Antihypertensive agents

 Hypertension: - is sustained increase of either SBP greater than

140mmHg or DBP greater than 90mmHg or both.
 The two consecutive BP measurement reading is ≥140/90 mmHg
Classification of HPN

Category Systolic(mmHg) Diastolic(mmHg)

Normal 100 - 139 60 - 90
High normal 120 – 139 80 - 89
Hypertension
Stage 1(mild) 140 - 159 90 – 99
Stage 2 (moderate) 160 - 179 100 – 109
Stage 3 (severe) >180 >110

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 Types of hypertension depend on causation.
1. Primary (essential) hypertension
 No identified cause
 Drugs can lower BP but they do not eliminate the underlying pathology.

 Risk factors:

 Increased salt intake

 Obesity,

 Genetics,

 Alcohol,

 Stress,
 Lack of exercise, age, cigarette smoking, diabetes,
hyperlipidemia
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 2. Secondary hypertension
 Has identified cause
 So it may be possible to treat that cause directly, rather than
relying on drugs for symptomatic relief
 As a result, some individuals can actually be cured
 Cause could be:
 Renal diseases
 Aortic constriction
 Secondary to drugs

12/18/20 by Tadele M. 3
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 Why we worry hypertension???
 It causes dangerous complications (target organ
damage) such as:

 Myocardial infarction
 Heart failure
 Retinopathy
 Stroke and
 Renal failure

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 Regulation of normal BP
• Arterial blood pressure is regulated within a narrow range
to provide adequate perfusion of the tissues without
causing damage to the vascular system.

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 Main sites and mechanisms of BP control
 There are four anatomical regulating sites

1. Arterioles

2. Post-capillary Venules

3. The heart

4. The kidneys

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Therapeutic goals in hypertension
 To lower the high blood pressure
 To reduce cardiovascular morbidity and mortality
 To prevent target (end) organ damage
 We have two options for management of HTN
 Non-pharmacological options
 Pharmacological options
 Using of medications to treat severe hypertension &
non responsive hypertension to life style modifications

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 Management of hypertension
I. Life style change
 Weight reduction
 Sodium restriction
 Alcohol restriction
 Aerobic exercise
 Smoking cessation

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 Antihypertensive

• Have around five groups of drugs.

1. Sympatholytics
2. Vasodilators
3. Diuretic
4. Calcium channel blockers
5. Alter angiotensin effects

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 1. Smpatholytics(adrenergic antagonists)
 Suppress the influence of the sympathetic NS.
• They classified as:
a. Adrenergic antagonists
I. Alpha blocker
II. Beta blocker
III. Alpha + Beta blocker
b. Centrally acting
c. Ganglion blocker  Pentolinium, Trimethaphan

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 α1-receptor antagonist
 Includes: prazosin, terazosin, doxazosin, alfuzosin
 MOA: α1-receptor antagonist initially reduce arterial
resistance & increase venous capacitance
 This causes sympathetically mediated reflex increase
heart rate & plasma renin activity
 But during long term therapy, vasodilatory effect persists
while CO, HR & renin activity return to normal level
 α1 blockers are used to:
 Treatment of hypertension

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 α1 blockers are not recommended as monotherapy for
hypertensive patients, so they are used in conjunction with
diuretics, β-blockers or other agents

Side effects
 First dose phenomenon: refers to orthostatic hypotension
which occurs within 90 minutes of the initial dose or after
a dosage increase

 Reflex tachycardia

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 Beta blockers
E.g. Propranolol, Metoprolol, atenolol
 Widely used antihypertensive drugs.
 At least three useful actions in hypertension.
 Blockage beta1 receptors  HR and contractility.
 Suppress reflex tachycardia caused by vasodilators.
 Kidney release of rennin  reducing angiotensin II
mediated vasoconstriction & aldosterone mediated
volume expansion.

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 Beta blockers …
b

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 Sudden discontinuation of β-blockers can lead to withdrawal
syndromes (severe HTN)
 Due to up regulation of the β-receptors
 NSAIDs can blunt the antihypertensive activity of β-blockers by:
 Inhibiting the production of PGI2
Adverse Effects
 Bradycardia
 Bronchoconstriction
 Hypoglycemia
 Disturb lipid metabolism
 Action on the CNS causes fatigue, insomnia, depression,
and sexual dysfunction.

