Anti hypertension drugs and treatment therapy for MBBS and MD students.

1. Pharmacotherapy of
Hypertension
Dr. Dayakar Marri
MD (Pharmacology)
JN Medical College, KLE University

2. Learning Objectives…
Introduction about BP & Etiology
 Hypertension mechanisms
 Anti hypertension drugs- Classification
Therapeutic uses

3. Definition:
The first number, called systolic blood pressure, measures the
pressure in arteries when heart beats.
The second number, called diastolic blood pressure, measures the
pressure in arteries when heart rests between beats.
If the measurement reads 120 systolic and 80 diastolic, you would
say, “120 over 80,” or write, “120/80 mmHg.”

4. BP=CO X TPR
Cardiac output affecting factors: Heart rate, Stroke volume,
Velocity flow, Cross section of blood vessels etc.
Total Peripheral Resistance affecting factors: Blood viscosity,
blood vessels radius and length, Blood Flow (Laminar, Turbulent)
etc.
Risk Factors:

5. Hypertension is classified into: On aetiology
 Primary hypertension: hypertension without any identifiable medical
cause (>95%).
Environmental
Genetic
 Secondary hypertension: hypertension due to a specific medical
pathology (<5%).

7. The current NICE guidelines (2011) have graded hypertension as:
According to JAC-10 & AHA guidelines:

13. A. Principles of blood pressure regulation
1. Blood pressure is regulated by the following:
a. Cardiac output
b. Peripheral vascular resistance
c. Volume of intravascular fluid (controlled at the kidney)
2. Baroreflexes adjust moment-to-moment blood pressure. Carotid
baroreceptors respond to stretch, and their activation inhibits
sympathetic discharge.
3. The renin–angiotensin system provides tonic, longer-term regulation
of blood pressure. Reduction in renal perfusion pressure results in
increased reabsorption of salt and water. Decreased renal pressure
stimulates renin production and leads to enhanced levels of
angiotensin II. This agent in turn causes resistance vessels to
constrict and stimulates aldosterone synthesis, which ultimately
increases the absorption of sodium by the kidney

14. B. Goal of therapy
1. The goal of therapy is to reduce elevated blood pressure, which
would ultimately lead to end organ damage, increased risk of
stroke, and MI.
2. This goal is achieved through the use of various drug classes, and
treatment often involves a combination of agents

17. I. Diuretics increase sodium excretion and lower blood volume.
1. Thiazide diuretics
a. Thiazide diuretics are effective in lowering blood pressure 10–15
mm Hg.
b. When administered alone, thiazide diuretics can provide relief for
mild or moderate hypertension.
c. Thiazide diuretics are used in combination with sympatholytic
agents or vasodilators in severe hypertension.
2. Loop diuretics are used in combination with sympatholytic agents
and vasodilators for hypertension refractory to thiazide treatment.
3. Potassium-sparing diuretics are used to avoid potassium depletion,
especially when administered with cardiac glycosides.
eg: Spironolactone, Eplerenone.

18. II. Adrenoceptor antagonists
1. β-Adrenoceptor antagonists (Beta blockers)
a. Propranolol
(1) Propranolol antagonizes catecholamine action at both β1- and
β2-receptors. It produces sustained reduction in peripheral
vascular resistance.
(2) Blockade of cardiac β1-adrenoceptors reduces heart rate and
contractility. β2- Adrenoceptor blockade increases airway
resistance and decreases catecholamine induced glycogenolysis
and peripheral vasodilation.
(3) Blockade of β-adrenoceptors in the CNS decreases sympathetic
activity.
(4) Propranolol also decreases renin release.
(5) Propranolol is used in mild-to-moderate hypertension

19. b. Nadolol , timolol, carteolol, pindolol, penbutolol
(1) These drugs are similar in action to propranolol and block both
β1- and β2- adrenoceptors.
(2) Nadolol has an extended duration of action.
(3) Pindolol, carteolol, and penbutolol have partial agonist activity
(sympathomimetic).
c. Metoprolol, atenolol, acebutolol, bisprolol
(1) These drugs are relatively selective for β1-adrenoceptors.
(2) Acebutolol has partial agonist activity.
d. Abrupt discontinuation of β -adrenoceptor blockers can worsen
angina and increase risk of MI. Dose should be gradually
reduced over a period of several weeks.

