|Interactions, incompatibilities of medicine
– Other antihypertensive drugs: The antihypertensive effect of Agilosart-H 50/12.5 can be increased in combination with other antihypertensive drugs.
– Agents affecting potassium: The potassium depletion effect of hydrochlorothiazide is minimized by the potassium retention effect of losartan. However, this effect of hydrochlorothiazide on serum potassium is likely to occur when combined with other drugs that cause potassium depletion and hypokalaemia (e.g. potassium depleting diuretics, corticosteroid, ACTH, salbutamol, amphotericin). In contrast, when hydrochlorothiazide is combined with potassium-sparing diuretics, potassium supplements, potassium containing salt substitutes, or other medicines increasing blood potassium levels, it may increase serum potassium.
– Lithium: Losartan increases serum lithium levels, in addition lithium renal clearance is reduced by thiazide. Caution should be exercised when lithium and Agilosart-H 50/12.5 are co-administered and serum lithium concentrations should be monitored carefully.
Other information about interactions of losartan:
– Losartan does not affect the pharmacokinetics of oral or intravenous digoxin.
– Coadministration of losartan and cimetidine led to an increase of about 18% in AUC of losartan but did not affect the pharmacokinetics of its active metabolite.
– Coadministration of losartan and phenobarbital led to a reduction of about 20% in the AUC of losartan and that of its active metabolite.
– Rifampicin, aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenytoin, may reduce the plasma concentration of losartan and its metabolites when concomitantly administered.
– Losartan increases the effect of amifostine, antihypertensive drugs, carvedilol, hypoglycemic agents, lithium, potassium-sparing diuretics, rituximab.
– Nonsteroidal anti-inflammatory drugs (NSAIDs), especially COX-2, combined with losartan may cause kidney failure, so renal function should be monitored.
Other drugs may interact with hydrochlorothiazide: Hydrochlorothiazide component of Agilosart-H 50/12.5 belonging to thiazide class of diuretics may interact with the following drugs:
– Alcohol, barbiturates, or antidepressants: May potentiate orthostatic hypotension.
– Antidiabetic drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required due to increased blood glucose.
– Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur.
– Pressor amines (e.g. norepinephrine): Possible decreased response to pressor amines, but not sufficient to preclude their use.
– Skeletal muscle relaxants (e.g. tubocurarine): Possible increased responsiveness to the muscle relaxant.
– Nonsteroidal anti-inflammatory drugs: In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Therefore, when hydrochlorothiazide and non-steroidal antiinflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
– Quinidine: Risk of torsades de pointes (ventricular tachycardia).
– The effect of oral anticoagulants and gout medication may be decreased.
– The effect of anesthetics, glycosides, vitamin D may be increased.
– Cholestyramine or colestipol resins: Cholestyramine or colestipol resins potentially bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract.
– Digitalis toxicity and risk of antiarrhythmias caused by concomitant use with QT-prolonging drugs, such as astemizole, terfenadine, halofantrine, pimozide and sotalol, may be increased.
– Allopurinol, tetracycline: Toxicity is increased when they are used in combination with thiazide.
– Herbal medicines: Avoid concomitant use with herbal medicines such as licorice, Angelica sinensis, Ephedra sp., Panax ginseng, yohimbe bark because they have effect on the diuretic effect of hydrochlorothiazide.
|Undesirable effects (ADRs)
Most adverse reactions have been mild and transient in nature and have not required discontinuation of therapy.
Common, ADR > 1/100
Cardiovascular disorders: Hypotension, chest pain.
Nervous system disorders: Insomnia, dizziness, fatigue.
Endocrine-metabolism disorders: Hypoglycaemia, hyperkalaemia.
Gastrointestinal: Diarrhea, dyspepsia.
Hematologic: Mild reduction of haematocrit and haemoglobin.
Neuromuscular-skeletal: Back pain, leg pain, muscle pain.
Renal and urinary disorders: Reduction in serum uric acid levels (at high doses), urinary tract infections.
Respiratory disorders: Cough (less likely to cause an uncontrollable cough than ACE inhibitors), nasal congestion, sinusitis.