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  The use of β antagonists should be avoided in patients
with:

 Asthma
 Sino trial or atrio-ventricular dysfunction
 In combination with other drugs that inhibit AV
conduction
 Diabetes mellitus

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 Non selective α & β antagonists
 Includes: labetalol, Carvedilol
 MOA: blocks both the α & β receptors producing vasodilation
& reduced CO
 Labetalol, when given IV reduces BP sufficiently rapidly which
makes it useful in management of hypertensive crises
 Have more profound effect on the β receptors than α
receptors

• Side effects
 Postural hypotension, GI distress, Tiredness, Sexual
dysfunction, Skin rashes

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 Centrally acting antihypertensive agents

– Includes: methyldopa, clonidine, guanfacine, guanbenze

Methyldopa

 Is a centrally acting antihypertensive agent

 Is a prodrug & produces its antihypertensive effect via
active metabolite

 Methyldopa is preferred drug for treatment of HTN during

pregnancy

b/s it is safe for both the mother & infant

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Side effects
 Sedation
 Occasional depression
 Dryness of mouth
 Serious but rare hepatotoxicity
 So methyldopa is C/I in patients with hepatic disease
 Can also cause hemolytic anemia

12/18/20 by Tadele M. 19
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 Q1.
Which of the following beta receptor antagonists is
preferable in patients with asthma, diabetes or peripheral
vascular diseases?
A. Propranolol
B. Metoprolol
C. Nadolol
D. Timolol
12/18/20 by Tadele M. 20
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2. This drug reduces blood pressure by acting on vasomotor centers
in the CNS:
a)Labetalol b) Clonidine c)Enalapril d)Nifedipine
3. All of the following are central acting antihypertensive drugs
EXCEPT:
a)Methyldopa b) Clonidine c) Moxonidine d) Minoxidil
4. A ganglio blocking drug for hypertension treatment is: a)
Hydralazine b) Tubocurarine c) Trimethaphan d) Metoprolol
5. select the sympatholythic drug: a) Labetalol b) Prazosin c)
Guanethidine d) Clonidin
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10. Choose the selective blocker of beta-1 adrenoreceptors: a)
Labetalol b) Prazosin c) Atenolol d) Propranolol
11. Pick out the drug – an alpha and beta adrenoreceptors blocker:
a) Labetalol b) Verapamil c) Nifedipine d) Metoprolol
12. This drug inhibits the angiotensin-converting enzyme: a)
Captopril b) Enalapril c) Ramipril d) All of the above
13. This drug is a directly acting vasodilator: a) Labetalol b)
Clonidine c) Enalapril d) Nifedipine

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6. This drug is a directly acting vasodilator: a) Labetalol b)
Clonidine c) Enalapril d) Nifedipine
7. Pick out the diuretic agent for hypertension treatment: a)
Losartan b) Dichlothiazide c) Captopril d) Prazosin
8. This drug blocks alpha-1 adrenergic receptors: a) Prazosin b)
Clonidine c) Enalapril d) Nifedipine
9. This drug activates alpha-2 adrenergic receptors: a) Labetalol b)
Phentolamine c) Clonidine d) Enalapril

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 2. Vasodilators

 Hydralazine,
 Minoxidil
 Diazoxide
 Sodium nitroprusside

 Produce vasodilation by d/f mechanisms

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  Hydralazine
 MOA: It causes direct arteriolar smooth muscle
relaxation by unknown molecular mechanisms

 It doesn’t dilate venous smooth muscles & epicardial

coronary

arteries
 b/s of preferential dilation of arteries over veins,
postural hypotension is not common problem.

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• Vasodilation is associated with profound stimulation of SNS
resulting in:

Reflex tachycardia & force of contraction

Increased plasma renin activity & fluid retention

Both effects counteract the antihypertensive effect of

hydralazine

So it is usually given with sympatholytics & diuretics

 It is used for treatment of sever HTN & hypertensive
emergencies in pregnant women
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 Side effects & precautions
 Headache, nausea, hypotension, dizziness, palpitations,
myocardial ischemia, hemolytic anemia, Myocardial ischemia
occurs as result of:
 Reflex tachycardia (increases O2 demand)
 Hydralazine don’t dilate epicardial coronary arteries
 For this reason parenteral administration of hydralazine isn’t
advisable in patients with:
 Coronary artery disease
 Hypertensive patients with multiple CVS disorders
 Old age
 When combined with β-blockers & diuretics, hydralazine is well
tolerated

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  Minoxidil
 Efficacious in treating sever & resistant type of HTN
 MOA: it is a prodrug which is converted to active metabolite
 Produces arteriolar vasodilation with essentially no effect on the
capacitance vessels
 Minoxidil is reserved for sever HTN that responds poorly to other
antihypertensive drugs

 Should never be given alone

Should be given concurrently with diuretic & β-blockers

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 Side effects
 Fluid & water retention by:
 Increasing renin & aldosterone secretion
Controlled by using diuretics
 CVS effects
 Are consequences of reflex SNS activation
 Increased HR, FC & O2 consumption
 Myocardial ischemia patients with coronary artery
disease
 Hypertrichosis: excessive hair growth on face, back, arms &
legs

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 Diazoxide
• It is chemically related to the thiazide diuretics but has opposite
renal action i.e. causes Na & H2O retention.
• Used I.V. for hypertensive emergencies.
• It is also effective in oral rout but it is not suitable for long term
therapy because:-
 Causes marked fluid retention which leads expansion of plasma
volume.

