This document discusses antihypertensive drugs used to treat hypertension. It begins by defining hypertension and classifying it based on blood pressure levels. It then describes the normal regulation of blood pressure via baroreceptor reflexes and the renin-angiotensin-aldosterone system. The rest of the document is spent classifying and describing the mechanisms and effects of major classes of antihypertensive drugs, including diuretics, vasodilators, drugs affecting the sympathetic nervous system, beta-blockers, and others. Adverse effects and clinical uses are provided for many individual drugs.

1. Antihypertensive Drugs
By:Awgichew Shewasinad
[Bpharm, M.Sc. Pharmacology]
1

2. 2
Introduction
 A sustained increase in blood pressure (140/90
mm Hg) [on repeated BP measurement]
 Criteria for HTN in Adults
Classification Blood Pressure
(mm Hg)
Systolic Diastolic
Normal < 120 < 80
Pre-hypertension 120 – 139 80 – 89
Hypertension, Stage 1 140 – 159 90 – 99
Hypertension, Stage 2  160  100

3. Introduction Cont’d
 Is the most common cardiovascular disease in the
west (up to 27% of US adult population)
Varies with age, race, environment etc
 Is one of the most important risk factors for both
coronary artery disease and cerebrovascular
accidents
 Effective treatment of HTN reduces morbidity
and mortality
3

4. 4
Regulation of normal BP
 Arterial BP = CO x TPR
 There are four anatomical regulating sites
1. Arterioles
2. Post-capillaryVenules
3. The heart
4. The kidneys

5. Main sites and mechanisms of BP control
1. Baroreceptor reflex:
 Mediated by autonomic
nerves
2. Humoral mechanism:
 The Renin-Angiotensin-
Aldosterone system
(RAAS)
5

6. Baroreceptor reflex:
 For rapid adjustment of
BP
 Sensory input: receptors
on carotid sinus and
aortic arc
 Stimulus: stretch

7. 7
Baroreceptor reflex
If BP is increased
 Carotid receptors are stimulated by stretch of blood vessels
 Results in the inhibition of sympathetic discharge
If BP is decreased
 Stretch of blood vessels is reduced  ed baroreceptor
activity
  disinhibition of sympathetic discharge

8. Humoral Control
 For long term control of BP
 If mean arterial BP is reduced ,
− Renal perfusion pressure is reduced
− Increased reabsorption of salt &
water
− Increased secretion of renin and
the resulting increase in
Angiotensin II, which in turn causes
 Direct arteriolar vasoconstriction
 Increased secretion of aldosterone
8

9. 9
Classification of HTN
Based on etiology
 Primary (essential) HTN
85-90% of all cases
No cause is identified
 Secondary HTN
10-15% of cases
Identifiable cause present
 Due to disease and drug

10. Non-pharmacological therapy
1. Reduction of weight
2. Salt restriction - 5mg/d of salt
3. Alcohol restriction
4. Physical exercise
5. Relaxation & Biofeedback
6. K+ supplementation
7. Stop smoking
♣These lifestyle changes may also facilitate pharmacological
control of blood pressure.

11. 11
Classification of Antihypertensive
agents
1. Diuretics
 Loop diuretics eg. Furosemide
 Thiazide diuretics eg. hydrochlorothiazide
 K+ sparing diuretics eg.Triamterene
 Mechanism: reducing blood volume

12. 12
Classification (cont’d)
2. Antiadrenergic agents
I. Centrally acting α2 agonists
II. Ganglionic Nicotinic receptor blocking agents
III. Adrenergic neuron blocking agents
IV. Adrenergic receptor blocking agents
 α-AR blockers
 β-AR blockers
 mixed α-, β-AR blockers

13. 13
Classification (cont’d)
3. Vasodilators
 Arteriolar dilators
 Mixed artery & venous dilators
4. Blockers of production or action of Angiotensin II
 Angiotensin converting enzyme inhibitors
 Angiotensin II receptor blockers

