Combination Therapy in Hypertension: Renin-Angiotensin-Aldosterone System Inhibitor with a Diuretic or Calcium Channel Blocker

Introduction

Rationalage for Usage

Renin Angiotensin Aldosterone System

Renin-angiotensin aldosterone system (RAAS) [48,49] is a complex system comprising many peptides, receptors, and enzymes [50]. RAAS is considered a key element in maintaining the hemostatic of the body fluid, electrolytes, and arterial blood pressure [51]. The juxtaglomerular epithelioid cells [52,53], are found in the wall of renal afferent arterioles near the entrance of glomerular capillary networks, where most of the renin is synthesized. It functions as an aspartyl protease and is released from these cells in response to negative feedback for renal perfusion and blood pressure. The renin is encoded by chromosome 1 (1q32) containing the gene. It first produces a 406 amino acid pre-prorenin protein, which penetrates the rough endoplasmic reticulum. Here, a pre-part, 23 amino acids (signal peptide) are broken down and converted into prorenin (386 amino acids). Prorenin then moves to the Golgi apparatus where it is glycosylated. This prorenin is transformed into renin (340 amino acids) by prohormone convertases and the enzyme cathepsin B [54,55]. Angiotensinogen [56,57,58] is mostly produced by hepatocytes, adipocytes, proximal tubule epithelial cells, and astrocytes [59,60]. It is then quickly released into the extracellular space. The angiotensinogen gene, which has five exons and four introns, is located on chromosome 1 (1q42.2). Angiotensinogen protein has 485 amino acids, composed of a mature protein of 452 amino acids and a signal peptide of 33 amino acids [61]. Angiotensinogen is the only substrate for renin in the RAAS. Renin converts angiotensinogen into the decapeptide angiotensin I by cleaving the first ten amino acids from the N-terminal by proteolytic activity [62]. Subsequently, it undergoes conversion into the bioactive molecule angiotensin II by dicarboxylic peptidase angiotensin-converting enzyme (ACE), which cleaves two amino acids from the C-terminal of angiotensin I (figure-1) [63] and simultaneously breaks down and inactivate the vasodilator bradykinin [64,65]. ACE is abundantly present on the luminal surface of vascular endothelia of the lung and less found in the kidney. angiotensin I is biologically inactive and serves as a precursor for angiotensin Ⅱ [66,67,68]. Since angiotensin I is formed from angiotensinogen, whose activation is prompted by the rising plasma renin. So, renin is the first and rate-limiting step in RAAS [69]. Active Angiotensin II interacts with the plasma membrane receptors known as angiotensin type 1 (AT1) and type 2 (AT2) subtypes [70,71,72]. AT2 is mainly expressed in the brain, and adrenal glands, and has lower expression in other body organs. Activation of AT2 contributes to the suppression of vascular smooth muscle development and smooth muscle relaxation. In adult coronary arteries and the aorta, the presence of low-level AT2 receptors may aid in protecting tissues against ischemia. AT2 largely has a role in organ morphogenesis and prenatal development [73,74,75]. However, most of the physiological effects are mediated by the AT1 receptors. The AT1 receptor, present in the smooth muscle of the vascular wall, elicits considerable muscular contraction through the Gq class of G protein-coupled receptor (GPCR) signaling pathways [76,77]. When angiotensin II binds to the AT1 receptor found in smooth muscle, it initiates the activation of phospholipase C, responsible for hydrolyzing phosphoinositide into diacylglycerol (DAG) and inositol trisphosphate (IP3). IP3 activates both endoplasmic reticulum and cell membrane calcium channels, leading to a rise in intracellular calcium concentration. calcium binds to calmodulin, generating a calcium-calmodulin complex that activates myosin light chain kinase (MLCK). Consequently, MLCK phosphorylates the myosin light chain (MLC), resulting in the contraction of smooth muscle (as depicted in Figure 3) [78,79]. Previously, we mentioned that ACE inactivates the vasodilator bioactive product, Bradykinin. In normal physiology, Bradykinin interacts with endothelial-expressed bradykinin receptor type 2 (B2R) [80,81]. This interaction activates Gαq/11 signaling pathways, consequently, increasing cytoplasmic calcium concentration. The Calcium interacts with calmodulin, forming a calcium-calmodulin complex, that activates endothelial nitric oxide synthase (eNOS). eNOS is responsible for the conversion of L-arginine to L-citrulline, in this process, nitric oxide (NO) is reduced as a byproduct, which subsequently flows to the vascular smooth muscle [82]. in the smooth muscle, NO activates soluble guanylyl cyclase, which converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). This activation subsequently activates cGMP-dependent protein kinase I (cGKⅠ). The activated cGKI is responsible for the closing of the endoplasmic reticulum calcium channel and the dephosphorylation of the myosin light chain. Consequently, this allows smooth muscular relaxation (as depicted in Figure 3) [83,84]. Angiotensin II also stimulates the synthesis and release of aldosterone, a steroid hormone generated from cholesterol within the mitochondria of the zona glomerulosa cells in the adrenal cortex [85]. AT1Rs, present in these adrenal zona glomerulosa cells, belong to the Gq/11 family of GPCR-type proteins. The binding of angiotensin II on this receptor initiates the activation of phospholipase C-β (PLCβ), which in turn hydrolyzes phosphoinositide into diacylglycerol (DAG) and inositol trisphosphate (IP3) [86]. IP3 binds to the endoplasmic reticulum receptors, notably IP3R1, IP3R2, and IP3R3, resulting in the opening of calcium channels and increasing the cytoplasmic calcium concentration. This rise in calcium concentration causes the acceleration of aldosterone production and exocytosis of aldosterone vesicles via the activation of calcium/calmodulin-dependent kinases (CaMKs). Activated CaMKs stimulate the production of aldosterone synthetase CYP11B2 in cells, promoting the conversion of corticosterone to aldosterone. Simultaneously, diacylglycerol (DAG) activates protein kinase C (PKC), commencing a sequence of events where PKC and CaMKs collectively increase the amounts of steroidogenic acute regulatory protein (StAR). StAR possesses a cholesterol-binding site. following numerous intermediary stages, cholesterol ultimately undergoes conversion into aldosterone (as depicted in Figure 2) [87,88]. Aldosterone acts on the principal cells, located on the late distal tubule and collecting ducts of nephrons. Aldosterone is responsible for enhancing sodium reabsorption, promoting water retention, and increasing potassium excretion. Aldosterone is a mineralocorticoid, that quickly crosses the cell membrane and binds with intracellular mineralocorticoid receptors (MR) [89]. As a result, the production of serine/threonine protein kinase 1 (SGK 1) is increased and converted to active form through phosphorylation. Once active, SGK 1 phosphorylates ubiquitin ligase Nedd4-2, commencing its interaction with 14-3-3 proteins. The free ubiquitin ligase Nedd4-2 has a crucial role in suppressing the surface expression of the endothelial sodium channel (ENaC). Consequently, the density of ENaC on the apical membrane increases approximately 2-5 times. The high concentration of luminal Na⁺ flowing through ENaC generates a negative charge into the lumen, forcing the potassium ion secretion through the renal outer medullary potassium channel (ROMK) and chloride absorption (as depicted in Figure 2). Moreover, aldosterone also increases the transcription of the α and ß subunits of the Na1-K1-ATPase, accelerating the counter-transport mechanism for Na⁺ and K⁺ over the basolateral side [90]. In mice, the angiotensin AT1 receptor is expressed in the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO). In these areas most of the neurons are glutaminergic, their axon terminated to the paraventricular nucleus (PVN) of the hypothalamus. Within the PVN, magnocellular neurons are responsible for the synthesis of arginine vasopressin (AVP), that are stored in the posterior pituitary gland. Additionally, the PVN contains parvocellular neurons whose axonal extensions regulate the autonomic nervous system. Upon angiotensin binding to the AT1 receptor, increases the production of arginine vasopressin and simultaneously stimulates the sympathetic outflow [91]. Besides, substantial morphological evidence demonstrates that the axonal efferent from SFO is projected to the supraoptic nucleus. Intraventricular (i.v.t.) injection of Angiotensin II binds to both SFO and OVLT expressed AT1 receptor, activates vasopressin production, and considerably elevates AVP in plasma [92]. in summary, angiotensin Ⅱ strongly increases sympathetic outflow and AVP in plasma. The released vasopressin binds to the Gs class GPCR type V2 receptor in the principal cells of the distal tubule and collecting duct of the kidney. This binding results in a rise of cyclic adenosine monophosphate (cAMP) concentration through the activation of adenyl cyclase. Subsequently, cAMP stimulates protein kinase A (PKA), which phosphorylates intracellular storage vesicle Aquaporin 2 (AQP-2), enabling the migration and insertion of AQP-2 into the apical membrane. Water passage via AQP-2 raises blood volume, potentially contributing to elevated blood pressure. Additionally, vasopressin binds to the