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 Sodium Nitroprusside
 Is used for short term treatment of severe HTN
 MOA: works by releasing nitric oxide (NO) which leads to
vasodilation
 Is non selective vasodilator
 Given by continuous IV infusion
 Its primary use is to treat hypertensive emergencies
 Onset of action occurs with in 30 seconds & effect stays only for
2 minutes
 Metabolically it is degraded by the liver to thiocyanate, w/h is
excreted by the kidney
 Patients with impaired renal function are likely to develop
toxicities from thiocyanate
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Side effects
 Excessive hypotension; and
 Accumulation of cyanide
 Metabolic acidosis, arrhythmias etc
 Hypothyroidism (thiocyanate inhibits uptake of iodine

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 3. Diuretics
 Diuretics are drugs, which increase renal excretion of salt
and water that are principally used to remove excessive
extracellular fluid from the body.

 They are the mainstay of antihypertensive therapy

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 Classification of diuretics
The major groups are:
1. Thiazides and related diuretics: e.g. Hydrochlorothiazide,
Chlorthalidone, Bendrofluazide, Chlorothiazide, Indapamide,
Metolazone.

2. Loop diuretics: e.g. Furosemide, Ethacrynic acid, Bumetanide,

Torsemide.
3. Potassium sparing diuretics: Na CB (e.g. Triamterene,
Amiloride) and aldosterone antagonists (e.g. Spironolactone,
Eplerenone).

4. Carbonic anhydrase inhibitors e.g. Acetazolamide, topically

acting dorzolamide and brinzolamide
5. Osmotic diuretics e.g. Mannitol, Glycerol
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 Major locations of ion and water exchange in the nephron,
showing sites of action of the diuretic drugs.

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 Thiazide and related diuretics
 Most commonly used, reduce BP by two mechanisms:
 Reduction of blood volume (responsible for initial antihypertensive effect)
and
 Reduction of arterial resistance (responsible for long term
antihypertensive effect)
 Clinical use: hypertension, heart failure, hypercalciuria,
Adverse effects: hypokalemia, hyponatremia (hypovolumia
+ADH), hyperuricemia, volume depletion (orthostatic
hypotension or light- headedness), hypercalcemia,
hyperglycemia (impaired release of insulin
and tissue uptake of glucose),& hyperlipidemia.

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 Loop diuretics (high ceiling diuretics)

 MOA: inhibit Na–K–Cl transporter at the thick

ascending limb of the loop of Henle
Clinical use
 Edematous states
 Acute pulmonary edema and acute/chronic peripheral
edema
caused from heart failure or renal impairment,
hypertension
 Hypercalcemia
 Hyperkalemia
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 Side effect

 Hypokalema

 Ototoxicity

 Hyperuricemia

Hypomagnesemia

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 Potassium-sparing diuretics
 They act in the collecting tubule to inhibit Na+
reabsorption and K+ excretion .
 Based on mechanism of action:
A. Aldosterone antagonists: spironolactone and
eplerenone
B. Block Na+ transport channels: Triamterene and
amiloride
Aldosterone antagonists
MoA: they bind to mineralocorticoid receptors and blunt
aldosterone activity.
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 Triamterene and amiloride
 MoA: block Na+ transport channels, resulting
in a decrease in Na+/K+ exchange.
 They have a K+-sparing diuretic action similar to that
of spironolactone, their ability to block the Na+/K+-
exchange site in the collecting tubule

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 Clinical use of K sparing diuretics

 To prevent K loss during chronic therapy with other diuretics

 In combination therapy with other diuretic subclasses for greater
natriuresis.
HTN, HF and Cirrhosis

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 Side effect of K sparing diuretics
 Kidney stones
 Triamterene is poorly soluble and may precipitate, forming
kidney stones
 Metabolic acidosis, rare
 By inhibiting H secretion in parallel with K secretion:
acidosis

 Hyperkalemia

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 Osmotic diuretics
 Mannitol and glycerine/glycerol/ are freely filtered at the glomerulus and
are relatively inert pharmacologically and undergo limited reabsorption
by renal tubule

 Due to their ability to carry water with them into the tubular fluid.
 These are administered to increase significantly the osmolality of
plasma and tubular fluid.
 Because osmotic diuretics are used to effect increased water excretion
rather than Na+ excretion, they are not useful for treating conditions in

which Na+ retention occurs.

