ANTIHYPERTENSIVE THERAPY-market review 2013

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Basics of hypertension and available treatment.
Overview of mechanism of action, risks/benefits of various classes of drugs.
Prevalent prescription trends and future market review.

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  • High blood pressure is the biggest risk factor for CV disease.The global burden of hypertension is enormous. This was shown by a study that quantified the global burden of disease in 2001. The authors confirmed that high blood pressure, measured as systolic blood pressure greater than 115mmHg, is the largest CV risk factor worldwide. High blood pressure (BP) is responsible for 7.6 million premature deaths, which is 13.5% of the global total. About 54% of stroke and 47% of ischaemic heart disease worldwide are attributable to high blood pressure. Half of this burden is in people with clinical hypertension with the remainder being in those with lesser degrees of high blood pressure, making any increase in blood pressure of concern for patients. Patients between the ages of 45–69 years are responsible for half the burden of high blood pressure.1Hypertension is responsible for more deaths than any other single risk factor.2ReferencesLawes CM, et al. Global burden of blood-pressure-related disease, 2001. Lancet 2008;371:15131518. Lopez AD, et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006;367:1747–1757
  • High blood pressure is the biggest risk factor for CV morbidity and mortality.This figure depicts the number of deaths (right) or burden of disease, measured disability-adjusted life years (DALYs, left), with the size of each circle being proportional to the respective figure for people aged 30 years. Clearly, high blood pressure is the largest single contributing factor in both cardiovascular morbidity and mortality. Obesity affects non-cardiovascular diseases, including diabetes, endometrial and colon cancers, post-menopausal breast cancer, and osteoarthritis, shown as the portions of yellow circles that fall outside the cardiovascular disease circle. The mortality estimates exclude osteoarthritis, which results in morbidity but not direct deaths. Disease burden does include nonfatal health outcomes associated with diabetes and osteoarthritis (hence the larger size of the circle for obesity relative to those for blood pressure and cholesterol).1Globally, hypertension remains the most common risk factor for cardiovascular morbidity and mortality.1Despite massive and costly efforts to identify and treat hypertension, many patients do not have their blood pressure controlled, and even those whose blood pressure is controlled to established guidelines remain at risk of strokes and heart attacks.2ReferencesEzzati M, et al. Rethinking the “diseases of affluence” paradigm: global patterns of nutritional risks in relation to economic development. PloS Med 2005;2:e133.Kaplan NM, Opie, LH. Controversies in hypertension. Lancet 2006;367:168–176.
  • High blood pressure is a major CV risk factor in all world regions.1High blood pressure accounts for more than one-third of deaths and almost one-fifth of DALYs in Europe and central Asia.1The burden attributable to high blood pressure is greatest for stroke and ischaemic heart disease, and over 80% of this burden can be seen in low-income and middle-income regions.1While the blood-pressure-related attributable burden for deaths and DALYs is greatest in Europe and central Asia and lowest in sub-Saharan Africa, the effect of blood-pressure-related burden is still large in all economies. About 18% of all deaths and 9% of all DALYs were attributable to high blood pressure in high-income regions, and 13% and 6% in low-income or middle-income regions.1ReferenceLawes CM, et al. Global burden of blood-pressure-related disease, 2001. Lancet 2008;371:15131518.
  • Even when treated, blood pressure is often not controlled.Hypertension is poorly controlled, even in western industrialised societies, as revealed in a survey of studies on hypertension treatment and control.1Many patients, especially in Europe, are not even aware that they have hypertension. Age-adjusted awareness of hypertension was less than 70% worldwide and less than 50% in Europe.1Many patients were not treated even when they had been diagnosed  53% of those diagnosed in the US and ≤ 32% of those diagnosed in Europe are even treated for hypertension.1When considering hypertension control in the population as a whole (column labelled ‘Controlled’ in figure above), fewer than 30% of patients had their blood pressure reduced to recommended levels (<140/90 mmHg) worldwide, whereas only 510% of patients in Europe had their blood pressure controlled.1In those patients being treated for hypertension, 55% in the US, 47% in Canada and 1940% in Europe had their blood pressure controlled to recommended levels (<140/90 mmHg). Low treatment and control rates in Europe, combined with a higher prevalence of hypertension, could contribute to a higher CV risk compared with that in North America.1ReferenceWolf-Maier K, et al. Hypertension Treatment and Control in Five European Countries, Canada, and the United States. Hypertension 2004;43:10–17.
  • If hypertension is left uncontrolled, patients are at a higher risk for CV death. A meta-analysis of individual data from 1 million adults without previous vascular disease from 61 prospective observational studies of BP and mortality addressed the cause-specific death rate during a 10-year period among people who were initially aged 40, 50, 60, 70, or 80 years. The findings indicated that the risk for CV mortality doubles with each 20/10 mmHg increase in BP.1The rise in CV mortality was directly related to higher initial BP in every group.1With a 20 mmHg higher systolic BP (SBP) or a 10 mmHg higher diastolic BP (DBP), mortality from ischaemic heart disease was 2-fold higher, and mortality from stroke was greater than 2-fold higher.1These results indicate that both SBP and DBP were strongly related to vascular mortality in middle and old age.ReferenceLewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:19031913.
