Diltiazem

Intact vials should be stored under refrigeration and protected from freezing. Diltiazem HCl may be stored for up to one month at room temp but should then be destroyed. /Diltiazem HCl/

The photostability of diltiazem was studied in aq solns at different pH values. Firstly, the hydrolysis of the drug to desacetyldiltiazem in alkaline medium was evaluated and then the drug photodegradation under exposure to UVA-UVB radiation (solar simulator) was monitored by HPLC methods. The main photoproduct was isolated and characterized as diltiazem-S-oxide on the basis of the NMR and mass spectra. The HPLC method was also applied to the selective analysis of diltiazem in commercial formulations. Tests on mutagenicity and photomutagenicity of the drug were also carried out using Salmonella typhimurium TA 102 strain. In this testing the drug neither was mutagenic nor toxic.

8.02

8.06

pKa = 8.06

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Excitation of cardiac muscle involves the activation of a slow calcium inward current that is induced by L-type slow calcium channels, which are voltage-sensitive, ion-selective channels associated with a high activation threshold and slow inactivation profile. L-type calcium channels are the main current responsible for the late phase of the pacemaker potential. Acting as the main Ca2+ source for contraction in smooth and cardiac muscle, activation of L-type calcium channels allows the influx of calcium ions into the muscles upon depolarization and excitation of the channel. It is proposed that this cation influx may also trigger the release of additional calcium ions from intracellular storage sites. Diltiazem is a slow calcium channel blocker that binds to the extracellular site of the alpha-1C subunit of the channel, which is thought to be the S5-6 linker region of the transmembrane domain IV and/or S6 segment of domain III. Diltiazem can get access to this binding site from either the intracellular or extracellular side, but it requires a voltage-induced conformational changes in the membrane. Diltiazem inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. In isolated human atrial and ventricular myocardium, diltiazem suppressed tension over the range of membrane potentials associated with calcium channel activity but had little effect on the tension-voltage relations at more positive potentials. This effect is thought to be mediated by the voltage-dependent block of the L-type calcium channels and inhibition of calcium ion release from the ER stores, without altering the sodium-calcium coupled transport or calcium sensitivity of myofilaments. Through inhibition of inward calcium current, diltiazem exerts a direct ionotropic and energy sparing effect on the myocardium. Diltiazem fslows atrioventricular nodal conduction, which is due to its ability to impede slow channel function. Reduced intracellular calcium concentrations equate to increased smooth muscle relaxation resulting in arterial vasodilation and therefore, decreased blood pressure. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. Through its actions on reducing calcium levels in cardiac and vascular smooth muscles, diltiazem causes a reduction in the contractile processes of the myocardial smooth muscle cells and vasodilation of the coronary and systemic arteries, including epicardial and subendocardial. This subsequently leads to increased oxygen delivery to the myocardial tissue, improved cardiac output due to increased stroke volume, decreased total peripheral resistance, decreased systemic blood pressure and heart rate, and decreased afterload. Diltiazem lowers myocardial oxygen demand through a reduction in heart rate, blood pressure, and cardiac contractility; this leads to a therapeutic effect in improving exercise tolerance in chronic stable angina.

The effects of D-cis- and L-cis-diltiazem on the hydrogen peroxide (H2O2)-induced derangements of mechanical function and energy metab, and accumulation of intracellular Na+ were studied in isolated rat hearts. The intracellular concn of Na+ ([Na+]i) in the myocardium was measured using a nuclear magnetic resonance technique. H2O2 (600 uM) increased the left ventricular end-diastolic pressure, decreased the tissue level of ATP, and increased the release of lactate dehydrogenase from the myocardium. These alterations induced by H2O2 were significantly attenuated by D-cis-diltiazem (15 uM) or L-cis-diltiazem (15 uM). H2O2 (1 mM) produced a marked incr in the myocardial [Na+]i, which was effectively inhibited by ... D-cis-diltiazem (15 uM) or L-cis-diltiazem (15 uM). ... The protective action of D-cis- and L-cis-diltiazem may be due to their ability to inhibit the H2O2-induced incr in [Na+]i, at least in part.

The plasma elimination half-life is approximately 3.0 to 4.5 hours following single and multiple oral doses. The half-life may slightly increase with dose and the extent of hepatic impairment. The apparent elimination half-life for diltiazem as extended-release tablets after single or multiple dosing is 6 to 9 hours. The plasma elimination half-life is approximately 3.4 hours following administration of a single intravenous injection. The elimination half-lives of pharmacologically active metabolites are longer than that of diltiazem.

Clearance of diltiazem after oral ingestion follows first-order kinetics, with a half-life of 5-10 hr ... .

Diltiazem is subject to extensive first-pass metabolism, which explains its relatively low absolute oral bioavailability. It undergoes N-demethylation primarily mediated by CYP3A4. CYP2D6 is responsible for O-demethylation and esterases mediate deacetylation. There was large inter-individual variability in the circulating plasma levels of metabolites in healthy volunteers. In healthy volunteers, the major circulating metabolites in the plasma are N-monodesmethyl diltilazem, deacetyl diltiazem, and deacetyl N-monodesmethyl diltiazem, which are all pharmacologically active. Deacetyl diltiazem retains about 25-50% of the pharmacological activity to that of the parent compound. Deacetyl diltiazem can be further transformed into deacetyl diltiazem N-oxide or deacetyl O-desmethyl diltiazem. N-monodesmethyl diltilazem can be further metabolized to N,O-didesmethyl diltiazem. Deacetyl N-monodesmethyl diltiazem can be further metabolized to deacetyl N,O-didesmethyl diltiazem, which can be glucuronidated or sulphated. Diltiazem can be O-demethylated by CYP2D6 to form O-desmethyl diltiazem.

A major metabolite of diltiazem is desacetyldiltiazem, which has about 1/2 of diltiazem's potency as a vasodilator.

Diltiazem undergoes extensive metabolism in hepatic and extrahepatic tissues. Deacetyldiltiazem (M1) and N-demethyldiltiazem (MA) are 2 of the main basic metabolites of diltiazem that retain pharmacological activity. This drug impairs its own metab after chronic admin in the adult patient.

Diltiazem has known human metabolites that include O-Demethyldiltiazem and N-Demethyldiltiazem.

Diltiazem is metabolized by and acts as an inhibitor of the CYP3A4 enzyme. Half Life: 3.0 - 4.5 hours

EE92BBP03H

DILTIAZEM

Mechanisms of Action [MoA] - Calcium Channel Antagonists

Established Pharmacologic Class [EPC] - Calcium Channel Blocker

Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inhibitors

Diltiazem is a Calcium Channel Blocker. The mechanism of action of diltiazem is as a Calcium Channel Antagonist and Cytochrome P450 3A4 Inhibitor.

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

A class of drugs that act by selective inhibition of calcium influx through cellular membranes.

Agents that affect the rate or intensity of cardiac contraction, blood vessel diameter, or blood volume.

Drugs used to cause dilation of the blood vessels.

Diltiazem is readily absorbed from the gastrointestinal tract. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50 to 200 ng/mL. Following oral administration of extended formulations of 360 mg diltiazem, the drug in plasma was detectable within 3 to 4 hours and the peak plasma concentrations were reached between 11 and 18 hours post-dose. Diltiazem peak and systemic exposures were not affected by concurrent food intake. Due to hepatic first-pass metabolism, the absolute bioavailability following oral administration is about 40%, with the value ranging from 24 to 74% due to high interindividual variation in the first pass effect. The bioavailability may increase in patients with hepatic impairment.

Due to its extensive metabolism, only 2% to 4% of the unchanged drug can be detected in the urine. The major urinary metabolite in healthy volunnteers was N-monodesmethyl diltiazem, followed by deacetyl N,O-didesmethyl diltiazem, deacetyl N-monodesmethyl diltiazem, and deacetyl diltiazem; however, there seems to be large inter-individual variability in the urinary excretion of DTZ and its metabolites.

The apparent volume of distribution of diltiazem was approximately 305 L following a single intravenous injection in healthy male volunteers.

Following a single intravenous injection in healthy male volunteers, the systemic clearance of diltiazem was approximately 65 L/h. After constant rate intravenous infusion, the systemic clearance decreased to 48 L/h.

The protein binding of diltiazem is 80-90%, & the volume of distribution is approx 5.3 L/kg. Clearance of diltiazem after oral ingestion follows first-order kinetics, with a half-life of 5-10 hr, independent of the amount ingested. In sustained release preparations, however, the peak absorption time is delayed & the half-life may be very prolonged because of continued GI absorption.

Although the absorption of ... agents /like diltiazem/ is nearly complete after oral admin, their bioavailability is reduced, in some cases markedly, because of first-pass hepatic metab. The effects of these drugs are evident within 30-60 min of an oral dose ... . During repeated oral admin, bioavailability and half-life may incr because of saturation of hepatic metabolism. A major metabolite of diltiazem is desacetyldiltiazem, which has about 1/2 of diltiazem's potency as a vasodilator.