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Dr Deepthi S VaggeDr Deepthi S Vagge
MD PharmacologyMD Pharmacology
BMCRIBMCRI
JNC 7 criteria for diagnosis of
HTN
BP classification Blood pressure levels
SBP mmHg DBP mmHg
Normal <120 and <80
Pre-hype...
Targets of drug action
Counter-regulatory mechanisms –fall in BP

 Drugs inhibiting RAAS
 Calcium channel blockers
 Diuretics
 Direct Vasodilators


Types of RAAS
vasoconstriction, cell growth in heart and
arteries
Aldosterone secretion
Reabsorption of Na
Enhances sympathetic activity...

Drugs inhibiting the RAAS
Direct renin inhibitors
Inhibit the RAS at its origin
 MOA: It binds the active site of renin to block conversion of
angiotensinogen to AI
ALISKIREN:
Effects of aliskiren
Comment Strength
of evidence
Conclusion
Aliskiren is
more
effective
than
ramipril
Low 1 RCT–842 pt. 26 weeks duration. Ali...
Comment Strength of
evidence
Conclusion
2.aliskiren Vs irbesartan. 8week. n=652 randomised to receive
aliskiren 150mg /irb...

ADVANTAGES:
 Efficacy greater than ACE inhi/ ARB, safety equal
 The long t1/2
 Most comprehensive inhibition of the R...

Current status:
 Used in combination with other drugs for further
blood pressure control
DIRECT RENIN INHIBITORS UNDER TRIAL:
DRUG TRIAL NO. of Pt INTERVENTIO
N
END POINTS RESULTS
SPP635
SPP1148
SPP800
A Phase I...

ACE INHIBITORS:

Sulfhydryl-containing
ACE inhibitors
Dicarboxyl-containing
ACE inhibitors
Phosphorus-
containing ACE
inhibitors
Captopri...
 
 lack of postural hypotension
 No tachycardia
 
 Safe in asthamatics, diabetes, PVD
  Reduce the incidence of T2DM ...
 No deleterious effect on plasma lipid profile, no hyperuricemia
 Delay development of diabetic glomerulopathy
 Reverse...

 Stage I HTN :first choice if thiazides are not being used
 Stage II HTN: in combination with thiazides
 Drug of choi...

 MC-4232 is a combination of MC-1 and lisinopril. 
 MC-1 is a naturally occurring small molecule, a metabolite of
vita...
ANGIOTENSIN RECEPTOR
BLOCKERS
 Losartan
 Candesartan
 Irbesartan
 Valsartan
 Telmisartan
 Eprosartan
 Olmesartan medoxomil

Similar to ACE , but with better tolerability profile
Complete inhibition of AII actions
Result in indirect AT 2 rece...

 Intolerance to ACEI therapy and as an important option in the
treatment of patients with concurrent disorders such as ...

 Azilsartan medoxomil is an angiotensin receptor
blocker, approved in 2011the US Food and Drug
 Prodrug
 Azilsartan -...

Trial No.of pt Intervention End points Results
Phase III
Double-blind,
randomized,
placebo-
controlled
trial-
azilsartan...

Trial No pt Intervention End points Results
Phase III
Double-blind,
randomized
trial -azilsartan
Vs valsartan
984
SBP
15...

Drugs under trial: LCZ696 (valsartan + AHU337 neprolysin
inhibitor)
Trial Pt Efficacy end
point
Intervention Result
Phas...

Trial Particip
ants
Interventions and
duration
Primary end
point
Results
Irbe PS
200
400 800 Place
bo
A phase II
Randomi...

Drug combinations Rationale
RAAS Inhibitor + a low-dose, thiazide Improves efficacy and side
effect profile
RAAS Inhibit...

ACEIs, ARBs, and Direct Renin Inhibitors
for Treating Essential Hypertension ?
Evidence on the comparative long-term ben...
Efficacy Strength of evidence Evidence
ACE in & ARBs
have similar long
term effects on BP
control
Aliskiren more
effective...
Reducing
mortality and
major
cardiovascular
events:
Strength of
evidence
Evidence
ACE inhi = ARBs
??
Low (ACEI vs.
ARBs )
...
Safety profile Strength of evidence Evidence
Incidence of cough is more
with ACE inhi compared to
ARBs
High
(ACEI vs. ARBs...

