An Update

1. CHAIRPERSONS-PROF DR RANGARAJ RAMALINGAM DM
DR RAJEEV A DM
CANDIDATE- DR ABHISHEK RATHORE MD

2.  In hypertension, diuretics are recommended as
first-line therapy, especially because a network
metaanalysis found low-dose diuretics the
most effective first-line treatment for prevention
of cardiovascular complications.
Psaty BM, et al, JAMA 2003

3.  LOOP DIURETICS
 THIAZIDES
 THIAZIDE LIKE AGENTS
 POTASSIUM SPARING AGENTS

5. Category of
diuretic
Example Mechanism of
action
Site of action
Loop diuretic Furosemide Inhibits Na+ K+ 2Cl¯
cotransporter
Thick segment of
ascending limb
Thiazide Hydrochlorthiazide Inhibits
Na+Cl¯symporter
Early DCT
Thiazide like
agents
Chlorthalidone -----do----- -----do-----
K+ Sparing
diuretics
Spironolactone
Triamtrene
Inhibits action of
aldosterone
Inhibits Na+
reabsorption and
K+secretion
Late DCT and
cortical collecting
duct
------do-----

6.  Sulphonamides (except Ethacrynic acid)
 More urine vol. & less loss of Na+(Unlike Thiazides)
Why not used as Antihypertensive routinely???
24hr Na+ loss is insufficient to maintain slight vol.
contraction needed for Antihypertensive action.

7. Drug Dose Pharmacokinetics
Furosemide 10-20mg PO 2X for BP
20-80mg 2-3X for CHF
Onset of
action
10-20min
5min(IV)
Peak
Diuresis
1.5hr
Duration
of Action
4-5hr
2hr(IV)
Excretion
Renal
Absorption
10-100%
Bumetanide 0.5-2mg PO 1-2X for BP
5mg PO or IV for
Oliguria
Not Licensed for BP
~20min 75-90min 4-5hr Renal 80-100%
Torsemide 5-10mgPO or IV 10min 1hr(IV)
1-2hr(PO)
6-8hr(PO) Hepatic 80-100%
1mg Bumetanide = 40mg Furosemide
10mg Torsemide = 40mg Furosemide

8.  1. Superior fluid clearance for same degree
of natriuresis.
 2. work despite renal impairment
 3. High ceiling effect.

9. Indications Contraindications
Heart failure HF without fluid retension
Renal failure Dehydration
Hypertension Hypersensitivity
Hypertension Crisis
Hypercalcemia

10.  Hypokalemia
 Hyponatremia
 Hypovolemia
 Hyperglycemia
 Hyperuricemia
 Dyslipidemia
 Photosensitive skin eruptions
 Blood dyscrasias
 Ototoxicity - >4mg /min or Oral dose >1000mg
daily(Furosemide)

11.  Braking Phenomenon- loss of potency after
1st dose
 Long term tolerance- increase Na absoption
by distal nephron

12.  Most widely recommended 1st line therapy
for HTN
 Difference from loop diuretics:
1.Long duration of action
2.low ceiling Diuretic
3.less effective in renal dysfunction(s.cr >2mg/dl or GFR
<15-20ml/min)
4.Hypercalcemia

13. Diuretics Dose Duration of action
Hydrochlorthiazide 12.5-25mg(for BP)
25-100mg (for CHF)
16-24hr
Chlorthiazide 250-1000mg 6-12hr
Trichlormethiazide 1-4mg 24hr
Benzthiazide 50-200mg 12-18mg
Hydroflumthiazide ----do---- 12-24hr
Chlorthalidone 12.5-15mg(for BP) 40-60hr
Metolazone 2.5-5mg(for BP)
5-20mf(for CHF)
24hr
Xipamide 5mg(for BP) 6-12hr
Indapamide 1.25-2.5mg
1.25mg(prefered for BP)
2.5-5mg (for CHF)
24hr

14.  Metabolic side effects( No hypocalcemia)
 Sulphonamide immune S/E
 Intrahepatic jaundice
 Pancreatitis
 Blood dyscrasias
 Angitis
 Pneumonitis
 Interstitial nephritis
 Photosensitive dermatitis
 Erectile dysfunction

15.  JNC 7 recommends Thiazide as 1st line
drugs
 JNC 8- Among 1st line drugs

16. ACE-I AT-1 DIURETIC CA-ANTAGONISTS B-BLOCKERS
JNC 8 + + + + -
JNC 7 + + + + +
NSH + + + + -
AHA + + + + -
ESH/ESC + + + + +
WHO + + + + -

17.  Both HCTZ and CTD have demonstrated risk reduction
in clinical trials.
 However,the largest trials including
HDFP,MRFIT,SHEP,ALLHAT primarily used CTD as
initial therapy and more consistently showed reduction
in cardiovascular events than studies primarily used
HCTZ.

