This document discusses the pharmacotherapy of hypertension. It begins by defining hypertension and discussing its physiological regulation. It then covers the principles of antihypertensive therapy, classifying drugs by their primary mechanisms of action. The main drug classes discussed are diuretics, sympatholytics, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers, direct renin inhibitors, and vasodilators. For each class, it describes the pharmacological effects, therapeutic uses, dosing, and adverse drug reactions. It concludes by discussing lifestyle modifications and strategies for dosing antihypertensive drugs according to JNC8 guidelines.

1. Pharmacotherapy of Hypertension
Ankita Mishra
JNMCH
AMU,ALIGARH

2.  Chronic sustained elevation of systemic arterial blood pressure.
JNC 8 Recommendation
• Definitions of HTN and prehypertension not addressed, but thresholds for
pharmacologic treatment are defined.
Introduction

3.  Depending on methods of patient ascertainment
• Essential hypertension: ~80–95%
• Secondary hypertension: 5–20%

4. Physiological regulation of BP
 overlapping mechanism
• Neural:
• Baroreceptor, Chemoreceptor reflexes, RVLM
• Hormonal:
• Catecholamines, RAAS, Vasopressin
• Renal body fluid control system:
• Pressure natriuresis, diuresis

6. Principles of Antihypertensive Therapy
 Arterial pressure = cardiac output X peripheral vascular resistance.
• BP lowered by actions on TPR, CO, or both.
• CO -decreased by inhibiting myocardial contractility or by decreasing
ventricular filling pressure.
• Reduction in ventricular filling pressure - by actions on venous tone or on
blood volume via renal effects.
• TPR –decreased by acting on smooth muscle to cause relaxation of
resistance vessels.
• Or by interfering with activity of systems that produce constriction of
resistance vessels (sympNS, RAAS).

7. Classification of Antihypertensive Drugs by Their
Primary Site or Mechanism of Action

8. • Diuretics
• Thiazides & related agents (hydrochlorothiazide, chlorthalidone,
chlorothiazide, indapamide, metolazone)
• Loop diuretics (furosemide, bumetanide, torsemide, ethacrynic acid)
• K+-sparing diuretics (amiloride, triamterene, spironolactone)
• Sympatholytic drugs
• β receptor antagonists (metoprolol, atenolol, betaxolol, bisoprolol,
carteolol, esmolol, nadolol, nebivolol, penbutolol, pindolol, propranolol,
timolol)
• α receptor antagonists (prazosin, terazosin, doxazosin,
phenoxybenzamine, phentolamine)
• Mixed α-β receptor antagonists (labetalol, carvedilol)
• Centrally acting adrenergic agents (methyldopa, clonidine)

9. • Ca2+ channel blockers Verapamil, diltiazem, felodipine, nicardipine,
isradipine, amlodipine, clevidipine, nifedipine
• Angiotensin-converting enzyme inhibitors Captopril, enalapril, lisinopril,
ramipril, fosinopril, moexipril, perindopril, trandolapril
• AngII receptor antagonists Losartan, candesartan, irbesartan, valsartan,
telmisartan, eprosartan, olmesartan)
• Direct Renin Inhibitor Aliskiren
• Vasodilators 1.Arterial(hydralazine)
2.Arterial and venous (nitroprusside)

10. Diuretics
• THIAZIDE:
• Hydrochlorothiazide prototype drug.
• Exact mechanism of BP reduction is not certain.
• Initially decreases ECV by interacting with thiazide-sensitive NaCl co-
transporter (NCC) in DCT, enhancing Na+ excretion in urine, leading to fall
in CO.
• Long-term effect due to decreased vascular resistance;
• Thiazides directly or indirectly promote vasodilation.

11. • DOSE-12.5 mg- 25 mg daily of chlorthalidone or hydrochlorothiazide.
• Most patients respond within about 4-6 wks.
• ADRs- Hypokalemia, Hyperuricemia, Hypercalcaemia, Hyperglycaemia,
Hyperlipidaemia, Hypersensitivity reaction.