20. 2. α-Adrenoceptor antagonists
a. α -Adrenoceptor antagonists lower total peripheral resistance by
preventing stimulation (and consequent vasoconstriction) of α -
receptors, which are located predominantly in resistance vessels
of the skin, mucosa, intestine, and kidney.
 These drugs reduce pressure by dilating resistance and
conductance vessels.
b. The effectiveness of these drugs diminishes in some patients
because of tolerance.
(1) Prazosin, terazosin, and doxazosin
(a) These drugs are α 1-selective antagonists.
(b) These drugs are used in treating hypertension, especially in the
presence of CHF but use has diminished because no evidence of
reduced cardiovascular events with doxazosin was found in a
large clinical trial.

21. (c) Prazosin, terazosin, and doxazosin are often administered with a
diuretic and a β-drenoceptor antagonist.
(d) These drugs may produce initial orthostatic hypotension. Other
adverse effects are minimal.
(2) Phentolamine and phenoxybenzamine
(a) Phentolamine and phenoxybenzamine antagonize α 1- and α 2-
adrenoceptors.
(b) These drugs are used primarily in treating hypertension in the
presence of pheochromocytoma.
 Phentolamine is administered parenterally; phenoxybenzamine is
administered orally

22. 3. Labetalol and carvedilol
a. Labetalol is an α - and β-adrenoceptor antagonist.
b. Labetalol reduces heart rate and contractility, slows AV
conduction, and decreases peripheral resistance.
c. Labetalol is available for both oral and IV administration.
d. Labetalol is useful for treating hypertensive emergencies and in the
treatment of hypertension of pheochromocytoma.
e. Labetalol does not cause reflex tachycardia.
f. Carvedilol has a significantly greater ratio of β to α antagonist
activity than labetalol.

23. III. Agents that affect the renin–angiotensin system
1. Angiotensin converting enzyme (ACE) inhibitors
a. ACE inhibitors reduce vascular resistance and blood volume; they
lower blood pressure by decreasing total peripheral resistance.
b. ACE inhibitors include captopril , enalapril, lisinopril, ramipril,
fosinopril , benazepril, moexipril, quinapril, perindopril, and trandolapril.
c. These drugs are useful in treating mild-to-severe hypertension. Recent
studies have established beneficial effect in patients with angina, CHF,
cardiac ischemia, and post-MI.
d. ACE inhibitors may be less effective in African Americans than in
Caucasians.

24. 2. Angiotensin II receptor antagonists: losartan potassium
a. These drugs block angiotensin II type-1 (AT-1) receptors.
b. The effects of these drugs are similar to those seen with ACE
inhibitors.
c. These drugs are effective as monotherapy for hypertension.
3. Inhibitors of renin activity: aliskiren
a. Aliskiren inhibits renin and thereby reduces the production of all
angiotensins.
b. Initial clinical trials have combined aliskiren with a diuretic or an
ARB and its effectiveness seems comparable to ARBs.
c. Adverse effects are fewer compared to ACE inhibitors but include
diarrhea, headache, and dizziness

25. IV. Calcium channel-blocking agents
1. Calcium channel-blocking (CCB) agents inhibit the entry of
calcium into cardiac and smooth muscle cells by blocking the L-
type Ca2+-channel; they lower blood pressure by reducing
peripheral resistance.
2. CCBs used for treatment of hypertension include verapamil,
nifedipine, nicardipine, nisoldipine , isradipine, amlodipine ,
felodipine , and diltiazem.
3. CCBs are effective in the treatment of mild-to-moderate
hypertension.
4. When combined with a β-adrenoceptor antagonist, these agents may
lower blood pressure to a greater extent than when either class of
drug is administered separately.
5. Short-acting preparations of the dihydropyridines such as nifedipine
have been associated with an increase in cardiovascular mortality
and events, including MI and increased anginal attacks.

