perhexiline

Absorption

Well absorbed (>80%) from the gastrointestinal tract following oral administration.

Toxicity

Oral LD50 rat: 2150 mg/kg; Oral LD50 Mouse: 2641 mg/kg. Short term adverse effects include nausea, transient dizziness, hypoglycaemia in diabetic patients, and torsade de pointes (rare).

Originator

Pexid, Merrell-Tourade ,France ,1973

The Uses of perhexiline

Vasodilator (coronary).

Indications

For the management of severe angina pectoris.

Background

Perhexiline is a coronary vasodilator used especially for angina of effort. It may cause neuropathy and hepatitis.

Definition

ChEBI: Perhexiline is a member of piperidines. It has a role as a cardiovascular drug.

Manufacturing Process

1,1-Dicyclohexyl-2-(2'-pyridyl)ethanol hydrochloride (5 grams) was dehydrated by heating with 25 ml of concentrated hydrochloric acid at steam bath temperature for 10 minutes. 70 ml of water were added to the reaction mixture to give the crystalline hydrochloride salt. The product, 1,1dicyclohexyl-2-(2'-pyridyl)ethylene hydrochloride, was recrystallized from methanol-ethyl acetate to yield a white solid melting at 150°-151.5°C.
1,1-Dicyclohexyl-2-(2'-pyridyl)ethylene hydrochloride (15 grams) in 150 ml of ethanol was hydrogenated in the presence of platinum oxide at about 60 pounds per square inch of hydrogen pressure. The product, 1,1-dicyclohexyl2-(2'-piperidyl)ethane hydrochloride, crystallized from a mixture of methanol and methyl ethyl ketone as a white solid melting at 243° to 245.5°C.
The hydrochloride salt was neutralized with 10% sodium hydroxide solution and the free base so produced was dissolved in ether. The ether solution was dried over anhydrous magnesium sulfate. Addition of an excess of maleic acid in methanol to the solution yielded the acid maleate salt which melted at 188.5°-191°C.
The starting material was obtained by reacting ethyl formate with cyclohexylmagnesium bromide to give dicyclohexylcarbinol. That is oxidized to dicyclohexylketone and then reacted with α-picoline.

brand name

Pexid (Marion Merrell Dow).

Therapeutic Function

Coronary vasodilator

Pharmacokinetics

Used in the treatment of unresponsive or refractory angina. Perhexiline increases glucose metabolism at the expense of free-fatty-acid metabolism, enhancing oxygen efficiency during myocardial ischaemia. Perhexiline also potentiates platelet responsiveness to nitric oxide both in patients with angina and patients with acute coronary syndrome. The predominant mechanism of this particular perhexiline effect is an increase in platelet cGMP responsiveness. Perhexiline also may reduce the potential for nitric oxide clearance by neutrophil-derived oxygen. Perhexiline relieves symptoms of angina, improves exercise tolerance, and increases the workload needed to induce ischaemia when used as monotherapy. The primary therapeutic roles for perhexiline are as short-term therapy (less than 3 months duration) in patients with severe ischaemia awaiting coronary revascularisation or long-term therapy in patients with ischaemic symptoms refractory to other therapeutic measures.

Enzyme inhibitor

This calcium-blocking vasodilator (FW = 277.49 g/mol; CAS 6621-47-2; typically supplied as the maleate or HCl salt), also known as Pexid? and 2- (2,2-dicyclohexylethyl)piperidine, is used to treat angina. It does so by targetting carnitine palmitoyltransferase-1 (CPT-1), an enzyme that controls the access of long chain fatty acids to the mitochondrial site of b-oxidation, showing concentration-dependent inhibition in vitro, using rat cardiac mitochondria, IC50 = 77 μM, and hepatic mitochondria, IC50 = 148 μM. Amiodarone, another drug with anti-anginal properties, likewise inhibits cardiac CPT-1 (IC50 = 228 μM). The rank order of potency for inhibition was malonyl-CoA > 4-hydroxyphenylglyoxylate = perhexiline > amiodarone = monohydroxy-perhexiline. Inhibition was competitive with respect to palmitoyl-CoA but non-competitive inhibition with respect to carnitine. This shifts myocardial metabolism from fatty acid to glucose utilisation which results in increased ATP production for the same O2 consumption and consequently increases myocardial efficiency. (See also Meldonium) Other Target(s): CYP2D6; glutathione S-transferase; Mg2+-ATPase; NADH dehydrogenase; Na+ /K+ -exchanging ATPase; b-oxidation; oxidative phosphorylation; and succinate dehydrogenase.

Metabolism

The principal metabolites of perhexiline in man are monohydroxyperhexiline (which is excreted, in part, conjugated with glucuronic acid) and dihydroxyperhexiline that accounts for a relatively small proportion of the total metabolites. Two unidentified metabolites have also been found in the faeces. The pharmacological activity of the metabolites is not known. Hydroxylation of perhexiline is controlled by cytochrome P450 2D6 (CY P450 2D6).