Nifetolol
Nifetolol Uses, Dosage, Side Effects, Food Interaction and all others data.
The synthesis of atenolol resulted from attempts to produce a β-adrenoceptor antagonist that would competitively block β1 (cardiac) receptors but have no effect on β2-receptors. It is classified as a β1 selective (cardioselective) β-adrenergic receptor antagonist with no membranestability activity and no partial agonist activity. It is markedly the most hydrophilic of the currently available β- blockers and thus penetrates the lipid of cell membranes poorly
Atenolol is a cardio-selective beta-blocker and as such exerts most of its effects on the heart. It acts as an antagonist to sympathetic innervation and prevents increases in heart rate, electrical conductivity, and contractility in the heart due to increased release of norepinephrine from the peripheral nervous system. Together the decreases in contractility and rate produce a reduction in cardiac output resulting in a compensatory increase in peripheral vascular resistance in the short-term. This response later declines to baseline with long-term use of atenolol. More importantly, this reduction in the work demanded of the myocardium also reduces oxygen demand which provides therapeutic benefit by reducing the mismatch of oxygen supply and demand in settings where coronary blood flow is limited, such as in coronary atherosclerosis. Reducing oxygen demand, particularly due to exercise, can reduce the frequency of angina pectoris symptoms and potentially improve survival of the remaining myocardium after myocardial infarction. The decrease in rate of sinoatrial node potentials, electrical conduction, slowing of potentials traveling through the atrioventricular node, and reduced frequency of ectopic potentials due to blockade of adrenergic beta receptors has led to benefit in arrhythmic conditions such as atrial fibrillation by controlling the rate of action potential generation and allowing for more effective coordinated contractions. Since a degree of sympathetic activity is necessary to maintain cardiac function, the reduced contractility induced by atenolol may precipitate or worsen heart failure, especially during volume overload.
The effects of atenolol on blood pressure have been established, although it is less effective than alternative beta-blockers, but the mechanism has not yet been characterized. As a β1 selective drug, it does not act via the vasodilation produced by non-selective agents. Despite this there is a sustained reduction in peripheral vascular resistance, and consequently blood pressure, alongside a decrease in cardiac output. It is thought that atenolol's antihypertensive activity may be related to action on the central nervous system (CNS) or it's inhibition of the renin-aldosterone-angiotensin system rather than direct effects on the vasculature.
Atenolol produces CNS effects similar to other beta-blockers, but does so to a lesser extent due to reduces ability to cross the blood-brain barrier. It has the potential to produce fatigue, depression, and sleep disturbances such as nightmares or insomnia. The exact mechanisms behind these have not been characterized but their occurrence must be considered as they represent clinically relevant adverse effects.
Nifedipine is an inhibitor of Calcium Channel Blocker that blocks the transmembrane influx of Calcium ions into muscle cells. Nifedipine has selective effects as a dilator of arterial vessels. Nifedipine dilates main coronary and systemic arteries. As a result blood pressure falls and this elicits a sympathetic reflex response causing tachycardia and an increased cardiac output. Pulmonary arterial pressure also falls. Nifedipine has direct negative inotropic effects on cardiac muscles and these effects are seen at higher doses than dose which causes arterial vasodilatation.
Nifedipine is an inhibitor of L-type voltage gated calcium channels that reduces blood pressure and increases oxygen supply to the heart. Immediate release nifedipine's duration of action requires dosing 3 times daily. Nifedipine dosing is generally 10-120mg daily. Patients should be counselled regarding the risk of excessive hypotension, angina, and myocardial infarction.
| Trade Name | Nifetolol |
| Generic | Nifedipine + Atenolol |
| Weight | 20mg |
| Type | Tablet |
| Therapeutic Class | |
| Manufacturer | Anglo French Drugs & Industries Limited |
| Available Country | India |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Atenolol is used for: Hypertension, Angina pectoris, Cardiac arrhythmia, Myocardial infarction
Nifedipine is used for the management of all types of essential & renal hypertension. Also used for the management of hypertension during pregnancy & during coronary by pass surgery.
Nifedipine is also used for prophylaxis and the treatment of unstable & variant angina, myocardial infarction, and silent myocardial ischaemia. Moreover Nifedipine is also used in Raynaud's phenomenon & heart failure.
