INTRODUCTION:

Inflammatory response syndrome is the most extreme form of inflammatory response and may be life threatening in critically ill patient. Inflammation is a response of vascularized tissues to infection and damaged tissues that bring cell and molecule of the host defense from the circulation to the sites where they are needed, in order to eliminate the offending agents Inflammation is a critical homeostatic process that is activated by cellular injury regardless of the mechanism of that injury. Inflammation does not mean infection even when an infection causes Inflammation. Infection is caused by a bacterium, virus &fungus, while inflammation is the body’s response to it. Inflammation may not able to overcome large numbers of microorganisms.^1,2,3

Defination:

Inflammation is the reaction of tissues to injury. A well-organized cascade of fluid and cellular changes within living tissues is involved.

Inflammation Symptoms:

· Rubor (redness)

Acutely visible red small blood damaged inflamed tissue due to vessel dilation within the area (hyperemia)

· Tumor (swelling)

· Calorie (heat)

Skin temperature increases are easily detected. It is caused by increased blood flow (hyperemia) in the area, which causes vascular dilation and the delivery of warm blood to the area.

· Dolor (pain)

Pain is caused by the stretching and distortion of tissues caused by inflammatory edoema, as well as some of the chemical mediators of acute inflammation, particularly bradykinin and some prostaglandins.⁴

Non-functional (loss of function):

Inflammation is somewhat arbitrarily divided into acute and chronic inflammation, but in reality the two often form a continuum. Many causes of tissue damage induce an acute inflammatory response, but some types of insults can elicit a typical chronic inflammatory response from the outset (eg, viral infections, foreign body reactions, and fungal infections).

Effects of inflammation:

The effects of inflammation can be both local and systemic. Systemic effects of acute inflammation include fever, malaise, and leukocytosis. The local effects are usually clearly beneficial, such as the destruction of invading microorganisms, but at other times they appear to serve no apparent function or may even be harmful.

Types of inflammation:

Depending on the host defense capacity of the response, inflammation can be classified as:

A) Acute inflammation

B) Chronic inflammation

A) Acute inflammation:

Acute inflammation can be divided into the following two events:

1) Vascular events

2) Cellular events

Closely related to these two processes is the release of mediators of acute inflammation, which will be discussed later.

1) Vascular events:

Relaxation of vascular smooth muscle leading to tissue perfusion with blood (hyperemia).

2) Mobile events:

Cellular events are the result of activation of inflammatory cells and repair tissue.

a) margination/ rolling/adhesion of WBC (white blood cells) in capillaries and venules

b) emigration of WBCs from the postcapillaryvenules into the tissue (exudation)

c) accumulation of white blood cells in places of injury

d) Activation of inflammatory cells and production of chemical mediators

● DOLOR stimulus removal:

Acute inflammation can be defined as an early response to local injury in vascularized tissue. The purpose of this is to deliver plasma and blood cells to damaged tissue. His difficult stage. This stage can be divided into vascular and cellular events, although both components act in concert, simultaneously.

Fig.No.1Acute Inflammation

a) Vascular Events of Acute Inflammation:

In the early stages of inflammation, the affected tissue becomes red and swollen due to increased blood flow and edema fluid. The vascular events of the acute inflammatory response involve three main processes.

· Changes in the caliber of the container and consequently the flow rate

· Increased vascular permeability and

· Formation of liquid exudate

Vessel walls also change during acute inflammation to allow inflammatory cells to adhere and get out into the tissue where they are needed. Below are two graphics for illustration.

b) Cellular Exudates:

I) Leukocyte-Endothelial Interactions:

The hyperemic phase is followed by increased vascular permeability and blood viscosity increases and blood flow slows down. As blood flow begins to slow again, blood cells begin to flow closer to the vessel wall, rather than the axial flow. This is called margination of leukocytes. Then, leukocytes begin to roll along the surface of the endothelium in the blood vessel and eventually line up along the vascular endothelium. As a result of the interaction between leukocytes and adhesion molecules of endothelial cells, leukocytes then adhere to the endothelium. After the formation of adhesion, the next step is the emigration of leukocytes into the extravascular space. Visit each of the above links for a thorough discussion of margination, rolling, adhesion and emigration. To summarize, the leukocyte edge is mediated by vasodilation and slowing of blood flow. Rolling results from the initial interaction of leukocytes.

Expression of these molecules on cells increases as cells are activated by inflammatory cytokines. Firm adhesion occurs after greater interaction of adhesion molecules and this interaction leads to emigration.^5,6,7

Fig 3: Leukocyte-Endothelial Interaction

B) Chronic inflammation:

This type of inflammation is a long-term process in which tissue destruction and inflammation occur simultaneously.

This can be caused by one of the following 3 ways

1. Chronic inflammation after acute inflammation:

If tissue destruction continues, infectious agents survive and persist in small amounts at the site of acute inflammation, eg osteoporosis, pneumonia.

1. Repeated attacks of acute inflammation:

When repeated attacks of acute inflammation culminate in the chronicity of the process, for example, repeated acute infection of the gallbladder leads to chronic cholecystitis.

2. Chronic inflammation starting de novo:

When the organism is infected with a low pathogen. The city has been chronic since the beginning, e.g. mycobacterium tuberculosis infection. Inflammation is different because the response to it is also different because different types of tissues and cells are involved in this process. Types of chronic inflammations:

1. Non-specific:

It is not site-specific or has no properties, generating a chronic inflammatory reaction with the formation of granulation tissue and healing by fibrosis, e.g. chronic ulcers.

