Classification of ANTI-HYPERTENSIVE

Defination :-

A condition in which the blood pressure of systemic artery increases beyond thenormal pressure is known as hypertension.

Therefore to deliver blood to tissues, the heart works harder to overcome the increased systemic pressure.

This increased systemic arterial pressure puts strain on the heart and other arteries, thus resulting in high blood pressure

Based on the degree of severity, hypertension can be graded as:

1) Mild: Diastole up to 104mmHg,
2) Moderate: Diastole105-114mmHg, and
3) Severe: Diastole more than 115mmHg.

Symptoms of hypertension are:

1) Chest pain, 2) Confusion,
3) Ear noise or buzzing (tinnitus), 4) Irregular heartbeat (arrhythmia),
5) Nosebleed (epistaxis), 6) Exhaustion (lethargy), and
7) Vision changes.

Therapy for hypertensive patients aims at reducing the increased blood pressure.

This is accomplished by administration of drugs from different classes; t reatment

is often given in the form of a combination of several agents. If left untreated, it

would result in organ damage, thus an increased risk for MI and stroke

1.3.2. Classification

The antihypertensive agents are classified into the following classes:

1) Diuretics

i) Thiazides: Hydrochlorothiazide, Chlorthalidone, and Indapamide.
ii) Loop Diuretics: Furosemide, Bumetanide, and Torsemide.
iii) K+ Sparing Diuretics: Spironolactone, Amiloride, and Triamterene.

2) Angiotensin Converting Enzyme Inhibitors: Captopril, Enalapril, Lisinopril,

Ramipril, Perindopril, Fosinopril, Trandolapril, Quinapril, and Benazep ril.

3) Angiotensin II Receptor Antagonists: Losartan, Candesartan, Valsartan,

Eprosartan, and Irbesartan.

4) Ganglion Blockers: Trimethaphan.

5) Adrenergic Drugs

i) Centrally Acting D rugs: Clonidine, Methyldopa, Guanabenz, and
Guanfacine.
ii) Adrenergic Neuron Blockers: Guanethidine and Reserpine.
iii) Sympatholytics (Adrenergic Receptor Blockers)

a) Alph Blockers: Prazosin, Terazosin, Doxazosin, Phenoxybenzamine,
and Phentolamine.
b) Beta Blockers: Propranolol, Atenolol, Esmolol, and Metoprolol.
c) Alpha + Beta Blockers: Labetalol and Carvedilol..

Introduction

When a heart fails to pump blood in a quantity sufficient to fulfil the body

requirements, a condition of Congestive Heart Failure (CHF) occurs, which is

also known as a Heart Failure (HF).

CHF is caused due to:

1) Narrowing of the arteries supplying blood to the heart muscles,
2) Any congenital heart defects,
3) Endocarditis (infection in heart valves) or myocarditis (infection of heart muscles),
4) Cardiomyopathy (disease of the heart muscles),
5) Any long -term heart valve disease (due to past rheumatic fever or other causes) and high blood pressure, and
6) Past history of the patient who has suffered from myocardial infar ction or heart attack and the injured tissue obstructs the normal functioning of heart.

Some common symptoms of CHF are:

1) Fatigue, 2) Swelling or oedema,

3) Shortness of breath, and 4) Increased urination.

1.2.2. Classification

The following drugs are employed in the treatment of CHF:

1) Drugs with Positive Inotropic Effects

i) Cardiac Glycosides: Digoxin, Digitoxin, and Ouabain.
ii) Bipyridines/Phosphodiesterase Inhibitors: Amrinone and Milrinone.
iii) β-Adrenergic Agonists: Dobutamine and Dopamine.

2) Drugs without Positive Inotropic Effects

i) Diuretics: Thiazides, Furosemide, and Spironolactone.
ii) Angiotensin Antagonists: ACE inhibitors and Losartan.
iii) β-Adrenergic Antagonists: Bisoprolol, Carvedilol, and Metoprolol.
iv) Vasodilators: Nitrates and Hydralazine.

1.2.3. Cardiac Glycosides

Cardiac glycosides are derived from plant derivatives and are steroidal in nature .

A glycoside is a sugar-containing compound in which one of the hydroxyl groups

of the sugar molecule is replaced with another compound.