Uncommon: 1/1000 < ADR < 1/100
Cardiovascular disorders: Orthostatic hypotension, chest pain, second degree A-V block, palpitations, sinus bradycardia, tachycardia, facial edema, flushing.
Nervous system disorders: Anxiety, ataxia, confusion, depression, migraine, headache, sleep disorder, fever, vertigo.
Skin and subcutaneous tissue disorders: Alopecia, dermatitis, dry skin, erythema, photosensitivity, pruritus, urticaria, bruise, rash.
Endocrine-metabolism disorders : Gout.
Gastrointestinal disorders: Anorexia, constipation, flatulence, vomiting, ageusia, gastritis.
Urogenital disorders: Impotence, decreased libido, urinary frequency, nocturia.
Hepato-biliary disorders: Increase in hepatic enzymes and bilirubin.
Neuromuscular-skeletal: Paresthesia, tremor, bone pain, muscle weakness, joint swelling, myalgia.
Eye disorders: Blurred vision, conjunctivitis, decreased vision, burning/stinging in the eye.
Ear disorders: Tinnitus.
Renal and urinary disorders: Urinary tract infections, mild increase in urea or creatinine serum levels.
Respiratory disorders: Dyspnea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion.
Hydrochlorothiazide can cause excessive loss of potassium. This effect is dose-dependent and can be reduced with low dose (12.5mg/day), the optimal dose for initial treatment of hypertension, and minimizing adverse reactions. Thiazide diuretics often cause hyponatremia.
Common, ADR > 1/100
Body as a whole: Fatigue, dizziness, vertigo, headache.
Circulatory system: Orthostatic hypotension.
Metabolism disorders: Hypokalemia, hyperuricemia, hyperglycemia, hyperlipidemia (high doses).
Uncommon: 1/1000 < ADR < 1/100
Circulatory system: Postural hypotension, arrhythmia.
Gastrointestinal disorders: Nausea, vomiting, anorexia, constipation, diarrhoea, spasms.
Skin disorders: Urticaria, rash, photosensitivity.
Metabolism disorders: Hypomagnesaemia, hyponatremia, hypercalcemia, alkalosis generated by chloride depletion, hypophosphatemia.
Rare: ADR < 1/1000
Body as a whole: Anaphylactic reactions, fever.
Blood and lymphatic system disorders: Leukopenia, agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia.
Nervous system disorders: Paresthesia, sleep disorder, depression.
Skin and subcutaneous tissue disorders: Vasculitis, purpuric rash, erythema multiforme, dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome.
Hepato-biliary disorders: Hepatitis, jaundice (intrahepatic cholestatic jaundice), pancreatitis.
Respiratory disorders: Dyspnea, pneumonia, pulmonary edema (anaphylactic reaction), respiratory distress.
Urogenital disorders: Kidney failure, interstitial nephritis, impotence.
Eye disorders: Blurred vision.
Hyperuricemia can trigger a potential gout. Postural hypotension may occur when taken concurrently with alcohol, anesthetics and tranquilizers.
Management of ADRs:
Reduce the dosage or discontinue the drug if adverse reactions occur.
Treatment of excessive blood pressure decrease: Place the patient in supine position. In case of severe hypotension, Sodium chloride 0.9% intravenous infusion is required to increase fluid volume.
Agilosart-H 50/12.5 tablet contains losartan and hydrochlorothiazide, which are used once daily in fixed-dose combination to control high blood pressure. This effect is thought to be a result of the complimentary actions of both components, causing additive effect on blood pressure reduction, reducing blood pressure to a greater degree than either component alone.
Losartan is a specific and selective antagonist on angiotensin II receptors while hydrochlorothiazide is a thiazide diuretic. The combination of two drugs results in synergistic effects on blood pressure reduction. The effect of treatment for hypertension is usually higher when a small dose of thiazide diuretics such as hydrochlorothiazide is combined with angiotensin II receptor antagonist.
Moreover, due to the diuretic effect, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, reduces serum potassium, and increases angiotensin II levels. Administration of losartan blocks all the physiologically relevant actions of angiotensin II and through inhibition of aldosterone could tend to attenuate the potassium loss associated with the diuretic.