26. V. Other drugs
1. Centrally acting sympathomimetic agents reduce peripheral
resistance, inhibit cardiac function, and increase pooling in
capacitance venules.
a. Methyldopa
(1) Methyldopa has an active metabolite, a-methyl-norepinephrine, a
potent false neurotransmitter.
(2) Methyldopa activates pre-synaptic inhibitory α-adrenoceptors and
postsynaptic α2- receptors in the CNS and reduces sympathetic
outflow. It decreases total peripheral resistance.
(3) Methyldopa reduces pressure in standing and supine positions.
(4) Methyldopa is used to treat mild-to-moderate hypertension; it can
be added to the regimen when a diuretic alone is not successful.
(5) Methyldopa produces adverse effects that include drowsiness, dry
mouth, and GI upset. Sexual dysfunction may occur and reduce
compliance.

27. b. Clonidine
(1) Clonidine stimulates postsynaptic α 2-adrenoceptors in the central
nervous system (CNS) and causes reduction in total peripheral
resistance.
(2) Clonidine is frequently combined with a diuretic.
(3) Clonidine commonly produces drowsiness and lethargy, dry mouth,
and constipation.
(4) This drug is available as a transdermal patch (Catapres-TTS) that
allows weekly dosing.

28. c. Guanabenz acetate
(1) Guanabenz acetate activates central α 2-adrenoceptors and
inhibits sympathetic outflow from the brain, which results in
reduced blood pressure.
(2) This drug is used in mild-to-moderate hypertension, most
commonly in combination with a diuretic.
(3) Guanabenz acetate most commonly produces sedation and dry
mouth as adverse effects but with reduced frequency compared to
clonidine.

29. 2. Adrenergic neuronal blocking drugs
a. Reserpine
(1) Reserpine eliminates norepinephrine release in response to nerve
impulse by preventing vesicular uptake. It depletes norepinephrine
from sympathetic nerve terminals in the periphery and in the
adrenal medulla.
(2) Reserpine is used in mild-to-moderate hypertension.
(3) Reserpine most commonly produces GI disturbances, Mental
depression, sometimes severe, may result, especially with high
doses; use of reserpine is contraindicated in patients with a history
of depression.

30. 3. Vasodilators
a. Vasodilators relax smooth muscle and lower total peripheral
resistance, thereby lowering blood pressure.
b. The use of vasodilators is declining as a result of newer modalities,
such as ACE inhibitors and calcium channel-blocking agents,
which are more effective with fewer adverse effects.
(1) Hydralazine
(a) Hydralazine reduces blood pressure directly by relaxing arteriolar
muscle. This effect is probably mediated by increasing K+ efflux
and decreasing Ca2+ influx, and increasing the production of nitric
oxide.
(b) Hydralazine elicits the baroreceptor reflex, necessitating
coadministration with a diuretic to counteract sodium and water
retention and a β-blocker to prevent tachycardia.
(c) This drug is used to treat chronic hypertension and in hypertensive
crises accompanying acute glomerular nephritis or eclampsia.
(d) Hydralazine may cause a lupusl ike syndrome

31. (2) Minoxidil
(a) Minoxidil has effects similar to hydralazine.
Minoxidil acts to increase K+ efflux, which hyperpolarizes cells and
reduces the activity of L-type (voltage-sensitive) calcium channels.
Minoxidil vasodilates predominantly arteriolar vessels.
(b) Minoxidil also elicits the baroreceptor reflex, necessitating use of a
beta-adrenoceptor antagonist and a diuretic.
(c) Minoxidil is useful for long-term therapy of refractory
hypertension.
(d) Minoxidil produces hirsutism, an advantage in formulations that
are now used to reduce hair loss in both males and females.

