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Pharmacology: Pharmacodynamics: Mechanism of Action: Amlodipine: Amlodipine is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac and vascular smooth muscles are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.
Amlodipine inhibits calcium ion influx across cell membrane selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of dissolution with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and a decrease in blood pressure.
Hydrochlorothiazide: Hydrochlorothiazide (HCTZ), a thiazide diuretic, increases the excretion of water by inhibiting the reabsorption of sodium and chloride ions at the distal renal tubule. The excretion of potassium and magnesium is also increased while the elimination of calcium and uric acid is decreased. Thiazide diuretics usually do not affect the normal blood pressure. When chronically administered, thiazide diuretics decrease peripheral vascular resistance. The exact mechanism responsible for lowered peripheral resistance is not known, however, excretion of urinary sodium by the kidneys is required to achieve blood pressure reduction.
Indirectly, the diuretic action of HCTZ reduces plasma volume, with consequent increases in plasma renin activity, aldosterone secretion, urinary potassium loss, and decrease in serum potassium.
Diuresis begins with 2 hrs, peaks in about 4 hrs and lasts about 6-12 hrs after oral administration of HCTZ.
Pharmacokinetics: Amlodipine: After oral administration of therapeutic doses of amlodipine, peak plasma concentrations are reached between 6 and 12 hrs. Absolute bioavailability has been estimated to be between 64% and 90%. The volume of distribution is approximately 20 L/kg. Amlodipine's bioavailability is not altered by the presence of food.
Amlodipine is extensively (about 90%) converted to inactive metabolite via hepatic metabolism with 10% of the parent compound and 60% of the metabolite excreted in the urine. Studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination t½ of about 30-50 hrs. Steady state plasma levels of amlodipine are reached after 7-8 days of consecutive dosing.
The pharmacokinetics of amlodipine is not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in area under the concentration-time curve (AUC) of approximately 40-60%; a lower initial dose may be required in these patients. A similar increase in AUC was observed in patients with moderate to severe heart failure.
Hydrochlorothiazide: HCTZ is well absorbed from the gastrointestinal tract. Oral bioavailability is approximately 65-75%. After oral administration of HCTZ at doses of 12.5-100 mg, peak plasma concentrations of 70-490 ng/mL are observed within 1-5 hrs of dosing.
Approximately 40-60% of the drug is bound to plasma proteins. The drug crosses the placenta, but not the blood-brain barrier and is distributed in breast milk. It appears to be preferentially bound to red blood cells.
HCTZ is not metabolized but is eliminated rapidly as unchanged drug in the urine. HCTZ's elimination t½ ranged from 5.6-15 hrs when plasma levels were followed for at least 24 hrs. At least 61% of the oral dose is eliminated unchanged within 24 hrs. Increased HCTZ plasma concentrations and a prolonged elimination t½ have been reported in patients with renal impairment.
