Therapeutic perspectives in hypertension


Published on

  • Be the first to comment

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide
  • The current agreement
    for hypertension from the European Society of
    Hypertension (ESH), European Society of Cardiology
    (ESC), and the World Health Organization-International
    Society of Hypertension (WHO-ISH) as well as British
    hypertensive society (BHS) and the American Seventh
    Joint National Committee on Prevention, Detection,
    Evaluation, and Treatment of High Blood Pressure
    (JNC 7) identify an individual with hypertension if the
    systolic blood pressure (SBP) is ≥140 mm Hg and or
    the diastolic blood pressure (DBP) is ≥90 mm Hg
  • 1898-Tiegerstedt and Bergman found that crude saline extracts of the kidney contained a pressor substance that they named renin.
    1934 –Goldblatt and his colleagues demonstrated that constriction of the renal arteries produced persistent hypertension in dogs.
    1940 -Braun-Menéndez - plasma substrate angiotensinogen.
    1950s -two forms of angiotensin were recognized
    reported that renin was an enzyme that acted on a plasma protein substrate to catalyze the formation of the actual pressor material, a peptide, that was named hypertensin by the former group and angiotonin by the latter. These two terms persisted for nearly 20 years until it was agreed to rename the pressor substance angiotensin and to call the plasma substrate angiotensinogen. I
    In 1898, Tiegerstedt and Bergman found that crude saline extracts of the kidney contained a pressor substance that they named renin. In 1934, Goldblatt and his colleagues demonstrated that constriction of the renal arteries produced persistent hypertension in dogs. In 1940, Braun-Menéndez and his colleagues in Argentina and Page and Helmer in the U.S. reported that renin was an enzyme that acted on a plasma protein substrate to catalyze the formation of the actual pressor material, a peptide, that was named hypertensin by the former group and angiotonin by the latter. These two terms persisted for nearly 20 years until it was agreed to rename the pressor substance angiotensin and to call the plasma substrate angiotensinogen. In the mid-1950s, two forms of angiotensin were recognized, a decapeptide (angiotensin I [AngI]) and an octapeptide (angiotensin II [AngII]) formed by proteolytic cleavage of AngI by an enzyme termed angiotensin-converting enzyme (ACE). The octapeptide was shown to be the more active form, and its synthesis in 1957 by Schwyzer and by Bumpus made the material available for intensive study.
    It was later shown that the kidneys are important for aldosterone regulation and that angiotensin potently stimulates the production of aldosterone in humans. Moreover, renin secretion increased with depletion of Na+. Thus, the RAS came to be recognized as a mechanism to stimulate aldosterone synthesis and secretion and an important homeostatic mechanism in the regulation of blood pressure and electrolyte composition.
    In the early 1970s, polypeptides were discovered that either inhibited the formation of AngII or blocked AngII receptors. These inhibitors revealed important physiological and pathophysiological roles for the RAS and inspired the development of a new and broadly efficacious class of antihypertensive drugs: the orally active ACE inhibitors. Studies with ACE inhibitors uncovered roles for the RAS in the pathophysiology of hypertension, heart failure, vascular disease, and renal failure. Selective and competitive antagonists of AngII receptors were developed that yielded losartan, the first orally active, highly selective, and potent nonpeptide AngII receptor antagonist. Subsequently, many other AngII receptor antagonists have been developed. Recently aliskiren, a direct renin inhibitor, was approved for antihypertensive therapy (see Chapter 27).
  • Rate-limiting step : cleaving the N-terminal portion of a large molecular weight globulin, angiotensinogen, to form the biologically inert decapeptide Ang- 1(1-10)
    primary source is liver, also in kidney, brain, heart, vascular, adrenal gland, ovary, placenta, and adipose tissue.
  • Ang III and IV- in tissue with high levels of aminopeptidases A and N, such as brain and kidney tissue.
    Ang III - in CNS , play an important role in tonic blood pressure maintenance and in hypertension.
    Ang IV [(3-8)] is a hexapeptide . Some report that Ang IV is a vasorelaxative agent and this effect is contributed to activation of endothelial NOS. Angiotensin IV (AngIV), also called Ang(3–8), is formed from AngIII through the catalytic action of aminopeptidase M and has potent effects on memory and cognition. Central and peripheral actions of AngIV are mediated through specific AT4 receptors identified as insulin-regulated amino peptidases (IRAPs). AngIV binding to AT4 receptors inhibits the catalytic activity of IRAPs and enables accumulation of various neuropeptides linked to memory potentiation. Other actions include renal vasodilation, natriuresis, neuronal differentiation, hypertrophy, inflammation, and extracellular matrix remodeling (Ruiz-Ortega et al., 2007). Analogs of angiotensin IV are being developed for their therapeutic potential in cognition in Alzheimer disease or head injury (Albiston et al., 2007).
    others: Cooperative effect of Ang IV on angiotensin II type 1 (AT1)-receptor signaling
  • Prorenin is the enzymatically inactive precursor of reninRenin is produced and stored in granular JG cells in kidney. Renin is the major determinant of the rate of AngII production. It is synthesized, stored, and secreted by exocytosis into the renal arterial circulation by the granular juxtaglomerular cells (Figure 26–2) located in the walls of the afferent arterioles that enter the glomeruli. Renin is an aspartyl protease that cleaves the bond between residues 10 and 11 at the amino terminus of angiotensinogen to generate AngI. The active form of renin is a glycoprotein that contains 340 amino acids. It is synthesized as a preproenzyme of 406 amino acid residues that is processed to prorenin. Prorenin is proteolytically activated by proconvertase 1 or cathepsin B enzymes that remove 43 amino acids (propeptide) from its amino terminus to uncover the active site of renin (Figure 26–3). The active site of renin is located in a cleft between the two homologous lobes of the enzyme. Nonproteolytic activation of prorenin, central to the activation of local (tissue) RAS, occurs when prorenin binds to the prorenin/renin ((pro)renin) receptor, resulting in conformational changes that unfold the propeptide and expose the active catalytic site of the enzyme. (Danser et al., 2005). Both renin and prorenin are stored in the juxtaglomerular cells and, when released, circulate in the blood. The concentration of prorenin in the circulation is ~10-fold greater than that of the active enzyme. The t1/2 of circulating renin is ~15 minutes.
    Renin is the major determinant of the rate of AngII production. It is synthesized, stored, and secreted by exocytosis into the renal arterial circulation by the granular juxtaglomerular cells (Figure 26–2) located in the walls of the afferent arterioles that enter the glomeruli. Renin is an aspartyl protease that cleaves the bond between residues 10 and 11 at the amino terminus of angiotensinogen to generate AngI. The active form of renin is a glycoprotein that contains 340 amino acids. It is synthesized as a preproenzyme of 406 amino acid residues that is processed to prorenin. Prorenin is proteolytically activated by proconvertase 1 or cathepsin B enzymes that remove 43 amino acids (propeptide) from its amino terminus to uncover the active site of renin (Figure 26–3). The active site of renin is located in a cleft between the two homologous lobes of the enzyme. Nonproteolytic activation of prorenin, central to the activation of local (tissue) RAS, occurs when prorenin binds to the prorenin/renin ((pro)renin) receptor, resulting in conformational changes that unfold the propeptide and expose the active catalytic site of the enzyme. (Danser et al., 2005). Both renin and prorenin are stored in the juxtaglomerular cells and, when released, circulate in the blood. The concentration of prorenin in the circulation is ~10-fold greater than that of the active enzyme. The t1/2 of circulating renin is ~15 minutes.
    Preprorenin >>> prorenin >>> renin .
    sequential cleavage of the N-terminal 20 and 46 amino acids of preprorenin.
    kidney also releases unprocessed prorenin via a constitutive pathway
    prorenin accounts for about 70% to 90% of the immunoreactive renin.
