Drugs used to treat hypertension
Desirable to know/learn
• Classification of Antihypertensive
• Antihypertensive mechanisms: Diuretics, ACE inhibitors,
ARBs, Beta-blockers, alpha-blockers, CCBs, Vasodilators and
central sympatholytics
• Present status of above mentioned group of Drugs
• Common Adverse effects of above groups of Drugs
• Pharmacotherapy of Hypertension
• Pharmacotherapy of hypertensive emergencies
• Preparation and dosage of commonly used drugs of above
mentioned groups
Introduction
Hypertension
> 140 mmHg
> 90 mmHg
****************************************************
Systolic Blood
Pressure (SBP)
Diastolic Blood
Pressure (DBP)
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
Hypertension
- risk factor for: ischemic heart disease, stroke, renal failure
and heart failure
Classification of BP
Category
• Normal
• High normal
Hypertension
• Stage 1
• Stage 2
• Stage 3
• Stage 4
Systolic
<130
<139
Diastolic
<85
<89
140-159
160-179
180-209
>210
90-99
100-109
110-119
>120
Hypertension
Essential (primary)
Secondary
- most (90-95 %) patients with
persistent arterial hypertension
- genesis of hypertension unknown
- predisposing factors:
- is secondary to some
distinct disease:
susceptive
(obesity, stress, salt intake, lack of
Mg2+, K+, Ca2+, ethanol  dose,
smoking)
non-susceptive
(positive family history, insulin
resistance, age, sex, defect of
local vasomotoric regualtion)
Renal + renovascular disease
(artery stenosis)
Hormonal defects
(Cushing´s syndrome,
phaeochromocytoma)
Mechanical defect
(coarctation of aorta)
Hypertension in pregnancy
Drug-induced hypertension
(sympatomimetics,
glucocorticoids)
Neurologic disease
Antihypertensive Drugs
1. Diuretics:
•
Thiazides: Hydrochlorothiazide, chlorthalidone
•
High ceiling: Furosemide
•
K+ sparing: Spironolactone, triamterene and amiloride
MOA: Acts on Kidneys to increase excretion of Na and H2O – decrease in
blood volume – decreased BP
2. Angiotensin-converting Enzyme (ACE) inhibitors:
•
Captopril, lisinopril., enalapril, ramipril and fosinopril
MOA: Inhibit synthesis of Angiotensin II – decrease in peripheral resistance
and blood volume
3. Angiotensin (AT2 R) blockers:
•
Losartan, candesartan, valsartan and telmisartan
MOA: Blocks binding of Angiotensin II to its receptors
Antihypertensive Drugs
4. Centrally acting:
• Clonidine, methyldopa, Moxonidine
MOA: Act on central α2A receptors to decrease sympathetic outflow – fall
in BP
5. ß-adrenergic blockers:
• Non selective: Propranolol (others: nadolol, timolol, pindolol, labetolol)
• Cardioselective: Metoprolol (others: atenolol, esmolol, betaxolol)
MOA: Bind to beta adrenergic receptors and blocks the activity
• ß and α – adrenergic blockers:
• Labetolol and carvedilol
6. α – adrenergic blockers:
• Prazosin, terazosin, doxazosin, (phenoxybenzamine and phentolamine)
MOA: Blocking of alpha adrenergic receptors in smooth muscles vasodilatation
Antihypertensive Drugs –
7. Calcium Channel Blockers (CCB):
• Verapamil, diltiazem, nifedipine, felodipine, amlodipine, nimodipine
etc.
MOA: Blocks influx of Ca++ in smooth muscle cells – relaxation
of SMCs – decrease BP
8. K+ Channel activators:
• Diazoxide, minoxidil, pinacidil and nicorandil
MOA: Leaking of K+ due to opening – hyper polarization of
SMCs – relaxation of SMCs
9. Vasodilators:
• Arteriolar – Hydralazine (also CCBs and K+ channel activators)
• Arterio-venular: Sodium Nitroprusside
ACE inhibitors
•Captopril, lisinopril., enalapril, ramipril and
fosinopril etc.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACEI)
Captopril, enalapril, quinapril, lisinopril, perindopril, ramipril
Clinical Indications
- hypertension where thiazide diuretics and beta-blockers are
contraindicated
- useful in hypertensive patients with heart failure (beneficial effect)
- can limit the size of myocardial infarction
- diabetic nephropathy
ACE inhibitors
Drug
Duration of
effect (hours)
Short-acting:
captopril
Medially-acting:
enalapril
6-8
12
quinapril
perindopril
Long-acting:
lisinopril
spirapril
ramipril
24
AT2 RECEPTOR BLOCKERS
losartan, valosartan, irbesartan
- the receptor blockers - competitively inhibit angiotensin II at its AT1
receptor site


most of the effects of angiotensin II - including vasoconstriction
and aldosterone release - are mediated by the AT1 receptor
(angiotensin II synthesis in tissue is not completely dependent
only on renin release, e.g. in heart, but could be promote by serinprotease - stronger influence on the myocard remodelling)
Thiazides — particularly indicated for hypertension in the elderly; a contraindication is gout;
Beta-blockers — indications include myocardial infarction, angina; compelling
contra-indications include asthma, heart block;
ACE inhibitors — indications include heart failure, left ventricular dysfunction
and diabetic nephropathy; contra-indications include renovascular disease and
pregnancy; when thiazides and beta-blockers are contra-indicated, not tolerated,
or fail to control blood pressure
Angiotensin-II receptor antagonists are alternatives for those who cannot
tolerate ACE inhibitors because of persistent dry cough, but they have the same
contra-indications as ACE inhibitors;
Calcium-channel blockers. a) Dihydropyridine calcium-channel blockers
are valuable in isolated systolic hypertension in the elderly when a low-dose
thiazide is contra-indicated or not tolerated. b) ‘Rate-limiting’ calcium-channel
blockers (e.g. diltiazem, verapamil) may be valuable in angina; contraindications include heart failure and heart block;
Alpha-blockers — a possible indication is prostatism; a contra-indication is
urinary incontinence.
