Antihypertensive and diuretic agents.ppt

Antihypertensive and diuretic agents.ppt

1. Introduction
•Hypertension is the most common CV disease
•Definition: either a sustained SBP of greater than 130 mm
Hg or a sustained DBP of greater than 80 mm Hg
•HTN can lead to cerebrovascular accidents (strokes), CHF, MI,
and renal damage
•The incidence of morbidity and mortality significantly
decreases when HTN is diagnosed early and is properly treated

2. Normal <120 and <80 Encourage
Elevataed 120-129 or <80 Yes
Stage 1
hypertension 130-139 or 80-89 Yes
Stage 2
hypertension ≥140 or ≥90 Yes
Systolic BP,
mm Hg*
BP
Classification
Lifestyle
Modification
Diastolic BP,
mm Hg
JAHA's 2017 Hypertension Clinical Guidelines

3. Etiology of HTN
I.Essential or primary hypertension
Accounts for 90% of cases
˃
No single identifiable cause (idiopathic)
It is usually caused by a combination of several (multifactorial)
abnormalities
A number of factors increase the risk of developing essential
HTN: age, genetics, environment (e.g. stress, sodium intake,
alcohol), weight, and race
II.Secondary hypertension
–Account for 10-15% of cases
–Secondary to a known organic disease, such as renovascular
disease or pheochromocytoma
–Correction of the underlying may result in a fall in BP

4. Determinants of Arterial Pressure
Mean Arterial
Pressure= X
Arteriolar
Diameter
Heart
Rate
Filling
Pressure
Contractility
Blood Volume Venous Tone
Cardiac outputPeripheral resistance

5. Normal regulation of blood pressure
BP is maintained by moment-to-moment regulation at four anatomic
sites: arterioles, postcapillary venules (capacitance vessels), heart,
& the kidney
The function of these four control sites is controlled/coordinated
mainly by two overlapping control mechanisms:
–The baroreflexes, which are mediated by the sympathetic
nervous system
– The renin-angiotensin-aldosterone system [RAAS]

7. Ang, angiotensin.
Reid IA. Adv Physiol Edu. 1998;20:S236-S245.
 BLOOD PRESSURE
BLOOD VOLUME
Activation of
Baroreceptor
Reflexes
 Renal Sympathetic
Nerve Activity
Beta-adrenergic
Stimulation
 RENIN
SECRECTION
 Renal Artery
Pressure
Renal
Baroreceptor
 BLOOD PRESSURE
BLOOD VOLUME
Systemic
Vasoconstriction
 Plasma
Ang II
 Aldosterone
Secretion
 Plasma
Ang I

8. Treatment Aims
•The aim of therapy is straightforward:
1)Reduction of blood pressure to within the normal
range
2)Reduction of CV and renal mortality & morbidity

9. Treatment strategies
•It is important to match antihypertensive drugs to the particular
patient
•Certain subsets of the hypertensive population respond better to
one class of drug than they do to another:
Black patients respond well to diuretics and calcium-channel
blockers, but therapy with β-blockers or ACE inhibitors is
often less effective
Calcium-channel blockers, ACE inhibitors, and diuretics are
favored for treatment of hypertension in the elderly, whereas β-
blockers and α-antagonists are less well tolerated.
•HTN may coexist with other diseases that can be aggravated by
some of the antihypertensive drugs . Examples??

10. Antihypertensive agents
Drugs lower blood pressure by actions on peripheral resistance,
cardiac output, or both
All antihypertensive agents act at one or more of four anatomic
control (arterioles, postcapillary venules, heart, & the kidney)
and produce their effects by interfering with normal mechanisms
of blood pressure regulation
Antihypertensive agents can be categorized according to the
principal regulatory site or mechanism on which they act:
1.Diuretics
2.Direct vasodilators
3.Sympathoplegic agents
4.Agents that block production or action of angiotensin

11. I. Diuretics

12. A "diuretic" is an agent that increases urine volume
Clinically useful diuretics also increase the rate of Na
+
excretion (natriuresis)
and of an accompanying anion, usually Cl
–
Diuretics lower BP by increasing Na+ and H2O excretion, causing a decrease in
blood volume and cardiac output
Diuretics
1)Inhibitors of renal ion transporters: decrease the reabsorption of
Na
+
and other ions, such as Cl
-
, at different sites in the nephron
a)Loop diuretics
b)Thiazide Diuretics
2)Agents that alter water excretion
3)Aldosterone antagonists
4)Carbonic anhydrase inhibitor