  • n the year 2002, a new component of RAS was identified in human mesangial cells and named the (pro)renin receptor (PRR) because PRR binds both renin and prorenin [23]. The PRR gene is identical to ATPase 6 accessory protein2 (ATP6AP2) and is located on the X chromosome. PRR gene encodes a 350-amino-acidand ubiquitously expresses a single transmembrane protein with a large N-terminal extracellular domain which binds both renin and prorenin with affinities in the nanomolar range [64, 65]. Immunofluorescence observed by confocal microscope demonstrated that PRR was located on the cell surface, as well as intracellular compartments especially on the perinuclear space [22, 23, 66]. In vitro binding studies have shown that prorenin binds to PRR with a 3-4 fold higher affinity than renin, indicating that prorenin is a preferred ligand for PRR compared with renin [64, 65]. The binding of renin to PRR increases enzymatic activity 5-fold higher than the nonreceptor-bound renin [23]. The binding of prorenin to PRR induces a conformational change; the prosegment is removed from the catalytic cleft and the active site is accessible to AGT leading to full nonproteolytic activation of prorenin [23]. Interestingly, this phenomenon is reversible and prorenin eluted from the receptor reverts to its inactive form. The binding of renin to PRR is independent of the active site and receptor-bound renin or prorenin is not internalized or degraded [64, 67]. Thus, the discovery of the PRR has shed light on an alternate pathway for nonproteolytic activation of prorenin. Although the formation and role of intracellular Ang II has been previously reported [68, 69], there is a lack of attention to whether the intracellular PRR and prorenin contributes to the intracellular Ang II formation. It is likely that in tissues lacking a mechanism to cleave prorenin to renin, activation of prorenin via binding to PRR may contribute to intracellular Ang II formation. Several in vitro studies have been completed to assess the ability of prorenin to form Ang II via binding to the PRR. At a concentration of nanomolar range, which is much higher than the circulation level in physiological conditions, prorenin binds to PRR and exhibits enzymatic activity similarly to that of renin [64]. Furthermore, a recent in vitro study showed that the PRR activation by prorenin to generate Ang II requires about 800 fold higher prorenin concentration above normal plasma levels; the Ang II-independent activation requires an even higher prorenin concentration [70]. Combining these observations, prorenin may act mainly in the tissues either extracellularly or intracellularly, where its concentration may be high enough to activate Ang II-dependent or independent signals [70].
    Transgenic rats with human PRR expression in vascular sm
  • Ninety percent of patients with mild to moderate hypertension will be controlled by the combination of an ACE inhibitor and either a Ca2+ channel blocker, a adrenergic receptor blocker, or a diuretic. Diuretics augment the antihypertensive response to ACE inhibitors by rendering the patient's blood pressure renin dependent. Several ACE inhibitors are marketed in fixed-dose combinations with a thiazide diuretic or Ca2+ channel blocker for the management of hypertension
    2. reduces afterload and systolic wall stress, and both cardiac output and cardiac index increase, as do indices of stroke work and stroke volume. In systolic dysfunction, AngII decreases arterial compliance, and this is reversed by ACE inhibition
    3. started immediately during the acute phase of myocardial infarction and can be administered along with thrombolytics, aspirin, and adrenergic receptor antagonists
    4. retinopathy progression in type 1 diabetics and attenuate the progression of renal insufficiency in patients with a variety of nondiabetic nephropathies . or delays the progression of renal disease. Renoprotection in type 1 diabetes, as defined by changes in albumin excretion, also is observed with lisinopril. The renoprotective effects of ACE inhibitors in type 1 diabetes are in part independent of blood pressure reduction. In addition, ACE inhibitors may decrease retinopathy progression in type 1 diabetics and attenuate the progression of renal insufficiency in patients with a variety of nondiabetic nephropathies (Ruggenenti et al., 2010).
  • zilsartan medoxomil (AZM, TAK-491) is a recently developed angiotensin receptor blocker (ARB) that has a number of specific characteristics [3]. It is structurally similar to candesartan except that it bears a 5-oxo-1,2,4-oxadiazolemoiety in place of the tetrazole ring [4]. Further it has a carboxyl group at the 7-position of the benzimidazole ring, which is believed to result in insurmountable receptor antagonism [3,5]. This insurmountable binding of AZM to the AT1receptor may contribute to its potent and long-lasting antihypertensive activity.Azilsartan medoxomil is a prodrug that is quickly hydrolyzed to the active moiety azilsartan, a potent and highly selective ARB with estimated bioavailability of 60% and elimination half-life of 12 hours.12 The other major metabolite, M-II, is formed via CYP2C9 and has low affinity for the angiotensin II type 1 receptor. On the basis of dose-ranging studies and supporting pharmacokinetic data, the expected plateau of BP reduction for azilsartan medoxomil in the large majority of patients with hypertension is 40 or 80 mg once daily.
  • ARBs have teratogenic potential and should be discontinued in pregnancy. In patients whose arterial blood pressure or renal function is highly dependent on the RAS (e.g., renal artery stenosis), ARBs can cause hypotension, oliguria, progressive azotemia, or acute renal failure. ARBs may cause hyperkalemia in patients with renal disease or in patients taking K+ supplements or K+-sparing diuretics. ARBs enhance the blood pressure–lowering effect of other antihypertensive drugs, a desirable effect but one that may necessitate dosage adjustment. There are rare postmarketing reports of anaphylaxis, abnormal hepatic function, hepatitis, neutropenia, leukopenia, agranulocytosis, pruritus, urticaria, hyponatremia, alopecia, and vasculitis, including Henoch-Schönlein purpura.
  • Pepstatin - The first synthetic renin inhibitor but required parenteral administration.
    Oral agents : enalkiren, remikiren, and zankiren had limited clinical use
    poor bioavailability (<2%)
    short halflives
    weak antihypertensive activity .
    The earlier renin inhibitors were orally inactive peptide analogs of the prorenin propeptide or analogs of renin-substrate cleavage site. Orally active, first-generation renin inhibitors (enalkiren, zankiren, CGP38560A, and remikiren) were effective in reducing AngII levels, but none of them made it past clinical trials due to their low potency, poor bioavailability, and short t1
    Aliskiren's inhibition of renin leads to diminished production of AngI—and ultimately AngII and aldosterone—with a resulting fall in blood pressure. Aliskiren along with ACE inhibitors and AT1 receptor antagonists lead to an adaptive increase in the plasma concentrations of renin; however, because aliskiren inhibits renin activity, plasma renin activity does not increase as occurs with these other classes of drugs
  • gene - a single copy on the X chrmosome.
    highly expressed in fetal mesenchymal tissues
    clearly detectable in the adult kidney, heart, and blood vessels. mediate vasodilation by stimulating the production of BK, NO, and cGMP
    activates phospholipase A2 and prostaglandin generation. In the heart, the AT2 receptor inhibits growth and remodeling, induces vasodilation, and is up-regulated in pathological states
    Activation of the AT2 receptor mediates at least some of the beneficial effects of AT1 receptor blockade via a BK/NO/cGMP pathway.
    This paradigm opens the door for potential synergistic therapeutic effects of AT2 receptor agonists in combination with AT1 receptor blockers.
  • he new T-type channels were much different from the L-type calcium channels due to their ability to be activated by more negative membrane potentials, had small single channel conductance, and also were unresponsive to calcium antagonist drugs that were present.[1] These distinct calcium channels are generally located within the brain, peripheral nervous system, heart, smooth muscle, bone, and endocrine system.[2]
    The distinct structures of T-type calcium channels are what allow them to conduct in these manners, consisting of a primary α1subunit. The α1 subunit of T-type channels is the primary subunit that forms the pore of the channel, and allows for entry of calcium.
