Cilidin Trio

Cilidin Trio Uses, Dosage, Side Effects, Food Interaction and all others data.

Chlortalidone prevents reabsorption of sodium and chloride by inhibiting the Na+/Cl− symporter in the distal convoluted tubule. Thiazides and related compounds also decrease the glomerular filtration rate, which further reduces the drug's efficacy in patients with kidney impairment (e.g. kidney insufficiency). By increasing the delivery of sodium to the distal renal tubule, chlortalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism (i.e. apical ROMK/Na channels coupled with basolateral NKATPases). This can result in hypokalemia and hypochloremia as well as a mild metabolic alkalosis; however, the diuretic efficacy of chlortalidone is not affected by the acid-base balance of the patient being treated.

Initially, diuretics lower blood pressure by decreasing cardiac output and reducing plasma and extracellular fluid volume. Eventually, cardiac output returns to normal, and plasma and extracellular fluid volume return to slightly less than normal, but a reduction in peripheral vascular resistance is maintained, thus resulting in an overall lower blood pressure. The reduction in intravascular volume induces an elevation in plasma renin activity and aldosterone secretion, further contributing to the potassium loss associated with thiazide diuretic therapy.

Cilnidipine acts on the L-type calcium channels of blood vessels by blocking the incoming calcium and suppressing the contraction of blood vessels, thereby reducing blood pressure. Cilnidipine also works on the N-type calcium channel located at the end of the sympathetic nerve, inhibiting the emission of norepinephrine and suppressing the increase in stress blood pressure.

Administration of cilnidipine has been shown to present an antisympathetic profile in vitro and in vivo. It decreases blood pressure safely and effectively without excessive blood pressure reduction or tachycardia.

Olmesartan medoxomil is a potent, orally active, selective angiotensin II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin- aldosterone system (RAAS) and plays a significant role in the pathophysiology of hypertension via the type 1 (AT1) receptor.

Overall, olmesartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium.

Hypotension in Volume- or Salt-Depleted Patients

In patients with an activated renin-angiotensin aldosterone system, such as volume-and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with olmesartan. Initiate treatment under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Cilidin Trio
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Cilidin Trio
Generic	Olmesartan + Chlorthalidone + Cilnidipine
Weight	20mg
Type	Tablet
Therapeutic Class
Manufacturer	Lloyd Healthcare Pvt Ltd
Available Country	India
Last Updated:	September 19, 2023 at 7:00 am

Uses

Chlorthalidone is used for the management of hypertension. Chlorthalidone is used for adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis and corticosteroid and estrogen therapy.

Cilnidipine is used for the management of hypertension for end-organ protection. It is reported to be useful in elderly patients and in those with diabetes and albuminuria. Cilnidipine has been increasingly used in patients with chronic kidney disease.

Hypertension is the term used to describe the presence of high blood pressure. The blood pressure is generated by the force of the blood pumped from the heart against the blood vessels. Thus hypertension is caused when there is too much pressure on the blood vessels and this effect can damage the blood vessel

Olmesartan is used for the treatment of mild to moderate essential hypertension. Olmesartan may be used alone or in combination with thiazide diuretic.

Cilidin Trio is also used to associated treatment for these conditions: Calcium NephrolithiasisHigh Blood Pressure (Hypertension)Diabetic Nephropathy, High Blood Pressure (Hypertension), Severe Hypertension, Moderate Hypertension

How Cilidin Trio works

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.

Olmesartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which also includes telmisartan, candesartan, losartan, valsartan, and irbesartan. ARBs selectively bind to angiotensin receptor 1 (AT1) and prevent the protein angiotensin II from binding and exerting its hypertensive effects. As the principal pressor agent of the renin-angiotensin system, Angiotensin II causes vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis. Overall, olmesartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium.

Olmesartan also effects on the renin-angiotensin aldosterone system (RAAS) plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS, which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and preventing ventricular hypertrophy and remodelling.