*BNF 51th edition, 2006
A single antihypertensive drug is often not adequate and other
antihypertensive drugs are usually added in a step-wise manner until control
is achieved. Unless it is necessary to lower the blood pressure urgently, an
interval of at least 4 weeks should be allowed to determine response.
Where two antihypertensive drugs are needed → 1. an ACE inhibitor or an
angiotensin-II receptor antagonist or a beta-blocker may be combined with →
2. either a thiazide or a calcium-channel blocker.
If control is inadequate with 2 drugs, a thiazide and a calcium-channel
blocker may be added. In patients at high risk of diabetes it is best to avoid a
combination of a beta-blocker and a thiazide. In patients with primary
hyperaldosteronism, spironolactone is effective.
*BNF 51th edition, 2006
Treatment of Hypertension – General
principles
• Stage I:
• Start with a single most appropriate drug with a low dose.
Preferably start with Thiazides. Others like beta-blockers, CCBs,
ARBs and ACE inhibitors may also be considered. CCB – in case
of elderly and stroke prevention. If required increase the dose
moderately
• Partial response or no response – add from another group of
drug, but remember it should be a low dose combination
• If not controlled – change to another low dose combination
• In case of side effects lower the dose or substitute with other
group
• Stage 2: Start with 2 drug combination – one should be
diuretic
Treatment of Hypertension –
combination therapy
• In clinical practice a large number of patients require
combination therapy – the combination should be rational
and from different patterns of haemodynamic effects
• Sympathetic inhibitors (not beta-blockers) and vasodilators +
diuretics
• Diuretics, CCBs, ACE inhibitors and vasodilators + beta blockers
(blocks renin release)
• Hydralazine and CCBs + beta-blockers (tachycardia countered)
• ACE inhibitors + diuretics
• 3 (three) Drug combinations: CCB+ACE/ARB+diuretic;
CCB+Beta blocker+ diuretic; ACEI/ARB+ beta blocker+diuretic
Treatment of Hypertension.
• Never combine:
• Alpha or beta blocker and clonidine - antagonism
• Nifedepine and diuretic synergism
• Hydralazine with DHP or prazosin – same type of action
• Diltiazem and verapamil with beta blocker – bradycardia
• Methyldopa and clonidine
• Hypertension and pregnancy:
• No drug is safe in pregnancy
• Avoid diuretics, propranolol, ACE inhibitors, Sodium
nitroprusside etc
• Safer drugs: Hydralazine, Methyldopa, cardioselective beta
blockers and prazosin
Hypertension in pregnancy
Methyldopa is safe in pregnancy.
Beta-blockers are effective and safe in the third trimester. Modifiedrelease preparations of nifedipine [unlicensed] are also used for
hypertension in pregnancy.
Intravenous administration of labetalol can be used to control
hypertensive crises; alternatively, hydralazine may be used by the
intravenous route.
Magnesium sulphate in pre-eclampsia and eclampsia
Hypertensive Emergencies
• Cerebrovascular accident or head injury with high BP
• Left ventricular failure with pulmonary edema due to hypertension
• Hypertensive encephalopathy
• Angina or MI with raised BP
• Acute renal failure with high BP
• Eclampsia
• Pheochromocytoma, cheese reaction and clonidine withdrawal
• Drugs:
• Sodium Nitroprusside (20-300 mcg/min) – dose titration and monitoring
• GTN (5-20 mcg/min) – cardiac surgery, LVF, MI and angina
• Esmolol (0.5 mg/kg bolus) and 50-200mcg/kg/min - useful in reducing
cardiac work
• Phentolamine – pheochromocytoma, cheese reaction and clonidine
withdrawal (5-10 mg IV)