    T-type calcium channels function to control the pace-making activity of the SA Node within the heart and relay rapid action potentials within the thalamus. These channels allow for continuous rhythmic bursts that control the SA Node of the heart.[3]
    Pharmacological evidence of T-type calcium channels suggest that they play a key role in diseases such as absence epilepsy, diabetes, and several forms of cancer. Further research is continuously occurring to better understand these distinct channels, as well as create drugs to select for these channels.
  • Recently, a growing body of evidence has accumulated
    depicting important roles of T-type Ca2 channels in the
    regulation of cardiovascular function, such as generation of
    pacemaker potential and regulation of arterial resistance.3,4
    T-type Ca2 channels are found in various cell types, including
    neurons, cardiomyocytes, vascular smooth muscle cells,
    and endocrine cells, where they participate in a variety of
    physiological processes, such as low-threshold Ca2 spike
    generation, action potential firing, pacemaking, impulse conduction,
    maintenance of myogenic tone,Combined L-/T-type Ca2 channel blockers may possess
    greater efficacy than classical L-type Ca2 channel
    blockers in the management of blood pressure and renal
    function. In a recent clinical investigation, 80% of
    patients displayed a significant reduction of blood pressure
    or achieved optimal blood pressure after a switch from
    amlodipine to benidipine. Moreover, the changeover improved
    urinary protein excretion and glomerular filtration
    rate, which correlated with reduced urinary protein.7 These
    observations are consistent with better antihypertensive
    and renoprotective effects of the combined L-/T-Ca2
    channel blockers. In addition, combined L-/T-type Ca2
    channel blockers possess a superior endothelial effect. The
    endothelial function index, a ratio of flow-mediated
    dilatation:nitroglycerin-mediated dilatation, was significantly
    increased in patients with essential hypertension
    after treatment of efonidipine but not nifedipine. Meanwhile,
    urinary excretion 8-hydroxy-2-deoxyguanosine
    and serum malondialdehyde-modified low-density lipoprotein
    were decreased by efonidipine but not nifedipine,
    indicating a likely role of oxidative stress reduction in the
    efonidipine-induced improvement of vascular endothelial
    dysfunction.8 A schematic diagram is provided illustrating
    the benefit of combined L-/T-type Ca2 channel blockers
  • It is believed that combined
    L-/T-type Ca2 channel blockers equalize the hydrostatic
    pressure across the capillary bed through equal arteriolar and
    venular dilatation, thus reducing vasodilatory edema
    Suppress mesangial cell proliferation by inhibiting activator protein-1 (AP-1)
    Cell cycle transition from the G1 to S phase
    Modulate gene transcriptions
  • AZL, a newly developed and commercially used novel long-acting DHP-based calcium antagonist has been reported to be effective in treating ischemic heart disease and cardiac remodeling after myocardial infarction (MI) [3] and reduce blood pressure without increasing the heart rate in patients with hypertension [33,34]. In the experimental animals, AZL revealed anti-atherosclerotic effects independent of its blood pressure-lowering actions [35]. In another study, AZL prevented the TNF-induced endothelial cell activation via its antioxidative properties [36]. AZL also inhibited H2O2-induced cell death in neonatal rat cardiomyocytes [37]. However, the effects of AZL on diabetes induced cardiac damage have not been studied.
  • Cilnidipine: A New Generation Ca2+ Channel Blocker with
    Inhibitory Action on Sympathetic Neurotransmitter Releasecilnidipine attenuates NE release from sympatheticnerve endingsinhibits N-type Ca2+channels in addition to L-type Ca2+ channels
  • levidipine (Cleviprex), a late-generation dihydropyridine calcium channel antagonist available as a lipid emulsion for intravenous infusion, is approved in the US for the reduction of blood pressure (BP) when oral therapy is not feasible or desirable.L-type calcium channels in a voltage-dependent manner and exhibits a high degree of vascular selectivity in vitro. The BP-lowering effects of the drug are rapid and dose dependent, and are achieved by decreasing systemic vascular resistance without affecting venous capacitance vessels or cardiac filling pressures, with offset of effect within 5-15 minutes. Clevidipine had greater effects on arterial vasodilation and lesser effects on venodilation compared with sodium nitroprusside in hypertensive post-coronary artery bypass graft (post-CABG) patients. Clevidipine was not associated with reflex increases in heart rate in normotensive post-CABG patients or post-cardiac surgery patients, although elevations in heart rate were seen in healthy volunteers, cardiac surgery patients who received the drug preoperatively, and patients with acute severe hypertension. Data from animal studies suggest that clevidipine may protect against myocardial and renal injury caused by ischemia and/or reperfusion. Steady-state concentrations of clevidipine in arterial and venous blood were rapidly attained (within approximately 2 or approximately 10 minutes) in healthy volunteers receiving infusions of 0.91 or 3.2 mug/kg/min. The relationship between intravenous clevidipine infusion dose and steady-state blood concentration was linear over wide dose ranges in patients with mild to moderate hypertension and in healthy volunteers. Clevidipine is highly plasma protein bound and rapidly distributed, and has a low volume of distribution at steady state. It is rapidly metabolized via hydrolysis by esterases in the blood and extravascular tissues to a major metabolite that is inactive as an antihypertensive. Concentrations of clevidipine in the blood fall rapidly in a multiphasic fashion after termination of infusion. The initial phase is rapid (half-life of approximately 1 minute) and accounts for the majority of clevidipine exposure after an intravenous bolus dose and for 85-90% of its elimination; the terminal elimination half-life is approximately 15 minutes. Clevidipine metabolites are excreted mainly via the urine and feces and the drug has a high mean total blood clearance. The clearance of clevidipine was significantly lower during hypothermic cardiopulmonary bypass than before the procedure. THERAPEUTIC EFFICACY: Intravenous clevidipine, administered by infusion, was effective in the treatment of both acute preoperative and postoperative hypertension in adult cardiac surgery patients in two large, well designed, phase III trials. Few clevidipine recipients had evidence of treatment failure, whereas most placebo recipients failed treatment (primary endpoint) and the between-group difference was significant.Clevidipine Newer drugs Trial No pt Intervention End points Results ESCAPE-1 Phase III, double- blind, randomized, placebo- controlled study -clevidipine in preoperative hypertensio n 105 hypertensive scheduled for cardiac surgery with hypertension Clevidipine (53) placebo (52) Preoperative ly   incidence of treatment failure (to decrease SBP by >15% from baseline at any time within the 30- minute BP target levels reached Clevidipine : 92.5% (49 of 53 patients placebo (7.5%) P<0.0001).    
     Trial No pt Intervention End points Results ESCAPE-2 Phase III, double-blind, randomized, placebo- controlled, multi-center study -clevidipine in postoperativ e hypertension after cardiac surgery 110 patients with SBP>140 mm Hg within 4 hours of admission to a postoperativ e setting,. clevidipine (61) placebo (49)   the incidence of treatment failure (the inability to decrease SBP by >15% from baseline). Target BP reached Clevidipine : 91.8%   Placebo: 20.4%
     Trial No pt Intervention End point results VELOCITY The phase III prospective, open-label, single-arm study - clevidipine in Treatment Acute Severe Hypertension 117 patients the ER or ICU with SBP>180 and/or DBP>115 mm Hg The initial dose of clevidipine was 2 mg/hr for 3 minutes the dose was doubled every 3 minutes as needed to a maximum dose of 32
    mg/hr, which was then continued for 18-96 hours Achieving of a patient- specific systolic blood pressure range the first 30 minutes of infusion; 88.9% of patients (104/117) receiving clevidipine achieved their target SBP range within 30 minutes of treatment initiation, with a median time-to-target of 10.9 minutes
  • Increase insulin sensitivity
    Nitric oxide, activation of 2 receptors, blockade of 1 receptors
    Blockade of Ca2+ entry, opening of K+ channels
    Receptor antagonists generally do not reduce blood pressure in patients with normal blood pressure. However, these drugs lower blood pressure in patients with hypertension. Despite their widespread use, the mechanisms responsible for this important clinical effect are not well understood. The release of renin from the juxtaglomerular apparatus is stimulated by the sympathetic nervous system by means of 1 receptors, and this effect is blocked by receptor antagonists (Chapter 25). However, the relationship between this phenomenon and the fall in blood pressure is not clear. Some investigators have found that the antihypertensive effect of propranolol is most marked in patients with elevated concentrations of plasma renin, as compared with patients with low or normal concentrations of renin. However, receptor antagonists are effective even in patients with low plasma renin, and pindolol is an effective antihypertensive agent that has little or no effect on plasma renin activity.
