Telopin SR

Uses

Management of hypertension where therapy with either a calcium channel blocker or a beta-blocking drug proves inadequate.

Management of chronic stable angina pectoris where therapy with calcium channel blocker or a β-adrenoceptor blocking drug proves inadequate.

Telopin SR is also used to associated treatment for these conditions: Alcohol Withdrawal Syndrome, Angina Pectoris, Atrial Fibrillation, Heart Failure, High Blood Pressure (Hypertension), Migraine, Myocardial Infarction, Refractory Hypertension, Secondary prevention Myocardial infarction, Supra-ventricular Tachyarrhythmias, Thyrotoxicosis, Ventricular TachyarrhythmiasAchalasia, Anal Fissures, Chronic Stable Angina Pectoris, High Blood Pressure (Hypertension), Hypertensive Emergency, Premature Labour, Proctalgia, Pulmonary Edemas, Pulmonary Hypertension (PH), Raynaud's Phenomenon, Ureteral Calculus, Vasospastic Angina

How Telopin SR works

Atenolol is a cardioselective beta-blocker, called such because it selectively binds to the β1-adrenergic receptor as an antagonist up to a reported 26 fold more than β2 receptors. Selective activity at the β1 receptor produces cardioselectivity due to the higher population of this receptor in cardiac tissue. Some binding to β2 and possibly β3 receptors can still occur at therapeutic dosages but the effects mediated by antagonizing these are significantly reduced from those of non-selective agents. β1 and β2 receptors are G_s coupled therefore antagonism of their activation reduces activity of adenylyl cyclase and its downstream signalling via cyclic adenosime monophosphate and protein kinase A (PKA).

In cardiomyocytes PKA is thought to mediate activation of L-type calcium channels and ryanodine receptors through their phosphorylation. L-type calcium channels can then provide an initial rise in intracellular calcium and trigger the ryanodine receptors to release calcium stored in the sarcoplasmic reticulum (SR) and increased contractility. PKA also plays a role in the cessation of contraction by phosphorylating phospholamban which in turn increases the affinity of SR Ca²⁺

Similar inihibitory events occur in the bronchial smooth muscle to mediate relaxation including phosphorylation of myosin light-chain kinase, reducing its affinity for calcium. PKA also inhibits the excitatory G_q coupled pathway by phosphorylating the inositol trisphosphate receptor and phospholipase C resulting in inhibition of intracellular calcium release. Antagonism of this activity by beta-blocker agents like atenolol can thus cause increased bronchoconstriction.

Nifedipine blocks voltage gated L-type calcium channels in vascular smooth muscle and myocardial cells. This blockage prevents the entry of calcium ions into cells during depolarization, reducing peripheral arterial vascular resistance and dilating coronary arteries. These actions reduce blood pressure and increase the supply of oxygen to the heart, alleviating angina.

Dosage

Telopin SR dosage

Adult:

• Hypertension : One capsule daily swallowed with water. If necessary, the dosage may be increased to 1 capsule dosed every 12 hours.
• Angina : One capsule every 12 hours swallowed with water. Where additional efficacy is necessary, prophylactic nitrate therapy or additional nifedipine may be of benefit.

Elderly: Dosage should not exceed 1 capsule daily in hypertension or 1 capsule twice daily in angina.

Pediatric: Safety and effectiveness in pediatric patients have not been established.

Side Effects

The following undesired events have been reported:

• Cardiovascular: flushing, edema
• CNS: dizziness, headache
• Gastrointestinal: gastrointestinal disturbance
• Haematological: purpura
• Reproductive: impotence
• Others: fatigue

Toxicity

LD₅₀ Values

Mouse: 2 g/kg (Oral), 57 mg/kg (IV), 134 mg/kg (IP), 400 mg/kg (SC)

Rat: 2 g/kg (Oral), 77 mg/kg (IV), 600 mg/kg (SC)

Rabbit: 50 mg/kg (IV)

Carcinogenicity & Mutagenicity

Studies in rats and mice at doses of 300 mg/kg/day, equivalent to 150 times maximum recommended human dose, for durations of 18 and 24 months showed no carcinogenicity. One study in rats at doses of 500-1500 mg/kg/day, 250-750 times maximum human dose, resulted in increases benign adrenal medullary tumors in both sexes and increase mammary fibroadenomas in females.

Atenolol showed no mutagenicity in the Ames test using S. typhinarium, dominant lethal test in mice, or in vivo cytogenetics test in chinese hamster ovary cells.

