Pharmacology – I [PHL 313]

Antihypertensive Drugs

Dr. Mohammad Nazam Ansari

Antihypertensive drugs, Hypertension - Introduction

Hypertension is a condition that afflicts almost 1 billion people worldwide and is

a leading cause of morbidity and mortality.

Hypertension may defined as an abnormal

elevation of either SBP or DBP

SBP: systolic blood pressure

DBP: diastolic blood pressure

When the left ventricle ejects blood into the

aorta, the aortic pressure rises. The maximal

aortic pressure following ejection is termed

the systolic blood pressure (SBP)

As the left ventricle is relaxing and refilling,

the pressure in the aorta falls. The lowest

pressure in the aorta, which occurs just

before the ventricle ejects blood into the

aorta, is termed the diastolic blood pressure

(DBP) *Arterial pressures less than 90/60 mmHg are

considered hypotension, and therefore not normal

Antihypertensive drugs, Hypertension - Introduction

Causes of Hypertension: The are two basic types of hypertension:

I. Primary (essential) hypertension: The majority of patients (90-

95%) have essential hypertension, which is a form with no

identifiable underlying cause.

This form of hypertension is commonly treated with drugs in

addition to lifestyle changes (e.g., exercise, proper nutrition,

weight reduction, stress reduction).

II. Secondary hypertension: A smaller number of patients (5-10%)

have secondary hypertension that is caused by an identifiable

underlying condition such as thyroid disease, pregnancy, Renal artery

stenosis, Chronic renal disease, Primary hyperaldosteronism, Stress

etc.

Patients with secondary hypertension are best treated by

controlling or removing the underlying disease or pathology,

although they may still require antihypertensive drugs

Consequences of Hypertension

• Heart diseases

– Myocardial infarction (MI)

– Heart failure

– Angina pectoris

• Kidney disease

• Stroke

Antihypertensive drugs, Introduction

Each time the heart beats, a volume of blood (stroke volume “SV”) is ejected.

This stroke volume (SV), times the number of beats per minute (heart rate “HR”), equals

the cardiac output (CO); i.e., CO = SV x HR

Thus, cardiac output is the volume of blood being pumped by the heart, in particular by a

ventricle in a minute.

Stroke volume is expressed in ml/beat and heart rate in beats/minute. Therefore, cardiac

output is in ml/minute

Peripheral resistance (PR) refers to the resistance to blood flow offered by all of the

systemic vasculature, excluding the pulmonary vasculature.

Mechanisms that cause vasoconstriction increase PR, and those mechanisms that

cause vasodilatation decrease PR.

Therefore, patients with primary hypertension are generally treated with drugs that:

1. reduce blood volume (which reduces central venous pressure and cardiac output)

2. reduce peripheral resistance, or

3. reduce cardiac output by depressing heart rate and stroke volume

Blood Pressure = CO X Peripheral Resistance

Antihypertensive drugs

1. Diuretics

2. Angiotensin Converting Enzyme Inhibitors (ACE inhibitors)

3. Angiotensin Receptor blockers

4. Renin Inhibitors

5. Calcium Channel Blockers

6. Potassium Channel openers

7. α1-adrenoceptor antagonists (α1-blockers)

8. β-Blockers

9. α2-adrenoceptor agonists

10. Peripheral Vasodilators

1. Diuretic Mechanism of action Water follows Na+

Proximal convoluted tubule (PCT) reabsorbs 65% of filtered Na, 20-25% of

all Na is reabsorbed in the loop of Henle, 5-10% in distal convoluted tubule

(DCT) & 3% in collecting ducts

If it can not be absorbed it is excreted with the urine

Diuretics act on the kidney to enhance sodium and water excretion urine

output by the kidney (i.e., promote diuresis) blood volume preload

Reducing blood volume not only reduces central venous pressure, but even

more importantly, reduces cardiac output

Side Effects: electrolyte losses [Na+ (hyponatremia) & K+ (hypokalemia)],

fluid losses [dehydration], myalgia, Nausea, Vomiting, Diarrhea, Dizziness,

hyperglycemia, hyperlipidemia, hypercalcemia

Example: Thiazides: Chlorothiazide (Diuril®) & Hydrochlorothiazide (HydroDIURIL®)