Calcium channel blockers
MOA:
DIHYDROPYRIDINES
 
SHORT ACTING
Nifedipine
Nicardipine
Nimodipine
 
INTERMEDIATE ACTING
Nisoldipine
Nitrendipine
I...
Advantages
More beneficial in elderly
 Safe in asthama, PVD
 Lipid profile, uric acid levels or glucose metabolism not ...

 Preferred in elderly hypertensives
 They have stroke prevention potential
 Next to ACE inhi in reducing albuminuria ...
 Clevidipine
Newer drugs
Trial No pt Intervention End points Results
ESCAPE-1
Phase III,
double-
blind,
randomized,
place...

Trial No pt Intervention End points Results
ESCAPE-2
Phase III,
double-blind,
randomized,
placebo-
controlled,
multi-cen...

Trial No pt Intervention End point results
VELOCITY
The phase III
prospective,
open-label,
single-arm
study -
clevidipin...
DIURETICS:

MOA :

Current status:
Thiazides Loop K+ sparing
First choice in
treatment of
essential HTN esp.
in elderly.
Overcoming
resista...
COMBINATION RATIONALE
Diuretic and a CCB results Side effect profile improved.
b-Blockers+ Diuretics Efficacy improved
Th...

DIRECT VASODILATORS:
ARTERIAL
VASODILATORS:
 Hydralazine
 Minoxidil
 Diazoxide
 Fenoldopam
ARTERIOLAR +VENOUS
VASODI...

Drugs MOA Role in HTN AE
Hydralazine Activate K channels
Generate NO &
stimulate cGMP
Moderate HTN not
controlled by bet...

Drugs MOA Role in HTN AE
Fenoldopam D1 receptor agonist—
dilation of peripheral
arteries and natriuresis
Hypertensive
em...

Thank you
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ANTI HYPERTENSIVE AGENTS [MEDICINAL CHEMISTRY] BY P.RAVISANKAR, HYPERTENSION,TYPES,CAUSES OF HYPERTENSION, CLASSIFICATION, MECHANISM OF ACTION, SAR, ACE INHIBITORS, ARB , DIURETICS(WATER PILLS), TIPS TO STOP SILENT KILLER.
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Recent advances in treatment of Hypertension -- Drugs inhibiting RAAS, Diuretics, Calcium channel blockers, Vasodilators

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Recent advances in treatment of Hypertension -- Drugs inhibiting RAAS, Diuretics, Calcium channel blockers, Vasodilators