13. Principles important for understanding effects of
diuretics
Interference with Na
+
reabsorption at one nephron site:
--- interferes with other renal functions linked to it
---leads to increased Na
+
reabsorption at other sites
Increased flow and Na
+
delivery to distal nephron stimulates K
+
(and H
+
)
secretion
-----------------------------------------------------------------------------------------------------
Diuretics alone often provide adequate treatment for mild or moderate essential
HTN
Low-dose diuretic therapy is safe, inexpensive, and effective in preventing stroke,
MI, and CHF, all of which can cause mortality
Diuretics are used in combination with sympathoplegic and vasodilator drugs to
reverse Na
+
and H
2
O retention observed with other antihypertensive agents

15. Loop (high ceiling) diuretics
Agents: Bumetanide, furosemide (Prototype),
torsemide,ظفح & ethacrynic acid
Loop diuretics are the most powerful diuretics, capable
of causing the excretion of 15-25% of filtered Na
+

16. Blocked by
loop diuretics

17. I. Loop diuretics
mechanism of action
1.Loop diuretics inhibit luminal Na
+
/K
+
/2Cl
–
transporter in the
thick ascending loop of Henle's (TAL)
2.Loop diuretics induce expression and synthesis PGE
2
, which
blunts both Na
+
reabsorption in the TAL and ADH-mediated
water transport in collecting tubules
3.Loop diuretics increases renal blood flow via prostaglandin
actions on kidney vasculature & reduce pulmonary
congestion and left ventricular filling pressures in heart failure
before measurable increase in urinary output

18. Loop diuretics
Diuretic Response
1.Increase in the urinary excretion of Na
+
and Cl
-
owing

to blockade of Na
+
/K
+
/2Cl
–
transporter
2.Increase the excretion of Mg
2+
and Ca
2+
:
–Lumen-positive potential that comes from K
+
recycling is
diminished, which normally drives divalent cation
reabsorption in the loop
3.Increase the excretion of K
+
and H
+
due to increased
delivery of Na
+
to the distal tubule

19. Loop diuretics
Pharmacokinetics
Loop diuretics are administered orally or parenterally.
They are rapidly absorbed
They are eliminated by the kidney by glomerular
filtration and tubular secretion
Their duration of action is relatively brief: furosemide is
2–3 hours and torsemide is 4–6 hours
Half-life depends on renal function

20. Loop diuretics
Clinical uses
1.Edematous conditions: DOC for reducing the acute pulmonary
edema of heart failure
2.Hypertension: Loop diuretics (e.g. furosemide) are used in
moderate, severe, and malignant hypertension
3.Severe hypercalcemia
4.Hyperkalemia
5.Acute Renal Failure
6.Anion overload

21. Loop diuretics
Adverse effects
1.Ototoxicity
2.Acute hypovolemia: with CV complications (e.g
hypotension, shock, and cardiac arrhythmias)
3.Hypokalemic Metabolic Alkalosis
4.Hypomagnesemia
5.Hyperuricemia
6.Allergic Reactions: allergic reactions are much less common
with ethacrynic acid

22. II. Thiazide Diuretics
Agents: hydrochlorothiazide, chlorothiazide, metolazone,
chlorthalidone, & indapamide ظفح
mechanism of action
Thiazides inhibit Na
+
& Cl
-
reabsorption from the luminal
side of epithelial cells in the distal convoluted tubules
(DCT) by blocking the Na
+
/Cl
–
cotransporter (NCC)

24. Thiazides diuretics
Diuretic Response
the primary site of action for thiazide diuretics is the DCT.
Thiazide diuretics work by inhibiting the sodium-chloride cotransporter
(NCC) in the distal convoluted tubule of the kidney nephron. the net effect of
thiazide diuretics is an increased excretion of both sodium and water,
leading to a decrease in blood volume.
Thiazide diuretics enhance Ca
2+
reabsorption:
In the distal convulated tubule (DCT), lowering of intracellular Na
+
by
thiazide-induced blockade of Na
+
entry enhances Na
+
/Ca
2+
exchange in the
basolateral membrane, and increases overall reabsorption of Ca
2+
In the proximal convulated tubule (PCT), thiazide-induced volume depletion
leads to enhanced Na
+
and passive Ca
2+
reabsorption