18.  Major Outcomes in High-Risk Hypertensive Patients Randomized to ACE
Inhibitor or CCB vs Diuretic The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT)
 ~35000 patients
 Amlodipine or Lisinopril vs Chlorthalidone
(2.5-10mg) (10-40mg) (12.5-25mg)
Conclusion Thiazide-type diuretics are superior in preventing 1 or more major
forms of CVD and are less expensive. They should be preferred for first-step
antihypertensive therapy.
JAMA. 2002;288(23):2981-2997

19.  Multiple Risk Factor Intervention Trial (MRFIT)
 8012 patients
 HCTZ vs CTD
(50-100mg) (upto 50mg)
Conclusion Through 48 and 84 months of follow up BP and LVH
decrease more by CTD than HCTZ.
HYPERTENSION 2011:58;1001-1007

20.  Systolic Hypertension in Elderly Programme (SHEP Trial)
 Conclusion-In persons aged 60 years and over with
ISH, low-dose chlorthalidone (12.5mg)reduced the
incidence of total stroke by 36% & major cardiovascular
events were also reduced.
JAMA. 1991 Jun 26;265

21.  HYPERTENSION DETECTION AND FOLLOW-UP PROGRAM
(HDFP)
 10,900 PATIENTS
Conclusion- CTD reduced BP and Mortality.
JAMA 1979:242(23):2562-2571

22. ACCOMPLISH Trial
Total patients- 11500
 CONCLUSIONS-The benazepril–amlodipine
combination was superior to the benazepril–
hydrochlorothiazide combination in reducing CV
events in patients with hypertension who were at
high risk for such events
N Engl J Med 2008; 359:2417-2428

23.  Total patients- 19,000
 Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg
 Amlodipine 5–10 mg ± perindopril 4–8 mg prn
Amlodipine-based regimen was beneficial in lowering BP and
prevention of CV events compared to beta-blocker ± diuretic-based
regimen
Dahlöf B et al. Lancet. 2005;366:895-906.
.

24.  in 6000 hypertensive patients aged 65-84 years.
 Total patients-6083
 Enalapril vs HCTZ
 Conclusion- Enalapril is superior in decreasing
morbidity and mortality.
Clin Exp Hypertens. 1997 Jul-Aug;19

25.  In a Metaanalysis of 108 trials of HCTZ and
29 trials of CTD ,CTD was somewhat better
in lowering SBP at the cost of more
hypokalemia.
Ernst ME et al,Am J Hypertension 2010,April 23(4)

26.  Head-to-head comparisons of HCTZ with
indapamide and chlorthalidone:
antihypertensive and metabolic effects.
 14 RCT with 883 patients
 Conclusion- Like CTD, INDAP is more potent than HCTZ at
commonly prescribed doses without evidence for greater adverse
metabolic effects.
Roush GC,Hypertension 2015 May;65(5)

27.  Lower doses of HCTZ and CTD gave approximately as
much as BP reduction as did the higher.
 Low dose should be used to avoid metabolic problems
especially in elderly.
Carter BL et al,Hypertension 2004 Jan;43(1):4-9.

28.  SHEP
 Swedish Trial in Old Patients with Hypertension-2
(STOP-2)
 Medical Research Council (MRC)
 Treatment of Mild Hypertension Study (TOMHS)

29.  Vasodilation property
 *More lipid & Glucose neutral than other
thiazides.
 Max T/P Ratio of 100%
 Reduce BP variability.( X-CELLENT study)
* Curr Med Res Opin 2005;21:37-46
Drugs Safety 2001;24:1155-65.