  • The threshold for hypertension must be considered flexible, being higher or lower based on the total cardiovascular risk of each individual.Patients can be classed according to their approximate absolute 10-year risk of cardiovascular disease as low (15%), moderate (15–20%), high (20–30%) or very high (30%) based on Framingham criteria, or an approximate absolute risk of fatal cardiovascular disease as low (4%), medium (4–5%), high (5–8%) or very high (8%), based on the SCORE chart.1An Expert Committee appointed by the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) prepared these guidelines, and they have been endorsed by the International Society of Hypertension (ISH).1ReferenceEuropean Society of Hypertension – European Society of Cardiology. 2007 guidelines for the management of arterial hypertension. J Hypertens 2007;25:1105–1187.
  • All four advisory bodies are in agreement that BP should be maintained below 140/90 mmHg. Further lowering is beneficial.14BP should be lowered below 130/80 mmHg in some cases:Diabetic and renal patients14Post-stroke and post-MI patients, according to ESH-ESC 2007 guidelines.1Patients with cardiovascular disease, according to WHO-ISH and BHS IV 2006.3,4Clearly, all four sets of guidelines are giving very similar advice. Of course, this is just advice and the physician must make individual clinical decisions based on each particular patient’s symptoms and history.ReferencesEuropean Society of Hypertension – European Society of Cardiology. 2007 guidelines for the management of arterial hypertension. J Hypertens 2007;25:1105–1187.Chobanian AV, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003;289:2560–2572. Whitworth JA. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003;21(11):19831992.Williams B, et al. The BHS Guidelines Working Party Guidelines for Management of Hypertension: Report of the Fourth Working Party of the British Hypertension Society, 2004 - BHS IV. J Hum Hypertens 2004;18:139185.
  • ReferenceChobanian AV, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003;289:2560–2572.
  • Although diuretics are the drugs of choice for uncomplicated hypertension, the presence of ‘compelling indications’ can dictate the initial use of other drug classes.1This is a section of the full treatment algorithm, focussing on the choice of antihypertensive class.1The JNC 7 guidelines recommend lifestyle modifications as an intervention in all patients.1Patients with stage 2 hypertension (SBP/DBP ≥160/≥100 mmHg) should receive initial therapy with combination treatment.1ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; CCB, calcium channel blocker. ReferenceChobanian AV, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003;289:2560–2572.
  • Regardless of the drug employed, monotherapy only achieves the target BP in a limited number of hypertensive patients.1Use of one or more antihypertensive agent is usually necessary to achieve the target BP in the majority of patients.1A wide range of agents exist that are effective and well tolerated. This is a section of the full ESH-ESC treatment algorithm, focussing on the choice of antihypertensive class.1ReferenceEuropean Society of Hypertension – European Society of Cardiology. 2007 guidelines for the management of arterial hypertension. J Hypertens 2007;25:1105–1187.
  • The renin-angiotensin-system has been recognized as the key player in blood pressure control via the modulation of these two important routes.The renin–angiotensin system (RAS) is a physiological sequence controlled by hormone release that is activated when renal blood pressure is altered.The sequence is as follows:1Renin is secreted by the juxtaglomerular cells within the kidney when blood pressure falls. The enzymatic action of renin hydrolyses angiotensinogen circulating in the bloodstream, forming angiotensin I.Angiotensin-converting enzyme (ACE) generates angiotensin II from angiotensin I.Angiotensin II causes vasoconstriction by acting on the smooth muscles of arterioles, thus increasing blood pressure. Angiotensin II also triggers the release of the aldosterone from the adrenal glands.Aldosterone released from the adrenal glands and ADH from the pituitary gland stimulate the kidneys to reabsorb sodium and fluid into the blood, thereby increasing blood volume and, hence, blood pressure.All major successful classes of antihypertensive drugs work primarily through the RAS (beta-blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers) or are closely related to the system (diuretics and calcium channel blockers both activate the renin system).Reference:Brown. Renin: friend or foe? Heart 2007;93:1026–33
  • The RAS is involved in the regulation of blood pressure and blood volume, and is the site of action of ACE inhibitors and ARBs.The RAS system helps to regulate long-term BP and blood volume in the body by production of aldosterone, a corticosteroid that regulates electrolyte balance. Renin, an aspartyl protease, is produced in the kidneys and released into the plasma in response to a drop in BP or volume. It catalyses the conversion of an inactive peptide angiotensinogen to angiotensin I. Angiotensin I is converted to its active form, angiotensin II, by the ACE. ACE also has an important role in the breakdown of bradykinin, a potent vasodilator.3Angiotensin I can be converted to angiotensin II by other pathways with enzymes such as chymase that do not involve ACETwo subtypes of angiotensin II cellular receptors have been well characterised: angiotensin II type 1 (AT1) and type 2 (AT2). The AT1 mediates all the known actions of angiotensin II on BP control.1 Less is known about the functions of the AT2 receptor. It is known to inhibit cell proliferation and reverse AT1 receptor-induced hypertrophy and is thought to modulate neuroplasticity, vascular regeneration and apoptosis.1,2 ACE inhibitionACE inhibitors inhibit the action of ACE and hence there is no production of angiotensin II from angiotensin I, which leads to decreased systemic arteriolar resistance and decreased diastolic and systolic BP. Increased concentrations of the vasodilator bradykinin occur because its degradation is also inhibited. Although the actions of bradykinin may contribute to the positive haemodynamic effects seen with ACE inhibitors, it may also be responsible for some of the adverse effects such as dry cough, hypotension and angio-oedema.5 Other pathways – e.g. chymase – continue to produce angiotensin II, which can lead to a gradual return of angiotensin levels to baseline, a phenomenon termed ‘angiotensin II