25. Blocked by
thiazide diuretics

26. Thiazide diuretics
Pharmacokinetics
All thiazides can be administered orally, but there are differences in their
metabolism
Chlorothiazide is the only thiazide available for parenteral
administration
Plasma protein binding varies considerably among thiazide diuretics,
and this parameter determines the contribution that filtration makes to
tubular delivery of a specific thiazide
***All thiazides are secreted by the organic acid secretory system in the
proximal tubule and compete with the secretion of uric acid by that
system--- causing Hyperurecemia

27. Thiazides & related compounds
Clinical uses
1.Hypertension: Thiazides are the most frequently used class of
antihypertensive agents. They are appropriate for most patients
with mild or moderate hypertension and normal renal and
cardiac function
2.Edematous conditions (e.g. heart failure): loop diuretics are
usually preferred
3.Renal calcium stones
4.Nephrogenic diabetes insipidus [explained in next slide]

28. Mechanism of action of the paradoxical effect of thiazide diuretics on
Nephrogenic diabetes insipidus (NDI)
Magaldi A J Nephrol. Dial. Transplant. 2000;15:1903-1905
© European Renal Association-European Dialysis and Transplant Association

29. Thiazide Diuretics
Adverse effects
1.Hyponatremia
2.Hypokalemic Metabolic Alkalosis
3.Hyperuricemia
4.Hyperglycemia: due to both impaired pancreatic release of
insulin and diminished tissue utilization of glucose
4.Hyperlipidemia: thiazides cause a 5–15% increase in total serum
cholesterol and LDL
5.Allergic Reactions
6.Weakness, fatigability, and paresthesias
7.Impotence probably related to volume depletion

30. III. Potassium sparing diuretics
•Potassium-sparing diuretics act in the collecting tubule to inhibit
Na
+
reabsorption and K
+
excretion by:
–Direct pharmacologic antagonism of mineralocorticoid
receptors (e.g. Spironolactone and eplerenone )
–Inhibition of Na
+
influx through ion channels in the luminal
membrane ( e.g. amiloride and triamterene)

31. Potassium sparing diuretics:
Aldosterone antagonists
Agents: spironolactone and eplerenone
mechanism of action
Competitively inhibit the binding of aldosterone to the
minerlocorticoid receptors (MR)
MR-aldosterone antagonist complex is not able to induce the
synthesis of Na+/K+ exchange sites of the collecting tubule that
are normally synthesized in response to aldosterone
Thus, a lack of mediator proteins prevents Na
+
reabsorption and,
therefore, K
+
and H
+
secretion
**** Potassium-sparing diuretics prevent K+ secretion by
antagonizing the effects of aldosterone in collecting tubules

32. Potassium sparing diuretics:
Inhibitors of renal epithelial Na+ influx
Agents: amiloride and triamterene
mechanism of action
•Directly interfere with Na
+
entry through the epithelial Na
+
channels (ENaC) in the apical membrane of the collecting tubule
•Since K
+
secretion is coupled with Na
+
entry in this segment, these
agents are also effective potassium-sparing diuretics.

34. Potassium sparing diuretics
Clinical uses
1.Diuretic: spironolactone is often given in conjunction with a
thiazide or loop diuretic to prevent K
+
wasting
2.Aldosteronism (or hyperaldosteronism)
3.Heart failure: spironolactone prevents the remodeling that
occurs as compensation for the progressive failure of the heart

35. Potassium sparing diuretics
Adverse effects
1.Hyperkalemia:
Special consideration with:
1.Patients with chronic renal insufficiency are especially vulnerable and
should rarely be treated with these diuretics
2.Oral K+ administration should be discontinued if K+-sparing diuretics
are administered
3.Concomitant use of other agents that blunt the RAS (β blockers, ACE
inhibitors, ARBs) increases the likelihood of hyperkalemia
1.Hyperchloremic Metabolic Acidosis
2.Gynecomastia reported with
­spironolactone. Eplerenone is
free of such effects

