dl-cis-Diltiazem

414.5 g/mol

414.52

255-796-4

EE92BBP03H

DTXSID9022940

C61725

White crystalline powder

C - Cardiovascular system

84.4 Ų

2.7 (LogP)|log Kow = 2.70|2.8

187-188|209.75 °C|212 °C (decomposes)|231°C

Decomposes

0.00 M|Soluble in methanol or chloroform|In water, 465 mg/l @ 25 °C|1.68e-02 g/L

Diltiazem hydrochloride tablets should be stored in tight, light-resistant, and extended-release capsules in tight containers at 15-30 °C, unless otherwise specified by the manufacturer. /Diltiazem hydrochloride/|Extended-release tablets containing diltiazem malate alone or in fixed combination with enalapril maleate should be stored in well-closed containers at 15-30 °C. /Diltiazem malate/|Diltiazem hydrochloride injection in vials should be refrigerated at 2-8 °C; freezing of the injection should be avoided. Diltiazem hydrochloride injection may be stored at room temp for up to 1 month; after that time, the injection should be discarded. Diltiazem hydrochloride powder for injection in single-use vials ... or in single-use syringes ... should be stored at a room temp of 15-30 °C; freezing of the powder for injection should be avoided. Following reconstitution of diltiazem hydrochloride powder for injection from single-dose vials and transferred to polyvinyl chloride (PVC) bags ... or after actuation of the single-use syringe, the reconstituted solns of diltiazem hydrochloride are stable for 24 hr at controlled room temp; unused portions of reconstituted soln in the PVC bags or single-use syringes should be discarded after this period. /Diltiazem hydrochloride/

pKa = 8.06

197.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|197.3 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated]

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.

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.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl diltiazem hydrochloride and diltiazem maleate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Diltiazem hydrochloride, diltiazem maleate/

**Clinical Toxicity and Overdose** The oral LD50 ranges from 415 to 740mg/kg in mice and 560 to 810 mg/kg in rats. The oral LD50 in dogs is considered to be in excess of 50 mg/kg. A dose of 360 mg/kg resulted in lethality in monkeys. The intravenous LD50 is 60 mg/kg in mice and 38 mg/kg in rats. Cases of overdose from doses ranging from less than 1 g to 18 g have been reported with diltiazem, with several cases involving multiple drug ingestions resulting in death. Overdoses were associated with bradycardia, hypotension, heart block, and cardiac failure that may manifest as dizziness, lightheadedness, and fatigue. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. Diltiazem overdose should be responded with appropriate supportive measures and gastrointestinal decontamination. Bradycardia and heart block can be treated with atropine at doses ranging from 0.60 to 1.0 mg. In the case of bradycardia, if there is no response to vagal blockage, cautious administration of isoproterenol should be considered. Cardiac pacing can also be used to treat fixed high-degree AV block. In the case of heart failure, blood pressure may be maintained with the use of fluids and vasopressors, as well as inotropic agents such as [isoproterenol], [dopamine], or [dobutamine]. Other appropriate measures include ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium. Diltiazem does not appear to be removed by peritoneal or hemodialysis. **Non-clinical toxicity** In a 24-month study in rats receiving oral doses of up to 100 mg/kg/day, there was no evidence of carcinogenicity. There was also no mutagenic response _in vitro_ or _in vivo_ in mammalian cell assays or _in vitro_ bacterial assays. No evidence of impaired fertility was observed in a study performed in male and female rats receiving oral doses of up to 100 mg/kg/day. **Pregnancy and Lactation** In reproduction studies in animals, administration of diltiazem at doses ranging from five to twenty times the daily recommended human therapeutic dose resulted in cases of the embryo and fetal lethality and skeletal abnormalities, and an increase in the risk of stillbirths. There have been no up-to-date controlled studies that investigated the use of diltiazem in pregnant women. The use of diltiazem in pregnant women should be undertaken only if the potential benefit justifies the risk to the fetus. Diltiazem is excreted in human milk, where one report suggests that the concentrations in breast milk may approximate serum levels; therefore, the decision should be made to either discontinue nursing or the use of the drug after careful consideration of the clinical necessity of diltiazem therapy in the nursing mother. **Use in special populations** As there is limited information on the variable effects of diltiazem in geriatric patients, the initial therapy of diltiazem should involve the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Currently, there are no specific dosing guidelines for patients with renal or hepatic impairment.