escape’.6Selective AT-1 receptor blockadeAlthough ACE inhibitors block RAS at the enzymatic level, ARBs specifically inhibit the RAS at the receptor site. AT1 receptor blockers induce a dose-dependent blockade of angiotensin II-induced effects, resulting in a reduction in BP, cardiac and vascular hypertrophy, proteinuria and glomerular sclerosis. ARBs may provide end-organ protection by blocking angiotensin II via the AT1 receptor, while leaving the AT2 receptor unopposed. The AT2 receptor, present only at low levels in adult tissues, are currently being debated. The AT2 receptor is thought to exert opposing effects on the AT1 receptor and, therefore, there are beneficial effects in the CV system8 and tissue-protective effects beyond the effects on blood pressure. ReferencesCrowley SD, et al. AT(1) receptors and control of blood pressure: the kidney and more. Trends Cardiovasc Med 2007;17:30–34.Gendron L, et al. The angiotensin type 2 receptor of angiotensin II and neuronal differentiation: from observations to mechanisms. J Mol Endocrinol 2003;31:359–372.Gainer JV, et al.Effect of bradykinin-receptorblockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998;339:1285–1292.Hurairah H & Ferro A. The role of the endothelium in the control of vascular function. Int J ClinPract 2004;58:173–183.Chen R, et al. Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. Hypertension 2003;42:542–547.Hanon S, et al. Persistent formation of angiotensin II despite treatment with maximally recommended doses of angiotensin converting enzyme inhibitors in patients with chronic heart failure. J Renin Angiotensin AldosteroneSyst 2000;1:147–150. Doggrell SA.Angiotensin AT-1 receptorantagonism: complementary or alternative to ACE inhibition in cardiovascular and renaldisease? Expert Opin Pharmacother 2002;11:1543–1556.Steckelings UM, et al. The AT2 receptor – matter of love and hate. Peptides 2005;26:1401–1409.
  • BP control is much more likely when patients take their medication.This retrospective review of medical and pharmacy claims over a 4-year period (1999–2002) from 13 US health plans showed that patients were more likely to achieve BP control (defined according to JNC VI guidelines, i.e. <140/90 mmHg or <130/85 mmHg in patients with diabetes) if they had high levels of medication adherence measured using the medication possession ratio (MPR).1The MPR was used to classify patients into three adherence levels: high (80–100%; n = 629), medium (50–79%; n = 165), and low (<50%; n = 46).Highly adherent patients were 45% more likely to achieve BP control than those with medium or low adherence after controlling for age, gender and co-morbidities (odds ratio = 1.45; p=0.026).1ReferenceBramley TJ, et al. Relationship of blood pressure control to adherence with antihypertensive monotherapy in 13 managed care organizations. J Manag Care Pharm 2006;12:239–245.
  • Treatment discontinuation has important clinical implications as it may be a major determinant of poor BP control.A large cohort study in Lombardia, Italy, assessed the rates and determinants of treatment discontinuation or switching of initial antihypertensive drug therapy in 445,356 subjects aged 40–80 years.1The figure shows the cause-specific hazard ratio for discontinuation using treatment with ACE inhibitors as the reference. The discontinuation rate was lower in patients initially treated with ARBs and higher in patients treated with all other drug classes.1Discontinuation of the initial single antihypertensive drug treatment was found to be common (cumulative incidence of discontinuation being 33% at 6 months, 41% at 1 year, and 50% at 5 years).1Switching to another monotherapy occurred at lower rates (15%, 17% and 19% at 6 months, 1 year, and 5 years, respectively), as did switching a combination therapy (14%, 18% and 25% at 6 months, 1 year, and 5 years, respectively).1Treatment discontinuation rates differed between treatments with different antihypertensive drug classes, the best stay-on treatment rate was observed with blockers of the renin-angiotensin system (RAS).1The maximum discontinuation rates occurred with the initial use of diuretics and β-blockers monotherapy.1ReferenceCorrao G, et al. Discontinuation of and changes in drug therapy for hypertension among newly-treated patients: a population-based study in Italy.J Hypertens 2008;26:819–824
  • In the vast majority of hypertensive patients, effective BP control can only be achieved by combination of at least two antihypertensive drugs.1In several recent antihypertensive trials, combination therapy was allowed in order to achieve blood pressure goals.2,3 These trials are show in this slide, along with the average in-trial SBP achieved.The average number of medications required by patients in the trial is also shown. It is evident that the widespread use of combination therapy was needed to achieve blood pressure goals.Reference:European Society of Hypertension – European Society of Cardiology. 2007 guidelines for the management of arterial hypertension. J Hypertens 2007;25:1105–1187.Bakris et al. The importance of blood pressure control in the patient with diabetes. Am J Med 2004;116(5A):30S–8 Dahlöf et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.Lancet 2005;366:895–906
  • The 2007 ESH/ESC guidelines recommended several two-drug combinations as suitable for clinical use.1However, since those guidelines new clinical trial evidence has shown that the reduction of cardiovascular events is particularly effective with the combination of a diuretic with an ACE inhibitor or an angiotensin receptor antagonist or a calcium antagonist, and for the ACE inhibitor/calcium antagonist combination.2The 2009 reappraisal of the guidelines also states that angiotensin receptor antagonist/calcium antagonist combination also appears to be rational and effective. These combinations can thus be recommended for priority use.Although there is evidence that a combination of beta-blocker and diuretic also improves outcomes, this combination increase the risk of developing diabetes and should be avoided, unless required for other reasons, in predisposed patients.Reference:European Society of Hypertension – European Society of Cardiology. 2007 guidelines for the management of arterial hypertension. J Hypertens 2007;25:1105–1187.Manchia et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009; 27: 2121-58
  • Reference:1. Philip A Carpino*1 & Declan Flynn2, Review of companies and drug classes in the 2007–2011 antihypertensive patent literature, Pharm. Pat. Analyst (2012) 1(1), 45–64 .