Digoxin, digitoxin, and ouabain are the commonly used cardiac glycosides.

Often, the term digitalis refers to the complete group of cardiac glycosides as all

the drugs in this group exert the same effects on the heart. They differ only in

lipid solubility, rapidity, degree of absorption, protein binding, metabolic

pathway, and excretion.

1.2.3.1. Mechanism of Action

The mechanism of action of digitalis can be explained as follows (figure 1.2):

1) Digitalis exerts a positive inotropic effect due to its ability to potentiate the

excitation-contraction coupling. This is possible since digitalis increases the

concentration of free intracellular Ca2+ ions.

2) It inhibits the membrane bound Na +/K+-ATPase transport system (sodium

pump), resulting in increase of intracellular Na + ions and loss of intracellular

K+ ions.

3) As Na+ ions accumulate inside the cell, it activates a Na +/Ca2+ carrier system

(a non -enzymatic protein carrier) within the membrane. The activation of

Na+/Ca2+carrier system results in an increase in the influx of Ca 2+ ions. Three

Na+ ions are exchanged for each Ca2+ ion, thereby generating an electrogenic

potential by this exchanger.

4) Normally, the concentration of Ca2+ ions around the myofilaments is lowered by

the Ca2+ ion pump in the Sarcoplasmic Reticulum (SR). The energy for driving

this pump is obtained by ATP hydrolysis carried out by Na +/K+-ATPase.

However, digitalis inhibits this enzyme and hence less energy is available for

driving the Ca2+ ion pump. Thus, the supply of Ca2+ ions from SR around the

myofilaments increases, which in turn activates the contractile machine ry.

5) The binding of digitalis to sodiu m pump is inhibited by the K+ ions present in

the serum. Hence, conditions of hypokalaemia facilitate the action of

digitalis. On the other hand, conditions of hyperkalaemia can decrea se

cardiac toxicity. Arrhythmia induced by digitalis, is increased by co nditions

of hypercalcaemia or hypomagnesaemia.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)

5.1.1. Introduction Non-Steroidal Anti -Inflammatory Drugs (NSAIDs) are used to treat inflammation, mild -to-moderate pain, and fever. Specific uses include the treatment of headache, arthritis, sports injuries, and menstrual cramps. Aspirin is used to inhibit the clotting of blood and prevent strokes and heart attacks in individuals at high risk. NSAIDs are also included in many cold and allergic preparations. The incidence of side effects depends on the drugs. The most common side effects of NSAIDs are GIT disturbances, like nausea, vomiting, constipation, diarrhoea, peptic ulcer, and decreased appetit e. They may also cause fluid retention which leads to oedema. The most serious side effects are liver failure, kidney failure, ulcers, and continued bleeding after an injury or surgery.

The individuals who are allergic to NSAIDs develop breath lessness on administration of NSAIDs. Asthma patients are at higher risk a nd suffer from severe allergic reaction s. Reye’s syndrome may occur in children and teenagers if they have administered aspirin when suffering from chicken pox or influenza. Thus, children and teenagers with suspected or confirmed chicken pox or influenza should not be administered with aspirin and salicylate. Drugs reducing the raised body temperature are antipyretics. Inflammation caused by Prostaglandin (PGE 2) is cured or prevented by using antiinflammatory agents . These drugs are extensively used for relieving minor aches, fever, pains, and for symptomatic treatment of rheumatoid arthritis, rheumatic fever, and osteoarthritis.

5.1.2. Mechanism of Action NSAIDs inhibit Cycloxygenase (COX) enzyme, which catalyses the synthesis of cyclic endoperoxides from arac hidonic acid to form PGs . There are two COX isoenzymes, i.e., COX -1 and COX -2. PGs which are associated with normal cellular activit y (protection of gastric mucosa and maintenance of kidney function) are produced by COX -1, while COX-2 produces PGs at the inflammation sites.