Diltiazem therapy is associated with a low rate of mild and transient elevations in serum aminotransferase levels which are usually asymptomatic and often resolve even with continuation of therapy. Clinically apparent, acute liver injury with jaundice due to diltiazem is rare and only isolated case reports have been published. In large case series of drug induced liver injury, calcium channel blockers are rarely mentioned. Most cases attributed to diltiazem have been marked by a short latency period (3 to 14 days) and features of hypersensitivity with fever, rash and eosinophilia. The pattern of liver injury was ranged from cholestatic to hepatocellular. Jaundice is often absent and usually mild. Autoantibody formation has not been described. Thus, liver injury from diltiazem is likely to be idiosyncratic in nature and is typically mild and self-limited with resolution within 4 to 8 weeks of stopping. Acute hepatic injury is listened as a possible adverse event in the diltiazem product label.

Diltiazem interacts with Propranolol reducing oral clearance with increased concns of propanolol by inhibition of first-pass metab. Propanolol dose may need to be reduced. /from table/|Diltiazem interacts with cyclosporine increasing cyclosporine concns. Reduce cyclosporine dose after starting... diltiazem; monitor cyclosporine concns. /from table/|Diltiazem interacts with disopyramide, flecainide /causing/ cardiac failure by additive depression of myocardial contractility. Avoid use if possible, particularly in patients with impaired myocardial function. /from table/|Diltiazem interacts with Amiodarone, flecainide /causing/ sinus arrest, heart block by additive depression of sinus node function & AV nodal conduction. Use combination with extreme caution. /from table/|For more Interactions (Complete) data for DILTIAZEM (15 total), please visit the HSDB record page.

Diltiazem is about 70-80% bound to plasma proteins, according to _in vitro_ binding studies. About 40% of the drug is thought to bind to alpha-1-glycoprotein at clinically significant concentrations while about 30% of the drug is bound to albumin.

SURFACE WATER: In a survey conducted by the United States Geological Survey, diltiazem was detected at a max concn of 0.049 ug/l (0.021 ug/l median concn, 0.012 ug/l reporting level) at a 13.1% frequency in 84 submitted water samples from a network of 139 US stream sampling sites across 30 states during 1999-2000(1).

Diltiazem is excreted into human milk.

A 15-yr-old woman was admitted to the ICU after ... auto-intoxication with 10 tablets of 200 mg diltiazem sustained release. ... Max plasma lactate concn was 10 mmol/l and the highest measured plasma diltiazem level was 500 micrograms/l.

**Oral** Indicated for the management of hypertension, to lower blood pressure, alone or in combination with other antihypertensive agents. Indicated for use to improve exercise tolerance in patients with chronic stable angina. Indicated for the management of variant angina (Prinzmetal's angina). **Intravenous** Indicated for the short-term management of atrial fibrillation or atrial flutter for temporary control of rapid ventricular rate. Indicated for the rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm. This includes AV nodal reentrant tachycardias and reciprocating tachycardias associated with an extranodal accessory pathway such as the WPW syndrome or short PR syndrome. **Off-label** Indicated for off-label uses in anal fissures (as topical formulation), migraine prophylaxis, cramps in lower leg related to rest, pulmonary hypertension, idiopathic dilated cardiomyopathy, and proteinuria associated with diabetic nephropathy.

Diltiazem hydrochloride is a first generation calcium channel blocker that is widely used in the therapy of hypertension and angina pectoris. Diltiazem therapy is associated with serum enzyme elevations and has been linked to rare instances of clinically apparent liver injury.

Diltiazem ... may reduce the incidence of reinfarction in patients with a first non-Q-wave infarction who are not candidates for a beta-adrenergic receptor antagonist.|... Diltiazem ... /has/ been shown to provide symptomatic relief in Raynaud's disease.|Diltiazem ... /is/ indicated, alone or in combination with other agents, for treatment of hypertension. /Included in US product labeling/|... Parenteral diltiazem /is/ indicated in the treatment of supraventricular tachyarrhythmias. Diltiazem ... produces rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardia (including those associated with accessory bypass tracts, such as Wolff-Parkinson-White [W-P-W] or Lown-Ganong-Levine [L-G-L] syndrome) in patients who do not respond to vagal maneuvers {161} when the atrioventricular (AV) node is required for reentry to sustain tachycardia {125}. Parenteral diltiazem ... also produces temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation. ... /Included in US product labeling/|For more Therapeutic Uses (Complete) data for DILTIAZEM (16 total), please visit the HSDB record page.