  • 1. International Society of Hypertension, World Hypertension, and Three New Classes of Antihypertensive Drugs. Medscape. Jun 26, 2008.
  • Reference :1. http://www.gbiresearch.com/Report.aspx?ID=Antihypertensives-Market-to-2016-Generic-Erosion-Following-Patent-Expiry-of-Major-ARBs-to-Impact-the-Market&ReportType=Industry_Report&Title=Pharmaceuticals_and_Healthcare
  • Reference :1. http://www.gbiresearch.com/Report.aspx?ID=Antihypertensives-Market-to-2016-Generic-Erosion-Following-Patent-Expiry-of-Major-ARBs-to-Impact-the-Market&ReportType=Industry_Report&Title=Pharmaceuticals_and_Healthcare
  • ANTIHYPERTENSIVE THERAPY-market review 2013

    1. 1. CURRENT TRENDS IN HYPERTENSION THERAPY Presented By POOJA SHARMA (M. Pharm Pharmacology)
    2. 2. Disease overview • Hypertension (HTN) or high blood pressure, sometimes called arterial hypertension, is a chronic medical condition in which the blood pressure in the arteries is elevated. • This requires the heart to work harder than normal to circulate blood through the blood vessels.
    3. 3. The Truth is It is only a marker of the bigger problem Hypertension is a multi-organ systemic disease What we record as B.P. The Problem is Hypertension is asymptomatic in 85% of cases
    4. 4. What three factors contribute to blood pressure?
    5. 5. Epidemiology
    6. 6. Hypertension: the world’s number 1 CV risk factor • 7.6 million premature deaths worldwide • 13.5% of global total deaths • Causes more deaths than any other risk factor, including smoking or high cholesterol
    7. 7. Hypertension is the most powerful risk factor for cardiovascular morbidity and mortality Global burden of disease 16 million 7–8 million 4–3 million 2–3 million Global mortality 128 million 59 million 39 million 30 million All cardiovascular High BP High cholesterol Overweight and obesity Ezzati et al. PloS Med 2005;2:e133
    8. 8. Hypertension is a leading cause of death and disability in all regions Region Death Disability* East Asia & Pacific 13.6% 6.5% Europe & Central Asia 35.0% 19.6% Latin America & The Caribbean 13.0% 5.1% Middle East & North Africa 16.5% 6.1% South Asia 9.6% 4.3% Sub-Saharan Africa 4.0% 1.7% Low-/ middle-income economies 12.9% 5.6% High-income economies 17.6% 9.3% World 13.5% 6.0% Lawes et al. Lancet 2008;371:1513–8
    9. 9. BP is often not controlled, even when treated 0 10 20 30 40 50 60 70 80 Aware Treated Controlled USA Canada Italy Sweden Spain England Germany Wolf-Maier et al. Hypertension 2004;43:10–17 * Threshold of SBP/DBP 140/90 mm Hg
    10. 10. Each 20/10 mm Hg BP increase doubles the risk of CV mortality 1-fold 2-fold 4-fold 8-fold 0 2 4 6 8 10 SBP/DBP, mm Hg * Individuals aged 40–69 years (N = 1 million). Lewington S, et al. Lancet. 2002;360:1903–1913.
    11. 11. Hypertension adds to other CV risk factors Other risk factors SBP 120–129 DBP 80–84 SBP 130–139 DBP 85–89 SBP 140–159 DBP 90–99 SBP 160–179 DBP 100–109 SBP ≥180 DBP ≥110 None Average risk Average risk Low added risk Moderate added risk High added risk 1−2 Low added risk Low added risk Moderate added risk Moderate added risk Very high added risk ≥3, OD, MS or diabetes Moderate added risk High added risk High added risk High added risk Very high added risk CV or renal disease Very high added risk Very high added risk Very high added risk Very high added risk Very high added risk MS, metabolic syndrome; OD, subclinical organ damage ESH–ESC Guidelines. J Hypertens 2007;25:1105–1187
    12. 12. Treatment goals and algorithms
    13. 13. Treatment Goal The Truth is Keep B.P. < 140/90 mm Hg in each patient This may be revised to 120/80 may be ? 110/70 It is essential to keep the B.P at or below the goal But, It also matters how the goal B.P. is achieved ! Goal BP
    14. 14. Current BP targets according to guidelines JNC VII 2003 ESH-ESC 2007 WHO-ISH BHS IV 2006 <140/90* <140/90 SBP <140 <140/90 <130/80 <130/80 <130/80 According to national guidelines DM renal DM renal post stroke post MI DM renal CVD DM renal CVD * Lower if tolerated
    15. 15. Blood Pressure Classification Seventh Joint USA National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure -JNC 7, JAMA, May 21, 2003, and USA Government Printing Office publication.