Both COX -1 and COX -2 with different level of selectivity are inhibited by NSAIDs. An elaborated mechanism of action of NSAIDs can be studied with respect to the following effects: 1) Anti-Inflammatory Effects: These effects of NSAIDs include:

i) This effect of NSAIDs is due to the inhibition of COX enzymes that produce prostaglandin H synthase by converting arachidonic acid into prostaglandins, TXA2, and prostacyclin.

ii) Aspirin irreversibly inactivates COX -1 and COX -2 by acet ylation of a specific serine residue. This distinguishes it from other NSAIDs, which reversibly inhibit COX-1 and COX-2.

iii) NSAIDs have no effect on lipoxygenase , and therefore do not inhibit leukotriene production.

iv) Additional anti-inflammatory mechanisms may include interference with the potentiative action of other mediators of inflammation (bradykinin, histamine, and serotonin), modulation of T -cell function, stabilisation of lysosomal membranes, and inhibition of chemotaxis.

2) Analgesic Effects: These effects of NSAIDs include:

i) This effect of NSAIDs is related to the peripheral inhibition of prostaglandin production, but it may also be due to the inhibition of pain stimuli at a sub-cortical site.

ii) NSAIDs prevent the potentiating action of prostaglandins on endogenous mediators of peripheral nerve stimulation (e.g., bradykinin).

3) Antipyretic Effect s: These effects of NSAIDs is related to inhibition of production of prostaglandins induced by interleukin-1 (IL-1) and interleukin6 (IL -6) in the hypothalamus and the “re -setting” of the thermoregulatory system, leading to vasodilatation and increased heat loss

5.1.3. Classification

The NSAIDs are classified as follows:

1) Non-Selective COX Inhibitors (Conventional NSAIDs) i) Salicylates: Aspirin, Diflunisal, Salsalate, Sodium salicylate, Salol, Salicylamide, Benorilate, and Choline salicylate. ii) Pyrazolone Derivatives: Phenylbutazone and Oxyphenbutazone.

iii) Indole Derivatives: Indomethacin and Sulindac.

iv) Propionic Acid Derivatives: Ibuprofen, Naproxen, Ketoprofen, and Flurbiprofen.

v) Anthranilic Acid Derivatives: Mefenamic acid.

vi) Aryl-Acetic Acid Derivatives: Diclofenac.

vii) Oxicam Derivatives: Piroxicam and Tenoxicam.

viii) Pyrrolo-Pyrrole Derivatives: Ketorolac.

2) Preferential COX-2 Inhibitors: Nimesulide, Meloxicam, and Nabumetone. 3) Selective COX-2 Inhibitors: Celecoxib, Rofecoxib, and Valdecoxib. 4) Analgesic-Antipyretics with Poor Anti-Inflammatory Action i) Para-Aminophenol Derivatives: Paracetamol (Acetaminophen). ii) Pyrazolone Derivatives: Metamizol (Dipyrone) and Propiphenazone. iii) Benzoxazocine Derivatives: Nefopam

5.1.4. Salicylates - Aspirin For nearly 200 years aspirin is in use for clinical purposes. Earlier it was derived from willow bark but now it is synthesised.

5.1.4.1. Mechanism of Action

The analgesic, antipyretic, and anti-inflammatory effects of aspirin are exerted by the acetyl and the salicylate portions of the intact molecule as well by the active salicylate metabolite. Aspirin directly and irreversibly inhibits the activity of COX-1 and COX-2 to decrease the formation of precursors of prostaglandins and thromboxanes from arachidonic acid. This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen) which are reversible inhibitors. Salicylate may competitively in hibit prostaglandin formation. Aspirin’s anti - rheumatic (non-steroidal anti-inflammatory) actions are a result of its analgesic and anti-inflammatory mechanisms.

5.1.4.2. Pharmacokinetics

Aspirin on oral administration is absorbed quickly, mostly from the upper pa rt of small intestine (due to large surface area and also where the drug is mostly ionised) and partly from the stomach (where the drug is moslty unionised). After absorption, aspirin rapidly hydrolyses into acetic acid and salicylate bound to plasma prote ins (especially albumin ). However, the unbound fraction of salicylate increases with the increase in serum concentration. Salicylate biotransformation increases in the mitochondria and hepatic endoplasmic reticulum. Salicylate formed by hydrolysing aspirin can be excreted as such or as water-soluble conjugates like ether, salicyluric acid (the glycine conjugate), or

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