14. 14
DIURETICS
 Are antihypertensive alone, and enhance the efficacy of other
antihypertensive drugs
 Exact mechanism for reduction of arterial BP is not certain
Initial  in extracellular volume  fall in CO
Maintained hypotensive effect during long-term therapy is
due to  in vascular resistance; CO returns to pretreatment
values and extracellular volume returns almost to normal

15. 15
Loop diuretics
 Are most potent diuretic
 Block Na+/K+/2Cl- transport in thick ascending loop of henle
 Include such drugs as furosemide, bumetanide, ethacrynic acid,
torsemide
 Used in severe HTN
When multiple drugs with Na+ retaining properties are used
In case of renal insufficiency
In case of CHF or cirrhosis

16. 16
Thiazide diuretics
 Less potent diuretics
 Block Na+/Cl- cotransport in the distal convoluted
tubule
 Include: chlorothiazide, indapamide
hydrochlorothiazide, chlorthalidone,
 Used in mild to moderate HTN
Along with other antihypertensive agents
In patients with normal renal & cardiac function

17. 17
K+ sparing diuretics
 Weakest in diuretic potency
 Act distally in the collecting duct to either inhibit
binding of aldosterone to mineralocorticoid receptors
or inhibit epithelial Na+ channel (ENaC)
 Avoid excessive K+ depletion
 Drugs include spironolactone, triamterene and
amiloride

18. 18
Vasodilators
1. Oral vasodilators
 Hydralazine, Minoxidil
 Used for long term treatment of HTN
2. Parenteral vasodilators
 Nitroprusside, Diazoxide
 For treatment of hypertensive emergencies
3. Ca++ channel blockers
 Verapamil, Diltiazem
 For long term treatment of HTN & treatment of
hypertensive emergencies

19. 19
Mechanism (vasodilators)
 All reduce TPR by relaxing arteriolar smooth muscle
Elicit baroreceptor & renal reflexes
 Cause tachycardia and salt & water retention
 Vasodilators should be combined with other
antihypertensive agents
 To counteract the reflex adverse effects

20. 20
Hydralazine
 Causes direct relaxation of arteriolar smooth muscle,
but does not relax veins
 The vasodilation induces powerful stimulation of
sympathetic system (ed HR and contractility, ed
plasma renin activity, and fluid retention)
 Postural hypotension is not common
 Well absorbed after oral administration

21. 21
Adverse effects
 Tachycardia, aggravation of angina, fluid retention,
headache, sweating, flushing, nausea, anorexia
Uses:
◦ Severe HTN & hypertensive emergencies in pregnant
women

22. 22
Minoxidil
 Metabolized by hepatic sulfotransferase to the active
molecule, minoxidil N-O sulfate
 Activates ATP-modulated K+ channel and results in
hyperpolarization & relaxation of smooth muscle (edTPR)
 ed CO (activation of sympathetic system)
 Potent stimulator of renin release
 Has no effect on capacitance vessels
 Well absorbed orally

23. 23
Adverse effects
 Retention of salt and water
 CVS effects:  in HR, myocardial contractility, and
myocardial O2 consumption
 Hypertrichosis (due to K+ channel activation).
*Topical minoxidil is marketed for the treatment of baldness.
Therapeutic use
 Severe HTN that does not respond to other agents

24. 24
Sodium nitroprusside
 Potent , parentally administered vasodilator
 Activates guanylyl cyclase via release of NO
 Dilates both arteriolar & venular vessels
 Has rapid onset (30 s) & brief duration of effect (3 min)
 Causes only a modest in HR and an overall reduction in
myocardial demand for oxygen
 Metabolically degraded by the liver to thiocyanate, which are
excreted by the kidney (patients with impaired renal function
likely to develop toxicities)
  plasma renin activity

25. 25
Adverse effects are secondary to
 Excessive lowering of BP; and
 Accumulation of CN-
Metabolic acidosis, arrhythmias etc
Hypothyroidism (thiocyanate inhibits uptake of iodine)
Therapeutic use
 Treatment of hypertensive emergencies (continuous IV
infusion)