    16. 16. Hypertension treatment algorithm (JNC 7)
    17. 17. Hypertension treatment algorithm (ESH 2007) Choose between Low-dose 2-drug combinationLow-dose single agent Not at BP goal Full dose of single agent Switch to different agent at low dose Full dose of 2-drug combination Add a third drug at low dose Not at BP goal2–3 drug combination at full dose Full doses of 2–3-drug combination Full-dose single agent Marked BP elevation High/very high CV risk Lower BP target Mild BP elevation Low/moderate CV risk Conventional BP target ESH–ESC Guidelines. J Hypertens 2007;25:1105–1187
    18. 18. Approaching Hypertension Pharmacologic treatment
    19. 19. Enalapril Lisinopril Ramipril Quinapril Perindopril Hypertension The Many Faces of HT Therapy Today
    20. 20. • Guidelines on the choice of agents and how best to step up treatment for various subgroups have changed over time and differ between countries. • The best first line agent is disputed. The Cochrane collaboration, WHO and the US guidelines supports low dose thiazide-based diuretic as first line treatment. • The UK guidelines emphasize calcium channel blockers in preference for people over the age of 55 years or if of African or Caribbean family origin, with angiotensin converting enzyme inhibitors used first line for younger people. In Japan starting with any one of six classes of medications including: CCB, ACEI/ARB, thiazide diuretics, beta-blockers, and alpha-blockers is deemed reasonable while in Canada all of these but alpha-blockers are recommended as options.
    21. 21. AGE Younger (< 55) High Renin HT Renin ACEi, Beta-blocker Ca++-blocker, Diuretic)(AB/CD = Dickerson et al. Lancet 353:2008-11;1999 Older (> 55) Low Renin HT ACEi BB A + B A + B + D DiureticCCB D + C + A D + C I II III III II I AB/CD Rule – HT Treatment
    22. 22. Each of the main classes of anti-hypertensive drugs affects the renin-angiotensin system Brown. Heart 2007;93:1026–33 Diuretic Calcium channel blocker ACE inhibitor Angiotensin receptor blocker Beta-blockers Kidney ACE Angiotensin I Angiotensin II AT1 receptor Arteries – vascular tone Na+ Renin Angiotensinogen ++ Renin Volume – – – –
    23. 23. Bradykinin/NO Inactive fragments Angiotensin I Angiotensin II ACEI and ARBs block the renin-angiotensin system (RAS) in different ways ARB ACE-independent ANG II formation by Chymase, etc. AT2 RECEPTOR Vasodilation Natriuresis Tissue regeneration Inhibition of inappropriate cell growth Differentiation Anti-inflammation Apoptosis ACEACE Inhibitor AT1 RECEPTOR Vasoconstriction Sodium retention SNS activation Inflammation Growth-promoting effects Aldosterone Apoptosis SNS = sympathetic nervous system Hanon S, et al. J Renin Angiotensin Aldosterone Syst 2000;1:147–150; Chen R, et al. Hypertension 2003;42:542–547; Hurairah H, et al. Int J Clin Pract 2004;58:173–183; Steckelings UM, et al. Peptides 2005;26:1401–1409
    24. 24. DIURETICS First and Best Choice Can be combined with A, B, C βBlockers Good third Choice Can be combined with A, D Ca channel Blockers Fourth Choice, Useful Can be combined with D, A ACEI and ARB Second Best Choice Can be combined with D, B, C D Diuretics A ACEI, ARB B β-Blockers C Ca-Blockers D A B C The A B C D classes
    25. 25. KNOW ME WELL I am ‘D’ for DIURETIC  My Good aspects Fluid depletion, Na washout, Low cost Improve CHF, Systolic function, Ca saving Reduce LVH, Morbidity & Mortality  My Bad aspects Potassium washout, ↑ in Uric acid, ↑ Ca Adverse on Lipids, Glucose control  Don’t use me in Gout, Hypokalaemia Dyslipedemia, Uncontrolled DM DIURETIC
    26. 26. Diuretics help the kidneys eliminate excess salt and water from the body's tissues and blood. Loop diuretics: Bumetanide, ethacrynic acid, furosemide, torsemide. Thiazide diuretics: Epitizide, hydrochlorothiazide, chlorothiazide, bendroflumethiazide Thiazide-like diuretics: Indapamide, chlorthalidone, metolazone. Potassium-sparing diuretics: Amiloride, triamterene, spironolactone Only the thiazide and thiazide-like diuretics have good evidence of beneficial effects on important endpoints of hypertension, and hence, should usually be the first choice when selecting a diuretic to treat hypertension. The reason why thiazide-type diuretics are better than the others is (at least in part) thought to be because of their vasodilating properties.