36. II. Sympathoplegic agents

37. Drugs that Alter Sympathetic Nervous System
Function
•Sympathoplegics are drugs that reduce BP by depressing
the function of the sympathetic control of CV function
•Are subdivided by anatomic site of action:
1.CNS-active agents: they reduce sympathetic outflow from
vasomotor centers in the brainstem and allow these centers
to retain or even increase their sensitivity to baroreceptor
control
2.Ganglionic blocking drugs (e.g. hexamethonium and
trimethophan)

38. Drugs that Alter Sympathetic Nervous System
Function
3.Postganglionic sympathetic nerve terminal blockers:
either by inhibiting neurotransmitter release (e.g.
guanithidine) or by depleting the stores of norepinephrine
(e.g. reserpine)
4.Adrenoceptor blockers: by antagonizing the actions of
norepinephrine on effector cells

39. ACE, angiotensin-converting enzyme; AI, angiotensin I; AII, angiotensin II; ET-1, endothelin-
1; NA, noradrenaline; NO, nitric oxide

40. Centrally acting sympathoplegic drugs:
Clonidine
•It stimulate the α
2A
subtype of α
2
adrenergic receptors in the
brainstem
•Blood pressure lowering results by an effect on both cardiac
output and peripheral resistance
•Clonidine decreases renal vascular resistance and maintenance
of renal blood flow
•The most common: sedation, dry mouth, and drowsiness
•Contraindicated in patients who are at risk for mental depression
•Severe hypertensive crisis mediated when clonidine is suddenly
withdrawn

41. Centrally acting sympathoplegic drugs
α-Methyldopa
•It is now used primarily for HTN during pregnancy
•It rapidly enters the brain, where it accumulates in
noradrenergic nerves, is converted to α-
methylnorepinephrine (α
2 adrenergic receptors agonist)
•Renal blood flow and GFR are not reduced
•The most common undesirable effect of methyldopa is
sedation and drawsiness
•Other side effects include hyperprolactinemia

42. Adrenoceptor antagonist
•Agents: β-blockers and α
1-blockers
•Useful for lowering BP in mild to moderate HTN
•Especially useful in preventing the reflex tachycardia
that often results from treatment with direct
vasodilators
•Beta-blockers are recommended first-line drug
therapy for HTN when concomitant disease is
present (e.g. MI and CHF)

43. III. Vasodilators

44. Vasodilators
All of these agents relax smooth muscle of arterioles, thereby
decreasing systemic vascular resistance
Vasodilators act by four major mechanisms:
1)Release of nitric oxide
2)Opening of potassium channels
3)Blockade of calcium channels
4)Activation of D
1 dopamine receptors
The induced vasodilation is associated with powerful stimulation of
the sympathetic nervous system, likely due to baroreceptor-
mediated reflexes>>>>>increased heart rate and contractility,
increased plasma renin activity, and fluid retention

45. Mechanism Examples
Release of nitric oxide from drug or
endothelium
Nitroprusside, hydralazine,
nitrates

Reduction of calcium influx Verapamil, diltiazem,
nifedipine
Hyperpolarization of smooth muscle membrane
through opening of potassium channels
Minoxidil, diazoxide
Activation of dopamine receptors
resulting in dilation of peripheral arteries and
natriuresis
Fenoldopam
Mechanisms of Action of Vasodilators

46. Angiotensin II receptor
antagonists
Losartan
Valsartan
Ca
2+
-channel blockers
Dihydropyridines
Verapamil
Diltiazem
K
+
-channel activators
Minoxidil
Diazoxide
Activators of the
NO/guanylate cyclase pathway
Hydralazine
Nitroglycerin
Nitroprusside
 -Adrenoceptor
antagonists
Prazosin
Terazosin
K
+
Ca
2+
NO
Sites of action of drugs that relax vascular smooth muscle

47. Oral Vasodilators
Hydralazine
Its actions are largely confined to vascular smooth muscle and occur
predominantly on the arteries & arteriole
Mechanism of action: Hydralazine apparently acts through the
release of NO from endothelial cells: which activates the
guanylyl cyclase-cyclic GMP-PKG pathway, leading to
vasodilation
Toxicity include:
Compensatory responses (tachycardia, water and salt retention)
Immunological reactions chiefly in slow acetylator the drug
(arthralgia, myalgia, skin rashes, and fever that resembles lupus
erythematosus)