26. 26
Ca2+ channel blockers (CCB)
 Inhibit Ca++ influx in to arteriolar smooth muscle
 Cause arteriolar dilatation (little effect on veins) ; hence reduceTPR
Specific drug classes
 Dihydropyridines: Nifedipine, Nicardipine
 Potent arteriolar vasodilators
 Less effect on heart rate & contractility
 Adverse effectsTachycardia, headache, flushing, peripheral edema
 Phenylalkylamine:Verapamil
 Decrease heart rate & contractility
 Adverse effects: headache, dizziness, edema, bradycardia
 Benzothiazepines: Diltiazem
 Intermediate effect on heart rate and blood vessels

27. CCB…..
Therapeutic uses
 Maintenance (long term) treatment of HTN
 hypertensive emergencies
 HTN coexisting with
Ischemic heart disease, Chronic pulmonary
disease, DM, andVariant angina
27

28. Adverse effects
Dihydropyridines
 Flushing, headache, dizziness, excessive
hypotension, peripheral edema (dose related) and
reflex tachycardia (with short-acting nifedipine ); less
common---GI disturbance (nausea, constipation,
anorexia, GERD)
Non-dihydropyridinem
 Headache, dizziness, flushing, GI disturbances,
nausea, constipation (esp. verapamil), anorexia,
GERD
 Verapamil (most marked negative inotropic action…
contraindicated in heart failure, heart block)
 CCBs, particularly nifedipine, have been associated
with gingival overgrowth or hyperplasia

29. 29
Drugs that alter sympathetic nervous
system function
Primary mechanism of action
 sympathetic activity to heart &/or blood vessels →
decease CO and/or TPR
All the drugs elicit compensatory renal effects
 Sodium & water retention  expand blood volume
 Effective if used concomitantly with diuretics

30. 30
Centrally acting 2 agonists
Drugs: clonidine, guanfacine, guanabenz, -methyldopa
Acts centrally to reduce sympathetic outflow
 Lower BP primarily by stimulating 2-AR in the
brainstem⇒ ↓sympathetic outflow from the vasomotor
center and ↑vagal tone
 Also through peripheral stimulation of presynaptic 2 -AR
to ↓sympathetic tone (↓NE release)
 ↓sympathetic activity + ↑ parasympathetic activity⇒ ↓
HR, CO, TPR, plasma renin activity, and baroreceptor
reflexes

31. Methyl dopa
−is a prodrug and must be converted in the CNS to
active α - methyl norepinephrine to exert the effect
on blood pressure
−The decrease in sympathetic out flow from the
medula results either in decrease of peripheral
resistance or cardiac output.
31

32. Methyl dopa cont…
Uses
 Mild to moderate hypertension.
Side effects
 CNS - Sedation, headache, dizziness
 GIT - dry mouth, nausea,vomiting
 Others - Postural hypotension, impotence, allergic
reactions.
32

33. Clonidine
 Reduce cardiac output due to decreased heart rate and
relaxation of capacitance vessels, with a reduction in peripheral
vascular resistance.
 Reduction in arterial blood pressure is accompanied by
decreased renal vascular resistance and maintenance of renal
blood flow.
33

34. Clonidine cont....
 As with methyldopa, clonidine reduces blood pressure in the
supine position and only rarely causes postural hypotension
 Pressor effects of clonidine are not observed after ingestion of
therapeutic doses of clonidine, but severe hypertension can
complicate a massive overdose
34

35. Clonidine cont....
Pharmacokinetics & Dosage
 Clonidine is lipid-soluble & rapidly enters the brain
 However, as is not the case with methyldopa, the dose-response
curve of clonidine is such that increasing doses are more
effective (but also more toxic)
 A transdermal preparation of clonidine that reduces BP for 7 days
after a single application is also available.
 This preparation appears to produce less sedation than clonidine
tablets but is often associated with local skin reactions
35