    27. 27. KNOW ME WELL I am ‘A’ for ACEI and ARB  My Good aspects Improve Diastolic function, Systolic function Control Proteinuria, Very favourable in DM Improve Coronary Ischemia, Good on Lipids Reduce LVH, Morbidity & Mortality  My Bad aspects Bradykinin accumulation, Angio-edema ↑ Serum K , ↓ GFR  Don’t use me in Pregnancy, Creatinine is > 3 mg%, ↑ K 5.0 meq Bilateral Renal Artery Stenosis, Angio-edema
    28. 28. ACE inhibitors can be divided into three groups based on their molecular structure: Sulfhydryl-containing agents Captopril , the first ACE inhibitor Zofenopril Dicarboxylate-containing agents This is the largest group, including: Enalapril Ramipril Quinapril Perindopril Lisinopril Benazepril Imidapril Zofenopril Trandolapril Phosphonate-containing agents Fosinopril is the only member of this group
    29. 29. Angiotensin II receptor antagonists Pressor inhibition at trough level - this relates to the degree of blockade or inhibition of the blood pressure-raising effect of angiotensin II. However, pressor inhibition is not a measure of blood pressure- lowering (BP) efficacy per se. The rates as listed in the US FDA Package Inserts (PIs) for inhibition of this effect at the 24th hour for the ARBs are as follows: (all doses listed in PI are included) Valsartan 80 mg 30% Telmisartan 80 mg 40% Losartan 100 mg 25–40% Irbesartan 150 mg 40% Irbesartan 300 mg 60% Azilsartan 32 mg 60% Olmesartan 20 mg 61% Olmesartan 40 mg 74%
    30. 30. I am ‘B’ for βBlocker  My Good aspects ↓Heart rate, ↓Force of contraction, ↓Conduction ↓Myocardial O2 demand, Improve Ischemia Improve QUALY in CHD, Useful in CHF, Migraine  My Bad aspects Constrict peripheral vessels, Bradycardia Unfavourable on Lipids, Glucose  Don’t use me in Bradycardia, Conduction defects, Caution in CHF Prinzmetal Angina, MSD, PVD, BA, COPD, Dys lipid Pheochromocytoma, Chronic smokers β Blocker KNOW ME WELL
    31. 31. Nonselective agents Alprenolol, Bucindolol, Carteolol, Carvedilol (has additional α- blocking activity) Labetalol (has additional α-blocking activity), Nadolol, Oxprenolol (has intrinsic sympathomimetic activity), Penbutolol (has intrinsic sympathomimetic activity) β1-selective agents Also known as cardioselective Betaxolol, Bisoprolol, Celiprolol, Esmolol, Metoprolol, Nebivolol (also increases nitric oxide release for vasodilation) β2-selective agents Butaxamine (weak α-adrenergic agonist activity): No common clinical applications, but used in experiments. ICI-118,551: Highly selective β2-adrenergic receptor antagonist—no known clinical applications, but used in experiments due to its strong receptor specificity. β3-selective agents SR 59230A (has additional α-blocking activity): Used in experiments.
    32. 32. KNOW ME WELL I am ‘C’ for Ca channel Blocker  My Good aspects Vasodilatory, Suitable in elderly, Low cost Anti arrhythmic (Verapamil), ↑Coronary BF (Diltz) Neutral on lipidemia, Vasospastic Angina  My Bad aspects Fluid retention, Impair failing heart Adverse on Glucose control.  Don’t use me in Tachycardia, arrhythmias, CHF, Uncontrolled DM, Volume overload
    33. 33. • Dihydropyridine CCBs are often used to reduce systemic vascular resistance and arterial pressure, but are not used to treat angina because the vasodilation and hypotension can lead to reflex tachycardia. Amlodipine, Aranidipine, Azelnidipine, Barnidipine, Benidipine, Cilnidipine, Clevidipine, Isradipine, Efonidipine, Felodipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Manidipine, Nicardipine,Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine. • Phenylalkylamine CCBs are relatively selective for myocardium, reduce myocardial oxygen demand and reverse coronary vasospasm, and are often used to treat angina. Verapamil • Benzothiazepine CCBs by having both cardiac depressant and vasodilator actions, are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation. Diltiazem (Cardizem) • Nonselective mibefradil, bepridil, fluspirilene, and fendiline.
    34. 34. RENIN INHIBITORS • These drugs inhibit the first and rate-limiting step of the renin- angiotensinaldosterone system (RAAS), namely the conversion of angiotensinogen to angiotensin I. • Aliskiren is effective in lowering blood pressure, but as of 20 April 2012 the US Food and Drug Administration (FDA) issued a warning of possible risks when using aliskiren or blood pressure medicines containing aliskiren with ACE inhibitors and angiotensin receptor blockers (ARBs) in patients with diabetes or kidney (renal) impairment. They advised that such drug combinations should not be used in patients with diabetes because of the risk of causing renal impairment, hypotension, and hyperkalemia and that aliskiren should not be used with ARBs or ACE inhibitors in patients with moderate to severe renal impairment. However, they also recommend that patients should not stop taking aliskiren without talking to a healthcare professional. • Aliskiren in combination with hydrochlorothiazide was approved by the FDA in 2008
    35. 35. The importance of treatment adherence
    36. 36. Patients who are adherent are more likely to attain BP control Controlled BP (%) * <140/90 mmHg or <130/85 mmHg for patients with diabetes Bramley et al. J Manag Care Pharm 2006;12:239–45 0 5 10 15 20 25 30 35 40 45 50 Low (<50%) Medium (50-79%) High (>=80%) 45% greater probability of control Adherence (n = 165)(n = 46) (n = 629)