    Presynaptic receptors enhance the release of NE from sympathetic neurons, but the importance of diminished release of NE to the antihypertensive effects of antagonists is unclear. Although blockers would not be expected to decrease the contractility of vascular smooth muscle, long-term administration of these drugs to hypertensive patients ultimately leads to a fall in peripheral vascular resistance (Man in't Veld et al., 1988). The mechanism for this important effect is not known, but this delayed fall in peripheral vascular resistance in the face of a persistent reduction of cardiac output appears to account for much of the antihypertensive effect of these drugs. Although it has been hypothesized that central actions of blockers also may contribute to their antihypertensive effects, there is relatively little evidence to support this possibility, and drugs that poorly penetrate the blood-brain barrier are effective antihypertensive agents.
    As indicated, some receptor antagonists have additional effects that may contribute to their capacity to lower blood pressure. These drugs all produce peripheral vasodilation; at least six properties have been proposed to contribute to this effect, including production of nitric oxide, activation of 2 receptors, blockade of 1 receptors, blockade of Ca2+ entry, opening of K+ channels, and antioxidant activity. The ability of vasodilating receptor antagonists to act through one or more of these mechanisms is depicted in Table 12–4 and Figure 12–9. These mechanisms appear to contribute to the antihypertensive effects by enhancing hypotension, increasing peripheral blood flow, and decreasing afterload. Two of these agents (e.g., celiprolol and nebivolol) also have been observed to produce vasodilation and thereby reduce preload
  • Carvedilol possesses two distinct antioxidant properties: it is a chemical antioxidant that can bind to and scavenge reactive oxygen species (ROS), and it can suppress the biosynthesis of ROS and oxygen radicals. Carvedilol is extremely liphophic and is able to protect cell membranes from lipid peroxidation. It prevents low density lipoprotein (LDL) oxidation, which in turn induces the uptake of LDL into the coronary vasculature. Carvedilol also inhibits ROS-mediated loss of myocardial contractility, stress-induced hypertrophy, apoptosis, and the accumulation and activation of neutrophils. At high doses, carvedilol exerts Ca2+ channel-blocking activity. Carvedilol does not increase receptor density and is not associated with high levels of inverse agonist activity (Cheng et al., 2001; Dandona et al., 2007; Keating and Jarvis, 2003
    Carvedilol is rapidly absorbed following oral administration, with peak plasma concentrations occurring in 1-2 hours. It is highly lipophilic and thus is extensively distributed into extravascular tissues. It is > 95% protein bound and is extensively metabolized in the liver, predominantly by CYP2D6 and CYP2C9. The t1/2 is 7-10 hours. Stereoselective first-pass metabolism results in more rapid clearance of S(–)-carvedilol than R(+)-carvedilol. No significant changes in the pharmacokinetics of carvedilol were seen in elderly patients with hypertension, and no change in dosage is needed in patients with moderate to severe renal insufficiency (Cleland, 2003; Keating and Jarvis, 2003). Because of carvedilol's extensive oxidative metabolism by the liver, its pharmacokinetics can be profoundly affected by drugs that induce or inhibit oxidation. These include the inducer, rifampin, and inhibitors such as cimetidine, quinidine, fluoxetine, and paroxetine.
  • Pharmacokinetic characteristics of prazosin are listed in Table 11–2. Terazosin is also extensively metabolized but undergoes very little first-pass metabolism and has a half-life of 12 hours. Doxazosin has an intermediate bioavailability and a half-life of 22 hours.
    Terazosin can often be given once daily, with doses of 5–20 mg/d. Doxazosin is usually given once daily starting at 1 mg/d and progressing to 4 mg/d or more as needed. Although long-term treatment with these blockers causes relatively little postural hypotension, a precipitous drop in standing blood pressure develops in some patients shortly after the first dose is absorbed. For this reason, the first dose should be small and should be administered at bedtime. Although the mechanism of this first-dose phenomenon is not clear, it occurs more commonly in patients who are salt- and volume-depleted.
    Aside from the first-dose phenomenon, the reported toxicities of the 1 blockers are relatively infrequent and mild. These include dizziness, palpitations, headache, and lassitude. Some patients develop a positive test for antinuclear factor in serum while on prazosin therapy, but this has not been associated with rheumatic symptoms. The 1 blockers do not adversely and may even beneficially affect plasma lipid profiles, but this action has not been shown to confer any benefit on clinical outcomes.
  • Dose in AM or afternoon to avoid nocturnal diuresis
    Generally reserved for diuretic-induced hypokalemia patients
    Weak diuretics, generally used in combination with thiazide diuretics to minimize hypokalemia
    Adverse effects:
    may cause hyperkalemia especially in combination with an ACE inhibitor, angiotensin-receptor blocker or potassium supplements
    avoid in patients with CKD or diabetes
  • Eplerenone does not inhibit any cytochrome isoenzymes.
    Inhibitors of CYP3A4 such as ketoconazole caused a fivefold
    increase in exposure, while less potent inhibitors of CYP3A4
    (erythromycin, saquinavir, verapamil, and fluconazole) yielded a
    twofold increase in exposure. St. John’s wort caused a small (30%)
    decrease in the area under the curve. Grapefruit juice caused a
    small (25%) increase in exposure
  • Considerable evidence indicates that amiloride blocks epithelial Na+ channels in the luminal membrane of principal cells in late distal tubule and collecting duct. The amiloride-sensitive Na+ channel (called ENaC) consists of three subunits (, , and ) (Kleyman et al., 1999). Although the subunit is sufficient for channel activity, maximal Na+ permeability is induced when all three subunits are coexpressed in the same cell, probably forming a tetrameric structure consisting of two subunits, one subunit, and one subunit. Studies in Xenopus oocytes expxressing ENaC suggest that triamterene and amiloride bind ENaC by similar mechanisms. The Ki of amiloride for ENaC is submicromolar, and molecular studies identified critical domains in ENaC that participate in amiloride binding (Kleyman et al., 1999). Liddle syndrome is an autosomal dominant form of low-renin, volume-expanded hypertension that is due to mutations in the or subunits, leading to increased basal ENaC activityOnset and duration of its action are determined by the kinetics of the aldosterone response in the target tissue
    The epithelial sodium channel (ENaC) is a principal site for sodium reabsorption and as such may participate importantly in blood pressure (BP) regulation. Amiloride, a direct inhibitor of ENaC, characteristically has mild antihypertensive properties, consistent with ENaC having more minor influences on BP regulation. Counter-regulatory influences may, however, prevent amiloride from effectively lowering BP. Aldosterone secretion is known to increase in response to the reduced sodium reabsorption that follows amiloride inhibition of ENaC, and because aldosterone upregulates ENaC function, we considered the possibility that secondary hyperaldosteronism mitigates the ability of amiloride to reduce BP. In 
  • Vascular endothelial cells produce a number of important vasodilator and constrictor substances.• Prostacyclin and nitric oxide (NO) are potent vasodilators secreted by vascular endothelium.• The isolation of endothelium-derived vasodilators initiated a search for counterbalancing constricting factors (or EDCFs).• A long-acting vasoconstrictor substance was isolated from porcine aortic endothelial cells in 1988, and named endothelin.