Gq class GPCR type V1 receptor in vascular smooth muscle. This interaction stimulates the activation of protein kinase C (PKC). The resultant signaling cascade ultimately leads to blood vessel constriction and heightened peripheral resistance (Figure 3) [93,94,95]. Angiotensin Ⅱ stimulates the thirst center, causing feeling thirsty and increasing water intake, so high blood volume may increase BP [96,97]. The overactivation of the sympathetic nervous system (SNS) leads to increased secretion of nor-epinephrine from postganglionic sympathetic fibers [98,99,100]. Nor-epinephrine binds largely to myocyte-expressed β-adrenergic receptors, particularly beta-1 receptors [101,102]. This binding increases intracellular cAMP concentration and activates PKA by adenyl cyclase. Consequently, a positive ionotropic effect led to an increase in heart rate. Additionally, it stimulates the secretion of calcium ions from the sarcoplasmic reticulum, resulting in more forceful contractions of the myocyte, potentially increasing stroke volume and blood pressure [103,104,105]. Besides, nor-epinephrine (NE) also binds to arteries, arterioles, and veins smooth muscle expressing α1 and α2 receptors, beginning downstream signaling cascades. This process, over many steps, activates calmodulin-dependent myosin light chain kinase, which phosphorylates myosin light chain. Subsequently, the binding between actin and myosin filaments causes smooth muscle contraction. Postganglionic sympathetic nerves also release other vasoconstrictor neurotransmitters such as neuropeptide Y (NPY) or ATP [106]. The axon of the postganglionic sympathetic nerve has angiotensin receptors. When angiotensin II binds to these receptors, it suppresses the reuptake of nor-epinephrine and further magnifies peripheral resistance [107]. The Beta-adrenergic receptor expresses the zona glomerulosa cell. Sympathetic stimulation of this receptor also triggers renin secretion and further accelerates the renin-angiotensin-aldosterone system [108]. All the way, directly and indirectly, the overactivation of the angiotensin aldosterone system contributes to high blood pressure. Various pharmacological treatments are designed to target specific components within the RAAS (as depicted in Figure 1). Angiotensin-converting enzyme inhibitors act by preventing the synthesis of angiotensin II, suppressing the renin-angiotensin-aldosterone system. This action lowers downstream effects mediated by the AT1 receptor, such as vascular muscle constriction, salt and water retention, and sympathetic outflow [109]. However, angiotensin Ⅱ synthesis is not fully controlled because angiotensin Ⅱ also synthesized by various additional ACE-independent alternative pathways in tissues such as chymase, kallikrein, cathepsin G, and elastase- 2 system [110]. Although ACEI is tolerated well in patients, it induces 5% to 35% dry cough and 0.2% to 0.7% angioedema [111]. ACEI inhibits the enzymatic cleavage of Bradykinin, increased plasma concentration of Bradykinin, activating the B2 receptor leads to vasodilation. most common ACEI are Benazepril, Captopril, Cilazapril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, Tradolapril, Delapril and Imidapril [112]. AT1 receptor blocker is considered an effective and well-tolerated antihypertensive drug; selective inhibition of the AT1 receptor not only suppresses vasoconstriction effect and vascular hypertrophy but also increases angiotensin Ⅱ through compensatory response. The highly concentrated angiotensin Ⅱ may provide further pharmacological advantages by activating the AT2 receptor subtype. most common AT1 receptor blockers are Losartan, Valsartan, Irbesartan, Eprosartan, Telmisartan, and Candesartan [113]. Angiotensin receptor blockers (ARBs) don’t affect ACE. As a result, ARBs offer the advantage of bypassing the side effects created by ACE inhibitors (ACEIs) and avoiding the bradykinin-changing effect. Aliskiren (ALI) only drug that directly inhibits the renin. This medicine became clinically available as an orally active antihypertensive treatment and was authorized in 2007 [114]. By inhibiting the primary rate-limiting phase of RAAS, the activity of renin in plasma declines, preventing the synthesis of angiotensin II and decreasing aldosterone levels without interfering with bradykinin metabolism or the AT1 receptor. ACE inhibitors (ACEIs) and ARBs produce a compensatory response and increase renin levels in plasma, which can lead to inadequate inhibition of the RAAS system. ACE inhibition increases the angiotensin I level, which might then undergo conversion to angiotensin II via ACE-independent mechanisms. ARBs enhance the levels of Angiotensin II, potentially competing for receptor occupancy with the medication [115].

