Diltiazem Hydrochloride Tablets USP 60 mg

Indications

• Hypertension
• Angina pectoris
• Supraventricular tachycardia
• Atrial fibrillation
• Rate control in atrial flutter

Dosage

Children: For children, refer to BNF for Children for appropriate dosing

Adults: The usual adult dosage for hypertension is 30 mg to 60 mg three times daily, which may be increased based on response, not exceeding 360 mg per day.

Mechanism of action

Diltiazem acts by binding to the extracellular site of L-type calcium channels, particularly the alpha-1C subunit. This binding inhibits the influx of extracellular calcium across myocardial and vascular smooth muscle membranes during depolarization. As a result, diltiazem decreases contractility (negative inotropic effect), heart rate (negative chronotropic effect), and vascular resistance, thereby lowering blood pressure and improving coronary blood flow.

Pharmacodynamics

Diltiazem exerts multiple pharmacodynamic effects, including vasodilation and reduction of systemic vascular resistance. It lowers blood pressure, decreases heart rate, and inhibits conduction through the sinoatrial and atrioventricular nodes. This results in a therapeutic profile that reduces the risk of cardiovascular events such as strokes and myocardial infarctions. Diltiazem is classified as a negative inotrope and chronotrope, making it effective in conditions like hypertension and angina.

Pharmacokinetics

Diltiazem is well absorbed after oral administration, with peak plasma concentrations occurring within 1-2 hours. It undergoes extensive hepatic metabolism, predominantly via cytochrome P450 enzymes, leading to both active and inactive metabolites. The drug has a half-life ranging from 3 to 5 hours, allowing for once or twice daily dosing. It is primarily excreted in the urine as metabolites, with a small percentage excreted unchanged.

Contra-indications

• Severe hypotension
• Hypersensitivity to diltiazem or any of its components
• Sick sinus syndrome
• Second or third-degree AV block
• Severe left ventricular dysfunction
• Concurrent use with ivabradine

Adverse effects

• Peripheral edema
• Headache
• Dizziness
• Nausea
• Bradycardia
• Hypotension
• Constipation
• Fatigue

Interactions

• Amiodarone: Severe (increases risk of cardiodepression)
• Intravenous dantrolene: Severe (increases risk of acute hyperkalaemia and cardiovascular collapse)
• Calcium channel blockers: Increased concentration of carbamazepine
• Carbamazepine: Moderate (decreases exposure)
• Diltiazem and antiepileptics: Moderate (increases concentration)
• Diltiazem and carbamazepine: Moderate (increases concentration)
• Diltiazem and fostamatinib: Moderate (increases exposure)
• Diltiazem and statins: Moderate (increases exposure)
• Diltiazem and atorvastatin: Moderate (increases exposure)
• Cimetidine: Moderate (increases exposure)
• Enzalutamide: Unknown (decreases exposure)

Precautions

• Monitor blood pressure regularly
• Use with caution in patients with liver or kidney impairment
• Caution in patients with a history of heart failure
• Avoid abrupt withdrawal after prolonged therapy

Pregnancy

Diltiazem should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult with healthcare professionals for guidance.

Breast-feeding

Diltiazem is excreted in breast milk. Caution is advised when administered to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral tablets
• Extended-release capsules
• Injection solution

Indications

• Prophylaxis and treatment of angina pectoris
• Management of hypertension
• Control of ventricular rate in atrial fibrillation and atrial flutter

Dosage

Children: For children aged 12-17 years, the dosage is 30-60 mg 2-3 times a day. For neonates, 20-25 micrograms/kg

Adults: Initially 60 mg three times a day, adjusted according to response; maximum 360 mg per day. In the elderly, initially 60 mg twice daily, adjusted according to response; maximum 360 mg per day.

Mechanism of action

Diltiazem exerts its effects by blocking L-type calcium channels in the vascular smooth muscle and cardiac tissue. This blockade results in relaxation of vascular smooth muscle, leading to vasodilation and reduced peripheral vascular resistance. Additionally, it decreases myocardial contractility and heart rate by affecting the conduction system of the heart, which is beneficial in managing angina and arrhythmias.

Pharmacodynamics

Diltiazem lowers blood pressure by causing vasodilation, which reduces the workload on the heart. It has a negative inotropic effect, which decreases the strength of heart contractions. The drug also has antianginal effects, as it improves oxygen delivery to the heart muscle by reducing myocardial oxygen consumption. The onset of action is generally within 30 minutes to 1 hour for oral formulations, with peak effects occurring after several hours.

Pharmacokinetics

Diltiazem is well absorbed from the gastrointestinal tract, with a bioavailability of about 40-50% due to first-pass metabolism in the liver. It is extensively metabolized in the liver, with a half-life ranging from 3-5 hours for immediate-release formulations, and longer for sustained-release forms. The drug is excreted primarily in urine, both as metabolites and unchanged drug. Dose adjustments may be necessary in cases of hepatic impairment.

Contra-indications

• Severe bradycardia
• Sick sinus syndrome
• Significant aortic stenosis
• History of hypersensitivity to diltiazem or other calcium channel blockers
• Hyaline membrane disease in neonates

Adverse effects

• Headache
• Dizziness
• Fatigue
• Nausea
• Vomiting
• Peripheral edema
• Bradycardia
• Hypotension
• Gingival hyperplasia

Interactions

• May enhance the effects of other antihypertensives
• Increased risk of bradycardia with beta-blockers
• Caution with digoxin due to potential for increased plasma concentrations
• Avoid use with strong CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) as it may increase diltiazem levels

Precautions

• Use with caution in patients with hepatic or renal impairment
• Monitor heart rate and blood pressure regularly
• Use with caution in patients with a history of heart failure
• Gradual withdrawal is recommended to avoid rebound hypertension

Pregnancy

Manufacturer advises to avoid use, the risk to the fetus should be balanced against the risk of uncontrolled maternal hypertension.

Breast-feeding

Manufacturer advises to avoid use due to lack of information on excretion in breast milk.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 30 mg, 60 mg, 90 mg
• Extended-release capsules: 120 mg, 240 mg
• Oral suspension: 5 mg/5 ml

Mechanism of action

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 act

Pharmacodynamics

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.