  • In the endothelium, ET-1 is predominantly released
    toward the vascular smooth muscle, suggesting a
    paracrine role.21 ET-1 is also produced by other cells involved
    in vascular disease, such as leukocytes,22 macrophages,23
    smooth muscle cells,24 cardiomyocytes,25,26 and mesangial
    cells,27,28 and its synthesis is regulated in an autocrine
    fashion. The binding of ET-1 to ETA receptors activates phospholipase
    C, which leads to an accumulation of inositol triphosphate and
    intracellular calcium116,117 and, in turn, to long-lasting vasoconstriction.
    2,5,118 The activation of ETA receptors also induces cell
    proliferation in different tissues.30,119 In contrast, the activation
    of endothelial ETB receptors stimulates the release of NO and
    prostacyclin,120,121 prevents apoptosis,122 and inhibits ECE-1
    expression in endothelial cells.63 ETB receptors also mediate the
    pulmonary clearance of circulating ET-1123 and the reuptake of
    ET-1 by endothelial cells
  • substantially reduces arterial blood pressure in patients with essential or resistant essential hypertension
    12ET antagonists are contraindicated
    during pregnancy and in women with child-bearing
    potential. In clinical tr
  • Craniofacial abnormalities
  • ase 2 trials with darusentan in hypertension were encouraging, however, showing significant dose-dependent reductions in systolic BP with various doses among patients with moderate hypertension and in those with resistant hypertension. Darusentan was originally under development by a company named Myogen, which in 2006 became a wholly owned subsidiary of Gilead Sciences.
  • Vasopeptidase inhibitors are a new class of drugs that
    have dual inhibitory effects on two key enzymes
    involved in the metabolism of vasoactive peptides.
    Essentially, they inhibit angiotensin-converting
    enzyme (ACE), thereby blocking the generation of
    angiotensin II (Ang II); at the same time they prevent
    the breakdown of natriuretic peptides by the enzyme
    neutral endopeptidase. The combination of reduction
    of Ang II on a background of increased natriuretic
    peptide activity has several potential advantages for
    the treatment of cardiovascular and renal disease and
    in particular, hypertension and congestive heart failure
    (CHF). Several vasopeptidase inhibitors, such as
    sampatrilat, fasidotril, gemopatrilat and omapatrilat
    (VanlevTM, the most clinically developed vasopeptidase
    inhibitor to date) are under intensive clinical
    investigation. Re
  •  LCZ696 is a first-in-class angiotensin receptor
    neprilysin inhibitor (ARNI) that provides neprilysin
    (NEP) inhibition and blockade of the AT1 receptor
  • LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) which provides concomitant inhibition of NEP and the angiotensin receptor. Ingestion of LCZ696 delivers systemic exposure to AHU377 (which is then rapidly metabolized to LBQ657, a specific NEP inhibitor) and to valsartan (an angiotensin II receptor blocker). LCZ696 treatment is associated with dose-dependent increases in plasma cGMP, renin activity and angiotensin II, consistent with the drug’s dual mechanism of action; a dose of 200-400 mg LCZ696 achieves approximately 90% of its maximal NEP inhibition [2].
  • The Omapatrilat in Persons with Enhanced
    Risk of Atherosclerotic events (OPERA) trial
    Because of this, the Omapatrilat Cardiovascular
    Treatment Assessment Versus Enalapril (OCTAVE)
    study was set up to compare omapatrilat against
    enalapril on the incidence of angio-oedema in
    patients with hypertension.
    OVERTURE trial,48 both omapatrilat and enalapril
    were generally safe and well tolerated; however,
    the incidence of angio-oedema
  • Facilitation of natriuresis/diuresis by increasing intrarenal vasodilator and natriuretic peptides
  • CYT006-AngQb(Cytos Biotechnology AG, Switzerland), a viruslike particle-based conjugate vaccine that targets angiotensin II.
    An immunological approach might offer similar advantages to those
    expected from gene-based strategies. Recently, two antihypertensive
    vaccines were developed: PMD3117 against Ang I and Cyt006
    against Ang II. Despite some excitement the results were rather
    disappointing. Although Cyt006 reduced BP in SHR,130 it achieved
    inferior BP reduction (9/4 mmHg)131 compared with conventional
    antihypertensives. In further studies Cyt006 failed to reproduce
    this BP reduction, despite shorter dosing intervals and higher antibody
    titres,132 and PMD3117 did not decrease BP, despite some
    degree of RAAS blockade.133 In addition, the proposed vaccination
    atWeek 0, 4, and 12131 or 0, 2, 4, 6, and 10132 might not be appealing
    enough to improve patient compliance. On the other hand,
    while previous anti-renin vaccinations were associated with
    severe kidney disease,134,135 PMD3117 and Cyt006 were well
    tolerated in Phase I study130,133 and Cyt006 also blunted early
    morning surge in BP.131
  • Recently, in an extensive search for vasoactive kidney-related proteins,
    a novel catecholamine peptidase, renalase, was discovered.
    112 Its basal plasmatic activity is very low, but it can be
    increased by catecholamines,113 which it in turn metabolizes.112
    Kidneys are probably the major source of circulating renalase as
    in subnephrectomized rats or in patients with end-stage renal
    failure the renalase production in the heart, muscle, or liver
    could not compensate the deficit of kidney-produced renalase.
    112,113 Renalase down-regulation or knock-out is associated
    with increased catecholamine levels, BP and higher susceptibility
    to ischaemic myocardial damage,114 – 116 which are prevented by
    supplementation with recombinant renalase.116 Because one renalase
    polymorphism was associated with essential hypertension117
    and increased CV risk in patients with coronary heart disease,115
    certain patients might be identified that could especially benefit
    from renalase substitution.
    Although some concerns due to the metabolization of the renal
    vasodilator dopamine by renalase118 were raised, no alterations in
    renal function were observed in renalase knock-outs supplemented
    with recombinant enzyme.116 Regardless of the therapeutic
    potential and safety of renalase administration, its
    discovery might have provided a novel important pathophysiological
    link between the kidney, sympathetic tone, and BP.
  • a percutaneous, catheter-based radiofrequency
    ablation for renal sympathetic denervation has been develop
    potentiated BP
    control by losartan120 in rats with chronic Ang II infusion. Adenoviral
    transfer of endothelial NO-synthase and kallikrein genes
    improved endothelial dysfunction121 and cardiac remodelling122
    in SHR. Even more promising results were reported with suppression
    of vasoconstrictor expression by the use of cDNA antisenseAlthough being exciting, until more safe and reliable methods of
    nucleic acid transfer are established, gene-based therapies are unlikely
    to offer substantial advantage over pharmacological therapies
    and will rather provide a valuable experimental tool.
  • Dietary Na+ restriction is a valuable adjunct to the management of such refractory patients and will minimize the dose of diuretic that is required. This can be achieved by a modest restriction of Na+ intake to 2 g daily. More stringent Na+ restriction is not feasible for most patients. Because the degree of K+ loss relates to the amount of Na+ delivered to the distal tubule, such restriction of Na+ can minimize the development of hypokalemia and alkalosis. The effectiveness of thiazides as diuretics or antihypertensive agents is progressively diminished when the glomerular filtration rate falls below 30 mL/min. One exception is metolazone, which retains efficacy in patients with this degree of renal insufficiency
  • Diastolic BP of 90mm Hg or higher or systolic BP of 140mm Hg or higher after 20wks of gestation in a woman with previously normal BP.
