[5] These events can trigger the development ofectopic pacemaker in the heart, which emit abnormal impulses at random times during thecardiac cycle. An arrhythmia can present itself as eitherbradycardia ortachycardia.[5] Untreated arrhythmias may progress toatrial fibrillation orventricular fibrillation.[5] Treatment is aimed at normalizing cardiac rhythm by altering ion flow across the membrane.Antiarrhythmic agents can reduce arrhythmia related symptoms such aspalpitations orsyncope; however, they often have a narrowtherapeutic index and can also beproarrhythmic.[4]
Wolff–Parkinson–White syndrome (WPW) is apre-excitation syndrome in which individuals are predisposed to supraventricular tachyarrhythmias (rapid and irregular heart beats).[6] People with this condition have an extra or accessoryatrioventricular conduction pathway that causes re-entry tachycardia.[6] WPW is characterized by a shortPR interval (<0.12 second) and a prolonged, slurredQRS complex (>0.12 seconds).[6]
Fast-acting voltage-gated sodium channels (Nav1.5) found in high concentrations in the ventricular myocytes, open at a membrane potential of −80 mv in typical cardiac rhythm. This will result in a rapid upstroke of anaction potential that leads to contraction of the ventricles.[7] Class 1c drugs have localanesthetic properties and have a high affinity for open Nav1.5 (but not closed or inactive Nav1.5), thus irreversibly binding and reducing the fast Na+ influx. Interactions of Lorcainide with Nav1.5 are time and voltage dependent. Class 1c drugs have a characteristically slow dissociation rate, which will slow the upstroke duration and amplitude of ventricular myocytes’ action potential and prolong the PR, QRS and QT intervals of anECG.[8] Lorcainide also increases the ventricular fibrillation threshold in a dose-dependent fashion.[8] Overall, Lorcainide causes a decrease in tachycardiac events, but also reduced ventricular contractilityejection fraction. The effect onsinus node function is controversial, as some researchers have noted a decreased sinus cycle length and increase in sinus node recovery, whereas others have observed no change.[8]
Lorcainide inhibits adenosine 5’-triphosphate (ATP)-hydrolytic action of myocardial Na+K+ATPase in-vitro in a concentration dependent manner. The mode of action and the implications of this finding are not well known.[9]
Lorcainide exhibits a prolonged duration of action (approximately 8-10 hrs), is well absorbed when taken orally and has a good safety profile as well as a good drugefficacy.[4] Hematologic, biochemical and urinary analysis of Lorcainide revealed no significant abnormalities.[2] However, an increased prevalence of central nervous system effects, including headache, dizziness and sleep disturbances have been associated with oral dosages of Lorcainide when compared to intravenous administration. This could be due to a greater accumulation of plasma Noriorcainide when exposed to oral Lorcainide. Noriorcainide, an N-dealkylated derivative, is an active metabolite of Lorcainide. It is as potent as its parent compound with similar antiarrhythmic efficacy, wherein it suppresses chronic premature ventricular complexes.[8] It has a half life of 26.5 +-7.2 hrs.[2]
The starting material is theimine formed by combining4-chloroaniline andN-carbethoxy-4-piperidone, which isreduced withsodium borohydride and thenacylated with theacid chloride ofphenylacetic acid to produce anamide. Selectivehydrolysis withhydrobromic acid, followed byalkylation withisopropyl bromide gives lorcainide.[10][11]