Figure 1. Drug action site of Angiotensin Ⅱ synthesis pathway.

Figure 1. Drug action site of Angiotensin Ⅱ synthesis pathway.

Figure 2. angiotensin system blocker reduce the synthesis of aldosterone synthesis and its effect on principle cell.

Figure 2. angiotensin system blocker reduce the synthesis of aldosterone synthesis and its effect on principle cell.

Figure 3. By blocking of angiotensin system, reduce the effect of norepinephrine (NE), anti-diuretic hormone (ADH), and angiotensin Ⅱ on vascular smooth muscle, resulting in the reduction of vascular smooth muscle contraction. muscle relaxation is facilitated by bradykinin.

Figure 3. By blocking of angiotensin system, reduce the effect of norepinephrine (NE), anti-diuretic hormone (ADH), and angiotensin Ⅱ on vascular smooth muscle, resulting in the reduction of vascular smooth muscle contraction. muscle relaxation is facilitated by bradykinin.

Calcium Channel Blocker

The calcium channels, biochemically well-defined a complex protein, comprising a pore-forming alpha (α1) 1 subunit, one out of ten, alongside four unique auxiliary subunits: a beta (β), α2, a delta (δ), and a gamma (γ) subunit [116]. The biggest α1 subunit (190-250 kDα) forms a Ca²⁺ permeable pore. This α1 subunit of the calcium channel is arranged into four repeating homologous domains, known as (I-IV), with each domain including tightly packed six transmembrane segments (S1-S6). Within the S4 region sits the gating charges, responsible for starting conformational alterations that open the pores in response to changes in the electric field. Meanwhile, the pore loop between the transmembrane segments, S5 and S6 of each domain, modulates ion conductance and selectivity [117]. The β subunit primarily contacts with the inner surfaces of domains I and II of the α1 subunit, positioned on the cytoplasmic side. In contrast, the γ subunit spans the cell membrane, including four transmembrane regions that largely interact with domain IV of the α1 subunit. Additionally, the proteolytically processed α2δ subunit, positioned extracellularly and linked by disulfide connections, largely interfaces with the extracellular surface of domains I–III of the alpha 1 subunit [118]. The alpha 1 subunit functions not only as the pore formation but also determines the channel type. Voltage-gated calcium channels are classified into three types: Cav1, Cav2, and Cav3. These channels obtained their names from the chemical symbol of the principal permeating ion (Ca). The main physiological regulator (voltage) is indicated by a subscript (CaV). The number represents the CaV channel α1 subunit gene subfamily (varying from 1 to 3) and the sequence in which the alpha 1 subunit was discovered within that subfamily (from 1 to n) [119]. To date, ten different α1 subunits, encoded by the CACNA1x genes, have been found. The Cav1 subfamily (CaV1.1 to CaV1.4), represents L-type channels (where ‘L’ stands for Long-lasting). The CaV2 subfamily (CaV2.1 to CaV2.3), includes P/Q-type and N-type channels. Finally, the Cav3 subfamily (CaV3.1 to CaV3.3), represents T-type channels [120]. in which the L-type calcium channel is highly expressed on the vascular smooth muscle, myocyte, and nodal tissue in the heart. The influx of calcium ions through this channel helps maintain the membrane potential more positively, releasing calcium ions from the endoplasmic reticulum (calcium-induced calcium release) and stimulating smooth muscle and cardiac myocytes to contract [121]. All L-type channels have the same pharmacological profile, and their conformational shift is susceptible to numerous drugs that selectively block L-type calcium channels. This medication allosterically binds to three separate receptor sites on the L-type calcium channel, inhibiting calcium influx into the cytoplasm (as depicted in Figure 4) [122]. From a pharmacological and clinical perspective, the calcium channel blocker is classified into dihydropyridines and non-dihydropyridines. The dihydropyridines (e.g., amlodipine, nifedipine, felodipine, nimodipine, lacidipine) selectively bind with L-type calcium channel, that expressed on the vascular smooth muscle, resulting in reduced peripheral resistance due to relaxing vascular smooth muscle (pronounce vasodilation). Non-dihydropyridine (verapamil, diltiazem) is less tissue-specific; it binds both cardiac and vascular smooth muscle-expressed L-type calcium channels, resulting in diminished cardiac output due to negative ionotropic, chronotropic, and dromotropic effects. Although non-dihydropyridines decrease heart rate dihydropyridine is prone to increase heart rate due to sympathetic activation by pronounced vasodilation [123,124]. Some of the most typical side effects associated with dihydropyridine calcium channel blockers are peripheral edema, lightheadedness, flushing, headaches, and gingival hyperplasia, as well as the treatment with non-dihydropyridine calcium channel blockers associated with constipation (25%) and bradycardia. In some cases, CCB increases the tendency of gastrointestinal bleeding, probably in older patients due to inhibition of platelet aggregation [125]. The calcium channel blocker is used in not only the treatment of Hypertension but also some other vasospasm-related diseases such as Raynaud’s phenomenon, migraine and cluster headaches, high-altitude pulmonary edema, and even premature labor due to its vasodilation effect [126].

