PHARMACOLOGY

Lectures 7&8:
Antihypertensive Drugs.
 Identify factors that control blood pressure
 Outline the pharmacologic classes of drugs used in treatment of
hypertension
 Describe the mechanism of action, therapeutic uses & common
adverse effects and contraindications of each class of drugs
 Select the suitable antihypertensive drug to treat a specific
patient according to efficacy, safety, suitability & cost

Before studying this lecture  Important.

we advise you to study
physiology “regulation of BP”
 Extra notes.
and revise pharmacology  Mnemonic.
lectures of this block.  Link
 Introduction to hypertension
High blood pressure (Hypertension) is a common condition in which the long-term
force of the blood against artery walls is high enough that it may eventually cause
health problems.

Epidemiology:
Prevalence: 25-30% of adult population, Only 6% of diagnosed hypertensive patients
have goal BP even after correct treatment.
In majority of cases, hypertension persists for years without any symptoms, thus called
“silent killer”. Eventually, it may lead to many complications including end-organ
failure* and death (Leading cause).
* End organ or target organ damage usually refers to damage occurring in
major organs fed by the circulatory system (heart, kidneys, brain, eyes) which can
sustain damage due to uncontrolled hypertension, hypotension, or hypovolemia.

Classified into 2 types:

1- Primary (essential) Hypertension:
mostly no identifiable cause; tends to develop gradually over years.
2- Secondary Hypertension:
• secondary to another disease (e.g., Kidney problems, Adrenal gland tumors,
Cushing syndrome) it occurs suddenly and causes higher BP than the primary.
• Drug-induced hypertension, caused by a response to medication, as:
 Alcohol, cocaine, Antidepressants, Caffeine, Corticosteroids, Cyclosporine,
Erythropoietin, Estrogens, Nasal decongestants, NSAIDs.
 Rebound hypertension occurs when blood pressure rises after you stop taking or
lower the dose of a drug (typically a hypertension medication, e.g. clonidine).
Stages of hypertension:

Hypertensive emergency < 180 or < 120

Video: Factors Affecting Blood Pressure Figure: Body Response to hypotension

 Management of hypertension
1. Lifestyle modification:
Risk factors for hypertension include:
• Old age, Obesity, Tobacco, Lack of physical activity
• Certain chronic conditions (e.g., such as kidney disease and diabetes)
• Increased salt (sodium), Decreased potassium & Vitamin 6 in the diet
Thus patients with hypertension should follow some lifestyle modification, as
weight loss, physical activity, sodium reduction and smoking cessation.
2. Drug Therapy:
Drug therapy is indicated to achieve target BP = > 140/ 90 mm Hg
* (target BP for diabetics = > 130/80 mm Hg)

Drug Management of Hypertension:

Classification of Drug Examples
Diuretics Hydrochlorothiazide, Chlorthliazide and
chlorthalidone, Furosemide
Drugs acting Angiotensin receptor Losartan, valosartan, Candesatran,
on the renin- Blockers Telmisartan & irbesartan
angiotensin-
ACE Inhibitor captopril, lisonopril, enalapril, ramipril
aldosterone
system (RAAS)
Calcium channel blockers Verapamil, Diltiazem & Nifedipine
Vasodilators Hydralazine, Minoxidil, Diazoxide, &
Na-nitropruside
Drugs acting β- Adrenoceptor Blockers Nadolol, Bisoprolol, Atenolol, metoprolol,
on propranolol, Labetalol, & carvidalol
sympathetic
α - Adrenoceptor Blockers Prazosin, doxazosin & Terazosin
nervous
system Centrally acting Clonidine & α methyl dopa
sympatholytic

Antihypertensive drugs are used in combinations for the following reasons:

1. To achieve synergism (improve effects), and thus decrease side effects by decreasing
the pharmacological individual dose.
2. Appose side effects for one another.
Note: drugs from the same class or drugs with the same mechanism of action should NOT
be combined together, as they may cause resistance and increase side effects.
 Diuretics & ARBs
Diuretics Drugs:
Potassium-sparing
Group: Thiazides Loop diuretics
diuretics
Hydro-chlorothiazide, Furosemide • Amiloride
Chlorthliazide and (more potent diuresis but a • Aldosterone
Example chlorthalidone smaller decrease in PVR) antagonists (mainly
spironolactone)
Thiazide diuretics can be • hypertension with renal minimal effect on lowering
used as initial drug impairment BP, but used in combination
Uses therapy for Mild to • manage symptoms of with loop diuretics and
Moderate hypertension heart failure and edema. thiazides to reduce potassium
loss induced by these diuretics

The initial diuresis lasts 4-6 weeks and then replaced by a decrease in PVR.
E.g. thiazide diuretics lower BP initially by increasing sodium and water excretion. This
Mechanism causes a decrease in extracellular volume, resulting in a decrease in cardiac output and
renal blood flow. With long-term treatment, plasma volume approaches a normal value,
but a hypotensive effect persists that is related to a decrease in peripheral resistance.

