2. Physiologically, the cardiac output as well as peripheral
resistance are controlled mainly by three overlapping
mechanisms:
a. The baroreflexes, mediated by the autonomic nervous system
b. The renin-angiotensin-aldosterone system
C. A local release of hormones from vascular endothelium,
e.g.nitric oxide (NO) which dilates and endothelin 1 which
constricts blood vessels
3. Joint National Committee (JNC) classifies hypertension as follows
Category SBP mmHg DBP mmHg
Normal <120 and <80
Prehypertension 120–139 or 80–89
Hypertension, Stage 1 140–159 or 90–99
Hypertension, Stage 2 ≥160 or ≥100
4. General approaches to the treatment of
hypertension:
The use of diuretics to reduce the blood
volume.
Drugs that interfere with the RAAS and
Drug induced reduction in PVR, Cardiac output
or both.
5. Beta – blocking drugs
• In Mild to moderate hypertension.
• Mechanism:
Reduction in heart rate and myocardial contractility.
Reduced renin secretion
Reduction in central sympathetic outflow by blocking
presynaptic β-receptors centrally.
Stimulation of prostacyclin synthesis in vascular beds.
Blockade of peripheral facilitatory presynaptic β2-
receptors to reduce NE release and
Increase in natriuretic peptide secretion caused by β-
blockade.
Blockade of ADH from posterior pituitary. Β1 action.
6. • Earlier, these were employed as a first step in the
management of essential hypertension.
• However, now these are often used in conjunction with a
diuretic when monotherapy is not satisfactory.
• The combination of β-blockers, a diuretic and a vasodilator is
very effective in patients who are resistant to other
antihypertensive regimens.
• Besides HT, β-blockers are also used for the treatment of:
o supraventricular tachyarrhythmias
o previous MI and
o angina pectoris.
7. Should not be used in :
• Insulin dependent diabetes,
• Bronchial asthma or
• COPD
• Raynaud’s phenomenon,
• Variant angina and
• Acute congestive cardiac failure.
8. Adverse effects:
• Fatigue, lethargy, decreased libido and
unfavourable lipid profile.
• May produce rebound hypertension,
tachycardia and anginal pain , upon sudden
withdrawal of β – blockers.
The withdrawal syndrome involves up –
regulation and hyper – responsiveness of β –
adrenoceptors
9. • The non – selective (β1+ β2) beta – blockers:
propranolol, sotalol, nadolol, pindolol and oxprenolol.
Salient features about non selective blockers:
• Sotalol has low lipid solubility with negligible first –pass
metabolism. It has an additional K+ channel blocking and
class III antiarrhythmic property independent of β-blocking
property.
• Nadolol has longer half life and once daily dosage. It does
not cross BBB and has least first pass metabolism.
• Pindolol and oxprenolol possess some inherent intrinsic
sympathomimetic actions useful in patients prone to
bradycardia or those with low cardiac reserve.
10. Selective β1-blockers used therapeutically:
• Metoprolol, atenolol, esmolol, acebutolol, celiprolol and nebivolol.
Salient Features:
CARDIOSELECTIVE
Acebutolol and celiprolol possess ISA.
Safer in patients having concomitant asthma, diabetes, Raynaud’s
phenomenon and in those who have unfavourable lipid profile.
Atenolol does not cross BBB and has longer duration of action
than metoprolol. Nebivolol is a new hybrid drug possessing β1
adrenoceptor blockade plus vasodilating properties(3 rd
generation)
Esmolol is an ultrashort acting β1-adrenoceptor antagonist.
11. Mixed (α+β) Antagonists
Labetalol exhibits:
• selective blockade of α1 adrenoceptor,
• inhibition of neuronal uptake of NE,
• blockade of β1 receptors,
• partial agonist activity at β2 and
• some direct vasodilator properties.
• Useful in phaeochromocytoma and for controlling rebound HT after
clonidine withdrawal. Treatment of black hypertensive patients
• Postural hypotension and hepatotoxicity are main side effects.
• Carvedilol is a β1+ β2 and α1 adrenoceptor blocker
• It inhibits free radical induced lipid peroxidation and also prevents
vascular smooth muscle mitogenesis.
