This presentation deals with the most common antihypertensive drugs used in our day-to-day practice. The common 4 ABCDs (Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, calcium channel blockers, diuretics)

1. Antihypertensive Drugs
Dr. Karun Kumar
JR – II
Dept. of Pharmacology

3. Definition
• SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg
• 95% (Primary HTN  no specific cause) [obesity,
lack of exercise, metabolic syndrome (abdominal
obesity, hyperlipidemia, and insulin resistance), ↑
Na & alcohol intake]
• 5% (sec. HTN  CKD/hyperald.) These include
• Vascular endothelial cell dysfunction  HTN

4. Role of endothelium
• Endothelium regulates vascular smooth muscle
tone through the synthesis & release of relaxing
factors such (NO & PGI2) & vasoconstr. factors
(endothelin-1 & angiotensin II)
• Angiotensin II  Vascular injury (activating growth
factors that cause vascular smooth muscle
proliferation and hypertrophy as well as fibrotic
changes in the vascular wall)
• Oxidative stress ↑ vasoconstr. F & ↓ relaxing
factors
• Several antiHTN drugs, (carvedilol,ACE, AT1)
counteract endothelial cell dysfunction

7. Regulation of Blood Pressure
• Short term  SNS (Baroreceptor reflex)
• Long term  Kidneys (RAAS)
• Blood-borne subst. (Vasopressin & Ang II  v.c.)
• Locally released adenosine, serotonin, endothelin,
and PGs also affect arteriolar smooth muscle tone
Compensatory Rx 
1. Reflex tachycardia,
2. fluid ret. By kidneys
3. activation of RAAS

8. Diuretics
• ↑ renal Na excretion (anti-HTN activity) thiazide
diuretics (DOC) foll. By loop
• longer antiHTN effect than the loop diuretics
• The thiazides tend to promote calcium retention
• The loop diuretics enhance urinary calcium loss

9. Thiazide and Related Diuretics
• 2 mechanisms
1. Short term  (↓ BV  ↓ CO)
2. Long term  ↓ PVR (↓ Na content of arteriolar
smooth muscle cells  ↓ muscle contraction in
response to vasopressors (NE, angiotensin)
• Hydrochlorothiazide, Indapamide & Chlorthalidone
• Indapamide  Added benefit (vasodilation via CCB)

10. • Hydrochlorothiazide  mild to moderate HTN (ACE
i. or CCB may be preferable)
• Thiazide diuretics are used in combination with
another class of antihypertensive agent, because
the two drugs have additive or synergistic effects
on blood pressure.
• Using a low dosage of a thiazide diuretic (e.g., 12.5
to 50 mg of hydrochlorothiazide per day) usually
produces a maximal antihypertensive effect with
minimal hypokalemia.
• Higher dose  more hypokalemia but does not
have a greater effect on blood pressure.

11. Adverse Effects
• Thiazides elevate plasma levels of glucose, uric
acid, and lipids in some patients.
• Hematologic toxicity and aggravate hepatic disease.
(less common)
• Evoke a compensatory increase in renin secretion,
(used with Ace i) least expensive agents available
for treating hypertension.

12. Advantages of thiazides
1. Offer protection against osteoporosis (↓ Ca exc.)
2. Least expensive agents available for HTN
3. Effective and relatively safe when serum
potassium, glucose, uric acid, and lipid levels are
monitored appropriately

13. Loop Diuretics
• Greater natriuretic effect & less effective than
thiazide diuretics in the treatment of hypertensive
patients with normal renal function.
• For this reason, loop diuretics are usually reserved
for use in hypertensive patients who have poor
renal function and a serum creatinine level greater
than 2.3 mg/dL.

14. Potassium-Sparing Diuretics
• Mild natriuretic effect, and they reduce renal
potassium excretion and thereby prevent
hypokalemia caused by thiazide and loop-acting
diuretics.
• Eplerenone is similar to spironolactone but has
fewer endocrine side effects.
• Eplerenone has been found to cause regression of
left ventricular hypertrophy in hypertensive
patients and regression of microalbuminuria in
patients with type 2 diabetes.

15. SYMPATHOLYTIC DRUGS
• The sympatholytic drugs used in the treatment of
hypertension include adrenoceptor antagonists and
the centrally acting α2-adrenoceptor agonists.

16. α-Adrenoceptor Antagonists
• Not recommended bcoz Evoke reflex activation of
the SNS (↑ HR, ↑contractility  ↑ O2 demand)
• Because they activate the RAAS system & cause
fluid retention given with a diuretic.
• Cause orthostatic hypotension, “first dose” syncope
(Prevented by beginning treatment with a low dose
of the blocker at bedtime and withholding the
diuretic for a day until the body adjusts to the
lowered blood pressure)

17. β-Adrenoceptor Antagonists
• Cardiac β1-receptors  ↓ CO (↓HR & contractility
• β1-receptors in renal JG cells  inhibits renin sec.
• Also, ↓ sympathetic outflow from CNS
• Beneficial eff. in HTN persons with CVD
• Coronary heart disease  ↓ myocardial ischemia
• MI  Cardioprotective (↓ HR & vent. Arrhythmias)
• Heart failure  Improve symptoms & survival
• Role of β-blockers in treating HTN without CVD 
Less clear