Figure 4. General mechanism of calcium channel blocker, resulting in vascular smooth muscle relaxation and reduced heart performance.

Figure 4. General mechanism of calcium channel blocker, resulting in vascular smooth muscle relaxation and reduced heart performance.

Clinical Trial Evaluation

Benazepril/Amlodipine vs. Benazepril/Hydrochlorothiazide (ACCOMPLISH TRAIL)

The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) [158], randomized 11506 patients (male 60.5%, black origin 12.27%, white origin 83.39%, mean age 68 years, Serum creatinine 139·7 μ mol/L with chronic kidney disease, 81·33 μ mol/L without chronic kidney disease, urinary albumin-to-creatinine ratio 28·8 mg/mmol with chronic kidney disease and 8·7 mg/mmol without kidney disease) with Hypertension, of whom 5744 patients received benazepril(20-40mg/d) and amlodipine (5 mg/d) and 5762 patient receive benazepril (20-40mg/d) plus hydrochlorothiazide (12.5 mg/d). After a mean follow-up 2.9 years, both groups showed excellent blood pressure control; mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril–amlodipine group and 132.5/74.4 mm Hg in the benazepril–hydrochlorothiazide group. The benazepril plus amlodipine receiving group was superior to the benazepril–hydrochlorothiazide receiving group in reducing the primary endpoint of progression of chronic kidney disease (1.97% in amlodipine based vs. 3.62% in hydrochlorothiazide based, HR 0·52, [95% CI 0·41–0·65]; p<0·0001). the adverse event in patients with chronic kidney disease, peripheral edema was more frequent in benazepril plus amlodipine than in benazepril plus hydrochlorothiazide (33·7% in amlodipine-based vs. 16·0% in hydrochlorothiazide based, p< 0.0001. The study also shows that in patients with chronic kidney disease, angioedema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group (1.6% in amlodipine based vs. 0.4% in hydrochlorothiazide based, p = 0.15). In patients without chronic kidney disease, Dizziness, hypokalemia, and Hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group.

Table 1. Pharmacokinetic properties of the hypertensive drug.

Table 1. Pharmacokinetic properties of the hypertensive drug.