12. • OTHER DIURETIC ANTIHYPERTENSIVE AGENTS
• Thiazide diuretics more effective antihypertensive than loop diuretics.
• Not preferred in mild to moderate HTN.
• Efficacy of loop diuretics in producing a rapid and profound natriuresis can
be detrimental for HTN.
• Useful in patients with azotemia or with pulmonary edema.

13. • Amiloride [K+-sparing diuretic] has some efficacy in lowering BP.
• Spironolactone, lowers BP but has significant ADRs, especially in men
(e.g., erectile dysfunction, gynecomastia, benign prostatic hyperplasia).
• Should be used cautiously with frequent measurements of K+
concentrations in plasma.
• Renal insufficiency is a relative contraindication to the use of K+-sparing
diuretics.
• Concomitant use of an ACEI or an ARA magnifies risk of hyperkalemia.

14. Sympatholytic Agents
• β RECEPTOR ANTAGONIST
• MOA- Reduction in myocardial contractility, HR and CO ; blockade of JG
complex β receptor, reducing renin secretion- diminishing production of
circulating AngII; nebivolol and celiprolol promotes endothelial cell
dependent vasodilation via activation of NO pathway.
• PHARMACOLOGICAL EFFECTS
• Vary in selectivity for β 1 receptor, presence of ISA and vasodilating
capacity.
• Drugs without ISA - initial reduction in CO and a reflex-induced rise in TPR ,
no net change in BP.
• Drugs with ISA -lesser decreases in HR and CO;

15. • THERAPEUTIC USES- Provide effective therapy for all grades of HTN.
• Once- or twice-daily administration.
• Elderly and African-Americans show less response.
• The combination of a β antagonist, a diuretic, and a vasodilator is effective if
third drug required.
• Highly preferred for hypertensive patients with MI, IHD, CHF.
• ADRs- Bradycardia, cold extremities, sleep disturbance, bronchoconstriction,
hypoglycaemia, rebound HTN (withdrawal).

16. • α1 ADRENERGIC RECEPTOR ANTAGONISTS
• PHARMACOLOGICAL EFFECTS
• Initially, reduce arteriolar resistance and increase venous capacitance and
cause a sympathetically mediated reflex increase in HR and plasma renin
activity.
• Long-term therapy- vasodilation persists, but CO, HR, and plasma renin
activity return to normal.
• Retention of salt and water occurs in many patients during continued
administration- attenuates the postural hypotension.
• Reduce triglycerides, LDL and increase HDL.

17. • THERAPEUTIC USES
• Not recommended as monotherapy.
• Used with diuretics, β blockers, and other antihypertensive agents.
• Use for hypertensive patients with BPH, because they also improve urinary
symptoms.
• ADRs- Postural hypotension, impotence, nasal congestion, Na+ and water
retention.

18. • COMBINED α1 AND β ADRENERGIC RECEPTOR ANTAGONISTS
• LABETALOL- α1antagonist, nonselective β antagonist with partial agonist
activity.
• Can reduce BP sufficiently rapidly to be useful for the treatment of
hypertensive emergencies.
• CARVEDILOL- is a β antagonist with α1 antagonist activity.
• Approved for hypertension and symptomatic HF.
• Reduces mortality in patients with CHF when used as an adjunct to
therapy with diuretics and ACE inhibitors.
• Not be given in decompensated HF.

19. • METHYLDOPA
• Centrally acting agent; Prodrug
• Analog of DOPA- metabolized by a.a decarboxylase – methyldopamine-
converted to -methylnorepinephrine -Stored in secretory vesicles of
adrenergic neurons, substituting for NE.
• Inhibit adrenergic neuronal outflow in CNS.
• Agonist at presynaptic α2 adrenergic receptors in brainstem, attenuating NE
release.
• THERAPEUTIC USE- HTN during pregnancy; effective and safe for mother and
fetus.
• Dose is 250 mg twice daily.
• Single daily dose at bedtime minimizes sedative effects, twice daily is
required for some.