18. • Most clinical guidelines  ACEi,ARB,CCB/diuretic
for HTN without preexisting heart disease.
• The β-blockers are usually well tolerated and only
rarely cause orthostatic hypotension or produce
hepatic, renal, or hematopoietic toxicity. Data from
clinical trials suggest that β-blockers are only
slightly more likely than a placebo to cause fatigue,
sleep disturbances, and sexual dysfunction, but
physically active persons may fid that β-blockers
reduce exercise capacity as a result of a reduction
in heart rate.
• β-blockers ↓ insulin sensitivity (exc. 3rd gen.)
• Also, nonsel. β-blockers delay recovery from
hypoglycemia by blocking β2-receptor–mediated
glycogenolysis and hepatic glucose production

19. • Atenolol  Less lipophilic (fewer CNS s/e)
• Labetalol  chr. HTN & HTN emergencies. Because
of its α-adrenoceptor–blocking activity, it can cause
orthostatic hypotension.
• Esmolol (i.v.)  HTN in surgical patients & in
persons with HTN emergencies
• Carvedilol has antioxidant properties that can
protect the vascular wall from free radicals that
damage blood vessels and thereby contribute to
the progression of cardiovascular disease.
• Nebivolol (3rd gen.)  selective β1-blocker with
antioxidant properties; ↑ endothelial NO rel.
(vasodilating effect) Nebivolol provides another
option for treating hypertension in patients with
heart failure, diabetes, and cardiac arrhythmias

20. Centrally Acting Drugs
• Clonidine, guanfacine, and methyldopa. (↓ symp.
outflow from VMC of medulla [α2-r] ) [↓ PVR]
• Methyldopa  converted to an active metabolite
(methylnorepinephrine) by central neurons, which
then activates α2-receptors.
• Clonidine  HTN urgencies (↓ BP to a safe level)s
also ↓ SNS symptoms of alcohol, opioid, or
nicotine withdrawal
• Methyldopa  HTN in pregnant women

21. side effects
• sedation, dry mouth, and impaired mental acuity.
• Severe rebound hypertension can occur if they are
discontinued abruptly, and the dosage should be
tapered gradually over 1 to 2 weeks if treatment is
to be stopped.
• Methyldopa is well known for its ability to cause
immunologic effects, including a Coombs-positive
hemolytic anemia, autoimmune hepatitis, and
other organ dysfunction.
• TCAs block eff. of centr. acting sympatholytic drugs

22. Angiotensin inhibitors
1. Angiotensin converting enzyme (ACE) inhibitors,
2. Angiotensin receptor blockers (ARBs)
3. Direct renin inhibitor called aliskiren.
• ACEi & ARBs  preferred drugs for the initial HTN
t/t. Also, reduce the risk of stroke & they are
particularly useful in persons with diabetes or heart
failure.

28. Angiotensin-Converting Enzyme
Inhibitors

30. Stimuli to inc. renin
1. ↓ arterial pressure in renal afferent arterioles
2. ↓ NaCl concentration in the distal renal tubule
3. SNS activation of β1-receptors on renal JG cells
• Renin  protease enzyme
• Angiotensin II activates AT1 and AT2.

31. AT1 receptors
• Coupled with enzymes that ↑ IP3 & ↓ cAMP
• Effects activation of AT1 receptors
1. Contraction of vascular smooth muscle (v.c.)
2. Sec. of aldosterone from adrenal cortex
3. ↑ reabsorption of sodium from the PCT
4. ↑ release of NE from sympathetic nerves
5. stimulation of cell growth in the arteries and
heart
• AT2 receptors appear to have roles in
cardiovascular and metabolic functions

32. • ACE  Inactiv. bradykinin, vasodilator peptide.
• ↑ renal PG synthesis
• Ang II ↑ toward pretreatment levels during long-
term ACE inhibitor therapy as a result of a
compensatory increase in renin secretion.
• This effect can be prevented by adding the direct
renin inhibitor aliskiren to the treatment regimen
• ACE inhibitors primarily lower BP by ↓ PVR
• ↓ arterial pressure (afterload) & venous pressure
(cardiac preload)

33. Adverse Effects
• Fetal & neonatal injury (Pregnant women)
• RF in pts. with bilateral renal artery stenosis
(depend on Ang II to maintain RBF & GF)
• Most common side effect  Dry cough,
angioedema (bradykinin
• Rash and an abnormal taste sensation may occur in
persons receiving captopril, which has a sulfhydryl
group as the zinc-binding moiety.

34. Interactions
• Anti-HTN action augmented by diuretics and CCBs
• interact with potassium-sparing diuretics and
potassium supplements to increase serum
potassium levels and cause hyperkalemia.
• They can also increase serum lithium levels and
provoke lithium toxicity in patients receiving lithium
compounds for the treatment of bipolar disorder.
• NSAIDs, such as ibuprofen, can impede the effects
of ACE inhibitors & other antihypertensive agents.