    It should be documented on atleast 2 occasions measured 4hrs apart.
    Proteinuria : It is defined as the urinary excretion of 300mg/L or more of protein in a 24hr urine collection. (correlates with reagent strip >1+ i.e. >30mg/dlDevelops in late pregnancy, after 20 weeks gestation.
    Resolves by 12 weeks postpartum.
    Can progress onto preeclampsia.
    Often when hypertension develops <30 weeks gestation.
    Indications for and choice of antihypertensive therapy are the same as for women with preeclampsia.
  • Goal SBP<160 and DBP<110 in pre-and- intrapartum periods.
    Platelets < 100 000, BP should be maintained < 150/100
    Continue MgSO4 till 24hrs postpartum to avoid convusion.
    Nimodepine 60 mg oral 4hrly: drug of choice in mild elevated BP with impending signs/ eclampsia.
    Phenytoin :
    loading dose 10-15 mg/kg slow iv f/b maint dose 100mg iv every 6-8hrly.
    For prophylaxis 100mg iv/im 4hrly.
    Oral phenytoin should be continued in postpartum period.
    Postpartum i.v. Furosemide should be given aggresively for early recovery.
    Start IV fluids at low rate 100ml/hr.
    Antihypertensive : 1st drug of choice in severe HTN is iv Labetalol.
    Deliver the pt
    IV Magnesium to prevent seizures
    Drug of choice:
  • The Seventh Report of the Joint National
    Committee on prevention, evaluation and
    treatment of high blood pressure
    (JNC 7) recommendations were published
    in JAMA 2003; vol. 289; n˚19: 2560-2572
    • A new controversial category was
  • Therapeutic perspectives in hypertension

    1. 1. Recent advances in Hypertension Management Speaker: Dr.Rachana Menon
    2. 2. Contents  Definition  Pathophysiology  Management of Hypertension  Newer Antihypertensives  Hypertensive Emergency  Recent guildelines
    3. 3. Hypertension  Rise of blood pressure above the normal level is called hypertension CO PVR
    4. 4. Hypertension (Contd.)  European Society of Hypertension  European Society of Cardiology  World Health Organization-International Society of Hypertension  British hypertensive society  Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) SBP is ≥150 mm Hg DBP is ≥90 mm Hg
    5. 5. Why to treat HTN?
    6. 6. 2014 GUIDELINES- JNC 8
    7. 7. Antihypertensives • Diuretics – Thiazide – Loop diuretics – Aldosterone antagonists – K-sparing • Adrenergic inhibitors – Peripheral agents – Central (α-agonists) – alpha -blockers – beta-blockers – Alpha+beta-blockers • Direct Vasodilators • Calcium channel blockers – Dihydropyridine – Non dihydropyridine • ACE-inhibitors • Angiotensin-II blockers
    8. 8. Historical Perspective 1898 – Tiegerstedt and Bergman 1934 – Goldblatt and his colleagues 1940 – Braun-Menéndez - Angiotensionogen 1950s – Two forms of angiotensin were recognized 1970s – The formation of AngI or blocked AngII receptors
    10. 10. What causes Renin release Hypotension Hypovolemia Strech Receptors Sympathetic tone
    11. 11. AT 1 Receptor AT 2 Receptor Vasoconstriction Vasodilation Cell growth & Proliferation Anti-growth Promotes Reabsorption of Na & Water Natriuresis Produces Free radicals Produces Nitric oxide (Vasodilation) Induces growth factors , Endothelin and Plasminogen Activator Inhibitor 1(PAI-1)
    12. 12. Preprorenin >>> prorenin >>> renin
    13. 13. The (Pro) Renin Receptor ORGAN DAMAGE
    14. 14. Compelling Indications for Certain Drug Classes Recommended Drugs Compelling Indication Diuretic ACEI BB ARB CCB Aldo ANT Heart failure ₀ ₀ ₀ ₀ ₀ Post-MI ₀ ₀ ₀ High coronary disease risk ₀ ₀ ₀ ₀ Diabetes ₀ ₀ ₀ ₀ ₀ Chronic kidney disease ₀ ₀ Recurrent stroke prevention ₀ ₀
    15. 15. Newer agents Structure Pharmacokinet ics Adverse effects Dose Lisinopril Carboxy 30% BA t1/2 ~12 h 5-40 mg Benazepril Ester 37% BA t1/2 11 h 5-80 mg Fosinopril phosphinate BA 36% t1/2 11.5 h 10-80 mg Trandolapril Ester 10% BA biphasic elimination kinetics t1/2 11 h 1-8 mg Quinapril Esterases t1/2 25 h 5-80 mg Moexipril Esterases ~13- BA t1/2 12 h 7.5-30 mg Cough Hypotension Hyperkalemia Angiodema
    16. 16. ACE Inhibitors – Clinical Summary  Normalise BP in ~50% of patients with mild to moderate HTN.  Left Ventricular Systolic Dysfunction  Acute Myocardial Infarction  DM and RF Antacids – BA Capsaicin – WORSEN Cough NSAIDs - response to ACE inhibitors K+ -sparing diuretics and K+ supplements may exacerbate hyperkalemia plasma levels of digoxin /lithium Hypersensitivity reactions to allopurinol.
    17. 17. Newer ARB – AZILSARTAN  AT1 receptor anatagonist  Azilsartan medoxomil – pro drug  Hydrolyzed to the active moiety azilsartan, a BA 60% t½ 12 hours  The other major metabolite, M-II, is formed via CYP2C9  40 or 80 mg once daily 2011, FDA approved- Mild/ Moderate Htn
    18. 18. Therapeutic Uses of AngII Receptor Antagonists ARB’s Indication Dose Clinical trial Irbesartan Diabetic nephropathy/ AF 300 mg IDNT (2003) Losartan Diabetic nephropathy/ Stroke/ HF/ Portal HTN 40/80 mg ELITE study LIFE (1998) Valsartan HF/ Htn/ Post MI 80/160 mg ValHeFt (2001) Telmisartan Htn/HF 40/80 mg ONTARGET (2008) Candesartan PreHtn/ HF 4,8,16,32 mg CHARM- Additive(2007)
    19. 19. Direct Renin Inhibitors LMW non-peptide that is a potent competitive inhibitor of renin ALISKIREN
    20. 20. Direct Renin Inhibitors (Contd.)  U.S. FDA in 2007 for the treatment of hypertension  150 or 300 mg/day – Monotherapy/ FDC  t1/2 is 20-45 hours., BA poor, Fatty meal  Metabolism- CYP3A4  Elimination is mostly as unchanged drug in faeces Marketing stopped after July 2012
    21. 21. AVOID66 Type 2 diabetes with hypertension and proteinuria Allkiren (150 → 300 mg) + losartan (100 mg) Placebo + losartan (100 mg) 24 weeks Primary Change in UACR Secondary Proportion of patients with ≥ 50% reduction in UACR Change in BP ALOFT67 Stable heart failure and raised BNP levels (> 100 pg/ml) Allkiren (150 mg) + standard therapy (including ACE inhibitor or ARB, and beta-blocker Placebo + Standard therapy 12 weeks Primary Safety and tolerability Secondary Change in BNP Change in NT- proBNP Change in plasma aldosterone
    22. 22. ALLAY80 Overweight with hypertension and LV hypertrophy 465 Allskiren (150 → 300 mg) Losartan (50 → 100 mg) Allkiren/losartan (150 → 300/50 → 100 mg) 36 weeks Primary Change in LV mass index Secondary Proportion of patients with ≥ 50% reduction in UACR Change in BP AGELES S85 65 years of age, with systolic hypertension (140 to < 180 mmHg 912 Allskiren (150 → 300 mg) + optional HCT and amlodipine Rampiril (5 → 10 mg) + optional HCT and amlodipine 36 weeks Primary Change in SBP at Week 12 (i.e. monotherapy phase) Secondary Change in BP at study endpoint Safety and tolerability
    23. 23. DIRECT RENIN INHIBITORS UNDER TRIAL  SPP635 – Mild to Moderate Hypertension-2006  - Phase II Study to Investigate the Efficacy and Safety of SPP635 in Diabetic and Hypertensive Patients With Albuminuria  SPP1148 – Preclinical trial 2007  SPP800 A – Preclinical trial 2008