  1. 1. Dr Deepthi S VaggeDr Deepthi S Vagge MD PharmacologyMD Pharmacology BMCRIBMCRI
  2. 2. JNC 7 criteria for diagnosis of HTN BP classification Blood pressure levels SBP mmHg DBP mmHg Normal <120 and <80 Pre-hypertension 120-139 Or 80-89 Hypertension -I 140-159 Or 90-99 Hypertension -II >/= 160 Or >/= 100
  3. 3. Targets of drug action Counter-regulatory mechanisms –fall in BP
  4. 4.   Drugs inhibiting RAAS  Calcium channel blockers  Diuretics  Direct Vasodilators
  5. 5.
  6. 6.  Types of RAAS
  7. 7. vasoconstriction, cell growth in heart and arteries Aldosterone secretion Reabsorption of Na Enhances sympathetic activity Vasodilation Antiproliferative promotes apoptosis fetal tissue development
  8. 8.  Drugs inhibiting the RAAS
  9. 9. Direct renin inhibitors Inhibit the RAS at its origin
  10. 10.  MOA: It binds the active site of renin to block conversion of angiotensinogen to AI ALISKIREN:
  11. 11. Effects of aliskiren
  12. 12. Comment Strength of evidence Conclusion Aliskiren is more effective than ramipril Low 1 RCT–842 pt. 26 weeks duration. Aliskiren 150mg /ramipril 5mg. Mean reductions in BP: Aliskiren 150mg -17.9/13.3 ramipril 5mg. -15.2/12. P<0.0001 Plasma renin concentration was increased in both groups , PRA was reduced in aliskiren . No SAE Aliskiren is as effective as ARB Low 2 RCTs compared aliskiren to ARB 1.aliskiren Vs losartan. 4 weeks, n=226. Randomized to losartan 100mg. aliskiren 150mg, aliskiren 300mg p=0.0002 Mean reduction in BP were losartan 100mg -11.4/-5.5; aliskiren 150mg --10/-5.7; aliskiren 300mg -11.8/-5.7 Efficacy and evidence
  13. 13. Comment Strength of evidence Conclusion 2.aliskiren Vs irbesartan. 8week. n=652 randomised to receive aliskiren 150mg /irbesartan 150mg Mean reduction in BP: aliskiren 150mg:-10.9/-9.4 irbesartan 150mg: -12.5/-9.1 p<0.0001 BP control rate was similar in all groups Aliskiren + valsartan more effective than either monotherapy Low 1 RCT Aliskiren +valsartan Vs aliskiren Vs valsartan 8week, n=1,797, randomized to either of the three groups Mean reduction in BP Aliskiren 300mg -13/9mmhg Valsartan 320mg: -12.9/-9.7 mmhg Aliskiren + valsartan: -17.2/ -12.2 mmhg P<0.0001
  14. 14.  ADVANTAGES:  Efficacy greater than ACE inhi/ ARB, safety equal  The long t1/2  Most comprehensive inhibition of the RAAS, reducing PRA, Ang I, Ang II, and aldosterone  No dose adjustment in elderly, liver or moderate renal impairement
  15. 15.  Current status:  Used in combination with other drugs for further blood pressure control
  16. 16. DIRECT RENIN INHIBITORS UNDER TRIAL: DRUG TRIAL NO. of Pt INTERVENTIO N END POINTS RESULTS SPP635 SPP1148 SPP800 A Phase IIa, Double-Blind, Placebo- Controlled trial -SPP635 in Mild to Moderate Hypertension Phase I Preclinical trial n:35 mild to moderate HTN SPP635 OD (20) Placebo(15) For 4 weeks Mean reduction in sitting SBP Mean reduction in sitting DBP SPP635 -17.9 -9.8 NO SAE PLA -3.1 -2.4 p<0.001 SPP635 Presently Phase IIa Study to Investigate the Efficacy and Safety of SPP635 in Diabetic and Hypertensive Patients With Albuminuria
  17. 17.  ACE INHIBITORS:
  18. 18.  Sulfhydryl-containing ACE inhibitors Dicarboxyl-containing ACE inhibitors Phosphorus- containing ACE inhibitors Captopril Enalapril Lisinopril Benazepril Quinapril Moexipril Ramipril Trandolapril Perindopril Fosinopril CLASSIFICATION
  19. 19.    lack of postural hypotension  No tachycardia    Safe in asthamatics, diabetes, PVD   Reduce the incidence of T2DM in high risk individuals  Renal blood flow is well maintained ADVANTAGES
  20. 20.  No deleterious effect on plasma lipid profile, no hyperuricemia  Delay development of diabetic glomerulopathy  Reverse left ventricular hypertrophy and increased wall:lumen ratio  No rebound hypertension on withdrawal  Reduce cardiovascular morbidity and increase life expectancy of hypertensives
