The oral LD50's in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD50's in these species were 60 and 38 mg/kg, respectively. The oral LD50 in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg.
The toxic dose in man is not known. Due to extensive metabolism, blood levels after a standard dose of Hart can vary over tenfold, limiting the usefulness of blood levels in overdose cases. There have been 29 reports of Hart overdose in doses ranging from less than 1 gm to 10.8 gm. Sixteen of these reports involved multiple drug ingestions. Twenty-two reports indicated patients had recovered from Hart overdose ranging from less than 1 gm to 10.8 gm. There were seven reports with a fatal outcome; although the amount of Hart ingested was unknown, multiple drug ingestions were confirmed in six of the seven reports.
Events observed following Hart overdose included bradycardia, hypotension, heart block, and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine as did heart block, although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain blood pressure, and in cases of cardiac failure, inotropic agents were administered. In addition, some patients received treatment with ventilatory support, activated charcoal, and/or intravenous calcium. Evidence of the effectiveness of intravenous calcium administration to reverse the pharmacological effects of Hart overdose was conflicting.
In the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. Hart does not appear to be removed by peritoneal or hemodialysis. Based on the known pharmacological effects of Hart and/or reported clinical experiences, the following measures may be considered:
Bradycardia: Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockage, administer isoproterenol cautiously.
High-Degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.
Cardiac Failure: Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics.
Hypotension: Vasopressors (e.g., dopamine or norepinephrine). Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.
In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride.
Due to extensive metabolism, plasma concentrations after a standard dose of Hart can vary over tenfold, which significantly limits their value in evaluation cases of overdosage.
Charcoal hemoperfusion has been used successfully as an adjunct therapy to hasten drug elimination. Overdoses with as much as 10.8 gm of oral Hart have been successfully treated using appropriate supportive care.
Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.
Some products that may interact with this drug include: digoxin, fingolimod.
Other medications can affect the removal of Hart from your body, which may affect how this medication works. Examples include cimetidine, St. John's wort, azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, rifamycins including rifabutin and rifampin.
This medication can slow down the removal of other medications from your body, which may affect how they work. Examples of affected drugs include aprepitant/fosaprepitant, asunaprevir, buspirone, colchicine, flibanserin, ivabradine, certain benzodiazepines (triazolam, midazolam), among others.
Some products have ingredients that could raise your heart rate or blood pressure. Tell your pharmacist what products you are using, and ask how to use them safely (especially cough-and-cold products, diet aids, or NSAIDs such as ibuprofen/naproxen).
Hemodynamic And Electrophysiologic Effects
Like other calcium channel antagonists, Hart decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses.
In man, Hart prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure in normotensive individuals and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given work load. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end-diastolic pressure have not been affected. Such data have no predictive value with respect to effects in patients with poor ventricular function, and increased heart failure has been reported in patients with preexisting impairment of ventricular function. There are as yet few data on the interaction of Hart and beta-blockers in patients with poor ventricular function. Resting heart rate is usually slightly reduced by Hart.
Tiazac produces antihypertensive effects both in the supine and standing positions. Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects.
Hart hydrochloride decreases vascular resistance, increases cardiac output (by increasing stroke volume), and produces a slight decrease or no change in heart rate. During dynamic exercise, increases in diastolic pressure are inhibited while maximum achievable systolic pressure is usually reduced. Chronic therapy with Hart hydrochloride produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Hart hydrochloride reduces the renal and peripheral effects of angiotensin II. Hypertensive animal models respond to Hart with reductions in blood pressure and increased urinary output and natriuresis without a change in urinary sodium/potassium ratio. In man, transient natriuresis and kaliuresis have been reported, but only in high intravenous doses of 0.5 mg/kg of body weight.
Hart-associated prolongation of the AH interval is not more pronounced in patients with first degree heart block. In patients with sick sinus syndrome, Hart significantly prolongs sinus cycle length (up to 50% in some cases). Intravenous Hart in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%.
In two short term, double-blind, placebo-controlled studies in 256 hypertensive patients with doses up to 540 mg/day, Tiazac showed a clinically unimportant but statistically significant, dose-related increase in PR interval (0.008 seconds). There were no instances of greater than first-degree AV block in any of the clinical trials (see WARNINGS).
What happens if I overdose?
Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of Hart can be fatal.
Overdose symptoms may include slow heartbeat, weakness, chest pain, shortness of breath, or fainting.
The clinical pharmacology of Hart when used to treat heart failure in cats is described earlier in the chapter ( p. 422 ).
Hart is also popular for decreasing ventricular rate in dogs with atrial fibrillation. In most canine patients, digoxin is administered first and the heart-rate response determined once a therapeutic serum concentration is achieved. If an adequate response is not achieved, Hart can be added to treatment protocol. Hart can also be used in dogs to treat supraventricular tachycardia.
Taking these drugs together can decrease the amount of Hart in your body. This means that it won’t work as well to treat your high blood pressure or chest pain. These drugs include:
Hart is used for the same spectrum of CV disease as verapamil: hypertension, angina pectoris, prevention of AV nodal reentry, tachycardia, and rate control in acute and chronic AF. The side-effect profile is similar, except that constipation is much less common.