36. Clonidine cont....
Toxicity
 Dry mouth and sedation are common and should not be given
to patients who are at risk for mental depression and should be
withdrawn if depression occurs during therapy.
 Withdrawal of clonidine after protracted use, particularly with
high dosages (more than 1 mg/d), can result in life-threatening
hypertensive crisis mediated by increased sympathetic nervous
activity. [rebound effect of clonidine]
36

37. Rebound effects of Clonidine results in:
 Patients exhibit nervousness
 tachycardia
 headache and sweating
What is a solution for the rebound effect of clonidine?
 If the drug must be stopped, it should be done gradually
while other antihypertensive agents are being
substituted
37

38. Clonidine cont….
Drug interaction
 Concomitant treatment with tricyclic antidepressants may
block the antihypertensive effect of clonidine. WHY?
◦ The interaction is believed to be due to α -adrenoceptor-
blocking actions of the tricyclics
38

39. 39
Ganglionic nicotinic receptor blockers
Eg.Trimethaphan
 Are of historical value
 Currently no longer in use due to intolerable adverse effects
 Adverse effects
Sympathetic: orthostatic hypotension, sexual dysfunction ...
Parasympathetic: constipation, urinary retention, dry mouth,
blurring of vision..

40. 40
Adrenergic neuron blocking agents
Reserpine
 An alkaloid from the root of Rauwolfia serpentina
 MOA
Inhibits the vesicular catecholamine transporter that
facilitates vesicular storage
Results in pharmacological sympathectomy
Depletes amines in CNS and peripheral adrenergic
neuron

41. 41
 Pharmacological Effects
 in CO and TPR,  in HR, renin secretion
Salt and water retention
 Adverse effects
Sedation, impaired concentration, depression that can
lead to suicidal attempt
Contraindicated in patients with a history of depression.
Nasal stuffiness, exacerbation of peptic ulcer disease
 Therapeutic use: mild to moderate hypertension

42. 42
Guanethidine
 MOA
Transported into neuronal terminals by uptake1
Concentrated in vesicles and deplete NE
 Adverse effects
Marked orthostatic hypotension, bradycardia
Doesn’t cross the BBB; hence no central adverse effects
 Therapeutic use:
Reserved for the treatment of severe HTN
 Due to severe adverse effects & its high efficacy.

43. β-adrenoceptor blockers
Drugs differ in
 Lipid solubility
 Selectivity for the 1-AR subtype
 Presence/absence of intrinsic sympathomimetic activity
 All have similar antihypertensive efficacy

44. 44
Drugs with out ISA
 Initially reduce CO, TPR; no change in BP.
 Latter TPR returns to pretreatment values while CO
remains reduced, hence BP is reduced
Drugs with ISA: less effect on HR & CO (at rest)
 ReduceTPR reduced BP (β2- stimulation)
Precautions
 Asthma , SA or AV nodal dysfunction
 CHF, DM
 NB: Sudden discontinuation causes rebound HTN

45. β-adrenoceptor blockers
Cardioselective/
β1 selective
Nonselective ISA
Mixed (1,β1)
blockers
Cardioselecti
ve
and
vasodilatory
Atenolol
Betaxolol
Bisoprolol
Metoprolol
Esmolol
Nadolol
Propranolol
Timolol
Acebutolol
Carteolol
Penbutolol
Pindolol
Labetalol,
carvedilol
Nebivolol

46. 46
1-AR blockers
 Prazocine, Doxazocine, Terazocine etc..
 Initially reduce arteriolar resistance and increase venous
capacitance  reduce BP
 Then sympathetically mediated reflex increase in heart rate and
plasma renin activity
 On long term use, vasodilatation persists; but the CO, HR, and
renin activity return to normal
  in BP