    37. 37. Treatment adherence is highest with ARBs ARB, angiotensin II receptor blocker; CI, confidence interval * Relative to ACE inhibitors after 1 year of treatment Corrrao et al. J Hypertens 2008;26:819-24. 0.5 1.0 2.0 Diuretics β-blockers α-blockers Calcium channel blockers ACE inhibitors ARBs 1.83 1.64 1.23 1.08 1.00 0.92 - + Cause-specific hazard ratio (95% CI) for discontinuation* Total n = 445,356
    38. 38. Persistence with hypertensive therapy
    39. 39. Monotherapy or combination treatment for hypertension
    40. 40. • Antihypertensive monotherapy is effective in only about 40-60% of hypertensive patients, irrespective of the category of the agent that is used. • Most of the responders are Stage I hypertensives. Therefore, there is frequently a need for the use of two medications with different mechanisms of action. • Should therapy be started with two drugs or a combination? Monotherapy
    41. 41. Average no. of antihypertensive medications 1 2 3 4 Trial (SBP achieved) ASCOT-BPLA (136.9 mmHg) ALLHAT (138 mmHg) IDNT (138 mmHg) RENAAL (141 mmHg) UKPDS (144 mmHg) ABCD (132 mmHg) MDRD (132 mmHg) HOT (138 mmHg) AASK (128 mmHg) The majority of hypertensive patients need combination therapy to achieve their BP target (SBP) Bakris et al. Am J Med 2004;116(5A):30S–8 Dahlöf et al. Lancet 2005;366:895–906
    42. 42. Hypertension – Why Combinations ?  If goal BP is not achieved by a single drug in full dose  Then adding another agent will help achieve the goal BP  Two agents sometimes nullify each others side effects  Fixed dose combinations will reduce the no. of tablets  Once daily formulations are good for compliance  Sustained release or Long Acting formulations for 24 h BP control  If three drugs can’t achieve goal BP – Resistant HT
    43. 43. Diuretics β-blockers α-blockers ACEi CCB ARB Adapted from Mancia et al. J Hypertens 2007;25:1105–87 Manchia et al J Hypertens 2009; 27: 2121-58 Diuretics ACEi CCB ARBONTARGET ACCOMPLISH HYVET 2007 2009 ESH-ESC treatment recommendations
    44. 44. Drug Combinations
    45. 45. Hypertension – Rational Drug Combinations ACEI and ARB = A Beta Blockers = B Calcium Channel (CCB) = C Diuretics Drugs= D D and A combination is excellent - Ramace H, Losar H, Enace D D and B combination second - Betaloc H, Atecard D, Tenoric D and C combination sixth - Amlogaurd H, Stamlo D A and B combination Third - Losar A, Cardif Beta A and C combination fourth - Amlopres L, Hipril A, Amlo LS B and C combination fifth - Amlo AT, Amlobet, Beta Nicardia Diuretics = D – Rank 1 ACEI and ARB = A – Rank 2 Beta Blockers = B – Rank 3 CCB = C – Rank 4
    46. 46. Some Irrational Combinations Beta blockers + Beta1 stimulants - Rebound HT, Paradoxical BP ↑ Beta blockers + Vepapamil - Extreme bradycardia, HB, CHF Thiazide + Furesemide - Potential volume ↓ and K ↓ CCB + Thiazide- No RCTs to support the additive Prazocin + Beta blocker - They nullify the effects of each other Verapamil / Dilzem + Nefidepine -No rationale (cardiac actions contridic) Beta blocker + ACEI Not for HT alone, Good for CHF, MI, IHD Sub clinical doses of two drugs Try one drug in good dosage, then add Two drugs of same class - No rationale (like Enalapril + Ramipril) (Atenelol + Metoprolol, Nefidepine + Amlo)
    47. 47. Incidence of New Onset Diabetes with Various Medications. How significant is it?
    48. 48. Risk of Hyperglycemia with Use of Antihypertensive Drugs Thiazide Central antiadrenergic agents Peripheral antiadrenergic agents ACE inhibitors B-Blockers Calcium channel blockers Vasodilators >1 Agent without thiazide >1 Agent with thiazide 0.5 1 1.5 2 2.5 3 Decreased Risk Increased Risk Adjusted ORs and 95% CI Gurwitz J H. Arch Intern Med 1993;118:273-278 Decreased Risk Increased Risk
    49. 49. Ongoing trends Review of companies and drug classes in the 2007–2011 antihypertensive patent literature
    50. 50. Future treatment options
    51. 51. Orally Active Aminopeptidase A Inhibitor -- a Prototype for a New Antihypertensive Drug Class • RB150, an orally active prodrug that inhibits brain but not systemic renin-angiotensin system (RAS) activity, reducing blood pressure in an experimental animal model, is reported. • Previous research indicated that in the brain, conversion of Ang II to Ang III, which is catalyzed by aminopeptidase A (APA), is a necessary step in increasing blood pressure. They used specific and selective APA inhibitors to show that Ang III is one of the main effector peptides of the brain RAS , exerting tonic stimulatory control over BP in hypertensive rats. APA, therefore, is a potential therapeutic target for the treatment of hypertension.
    52. 52. Identification of Angiotensin-Converting Enzyme-2 Activators as Potential Antihypertensive Drugs • ACE 2, a homolog of ACE, is a key RAS enzyme involved in balancing the adverse effects of angiotensin II on the cardiovascular system. It is known to degrade angiotensin II (Ang II) to generate angiotension which has vasodilatory and antiproliferative effects. Blocking AngII with ACE inhibitors or angiotensin receptor blockers (ARBs) has been shown to increase cardiac ACE 2 expression. • Altered expression of ACE 2 is associated with cardiac, renal, and vascular dysfunction.