Dosage

Cilidin Trio dosage

Therapy should be initiated with the lowest possible dose and then titrated according to individual patient response. A single dose given in the morning with food is recommended; divided doses are unnecessary.

Edema: Up to 50 mg daily.

Hypertension: 25 mg daily in the morning, increased to 50 mg daily if necessary.

Heart failure: 25-50 mg daily in the morning, increased if necessary to 100-200 mg daily (reduce to lowest effective dose for maintenance).

Maintenance doses may often be lower than initial doses and should be adjusted according to the individual patient.

5-10 mg once daily, increase to 20 mg once daily if necessary.

Adult:Dosage must be individualized. The usual initial dose is 10 mg once daily. In patients whose blood pressure is not adequately controlled at this dose, the dose may be increased to 20 mg once daily as the optimal dose. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of Olmesartan may be increased to 40 mg. Doses above 40 mg do not appear to have greater effect.

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

Geriatric Use: Of the total number of hypertensive patients receiving Olmesartan Medoxomil in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. No overall differences in effectiveness or safety were observed between elderly patients and younger patients.

Side Effects

Dry mouth, thirst, nausea, vomiting, feeling weak, drowsy, restless, or light-headed, fast or uneven heartbeat, muscle pain or weakness, urinating less than usual or not at all, easy bruising or bleeding, unusual weakness, red or purple spots on skin, numbness or tingly feeling, nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools.

Dizziness; flushing; headache; hypotension; peripheral oedema; tachycardia; palpitations; GI disturbances; increased micturition frequency; lethargy; eye pain; depression; ischaemic chest pain; cerebral or myocardial ischaemia; transient blindness; rashes; fever; abnormal liver function; gingival hyperplasia; myalgia; tremor; impotence.

Common or very common: Arthritis, chest pain, cough, fatigue, gastro-intestinal disturbances, haematuria, hypertriglyceridaemia, hyperuricaemia, influenza-like symptoms, musculoskeletal pain, peripheral edema, pharyngitis, rhinitis, urinary-tract infection.

Uncommon: Angina, rash, vertigo.

Very rare: Headache, myalgia, pruritus, thrombocytopenia, urticaria.

Toxicity

The percentage of reports of cilnidipine that express drug toxicity reported as side effects are 5.26%.

The reported LD50 of olmesartan in dogs was reported to be greater of 1500 mg/kg. Overdose is expressed as hypotension, tachycardia, and bradycardia when there is parasympathetic stimulation. In case of overdose, supportive treatment is recommended.

Olmesartan was shown to be safe on carcinogenic and fertility studies. However, in in vitro mutagenic studies showed a potential to induce chromosomal aberrations in cells and it tested positive for thymidine kinase mutations in the mouse lymphoma assay.

Precaution

Renal impairment: Chlorthalidone dosage should be reduced in moderate renal failure - every 24 or 48 h - and should not be used in advanced renal failure.

Liver disease: There is a risk of precipitating hepatic encephalopathy in patients with liver cirrhosis and ascites.

Use in pregnancy: It is better to avoid Chlorthalidone as it crosses the placenta.

Use in Lactation: In lactating mother, significant amount of Chlorthalidone enter breast milk; like other long-acting thiazides, it can suppress lactation. Chlorthalidone should not be prescribed for lactating mother.

Hypotension, poor cardiac reserve, heart failure. Sudden withdrawal may exacerbate angina. Discontinue in patients who experience ischemic pain following administration. Pregnancy, lactation.

Fetal/Neonatal Morbidity and Mortality: Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature of patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, Olmesartan Medoxomil should be discontinued as soon as possible.

Hypotension in Volume- or Salt-Depleted Patients: In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Olmesartan Medoxomil. Treatment should start under close medical supervision. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline.

Interaction

Chlorthalidone may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic peripheral adrenergic blocking drugs.