20. • ADRs- Sedation, depression, dryness of the mouth, diminished libido,
parkinsonian signs, hyperprolactinemia, gynecomastia and galactorrhea,
hepatotoxicity, hemolytic anemia.

21. • α 2 RECEPTORS AGONIST-
• Clonidine prototype.
• Stimulate α 2A subtype of α 2 receptors in brainstem, resulting in a
reduction in sympathetic outflow from CNS.
• At higher doses, these drugs can activate α 2B subtype on vascular smooth
muscle cells.
• THERAPEUTIC USE- Not a leading option for monotherapy of HTN.
• Effectively lower BP in some patients who have not responded to other
agents.

22. • Used in hypertensive for diagnosis of pheochromocytoma. [lack of
suppression of plasma concn. of NE to >500 pg/mL 3 hours after oral dose
of 0.3 mg of clonidine suggests tumor presence].
• ADRs-
• Sedation, xerostomia (parotid gland swelling and pain), postural
hypotension, sleep disturbances, restlessness, depression, bradycardia
and sinus arrest, contact dermatitis(transdermal).
• Sudden discontinuation of clonidine α2 adrenergic agonists may cause a
withdrawal syndrome.

23. Ca2+ Channel Antagonists
• Bind to α1 subunit of L-type Ca2+ channels and reduce Ca2+ flux through
voltage sensitive channel.
• PHARMACOLOGICAL EFFECTS-
• Actions in Vascular Tissue- relax arterial smooth muscle, less effect on
venous beds, do not affect cardiac preload.
• Verapamil less potent vasodilator than dihydropyridine.
• Actions in Cardiac Cells- Verapamil-direct negative chronotropic,
dromotropic & inotropic effects; less with DHP
• Greater degree of peripheral vasodilation seen with DHP- sufficient
increase in symp. tone reflexly to overcome negative inotropic effect.

24. • THERAPEUTIC USE- given alone or in combination with other drugs for HTN.
• Can achieving BP control as monotherapy in elderly subjects and African-
Americans.
• May be preferred in patients with isolated systolic HTN.
• ADRs- GERD, Urinary retention, Rash, Elevations of liver enzymes.
• Nifedipine- Tachycardia, Worsening of angina, Headache, Hypotension, Fluid
retention.
• Verapamil- Bradycardia, Transient asystole, HF exacerbation, Constipation.

25. Angiotensin-Converting Enzyme Inhibitors
• Captopril was first agent to be developed for treatment of HTN.
• Blocks the conversion of ANG I to ANG II.
• Also inhibit degradation of bradykinin.
• THERAPEUTIC USE- ACEI lower BP to some extent in most patients.
• Response more in young and middle-aged Caucasian patients.
• Preferred initial agent in diabetic and CRD patients.
• Patients with hypertension and IHD are candidates for ACEI.
• ADRs- Dry cough, Hyperkalemia, Renal failure, Angioneurotic oedema,
Teratogenic, altered taste sense

26. AT1 Receptor Antagonists
• By antagonizing AngII, these agents relax smooth muscle and promote
vasodilation, increase renal salt and water excretion, reduce plasma volume,
and decrease cellular hypertrophy.
• Also theoretically overcome some disadvantages of ACEI.
• THERAPEUTIC USES- Appear to be as effective as ACEI in HTN.
• Full effect on BP typically not until abt 4 wks.
• If BP is not controlled by AT1 antagonist alone, a second drug acting by a
different mechanism (e.g., a diuretic or Ca2+ channel blocker) may be added.
• ADRs- Hypotension, Hyperkalemia, Renal failure, Teratogenicity.

27. Direct Renin Inhibitors
• Aliskiren- the first orally effective agent.
• Directly and competitively inhibits catalytic activity of renin.
• Inhibit capacity of renin to produce AngI from angiotensinogen.
• THERAPEUTIC USES- Can be given as monotherapy with dose-dependent
increasing efficacy at 150-300 mg/day.
• Action appears to persist for 24 hrs.
• Combination with hydrochlorothiazide -greater lowering of BP.