Loop Diuretics: Furosemide (Lasix®), bumetanide (Bumex®)

Potassium Sparing Diuretics: Spironolactone (Aldactone®)

http://en.wikipedia.org/wiki/File:Physiology_of_Nephron.png

Renin-Angiotensin system antagonists

Aldosterone

Sympathetic

activation

Growth

factor

stimulation

Na+ retention

H2O retention

K+ excretion

Mg+ excretion

Vascular

smooth muscle

constriction

Angiotensin

converting

enzyme (ACE)

Angiotensin II

Liver secretes

angiotensinogen

Kidneys secrete

renin

Angiotensinogen Angiotensin I

Adrenal cortex secretes aldosterone

Blood Renin

The Renin-Angiotensin-Aldosterone

(RAA) System

2. ACE inhibitors Mechanism of action:

Dilate arteries and veins by blocking formation of angiotensin

II (AII, a vasoconstrictor) vasodilatation, thus reduces

arterial pressure, preload and afterload on the heart

Promote renal excretion of sodium and water. This reduces

blood volume, venous pressure and arterial pressure

Therapeutic uses: Hypertension, Heart failure, Myocardial

infarction (MI), Diabetic and nondiabetic nephropathy

Adverse effects: Dry cough*, Angioedema, Hyperkalemia,

Renal failure, Neutropenia, rashes, hypotension

Contraindications: Pregnancy - renal failure in infants, renal

impairment.

Examples: Captopril, Enalapril, Lisinopril, Quinapril, Ramipril,

Benazepril, Fosinopril

3. Angiotensin Receptor Blockers (ARBs)

Mechanism of action:

ARBs are receptor antagonists that block type 1 angiotensin II receptors on

blood vessels and other tissues such as the heart

Cause dilatation of arterioles and veins

Decrease release of aldosterone

Increase renal excretion of sodium and water, Reduce excretion of potassium

These drugs have similar effects to ACE inhibitors

Can be used in certain conditions when ACEIs are contraindicated

(angioneurotic edema, cough)

Therapeutic uses: Hypertension, Heart failure,

Diabetic nephropathy, Myocardial infarction,

Stroke prevention, Migraine headache

Adverse effects: Angioedema, Fetal harm, Renal failure

Examples: Losartan, Valsartan, Irbesartan, Candesartan, Telmisartan,

Olmesartan

4. Renin Inhibitors

Mechanism of action:

Renin inhibitors produce vasodilatation by inhibiting the

activity of renin, which is responsible for stimulating

angiotensin II formation

These drugs have similar effects to ACE inhibitors and ARBs

and are used for the same indications (hypertension, heart

failure)

Example: Aliskiren (first-in-class oral renin inhibitor)

Remikiren (underdevelopment)

5.Calcium Channel Blockers (CCBs): Mechanism of action. These drugs bind to L-Type calcium channels located on the vascular

smooth muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and

atrioventricular nodes).

These channels are responsible for regulating the influx of calcium into

muscle cells, which in turn stimulates smooth muscle contraction and

cardiac myocyte contraction.

Therefore, by blocking calcium entry into the cell, CCBs cause vascular

smooth muscle relaxation (vasodilatation), decreased myocardial force

contraction, decreased heart rate, and decreased conduction velocity

within the heart, particularly at the atrioventricular node (AV node).

Therapeutic Uses: Angina pectoris, Tachycardia, Hypertension

Side Effects: Cardiovascular: hypotension, palpitations & reflex tachycardia

Gastrointestinal: constipation & nausea

Other: rashes, facial flushing & peripheral edema

Examples: Diltiazem, Verapamil, Nifedipine, Amlodipine, Felodipine

6.Potassium Channel Openers:

Mechanism of action.