Therapeutical class	Maximum time to plasma concentration	Bioavailability	Half-life	Volume of distribution	Protein binding	Clearance	Refer-once
CCB Amlodipine	6-8h	64%	40-50h	21L/kg	98%	0.23-0.4L/h/kg	[159]
Felodipine	0.5-5h	15%	25 h	10 L/kg	>99	1-1.5 L/min	[160]
Verapamil	2.2h	20%	2.7-4.8h	310-406 L	90%	875 ml/min	[161]
ARB Olmesartan medoxomil/Olmesartan	1.7–2.5h	26%	15 h	35L	99.7%	1.31 L/h	[162, 163]
valsartan	2h	23%	6.1h	17L	85-99%	2.2 L/h	[164]
Telmisartan	1h	43%	24h	500L	>99%	>800ml/min	[165]
Candesartan cilexetil/candesartan	3,5-6h	40%	3.5-11h	0.13L/kg	99.5%	0.0222 L/h/kg	[166, 167]
Eprosartan	1-2h	13%	5-9h	13L	98%	130ml/min	[168]
Irbesartan	1.3-3h	60-80%	11-18h	53-93L	90%	167ml/min	[166]
Losartan	1-2h	33%	1.7-2.1h	34.4 ± 17.9L	98.6–98.8%	4.3-5.6L/h	[169]
ACEI Benazepril/Benazeprilat	1.5h	37%	22.3h	8.7L	95%	1.4-1.7L/h	[170]
Captopril	0.75-1h	65%	2h	0.8 L/kg	23-31%	0.7L/h/kg	[171]
Enalapril/ enalaprilat	4h	36-44%	11h		50%	8-9.5L/h	[172,173]
Fosinopril/Fosinoprilat	2.8-3.1h	25-29%	11.5-12h	9.8-10.6L	95-99.8%	1.55-2.35 L/h	[174]
Lisinopril	8h	20-28%	12.6h	24L	no	6.36L/h	[175]
Quinapril/quinaprilat	2.5h	50-60%	3.2h	13.9L	97%	68 ml/min.	[176]
Diuretics hydrochlorothiazide	1.5-4h	60-70%	5.6-14.8h	275.3 L	40-68%		[177]

Table 2. Commonly prescribed combination drug for Hypertension.

Table 2. Commonly prescribed combination drug for Hypertension.

Combination type	Dose (mg)	Trade name	Cost
CCB+ACEI Amlodipine-benazepril Hydrochloride	2.5/10, 5/10, 5/20, 10/20	Lotrel	$14 ($215)- $16 ($390)
Enalaprilmaleate-felodipine	5/5	Lexxel
Trandolapril-verapamil	2/180, 1/240, 2/240, 4/240	Tarka	$47 ($185)- $65 ($185)
CCB+ARB Amlodipine/Olmesartan medoxomil	5/20,5/40,10/20,10/40	Azor	$23 ($280)- $28 ($350)
Amlodipine/Valsartan	5/160,320/5,10/160,10/320	Exforge	$20 ($270)- $25 ($385)
Amlodipine/Telmisartan	5/40,5/80,10/40,10/80	Twynsta	$50 (NA)- $55 ($240)
Diuretic+ACEI Benazepril-hydrochlorothiazide	5/6.25, 10/12.5, 20/12.5, 20/25	Lotensin HCT	$21 (NA)- $24 (NA)
Captopril-hydrochlorothiazide	25/15, 25/25, 50/15, 50/25	Capozide
Enalapril-hydrochlorothiazide	5/12.5, 10/25	Vaseretic	$10 (NA)- $10 ($395)
Fosinopril-hydrochlorothiazide	10/12.5, 20/12.5	Monopril/HCT
Lisinopril-hydrochlorothiazid	10/12.5, 20/12.5, 20/25	Prinzide, Zestoretic	$4 ($400)- $6 ($400)
Moexipril-hydrochlorothiazide	7.5/12.5, 15/25	Uniretic
Quinapril-hydrochlorothiazide	10/12.5, 20/12.5, 20/25	Accuretic	$17 ($150)
Diuretic+ARB Candesartan-hydrochlorothiazide	16/12.5, 32/12.5,32/25	Atacand HCT	$48 ($150)- $50 ($165)
Eprosartan-hydrochlorothiazide	600/12.5, 600/25	Teveten-HCT
Irbesartan-hydrochlorothiazide	150/12.5, 300/12.5	Avalide	$15 ($235)- $20 ($255)
Losartan-hydrochlorothiazide	50/12.5, 100/12.5,100/25	Hyzaar	$4 ($130)- $9 ($175)
Olmesartan medoxomil-hydrochlorothiazide	20/12.5,40/12.5,40/25	Benicar HCT	$14 ($225)- $16 ($310)
Telmisartan-hydrochlorothiazide	40/12.5, 80/12.5	Micardis-HCT	$47 ($220)
Valsartan-hydrochlorothiazide	80/12.5, 160/12.5, 160/25,320/12.5,320/25	Diovan-HCT	$14 ($270)- $18 ($420)

Information reference [178,179].

Pharmacological Treatment Strategy

Figure 5. treatment strategy for hypertension.

Figure 5. treatment strategy for hypertension.

Conclusions

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