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Candesartan is a synthetic, benzimidazole-derived angiotensin II receptor antagonist prodrug with antihypertensive activity. Candesartan selectively competes with angiotensin II for the binding of the angiotensin II receptor subtype 1 (AT1) in vascular smooth muscle, blocking angiotensin II-mediated vasoconstriction and inducing vasodilatation. In addition, antagonism of AT1 in the adrenal gland inhibits angiotensin II-stimulated aldosterone synthesis and secretion by the adrenal cortex; sodium and water excretion increase, followed by a reduction in plasma volume and blood pressure.
Candesartan lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS); it competes with angiotensin II for binding to the type-1 angiotensin II receptor (AT1) subtype and prevents the blood pressure increasing effects of angiotensin II. Unlike angiotensin-converting enzyme (ACE) inhibitors, ARBs do not have the adverse effect of a dry cough.
Mechanism of Action of Candesartan
Candesartan selectively blocks the binding of angiotensin II to AT1 in many tissues including vascular smooth muscle and the adrenal glands. This inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in an overall decrease in blood pressure. Candesartan is greater than 10,000 times more selective for AT1 than AT2. Inhibition of aldosterone secretion may increase sodium and water excretion while decreasing potassium excretion. Candesartan cilexetil is an ARB prodrug that is rapidly converted to candesartan, its active metabolite, during absorption from the gastrointestinal tract. Candesartan confers blood pressure lowering effects by antagonizing the hypertensive effects of angiotensin II via the RAAS. RAAS is a homeostatic mechanism for regulating hemodynamics, water, and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering the cardiovascular structure. Angiotensin II binds to two receptors: type-1 angiotensin II receptor (AT1) and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II.
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Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis. There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Candesartan has a much greater affinity (>10,000-fold) for the ATI receptor than for the AT2 receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because candesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of candesartan on blood pressure.
Indications of Candesartan
- High Blood Pressure
- Migraine Prevention
- Heart Failure
- Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems.
- Isolated systolic hypertension,
- Left ventricular hypertrophy
- Diabetic Nephropathies
- Second line agent in the treatment of congestive heart failure,
- Systolic dysfunction,
- Myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors
- Risk of stroke in patients with hypertension and left ventricular hypertrophy.
- Diabetic nephropathy with an elevated serum creatinine and proteinuria
- Chronic heart failure with reduced ejection fraction (NYHA Class II)
- Chronic heart failure with reduced ejection fraction (NYHA Class III)
- Chronic heart failure with reduced ejection fraction (NYHA Class IV)
Conta Indications of Candesartan
- Kidney problems
- Heart problems
- Recent excessive vomiting or diarrhea
- A condition called primary hyperaldosteronism.
- The high amount of potassium in the blood
- Renal artery stenosis
- Abnormally low blood pressure
- Liver problems
- Mild to moderate kidney impairment
- Pregnancy
- Decreased blood volume
Dosage of Candesartan
Strengths: 4 mg, 8 mg, 16 mg and 32 mg.
High Blood Pressure
- Children 6 to <18 years of age: The recommended starting dose is 4mg once a day.
- For patients weighing <50kg: In some patients whose blood pressure is not adequately controlled, your doctor may decide the dose needs to be increased to a maximum of 8mg once a day.
- For patients weighing ≥50kg: In some patients whose blood pressure is not adequately controlled, your doctor may decide the dose needs to be increased to 8mg once a day or to 16mg once a day.
