HYPERTENSION

AND
ANTIHYPERTENSIVE
AGENTS
Objective:
• Explain the pathophysiology of
hypertension
• Enumerate the drugs needed for
the management of HTN.
• Define diuretics according to its
MOA and A/E.
What is Hypertension?

• persistently elevated arterial blood

pressure

•A systolic reading greater than or 140

mmHg and a diastolic reading equal to or
greater than 90 mmHg
BLOOD PRESSURE CLASSIFICATION

NORMAL
<120/<80 mmHg

1. PREHYPERTENSION:
120-139 OR 80-89
 BLOOD PRESSURE CLASSIFICATION

2. STAGE I HYPERTENSION
140-159/90-99 mmHg
 BLOOD PRESSURE CLASSIFICATION

3. STAGE II HYPERTENSION
> 160 or > 100 mmHg
 ETIOLOGY

1. Primary, Essential or Idiopathic

hypertension
• No specific cause can be
identified
• The average age of onset is about
35 years
 ETIOLOGY

2. Secondary hypertension
• identifiable cause such as:
renal disease
adrenal hyperfunction
• usually develops between the ages of 30 and 50
 PREDISPOSING FACTORS
IN PRIMARY HYPERTENSION

• SMOKING
• HYPERLIPIDEMIA
• DIABETES MELLITUS
• FAMILY HISTORY OF CARDIOVASVULAR
DISEASES
• AGE
• OBESITY
• STRESS
• HIGH DIETARY INTAKE OF SATURATED FATS
AND SODIUM
• SEDENTARY LIFESTYLE
 Physiology

Determinants of Blood Pressure

BP= TPR x CO
where:
BP = blood pressure
TPR = total peripheral resistance
CO = cardiac output
 Physiology

Formula of Cardiac Output

CO = SV x HR
where:
CO = Cardiac Output
HR = Heart Rate
SV = Stroke Volume
*Volume that is pumped out by the
heart in every contraction
 Mechanisms of Blood Pressure Regulation

1. SYMPATHETIC NERVOUS SYSTEM.

Baroreceptors Reflex Arc/Postural Mechanism
• important in the moment-moment Control of BP

2. RAAS
• For long term control of BP
 Blood Pressure Regulation

↑ Sympathetic B1 activation ↑ CO
activity

Alpha1 activation ↑ PVR

↓ BP ↑ BP
↓ Renal ↑ Renin ↑ A. II
blood flow
↑ Aldosterone

↓ GFR ↑ Reabsorption of salt ↑ BV

and water
 3. MOSAIC THEORY
OTHER VASOACTIVE SUBSTANCES
INVOLVED IN THE NORMAL
MAINTENANCE OF NORMAL BLOOD
PRESSURE:
THESE INCLUDE:
• NITRIC OXIDE (Vasodilating factor)
• ENDOTHELIN (Vasoconstrictor peptide)
 3. MOSAIC THEORY

• BRADYKININ
• Potent vasodilator
• Inactivated by ACE

• ATRIAL NATRIURETIC PEPTIDE

• Naturally occuring diuretic
4. Fluid Volume regulation
Increased Fluid Volume

Increases venous system distention

thereby affecting cardiac output and
tissue perfusion.

These changes alter vascular

resistance therefore increasing
blood pressure
DIURETICS
Diuretics
• lower blood pressure by reducing the blood
volume and reduction in body sodium.

• They are the first agents tried in mild

hypertension and affect blood sodium level
and blood volume.

• However, they do cause electrolyte and

acid-base disturbances.
Diuretics
• A. thiazides
• B. the loop diuretics
• C. the potassium-sparing diuretics

• D. Osmotic diuretics
• E. Carbonic anhydrase inhibitors
 Anti – Hypertensive Agents

 DIURETICS  Loop Diuretics

 Anti – Hypertensive Agents
• DIURETICS • Thiazide
• Thiazide diuretics
Bendroflumethiazide
Benzthiazide
Chlorothiazide
Polythiazide
Trichloromethiazide
Hydrochlorothiazide
Hydroflumethiazide
 Anti – Hypertensive Agents