  21. 21.   Stage I HTN :first choice if thiazides are not being used  Stage II HTN: in combination with thiazides  Drug of choice: in HTN associated with diabetics, LVH, CHF, post MI, renovascular HTN CURRENT STATUS
  22. 22.   MC-4232 is a combination of MC-1 and lisinopril.   MC-1 is a naturally occurring small molecule, a metabolite of vitamin B6    Presently under Phase II MATCHED study (MC-1 and ACE Therapeutic Combination for Hypertensive Diabetics), evaluating the effects of MC-4232 in patients with coexisting diabetes and hypertension. DRUG UNDER TRIAL
  23. 23. ANGIOTENSIN RECEPTOR BLOCKERS
  24. 24.  Losartan  Candesartan  Irbesartan  Valsartan  Telmisartan  Eprosartan  Olmesartan medoxomil
  25. 25.  Similar to ACE , but with better tolerability profile Complete inhibition of AII actions Result in indirect AT 2 receptor activation Advantages
  26. 26.   Intolerance to ACEI therapy and as an important option in the treatment of patients with concurrent disorders such as heart failure and type 2 diabetes CURRENT STATUS:
  27. 27.   Azilsartan medoxomil is an angiotensin receptor blocker, approved in 2011the US Food and Drug  Prodrug  Azilsartan - active moiety   Newer drugs
  28. 28.  Trial No.of pt Intervention End points Results Phase III Double-blind, randomized, placebo- controlled trial- azilsartan, olmesartan, valsartan, and placebo. 1285 SBP 150–180 mm Hg Placebo Azilsartan 20 mg ( titr 40 mg) Azilsartan 40mg (titr 80mg ) olmesartan 20 mg ( titr 40 mg) valsartan 160 mg (titr 320mg) for 6 weeks reductions in 24-hour mean SBP at 6weeks azilsartan 40mg –14.3 mm Hg valsartan 320 mg –10.0 mmHg; P 0.001 olmesartan 40 mg –11.7 mm Hg P 0.009
  29. 29.  Trial No pt Intervention End points Results Phase III Double-blind, randomized trial -azilsartan Vs valsartan 984 SBP 150-180mm Hg Placebo Azilsartan 20mg (titr 40 mg) Azilsartan 40mg (titr 80 mg) Valsartan 160 mg (titr 320 mg) 24 weeks. reductions in 24-hour mean SBP at study end Azilsartan 40 mg –14.9 mm Hg Azilsartan 80mg -15.3 mm Hg valsartan 320 mg –11.3mmHg
  30. 30.  Drugs under trial: LCZ696 (valsartan + AHU337 neprolysin inhibitor) Trial Pt Efficacy end point Intervention Result Phase II Randomized, Double Blind, active comparator trial 1328 More than 20mmhg reduction in the SBP LCZ696 100mg (156) 200mg (169) 400mg (172) Valsartan 80mg (163) 160mg (166) 320mg (164) 47 (31%) 76 (45%) 87 (51%) 51 (31%) 49 (30%) 53 (33%
  31. 31.  Trial Particip ants Interventions and duration Primary end point Results Irbe PS 200 400 800 Place bo A phase II Randomized, Double-Blind, Placebo And Active- Controlled- PS433540 In Hypertension 261 Drug: irbesartan 300 mg OD (58) PS433540 200 mg OD (58) 400 mg OD (58) 800 mg OD (28) Placebo (59) The duration 12weeks Primary : Chage from baseline in mean SBP. Secondary: Chage from baseline in mean DBP. Percentage of patients achieving BP <140/90mmhg -10.7 -13.2 -14.2 -23.4 1.8 -7.1 -7.2 -9.2 -14.3 0.2 17% 21% 16% 28% 5% PS433540 : a dual acting angiotensin and endothelin receptor antagonist
  32. 32.  Drug combinations Rationale RAAS Inhibitor + a low-dose, thiazide Improves efficacy and side effect profile RAAS Inhibitor + CCB improves the tolerability profile of the CCB Renin inhibitor with an ARB More complete inhibition of RAAS RAAS Inhibitors + beta Blocker Combination may result in severe bradycardia. ACE Inhibitors + ARB More SE Combination therapy with RAAS inhibitors:
  33. 33.  ACEIs, ARBs, and Direct Renin Inhibitors for Treating Essential Hypertension ? Evidence on the comparative long-term benefits and harms of ACEIs, ARBs, and direct renin inhibitors, focusing on their use for treating essential hypertension in adults* * Advancing excellence I n health care ahrq.gov/reports/final.cfm 2011