• Therefore cardioprotective in patients of CCF
12. Alpha - Blockers
• Phenoxybenzamine, is non selective.
• α1-selective receptor antagonists like prazosin, terazosin and
doxazosin produce lesser tachycardia than non selective α
blockers, so more used now.
• These drugs reduce arterial pressure by dilating both the
resistance and capacitance vessels
Common adverse effects includes:
• Postural hypotension
• Retention of salt and water
• Terazosin and doxazosin have a longer duration of action
• Useful in patients with concomitant complications such as gout,
diabetes and hyperlipidaemia and male hypertensive patients
having benign prostatic hyperplasia
13. Centrally Acting Antihypertensive Agents
• These agents reduce sympathetic outflow from
vasopressor Centre
Methyldopa:
• Stimulates central α2 receptors to inhibit
adrenergic neuronal outflow from the brainstem
• Valuable in HT complicated by renal insufficiency
• It is the drug of choice for treating HT during
pregnancy
• The drug should be used in conjunction with a
diuretic
14. CLONIDINE:
• At lower plasma concentration, has lesser intrinsic
activity on postsynaptic α1 receptors.
Antihypertensive effect of clonidine is exerted by-
activation of α2 receptors at vasopressor centre.
Clonidine binds to and activates imidazoline I receptor which may
modulate the central α2 receptor activity
Clonidine also activates the presynaptic α2 receptors on
sympathetic post ganglionic neurons which suppresses
further release of NE from peripheral nerve endings.
Reduces renin release also and decreases renal vascular
resistance.
15. • The principal difference between clonidine and α-
methyldopa is that clonidine acts directly on central α2 –
adrenoceptors (AUTORECEPTOR) whereas α-methyldopa
must be converted to α-methyl NE to exert its
antihypertensive effects.
• A vasodilator can be added to the clonidine + diuretic
combination to treat the cases of refractory HT.
• It is also useful for HT complicated by renal disease, to
control diarrhea in patients with autonomic neuropathy, in
migraine prophylaxis, treatment of nicotine, alcohol &
opioid withdrawal.
16. • Not used as a first-line antihypertensive drug because of its side
effects and risk associated with rebound hypertension after its
abrupt withdrawal.
Adverse Effects:
Rebound hypertension due to supersensitivity of newly formed α
receptors-so its withdrawal to be gradual.
Dry mouth
Sedation
Nasal stuffiness
Constipation
Impotence
Contact dermatitis when used as patch
17. Moxonidine and Rilmenidine:
• Newer congeners of clonidine
• Longer plasma half-life and are said to be
selective for imidazoline (I 1) receptor
• Rebound hypertension is much less frequent
18. DIURETICS
• Na+ contributes to vascular resistance by increasing vessel stiffness.
• These effects are reversed by diuretics and salt restriction.
THIAZIDES:
• Thiazides are generally the diuretic of choice for essential
hypertension
• Indapamide is more potent and longer acting than
hydrochlorothiazide and possesses some intrinsic vasodilator
activity also.
• The main adverse effects of thiazides are:
• Hypokalaemia, hyperuricaemia, hypercalcaemia, hyperglycaemia,
hyperlipidaemia and hypochloraemic alkalosis.
• Thiazides should be avoided in hypertensive cases with concomitant
Diabetes mellitus, gout, hyperlipidaemia, renal insufficiency and
pregnancy. Indapamide can be used in diabetic hypertensives.
19. Loop Diuretics
• They are preferred in severe HT with cardiac and renal
insuffuciency.
• Loop diuretics promptly reduce pulmonary oedema in
CHF due to rapid diuresis which results in the decrease
in venous return and subsequently in the reduction in
right ventricular output. These drugs can convert
oliguric renal failure to non-olguric failure which helps
in management of renal failure.
• Adverse effects include hyperuricaemia,
hypercalciuria, hypomagnesaemia and hypokalaemia
• Indacrinone is useful for hypertensive patients having
gout as it inhibits proximal tubular uric acid absorption
also
20. k+ sparing diuretics
• Spironolactone is an aldosterone receptor antagonist
and hence antagonises Na+ retaining and K+
excreting actions of aldosterone.
• They are usually given along with thiazides to avoid
excess potassium depletion
• Concomitant use with ACE inhibitors should be
avoided because it will aggravate hyperkalemia.