    24. 24. AT2 RECEPTOR AGONIST • Nonpeptidic, orally active AT2R agonists • Potential novel class of drugs Promising target -HTN -STROKE -MYOCARDIAL FIBROSIS
    25. 25. Calcium Channel Blockers
    26. 26. DIHYDROPYRIDINES SHORT ACTING • Nifedipine Nicardipine Nimodipine INTERMEDIATE ACTING • Nisoldipine Nitrendipine Isradipine Lacidipine Clinidipine Lercanidipine LONG ACTING • Felodipine Benidipine NON DIHYDROPYRIDINE SHORT ACTING • Verapamil Diltiazem LONG ACTING • Bepridil
    27. 27. Calcium channel blockers Manidipine  Nilvadipine  Benidipine Efonidipine Mibefradil T + L TYPE Ca channel blockers 2nd generation
    28. 28. Newer Calcium channel Blockers  CLINIDIPINE  MEBUDIPINE  DIBUDIPINE  AZELNIDIPINE Superior Endothelia function Urinary protein excretion -GFR LDL , Vasodilation- Efonidipine Vasodilatory edema. –Mibefradil
    29. 29. Azelnidipine – 3rd generation  Azelnidipine is the newest Ca2+ channel blocker  Ltype channel  Noninferiority against amlodipine in phase III clinical trials. –Mid to Moderate HTN  No increase in HR –LVDF  Long duration of action – 24hrs  Headache and hot facial flushes Diabetic patients-CM MI ATHEROSCLEROSIS ANTI OXIDANT
    30. 30. CLINIDIPINE – 4th Generation
    31. 31.  Alone or in combination with other drugs  DOC- elderly with isolated systolic hypertension Angina pectoris  Treatment of supraventricular arrhythmias - Atrial Flutter - Atrial Fibrillation - Paroxysmal SVT Other uses
    32. 32. Clevidipine  Inhibits L-type calcium channels in a voltage-dependent manner  rapid and dose dependent  Arterial vasodilation and lesser effects on venodilation  highly plasma protein bound  Metabolism-Hydrolysis  Half-life i-15 minutes  IV formulation – lipid emulsion  AF and sinus tachycardia – ADR Escape trial Velocity trial Post-CABG patients Protection – MI/ renal changes Hypertension crisis
    33. 33. Advantages
    34. 34. Current status in elderly  Preferred in elderly hypertensives  They have stroke prevention potential next to ACE inhibitors in reducing albuminuria  Slowing disease progression in hypertensive / diabetic nephropathy  Cyclosporin induced hypertension in renal transplant
    35. 35. Adrenergic inhibitors
    36. 36. Drug MOA Kinetics ADR Clinical trial Nebevilol 10 mg Β1-antagonist endothelial NO- mediated vasodilator activity Highly protein- bound t ½- 10.3 hour Extensive first pass metabolism headache, dizziness, fatigue, nasopharyngitis Metabolic syndrome Celiprolol β1 antagonist (weak) vasodilating-NO production BA- 30%. unmetobolized. excretion is renal. Same Bucindolol HDL β1,2 -non- selective α1 - weak Well absorbed after oral. protein bound (87%), t1/2 of ~8 h Metabolism- liver Same BEST-survival benefit Carvedilol- Anti inflammatory Antioxidant Membrane stabilizing activity Vasodilation β1,2 - α1 - ANTAGONIST 95% protein bound t1/2 is 7 metabolism by the liver Hypotension-higer doses COPERNICUS- reduces mortality / attenuates MIcimetidine, quinidine, fluoxetine, and paroxetine
    37. 37. Alpha antagonist Prasozin Terasozin Doxazosin Phentolamine Phenoxybenzamine HTN CRISIS •Diagnosis and treatment of pheochromocytoma •Clonidine withdrawal syndrome •Cheese reaction Postural hypotension Combination with beta blocker
    38. 38. Diuretics  Epelerenone  Spironilactone  Amiloride  Thaizides
    39. 39. Eplerenone  Greater selectivity for the MR.  Bind to mineralocorticoid receptors and blunt aldosterone activity  Currently approved for use only in hypertension Experimental effects of eplerenone on aldosterone-associated cardiovascular and renal dysfunction Blockade in vivo of renal effects of hormone Reduced vascular inflammation and fibrosis Reduced post-MI fibrosis (but not healing) Reduced renal damage in experimental models of hypertension
    40. 40. Eplerenone (Contd.)  Metabolized via the CYP3A4 pathway half-life -4 to 6 hours  Hypertension trials-  EPHESUS trial  RALES trial  T ½ - 5hrs .Good BA  25- 50mg Heart failure secondary to myocardial infarction
    41. 41. Characteristics Spironolactone Eplerenone Clinical indication Severe (NYHA class III-IV) CHF with LV systolic dysfunction Essential hypertension Primary hyperaldosteronism Severe (NYHA class III-IV) CHF after myocardial infarction Essential hypertension Receptor binding affinity (aldosterone = 1) 1.1 X 10-1 5.1 X 10-3 Sex-steroid receptor cross- reactivity Yes Minimal Metabolism Hepatic Cytochrome P450, isoenzyme CYP3A4 Conversion to metbolites for effect Yes No Half-life, h 1.4 4 to 6 Excretion Renal and bile Renal and GI Administration With food to maximize absorption With or without food Recommended dose, mg/d Hypertension, 50 - 100; CHF, 25 - 200 Hypertension, 50 - 100; CHF, 25 -50 Drug interactions Potentiate hyperkalemia ACE - I NSAIDs Potentiate hypotension Hypertension, 50 - 100; CHF, 25 -50 Potentiate hyperkalemia ACE - I NSAIDs CYP3A4 inducers decrease
    42. 42. Spironolactone and Amloride Synthetic steroid that acts as a competitive antagonist to aldosterone. Several days before full therapeutic effect is achieved. Highly protein bound 10 hrs Long DOA 21 hrs Diarrhoea/skin rash/ hypotension Hyperkalemia – ADR
    43. 43. In Resistant Hypertension Aldosterone excess may be a more common cause Low-dose spironolactone Eplerenone FDC combination with THAIZIDE
    44. 44. Factors increasing the risk of hyperkalaemia during aldosterone blockade 1. Diminished renal function 2. Combined therapy with beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and direct renin nhibitors 3. Adjunct therapy with non-steroidal anti-inflammatory drugs 4. Ageing 5. Potassium supplements
    45. 45. A, B, C, D approach
    46. 46. Endothelins  21-AA peptide isolated from cultured porcine aortic endothelial cells, first reported in 1988  Potent vasoconstrictor peptide  Endothelial cells
    47. 47. Endothelin Receptors  ET a  G protein couple receptor  Primary vasoconstrictor  Mitogenesis  Vascular smooth cells  ET b  G protein couple receptor  Vasodilator  Inhibit growth factor
    48. 48. ET-1 as a key mediator in endothelial maintainance of tone and structure IP3/PLC PLA 2-PG I synthase
    49. 49. Constriction of afferent and efferent arterioles decrease GFR Preventing tubular reabsorption of sodium and water (ETB) Mitogenic effect on mesangial cells Positive chronotropic and inotropic effects Increased afterload / baroreceptor mediated decrease in HR. Mitogenic effect on cardiac myocytes Stimulates ACE and aldosterone release PULMONARY VASCULAR BED- Vasoconstriction through vascular smooth muscle cell
    50. 50. SYSTEMIC HYPERTENSION  Preclinical data on hypertension have been underscored by clinical studies in humans with essential hypertension  Nonselective ET-receptor antagonist bosentan  Selective ETA-receptor antagonist darusentan
