12.1 Mechanism of Action
The active ingredients in amlodipine, valsartan and hydrochlorothiazide target 3 separate mechanisms involved in blood pressure regulation. Specifically, amlodipine inhibits the contractile effects of calcium on cardiac and vascular smooth muscle cells. Valsartan inhibits the vasoconstrictor and vasoconstrictor effects of angiotensin II in heart, vascular smooth muscle, adrenal and kidney cells. and hydrochlorothiazide directly promotes renal sodium and chloride excretion leading to decreases in intravascular volume. A more detailed description of the mechanism of action of each individual component follows.
Amlodipine is a dihydropyridine calcium channel blocker 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 non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle depend on the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine selectively inhibits the influx of calcium ions into cell membranes, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detectedin vitrobut such effects have not been observed in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiological 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 binding and dissociation from the receptor binding site, resulting in a gradual onset of action.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a decrease in peripheral vascular resistance and a decrease in blood pressure.
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the major stressor of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of aldosterone synthesis and release, cardiac stimulation, and renal sodium reabsorption. Valsartan inhibits the vasoconstrictor and aldosterone secretory effects of angiotensin II by selectively inhibiting angiotensin II binding to AT1receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Therefore, its action is independent of angiotensin II synthesis pathways.
There is also an AT2receptor found in many tissues, but AT2not known to be related to cardiovascular homeostasis. Valsartan has a much higher affinity (about 20,000-fold) for AT1receiver than for AT2receiver. Elevated plasma angiotensin levels after AT1receptor blockade with valsartan can stimulate released AT2receiver. The major metabolite of valsartan is essentially inactive with affinity for AT1receiver about one-200ºthat of valsartan itself.
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. As valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical significance remains to be seen. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of angiotensin II receptors inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increase in plasma renin activity and circulating levels of angiotensin II does not overcome the effect of valsartan on blood pressure.
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing sodium and chloride excretion in approximately equal amounts. Indirectly, the diuretic action of hydrochlorothiazide decreases plasma volume, with consequent increase in plasma renin activity, increased aldosterone secretion, increased urinary potassium loss, and decreased serum potassium. Renin-aldosterone binding is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.
The mechanism of antihypertensive action of thiazides is unknown.
Amlodipine, valsartan, and hydrochlorothiazide have been shown to be effective in lowering blood pressure. The 3 components of amlodipine, valsartan, and hydrochlorothiazide lower blood pressure through complementary mechanisms, each acting at a distinct site and blocking different effector pathways. The pharmacodynamics of each individual component is described below.
Amlodipine, valsartan and hydrochlorothiazide have not been studied for indications other than hypertension.
After administration of therapeutic doses in hypertensive patients, amlodipine causes vasodilation, resulting in a decrease in supine and standing blood pressure. These reductions in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although acute intravenous administration of amlodipine reduces blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina pectoris, chronic oral administration of amlodipine in clinical trials has not resulted in clinically significant changes in heart rate or blood pressure in normotensive patients. .
With chronic once-daily administration, antihypertensive efficacy is maintained for at least 24 hours. Plasma concentrations correlate with effect in young and elderly patients. The magnitude of blood pressure reduction with amlodipine also correlates with the height of the elevation before treatment. Thus, subjects with moderate hypertension (diastolic pressure 105 to 114 mmHg) had a response about 50% greater than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). People with normal blood pressure did not show a clinically significant change in blood pressure (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in decreased renal vascular resistance and increased glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine generally showed a small increase in cardiac index without a significant effect on dP /dt or left ventricular end-diastolic pressure or volume. In haemodynamic studies, amlodipine was not associated with a negative inotropic effect when administered in the therapeutic dose range in intact animals and in humans, even when co-administered with β-blockers in humans. Similar findings, however, have been observed in normal or well-compensated heart failure patients with agents that have significant negative inotropic effects.