The toxic effects of sustained-release calcium channel blockers may be delayed more than 12 hr after ingestion. All patients with sustained-release calcium channel blocker overdose should be admitted to the hospital for observation, even if they are asymptomatic. /Calcium channel blockers/|Withdrawal of calcium channel blocking drugs from severely hypertensive patients, even in the absence of previous angina or myocardial infarction, may precipitate myocardial infarction. Worsening angina & myocardial infarction have been described after the withdrawal of calcium channel blocking agents in patients with normal coronary angiography who are being treated for ischemic chest pain. /Calcium channel blockers/|Patients with ventricular dysfunction, SA or AV nodal conduction disturbances, and systolic blood pressures below 90 mm Hg should not be treated with ... diltiazem, particularly iv.|The most common adverse cardiovascular effect noted with IV diltiazem is symptomatic or asymptomatic hypotension, which occurred in 3.2 or 4.3%, respectively, of patients receiving the drug in clinical trials. Hypotension or postural hypotension also was noted in approximately 1% or less of patients receiving oral diltiazem. If symptomatic hypotension occurs, appropriate therapy (e.g., placement of the patients in the Trendelenburg's position, plasma volume expansion) should be initiated. Hypotension occurred secondary to the vasodilating action of diltiazem on vascular smooth muscle. Vasodilation or flushing occurred in 1.7% of patients receiving IV diltiazem and in approximately 1% or less of patients receiving oral diltiazem in clinical trials.|For more Drug Warnings (Complete) data for DILTIAZEM (18 total), please visit the HSDB record page.

At /blood/ levels /of diltiazem/ above 6,100 ug/L, most patients die.

Diltiazem is an antihypertensive and vasodilating agent that works by relaxing the vascular muscle and reducing blood pressure. This is related to the long-term therapeutic effects, as lowering the blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Diltiazem inhibits the influx of extracellular calcium ions across the myocardial and vascular smooth muscle cell membranes during depolarization. Diltiazem is classified as a negative inotrope (decreased force) and negative chronotrope (decreased rate). It is also considered a rate-control drug as it reduces heart rate. Diltiazem is exerts hemodynamic actions by reducing blood pressure, systemic vascular resistance, the rate-pressure product, and coronary vascular resistance while increasing coronary blood flow. Diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In supraventricular tachycardia, diltiazem prolongs AV nodal refractories. As the magnitude of blood pressure reduction is related to the degree of hypertension, the antihypertensive effect of diltiazem is most pronounced in individuals with hypertension. In a randomized, double-blind, parallel-group, dose-response study involving patients with essential hypertension, there was a reduction in the diastolic blood pressure by 1.9, 5.4, 6.1, and 8.6 mmHg in the patients receiving diltiazem at doses of 120, 240, 360, and 540 mg, respectively. In patients receiving placebo, there was a reduction in the diastolic blood pressure by 2.6 mmHg.In a randomized, double-blind study involving patients with chronic stable angina, variable doses of diltiazem administered at night all caused an increased exercise tolerance in the after 21 hours, compared to placebo. In the NORDIL study of patients with hypertension, the therapeutic effectiveness of diltiazem in reducing cardiovascular morbidity and mortality was assessed. When using the combined primary endpoint as fatal and non-fatal stroke, myocardial infarction, and other cardiovascular death, fatal and non-fatal stroke was shown to be reduced by 25% in the diltiazem group. Although the clinical significance to this effect remains unclear, it is suggested that diltiazem may exert a protective role against cerebral stroke in hypertensive patients.

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. (See all compounds classified as Antihypertensive Agents.)|A class of drugs that act by selective inhibition of calcium influx through cellular membranes. (See all compounds classified as Calcium Channel Blockers.)|Agents that affect the rate or intensity of cardiac contraction, blood vessel diameter, or blood volume. (See all compounds classified as Cardiovascular Agents.)|Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)