• DIURETICS • Thiazide
• Thiazide-like diuretics
Chlorthalidone
Indapamide
With vasodilating activity
Metolazone
Quinethazone
 Use/s
• mild or moderate HPN and normal renal
and cardiac function

• CHF
• liver and renal disease
• Hypercalciuria
• Diabetes insipidus
 Anti – Hypertensive Agents

• DIURETICS • Thiazide

• excretion of :
water , sodium, chloride,
potassium, and bicarbonate

• excretion of:
calcium and uric acid
 Anti – Hypertensive Agents

• DIURETICS • Thiazide
Adverse effects:
• Hypokalemia
• contraindicated to patients under digitalis therapy.
• Hypercalcemia
• Hyperuricemia
• Hyperglycemia
• hyperlipidemia
 Anti – Hypertensive Agents

• DIURETICS • Loop Diuretics

I. Loop diuretics
Furosemide (prototype)
Bumetanide
Ethacrynic acid
Torsemide

• AKA high ceiling diuretics

 Anti – Hypertensive Agents

• DIURETICS • Loop Diuretics

Uses:
• acute pulmonary edema
• acute hypercalcemia
• Hyperkalemia
• Acute Renal Failure
• Anion Overdose (halide poisoning)
 Anti – Hypertensive Agents

• DIURETICS • Loop Diuretics

Adverse effects:
• Hypokalemic metabolic alkalosis
• Ototoxicity
• Hyperuricemia
• hypomagnesemia
 POTASSIUM SPARING DIURETICS

• Spironolactone
• Eplerenone
• AMILORIDE
• TRIAMTERENE
 Anti – Hypertensive Agents

• DIURETICS • Potassium Sparing

III. Potassium sparing diuretics

• direct pharmacologic antagonism of

mineralocorticoid receptors
(spironolactone, eplerenone)
• by inhibition of Na+ influx through ion
channels in the luminal membrane
(amiloride, triamterene).
Agents that alter water excretion
 • DIURETICS • Osmotic diuretic
IV. Osmotic agents
Mannitol
Glycerin
Isosorbide
Urea
 • DIURETICS • Osmotic diuretic
• They are easily filtered and poorly
reabsorbable solutes that alter the
diffusion of water relative to sodium by
binding with water.

• They pull water into the renal tubule

without sodium loss.
 • DIURETICS • Carbonic Anhydrase inhibitor

• V. Carbonic anhydrase inihibitors

Acetazolamide
Methazolamide
DIRECT VASODILATORS
 Anti – Hypertensive Agents
• VASODILATORS
• relax the smooth muscles and lower total
peripheral resistance
• Do not cause orthostatic hypotension or
sexual dysfunction
• Produce reflex stimulation of the heart
• Can increase plasma renin
• Commonly used with a diuretic or beta
blocker
 Anti – Hypertensive Agents
• VASODILATORS

• PARENTERAL
• Nitroprusside
• Diazoxide
• Fenoldopam

• Used to treat hypertensive emergencies

CALCIUM CHANNEL
BLOCKERS
 Classes

Calcium Channel Blockers

1. Phenylalkylamines
2. Benzothiazepines
3. 1,4-dihydropyridines
Calcium Channel Blockers • Block calcium channels (L-type) in heart and
blood vessels
• prolong depolarization
• block SA and AV node conduction
• heart block
• Vasodilators
 Calcium Channel Blockers
PHARMACOLOGY

• depress sinus node automaticity and slow AV node conduction

CO

BP
 USES:

Calcium Channel Blockers • Hypertension

• stable angina
• Dysrhythmias
• migraine headaches
• Raynaud phenomenon
• subarachnoid hemorrhage.
Angiotensin converting enzyme
(ACE) INHIBITORS

Used as monotherapy in step 2

management of HPN or in combination
with diuretics
 Anti – Hypertensive Agents

 (ACE) inhibitors • CAPTOPRIL

Description:
• a potent vasodilator
• Used in the treatment of HPN, CHF,
diabetic, nephropathy & LV
dysfunction following MI
• associated with fatal pancytopenia
and cough
 Anti – Hypertensive Agents