Amlodipine does not alter sinus node function or AV conduction in intact animals or humans. In patients with chronic stable angina pectoris, intravenous administration of 10 mg did not significantly alter A-H and H-V conductance and sinus node recovery time after stimulation. Similar results were obtained in patients receiving amlodipine and β-blockers at the same time. In clinical studies in which amlodipine was administered in combination with β-blockers in patients with hypertension or angina pectoris, no adverse effects on electrocardiographic parameters (ECG) were observed. In clinical studies with patients with angina pectoris alone, amlodipine treatment did not alter ECG intervals or produce higher degrees of AV block.
Amlodipine has indications other than hypertension, which are described in the full prescribing information.
Interactions with other drugs:
When amlodipine and sildenafil were used in combination, each agent exerted its own blood pressure-lowering effect independently.verInteractions with other drugs(7)].
Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% maximally, with about 30% inhibition persisting for 24 hours. No information is available on the effect of higher doses.
Removal of negative feedback from angiotensin II causes a 2- to 3-fold increase in plasma renin and a subsequent increase in plasma angiotensin II concentration in hypertensive patients. Minor decreases in plasma aldosterone have been observed following valsartan administration. very little effect on serum potassium was observed.
Administration of valsartan to patients with essential hypertension results in significant reductions in sitting, supine, and standing systolic blood pressure, usually with little or no postural change.
Valsartan has indications other than hypertension, which are described in its full prescribing information.
After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks at about 4 hours, and lasts about 6 to 12 hours.
Following oral administration of amlodipine, valsartan, and hydrochlorothiazide to normal healthy adults, peak plasma concentrations of amlodipine, valsartan, and HCTZ are reached at approximately 6 hours, 3 hours, and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan, and HCTZ from amlodipine, valsartan, and hydrochlorothiazide tablets are the same as when administered as single dosage forms.
The bioavailability of amlodipine, valsartan and HCTZ was not altered when amlodipine, valsartan and hydrochlorothiazide tablets were taken with food. Amlodipine, valsartan and hydrochlorothiazide can be taken with or without food.
Peak plasma concentrations of amlodipine are achieved 6 to 12 hours after administration of amlodipine alone. Absolute bioavailability was estimated to be between 64% and 90%. The apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients.
Amlodipine is extensively (approximately 90%) converted to inactive metabolites by hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.
Elimination of amlodipine from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels of amlodipine are achieved after 7 to 8 days of consecutive daily dosing.
Following oral administration of valsartan alone, peak plasma concentrations of valsartan are achieved within 2 to 4 hours. Absolute bioavailability is approximately 25% (range 10% to 35%).
The volume of distribution of valsartan at steady state after intravenous administration is 17 L, indicating that valsartan is not extensively distributed to tissues. Valsartan is highly bound to serum proteins (95%), mainly to serum albumin.
Valsartan exhibits biexponential decay kinetics after intravenous administration with a mean elimination half-life of approximately 6 hours. Recovery is primarily as unchanged drug, with only about 20% of the dose recovered as metabolites. The main metabolite, representing about 9% of the dose, is valeryl 4-hydroxy valsartan.in vitroMetabolism studies involving recombinant CYP450 enzymes have shown that the CYP2C9 isozyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP450 isozymes at clinically relevant concentrations. A CYP450-mediated drug interaction between valsartan and co-administered drugs is unlikely due to the low extent of metabolism.
Valsartan, when administered as an oral solution, is recovered mainly in feces (about 83% of the dose) and urine (about 13% of the dose). After intravenous administration, the plasma clearance of valsartan is approximately 2 L/h and its renal clearance is 0.62 L/h (approximately 30% of total clearance).
The estimated absolute bioavailability of hydrochlorothiazide after oral administration is approximately 70%. Peak plasma concentrations of hydrochlorothiazide (Cupper limit) are achieved within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide.
Hydrochlorothiazide is bound to albumin (40% to 70%) and distributed to erythrocytes. Following oral administration, hydrochlorothiazide plasma concentrations decline exponentially, with a mean distribution half-life of approximately 2 hours and an elimination half-life of approximately 10 hours.