Thus, the combination of losartan and hydrochlorothiazide increases the antihypertensive effect of this drug, which is sustained for 24 hour period, therefore it is used only once a day.
Losartan potassium, an angiotensin II receptor antagonist (Type AT1), is the first of a new class of agents to be introduced for the treatment of hypertension.
Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], a potent vasoconstrictor, is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays an important role in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex.
Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g. vascular smooth muscle, adrenal gland). Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor. Losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor. Angiotensin II receptor antagonists also have similar hemodynamic effects to ACE inhibitors, but angiotensin II receptor antagonists do not cause a common adverse effect observed with ACE inhibitors, that is dry cough.
Hydrochlorothiazide is a thiazide diuretic that increases the excretion of sodium chloride and water by inhibiting the reabsorption of sodium and chloride ions from the distal convoluted tubule. The excretion of other electrolytes also increases especially potassium and magnesium, while calcium is reduced. Hydrochlorothiazide also reduces carbonic anhydrase activity, resulting in increase of bicarbonate excretion, but this effect is usually weaker than that of Cl- excretion and does not significantly alter urine pH. Thiazide diuretics may also reduce the glomerular filtration rate. Thiazides have moderately diuretic effect, since about 90% of the sodium ion has been reabsorbed before reaching the distal tubule where hydrochlorothiazide exhibits its effect.
Hydrochlorothiazide is effective in lowering blood pressure, firstly, by reducing plasma volume and extracellular fluid associated with urinary sodium excretion. Thereafter, during the treatment, the antihypertensive effect depends on decreased peripheral vascular resistance, through the gradual adaptation of blood vessels to the decrease in Na+ concentration. Thus, the blood pressure lowering effect of hydrochlorothiazide is evident after 1-2 weeks, whereas a diuretic with rapid action exhibits its effect only few hours after administration. Hydrothorhloriazide may potentiate the action of other antihypertensive drugs.
– Following oral administration, losartan is well absorbed and undergoes substantial first-pass hepatic metabolism by cytochrome P450 enzymes (CYP2C9 và CYP3A4). Bioavailability of losartan is approximately 33%. Approximately 14% of the oral dose of losartan is converted to an active metabolite that is responsible for most of the angiotensin II receptor antagonism. The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively.
– Both losartan and its active metabolite are highly bound to plasma proteins (> 98%), primarily albumin and they do not cross the blood-brain barrier. The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively. Total plasma clearance of losartan and the active metabolite is about 600ml/min and 50ml/min, respectively, with renal clearance of about 75ml/min and 25ml/min, respectively.
– 35% of losartan dose is excreted in the urine and about 60% in the feces.
In patients with mild to moderate cirrhosis, the area under the curve (AUC) of losartan and the active metabolite was 5 times and two times higher than those in patients with normal liver, respectively. Losartan, or its E-3174 metabolite, is not removed uring haemodialysis.
– After oral administration, hydrochlorothiazide is relatively rapidly absorbed, about 65 to 75% of the dose, however this rate may decrease in patients with heart failure. Food can reduce its absorption. Hydrochlorothiazide accumulates in red blood cells. The drug is 40-68% bound to plasma proteins. Hydrochlorothiazide is mainly excreted by the kidney, largely as unchanged form. The elimination half-life of hydrochlorothiazide is about 9.5 to 13 hours, but may be prolonged in renal failure, thus, dosage adjustment is required. Hydrochlorothiazide crosses the placental barrier, is distributed to the fetus with high concentration.
– After oral administration diuresis begins within 2 hours, peaks in about 4 hours and lasts about 12 hours.
– Antihypertensive effect occurs more slowly and it may take a few weeks for hydrochlorothiazide to reach its full effect, even at the optimal daily dose between 12.5-25mg. It is important that the optimal antihypertensive effect of hydrochlorothiazide is usually achieved at the dose of 12.5mg. Current guidelines for treatment and clinical trials emphasize the recommendations that the lowest and optimal dose should be used to minimize the risk of adverse reactions. It takes sufficient time to evaluate the response to antihypertensive effect of hydrochlorothiazide because its effect on peripheral vacular resistance need time to exhibit apparently.