Co-pulse

Uses

Atenolol & Chlorthalidoneis combination is used for the treatment of hypertension.

Co-pulse 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 TachyarrhythmiasCalcium Nephrolithiasis

How Co-pulse 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.

Chlorthalidone prevents reabsorption of sodium and chloride through inhibition of the Na+/Cl- symporter in the cortical diluting segment of the ascending limb of the loop of Henle. Reduction of sodium reabsorption subsequently reduces extracellular fluid and plasma volume via an osmotic, sodium-driven diuresis. By increasing the delivery of sodium to the distal renal tubule, Chlorthalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism. The exact mechanism of chlorthalidone's anti-hypertensive effect is under debate, however, it is thought that increased diuresis results in decreased plasma and extracellular fluid volume which therefore requires decreased cardiac output and overall lowers blood pressure. Chlorthalidone has also been shown to decrease platelet aggregation and vascular permeability, as well as promote angiogenesis in vitro, which is thought to be partly the result of reductions in carbonic anhydrase–dependent pathways. These pathways may play a role in chlorthalidone's cardiovascular risk reduction effects.

Dosage

Co-pulse dosage

Chlorthalidone is usually given at a dose of 25 mg daily; the usual initial dose of Atenolol is 50 mg daily. Therefore, the initial dose should be one Chlorthalidone 25 & Atenolol 50 mg once a day. If an optimal response is not achieved, the dosage should be increased to one Chlorthalidone 25 & Atenolol 100 mgonce a day. Dose of two tablets once daily should not be used as initial therapy in elderly patients.

Side Effects

Atenolol and Chlorthalidone combination is usually well tolerated. Most adverse effects have been mild and transient. However dizziness, fatigue, vertigo, nausea, diarrhea and bradycardia have been reported rarely.

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.

Precaution

Atenolol and Chlorthalidone combination should be given with caution to patients with severe renal impairment, uncontrolled heart failure, impaired hepatic function or liver disease.

Interaction

Atenolol and Chlorthalidone combination may potentiate the action of other antihypertensives such as Clonidine, Diltiazem. Prostaglandin synthase inhibiting drugs e.g. Indomethacin may decrease the hypotensive effects of beta-blockers. This tablet should not be given with Lithium due to high risk of Lithium toxicity.

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.

Chlorthalidone has been shown to rapidly concentrate within erythrocytes and subsequently equilibrate via a slow diffusion back into the serum compartment, resulting in a large volume of distribution.

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.

Half Life

6-7 hrs.

40-50 hours

Clearance

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

Elimination Route

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

Approximately 50% of the administered dose is excreted unmetabolized through the kidney, and excretion is characterized by biphasic elimination with a rapid phase followed by a slow secretory phase.

Pregnancy & Breastfeeding use

Pregnancy Category D. Atenolol & Chlorthalidone combination can cause fetal harm to the developing baby and may appear in breast milk. So it should not be taken during pregnancy & lactation.

Contraindication

Atenolol and Chlorthalidone combination is contraindicated in hypersensitivity to this product or to sulfonamide-derived drugs. It is also contraindicated in patients with sinus bradycardia, heart block greater than first degree, cardiogenic shock, overt cardiac failure and anuria.

Special Warning

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

Use in elderly: Clinical studies of Atenolol & Chlorthalidone combination did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Acute Overdose

No specific information is available with regard to over dosage and Atenolol and Chlorthalidone in humans. Treatment should be symptomatic and supportive and directed to the removal of any unabsorbed drug by induced emesis, or administration of activated charcoal. Atenolol can be removed from the general circulation by hemodialysis. Further consideration should be given to dehydration, electrolyte imbalance and hypotension by established procedures.

Storage Condition

Store in cool and dry place, protected from light.

Innovators Monograph

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