About 70% of an orally administered dose of hydrochlorothiazide is excreted in the urine as unchanged drug.
Elderly patients have reduced clearance of amlodipine, resulting in increased peak plasma levels, elimination half-life and AUC. The exposure (as measured by AUC) of valsartan is 70% higher and the half-life is 35% longer in the elderly than in the young. A limited amount of data suggests that the systemic clearance of hydrochlorothiazide is reduced in healthy, hypertensive elderly compared with healthy young volunteers.
The pharmacokinetics of valsartan do not differ significantly between men and women.
Pharmacokinetic differences due to race have not been studied.
The pharmacokinetics of amlodipine are not significantly affected by renal impairment. There is no apparent correlation between renal function (as measured by creatinine clearance) and exposure (as measured by AUC) to valsartan in patients with varying degrees of renal impairment. Valsartan has not been studied in patients with severe renal impairment (creatinine clearance <10 mL/min). Valsartan is not removed from plasma by hemodialysis.
In a study in subjects with renal impairment, the mean elimination half-life of hydrochlorothiazide was doubled in subjects with mild/moderate renal impairment (30
Patients with hepatic impairment experienced reduced clearance of amlodipine, resulting in an increase in AUC of approximately 40% to 60%. On average, patients with mild to moderate chronic liver disease have twice the exposure (as measured by AUC values) to valsartan than healthy volunteers (matched for age, sex and weight) [verUse in specific populations(8.7)].
Interactions with other drugs
in vitrohuman plasma data show that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin and indomethacin.
Effect of other drugs on amlodipinem
Coadministration of cimetidine, magnesium aluminum hydroxide antacids, sildenafil, and grapefruit juice has no effect on amlodipine exposure.
CYP3A inhibitors: Coadministration of a daily dose of 180 mg diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in systemic exposure to amlodipine. Co-administration of erythromycin in healthy volunteers did not significantly alter the systemic exposure of amlodipine. However, strong CYP3A inhibitors (eg, itraconazole, clarithromycin) may increase amlodipine plasma concentrations to a greater extent [verInteractions with other drugs(7)].
Effect of amlodipine on other drugs
Coadministration of amlodipine does not affect exposure to atorvastatin, digoxin, ethanol, and prothrombin response time to warfarin.
Coadministration of multiple doses of amlodipine 10 mg with simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone.verInteractions with other drugs(7)].
A prospective study in renal transplant patients (N = 11) showed a mean increase of 40% in ciclosporin trough levels when amlodipine was given concomitantly verInteractions with other drugs(7)].
A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5- to 4-fold increase in tacrolimus exposure when coadministered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressors (N=6). However, a threefold increase in tacrolimus plasma exposure has been reported in a renal transplant patient (not expressing CYP3A5) after starting amlodipine for the treatment of post-transplant hypertension, resulting in a reduction in the tacrolimus dose. Regardless of CYP3A5 genotype status, the possibility of interaction with these drugs cannot be excluded [verInteractions with other drugs(7)].
No clinically significant pharmacokinetic interactions were observed when Diovan (valsartan) was coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but did not reduce heart rate more than atenolol alone.
Coadministration of valsartan and warfarin did not alter the pharmacokinetics of valsartan or the time course of the anticoagulant properties of warfarin.
The results of ain vitrostudies with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampicin, cyclosporine) or the efflux transporter (ritonavir) may increase systemic exposure to valsartan.
Drugs that alter gastrointestinal motility
The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (eg, atropine, piperidine), apparently due to a decrease in gastrointestinal motility and gastric emptying rate. On the other hand, prokinetic drugs may reduce the bioavailability of thiazide diuretics.
In one particular drug interaction study, administration of cholestyramine 2 hours before hydrochlorothiazide resulted in a 70% reduction in hydrochlorothiazide exposure. In addition, administration of hydrochlorothiazide 2 hours before cholestyramine resulted in a 35% reduction in hydrochlorothiazide exposure.
Antineoplastic agents (eg, cyclophosphamide, methotrexate)
The simultaneous use of thiazide diuretics can reduce the renal excretion of cytotoxic agents and enhance their myelosuppressive effect.