    51. 51. Bosentan  Non-selective ET-1 receptor antagonist  Vasodilatory effects  Pulmonary hypertension and CHF  5 -8 h.  BA- 50%  hepatic metabolism followed by biliary excretion  300-500 mg Longer half life
    52. 52. Darusentan • Selective ETA receptor antagonist • 10, 50, 100, 150, and 300 mg • orally bioavailable • t1/2 12.5 hours • Metabolized in the liver and excreted via the bile • Resistant Hypertension Increase in heart rate, facial flush, Facial edema
    53. 53. Vasopeptidase Inhibitors  Omapatrilat  Sampatrilat  Fasidotrilat  Gemopratilat
    55. 55. Characteristics of selected vasopeptidase inhibitors under clinical development Substance Dose Comments/Status Sampatrilat 30mg/kg Produced sustained reductions in blood pressure in African-Americans. Currently under clinical development after reformulation to improve bioavailability Gemopatrilat Antihypertensive actions, good oral efficacy. Phase I/II clinical trials for hypertension MDL-100240 High affinity inhibotor of both ACE and neutral endopeptidase; antihypertensive and natriuretic. Under clinical investigation for hypertension and congestive heart failure Fasidotril 10mg/kg Moderate antihypertensive effects. Natriuretic in animal experiments. Improved survival of rats after myocardial infarction. Phase II clinical trials for renovascular hypertension Z-13752A Phase I/II clinical evaluation for hypertension. Reduced severity of consequences of coronary artery occlusion in animal experiments Omapatrilat 10 mg Most advanced stage of clinical development OVERTURE and OCTAVE study recently completed
    56. 56. angiotensin receptor neprilysin inhibitor
    57. 57. Recent trials  OVERTURE trial  OCTAVE study  OPERA trial Angiodema Cough Hypotension
    58. 58. Potential benefits of vasopeptidase inhibitors  Reduction in BP through increase in natriuretic peptide activity and decrease in Ang II  Prevention of compensatory rise in aldosterone secretion  Broad spectrum of action in hypertension  Preservation of renal blood flow and GFR- diuresis  Reduction in pre-load and afterload in congestive heart failure
    59. 59. Vaccine-based strategies  Two antihypertensive vaccines were developed: PMD3117 against Ang I and Cyt006 against Ang II  lower (-9/-4 mm Hg) blood pressure  Week 0, 4, and 12 or 0, 2, 4, 6, and 10  Seems feasible and preventive employment against CV diseases
    60. 60. Renalase system • Vasoactive kidney-related proteins • novel catecholamine peptidase . • Renalase deficiency increases SBP and DBP Knock-out MOUSE MODEL – Down regulation of renalase • Supplementation with recombinant renalase - Dahl salt-sensitive rats and rats with chronic kidney disease. Kidneys-Urinary catecholamines
    61. 61. Gene therapy  Overexpression of ACE2 and AT2R delivered in viral vectors reduced cardiac remodelling.  Exciting, but more safe and reliable methods of nucleic acid transfer re required. Renal sympathetic denervation • Resistant hypertension • The Rheosw Pivotal Trial- electrical activation of the carotid baroreflex
    62. 62. Hypertension Polypill 5-mg Amlodipine/160-mg Valsartan/12.5-mg HCTHZ Maximum of 10/320/25.
    63. 63. Dietary changes  Modest restriction of Na+ intake to 2 g daily.  Diet high in fruits and vegetables and low-fat dairy products lowers blood  Alcohol  Cardio exercise  Yoga/ meditation/Music
    64. 64. Gestational Hypertersion • Definitive Treatment = Delivery • Major indication for antihypertensive therapy is prevention of stroke. – Diastolic pressure ≥105-110 mmHg or systolic pressure ≥160 mmHg • Choice of drug therapy: – Acute – IV labetalol, IV hydralazine, SR Nifedipine – Long-term – Oral methyldopa or labetalol
    65. 65. • Medical Management • Acute Therapy = IV Labetalol, IV Hydralazine, SR Nifedipine • Expectant Therapy = Oral Labetalol, Methyldopa, Nifedipine • Eclampsia prevention = MgSO4 • ACE inhibitors • Angiotensin receptor antagonists Labetalol orally in dose of 100-400 mg every 8-12hrly. Methyl dopa 250mg-500mg 6-8 hrly. Nifedipine 10-20mg bd - tds
    66. 66. Hypertension Urgency and Emergency
    67. 67. Hypertension Guidelines Hypertension Guidelines Date JNC JNC 7 2003 JNC 8 - Expected Release Date 2012 (TBC) NICE Guidelines NICE Guidelines 2011 ESC/ESH Hypertension Guidelines ESC Guideline 2007 Reappraisal of 2007 Hypertension Guidelines Sep-09
    68. 68. Compelling Indications Compelling Indication Initial Therapy Clinical Trial Basis Heart failure THIAZ, BB, ACEI, ARB, ALDO ANT ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES Post myocardial infarction BB, ACEI, ALDO ANT ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS High CAD risk THIAZ, BB, ACE, CCB ALLHAT, HOPE, ANBP2, LIFE, CONVINCE
    69. 69. Compelling Indications Compelling Indication Initial Therapy Options Clinical Trial Basis Diabetes THIAZ, BB, ACE, ARB, CCB NKF-ADA Guideline, UKPDS, ALLHAT Chronic Kidney Disease ACEI, ARB NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK Recurrent Stroke Prevention THIAZ, ACEI PROGRESS
    70. 70. JNC 8 REPORT 60 years, initiate pharmacologic treatment (SBP)150 mmHg or (DBP)90mmHg >60years,achieved SBP <140mmHg) treatment is well tolerated .Noadverse effects SBP< 140 Dose need not be adjusted <60 years, DBP -90mmHg Initiate treatment 18 years with CKD Initiate treatment –SBP<140mmHg and DBP<90mmHg 18years with DM Initiate treatment –SBP<140mmHg and DBP<90mmHg
    71. 71. nonblack population, including those with diabetes thiazide-type diuretic, CCB ACEI/angiotensin receptor blocker black population with/ out DM thiazide-type diuretic or CCB aged18 years with CKD ACEI or ARB
    72. 72.  Maintain goal BP.  Not achieved- increase the dose of the initial drug or add thiazide- type diuretic,CCB,ACEI, or ARB.  Should continue to assess BP  Not achieved with 2, add and titrate a third drug  Do not use an ACEI and ARB together in the same patient.  Not achieved - other classes can be used.  Referral to a hypertension specialist- GOAL not achieved/CKD/DM/HF
    73. 73. 2014 Hypertension Guideline  Critical question and review criteria defined by expert panel with input from methodology team  Initial systematic review by methodologists restricted to RCT evidence
    74. 74. 2014 Hypertension Guideline  Definition of hypertension and prehyerptension not addressed, but thresholds for pharmalogic treatment were defined  Similar treatment goals defined for all hypertensive populations except when evidence review supports different goals for a particular population  Lifestyle modifications recommended
    75. 75. 2014 Hypertension Guideline  Recommended selection among 4 specific medication classes (ACEI or ARB, CCB or diuretics) and doses based on RCT evidence  Recommended specific medication classes based on evidence review for racial, CKD, and diabetic subgroups  Panel created a table of drugs and doses used in the outcome trials