Diuretics are recommended as first-line therapy for hypertension. The document discusses various classes of diuretics including loop diuretics, thiazides, thiazide-like agents, and potassium sparing agents. It provides examples of drugs in each class, their mechanisms of action, and sites of action. The document summarizes evidence from clinical trials showing that thiazide diuretics like chlorthalidone are more effective than hydrochlorothiazide at reducing cardiovascular events in hypertension. Indapamide is discussed as an alternative to hydrochlorothiazide with similar efficacy and fewer metabolic side effects. Combinations of ACE inhibitors or calcium channel blockers with diuretics are also effective antihy
This presentation consists of various approaches to treat hypertension depending on severity. It also include treatment according to international guidelines. Classification and brief description of each antihypertensive agent has been mentioned.
Introduction to diuretics.
Therapeutic approaches.
Normal physiology of urine formation.
Classification of drugs .
Mechanism of action of Acetazolamide.
Mechanism of action of Thiazides.
Mechanism of action of Loop diuretics.
Mechanism of action of potassium sparing diuretics &aldosterone antagonists.
This presentation consists of various approaches to treat hypertension depending on severity. It also include treatment according to international guidelines. Classification and brief description of each antihypertensive agent has been mentioned.
Introduction to diuretics.
Therapeutic approaches.
Normal physiology of urine formation.
Classification of drugs .
Mechanism of action of Acetazolamide.
Mechanism of action of Thiazides.
Mechanism of action of Loop diuretics.
Mechanism of action of potassium sparing diuretics &aldosterone antagonists.
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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
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.
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
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.
30.
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%
37.
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.
Editor's Notes
In hypercalcemia furosemide used with NS
Less k i/t Arrythmias and ppts Digitalis toxicity
Uric acid l/t gout