48. Oral Vasodilators
Minoxidill
Minoxidil sulfate, the active metabolite,
Mechanism of action: activates the ATP-modulated K
+
channel
By opening K
+
channels in smooth muscle and thereby permitting K
+

efflux, it causes hyperpolarization and relaxation of smooth muscle
Toxicity include:
Severe compensetary responses (reflex tachycardia, sodium and
fluid retention)
Hypertrichosis (hirsutism)

49. Parenteral Vasodilators
Diazoxide
Diazoxide is an effective and relatively long-acting parenterally
administered that is occasionally used to treat hypertensive emergencies
Its onset of action is within 5 minutes and lasts for 4–12 hours
Mechanism of action:
Diazoxide opens potassium channels, thus hyperpolarizing and relaxing
smooth muscle cells
Toxicity include:
Compensatory responses (tachycardia, water and salt retention)
Hyperglycemia---Diazoxide inhibits insulin release from the
pancreas and is used to treat hypoglycemia secondary to
insulinoma [but diazoxide may rarely be used if accurate infusion pumps are not
available and/or close monitoring of blood pressure is not feasible]

50. Vasodilators
Calcium channel blockers (CCBs)
Dihydropyridines include: amlodipine, felodipine, isradipine, nicardipine,
nifedipineظفح, and nisoldipine
Non-Dihydropyridines include: verapamil and diltiazem ظفح
Mechanism of action:
All of the Ca
2+
channel blockers lower blood pressure by relaxing arteriolar smooth
muscle and decreasing peripheral vascular resistance
Dihydropyridine agents are more selective as vasodilators and have less
cardiac depressant effect than verapamil and diltiazemReflex sympathetic
activation with slight tachycardia
Non-Dihydropyridine agents ,verapamil and diltiazem have depressant effect
on the heart and may decrease heart rate and cardiac output tachycardia is
typically minimal to absent with verapamil and diltiazem

51. IV. Inhibitors of angiotensin

52. Introduction
The renin–angiotensin-Aldosterone system (RASS) is
important for the regulation of vascular smooth muscle
tone, fluid and electrolyte balance, and the growth of
cardiac and vascular smooth muscle
It participates significantly in the pathophysiology of
HTN, CHF, MI, diabetic nephropathy, and
atherosclerosis
Three generally accepted mechanisms are involved in the
regulation of renin secretion:
Reduced renal arterial pressure
Reduced Na
+
delivery at the distal renal tubule
Sympathetic neural stimulation

53. Angiotensinogen
Angiotensin I
Angiotensin II
Angiotensin III
Renin
ACE
None-ACE
pathways
(eg. Chymase)
1 2 3 7 8 9 10
NH
2
-Asp-Arg-Val…Pro-Phe-COOH
1 2 3 7 8 9 10
NH
2
-Asp-Arg-Val…Pro-Phe-COOH
1 2 3 7 8
NH
2
-Arg-Val…Pro-Phe-COOH
2 3 7 8
NH
2
-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH
aminopeptidase
Peptide fragments
Angiotensinases

54. Blood
Pressure
Rises
Vasoconstriction
-
+
A schematic portrayal of the homeostatic roles of the renin-angiotensin system
Blood Volume
Rises
Renin
Release
Na
+
Retention
Aldosterone
Secretion
Na
+
Depletion
Blood Volume
Falls
Blood
Pressure
Falls
Angiotensin
Formation

55. Angiotensin II receptors
Angiotensin receptors have been classified into two subtypes: AT
1
and AT
2
The effects of ang II are exerted through specific G protein-coupled
receptors
The major biological functions of ang II (CV regulation) are
mediated through the AT
1
receptor
AT
1
is located predominantly in vascular and myocardial tissue
and also in brain, kidney, and adrenal glomerulosa cells

56. Angiotensin II receptors
Effects mediated by AT
1 receptors include:
1.Generalized vasoconstriction, especially marked in efferent
arterioles of the kidney
2.Increased release of noradrenaline from sympathetic nerve
terminals, reinforcing vasoconstriction and increasing the rate and
force of contraction of the heart
3.Stimulation of proximal tubular reabsorption of Na
+