  34. 34. Efficacy Strength of evidence Evidence ACE in & ARBs have similar long term effects on BP control Aliskiren more effective than ramipril and as effective as ARB High (ACEI vs. ACEIs ) Low (DRI vs. ACEI,ARB ) 77 studies (70 RCTs, 5 nonrandomized controlled clinical trials, 1 retrospective cohort study, and 1 case-control study) 1,26,170 patients receiving an ACEI or an ARB were followed for periods from 12 weeks to 5 years (median 24 weeks). Based on 3 RCT These studies found the direct renin inhibitor to have a greater reduction in blood pressure compared to the ACEI ramipril (1 study ) and no significant difference compared to the ARB losartan (2 study).
  35. 35. Reducing mortality and major cardiovascular events: Strength of evidence Evidence ACE inhi = ARBs ?? Low (ACEI vs. ARBs ) Insufficient (DRI vs. ACEI,ARB ) In 21 studies that reported mortality, MI, or clinical stroke as outcomes among 38,589 subjects, 38 deaths and 13 strokes were reported. 3 of these 21 studies (including 1 death) evaluated
  36. 36. Safety profile Strength of evidence Evidence Incidence of cough is more with ACE inhi compared to ARBs High (ACEI vs. ARBs ) Insufficient (DRI vs. ACEI,ARB ) difference rates of cough 7.8 percent 4% higher in ACE inhibitors Withdrawals due to AE were more in ARB High (ACEI vs. ARBs ) Low (DRI vs. ACEI,ARB ) Withdrawals were 2.3% more with ARBs (5.4% vs. 3.1%). No statistically significant difference in the withdrawal rate
  37. 37.  Calcium channel blockers MOA:
  38. 38. 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
  39. 39. Advantages More beneficial in elderly  Safe in asthama, PVD  Lipid profile, uric acid levels or glucose metabolism not effected No renin release No postural hypotension , rebound phenomenon No tolerance Renal or cerebral perfusion, male sexual activity, physical work capacity not impaired Used in pregnancy
  40. 40.   Preferred in elderly hypertensives  They have stroke prevention potential  Next to ACE inhi in reducing albuminuria and slowing disease progression in hypertensive / diabetic nephropathy  cyclosporin induced hypertension in renal transplant Current Status :
  41. 41.  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).    
  42. 42.  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%
  43. 43.  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
  44. 44. DIURETICS:
  45. 45.  MOA :
  46. 46.  Current status: Thiazides Loop K+ sparing First choice in treatment of essential HTN esp. in elderly. Overcoming resistance to other antihypertensives Severe HTN associated with CRF, CHF Used with thiazides to prevent K loss Current Status
  47. 47. COMBINATION RATIONALE Diuretic and a CCB results Side effect profile improved. b-Blockers+ Diuretics Efficacy improved Thiazide Diuretics + Potassium- sparing Diuretics Side effect profile improved. Combination therapy
  48. 48.  DIRECT VASODILATORS: ARTERIAL VASODILATORS:  Hydralazine  Minoxidil  Diazoxide  Fenoldopam ARTERIOLAR +VENOUS VASODILATOR Sodium nitroprusside
  49. 49.  Drugs MOA Role in HTN AE Hydralazine Activate K channels Generate NO & stimulate cGMP Moderate HTN not controlled by beta blocker /diuretic Headache, nausea, nasal congestion, angina attack (due to tachycardia : reversible dessiminated lupus erythematosus Minoxidil Converted to active metabolite minoxidil sulfate which activates K channels Severe HTN, life threatening HTN, resistant HTN Hirsutism Diazoxide activates K channels HTN emergencies Na, water retention
  50. 50.  Drugs MOA Role in HTN AE Fenoldopam D1 receptor agonist— dilation of peripheral arteries and natriuresis Hypertensive emergencies esp in those with renal impairement Tachycardia, headache, flushing Increase intraocular pressure Hypokelemia, electrolyte disturbances Sodium nitroprusside Activates guanylyl cyclase either directly or through the release of NO---increase in intracellular cGMP--- vascular smooth muscle relaxation Hypertensive emergencies Tachycardia, headache, flushing Toxicity due to accumulation of cyanide/ thiocyanate
  51. 51.  Thank you
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