 (ACE) inhibitors • CAPTOPRIL

Mechanism of Action:
inhibit the converting enzyme peptidyl
dipeptidase
Inhibit the action of RAAS and stimulate the
action of kallikrein – kinin system

• ↓vascular resistance and blood volume and

they lower blood pressure by ↓ TPR.
 Anti – Hypertensive Agents

 (ACE) inhibitors • CAPTOPRIL

Use/s:
• used to treat mild to moderate
hypertension
• treats patients with diabetic
nephropathy because they diminish
proteinuria and stabilize renal function
• Also used in CHF
• They are less effective in African
Americans than in Caucasians.
 Anti – Hypertensive Agents

 (ACE) inhibitors • CAPTOPRIL

Adverse drug reaction/s:

• Cholestatic jaundice
• Angioedema
• acute renal failure
• Hypotension
• Syncope
• Neutropenia
 Anti – Hypertensive Agents

 (ACE) inhibitors • CAPTOPRIL

Adverse drug reaction/s:

• Anorexia
• Polyuria
• Oliguria
• idiosyncratic dry cough
• Hyperkalemia
 Anti – Hypertensive Agents

 (ACE) inhibitors • CAPTOPRIL

Minor toxic effects:

• altered sense of taste
• allergic skin rashes
• drug fever
 Anti – Hypertensive Agents

 (ACE) inhibitors • CAPTOPRIL

Contraindication:
• They are contraindicated in
pregnancy
• patients with renal dysfunction since
can cause decreased renal blood flow
(bilateral renal artery stenosis)
 PRODRUGS
ACE inhibitors
Enalapril (Vasotec)
• same indications as Captopril but
with IV preparation
Quinapril (Accupril)
• treatment of HPN & adjunct
treatment of CHF
Ramipril
• same indications as Quinapril
 DRUG-DRUG INTERACTIONS
ACE inhibitors
Non-steroidal anti-inflammatory drugs may
impair the hypotensive effects of ACE
inhibitors by blocking bradykinin-
mediated vasodilation.
 ACE INHIBITORS

• Fosinopril-Monopril
• Lisinopril- Prinivil
• Moexipril- Univasc
• Perindopril- Aceon
 ACE INHIBITORS

• Quinapril- Accupril
• Ramipril- Altace
• Tandolapril- Mavik
Angiotensin II receptor antagonists

Used alone or in combination therapy

 Anti – Hypertensive Agents

Angiotensin II receptor antagonists

Description:
• They have no effects on bradykinin metabolism and are
therefore more selective blockers of angiotensin effects than
ACE inhibitors.
 Anti – Hypertensive Agents

Angiotensin II receptor antagonists

Mechanism of Action:

selectively bind to AII receptors in vascular smooth muscles&

adrenal glands - block vasoconstriction & release of
aldosterone
 Anti – Hypertensive Agents

Angiotensin II receptor antagonists

Adverse drug reaction/s:

• Similar to those described in ACE inhibitors including hazard
of use during pregnancy, with the exception of cough and
agioedema because they have no effects on bradykinin.
 Angiotensin II receptor antagonists

1.Candesartan (Atacand)
- contraindicated in pregnancy because of associated fetal - abnormalities
2. Irbesartan (Avapro)
- with associated fetal abnormalities & death
3. Losartan (Cozaar)
4. Telmisartan (Micardis)
5. Eprosartan-Teveten
 ANGIOTENSIN RECEPTOR
BLOCKERS

• Olmesartan- Benicar
• Valsartan-Diovan
SYMPATHOPLEGIC DRUGS
SYMPATHOPLEGIC DRUGS
• Centrally acting sympathomimetic

Methyldopa
Clonidine
Guanabenz
Guanfacine
SYMPATHOPLEGIC DRUGS
• reduces the sympathetic outflow from
vasopressor centers in the brainstem
• Antihypertensive action:
stimulation of central
alpha2-adrenoceptors
Methyldopa
• analog of L-dopa and is converted to alpha-
methyldopamine and
alpha -methylnorepinephrine

• False neurotransmitter

• useful in the treatment of mild to

moderately severe hypertension
• ↓ SVR
Methyldopa
Side effects:
• Overt Sedation (frequent)
• persistent mental lassitude and
impaired mental concentration (long-
term)
• Lactation (↑prolactin secretion)
• (+) Coomb’s test (>12 mths)
Clonidine
• Binds to alpha2-receptors on presynaptic
adrenergic neurons