28. • Long-term outcome studies—including assessments of target organ
damage in heart, brain, kidneys—important in establishing its role.
• Concerns of higher ADRs and lesser benefit recently.
• ADRs- Diarrhea, Cough, Angioedema, Teratogenic, hyperkalemia.

29. Vasodilators
• HYDRALAZINE- no major role with introduction of newer agents.
• Hydralazine directly relaxes arteriolar smooth muscle.
• Do not relax venous smooth muscle.
• PHARMACOLOGICAL EFFECTS- Vasodilation associated with powerful
stimulation of SNS, due to baroreceptor-mediated reflexes-
• Increased HR & contractility, increased renin activity, fluid retention;
• These effects counteract the antihypertensive effect of hydralazine.

30. • THERAPEUTIC USES- No longer a first-line drug –unfavorable ADR profile.
• May have utility in treatment of severe HTN.
• Can be useful in HTN emergencies in pregnant women (preeclampsia).
• Usual oral dosage of is 25-100 mg BD.
• ADRs- Headache, Nausea, Hypotension, Palpitations, Tachycardia, Angina
pectoris, MI
• Drug-induced lupus syndrome, Serum sickness, Hemolytic anemia, Vasculitis,
Rapidly progressive glomerulonephritis.

31. • SODIUM NITROPRUSSIDE- nitrovasodilator that acts by releasing NO.
• NO activates guanylyl cyclase–cyclic GMP–PKG pathway, leading to
vasodilation
• Mimick production of NO by vascular endothelial cells.
• Mechanism of NO release not clear.
• Tolerance does’nt develop to nitroprusside.
• PHARMACOLOGICAL EFFECTS- Nonselective vasodilator
• Regional distribution of blood flow not affected by drug.
• Renal blood flow and GFR maintained.
• Modest increase in HR and overall reduction in myocardial O2 demand.

32. • THERAPEUTIC USES-
• Used primarily to treat hypertensive emergencies.
• Lower BP during acute aortic dissection;
• Improve CO in HTN with pulmonary edema not responding to other
treatment.
• Used to induce controlled hypotension during anesthesia -reduce bleeding
in surgical procedures.

33. • Unstable molecule- decompose under alkaline conditions or when
exposed to light.
• Given by continuous IV infusion.
• Onset of action within 30 secs; peak effect within 2 min, effect disappears
within 3 minutes.
• Administered as controlled continuous infusion;
• Available in vials that contain 50 mg.
• Contents dissolved in 2-3 mL of 5% dextrose in water.
• Added to 250-1000 mL of 5% dextrose in water giving 50-200 microg/mL.
• Fresh sol. should be used, bottle covered with an opaque wrapping.
• Majority respond to an infusion of 0.25-1.5 g/kg/min.

34. • ADRs- Hypotension;
• Cyanide accumulation leading to lactic acidosis-
• Occurs when sodium nitroprusside is infused at a rate >5 microg/kg/min
or in patients receiving doses ~2 microg/kg/min for a prolonged period.
• Mismatching of ventilation with perfusion.

36. Lifestyle Modifications to Manage
Hypertension
• Weight reduction; Attain and maintain BMI <25 kg/m2 .
• Dietary salt reduction; no more than 2,400 mg/day.
• Adapt DASH type dietary plan; Rich in fruits, vegetables, reduced content
of saturated and total fat.
• Moderation of alcohol consumption.
• Smoking cessation.
• Physical activity; Regular aerobic activity, e.g., brisk walking for 30 min/d.

37. Strategies to Dose Antihypertensive Drugs (JNC8)
Strategy Description
A Start one drug, to maximum dose, and then
add a second drug.
B Start one drug, then add a second drug
before achieving max dose of first.
C Begin 2 drugs at same time, as separate pills
or combination pill. Initial combination
therapy is recommended if BP is greater
than 20/10mm Hg above goal.

38. JNC 8 Hypertension Guideline Algorithm