36. Indications
1. mild to severe HTN
2. HTN with HF, MI, CKD, or DM
3. HF & HF with MI & significant LVD (a cardiac
ejection fraction of less than 40%).
4. In diabetic patients who exhibit early signs of
renal impairment (e.g., albuminuria and ↑ serum
creatinine levels), ACE inhibitors exert a
renoprotective effect.
5. Stroke (cerebroprotective effect of acei/arb)

38. Specific Drugs
• In each class, a different chemical group binds the
zinc ion in ACE
1. Sulfhydryl compound  Captopril
2. Phosphoryl agents  fosinopril; and the
3. Carboxyl derivatives  benazepril, enalapril,
lisinopril, quinapril, and ramipril.
Enalaprilat (i.v.); others are oral

39. Angiotensin Receptor Blockers
• Block AT1 receptors and reduce
1. Vasoconstriction
2. Aldosterone secretion
3. Sodium reabsorption by the proximal tubule
4. Norepinephrine release from SNS
• candesartan, irbesartan, losartan, telmisartan,
valsartan,
• Rarely cause the dry cough that occurs with ACE
inhibitors.
• Losartan  ↓ LVH, stroke risk & new onset DM

40. • Telmisartan
1. ↑ insulin sensitivity (PPAR γ)
2. Protects patients at increased risk of CVD
3. more powerful BP lowering ability than Ramipril
• The ARBs may cause hyperkalemia, neutropenia,
and elevated serum levels of hepatic
aminotransferase enzymes.
• Not be used during pregnancy

41. CAPTOPRIL
C  Cough
A  Allergies (Angioedema, urticarial, rashes)
P  Potassium level inc.
T  Taste alteration
O  On 1st dose hypotension (orthostatic)
P  Pregnancy, Pancreatitis (C/I)
R  Renal artery stenosis
I  Indomethacin & other NSAIDs
L  Lithium, Leukopenia, Liver toxicity

42. Direct Renin Inhibitor
• Aliskiren  Protects against compensatory ↑ in
Ang II

43. Vasodilators
• CCBs, hydralazine, minoxidil, and nitroprusside
• CCBs  HTN, angina, PVD & cardiac arrhythmias
• Block Ca channels in plasma membranes of smooth
muscle  relax vascular smooth muscle (v.d.)
• Arteriolar smooth muscle > venous smooth muscle
(↓ PVR ; no eff. on CO); also have natriuretic effect
• Diltiazem and verapamil also ↓ HR & CO
• amlo, felo, isra, nicar,nife evoke reflex tachycardia.

44. • Initial t/t (HTN) & combined with diur/Acei/arb.
• Protect against stroke, coronary heart disease, and
kidney disease.
• verapamil and diltiazem reduce protein excretion in
patients with kidney disease and may be used with
an ACE inhibitor or ARB for this purpose.
• Used in HTN with asthma
• Long-acting CCB (amlodipine or a SR formulation
such as the nifedipine gi system) for 24 hr BP dec.

45. Other Vasodilators
• Hydralazine and Minoxidil  Used with other anti-
HTN drugs to treat moderate to very severe HTN
• When used alone, they often evoke reflex
tachycardia & cause fluid retention, & ppt. angina
• Hydralazine  Lupus-like syndrome, whereas
minoxidil  hypertrichosis (excessive hair growth),
particularly in women & is used for alopecia

46. Nitroprusside
• Sodium n (i.v.)  HTN emergencies.
• metabolized to CN in RBCs  thiocyanate in the
presence of a sulfur donor.  accumulate (dur. Of
therapy with this drug is usually limited to a few
days
• Fenoldopam (i.v.)  HTN emergencies (D1 rec. &
produces vd in systemic vascular beds (coronary,
renal, & mesenteric vessels); kidney  dilates both
aff. & eff. Arterioles (↑RBF)

47. Management of Hypertension
• Lifestyle Modifications exercise,wt. loss, mod. of
alcohol intake & diet low in Na & adeq. K Ca Mg.
Fruits & vegetables & low sat. & total fat.
• Selection of Drug Therapy
• Stage I HTN  A+B (<55) ; C + D (>55)
• Stage II HTN  1 out of A/B + 1 out of C/D
• Step 3  A/B + C + D
• Step 4 (Resistant HTN)  A + B + C + D

48. hypertensive
emergencies and urgencies.
• Clonidine  Less-severe HTN urgencies (slowly ↓
BP)
• Ffenoldopam, nicardipine, labetalol, and sodium
nitroprusside.
• Hydralazine  HTN associated with eclampsia
• Nitroglycerin  HTN emergency in ac. cor. Ischemia
• Enalaprilat  Acute LVF
• Esmolol  Aortic dissection & periop. HTN

49. Pheochromocytoma
• Nonmalignant, catecholamine releasing tumors
located in the medulla of the adrenal gland.
(1/1000 of HTN)
• Highly vascularized & contain ↑ NE & E (HTN crisis)
• Treatment  surgical removal
• Pretreatment  phenoxybenzamine & β-blockers
• Metyrosine  Inhibits tyrosine hydroxylase and
subsequent biosynthesis of catecholamines.