    53. 53. Slow-Releasing Hydrogen Sulfide Compound With Potential as Antihypertensive Therapy • Hydrogen sulfide (H2S) is known to have cardiovascular effects such as the ability to dilate human blood vessels and protect the heart against ischemia/perfusion injury, and it also plays a role in hypertension. • Researchers have identified a slow-releasing H2S compound that mimics the generation of H2S in vivo. • In addition, the blood pressure lowering effect of the compound is without affecting heart rate and without weight loss or other signs of toxicity, suggests that it, or a compound like it, may be of a therapeutic benefit in cardiovascular disease.
    54. 54. • The compound GYY4137 was found to release H2S slowly both in aqueous solution in vitro and after intravenous or intraperitoneal administration in anesthetized rats in vivo. • It caused a slow relaxation of precontracted rat aortic rings and dilated the perfused rat renal vasculature by opening vascular smooth muscle adenosine triphosphate-sensitive potassium (KATP) channels.
    55. 55. • Aliskiren is a novel, completely nonpeptide, orally active renin inhibitor that blocks the first and rate-limiting step of the renin-angiotensin system. • Alagebrium, an advanced glycation end product (AGE) crosslink breaker, has been shown to reduce SBP in patients with uncontrolled systolic hypertension. • Progestin drospirenone and 17 beta-estradiol (DRSP/E2), developed for postmenopausal hormone replacement therapy, has been shown to lower both clinic and ambulatory SBP in postmenopausal women .
    56. 56. Antihypertensives Market to 2016 - Generic Erosion Following Patent Expiry of Major ARBs to Impact the Market
    57. 57. The global market: overview, opportunities and threats
    58. 58. The Global Anti-Hypertensive Market is Set to Show Flat Growth in the near Future In 2009, the global anti-hypertensive market was estimated to be worth $27.2 billion, representing a Compound Annual Growth Rate (CAGR) of 5.0% between 2002 and 2009. The market is forecast to reach $30 billion by 2016, indicating a CAGR of 1.5% between 2009 and 2016. The primary reason for slight and gradual growth in the market is the patent expiries of major blockbusters, which are expected to decrease the annual cost of therapy after 2007. The global anti-hypertensive market is expected to witness a series of patent expiries between 2007 and 2015, which includes most of the top selling blockbuster drugs in the anti-hypertensive market. The major drugs that are set to lose patent protection include Novartis’s Diovan (2012), Sanofi Aventis’s Avapro (2012), Novartis’s Exforge (2012), Takeda/AstraZeneca’s Blopress/Atacand (2012), Pfizer’s Revatio (2012), Actelion’s Tracleer (2015), and United Therapeutics Remodulin (2014).
    59. 59. All these drugs together accounted for more than $19.4 billion in revenues in 2009. Merck’s Cozaar patent expired in April 2010. The sales of Cozaar for the year 2009 were $3.6 billion. Pfizer’s Norvasc, which was once the world’s most prescribed drug for hypertension and angina, saw a sales decline of 12% in 2009 due to genericization in 2007. Thus, the series of upcoming patent expiries in the hypertension as well as PAH markets are set to lead to a decline in the market in the near future. However, due to increased usage of fixed dose-combinations and the entry of generics, the market is expected to rise slightly after 2015. The current anti-hypertensive pipeline does offer some promising novel products, such as SPP635, Actos, LCZ696, QT1571, ACT- 293987, PS-433540, Macitentan and Riociguat, indicated for the treatment of hypertension and PAH. However, the revenues generated from these products are not expected to completely make up for the revenue losses due to patent expiries. Thus, the overall global anti-hypertensive market is expected to show flat growth during the forecast period.
    60. 60. Top Six Companies Control Approximately 74% of the Market The current global anti-hypertensive market is significantly consolidated as the top six players control approximately 74% of the market. Novartis is the current market leader with its blockbuster product, Diovan. It is available in more than 100 countries. It has recorded sales of six billion in 2009. Other major products in the anti-hypertensive market of Novartis are Exforge, Tekturna/Rasilez, Lotrel and Lescol, controlling 43% of the total anti-hypertensive market. Merck follows Novartis with a 19% market share, primarily due to its top selling ARB, Cozaar. The sales of Cozaar are set to decline in the future as the patent on Cozaar expired in April 2010. Pfizer occupies the third position with its blockbuster drug Norvasc. Pfizer also marks its presence in the PAH market with its Revatio. Norvasc went off-patent in the year 2007. It was one of the blockbuster drugs in the anti-hypertensive market until this date. Takeda is the fourth player in the anti-hypertensive market, with its blockbuster drug Blopress.
    61. 61. The sales of Blopress are set to increase in the coming years. Takeda is followed by Actelion and Sanofi Aventis. Actelion is the market leader in PAH with its blockbuster drugs, Tracleer and Ventavis. Actelion and Sanofi Aventis control 8% and 7% of the total market. However, the market shares of the total players are expected to witness changes in the near future due to upcoming patent expiries. Novartis’s Diovan and Tekturna/Rasilez are set to expire in 2012. Exforge is set to expire in 2010. Merck’s Cozaar went off-patent in the year 2010. Merck and Pfizer have been registering negative growth in recent years due to patent expiries. Novartis, Takeda and Actelion have shown positive growth.
    62. 62. • The growth rate of the antihypertensive market is declining. These changes reflect the challenges faced by pharmaceutical companies over the next decade, as brand erosion and healthcare reforms impact heavily. • The slow and declining growth rate does not reflect a stationary market, but the battle between the drugs that make up the market.
    63. 63. We are still evolving towards finding an Ideal Antihypertensive
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