21. ACE Inhibitors
• Angiotensin Converting Enzyme Inhibitors
• Enalapril, Ramipril, Captopril, Lisinopril, Benazepril,
Perindopril
• All ACEI are prodrugs except captopril and lisinopril
• Ang – II is a vasoconstrictor and stimulates aldosterone
release and thus promotes Na+ retention.
• These are the drugs of first choice for treating all grades of
essential as well as renovascular hypertension.
• Most useful in diabetic nephropathy, left venticular
hypertrophy, CHF and in cases of post-myocardial remodeling.
• Adverse effects include:
• Hypotension after first dose, dry cough, angioneurotic
oedema, hyperkalemia, foetal hypotension with a risk of
foetal malformations administered during II and III trimester
of pregnancy and altered sense of taste (ageusia)
22. ARB s
• Angiotensin Receptor Blockers
• Specific antagonists of angiotensin II receptors(
AT 1 receptor)
• ARBs have no effect on bradykinin metabolism
and their use is generally restricted to patients
who do not tolerate ACEIs because of dry cough
or angioneurotic oedema.
• Adverse effect
- Hazardous during pregnancy
• Losartan is also effective in portal hypertension
due to cirrhosis of liver
23. CCB s
• Calcium channel blockers
• Block voltage dependent L-type Ca2+ channels and thus
reduce the frequency of the opening of these channels
response to depolarisation
• Four types:
• Voltage-sensitive Ca2+ channels
• L-type Ca2+ channels dominant in cardiac and smooth
muscles are blocked by CCBs.
• Currently CCBs enjoy the status of first-line
antihypertensive drugs.
• Also used in treatment of angina and cardiac arrhythmias
24. Advantages of CCBs:
• Their relaxant effects on large arteries is more beneficial in
elderly patients.
• They improve arterial compliance and retard atherogenesis
• These can be used safely in patients with asthma, angina and
PVD.
• No adverse effects on lipid profile, uric acid levels or glucose
metabolism.
• Postural hypotension, first dose effect or rebound
phenomenon are not observed
• These neither impair male sexual activity nor the physical
work capacity.
• They have no adverse effects on foetus
ALL THESE FACTORS MAKE CCBs 1St LINE ANTIHYPERTENSIVE DRUGS
25. Classification of CCBs
Dihydropyridines (DHPs)
• Short acting: Nifedipine, Nicardipine and Nimodipine
• Intermediate acting: Nisoldipine, Nitrendipine,
Lacidipine, Cilnidipine
• Long acting: Felodipine, Benindipine and Amlodipine
Non- dihydropyridines (Non – DHPs)
• Short acting: Verapamil, diltiazem
• Long acting: Bepridil
26.
27. Pharmacological Characteristics:
• Verapamil is relatively cardioselective, nifedipine is
relatively vascular smooth muscle selective while
diltiazem exhibits intermediate selectivity.
• Coronary artery dilator effects, including dilatation of
both epicardial and intramyocardial arteries which
prevent coronary spasm:
• Vasodilatory effects on peripheral and pulmonary
blood vessels
• All CCBs decrease heart rate contractility and
conduction velocity to a varied extent.
• Coronary vasodilation and reduction in peripheral
arterial resistance (↓in afterload)
28. • Used to treat HT and angina.
• Verapamil and diltiazem have nodal depressant effects.
• Reduce myocardial O2 demand and make them
suitable for treating angina, HT and supraventricular
tachycardias.
• CCBs are excellent antihypertensive drugs in (1) low
renin hypertensive patients
• (2)Elderly patients and (3) in pregnancy as well.
• Their antihypertensive effect is independent of Na-
intake or of concurrent use of NSAIDs (unlike ACEIs)
29. Adverse effects
• Headache, flushing and peripheral oedema.
• Reversible gingival hyperplasia (on Prolonged
use)
• Its negative inotropic effects are unsuited for
patients with LV dysfunction
• Contraindications: Unstable angina
• LV failure, aortic stenosis and obstructive
cardiomyopathy.
30. Amlodipine
• Amlodipine has a longer t1/2
• It has lesser first – pass metabolism, hence
bioavailability is consistent.
• Ankle oedema
• Approved for effort angina as well as for
hypertension
31. Nicardipine
• Shorter t1/2
• Coronary dilatation effect with lesser effect on
cardiac contractility as compared to nifedipine
• Angina and HT
34. Vasodilators
• Direct vasodilators
• Vasodilators decrease the total peripheral
resistance
• Relax arterial smooth muscle to a greater
extent than venous smooth muscle.
On chronic use
• Neuroendocrine and sympathetic reflexes
tend to counteract the fall in BP
35. Arteriolar vasodilators
• These include hydralazine, minoxidil, diazoxide
and fenoldopam
• Hydralazine and minoxidil, are used orally for
long-term outpatient therapy of HT
• Diazoxide and fenoldopam, are given
parenterally to treat hypertensive
emergencies.
36. • An increase in the k+ conductance results in
hyperpolarisation of cell membrane which
causes relaxation of vascular smooth muscle.
• These are usually administered in combination
with a diuretic and a β - blocker
• Triple combination -decrease in cardiac output
reduction in plasma volume and decrease in
TPR
37. Hydralazine
• Besides activating K+ channels, vasodilatation
due to hydralazine is partly endothelium
dependent and may involve generation of
nitric oxide and stimulation of cGMP
Use :Moderately hypertensive ambulatory
patients: second line in comb with diuretic/B
blocker
HT in preg , HT emergency(iv).
39. Minoxidil
• Active metabolite minoxidil sulfate which
activates k+ channel opening
• Severe HT that may be life- threatening or HT
associated with chronic renal failure or HT
that is resistant to other forms of therapy
• Side effects: headache, nasal congestion,
tachycardia and precipitation of anginal
attacks.local irritation,itching, burning
sensation
40. • Always administered in combination with a β-
blocker and a diuretic
• Topical minoxidil is now marketed as a
stimulant of hair growth for correcting male
type baldness
41. Diazoxide
• It opens k+ channels to produce long lasting
arteriolar dilatation with no effect on venules
• Slow I.V. injection or infusion is less effective as
the drug exhibits rapid and extensive protein
binding.
• Long – term oral or parenteral use is not suitable
because it causes hyperuricaemia,
hyperglycaemia and fluid retention.
• Diazoxide is used for the treatment of
hypertensive emergencies such as malignant HT,
hypertensive encephalopathy and eclampsia
42. Fenoldopam
• Agonist of dopamine receptor(D1) leading to
dilatation of peripheral arteries and natriuresis.
• Urine output, creatinine clearance, and Na+
excretion are increased by fenoldopam.
• Hypertensive emergency associated with
impaired renal function.
• Caution is required for its use in patients in whom
hypotension could be deleterious such as those
with acute cerebral infraction or haemorrhage.
43. Arteriolar+venous vasodilators
• Sodium nitroprusside : nitrovasodilator as it
releases nitric oxide
• Sodium nitroprusside activates guanylyl
cyclase either directly or through release of
nitric oxide.
• This results in an increase in the intracellular
levels of cGMP which provides vascular
smooth muscle relaxation.
44. • Decrease in peripheral vascular resistance and
in venous return.
• In patients with refractory heart failure, even
in absence of HT, it improves ventricular
performance, by reducing preload and
afterload
• Treatment of severe HT with acute MI or LVF.
• The aqueous solutions of sodium
nitroprusside are unstable and sensitive to
light.
46. Drug Therapy of the Hypertensive
Pregnant Patient
• Methyldopa: Drug of choice.
• Beta blockers (not early pregnancy).
• Hydralazine is the parenteral drug of choice.
• DHP CCB-
• Prazosin/clonidine
• Most agents if used prior to pregnancy may be
continued
– (except ACE-I OR A-II BLOCKERS)
47. Emergencies &
Urgencies
• HYPERTENSIVE
EMERGENCIES
– Require immediate blood
pressure reduction (not
necessarily to normal
range) to prevent or limit
target organ damage.
• HYPERTENSIVE URGENCIES
– Require reduction of
blood pressure within a
few hours
48. Hypertensive emergency
• Hypertensive emergency is a situation in which BP
must be reduced by 25mm Hg within one to two hours
to avoid the risk of severe morbidity and death.
• Progressive target organ damage.
• Emergencies include
-hypertensive encephalopathy
-Hypertensive nephropathy
-Intracranial haemorrhage, dissecting aneurysm,
pulmonary Oedema, unstable angina, myocardial
infraction or malignant hypertension (hypertension
associated with vascular damage and Papilloedema).
• Rapid and complete normalization of BP should be
avoided
49. Treatment of Hypertensive emergency
• Changes in cerebral blood flow
• Rapid normalization of BP would lead to
cerebral, coronary or renal ischaemia
• Oral –nifedipine , captopril, clonidine
• Parenteral
51. Sodium Nitroprusside
• Predictable titratable effect- doc
• It is an effective drug in treating hypertensive
crisis associated with encephalopathy,
nephropathy, pulmonary oedema and MI.
• used in combination with a β-blocker
especially in patients with aortic dissection.
• Needs infusion pump & cont monitoring
52. • GTN- venodialator, lowering BP after cardiac
surgery and in acute LVF; tolerance
• Hydralazine – used esp in eclampsia
• Esmolol – rapid action ; aortic dissection; also
used during surgery; along with Sod nit
• Labetalol-used in MI angina,eclampsia
• Phentolamine – hyperadrenergic states- pheo,
cheese reac,clonidine withdrawal
56. Joint National Committee (JNC) classifies hypertension as follows
Category SBP mmHg DBP mmHg
Normal <120 and <80
Prehypertension 120–139 or 80–89
Hypertension, Stage 1 140–159 or 90–99
Hypertension, Stage 2 ≥160 or ≥100
57. Goals of Therapy
BP <140/90 mmHg
BP <130/80 mmHg in patients
with diabetes or chronic kidney disease.
Achieve SBP goal especially in persons
>50 years of age.
58. Lifestyle Modification
Modification Approximate SBP reduction
(range)
Weight reduction 5–20 mmHg/10 kg weight loss
Adopt DASH eating plan 8–14 mmHg
Dietary sodium reduction 2–8 mmHg
Physical activity 4–9 mmHg
Moderation of alcohol
consumption
2–4 mmHg
61. Algorithm for Treatment of Hypertension
Not at Goal Blood Pressure (<140/90 mmHg)
(<130/80 mmHg for those with diabetes or chronic kidney disease)
Initial Drug Choices
Drug(s) for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.
With Compelling
Indications
Lifestyle Modifications
Stage 2 Hypertension
(SBP >160 or DBP >100 mmHg)
2-drug combination for most (usually
thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)
Stage 1 Hypertension
(SBP 140–159 or DBP 90–99 mmHg)
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.
Without Compelling
Indications
Not at Goal
Blood Pressure
Optimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
62. Classification and Management
of BP for adults
*Treatment determined by highest BP category.
†Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.
‡Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.
BP Class SBP DBP Lifestyle
Initial drug therapy
Without compelling
indication
Compelling
indications
Normal <120 <80 Encourage None None
Pre-
hypertension
120–
139
or 80–
89
Yes No antihypertensive drug
indicated.
Drug(s)
Stage 1
Hypertension
140–
159
or 90–
99
Yes Thiazide-type diuretics
for most. May consider
ACEI, ARB, BB, CCB, or
combination.
Other
antihypertensive
drugs (diuretics,
ACEI, ARB, BB,
CCB) as needed.
Stage 2
Hypertension
>160 or
>100
Yes Two-drug combination
(usually thiazide and
ACEI or ARB or BB or
CCB).
63. • Start with single dose ;Thiazide – doc
• ABCD
• Initiate therapy at lose
• If partial response, add another drug
• If no response, change the drug
• If side effect occurs, reduce dose or alter drug
• Majority of stage 2 HT start two drug comb
64. • White coat HT
• Resistant HT- despite full dose of three drug
goal BP not acheived
65. Conclusions
The initial approach to hypertension should start with ruling out
secondary causes, detecting and treating other cardiovascular risk
factors, and looking for target organ damage.
Treatment should always include lifestyle changes.
Medication use should be guided by the severity of HTN and the
presence of “compelling” indications.
Thiazide-type diuretics should be initial drug therapy for most, either
alone or combined with other drug classes.
Most patients will require two or more antihypertensive drugs