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 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.|Diltiazem is excreted into human milk.|The pharmacokinetic changes of diltiazem ... and its main metabolite, deacetyldiltiazem (DAD) were studied after oral admin of diltiazem to normal rabbits and mild and medium folate-induced renal failure rabbits. Diltiazem 10 mg/kg was given to the rabbits ... orally (n=6). Plasma concns of diltiazem and DAD were determined by a high performance liquid chromatography assay. The area under the plasma concn-time curves (AUC) and max plasma concn (Cmax) of diltiazem were significantly increased in mild and medium folate-induced renal failure rabbits. The metabolite ratio of the diltiazem to DAD were significantly decreased in mild and medium folate-induced renal failure rabbits. The volume of distribution (Vd) and total body clearance (CLt) of diltiazem were significantly decreased in mild and medium folate-induced renal failure rabbits. The elimination rate constant (beta) of diltiazem was significantly decreased in folate-induced renal failure rabbits, but that of DAD was significantly increased. These findings suggest that the hepatic metab of diltiazem was inhibited ... .|The pharmacokinetics of diltiazem in rabbits after subconjunctival and topical admin was studied. Diltiazem successfully penetrated the aq humor of rabbit eyes. The peak aq concns were 3.8 +/- 0.4 ug/ml after topical application and 15.3 +/- 1.1 ug/ml after subconjunctival injection. The peak aq concn was achieved 1/2 hrs after admin in both cases.

Diltiazem is subject to extensive first-pass metabolism, which explains its relatively low absolute oral bioavailability. It undergoes metabolism primarily mediated by CYP3A4. Diltiazem is reported to undergo deacetylation, N- demethylation, and O-demethylation, as well as conjugation reactions mediated by CYP450 enzymes, with CYP3A4 being the primary enzyme responsible for drug metabolism. Metabolites N-monodesmethyldiltiazem, desacetyldiltiazem, desacetyl-N-monodesmethyldiltiazem, desacetyl-O- desmethyldiltiazem, and desacetyl-N, O-desmethyldiltiazem have been identified in human urine. It is proposed that N-desmethyldiltiazem, deacetyldiltiazem, deacetyl-N-monodesmethyldiltiazem, and desacetyl-O- desmethyldiltiazem all retain pharmacological activity with varying potency. Desacetyldiltiazem is present in the plasma at levels of 10% to 20% of the parent drug and retains about 25-50% of the pharmacological activity to that of the parent compound. Radioactivity studies indicate the presence of other metabolites that persist in the plasma for 20 hours, compared to diltiazem that is detectable for 2 to 5 hours.|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 N-Demethyldiltiazem and O-Demethyldiltiazem.

The plasma elimination half-life is approximately 3.0 - 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.|Clearance of diltiazem after oral ingestion follows first-order kinetics, with a half-life of 5-10 hr ... .

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.

An adult dose of 10 ... calcium gluconate over 5 min may be used to reverse hypotension with careful monitoring of rhythm. A repeat bolus (after 10-15 min) or iv drip (of the 10% calcium gluconate soln) may be needed. Calcium levels must be monitored. The optimal calcium dosage required for the treatment of calcium channel blocker toxicity has not been determined. Hypercalcemia may be significant if more than 45 mEq of calcium is admin acutely. /Calcium channel blockers/|Glucagon exhibits chronotropic & inotropic effects in calcium channel blocker overdose. The binding of glucagon to its specific catecholamine-independent receptors activates adenyl cyclase & converts intracellular ATP to cyclic AMP. The intracellular cyclic AMP stimulates the uptake of calcium by the sarcoplasmic reticulum & plasma membrane-enriched fraction. Calcium is important for the coupling of the action potential of the contraction press. Increased intracellular calcium leads to increased myocardial contractility. This effect on myocardial cells appears to be influenced by the amount of circulating ionized calcium, the presence of phosphodiesterase inhibitors, & the degree of heart failure. Normal serum ionized calcium may be a prerequisite for full responsivity of myocardial cells to glucose. Iv glucagon ... is often followed by a rise in blood pressure. If an initial bolus ... is unsuccessful at increasing blood pressure, it appears reasonable to double that dose. If the hemodynamic status improves, a glucagon infusion can be started ... . Glucagon can be admin safely for as long as 48 hr with few ill effects. The most common adverse drug reactions associated with its use are nausea, emesis, & hyperglycemia. Careful monitoring of total serum calcium & preferably of total serum ionized calcium, as well as supplemental infusions of calcium chloride, appear to constitute an optimal management program. If these modalities do not restore the hemodynamic status, a bolus infusion of amrinone may be useful. Some recent literature reports anecdotal success with glucagon, although other reports describe the use of up to 10 mg of glucagon iv without clinical improvement. /Calcium channel blockers/|Various catecholamines & sympathomimetic agents, including isoproterenol, dopamine, dobutamine, epinephrine, & norepinephrine, have been used to counter the hypotensive effects of calcium channel blocker overdose, all with mixed results. It remains unclear which catecholamine or combination of catecholamines is better for the treatment of calcium channel blocker toxicity based on current data in the literature. On the basis of their pharmacologic profiles, beta-adrenergic receptor agonists such as dobutamine & isoproterenol would be logical choices when primarily cardiac chronotropy & inotropy are affected. Direct alpha-adrenergic receptor agonists may be a better choice if the toxicity is related primarily to decreased systemic vascular resistances. Combining alpha- & beta-adrenergic receptor agonists (such as dobutamine & norepinephrine) or using agents with both alpha- & beta-adrenergic effects (such as epinephrine) may ameliorate both cardiac dysfunction & decreased systemic vascular resistance. /Calcium channel blockers/|Cardiac pacing is indicated for significant bradycardia & high-grade conduction blocks. The incr in heart rate alone induced by cardiac pacing can improve cardiac output. Cardiac pacing (both external & internal) does not always capture or improve the hemodynamics in calcium channel blocker toxic patients. Intraaortic balloon counterpulsation directly augments cardiac output in the failing heart. By temporarily providing adequate cardiac output, it provides a window of opportunity for the metab & elimination of the offending calcium channel blocker. Cardiac pacing may be used in concert with intraaortic balloon counterpulsation for significant bradycardia & high-grade blocks. /Calcium channel blockers/|...A patient who developed tetany with sudden respiratory arrest after the infusion of iv diltiazem /is described/. The admin of calcium chloride rapidly resolved the patient's tetany with prompt recovery of respiratory function, averting the need for more aggressive airway management & ventilatory support. The emergency physician should be aware that life-threatening tetany may accompany the admin of iv diltiazem & that calcium chloride may be a rapid & effective remedy.