Reduce NE release

• clonidine also binds to imidazoline receptor,

which may also mediate antihypertensive
effects.
Clonidine
• decreased heart rate and relaxation of
capacitance vessels (↓ CO)

• ↓ peripheral vascular resistance, particularly

when patients are upright
Clonidine
• Withdrawal of Clonidne is associated with
REBOUND hypertension
S/Sx: nervousness, tachycardia, headache, and
sweating
Tx of the hypertensive crisis consists of:
• reinstitution of clonidine therapy or
• administration of alpha- and beta-
adrenoceptor-blocking agents.
Clonidine

Manifestations of toxicity:
• CNS depression, bradycardia, hypotension,
and, occasionally, hypothermia.

• Antidote: Naloxone
Ganglion-Blocking Agents
 • Mecamylamine
Ganglion-Blocking Agents • Oral
• w/CNS effects

• Trimethaphan
• Short-acting
• Parenteral (IV infusion)
• Lacks central effects (4° amine)
 MOA:
Ganglion-Blocking Agents
• competitively block nicotinic
cholinoceptors on postganglionic neurons
in both sympathetic and parasympathetic
ganglia
 Adverse effects:
Ganglion-Blocking Agents sympathoplegic
• excessive orthostatic hypotension and
sexual dysfunction
Parasympathoplegic
• constipation, urinary retention,
precipitation of glaucoma, blurred vision,
dry mouth
Adrenergic Neuron-Blocking
Agents
Adrenergic Neuron-Blockers
Guanethidine
Guanadrel
Bethanidine
debrisoquin
 MOA:
Adrenergic Neuron-Blockers
lower blood pressure by
preventing normal physiologic release of
norepinephrine
from postganglionic sympathetic neurons.

(w/ local anesthetic activity)

USE: For severe hypertension

Adrenergic Neuron-Blockers
Adrenergic Neuron-Blockers
Guanethidine
early in the course of therapy :
• ↓ CO due to bradycardia and relaxation of
capacitance vessels.
• With long-term therapy: ↓ PVR

• Compensatory effect:
sodium and water retention
 Guanethidine
Adrenergic Neuron-Blockers • Polar – no CNS effects
• long half-life (5 days)
• onset of sympathoplegia is gradual
(maximal effect in 1–2 weeks)
• DO NOT increase the dose at intervals
shorter than 2 weeks.
Adrenergic Neuron-Blockers Toxicities:
• postural hypotension, diarrhea (PS), and
impaired ejaculation (S)
*** rarely used nowadays
RESERPINE
• Used for treating mild to moderate
hypertension
MOA:
blocks the uptake and the storage of
biogenic amines
depletion of norepinephrine, dopamine, and
serotoninin both central and peripheral
neurons

↓CO ↓PVR
RESERPINE
• readily enters the brain
• depletion of cerebral amine stores causes:
sedation
mental depression
parkinsonism symptoms
• produces mild diarrhea and gastrointestinal
cramps and increases gastric acid secretion
Adrenoceptor Antagonists
 Beta 1
• coupled to Gs proteins
• cAMP --activates protein kinase A
• Opening of calcium channels
Beta receptor
 Anti hypertensive effect

1. Inhibition of prejunctional
beta receptors on the
terminal neurons
2. Inhibition of renin-
angiotensin system
3. Decreased central
sympathetic outflow
Beta blockers

* Decrease afterload and wall

stress
 Pharmacological effects
• Cardiovascular
• hypotension and bradycardia

• Pulmonary
• Respiratory depression and apnea
• CNS
• Delirium, coma, and seizures
Beta blockers

• Metabolic
BETA-blockers
• In severe hypertension:

Beta blockers prevent reflex tachycardia that often results

from treatment with direct vasodilators.
PROPRANOLOL
• the first -blocker shown to be
effective in hypertension and
ischemic heart disease.

