Pharmacology of NSAIDs, Anticoagulants, and Diuretics

Posted on Jan 28, 2026 in Medicine & Health

NSAIDs: Classification and Mechanism of Action

NSAIDs have the following group of drugs:

1. Analgesic
2. Antipyretic
3. Anti-inflammatory

Classification of NSAIDs

A. Nonselective COX Inhibitors (Traditional NSAIDs)

Salicylates: Aspirin
Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen.
Anthranilic acid derivative: Mefenamic acid
Aryl-acetic acid derivatives: Diclofenac, Aceclofenac.
Oxicam derivatives: Piroxicam, Tenoxicam.
Pyrrolo-pyrrole derivative: Ketorolac
Indole derivative: Indomethacin.
Pyrazolone derivative: A. Phenylbutazone, Oxyphenbutazone

B. Preferential COX-2 Inhibitors

Nimesulide, Meloxicam, Nabumetone.

C. Selective COX-2 Inhibitors

Celecoxib, Etoricoxib, Parecoxib.

D. Analgesic-Antipyretics with Poor Anti-inflammatory Action

Para-aminophenol derivatives: Paracetamol
Pyrazolone derivative: Metamizole, Propyphenazone.
Benzoxazocine derivative: Nefopam

Mechanism of Action of NSAIDs

1. Anti-inflammatory effect: Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine residue. This distinguishes it from other NSAIDs, which reversibly inhibit COX-1 and COX-2.

2. Analgesic effect:
A. The analgesic effect of NSAIDs is thought to be related to the peripheral inhibition of prostaglandin production; it may also be due to the inhibition of pain stimuli at a subcortical site.
B. NSAIDs prevent the potentiating action of prostaglandins on endogenous mediators of peripheral nerve stimulation (e.g., bradykinin).

3. Antipyretic effect:
1. The antipyretic effect of NSAIDs is believed to be related to the inhibition of production of prostaglandins induced by interleukin-1 (IL-1) and interleukin-6 (IL-6) in the hypothalamus, leading to the “resetting” of the thermoregulatory system, resulting in vasodilatation and increased heat loss.

Aspirin: Properties and Therapeutic Uses

• Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever.

• Aspirin is also used long-term to help prevent further heart attacks, ischaemic strokes, and blood clots in people at high risk. For pain or fever, effects typically begin within 30 minutes. Aspirin works similarly to other NSAIDs but also suppresses the normal functioning of platelets.

Mode of Action: Aspirin

Aspirin, an acetylated salicylate (acetylsalicylic acid), is classified among the nonsteroidal anti-inflammatory drugs (NSAIDs). These agents reduce the signs and symptoms of inflammation and exhibit a broad range of pharmacologic activities, including analgesic, antipyretic, and antiplatelet properties.

Aspirin causes several different effects in the body, mainly the reduction of inflammation, analgesia (relief of pain), the prevention of clotting, and the reduction of fever. Much of this is believed to be due to decreased production of prostaglandins and TXA2. Aspirin’s ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme.

A. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors. However, other effects of aspirin, such as uncoupling oxidative phosphorylation in mitochondria and the modulation of signalling through NF-κB, are also being investigated. Some of its effects are like those of salicylic acid.

Blood Coagulation and Clotting Factors

Coagulation or clotting is defined as the process in which blood loses its fluidity and becomes a jelly-like mass a few minutes after it is shed out or collected in a container.

Factors Involved in Blood Clotting

Coagulation of blood occurs through a series of reactions due to the activation of a group of substances. Substances necessary for clotting are called clotting factors. Thirteen clotting factors are identified:

Factor I: Fibrinogen
Factor II: Prothrombin
Factor III: Thromboplastin (Tissue factor)
Factor IV: Calcium
Factor V: Labile factor (Proaccelerin or accelerator globulin)
Factor VI: Presence has not been proven
Factor VII: Stable factor
Factor VIII: Antihemophilic factor (Antihemophilic globulin)
Factor IX: Christmas factor
Factor X: Stuart-Prower factor
Factor XI: Plasma thromboplastin antecedent
Factor XII: Hageman factor (Contact factor)
Factor XIII: Fibrin-stabilizing factor (Fibrinase)

Stages of Blood Clotting

Blood clotting occurs in three stages:

Formation of prothrombin activator.
Conversion of prothrombin into thrombin.
Conversion of fibrinogen into fibrin.

i. Intrinsic Pathway

For the formation of prothrombin activator: In this pathway, the formation of prothrombin activator is initiated by platelets, which are within the blood itself.

ii. Extrinsic Pathway

For the formation of prothrombin activator: In this pathway, the formation of prothrombin activator is initiated by the tissue thromboplastin, which is formed from the injured tissues.

Sequence of Events in the Extrinsic Pathway

i. Tissues that are damaged during injury release tissue thromboplastin (factor III). Thromboplastin contains proteins, phospholipids, and glycoproteins, which act as proteolytic enzymes.

ii. Glycoprotein and phospholipid components of thromboplastin convert factor X into activated factor X, in the presence of factor VII.

iii. Activated factor X reacts with factor V and the phospholipid component of tissue thromboplastin to form prothrombin activator. This reaction requires the presence of calcium ions.