/HUMAN EXPOSURE STUDIES/ An 18 yr old man ingested 720 mg of diltiazem & developed sinus tachycardia; one 300 mg ingestion of diltiazem by a 50 yr old was nontoxic. Similarly, a 120 mg diltiazem ingestion by an 18 month old was nontoxic. A 50 yr old ingested 5880 mg of diltiazem with beer, became hypotensive & had a short period of ventricular asystole; he survived.|/HUMAN EXPOSURE STUDIES/ A patient received diltiazem throughout pregnancy with twins. The infants were delivered at 37 wk gestation. There were no apparent maternal or fetal adverse effects throughout pregnancy, through the neonatal period, & up to 6 months later.|/HUMAN EXPOSURE STUDIES/ Diltiazem has both central & peripheral circulatory effects, although the central effects appear to predominate, placing it closer to the verapamil end of the spectrum. Diltiazem ... /has/ negative inotropic effects.|/HUMAN EXPOSURE STUDIES/ Oral admin of diltiazem results in a sustained fall in both heart rate and mean arterial blood pressure. Despite the fact that diltiazem and verapamil produce similar effects on the /sinoatrial/ and /atrioventricular/ nodes, the negative inotropic effect of diltiazem is more modest.|For more Human Toxicity Excerpts (Complete) data for DILTIAZEM (9 total), please visit the HSDB record page.

Aldizem

Available commercially as the (+)-cis-isomer hydrochloride salt.|Cardizem /Diltiazem hydrochloride/|Dilacor-XR /Diltiazem hydrochloride/|Tiazac|For more Formulations/Preparations (Complete) data for DILTIAZEM (6 total), please visit the HSDB record page.

Analyte: diltiazem hydrochloride; matrix: pharmaceutical preparation (tablet); procedure: liquid chromatography with detection at 240 nm and comparison to standards (assay purity) /diltiazem hydrochloride/|Analyte: diltiazem hydrochloride; matrix: pharmaceutical preparation (tablet); procedure: retention time of liquid chromatogram with comparison to standards (chemical identification) /diltiazem hydrochloride/|Analyte: diltiazem hydrochloride; matrix: pharmaceutical preparation (tablet); procedure: colorimetric reaction with ammonium thiocyanate and cobalt chloride (chemical identification) /diltiazem hydrochloride/|Analyte: diltiazem hydrochloride; matrix: pharmaceutical preparation (extended-release capsule); procedure: liquid chromatography with detection at 240 nm and comparison to standards (assay purity) /diltiazem hydrochloride/|For more Analytic Laboratory Methods (Complete) data for DILTIAZEM (10 total), please visit the HSDB record page.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals