This document discusses various classes of antihypertensive agents used to treat hypertension. It describes the mechanism of action, side effects, and clinical use of different classes including diuretics, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, alpha blockers, central sympatholytics, and vasodilators. Polydrug therapy is often required for more severe hypertension using combinations of first-line drugs from different classes.

2. These are agents used in treatment of hypertension are called
Anti-hypertensive agents.

3. 1. Diuretics
Thiazides - Chlorthiazide, Hydrochlorthiazide, bendrofluozide,
Clopamide, Cyclopenthiazide etc.
Loop diuretics - Flurosemide, Ethacrinic acid, Bumethamide etc.
Potassium-sparing diuretics - Spironolactone, Amiloride,
Triamterine

4. 2. ACE inhibitors (For remembering pril)
•Captopril, Enalapril, Lisinopril,
•Perindopril, Ramipril, Fosinopril, etc.
3. Angiotensin (AT1 receptor) blockers (For remembering sartan)
Losartan, Candesartan, Irbesartan, Valsartan, Telmisartan

5. 4. Calcium channel blockers (for remembering dipine)
•Verapamil, Diltiazem,
•Nifedipine, Felodipine, Amlodipine, Nitrendipine, Lacidipine,
etc.

6. 5. β Adrenergic blockers (For olol)
•Propranolol, Metoprolol, Atenolol, etc.
6. β + α Adrenergic blockers
•Labetalol, Carvedilol

7. 7. α Adrenergic blockers
•Prazosin, Terazosin, Doxazosin
•Phentolamine, Phenoxybenzamine
8. Central sympatholytics
•Clonidine, Methyldopa

8. 9. Vasodilators
•Arteriolar: Hydralazine, Minoxidil, Diazoxide
•Arteriolar + venous: Sodium nitroprusside

9. Diuretics
• These are the drugs that increase urine flow called diuretics.
• Also used in treatment of Hypertension.
• First -line drug.
• Diuretics have been the standard anti-hypertensive drugs over the past 4 decades.
• Low dose diuretic therapy is safe and effective in preventing HTN complications.
Examples.

10. 1.Thiazide diuretics
• Thiazides are the most effective diuretics to reduce blood pressure in
patients with normal renal function.
• The antihypertensives doses are lower that those required for diuretic effect.
• That also reduce blood pressure Both in supine and standing position.

11. Mechanism of Action :

12. Thiazide diuretics: clinical use
• Used for monotherapy of mild hypertension and for polydrug therapy of
more severe cases.
• Therapeutic expectation with monotherapy: 20/10 mmHg drop in 60% of
patients.
• Use low doses (ceiling effect) to minimize side-effects (K loss).
• Low-dose thiazide/low dose beta-blocker combo
• Can be used in conjunction with sympatholytics, ACEI, Ca-channel blockers

13. Thiazide Diuretics: side-effects
Major Side-effects:
a) K loss (minimized by using low doses, diet, use of combos with K-sparing diuretics).
b) hyperuricemia (excess of uric acid in the blood) (bad for gout)
c) hyperglycemia, glucose intolerance (bad for diabetes)
d) increase LDL & VLDL (bad for atherosclerosis)

14. Potassium-sparing diuretics
• Potassium-sparing diuretics, which block the epithelial sodium
channel (ENaC),
• are widely prescribed for hypertension as a second-line drug in patients
taking other diuretics (e.g. thiazide diuretics) and
• much less commonly prescribed as monotherapy.

15. a. Spironolactone – antagonizes effect of aldosterone
b. Triamterene – weak antihypertensive activity of its own

16. • Spironolactone or amiloride themselves lower BP slightly,
but they are used only in conjunction with a thiazide
diuretic.
•to prevent K+ loss and to augment the antihypertensive
action.

17. Mechanism of action

18. Therapeutic uses

19. LOOP DIURETICS
- shorter duration of action than thiazide-type diuretics;
reserved for use in subjects refractory to thiazides

21. - SIDE EFFECTS: dehydration, most metabolic effects as thiazides (ie.,
hypokalemia,impaired diabetes control, ↑LDL/HDL)
- Potassium supplements to compensate for hypokalemia

22. SYMPATHOPLEGIC AGENTS
A. Centrally-acting antihypertensive agents
Examples….
Clonidine,
Guanfacine,
Alpha-methyl-DOPA
(via its active metabolite alpha-methyl-
noradrenaline)

23. Mechanism of Action
• Clonidine stimulates alpha-
adrenoceptors in the brain stem.
• This action results in reduced
sympathetic outflow from the central
nervous system and decreases in
peripheral resistance, renal vascular
resistance, heart rate, and blood
pressure.