Stage 3: Conversion of Fibrinogen to Fibrin

The final stage of blood clotting involves the conversion of fibrinogen into fibrin by thrombin. Sequence of events in Stage 3:

i. Thrombin converts inactive fibrinogen into activated polypeptides from each fibrinogen molecule. The activated fibrinogen is called fibrin monomer.

ii. Fibrin monomer polymerizes with other monomer molecules and forms loosely arranged strands of fibrin.

iii. Later, these loose strands are modified into dense and tight fibrin threads by fibrin-stabilizing factor (factor XIII) in the presence of calcium ions.

All the tight fibrin threads are aggregated to form a meshwork of stable clot fibrinogen due to loss of 2 pairs.

Haematinics: Iron and Folic Acid

Haematinics: These are substances required in the formation of blood and are used for the treatment of anemias.

Anemia occurs when the balance between production and destruction of RBCs is disturbed by:
(a) Blood loss (acute or chronic)
(b) Impaired red cell formation due to:
– Deficiency of essential factors, i.e., iron, vitamin B12, folic acid.
– Bone marrow depression (hypoplastic anemia).
– Erythropoietin deficiency.
(c) Increased destruction of RBCs (hemolytic anemia).

Iron Distribution and Absorption

Iron: Iron has for long been considered important for the body. Lauha bhasma (calcined iron) has been used in ancient Indian medicine. According to Greek thought, Mars is the God of strength, and iron is dedicated to Mars; as such, iron was used to treat weakness, which is common in anemia.

Distribution of Iron in the Body:

Hemoglobin (Hb): 66%
Iron stores as ferritin and hemosiderin: 25%
Myoglobin (in muscles): 3%
Parenchymal iron (in enzymes, etc.): 6%

Iron Absorption:

The average daily diet contains 10-20 mg iron. Its absorption occurs all over the intestine, but the majority is in the upper part. Dietary iron is present either as heme or as inorganic iron. Absorption of heme iron is better (up to 35% compared to inorganic iron which averages 5%) and occurs directly without the aid of a carrier.

Factors Facilitating Iron Absorption:

Acid: By favoring dissolution and reduction of ferric iron.
Reducing substances: Ascorbic acid, amino acids containing SH radical. These agents reduce ferric iron and form absorbable complexes.
Meat: By increasing HCl secretion and providing heme iron.

Folic Acid

Folic acid: It occurs as yellow crystals which are insoluble in water, but its sodium salt is freely water-soluble. Chemically, it is Pteroylglutamic acid (PGA) consisting of pteridine + para-aminobenzoic acid (PABA) + glutamic acid.

Dietary sources: Liver, green leafy vegetables (spinach), egg, meat, milk. It is synthesized by gut flora, but this is largely unavailable for absorption.

Anticoagulants: Classification and Action

Anticoagulants: Drugs that help prevent the clotting (coagulation) of blood. Coagulation will occur instantaneously once a blood vessel has been severed. Blood begins to solidify to prevent excessive blood loss and to prevent invasive substances from entering the bloodstream.

Classification of Anticoagulants

1) Used In Vivo:

A) Parenteral Anticoagulants:

Indirect Thrombin Inhibitors: Heparin, Low molecular weight heparins, Fondaparinux, Danaparoid.
Direct Thrombin Inhibitors: Lepirudin, Bivalirudin, Argatroban.

B) Oral Anticoagulants:

Heparin is a non-uniform mixture of straight-chain mucopolysaccharides with MW 10,000 to 20,000. It contains polymers of two sulfated disaccharide units: D-glucosamine-L-iduronic acid and D-glucosamine-D-glucuronic acid. It is present in all tissues containing mast cells; richest sources are lung, liver, and intestinal mucosa.

Coumarin Derivatives: Bishydroxycoumarin (dicumarol), Warfarin sodium, Acenocoumarol, Ethylbiscoumacetate.
Oral Direct Thrombin Inhibitor: Dabigatran etexilate.
Indandione Derivative: Phenindione.
Direct Factor Xa Inhibitors: Rivaroxaban.

2) Used In Vitro:

A) Heparin
B) Calcium Complexing Agents: Sodium citrate, Sodium oxalate, Sodium edetate.

Anticoagulant Action of Heparin

Heparin activates plasma AT III.
Heparin-AT III complex binds to clotting factors of intrinsic and common pathways (Xa, IIa, IXa, XIa, XIIa, and XIIIa) and inactivates them.

Mechanism of Action (LMW Heparins)

Selectively inhibit factor Xa with little effect on IIa.
Act only by inducing conformational change in AT III.
Hence, LMW heparins have a smaller effect on aPTT and whole blood clotting time than unfractionated heparin (UFH).
Also, they have lesser antiplatelet action and less interference with haemostasis.
Lower incidence of haemorrhagic complications compared to UFH.
Elimination: Primarily by renal excretion.

Diuretics: Physiology and Classifications

Diuretic: A substance that promotes the excretion of urine (e.g., caffeine, nettles, cranberry juice, alcohol).
Natriuretic: A substance that promotes the renal excretion of Na+.