• very useful for lowering blood

pressure in mild to moderate
hypertension.
Beta blockers
Metoprolol
• Cardioselective
• Usual antihypertensive doses: 100 to
450 mg/d
Beta blockers
Beta blockers with long half-lives
Nadolol, Carteolol, Atenolol, Betaxolol, &
Bisoprolol

Partial agonists
Pindolol, acebutolol, and penbutolol
particularly beneficial for patients with
bradyarrhythmias or peripheral vascular disease
Beta blockers
MIXED alpha and beta blocker
Labetalol & Carvedilol

• labetalol
• useful in treating the HPN of pheochromocytoma
and hypertensive emergencies.
Beta blockers
Esmolol
• beta1-selective blocker
• rapidly metabolized by RBC esterases.
• It has a short half-life (9 minutes)
• administered by constant IV infusion.
• loading dose: 0.5–1 mg/kg, followed by a
constant infusion.
• used for management of intraoperative and
postoperative hypertension, and when
hypertension is associated with tachycardia.
 • Prazosin
Alpha1 blockers
MOA:
• blocks alpha1- receptors in arterioles and
venules producing vasodilatation
• blood pressure is reduced more in the upright
than in the supine position
Alpha1 blockers
USES:

• Hypertension
• Benign prostatic hyperplasia (BPH)
Alpha1 blockers
Adverse effects:

• Orthostatic hypotension
• Salt and water retention
• SYNCOPE
• first-dose phenomenon
• Mgt: first dose should be small and should be
administered at bedtime
ANTI- ANGINAL DRUGS

101
What is Angina?
Angina pectoris
• medical term for chest pain or discomfort
due to coronary heart disease.

• a symptom of a condition
called myocardial ischemia

102
What causes angina?
• inadequate myocardial blood flow due to
narrowing of larger coronary arteries.

OXYGEN deficit

• Insufficient blood supply is called ischemia.

103
Underlying causes:
• atherosclerotic change of the vascular wall
• Spasmodic constriction of coronary artery

104
Types of angina
• Stable angina
• Unstable angina
• Prinzmetal's angina
•

105
Stable angina
• or chronic stable angina
• episodes of chest discomfort are
usually predictable
• occur on exertion (such as running to catch a
bus) or under mental or emotional stress.
• Normally the chest discomfort is relieved with
rest, nitroglycerin or both.

106
Unstable angina
• Angina at rest
• the chest pain is unexpected

• The discomfort may be more severe and

prolonged than typical angina or be the first
time a person has angina.

107
What are the causes of unstable angina?
• reduced blood flow to the heart muscle
because the coronary arteries are narrowed
by fatty buildups (atherosclerosis).

• Abnormal constriction of the artery or partially

blocked by a blood clot.

• Inflammation and infection

108
Variant angina
• also called Prinzmetal's angina
• usually occurs spontaneously, and unlike
typical angina, it nearly always occurs when a
person is at rest.
• It doesn't follow physical exertion or emotional
stress, either.
• Attacks can be very painful and usually occur
between midnight and 8 a.m.

109
What causes this variant angina?

• transient coronary artery spasm.

•

110
Braunwald Cardiovascular Classification System of Angina
Pectoris
Class Activities Triggering Chest Pain

1 Strenuous, rapid, or prolonged exertion

Not usual physical activities (eg,
walking, climbing stairs)

111
Braunwald Cardiovascular Classification System of Angina
Pectoris
Class Activities Triggering Chest Pain

2 Walking rapidly, Walking uphill

Climbing stairs rapidly
Walking or climbing stairs after meals
Cold
Wind
Emotional stress

112
Braunwald Cardiovascular Classification System of Angina
Pectoris
Class Activities Triggering Chest Pain

3 Walking, even 1 or 2 blocks at usual

pace and on level ground
Climbing stairs, even 1 flight

4 Any physical activity

113
GOALS in the TREATMENT of Angina
to prevent myocardial hypoxia either by :

• raising blood flow (oxygen [O2] supply)

• or by lowering myocardial oxygen demand (O2
demand)

114
GOALS in the TREATMENT of Angina

1. Increasing cGMP
• cGMP facilitates the dephosphorylation of
myosin light chains, preventing the interaction of
myosin with actin.
• Important molecular donor of Nitric oxide
nitroprusside
organic nitrates

115
GOALS in the TREATMENT of Angina
2. Decreasing intracellular Ca2+
—Calcium channel blockers predictably cause
vasodilation

reduce Ca2+influx

reducing rate, contractility, and oxygen req’t

116
GOALS in the TREATMENT of Angina
3. Stabilizing or preventing depolarization of the
vascular smooth muscle cell membrane

• by increasing potassium permeability.