Clinical use
 Increase of urine volume
 Reduction of intracranial and intraocular pressure

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 4. Calcium channel blockers

They block the entry of calcium into muscle cells in

blood vessel walls causes dilation.

Mainly have two class of CCB depend on chemical

structure.
 Dihydropyridines: nifedipine, amlodipine,
felodipine, isradipine, nicardipine, nimodipine

Non-dihydropyridines: Verapamil, diltiazem

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 They differ not only in their basic chemical structure, but
also in their relative selectivity toward cardiac Vs
vascular L-type calcium channels.

 The most smooth muscle selective classes of CCBs are the

dihydropyridines.
 Because of their high vascular selectivity, these drugs are
primarily used to reduce SVR and arterial pressure,
primarily used to treat hypertension.

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 Non-dihydropyridines
 Verapamil is relatively selective for the myocardium,
and is less effective as a systemic vasodilator drug.
 Diltiazem is intermediate between verapamil and
dihydropyridines in its selectivity for vascular
calcium channels.

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 Side effects and contraindications
 Dihydropyridine CCBs can cause headache, excessive
hypotension, edema and reflex tachycardia.
 Long-acting dihydropyridines have been shown to be safer anti-
hypertensive drugs, in part, because of reduced reflex responses.
 Non-dihydropyridine CCBs can cause excessive bradycardia,
impaired electrical conduction (e.g., atrioventricular nodal block),
and depressed contractility.
 Therefore, patients having preexistent bradycardia, conduction
defects, or heart failure caused by systolic dysfunction should not
be given CCBs, especially non-dihydropyridines.
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 5. Alter Angiotensin action
• Includes
A. Angiotensin-converting enzyme inhibitors(ACEI)
B. Angiotensin II receptor blockers(ARBs)

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 ACE inhibitors
• Frequently prescribed ACE inhibitors include:
 Captopril, Enalapril, Lisinopril, Ramipril
Side effects: hypotension, cough, hyperkalemia, skin rash, Renal
impairment
Contraindication and precautions
 During pregnancy, Impaired renal function , hypovolemia or
dehydration,
Drug interaction
 With potassium supplements or potassium sparing diuretics, ACEIs can
cause hyperkalemia
 NSAIDs can blunt the antihypertensive effect of ACEIs by causing salt &
water retention & inhibiting PGI2 synthesis

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 Angiotensin II receptor blockers(ARBs)
e.g. Candesartan, Valsartan, Losartan

 They are alternatives to the ACE inhibitors.

 These drugs block the AT1 receptors, decreasing the activation

of AT1

receptors by angiotensin II.

 Their pharmacologic effects are similar to those of ACE

inhibitors in that they produce arteriolar and venous dilation and
block aldosterone secretion, thus lowering blood pressure and
decreasing salt and water retention
12/18/20 by Tadele M. 50
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 Side effects
• They are similar to ACE inhibitors except cough and
angioedema.

• N.B. ARBs should not be combined with an ACE inhibitor

for the t/t of hypertension due to similar mechanisms and
adverse effects.

• Also they are teratogenic  should not be used by

pregnant women.

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 FUNDAMENTALS OF ANTIHYPERTENSIVE THERAPY

 Life style changes should be tried first, if failed they should be

continued & drug therapy should be started.
 Treatment begins with a single drug; if the initial drug fails
another drug may be added or substituted.

Benefits of multidrug therapy

 Increase in chance of success
 Use of lower dose so that the frequency & the intensity of side
effects are reduced;
 one agent can offset the adverse effects of another
(vasodilator + beta blocker).

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 Q1

Which of the following act in the collecting tubule to

inhibit Na+ reabsorption and K+ excretion
A. Loop diuretics
B. Potassium sparing diuretics
C. Osmotic diuretics
D. Carbonic anhydrase inhibitors

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2. This drug is an inhibitor of renin synthesis:
A. Propranolol
B. Enalapril
C. Diazoxide
D. Losartan
3.The drug that can be angiotensin II receptor antagonist:
A. Clonidine
B. Captopril
C. Losartan
D. Diazoxide
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4. This drug routinely produces some bradychycardia:
A. Propranolol
B. Clonidine
C. Enalapril
D. Nifedipine
5. All of the following statements regarding vasodilators are true
EXCEPT:
A. Hydralazine causes tachycardia
B. Nifedipine is a dopamine receptor antagonist
C. Nitroprusside dilates both arterioles and veins
D. Minoxidil can cause hypertrichosis
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6. All of the following statements regarding verapamil are
true EXCEPT:
A. It blocks L-type calcium channels
B. It increases heart rate
C. It relaxes coronary artery smooth muscle
D. It depresses cardiac contractility

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