26. Adrenergic antagonists
• Adrenergic antagonists are mostly used for cardiovascular disease.
• The adrenergic antagonists are widely used for lowering blood pressure and
relieving hypertension.
• These antagonists have a been proven to relieve the pain caused by
myocardial infarction, and also the infarction size, which correlates with
heart rate.

28. Mechanism of action

30. ß-adrenergic blockers
• Non selective: Propranolol (others: nadolol, timolol,
pindolol, labetolol)
• Cardioselective: Metoprolol (others: atenolol, esmolol,
betaxolol)

31. Mechanism of Action
Bind to beta adrenergic receptors and blocks the
activity

32. Renin A I AII
Aldosterone secretion
Kidney
Kidney
Na loss
BV
Na loss
K retention
AP
BETA-BLOCKER
Cardiac rate
Cardiac output
Compensatory reflexes
Sympathoactivation renin / ang / aldo

34. Beta-adrenergic antagonists: side-effects
• Bronchoconstriction (minimized by using beta-1 selective drug; bad for
asthmatics)
• Increase in LDL/HDL ratio (bad for atherosclerosis)
• Depression, loss of energy (CNS effect)
• Increase AV node refractoriness (good for SVTs but could be bad if
abnormal SA or AV nodes)
• Decreased cardiac contractility (good for angina, good or bad for CHF)

35. Beta-adrenergic antagonists: side-
effects
• Block prodromal signs of hypoglycemia in insulin-dependant diabetics.
• Withdrawal: Rebound hypertension and cardiac ischemia
• Cold extremities. May precipitate or worsen Raynaud’s disease (vasospasm
of extremities due to beta-blockade of AV shunts). Labetatol (alpha + beta
blocker) or blocker with ISA may be prefered in this case.
• Adverse effect in patients with occlusive peripheral vascular disease
(Production or aggravation of intermittent claudication. IC is due to low calf
blood flow)

36. Beta-blockers: clinical use in
hypertension
• Can be used alone for monotherapy .
• combined with low dose thiazide
• Should not be combined with verapamil or diltiazem to avoid
excessive cardiac depression
• Can be combined with ACEI, dihydropyridines (cautiously), other
vasodilators.

37. Renin-angiotensin system

38. ACE inhibitors: mechanism of antihypertensive
action
• ACEIs  AII and  bradykinin (vasodilator).
• In the context of hypertension ACEIs work: by  preload and 
afterload via:
a)  arteriolar dilation ( TPR).
b) Na reabsorption by kidney (hemodynamic effect on kidney and
drop in aldosterone secretion). This reduces blood volume and preload
c)  release of NE (which lowers TPR and CO)
d)  cardiac contractility

39. ACEIs: mechanism of
action
Renin AI AII
Aldosterone secretion
Kidney
Kidney
Na loss
Arteriolar relaxation
BV
TPR
Na loss
K retention
AP
Reduced SND and NE
release
ACEI
venous tone
neg inotropic
effect
x
Bradykinin

40. ACEIs: side-effects/drug interactions
• SAFE, effective and well-tolerated. Few side-effects but some potentially
serious.
• Common side-effects are due to bradykinin accumulation : cough, skin
rashes, angioedema
• Hyperkalemia (bad in presence of K-sparing diuretic, good in presence of
thiazide)
• First dose orthostatic hypotension (can be severe in hypovolemic patient
e.g. using diuretics)
• Risk of severe foetal pbs.

41. Use of ACEIs in
hypertension
• Excellent first line agent for monotherapy in absence of renal
ischemia.
• Can be combined with beta-blockers or thiazides diuretics
(NOT with K-sparing diuretics) or alpha-1 blockers for
enhanced effectiveness.
• Not for pregnant women.
• Other major uses of ACEIs: diabetic nephropathy, CHF and
post MI treatment.

42. Angiotensin receptor
antagonists
• Prototype: Losartan.
• Block AT1 not AT2 receptors, no effect on bradykinin.
• Less efficacious than ACEIs (??)
• Effect potentiated by thiazide.
• Produces neither cough nor angiodema (bradykinin effects) but other
side-effects are the same as those of ACEIs.

43. Difference between ACEIs & AT1 blockers
AngII Bradykinin
AT1-R AT2-R
Vasoconstriction Vasorelaxation
AngII Bradykinin
AT1-R AT-2R
VasoconstrictionVasorelaxation
ACEIs AT1 R antagonists
Normal Reduced Increased

44. Dihydropyridine Ca channel blockers
•Mechanism of antihypertensive action: arteriolar
vasodilation, TPR drop.
•DHPs are slightly more potent antihypertensives
than verapamil or diltiazem
•Side-effects:
• a) orthostatic hypotension
• b) reflex tachycardia may lead to cardiac ischemia and/or arrhythmias
• (minimized by using slow-onset and long-lasting preps)
• c) headache, flushing, dizziness
d) pedal oedema.