Diuretics Action

Mainly promotes the excretion of Na+, Cl-, or HCO3- and water. The net result being:

Increase in urine flow.
Change in urine pH.
Change in the ionic composition of the urine and blood.

Diuretics are very effective in the treatment of:

Edema: CHF, pregnancy, and nutritional.
Nephrotic syndrome.
Diabetes insipidus.
Hypertension.
Cirrhosis of the liver and also lower the intracellular and CSF pressure.

Normal Physiology of Urine Formation

Two important functions of the kidney are:

To maintain a homeostatic balance of electrolytes and water.
To excrete water-soluble end products of metabolites.

Each kidney contains approximately one million nephrons and is capable of forming urine independently. The nephrons are composed of the glomerulus, proximal tubule, loop of Henle, and distal tubule.

Approximately 1200 ml of blood per minute flows through both kidneys.
Ions such as sodium, chloride, and calcium are reabsorbed.
Total amount of glucose, amino acids, vitamins, and proteins are reabsorbed.
The presence of these molecules in urine represents disorders. For example, proteins such as albumin in higher amounts cause albuminuria.

Classifications of Diuretics

A. Thiazide Diuretics:

a) Thiazides: Hydrochlorothiazide, Benzthiazide.
b) Thiazide-like: Chlorthalidone, Metolazone, Xipamide, Indapamide, Clopamide.

B. Loop Diuretics:

Furosemide, Bumetanide, Torasemide, Ethacrynic acid.

C. Potassium Sparing Diuretics:

Aldosterone Antagonist: Spironolactone, Canrenone, Eplerenone.
Directly Acting (Inhibition of Na+ channel): Triamterene, Amiloride.

D. Carbonic Anhydrase Inhibitors:

Acetazolamide, Brinzolamide, Dorzolamide.

E. Osmotic Diuretics:

Mannitol, Glycerine, Urea, Isosorbide.

Osmotic Diuretics

Do not interact with receptors or directly block renal transport. Activity is dependent on the development of osmotic pressure. Examples: Mannitol (prototype), Urea, Glycerol, Isosorbide.

Thiazide Diuretics

Active in the distal convoluted tubule. Examples: Chlorothiazide (prototype), Hydrochlorothiazide, Chlorthalidone, Metolazone.

Loop Diuretics

Active in the “loop” of Henle. Examples: Furosemide (prototype), Bumetanide, Torsemide, Ethacrynic acid.

Angina Pectoris and Antianginal Drugs

Angina pectoris is the chief symptom of ischemic heart disease (IHD) characterized by sudden, severe pain which may radiate to the left shoulder and surface of the left arm. Myocardial oxygen consumption depends on preload, afterload, and heart rate. When the oxygen supply to the myocardium is insufficient for its needs, myocardial ischemia develops.

Types of Angina

Stable Angina (Classical Angina): Pain is induced by exercise or emotion, both of which increase myocardial oxygen demand.
Unstable Angina: Classified between stable angina and myocardial infarction. What causes unstable angina? This occurs when an atheroma plaque ruptures and a blood clot may form, decreasing blood flow in the artery.
Variant Angina.

Risk Factors

Hyperlipidaemia
Hypertension
Diabetes
Smoking

Classification of Antianginal Drugs

Nitrates: Nitroglycerine, isosorbide dinitrate, isosorbide mononitrate.
Calcium Channel Blockers: Verapamil, diltiazem, amlodipine, nifedipine, nicardipine.
Beta-blockers: Propranolol, atenolol, metoprolol.
Potassium Channel Openers: Nicorandil, minoxidil, diazoxide.
Other Antianginals: Dipyridamole, aspirin, trimetazidine.

Nitrates

A. They are converted to nitric oxide. They activate vascular guanylyl cyclase which increases the synthesis of cGMP. This cGMP catalyzes the phosphorylation of protein kinases causing relaxation of the smooth muscles.

Pharmacokinetics: Organic nitrates are lipid-soluble and well absorbed from buccal mucosa. Action occurs in 5-7 min. Half-life is 2-5 hr.

Adverse Drug Reactions (ADR): Palpitation, fatigue, dizziness, postural hypotension.

Calcium Channel Blockers

Examples: Verapamil, Diltiazem, Amlodipine, Nifedipine, Nicardipine.

Mechanism of Action (MOA): The intracellular concentration of calcium plays an important role in maintaining the tone of smooth muscle and in the contraction of the myocardium.

Pharmacokinetic Action: Most of these agents have short half-lives (3 to 8 hours), are metabolized in the liver, and excreted in the urine.

ADR: Dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure. Peripheral edema is another commonly reported side effect of this class.

Beta-blockers

Examples: Propranolol, Atenolol, Metoprolol.

MOA: Blockade of cardiac β1 receptors results in decreased myocardial contractility and cardiac output. They reduce the BP due to a fall in the cardiac output. They also lower plasma renin activity and have an additional central antihypertensive action.

ADR: Bradycardia, fatigue, insomnia, sexual dysfunction, hypotension.

Potassium Channel Openers

Examples: Nicorandil, Minoxidil, Diazoxide.

MOA: Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium. This leads to relaxation and vasodilation.