These are drugs that activate (open) ATP-sensitive K+-

channels in vascular smooth muscle. Opening of these

channels, hyperpolarizes the smooth muscle, which closes

voltage-gated calcium channels and decreases intracellular

calcium, leadings to muscle relaxation and vasodilatation,

decreasing systemic vascular resistance and lowering blood

pressure.

Examples: Nicorandil, minoxidil sulphate

7.α1-Adrenoceptor Antagonists (α1-Blockers)

Mechanism of action.

These drugs block the effect of sympathetic nerves on blood

vessels by binding to α-adrenoceptors located on the vascular

smooth muscle. Most of these drugs acts as competitive

antagonists to the binding of norepinephrine to the smooth

muscle receptors

α-blockers dilate both arteries and veins because both vessel

types are innervated by sympathetic adrenergic nerves; however,

the vasodilator effect is more pronounced in the arterial

resistance vessels. Thus, they decrease systemic vascular

resistance (SVR) and lower blood pressure (BP).

Uses: Hypertension, Pheochromocytoma.

Adverse effects: Drowsiness, excitation,

headache, tachycardia, and dizziness.

Examples: doxazosin, prazosin, terazosin

Phosphatidylinositol

4,5-bisphosphate

inositol 1,4,5-

trisphosphate

Diacylglycerol

8.β-Blockers : Mechanism of action.

β-blockers are drugs that bind to β-adrenoceptors and thereby block the

binding of norepinephrine and epinephrine to these receptors. This

inhibits normal sympathetic effects that act through these receptors.

Thus, drugs decrease heart rate, conduction velocity and force of

contraction

The first generation of β-blockers were non-selective, meaning that

they blocked both β1 and β2 adrenoceptors. Second generation β-

blockers (β1-blockers) are more cardioselective in that they are relatively

selective for β1 adrenoceptors.

Uses: Hypertension, angina, prevent 2nd MI, tachyarrythmias.

Adverse effects: Bronchospasm, sedation, reflex tachycardia, depression,

and increased serum triglycerides.

Examples: Non-selective β -blockers: Propranolol , carvedilol, Sotalol, timolol,

Selective β1 blockers: Atenolol, Metoprolol

β1 : Eye, Kidney, Heart, salivary glands

β2 : Lung, blood vessels, GIT, liver,

9. α2-Agonists (Centrally Acting Sympatholytics)

Mechanism of action. Centrally acting sympatholytics block sympathetic activity by binding

to and activating α2-adrenoceptors inhibition of NE release.

This reduces sympathetic outflow to the heart thereby decreasing

cardiac output by decreasing heart rate and contractility

Reduced sympathetic output to the blood vessels decreases

sympathetic vascular tone, which causes vasodilatation and reduced

systemic vascular resistance, which decreases arterial pressure

Therapeutic Uses: Hypertension. Migraine prophylaxis,

Adverse Effects: Depression

Examples: Clonidine, Methylopa

10. Peripheral Vasodilators

Nitrovasodilators

NO release

Activate guanylyl cyclase and ↑cGMP

↓Intracellular calcium

Smooth muscle relaxation

Vasodilation

Preload and afterload reduction

Improved cardiac function

Mechanism of action

– Directly relaxes arteriole smooth muscle

– Decrease systemic vascular resistance (SVR) = decrease afterload

Therapeutic Uses

– Hypertension

– Angina pectoris

– Heart failure

– Myocardial infarction

– Peripheral vascular disease

Side effects:

– Hydralazine: Reflex tachycardia, postural hypotension

– Sodium nitroprusside: Cyanide toxicity in renal failure, CNS toxicity =

agitation, hallucinations, etc.

Example:

– Hydralazine

– Sodium Nitroprusside

– Diazoxide

Thank you