Other antihypertensives; aldesleukin; antipsychotics that cause hypotension; may modify insulin and glucose responses; quinidine; carbamazepine; phenytoin; rifampicin; cimetidine; erythromycin.

No significant drug interactions were reported in studies in which Olmesartan Medoxomil was co-administered with digoxin or warfarin in healthy volunteers. The bioavailability of Olmesartan was not significantly altered by the co-administration of antacids [Al(OH)3/Mg(OH)2]. Olmesartan Medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce or are metabolized by those enzymes are not expected.

Volume of Distribution

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.

Drugs on the group of dihydropyridines such as cilnidipine tend to have a large volume of distribution.

17 L[L5566]

Elimination Route

Cilnidipine presents a very rapid absorption with a maximum peaked concentration after 2 hours. Its distribution tends to be higher in the liver as well as in kidneys, plasma and other tissues. Cilnidipine does not present a high accumulation in the tissue after repeated oral administration.

Cilnidipine is reported to present very low bioavailability determined to be approximately 13%. This low bioavailability is suggested to be due to its low aqueous solubility and high permeability. Hence, efforts have been made in order to find an innovative formulation that can significantly improve the bioavailability of this drug. One of these formulations corresponds to the generation of polymeric nanoparticles which enhance the bioavailability by 2.5-3-fold.

When taken orally, the prodrug olmesartan medoxomil is rapidly absorbed in the gastrointestinal tract and metabolized to olmesartan. The esterification with medoxomil was created with the intention of increasing olmesartan bioavailability from 4.5% to 28.6%.

Oral administration of 10-160 mg of olmesartan has been shown to reach peak plasma concentration of 0.22-2.1 mg/L after 1-3 hours with an AUC of 1.6-19.9mgh/L. The pharmacokinetic profile of olmesartan has been observed to be nearly linear and dose-dependent under the therapeutic range. The steady-state level of olmesartan is achieved after once a day dosing during 3 to 5 days.[L5566]

Half Life

40-50 hours

The half-life of the hypotensive effect for cilnidipine is of about 20.4 min.

The mean plasma olmesartan half-life is reported to be from 10-15 hours after multiple oral administration.

Clearance

Total plasma clearance is 1.3 L/h and the renal clearance is 0.6 L/h.[L5566]

Elimination Route

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.

Cilnidipine gets eliminated through the urine in a proportion of 20% of the administered dose and 80% is eliminated by the feces.

The main elimination route of olmesartan is in the unchanged form through the feces. From the systemically bioavailable dose, about 10-16% is eliminated in the urine.

Pregnancy & Breastfeeding use

Pregnancy category B. Thiazides are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from chlorthalidone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

No specific information about USFDA pregnancy category. Caution should be exercised during Cilnidipine use in pregnancy. Nursing mothers should consult a physician before taking Cilnidipine.

Pregnancy Categories C (first trimester) and D (second and third trimesters).

Nursing Mothers: It is not known whether Olmesartan is excreted in human milk, but Olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Patients with anuria and known hypersensitivity to Chlorthalidone or other sulfonamide-derived drugs.

Cardiogenic shock; recent MI or acute unstable angina; severe aortic stenosis.

Olmesartan is contraindicated in patients who are hypersensitive to any component of this product.

Special Warning

Pediatric Use: Safety and effectiveness of Chlorthalidone tablets in pediatric patients have not been established.

Geriatric Use: Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment: Dose should not exceed 20 mg daily in moderate impairment.

Renal Impairment: Max. 20 mg daily if eGFR 20–60 mL/minute/1.73 m2. Avoid if eGFR less than 20 mL/minute/1.73 m2.

Acute Overdose

Symptoms of acute overdosage include nausea, weakness, dizziness, and disturbances of electrolyte balance. The oral LD50 of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote, but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution.

Only limited information is available regarding overdosage in humans. The most likely effect of overdosage is hypotension. In the event of overdosage, the patient should be carefully monitored and treatment should be symptomatic and supportive. No information is available regarding the dialysability of olmesartan.