Diuretics may be adequate in mild to moderate hypertension, according to ALLHAT,

Note chlorthalidone is superior to an ACE inhibitor, a calcium channel blocker and an alpha1-
adrenergic antagonist in preventing one or more cardiovascular events (CVD).

Angiotensin receptors blockers (ARB):

Losartan Valosartan Others

Has a Potent active metabolite. No Candesatran,
Pharmaco- Telmisartan
Effective Orally once daily (long half life). active metabolite
kinetics
Do not cross BBB.
• selective block of AT1 receptors, thus decreasing the activation of AT1 receptors by
angiotensin II. Blocking the receptor itself, not only the ACE enzyme.
Mechanis
• No effect on bradykinin, no cough, no angioedema.
m of action
• Produce more complete inhibition of angiotensin than ACE inhibitors, as there are
other enzymes (not only ACE) that can generate angiotensin
They may be used as first-line agents for the treatment of hypertension, especially in
Clinical patients with a compelling indication of diabetes, heart failure, or chronic kidney disease
Uses

ADRs As ACEI except cough and angioedema. (Thus can be used in asthmatic patients)
Contraindications Same contraindications as ACEI
 ACE inhibitors
Captopril Lisonopril Enalapril Ramipril
 ACE inhibitors decrease angiotensin II (vasoconstrictor) and increase bradykinin
Mechanism levels (vasodilator) by preventing its degradation by ACE.
 The antihypertensive effect of ACE inhibitors results primarily from vasodilatation
(reduction of peripheral resistance) without reflexively increasing cardiac output,
heart rate, or contractility.
 a fall in aldosterone production may also contribute.
Pharmaco- • Polar, excreted in urine  do not cross BBB
kinetics • Rapidly absorbed from GIT after oral administration. Food reduce their
bioavailabilitym thus should be taken on empty stomach.
• Have a long half-life and thus given only once daily.
• Enalapril & Ramipril are prodrugs, converted to the active metabolite in the liver
• Enalaprilat is the active metabolite of Enalapril, can be given by I.V.. route in
hypertensive emergency.
• It takes 2-4 weeks to see the full antihypertensive effect of ACEI
Clinical use • Essential hypertension, Particularly effective when hypertension results from excess
renin production (renovascular hypertension in white & young patients)
• Hypertension with chronic renal disease, ischemic heart disease, diabetes.
• Treatment of heart failure, by reducing both cardiac preload and afterload, thereby
decreasing cardiac work.
Adverse • Acute renal failure, especially in patients with bilateral renal artery stenosis.
Effects loss of Ag II results in Vasodilation of efferent renal arterioles, which leads to reduce
pressure in afferent arterioles and vasoconstriction, thus reducing renal blood flow
(especially if already reduced by renal artery stenosis) and thereby reducing GFR.
• Dry cough (due to increased bradykinin levels).
• Angioneurotic edema, swelling in nose, tongue, throat & larynx (caused by inhibition
of bradykinin metabolism which accumulate in bronchial mucosa)
• Severe hypotension in hypovolemic patients (e.g. patients taking diuretics) .
• Renal failure/ agensia (absence of kidneys) in the fetus, which will lead to
oligohydramnios (deficiency of amniotic fluid).
• First dose effect (severe hypotension), thus should be given at bed time and start
with small dose and increase the dose gradually.
• Hyperkalemia and hyperuricemia (may cause gout)
• Specific to captopril: skin rash, fever, dysgeusia (loss of taste), Proteinuria and
neutropenia. These effects are due to a sulfhydryl group in the molecule of captopril.
Contra- • Patients with bilateral renal artery stenosis (to avoid renal failure)
indications • hypovolemic patients (due to Severe hypotension)
• Pregnancy (2nd & 3rd trimester) may lead to fetal hypotension, anuria, renal failure
& malformation.
• Potassium-sparing diuretics, because ACEI may cause hyperkalemia.
• NSAISD, because they reduce their hypotensive effects by blocking bradykinin-
mediated vasodilatation.
 Calcium channel blockers