Reproductive Toxicity

No adverse effects on fertility were observed in either male or female mice after receiving doses of 200 mg/kg/day, equivalent to 200 times the maximum human dose. In humans, atenolol is known to cross the placenta and fetuses exposed to the drug have been reported to be smaller than expected considering gestational age. Embryo-fetal resorption has been observed in rats at doses of 50mg/kg/day, 50 times the max human dose, but not in rabbits at doses of 25mg/kg/day.

Lactation

Atenolol appears in breast milk at a ratio of 1.5-6.8 to plasma concentrations. It has been estimated that infant exposure occurs at 5.7-19.2% maternal weight-adjusted dosage. Effects in infants include bradycardia, hypothermia, and lethargy.

The oral LD₅₀ in rats is 1022mg/kg and in mice is 202mg/kg.

Patients experiencing an overdose may present with hypotension, sinus node dysfunction, atrioventricular node dysfunction, and reflex tachycardia. Overdose may be managed by monitoring cardiovascular and respiratory function; elevating extremities; and administering vasopressors, fluids, and calcium infusions.

Precaution

Due to its beta-blocker component this combination may increase the number and duration of angina attacks in patients with Prinzmetal's angina due to unopposed alpha receptor mediated coronary artery vasoconstriction. Due to its negative effect on conduction time, caution must be exercised if it is given to patients with first degree heart block.

Interaction

This combination must not be used in conjunction with calcium channel blockers with negative inotropic effects. eg. verapamil, diltiazem. Concomitant therapy with additional dihydropyridines, e.g. nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.

Volume of Distribution

Total Vd of 63.8-112.5 L. Atenolol distributes into a central volume of 12.8-17.5 L along with two peripheral compartments with a combined volume of 51-95 L. Distribution takes about 3 hrs for the central compartment, 4 hrs for the shallower peripheral compartment, and 5-6 hrs for the deeper peripheral compartment.

The steady state volume of distribution of nifedipine is 0.62-0.77L/kg and the volume of distribution of the central compartment is 0.25-0.29L/kg.

Elimination Route

Approximately 50% of an oral dose is absorbed from the gastrointestinal tract, with the remainder being excreted unchanged in the feces. Administering atenolol with food can decrease the AUC by about 20%. While atenolol can cross the blood-brain barrier, it does so slowly and to a small extent.

Sublingual dosing leads to a C_max of 10ng/mL, with a T_max of 50min, and an AUC of 25ng*h/mL. Oral dosing leads to a C_max of 82ng/mL, with a T_max of 28min, and an AUC of 152ng*h/mL.

Nifedipine is a Biopharmaceutics Classification System Class II drug, meaning it has low solubility and high intestinal permeability. It is almost completely absorbed in the gastrointestinal tract but has a bioavilability of 45-68%, partly due to first pass metabolism.

Half Life

6-7 hrs.

The terminal elimination half life of nifedipine is approximately 2 hours.

Clearance

Total clearance is estimated at 97.3-176.3 mL/min with a renal clearance of 95-168 mL/min.

The total body clearance of nifedipine is 450-700mL/min.

Elimination Route

85% is eliminated by the kidneys following IV administration with 10% appearing in the feces.

Nifedipine is 60-80% recovered in the urine as inactive water soluble metabolites, and the rest is eliminated in the feces as metabolites.

Pregnancy & Breastfeeding use

Contraindicated in women capable of childbearing or during pregnancy or during lactation.

Contraindication

This combination should not be used in patients with any of the following conditions: known hypersensitivity to either active component, or any other excipient or other dihydropyridines. Bradycardia; cardiogenic shock; hypotension; metabolic acidosis; severe peripheral arterial circulatory disturbances; second or third degree heart block; sick sinus syndrome; untreated phaeochromocytoma; uncontrolled heart failure; women capable of childbearing or during pregnancy or during lactation; patients with clinically significant aortic stenosis; patients with marked renal impairment. This combination should not be used for secondary prevention of myocardial infarction.

Special Warning

Use in Children: Safety and effectiveness in pediatric patients have not been established.

Acute Overdose

Symptoms: Bradycardia, hypoglycaemia, bronchospasm, hypotension and acute cardiac failure.

Treatment: Unabsorbed drug may be removed by gastric lavage, activated charcoal and a laxative. Symptomatic treatment may be required.

Storage Condition

Store in a cool and dry place protected from light and moisture.

Innovators Monograph

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