Nifetolol 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 Nifetolol 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 Gs 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 Gq 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
Nifetolol dosage
Hypertension: 50 mg once daily, the daily dose can be raised to 100 to 200 mg.
Angina pectoris: 50 to 100 mg daily.
Cardiac arrhythmia: Atenolol in low dose, 25-50 mg once daily, can be used in combination with digoxin to control the ventricular rate in atrial fibration or atrial flutter which is refractory to digoxin alone.
Nifedipine 10 mg:
- Angina: Initially 10 mg 3 times daily with food increased to 20 mg 3 times daily if necessary, in elderly patients, initially 5 mg 3 times daily.
- Raynaud's Phenomenon: 10 mg 3 times daily; maximum 60 mg daily. In urgent cases, the tablet should be dissolved under the tongue like a sublingual tablet. The effect occurs within some minutes.
Nifedipine 20 mg:
The starting dose for patients, not previously prescribed Nifedipine products is one tablet once daily. The recommended dose in hypertension and angina prophylaxis is 20 mg twice daily during or after food. Dosage may be adjusted within the range 10 mg twice daily to 40 mg twice daily.
Patients with liver dysfunction should commence therapy with 10 mg twice daily with careful monitoring.
Patients with renal impairment do not require adjustment of dosage.
Side Effects
In general, atenolol is well tolerated although in a small number of patients (approximately 2-3%) therapy must be withdrawn because of troublesome symptomatic adverse effects. The commonest of these are cold extrimities, fatigue, vivid dreams, insomnia, diarrhoea, constipation, impotence and paraesthesia. Bronchospasm has been occurred with atenolol although this is very much less common than with the non-selective β-blockers.
Headache, flushing, lethargy, gravitational oedema rash, nausea, increased frequency of micturation, eye pain, gum hyperplasia, depression, tremor, photosensitivity and few cases of jaundice have been reported. These reactions may regress on discontinuation of therapy. Its introduction may induce attacks of ischaemic pain in some patients with angina pectoris.
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
Patients already on a β-blocker must be evaluated carefully before Atenolol is administered. Atenolol may aggravate peripheral arterial circulatory disorders. Impaired Renal Function: Caution should be excised.
Tablets should be swallowed whole and should not be bitten, chewed or broken up. It should be used with caution in patient whose cardiac reserve is poor. Should be withdrawn if ischaemic pain occurs or existing pain worsens shortly after initiating treatment. Use in diabetic patients requires adjustment of their control. Since the absorption of the drug could be modified by renal disease, caution should be exercised in treating such patients.
Interaction
Catecholamine-depleting drugs (e.g., Reserpine) and Calcium channel blockers may have an additive effect when given with Atenolol. Clonidine and aspirin may have some drug reactions.
- ACE inhibitors: Enhanced hypotensive effect.
- Anti-arrythmics: Plasma concentration of quinidine is reduced.
- Anti-bacterials: Rifampicin possibly increases metabolism of Nifedipine.
- Anti-epileptics: Plasma concentration of phenytoin increases.
- Antipsychotics: Enhanced hypotensive effect.
- β-blockers: Occasionally severe hypotension and heart failure may occur.
- Cyclosporin: Plasma concentration of Nifedipine possibly increases.
- Muscle relaxants: Effect of muscle relaxants e.g. tubocurarine increases.
- Ulcer healing drugs: Metabolism of Nifedipine increases.
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 Cmax of 10ng/mL, with a Tmax of 50min, and an AUC of 25ng*h/mL. Oral dosing leads to a Cmax of 82ng/mL, with a Tmax 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
Pregnancy Category D. Caution should be exercised when Atenolol is administered to a nursing woman.
There are no adequate and well controlled studies in pregnant women. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Contraindication
Atenolol is contraindicated for: Second and third degree heart block, Untreated heart failure, Overt cardiac failure, Cardiogenic shock.
Cardiogenic shock, advanced aortic stenosis, nursing mothers, GI obstruction, inflammatory bowel disease, hypotension.
Special Warning
Safety and effectiveness in pediatric patients have not been established.
Acute Overdose
Overdosage with Atenolol has been reported with patients surviving acute doses as high as 5 gm. One death was reported in a man who may have taken as much as 10 gm acutely.
Storage Condition
Protect from strong light, store in a cool place in the original pack
Innovators Monograph
You find simplified version here Nifetolol