Dihydropyridine Non-Dihydropyridine
Class:
Nifedipine ,Nicradipine, amlodipin Verapmil Diltiazem
Example

act mainly on smooth muscle, act more on has

thus more selective as myocardium as intermediate
vasodilators than cardiac cardiac effect in
Characteristic depressants. They are, therefore, depressant between
particularly beneficial in treating
used in the treatment of atrial
hypertension.
fibrillation and re-entry
Supraventricular arrhythmias
• given orally (onset= 0.5-2h) and I.V. injection for emergency (onset=
1-3min), well absorbed.
• CCBs have Short half-life. Sustained-release preparations can permit
once-daily dosing, and thus preferred for the treatment of
Pharmaco- hypertension.
kinetics
verapamil and nifedipine are highly bound to plasma Diltiazem is
proteins ( more than 90%) less ( 70-80%)
Nifedipine Doesn't have an active Verapmil & Diltiazem have active
metabolite metabolites
Block the influx of calcium through calcium channels (Ca is important for
muscle contraction) resulting in:
Mechanism of
1- Peripheral vasodilatation (mainly in arterioles)
action
2- Decrease cardiac contractility.

1-Treatment of chronic hypertension with diabetes or angina

Clinical uses 2- Nicardipine can be given by I.V. route & used in hypertensive
emergency
Nifedipine: Reflex Tachycardia Peripheral edema Peripheral
& severe edema (ankle
Adverse Constipation edema)
effects Headache (due to Hypotension) – Flushing (due to vasodilation)
 Vasodilators
Sodium
Hydralazine Minoxidil Diazoxide
nitropruside
Arteriodilator Arterio &
Site of action venodilator
Direct Opening of potassium channels Release of nitric
Mechanism oxide (NO)
MNM: Na-nitroprusside
release NO

admin. Oral I.V infusion

1.Moderate-severe hypertension. 1.Hpertensive emergency
2. Hypertensive 2. correction of 2. Treat 2.Severe heart
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Hypotension, reflex tachycardia, palpitation, angina, 1. Severe

salt and water retention (edema) hypotension.
Adverse These ADRs are due to activation of the sympathetic 2. Headache,
effect system & the RAAS after vasodilators-induced fall in BP, palpation
and thus should be used in combination with a diuretic (disappear when
and a β-blocker. infusion is stopped)
3.Methemoglobin
lupus Hypertrichosis, Hyperglycemia, during Infusion
erythematosus thus thus 4.Cyanide toxicity
like syndrome Contraindicated Contraindicated (resulting in
metabolic acidosis,
Specific in females in diabetics
arrhythmias, Severe
adverse hypotension and
MNM: Minoxidil = MNM: Diazoxide= death)
effects
used only for men contraindicated in
5. Thiocyanate
diabetes.
toxicity
 α and β- Adrenoceptor – blockers
β- Adrenoceptor – blocking agents
Non-cardio selective cardio selective

Drug propanolol Metoprolol , Atenolol, Bisoprolol

uses 1- can be used in mild to moderate hypertension

2-In severe cases used in combination with other drugs
3-may take 2 weeks to optimal therapeutic response (as ACEI)
4-evedance support using it with patient has concomitant
coronary artery disease
5- When discontinued, ß- blockers should be withdrawn
gradually to avoid rebound hypertension (not as severe as
clonidine’s).
Mechanism of Decrease blood pressure by:
action 1- Decreasing cardiac output (blocking β1)
2- Decreasing renin release (blocking β1)
3- Central Mechanism (blocking β-R in CNS)
Adverse effect • Increased triglycerides
• Fatigue, Hypoglycemia.
• Mask the symptoms of Hypoglycemia in diabetic patients.
• Aggravate peripheral arterial disease (as Reynaud's disease)
• Erectile dysfunction
α-adrenoceptor blockers
Prazosin Doxazosin
short-acting, causes first dose Preferred, because of
hypotension & postural hypotension its long half- life
Mechanis • Block α-receptors in arterioles & venules
m of action • Reduce pressure by decreasing preload & afterload
Clinical Due to weaker outcome data and their side effect profile,
use α-blockers are no longer recommended as initial treatment for
hypertension, but may be used for refractory cases.
 Centrally acting sympatholytic drugs

Clonidine α methyl dopa

(Direct α2-agonist) (Indirect α2 agonist, converted
to methyl norepinephrine)
diminish adrenergic outflow from the C.N.S, & increase parasympathetic
Mechanism
outflow to the heart. This leads to reduced total peripheral resistance, and
of action
decreased BP.
• hypertension with renal disease Safely used in hypertension in
(it Does not decrease renal blood flow pregnancy (first-line)
or glomerular filtration)
uses • resistant hypertension
(BP that remains elevated despite
administration of an optimal three-drug
regimen that includes a diuretic, due to drug
misuse, drug interaction, compliance, etc.)

Adverse Sudden withdrawal of clonidine can

effect lead to rebound hypertension
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