32. (3) Sodium nitroprusside
(a) It dilates both resistance and capacitance vessels; it increases heart
rate but not output.
(b) This drug is frequently used in hypertensive emergencies because
of its rapid action. Continuous infusion is necessary to maintain
effects.
(c) Sodium nitroprusside is usually administered with furosemide.
(d) On initial infusion, it may cause excessive vasodilation and
hypotension.
(e) This drug can be converted to cyanide and thiocyanate.
 The accumulation of cyanide and risk of toxicity are minimized by
concomitant administration of sodium thiosulfate or
hydroxocobalamin.

33. (4) Diazoxide
(a) Diazoxide is used intravenously to reduce blood pressure rapidly,
usually in an emergency situation.
(b) Diazoxide is administered with furosemide to prevent fluid
overload.
(c) This drug is declining in use because of its unpredictable action and
adverse effects.
4. Fenoldopam is a selective agonist at dopamine DA1 receptors that
increases renal blood flow while reducing blood pressure.
Administered by infusion, it is a useful drug in the control of
emergency hypertension.

34. 5. Specialized vasodilators
a. Drugs used to treat pulmonary hypertension
(1) Ambrisentan is a selective endothelin A receptor antagonist used to
treat pulmory hypertension.
 Plasma endothelin-1 is elevated in patients with pulmonary
hypertension. Ambrisentan is administered orally.
 Peripheral edema is a common adverse effect of endothelin
receptor antagonists.
(2) Bosentan antagonizes both endothelin A and B receptors and
reduces pulmonary hypertension. Headache and edema are
common side effects.
(3) Use of both ambrisentan and bosentan is controlled by access
programs.

35. b. Drugs used to treat erectile dysfunction
(1) Drugs in this class include sildenafil citrate, tadalafil, and
vardenafil hydrochloride.
(2) Viagra was originally developed as an antianginal and
antihypertensive agent but proved very effective in treating
erectile dysfunction.
(3) These agents specifically inhibit phosphodiesterase type V, the
class of enzymes that are responsible for the breakdown of
cGMP.
 The type V isoform is expressed in reproductive tissues and the
lung. Inhibition of the breakdown of cGMP enhances the
vasodilatory action of NO in the corpus callosum and in the
pulmonary vasculature.

36. (4) These agents are useful in the treatment of erectile dysfunction,
and sildenafil citrate is approved for treatment of pulmonary
hypertension.
(5) The most common adverse effects of the phosphodiesterase type
V inhibitors are headache, flushing, ocular disturbances, and
abdominal pain.
The most serious adverse effects are cardiovascular: arrhythmias,
heart block, cardiac arrest, stroke, and hypotension.
(6) These drugs are contraindicated in patients taking nitrates,
because of exacerbation of the effects of these drugs, or in patients
taking α1-adrenoceptor antagonists such as doxazosin.

37. Future Approach for HTN
1.Recent Trends-Drug based therapy
2.Newer approach- Gene therapy and vaccine therapy
3.Device based therapy
 New targets and drugs
•RAS modulators- Pro rennin Receptor blockers-Handle region peptide
•Ang(1-7)/Mass receptor/ACE-2 Activator (DIZE)
Vaso peptide inhibitors: Neprilysin inhibitors (LCZ696)
Valsartan+Sacubitral)
ANP Agonists: PL-3994
Endothelin Converting Enzyme Inhibitors: Daglutril
Aldosterone synthase inhibitor: LCI 699, Fadrazole

38. 2.Gene based therapy:
Target: ACEII & AT2 receptor expression enhanced
(Adeniviral vactor—gene—Increase eNOS/NO)
Antisense gene for ACE &AT2 receptor
Vaccine: PMO 3117—Against Angiotensin-II
CYT 006-- Against Angiotensin-II
3.Device based therapy:
Renal Sympathetic denervation
Baro-reflex activation therapy
Arterio-Venous fistula