45. Non-selective Ca channel blockers:
mechanism of action
Arteriolar relaxation
TPR
Verapamil
AP
Cardiac contractility
Cardiac rate
CO
Compensatory reflexes
Sympathoactivation Kidney/ang/aldo

46. Non-selective Ca channel blockers: side-
effects
• Side-effects:
• a) SA node inhibition: probably good as it prevents the
baroreflex mediated tachycardia
b) increase in AV node refractoriness. Good for SVTs but
can produce AV block in patients with cardiac conduction
problems.
• c) decrease cardiac contractility

47. Ganglionic blockers
• Historical interest only. These drugs produce intolerable side-effects
(orthostasis, Na retention, GI and sexual dysfunction)
• trimethaphan was withdrawn in 1996
• mecamylamine still available but never used.

48. Reserpine
• Depletes NE from storage vesicles
• Major action is in CNS. Reduces sympathetic
outflow. Reasonably effective, especially with
thiazide.
• Side-effects: depression, sedation, GI
hyperactivity.
• Cheap, its only virtue.
•Little used at present.

49. Guanethidine
• Peripheral sympatholytic drug.
• Rides the NE transporter, dislodges NE from
vesicles and prevents exocytosis.
• Lots of side-effects: postural hypotension cerebral
ischemia, GI hyperactivity, sexual dysfunction
• Potentially very serious drug interactions
(tricyclics, indirectly acting sympathomimetics e.g.
cold medicines)
• Use in hypertension restricted to severe cases.
Must be combined with diuretic

50. Vasodilators:
• Hydralazine & Minoxidil
• Oral vasodilators used are used for long-term outpatient treatment of
severe hypertension in the context of a polydrug therapy.
• Work by reducing afterload (TPR).
• Cause marked Na retention and rapidly increase BV (pseudotolerance) i.e.
must be used in conjunction with diuretics.
• Cause marked reflex tachycardia and increased contractility (beta -mediated)
ergo must be used with beta-blockers.

51. Alpha-1 adrenergic antagonists
• Mechanism of action:
• a) antagonize effect of sympathetic tone in arteries
and veins (reduce TPR and preload)
b) reduce baroreflex via central action (thus
produce very little reflex tachycardia).
• Side-effects: few
• a) first-dose hypotension (Pb with older patients)
• b) retention of salt and water

52. Alpha 1-blockers: mechanism of action
Aldosterone
secretion
Arteriolar relaxation
TPR
AP
venous tone
Preload
Prazosin
Reflexes
Renin release
Na retention by kidney
Sympathoactivation
cardiac contractil
and rate

54. Alpha-1 adrenergic antagonists: therapeutic
use
1. Can be used for monotherapy of mild hypertension
2. May improve LDL/HDL ratio
3. Effects additive with thiazide diuretics and ACEI.
4. Should not be combined with vasodilators (e.g. dihydropyridines):
tachycardia.
5. Good for patients with benign prostatic hyperplasia.

55. Alpha-1 adrenergic antagonists: difference
between agents
•Prototype: prazosin
•Newer agents (terazosin, doxazosin) have longer
T1/2 .
•Newer agents can be given once a day.

56. Treatment of mild hypertension
• Nonpharmacological (salt restriction , exercise,
weight loss)
• Pharmacological: alternatives for initial treatment
include: a) monotherapy
with thiazide, ACEI, beta-blocker or alpha-1
blocker or calcium-channel blocker. Drug is
selected on the basis of efficacy,concurrent
pathologies and individual sensitivity to side-
effects. b) low thiazide/low beta-
blocker combo c) thiazide/ K sparing combo.

57. Principles of polydrug therapy
• Monotherapy is sufficient in only 55% of cases.
• In more severe cases 2 or 3 drugs have to be used.
• Each drug must belong to a different class
• The combination of 2 first-line drugs is
tried first. One of the drugs is likely to be
an ACEI.
• Vasodilators if used must be given with a diuretic and a
beta-blocker.

58. Treatment of hypertensive
emergencies
• Goal: produce a rapid but well controlled fall in BP.
• Context: hypertensive encephalopathy, eclampsia, pheo,
hypertension with pulmonary oedema, aneurism,
subarachnoid hemorrhage etc..
• Labetalol iv (alpha & beta blocker)
• I.v nitroprusside
• I.v. nitroglycerine
• hydralazine iv or im (eclampsia)
• iv phentolamine or phenoxybenzamine po (pheo)