Hypertension
- Initial dose: 16 mg orally once a day
- Maintenance dose: 8 to 32 mg/day orally in 1 to 2 divided doses
- Maximum dose: 32 mg/day
Congestive Heart Failure
- Initial dose: 4 mg orally once a day; double dose every 2 weeks, as tolerated, to target dose of 32 mg orally once a day
Pediatric Dose for Hypertension
1 to less than 6 years
- Initial dose: 0.2 mg/kg/day orally in 1 to 2 divided doses
- Maintenance dose: 0.05 to 0.4 mg/kg/day orally in 1 to 2 divided doses
6 to less than 17 years ,Less than 50 kg
- Initial dose: 4 to 8 mg/day orally in 1 to 2 divided doses
- Maintenance dose: 2 to 16 mg/day orally in 1 to 2 divided doses
Greater 50 kg
- Initial dose: 8 to 16 mg/day orally in 1 to 2 divided doses
- Maintenance dose: 4 to 32 mg/day orally in 1 to 2 divided doses
Side Effects of Candesartan
The most common
- Dry cough
- Depression
- Dizziness and light-headedness due to low blood pressure
- Fatigue, especially in the early stages
- Mouth dryness in the early stages
- The most common (a burning feeling in the chest, behind the breastbone or gullet)
- Abdominal or stomach pain
- Constipation
- Nausea, vomiting,
- painful or swollen gums
- numbness or heavy feeling in the jaw
- dull, aching pain in the hip, groin, or thigh
- stomach pain,
- a headache,
- reversible hair loss or thinning, and
- fever.
Common
- chills or fever
- headache, severe and throbbing
- joint or back pain
- muscle aching or cramping
- muscle pains or stiffness
- chest pressure or squeezing pain in chest
- excessive sweating
- sudden drowsiness or need to sleep
- coughing up blood
- liver problems–nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes)
- decreased amount of urine
Rare
- Anxiety
- change in vision
- chest pain or tightness
- confusion
- cough
- Agitation
- arm, back, or jaw pain
- blurred vision
- chest pain or discomfort
- convulsions
- extra heartbeats
- hallucinations
- headache
- irritability
- lightheadedness
- cold and clammy skin
- fast and shallow breathing
- swelling of your feet, legs, or hands purple spot on your skin caused by internal bleeding
- fast or abnormal heart rate or palpitations
- loss of appetite
- lower back, side, or stomach pain
- mental depression
- muscle pain or cramps
- Swelling of your feet or ankles
- Shortness of breath
- Nausea, fever, dark urine, loss of appetite
- Depression
Drug Interactions of Candesartan
Candesartan may interact with following drugs, supplements, & may change the efficacy of drugs
- antacids
- alpha blockers (e.g., alfuzosin, doxazosin, tamsulosin)
- angiotensin-converting enzyme inhibitors (ACEIs; captopril, enalapril, ramipril)
- “azole” antifungal medications (e.g., fluconazole, itraconazole, ketoconazole)
- barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
- benzodiazepines (e.g., clonazepam, diazepam, lorazepam)
- beta-blockers (e.g., atenolol, metoprolol, propranolol)
- carbamazepine
- cimetidine
- clopidogrel
- cyclosporine
- dasatinib
- dexamethasone
- diuretics (water pills; e.g., furosemide, hydrochlorothiazide, triamterene)
- duloxetine
- asthma medications (e.g., theophylline)
- diltiazem
- nitroglycerin
- nonsteroidal anti-inflammatory medications (NSAIDs; e.g., indomethacin, naproxen)
- oral diabetes medications (e.g., metformin, pioglitazone)
- pentoxifylline
- monoamine oxidase (MAO) inhibitors (e.g., phenelzine, selegiline, )
- other beta-blockers (e.g., propranolol, metoprolol)
- oxtriphylline
- verapamil
- fusidic acid
- haloperidol
- imatinib
- imipramine
- macrolide antibiotics (e.g., clarithromycin, erythromycin)
- metronidazole
- monoamine oxidase inhibitors (MAOIs; e.g., phenelzine, rasagiline, selegiline, )
- pentoxifylline
- phenytoin
- phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)
- quetiapine
- rituximab
- sertraline
- simvastatin
- tetracycline
- theophylline
- tocilizumab
- warfarin
Pregnancy & Lactation of Candesartan
FDA Pregnancy Category D
Pregnancy
Candesartan may cause severe harm to a fetus and should not be used during pregnancy. If you discover you are pregnant while taking this medication, stop taking it and tell your doctor at once. Women taking candesartan who are planning or trying to become pregnant should discuss other, more appropriate medications to control blood pressure with their doctor.
Lactation
It is not known if candesartan passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.
The safety and effectiveness of using this medication have not been established for the treatment of hypertension in children less than 6 years of age and for the treatment of heart failure in children less than 18 years of age.
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