39. TREATMENT OF HYPERTENSION
The aim of antihypertensive therapy is to prevent morbidity and
mortality associated with raised BP.
 Both systolic and diastolic BP predict the likelihood of target organ
damage (TOD)and complications such as:
• Cerebrovascular disease, TIA, stroke, encephalopathy.
• Hypertensive heart disease-left ventricular hypertrophy, HF.
• Coronary artery disease (CAD), angina, MI, sudden cardiac death.
• Arteriosclerotic PVD, retinopathy.
• Dissecting aneurysm of aorta.
• Glomerulopathy, renal failure.
Patients who have already suffered some TOD have greater risk of
further organ damage and death at any level of raised BP.

40. Risk of complications depends not only on the level of BP, but also
on other risk factors and existing target organ damage

41. The JNC8 have also identified compelling indications, mandate to
use of specific antihypertensive drugs with BP values lower than
140/90 mm Hg.
Moreover, presence of compelling indications may suggest fixing
a lower target BP value to be attained by drug therapy.

42. However, for patients aged ≥60 years the JNC 8 (2014) has
suggested threshold systolic BP value of 150 mm Hg for initiating
treatment, as well as to be the treatment goal (< 150 mm Hg).
 The threshold and goal diastolic BP value of 90 mm Hg is the
same as for patients <60 years age.
Studies has shown that effective use of antihypertensive drugs
reduces occurrence of stroke by 30- 50%, HF by 40- 50% and
CAD by ~ 15%.
•If the cause of hypertension can be identified (hormonal, vascular
abnormality, tumour, renal disease, drugs) all efforts should be made
to remove it.
•Nonpharmacological measures(life style modification- diet. Na+
restriction, aerobic activity or exercise, wt reduction, mental
relaxation, etc.) should be tried first and concurrently with drugs.

44. APPROACH TO THE PATIENT

45. HTN treatment: JNC 8 guidelines was released by the JNC ( joint national
committee ) in association with ACC ( American college of cardiology ) and AHA .

47. Combination therapy
diuretics, vasodilators, CCBs,
ACEIs
β blockers, clonidine,
methyldopa
Plasma renin activity
All sympathetic inhibitors
(exp b blocker)&
vasodilators ( expt CCB)
diuretics Fluid retention
Hydralazine and DHPs β blockers Tachycardia
β blockers vasodilator. Initial increase in t.p.r
Combinations to be
avoided
α or β adrenergic blocker clonidine antagonism of clonidine at
presynaptic receptor
Hydralazine DHP or prazosin similar pattern of
haemodynamic action
Verapamil or diltiazem β blocker Marked bradycardia, A-V
block

50. Hypertensive emergency/ urgency
Hypertensive Urgency:
• Systolic BP > 220 or diastolic BP > 120 mm Hg without overt signs
of end organ damage
•Blood pressure should be reduced within few hours
Hypertensive Emergency:
• Evidence of active end organ damage is labelled
•Reduction of BP within 1 hour to avoid the risk of serious
morbidity or death.
Include
Hypertensive encephalopathy
hypertensive nephropathy, intracranial hemorrhage, aortic dissection,
preeclampsia-eclampsia, unstable angina, myocardial infarction.

51. • Initial goal – reduce no more than 25% (within minutes to 1 or 2 hrs)
level of 160/100 mm Hg within 2–6 hours.
• Excessive reductions – harmful - avoid sublingual or oral fast-acting
nifedipine
• In acute ischemic stroke antihypertensives should only be used if BP >
180–200 mm Hg, BP reduced by 10-15%
•In hemorrhagic stroke minimize MAP <130mmhg
• Nicardipine I.V.- Is better tolerated and less toxic than Nitroprusside.