47. 47
Adverse effects
 Increased risk of CHF
Therapeutic use
 Not useful for monotherapy (should be combined with
β blockers, diuretics or other antihypertensive agents)
 For hypertensive patients with benign prostatic
hyperplasia

48. 48
Renin
 Synthesized, stored, and released by the renal
juxtaglomerular cells.
 Angiotensinogen synthesized in the liver
 Renin cleaves angiotensinogen to angiotensin I (rate limiting
step in the process), which is then cleaved by converting
enzymes to angiotensin II
Drugs that alter the formation or action of
Angiotensin II

49. 49
 Angiotensin Converting enzyme (ACE/peptidyl dipeptidase)
converts AGN I to AGN II
 AGN II
 Metabolized by angiotensinases to inactive metabolites

50. 50

51. 51

52. 52
Angiotensin converting enzyme inhibitors (ACE-I)
 Inhibit conversion of AG-I to AG-II
 Drugs include Captopril, Enalapril, Fosinopril…..
 Pharmacological effects
 Decrease PVR–due to reduced salt & water retention
 Prominent reduction in renal vascular resistance
 Inhibits inactivation of bradykinnin
 Reduced systemic BP – No change in HR & CO

53. 53

54. 54
 All ACEIs have similar
 Efficacy, therapeutic use
 Adverse effect profile, contraindications
 Pharmacokinetics-orally effective;
 Differ in absorption & hepatic first pass effect
 Elimination is in the urine;
 Therapeutic uses: HTN, Left ventricular hypertrophy,Acute MI ,
CRF

55. 55
 Adverse effects: generally well tolerated
 Hypotension, dry Cough, Angioedema, hyperkalemia,
Acute renal failure, Fetal damage, Skin rashes,
proteinuria, glycosuria, etc

56. 56

57. 57
Angiotensin II receptor blockers
 Antagonize the effects of angiotensin II
 Block preferentially AT1 receptors
 Vasodilation, Increase salt and water excretion
 Reduce plasma volume, and
 Decrease cellular hypertrophy.
 Do not affect inactivation of bradykinin (contrast to ACE-I),
hence do not cause dry cough & angioedema
 AT2 may elicit antiproliferative and antigrowth responses.

58. 58
Angiotensin II receptor blockers
 Peptides: Salarsan
 Non-peptides: orally active & potent
 Losartan,Valsartan,Telmisartan, Irbesartan
 Similar to ACEIs with regard to
 Pharmacological effect,Therapeutic use
 Adverse effects; and contraindications

59. 59
Conditions warranting special emphasis
Pregnancy: Drugs used to be taken prior to pregnancy can be
continued
 Except ACEIs & AT1 receptor antagonists
 Methyldopa is commonly used;Avoid β blockers
Elderly: use smaller doses; simpler regimens
 Monitor for adverse drug effects
DM: use drugs with fewer adverse effect on carbohydrate
metabolism
 ACEIs,AT1 receptor blockers, CCB, and α1-AR blockers
Asthma: avoid β- blockers

60. Conditions warranting special emphasis
Pregnancy
60

61. Conditions warranting special emphasis
Elderly
 Very elderly patients (>75 years of age) respond best to
thiazides and CCBs but less response with ACEIs,
ARBs, and β-blockers
 Prone to orthostatic hypotension and dizziness
 Use smaller than usual initial doses as initial therapy
 Monitor for adverse drug effects
61

62. Conditions warranting special emphasis
62
Race also affects drug selection
 African-American are more responsive to thiazide
diuretics and calcium-channel blockers than β-blockers or
ACEIs/ARBs

63. Consideration during comorbid conditions
63
 Osteoporosis [Thiazide Diuretics ]
 Atrial arrhythmias, migraine [β-blockers]
 Benign Prostatic Hyperplasia [ 1 – blockers]
 DM: use drugs with fewer adverse effect on carbohydrate
metabolism [ACEIs, AT1 receptor blockers, CCB, and α1-AR
blockers]
 Asthma: avoid β- blockers

64. Stepped-care approach
64