31. Placebo
Placebo
+ Placebo
+ Placebo
Indapamide SR 1.5 mg
+ Perindopril 2 mg
+ Perindopril 4 mg
M-2 M-1 M0 M3 M6 M9 M12 M18 M24 M60
The Trial:
International, multi-centre, randomised double-blind placebo controlled
Inclusion Criteria: Exclusion Criteria:
Aged 80 or more, Standing SBP < 140mmHg
Systolic BP 160 -199mmHg Stroke in last 6 months
+ diastolic BP <110 mmHg, Dementia
Informed consent Need daily nursing care
Primary Endpoint:
All strokes (fatal and non-fatal)
Target blood pressure
150/80 mmHg
Total Patients-3845

32. Reduction of 21% for total mortality (p=0.019)
39% for stroke mortality (p=0.046)
30% for stroke (p=0.055)
64% for heart failure (p<0.001)
34% for all cardiovascular events, a composite of
cardiovascular causes of stroke, myocardial infarction or heart
failure, (p<0.001)
Conclusion- Antihypertensive treatment with indapamide (sustained release),
with or without perindopril,in persons 80 years of age or older is beneficial.
HYVET-COG substudy- blood pressure lowering may reduce
or delay dementia

33. Regression of LVH in hypertensive patients treated with
indapamide SR 1.5 mg versus enalapril 20 mg
CONCLUSIONS:
Indapamide SR 1.5 mg was significantly more effective
than enalapril 20 mg at reducing LVMI in hypertensive
patients with LVH.
J Hypertens. 2000 Oct;18(10):1465-75.

34. Total patients-7121
ACEI vs Placebo --- NS difference in Stroke
ACEI + D(Indapamide)--- 43% reduction in Stroke
Conclusion- Perindopril + Indapamide is effective in BP reduction
with secondary prevention of stroke.

35. Patel A et al; ADVANCE Collaborative Group. Lancet. 2007;370:829-840.
Primary end point
(Combined macro- + microvascular events)
Total coronary events
Total renal events
Cardiovascular death
Total mortality
 9%
 14%
 21%
 18%
 14%
P=0.041
P=0.020
P<0.0001
P=0.027
P=0.025
Relative Risk
Reduction
0.5 1.0 2.0
Hazard ratio
THE ADVANCE STUDY...the largest randomised
trial of BP lowering in type 2 diabetes
Favours current
therapy + Peri/Inda
(n=5569)
Favours current
therapy + Placebo
(n=5571)

36. 1
• Routine treatment with 1, daily, single tablet, fixed
dose combination of perindopril-indapamide
2
• Of any type 2 diabetic patient seen in daily practice
3
• In addition to usual hypoglycaemic, antihypertensive,
lipid lowering, and anti platelet drugs
4
• Safely, reduces the risk of cardiovascular, renal, and
eye complications of diabetes, together with
associated mortality, by an average of at least 9%

38.  REASON study- Perindopril + Indapamide
vs Atenolol
 PICXEL study– Perindopril + Indapamide vs
Enalapril

39. Also Magnesium sparing diuretics.
Drug Dose Duration of
action
Amiloride 2.5-20mg 6-24 hr
Triamterene 25-200mg 8-12 hr
Spironolactone 25-200mg 3-5 days
Eplerenone 50-100mg 24 hr

40.  Advantages
 Less arrythmias
 No major loss of K+ and Mg
 No Diabetes or Gout(unlike thiazides)
 No reflex sympathetic activation
 T/t of Primary aldosteronism(Aldosterone blockers)
 Disadvantages
 Hyperkalemia
 Acidosis
 No use in Renal dysfunction.

41.  Spironolactone versus placebo, bisoprolol, and
doxazosin to determine the optimal treatment for
drug-resistant hypertension (PATHWAY-2): a
randomised, double-blind, crossover trial
 Conclusion- Spironolactone was the most effective
add-on drug for the treatment of resistant hypertension.
The superiority of spironolactone supports a primary
role of sodium retention in this condition.
Williams B et al. Lancet. Sept 2015.

42.  Amiloride 10 mg alone (n=132), HCTZ alone 25 mg (n=134) or a
combination of both at half dose (n=133) for 12 weeks.
 Conclusion- Amiloride-hydrochlorothiazide
combination superior to either alone for uncontrolled
hypertension
ESC Congress-Sept 2015.

43.  Eplerenone was as effective as enalapril in LVH
regression and BP control.
 The combination of eplerenone and enalapril was more
effective in reducing LV mass and systolic blood
pressure than eplerenone alone.
Circulation 2003 Oct 14;108(15)

44.  Most of outcome trials favour CTD than HCTZ.
 Indapamide – only thiazide with minimal metabolic Side effects.
 Indapamide may be the best Thiazide type diuretic to be
considered for Hypertension.
 Low dose diuretics shuold be considered especially in elderly to
avoid metabolic problems.
 Spironolactone is most effective add-on drug for Resistant
hypertension.