Alcohol, barbiturates or drugs
Enhancement of orthostatic hypotension may occur.
skeletal muscle relaxants
Possible increased response to muscle relaxants such as curare derivatives.
Thiazide-induced hypokalemia or hypomagnesemia may predispose the patient to digoxin toxicity.
Official answer. It does not matter what time of day you take amlodipine (morning or evening) but it is best to take it at the same time every day, when you are most likely to remember, for more even blood levels and therefore effectiveness.Can you take valsartan and amlodipine for high blood pressure? ›
Amlodipine and valsartan combination is used when a single medicine to lower your blood pressure is not enough. It is also used as the first medicine to treat your condition if your doctor feels that you need to take more than one blood pressure medicine. This medicine comes with a patient information insert.Is amlodipine film coated? ›
Amlodipine / Valsartan 5 mg / 80 mg film-coated tablets: Yellow rounded film-coated tablet of dimension approx. 9 mm.Should I take amlodipine, valsartan in the morning or at night? ›
If you take it once a day, your doctor may suggest that you take your first dose before bedtime, because it can make you feel dizzy. After the very first dose, you can take valsartan at any time, although it's best to take it at the same time every day.Should I take blood pressure medication before bed or in the morning? ›
This is a robust study that shows that people who take their blood pressure medication at night have better blood pressure control and have reduced risk of a cardiovascular event such as a stroke or heart attack.Does amlodipine make you pee at night? ›
Calcium channel blockers treat high blood pressure. They can decrease bladder contraction, which leads to increased urination. Examples, alone or in combination, include: Norvasc (amlodipine)What foods to avoid with valsartan amlodipine? ›
Potassium supplements, potassium-containing salt substitutes (No Salt, Morton Salt Substitute, and others), and even high-potassium foods (including Noni juice) should be avoided by those taking valsartan, unless directed otherwise by their doctor.How long does it take valsartan to stabilize blood pressure? ›
Valsartan starts to work after about 2 hours to reduce high blood pressure but it may take 2 to 4 weeks to work fully. If you have high blood pressure, you may not have any symptoms. In this case, you may not feel any different when you take valsartan.Does amlodipine and valsartan cause weight gain? ›
Weight gain has been reported by some people taking amlodipine but this is not a common side effect and some people have also reported weight loss. Weight gain with amlodipine may also be a symptom of edema, which is when you retain fluid, which may be particularly noticeable around your ankles or lower legs.What does film-coated mean on tablets? ›
A film coating is a thin polymer-based coat that is typically sprayed on to a solid pharmaceutical dosage form, such as a tablet, capsule, pellet or granule. Film coating can impact both its appearance and its pharmacokinetics making it an essential process in making the final drug product.
Film-coating is a process in which a tablet, capsule, or pellet is covered by a thin layer of film to protect it or make it easier to swallow. Applying a thin coating to tablets is called film-coating. The outer layer applied in film-coating makes tablets easier to swallow.Why are some pills film-coated? ›
Pharmaceutical film coating is considered a key part in the production of solid pharmaceutical dosage forms since it gives superior organoleptic properties products. In addition, it can improve the physical and chemical stability of dosage forms, and modify the release characteristics of the drug.Can I drink coffee while taking amlodipine? ›
If amlodipine makes you feel dizzy, stop what you're doing and sit or lie down until you feel better. Do not drive, ride a bike or operate tools or machinery until the dizziness passes. Try cutting down on coffee, tea and alcohol.Is it OK to eat bananas while taking valsartan? ›
Valsartan is used with caution with Food rich in potassium, such as bananas, nuts, and sweet potatoes, as it can lead to hyperkalemia.