• eg. nicorandil

117
ANTI- ANGINAL DRUGS

organic nitrates
calcium channel blockers
β-blockers

118
ORGANIC NITRATES

119
NITROGLYCERIN
• the prototype drug
• Although it is used in the manufacture of
dynamite, the formulations of nitroglycerin used
in medicine are not explosive.
• The conventional sublingual tablet form of
nitroglycerin may lose potency when stored in
plastic containers as a result of volatilization and
adsorption to plastic surfaces.

120
Effects of nitrates

121
 Preparations of nitroglycerin
• extended-release capsules containing 2.5, 6.5, 9, or
13 mg;
• 2% ointment with tape for application;
• patches (or transdermal delivery systems) which
deliver 0.1, 0.2, 0.3, 0.4, 0.6, or 0.8 mg of
nitroglycerin per hour;
• 4. buccal tablets containing 1, 2, or 3 mg of
nitroglycerin in an extended release formulation;
• 5. a translingual spray which delivers 0.4 mg of
nitroglycerin per spray;
• 6. sublingual tablets containing 0.15 or 0.3mg. 122
Isosorbide dinitrate (ISDN)
• converted to 5-mononitrate metabolite =
active metabolite
• (5-10 mg SL)

Isosorbide mononitrate (ISMN)

• With 100% bioavailability

123
Amyl nitrite
• highly volatile liquid.
• in fragile glass, ampules packed in a protective
cloth covering.
• The inhalation route provides very rapid
absorption
• the sublingual route avoids the hepatic first-pass
effect
• unpleasant odor and short duration of action
(obsolete)
• induces conversion of hemoglobin to
methemoglobin (methemoglobinemia) which can 124
Toxicity & Tolerance (Nitrosodilators)
1. Acute Adverse Effects
• The major acute toxicities of organic nitrates are
direct extensions of therapeutic vasodilation:
• orthostatic hypotension
• tachycardia
• throbbing headache

125
Toxicity & Tolerance
2. Tolerance
• Tachyphylaxis
• Monday headache and dizziness

Rationale:
• continuous use of the drugs – causes depletion
of sulfhydryl moieties in vascular smooth
muscles

126
 CALCIUM CHANNEL
BLOCKERS
decrease O2 demand by lowering aortic pressure

127
CALCIUM CHANNEL BLOCKERS
Mechanisms of Clinical Effects

Inhibits calcium entry into arterial smooth muscle

↓
decreased arteriolar tone and systemic vascular
resistance
resulting in decreased arterial and intraventricular
pressure
↓
decrease myocardial contractile force
↓
which reduces myocardial oxygen requirements 128
Effects of CCB’s

129
CALCIUM CHANNEL BLOCKERS

Verapamil
Diltiazem
Nifedipine

130
BETA BLOCKERS

131
Effects of Beta blockers

132
BETA BLOCKERS
• are extremely useful in the management of
stable angina.

hemodynamic effects:
decreased heart rate, blood pressure, and
contractility
—which decrease myocardial oxygen
requirements at rest and during exercise.

133
• Metoprolol tablet
• useful in the mgt of chronic stable angina
pectoris

134
Treatment with concurrent disorders:
• hypertensive patients
• monotherapy with either slow-release or
long-acting calcium channel blockers or
BETA-blockers

• normotensive patients = long-acting nitrates

• propranolol with nifedipine
• nifedipine and verapamil

135
Treatment with concurrent disorders:

• Unstable angina
• Antiplatelet agents with NTG, Beta blockers
• Refractory cases - CCBs

136
Treatment with concurrent disorders:

• acute treatment of vasospastic angina pectoris

• Nitrovasodilators
• Calcium channel blockers
• Relieve and prevents ischemic episodes

137