53. Hypertension in pregnancy:
• A sustained BP above 140/90 mm Hg during pregnancy has
implications both for the mother and the fetus:
Two types :
(a) A woman with pre-existing essential hypertension becomes
pregnant.
(b) Pregnancy induced hypertension; as in toxaemia of pregnancy—
preeclampsia

54. Antihypertensives found safer during pregnancy:
Hydralazine and Methyldopa (a positive Coombs’ test occurs,
but has no adverse implication).
Dihydropyridine CCBs: if used, they should be discontinued
before labour as they weaken uterine contractions.
Cardio selective β blockers and those with ISA, e.g. atenolol,
metoprolol, pindolol, acebutolol: may be used if no other choice.
Prazosin and clonidine—provided that postural hypotension can
be avoided.

55. Antihypertensives to be avoided during pregnancy
ACE inhibitors, ARBs: Risk of foetal damage, growth retardation.
Diuretics: Tend to reduce blood volume— accentuate
uteroplacental perfusion deficit (of toxaemia)—increase risk of foetal
wastage, placental infarcts, miscarriage, stillbirth.
Nonselective β blockers: Propranolol cause low birth weight,
decreased placental size, neonatal bradycardia and hypoglycaemia.
 Sod. nitroprusside: Contraindicated in eclampsia.

56. ANIMAL MODELS OF HYPERTENSION
1. Acute Renal Hypertension in Rats
2. Chronic Renal Hypertension in Rats
3. Chronic Renal Hypertension in Dogs
4. Neurogenic Hypertension in Dogs
5. DOCA- (Deoxycorticosterone acetate) salt Induced
Hypertension in Rats
6. Fructose Induced Hypertension in Rats
7. Genetic Hypertension in Rats
8. Hypertension Induced by Chronic NO-Synthase Inhibition
9. Pulmonary Hypertension Induced by Monocrotaline
10. Portal Hypertension in Rats .

57. Chronic model (one kidney one clip ) Renal HTN Rats
One kidney is clamped & other kidney is removed
Advantage - compensatory natriuersis & pressure diuresis is absent
with increased NA & water retention
Procedure
 Sprague Dawley rats - anesthetized – flank incision- kidney removed
– u shaped sliver clip on renal artery near aorta
4-5 weeks after clipping BP monitored if >150mmhg selected
Drug is administered pre & post drug 2 hr BP readings taken.

58. Chronic renal hypertension in dogs ( wrapping tech)
•Dog is anesthetized – midline abd incision - one kidney is wrapped
with cellophane & replaced Other kidney artery , vein & ureter is
ligated – abd closed
•Antibiotic treatment 3-4 days, temp monitored
•6 weeks BP recorded indirect tail cuff method/ carotid artery
•Test drug is given 5days
Day 1 readings every 2hours before giving drug
readings every 2 & 4 hr after giving drug
Day 3 & 4 readings every 2 & 4 hr after drug
•Evaluation – starting value is average of 2 reading before test drug
Test values are subtracted with this value

59. Fructose induced HTN in rats
•Feeding a high fructose diet induces hypertension and insulin
resistance
•Fructose feeding induce hypertension in normal in high salt fed
animals & increased AT 1 receptor
•Procedure : wistar rats caged seprated
10% fructose in drinking water
body wt, fluid & food intake, - measured
SBP & PR measured- tail cuff method
blood sample every 2nd week during treatment to
determine glucose ,insulin etc

60. DOCA (Deoxycorticosterone acetate) salt rats-
•Principle- mineralocorticoid increase BP by Na retention increase
in ECF
•Procedure – DOCA (mineralocorticoid) + high salt diet &unilateral
nephrectomy induces hypertension
• Sprague Dawley – anesthetized – flank incision –left kidney is
removed DOCA salt injected– NaCl orally
BP starts to increases after 1week upto 160-180 mmhg after 4 wks.

61. References
Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th
ed.
Essentials of Medical Pharmacology, K D. Tripathi, 8th ed
Pharmacology and Pharmacotherapeutics, RS Satoskar, 26th ed
Harrison’s Principles of Internal Medicine. 20th ed .New Delhi.
Mcgraw Hill Publications
http://circres.ahajournals.org (AHA Journal)

62. Thank you