This document discusses hypertension and its treatment with antihypertensive drugs. It defines hypertension and describes the types of hypertension. It explains the need to treat hypertension to prevent target organ damage like eye, brain, kidney and heart disease. It then discusses the normal blood pressure regulation mechanisms involving the heart, blood vessels, kidneys, baroreflex and renin-angiotensin system. The rest of the document summarizes the mechanisms, uses, and side effects of major classes of antihypertensive drugs like diuretics, beta-blockers, calcium channel blockers, ACE inhibitors, and angiotensin receptor blockers. It emphasizes that these drugs work by interfering with the normal blood pressure regulating mechanisms.

1. AKSHIT NAVERIA M.PHARM
(Department of Pharmacology)
Antihypertensive Drugs

2. Introduction
Hypertension
Systolic Blood
Pressure (SBP)
Diastolic Blood
Pressure (DBP)
≥ 140 mmHg ≥ 90 mmHg
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3. Types of
Hypertension
Essential Secondary
A disorder of unknown origin affecting the
Blood Pressure regulating mechanisms
Secondary to other disease processes
Environmental
Factors
Stress Na+ Intake Obesity Smoking
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4. Treatment – Why?
 To prevent target organ damage:
 Eye (retinopathy)
 Brain (stroke)
 Kidney (chronic renal disease)
 Heart (coronary artery disease, CHF)
 Peripheral arteries (atherosclerosis)
 Even asymptomatic hypertension needs to be
treated

5. Normal Blood Pressure Regulation
 Blood Pressure = Cardiac output (CO)
X Resistance to passage of blood
through precapillary arterioles (PVR)
 CO is maintained by Heart (3) and
postcapillary venules (2)
 PVR is maintained by arterioles (1)
 Kidney (4) controls BP by affecting
volume of intravascular fluid in long
term
 Baroreflex and renin-angiotensin-
aldosterone system regulate the
above 4 sites
 Local agents like Nitric oxide cause
vasodilation and decreases BP
 All antihypertensives act via
interfering with normal mechanisms

6. Baroreceptor Reflex Pathway

7. Antihypertensive Drugs
 Diuretics
 Thiazides, loop diuretics, K-sparing diuretics
 Sympathoplegic drugs
 ß-adrenergic blockers, α -adrenergic blockers, Centrally acting
drugs
 Direct vasodilators
 Calcium channel blockers, Minoxidil, Hydralazine, Sodium
nitroprusside
 Angiotensin antagonists
 Angiotensin-converting Enzyme (ACE) inhibitors, Angiotensin
receptor 1(AT1) blockers

8. Diuretics
 Mechanism of antihypertensive action:
 Initially: diuresis – depletion of Na+ and body fluid
volume – decrease in cardiac output
 Subsequently after 4 - 6 weeks, reduction in total
peripheral resistance (TPR)
 Thiazides: Hydrochlorothiazide
 Loop diuretics: Furosemide
 K+ sparing diuretics: Spironolactone, triamterene and
amiloride

9. Diuretics

10. Diuretics
 Thiazide diuretic is the first-choice drug in mild
hypertension
 Thiazide diuretic can be used with a potassium
sparing diuretic
 Example: Triamterene-H
 Loop diuretics are used only in complicated cases
 CRF, CHF marked fluid retention cases

11. Thiazide diuretics
 Adverse Effects (mostly seen in higher doses):
 Hypokalaemia
 Hyperglycemia: precipitation of diabetes
 Hyperlipidemia: rise in total LDL level – risk of stroke
 Hyperurecaemia: inhibition of uric acid excretion
 Hypercalcemia
 Thiazide diuretics reduce mortality and morbidity in
patients with BP

12. Beta-adrenergic blockers
 Mechanism of action:
 Reduction in CO
 Decrease in renin release from kidney (beta-1 mediated)
 Non-selective: Propranolol (others: nadolol, timolol, pindolol,
labetolol)
 Cardioselective: Metoprolol (others: atenolol, esmolol,
betaxolol)
 Advantages:
 Prevention of sudden cardiac death in post MI patients
 Prevention of CHF progression

13. Beta-adrenergic blockers
 Advantages of cardio-selective over non-selective:
 In asthma
 In diabetes mellitus
 In peripheral vascular disease
 Current status in treatment of BP:
 First line along with diuretics and ACEIs
 Preferred in angina pectoris
 Preferred in Post MI patients – useful in preventing
progression to CHF and mortality

14. Αlpha-adrenergic blockers
 Mechanism of action:
 Vasodilatation by blocking of alpha adrenergic
receptors in smooth muscles: Reduction in PVR,
reduction in CO by reduction in venomotor tone
 Specific alpha-1 blockers: prazosin, terazosin and
doxazosine
 Non selective alpha blockers (phenoxybenzamine,
phentolamine) are not used in chronic essential
hypertension
 Only used in pheochromocytoma

15. Αlpha-adrenergic blockers
 Adverse effects:
 Prazosin causes postural hypotension
 First-dose effect
 Fluid retention in monotherapy
 Advantages:
 Improvement of carbohydrate metabolism (diabetics)
 Improvement of lipid profile (↓ LDL, ↑ HDL)
 Treatment of benign prostatic hyperplasia (BPH)
 Current status in treatment of PB:
 Not used as first line agent, used in addition with other
conventional drugs which are failing – diuretic or beta
blocker