4.Secretion of aldosterone from the adrenal cortex
5.Cell growth in the heart and in arteries

57. Inhibitors of angiotensin
Three classes of drugs act specifically on the renin-
angiotensin system:
I.Angiotensin-converting enzyme inhibitors (ACEIs)
II.Angiotensin II receptor antagonists (ARBs)
III.Renin inhibitors (e.g. aliskiren)

59. Inhibitors of angiotensin
Angiotensin-converting enzyme (ACE) inhibitors
Agents: captopril, enalapril, lisinopril, benazepril, fosinopril,
moexipril, perindopril, quinapril, Ramipril ظفح, and trandolapril
Mechanism of action:
Vasodilatory activity results from both:
 an inhibitory action on the renin-angiotensin system (lower
vasoconstriction)
Stimulating action on the kallikrein-kinin system (increased
bradykinin)
Decrease the secretion of aldosteronem resulting in decreased
sodium and water retention
Bradykinin, a potent vasodilator, which works at least in part by stimulating release of nitric oxide
and prostacyclin

60. Angiotensinogen
Angiotensin I
Angiotensin II
Renin
ACE
None-ACE
pathways
(eg. Chymase)
Bradykinin
Inactive peptide
ACEI
AT
2R AT
1R
Aldosterone
Vasoconstriction
↑sympathatic activity
Na
+
, H
2O
retention
Sympathatic
output
Bradykinin
vasodilation
of vascular
smooth muscles

61. Inhibitors of angiotensin
Angiotensin-converting enzyme (ACE) inhibitors
Pharmacokinetics
ACE inhibitros, except captopril, are prodrugs that are converted by
hydrolysis , primarily in the liver to a converting enzyme inhibitor
(active agents)
All of the ACE inhibitors except fosinopril and moexipril are eliminated primarily by the kidneys; doses of
these drugs should be reduced in patients with renal insufficiency
ACEIs do not result in reflex sympathetic activation and can be
used safely in persons with IHD
Because the renal vessels are extremely sensitive to the
vasoconstrictor actions of AngII, ACEIs increase renal blood flow
via vasodilation of the afferent and efferent arterioles
The ACE inhibitors appear to confer a special advantage in the
treatment of patients with diabetes, slowing the development and
progression of diabetic glomerulopathy

62. ACE inhibitors- ADRs
1)Hypotention
2)Dry cough (5% to 20% of patients) due to increased level of bradykinin in the
pulmonary tree
ACE dose reduction or switching to an ARB is sometimes effective
3)Angioedema (0.1% to 0.5% of patients)
4)Hyperkalemia: patients with renal insufficiency or in patients taking K
+
-
sparing diuretics, K
+
supplements, β-blockers, or NSAIDs
5)Acute renal failure: Captopril, particularly when given in high doses to patients
with renal insufficiency, may cause neutropenia or proteinuria
•ACEI are contraindicated during the 2nd and 3rd trimesters of pregnancy
because of the risk of fetal hypotension, anuria, and renal failure, sometimes
associated with fetal malformations or death

63. Inhibitors of angiotensin
Angiotensin Receptor–Blockers (ARBs)
Agents: losartan, valsartan, candesartan ظفح, eprosartan, irbesartan,
telmisartan, and olmesartan
Mechanism of action:
Non-peptide competitive antagonists of the AT
1 angiotensin II receptor
****pharmacologic effects [produce vasodilation and block aldosterone secretion], benefits, and adverse drug
effects [ADEs] similar to those of ACE inhibitors in patients with HF and chronic kidney
disease
Benefits over ACEI drugs:
More selective blockers of angiotensin effects than ACEI
Have no effect on bradykinin metabolism- Unlike ACE inhibitors,
ARBs do not cause cough, and the incidence of angioedema with ARBs is
much less than with ACE inhibitors

64. Inhibitors of angiotensin
III. Selective renin inhibitor: Aliskiren
Mechanism of action:
Aliskiren functions by blocking the catalytic functions of this
enzyme by binding to the active site of renin, which inhibits
the conversion of angiotensinogen to angiotensin I and
reduces angiotensin II concentrations
•It lowers BP as effectively as ARBs, ACEI, and thiazides
•It can also be combined with other antihypertensive drugs,
such diuretics, ACEIs, ARBs, or CCBs