Usually, blood pressure starts to rise a few hours before a person wakes up. It continues to rise during the day, peaking in midday. Blood pressure typically drops in the late afternoon and evening. Blood pressure is usually lower at night while sleeping.Can drinking water lower blood pressure? ›
Still, you can make lifestyle changes to bring your blood pressure down. Something as simple as keeping yourself hydrated by drinking six to eight glasses of water every day improves blood pressure. Water makes up 73% of the human heart,¹ so no other liquid is better at controlling blood pressure.How long after you wake up should you take your blood pressure? ›
Your blood pressure should be checked in the morning, about an hour after you wake up, and in the evening, about an hour before you go to sleep, using the same arm each time. Taking 3 consecutive measurements (about 1 minute apart) will provide a more accurate understanding of your "true" blood pressure.What is the average blood pressure for a 70 year old? ›
2. Blood pressure of 70 year olds. Blood pressure at age 70 is recommended to be kept at 134/87 mmHg. According to some studies, the blood pressure of 70-year-old people usually ranges from 121/83 mmHg - 147/91 mmHg.What is the number one side effect of amlodipine? ›
1. Swelling in your legs or ankles. Swelling of the legs or ankles (edema) is one of the most common amlodipine side effects. It happens because amlodipine dilates your blood vessels, which improves blood flow.Does amlodipine affect eyes? ›
Amlodipine is a heart medication that is prescribed frequently for arrythmia treatment. It can affect the eyes in multiple ways. It can cause damage to the cornea and cause whorl keratopathy or can cause damage to blood vessels in the retina and result in anterior ischemic optic neuropathy.
Foods high in potassium also can interfere with some medications for high blood pressure and heart failure. It certainly would take more than one banana to raise potassium levels to a dangerous level for the average person, Spees said.Can I take amlodipine valsartan at night? ›
Administration of valsartan at bedtime as opposed to upon wakening improves the sleep-time relative blood pressure (BP) decline towards a more normal dipper pattern without loss of 24-h efficacy. Amlodipine, however, has been shown to be effective in reducing BP throughout the day and night, independent of dosing time.Why amlodipine is taken at night? ›
Overnight blood pressure control is important in order to lower your risk. If your medication wears off before your next dose is due, your blood pressure may be elevated for several hours while you sleep. You may also wake with high blood pressure. Taking your medication at bedtime may help prevent this issue.Should I take valsartan and amlodipine at the same time? ›
Amlodipine and valsartan combination is used when a single medicine to lower your blood pressure is not enough. It is also used as the first medicine to treat your condition if your doctor feels that you need to take more than one blood pressure medicine.How long does it take for amlodipine valsartan to work? ›
Valsartan starts to work after about 2 hours to reduce high blood pressure but it may take 2 to 4 weeks to work fully. If you have high blood pressure, you may not have any symptoms. In this case, you may not feel any different when you take valsartan. This does not mean that the medicine is not working.Does amlodipine affect sleep? ›
If you take too much. If you take more than your prescribed dose of amlodipine, it can make you feel dizzy and sleepy.Does amlodipine cause weight gain? ›
Amlodipine can cause weight gain. This side effect was not commonly reported in clinical trials of amlodipine, but it can still occur. It's important to note that amlodipine can cause ankle or leg swelling, which is a common side effect of the drug. And this swelling can cause weight gain.What Cannot be taken with amlodipine? ›
- antibiotics such as clarithromycin, erythromycin or rifampicin.
- calcium channel blockers like diltiazem or verapamil.
- itraconazole or ketoconazole, antifungal medicines.
- medicines to treat HIV or HCV (hepatitis C virus)
If you take blood pressure-lowering ACE inhibitors with potassium-rich foods, including bananas, avocados, tomatoes and dried apricots, you can get high potassium levels in your body, which can lead to potentially dangerous heart arrhythmias, Brown warns.Do bananas interfere with blood pressure medication? ›
Foods high in potassium also can interfere with some medications for high blood pressure and heart failure. It certainly would take more than one banana to raise potassium levels to a dangerous level for the average person, Spees said.
Potential Negative Interaction
Potassium supplements, potassium-containing salt substitutes (No Salt, Morton Salt Substitute, and others), and even high-potassium foods (including Noni juice) should be avoided by those taking valsartan, unless directed otherwise by their doctor.