16. Centrally-Acting Drugs
 Mechanism of action:
 Inhibition of adrenergic discharge in brain by agonizing
alpha-2 receptors: fall in PVR and CO
 Methyldopa
 Various adverse effects – cognitive impairement, postural
hypotension, hemolytic anemia
 Not used therapeutically now except in Hypertension during
pregnancy
 Clonidine
 Not frequently used now because of tolerance and
withdrawal hypertension

17. Calcium Channel Blockers -
Classification

18. Calcium Channel Blockers (CCBs)
 Mechanism of action:
 Blockade of L-type voltage-gated calcium channels in heart and
vessels: vascular smooth muscle relaxation (↓ PVR), negative
chronotropic and ionotropic effects in heart (↓CO)
 DHPs (amlodipine and nifedipine) have highest smooth muscle
relaxation followed by diltiazem and verapamil

19. Calcium Channel Blockers
 Advantages:
 Can be given to patients with
 Asthma with BP
 Angina with/without BP
 Peripheral vascular disease
 Prophylaxis of migraine
 Immediate acting Nifedipine is not encouraged
anymore
 Not first line of antihypertensive unless indicated

20. Vasodilators - Hydralazine
 Mechanism of action:
 Hydralazine molecules combine with receptors in the
endothelium of arterioles and causes Nitric oxide release –
relaxation of vascular smooth muscle – fall in PVR
 Adverse effects:
 Reflex tachycardia
 Salt and water retention
 Drug-induced lupus erythematosus
 Uses:
 Moderate hypertension when 1st line fails – with beta-
blockers and diuretics
 Hypertension in pregnancy

21. Vasodilators-Sodium Nitroprusside
 Mechanism of action:
 Rapidly produces nitric oxide to relax both resistance and
capacitance vessels (↓PVR and CO)
 Uses: Hypertensive Emergencies
 (slow infusion)

22. Vasodilators – Minoxidil
 Mechanism of action:
 Hyperpolarization of smooth muscles by opening potassium
channels and thereby relaxation of vascular smooth muscles
 mainly 2 major uses – antihypertensive and alopecia
 Rarely indicated in hypertension
 Only in life threatening chronic hypertensions e.g. in chronic renal
failure
 More often in alopecia to promote hair growth

23. Angiotensin Converting Enzyme (ACE)
Inhibitors
What is Renin – Angiotensin
System (RAS)?

24. RAS
 Renin is produced by juxtaglomerular cells of kidney
 Renin is secreted in response to:
 Decrease in arterial blood pressure
 Decrease in Na+ in tubular fluid
 Increased sympathetic nervous activity
 Renin acts on a plasma protein, Angiotensinogen, and cleaves it
to produce Angiotensin-I
 Angiotensin-I is rapidly converted to Angiotensin-II by ACE
(present in luminal surface of vascular endothelium)
 Angiotensin-II stimulates Aldosterone secretion from Adrenal
Cortex

25. RAS
Vasoconstriction
Na+ & water
retention
(Adrenal cortex)
Kidney
Increased
Blood Vol.
Rise in BP

26. RAS – Actions of Angiotensin-II
1. Powerful vasoconstrictor particularly arteriolar
2. It increases myocardial force of contraction (CA++
influx promotion)
3. Mitogenic effect – cell proliferation
4. Aldosterone secretion stimulation – retention of
Na++ and water in body
5. Vasoconstriction of renal arterioles – rise in IGP –
glomerular damage

27. Angiotensin-II
 What are the chronic ill effects?
 Volume overload and increased PVR
 Hypertension – long standing will cause ventricular
hypertrophy
 Cardiac hypertrophy and remodeling
 Renal damage
 Risk of increased CVS related morbidity and mortality
 ACE inhibitors reverse actions of Ang II

28. ACE Inhibitors
 Captopril, Enalapril, Ramipril, Fosinopril
etc.

29. ACEIs – Antihypertensive action
 RAS is overactive in 80% of hypertensive
cases and contributes to the maintenance of
vascular tone and volume overload
 RAS inhibition by ACEIs causes Lower PVR
and volume overload hence lower BP

30. ACEIs – Adverse effects
 Cough – persistent cough in 20% cases induced by inhibition of
bradykinin breakdown in lungs
 Hyperkalemia (routine check of K+ level)
 Acute renal failure (bilateral renal artery stenosis)
 Angioedema: swelling of lips, mouth, nose etc.
 Foetopathic: hypoplasia of organs, growth retardation etc
 Contraindications: Pregnancy, bilateral renal artery stenosis,
hypersensitivity and hyperkalaemia

31. Place of ACE inhibitors in HTN
 Drug of choice in:
 HTN with diabetes (nephroprotective)
 HTN with chronic renal disease
 HTN with CHF
 HTN with MI
 Minimal worsening of quality of life – general
wellbeing, sleep and work performance etc.

32. ACE inhibitors – other uses
 Congestive Heart Failure (CHF)
 Myocardial Infarction (MI)
 Diabetic Nephropathy

33. Angiotensin Receptor Blockers
(ARBs)
Angiotensin Receptors: Most of the physiological actions of
angiotensin are mediated via AT1 receptor
 ARBs block the actions of A-II: vasoconstriction, aldosterone
release
 No inhibition of ACE, therefore no accumulation of bradykinin
 Cough is rare with ARBs
 Indications of ARBs are similar to those of ACEIs.
 Examples: Losartan, candesartan, valsartan and telmisartan