2. Specific:

When the damaging agent causes characteristic and histological tissue reactions, eg leprosy, tuberculosis.

Cells involved in chronic inflammation:

1) Macrophages

The prima donna of chronic inflammation.

This designation includes related cells of bone marrow origin, namely monocytes and macrophages, Kupffer cells, sinus histiocytes, alveolar macrophages, microglial cells, etc.

a) Functions of macrophages:

Phagocytosis of particles, microbes and senescent cells.

Recruitment of T and B cells, at the same time that they themselves are recruited into inflammatory ones

Sites by action of lymphocytic products (obvious stimulation as long as the inciting stimulus remains) Emigrate relatively early in acute inflammation, within 48 hours. they are the predominant cell type and are "activated".

b) Epithelioid Macrophages:

Specialized macrophages with more abundant eosinophilic cytoplasm and eccentrically located, Roundshaped to oval nucleus, thus resembling epithelial cells. Possess numerous lysosomes and vacuolated cytoplasm. Have fewer receptors and less phagocytic activity; they specialize in secretion of cytokines. Can fuse together to form multinucleate giant cells.

c) Multinucleated giant cells:

As a result of the fusion of macrophages under the influence of IL-4 and IFN-γ.^8,9,10

There are different types including:

Langhans:

· Cores located on the periphery; occurs in most types of chronic inflammation.

· Foreign body: nuclei scattered throughout the cytoplasm of giant cells.

II) Touton:

A rosette of nuclei in the center may be in tumors of histiocytic (tissue macrophage) origin or xanthomas (masses composed of lipids, foamy macrophages, and giant cells; associated with disorders of lipid or triglyceride metabolism).

d) Participation of macrophages in chronic inflammation:

Continue to recruit monocytes from the circulation (if persistent agent) due to stable expression of chemotactic factors, eg C5a, IL-8, PDGF, TGF- The number of macrophages may also increase due to local proliferation (replication).

Macrophages can be activated by microbial products (eg LPS), cytokines (eg IFN-γ, IL-4) and other mediators. Activated macrophages immobilize and survive in sites of chronic inflammation. Macrophages cause tissue destruction even when properly activated. Actions of activated macrophages:

Cause of inflammation and tissue injury

· Reactive forms of oxygen and nitrogen

· Proteases

· Cytokines/chemokines

· Coagulation factors

· Metabolites of arachidonic acid repair / fibrosis, due to the production of:

· Growth factors (PDGF, FGF, TGFß)

· Fibrogenic cytokines

· Angiogenesis factors

· "Remodeling" collagenases

Lymphocytes and plasma cells T and B lymphocytes migrate to inflammatory sites.

T lymphocytes have a reciprocal relationship with macrophages that control chronic inflammation. Macrophages present “processed” antigen fragments on their surface Antigen-presenting macrophages interact with lymphocytes lymphocyte activation Lymphocyte-derived mediators are produced (e.g. IFN-γ) activation of other macrophages the cycle of lymphocytes and macrophages continues until the triggering antigen is removed or the response is otherwise modulated. B lymphocytes are also stimulated by macrophages and helper T lymphocytes (CD4) to become plasma cells and produce antigen-specific antibodies.¹¹

NSAIDs:

Introduction:

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat mild pain and to manage edema and tissue damage due to inflammatory joint disease (arthritis). A number of these drugs, in addition to their analgesic and anti-inflammatory effects, also have antipyretic effects and are therefore useful in the treatment of fever. Most of these drugs exert their therapeutic action by inhibiting prostaglandin biosynthesis, as described in the following sections. Some of the primary indications for NSAID therapy include:

Definition:

These are compounds released by one ce are compounds released by one cell type that bind to a type II that binds to a receptor of another cell type to a receptor of another cell type to influence the response by influencing the response of that other cell the other cell¹²

NSAIDs are a class of analgesics that reduce pain, fever, and inflammation. Since most episodes of back pain involve inflammation, NSAIDs such as ibuprofen and naproxen are often an effective treatment option.

Classification of NSAIDs:

1) Salicylates:

For example, aspirin, sodium salicylate

2) Propionic acid derivatives: e.g. ibuprofen, ketoprofen, naproxen.

3) Arylacetic acid derivatives: e.g. diclofenac, ketorolac

4) Indole derivatives: e.g. indomethacin, sulindac

5) Alkanones: Eg: Nabumeton.

6) Oxicams: Eg: piroxicam, tenoxicam

7) Anthranilic acid derivatives (fenamates): eg: mefenamic acid and flufenamic acid.

8) Pyrazolone derivatives: E.g. n-phenylbutazone, oxyphenbutazone, azapropazone.

9) Aniline derivatives (only analgesics): eg: paracetamol.

10)Selective COX 2 inhibitors: e.g. celecoxib, etoricoxib, rofecoxib, valdecoxib

11) Preferential COX 2 inhibitors: eg: meloxicam, etodolac, nabumetonenimesulide Salicylates:

Acetylsalicylic acid (aspirin):

Mechanism of action:

Aspirin irreversibly inhibits the cyclooxygenase enzyme, thus blocking the synthesis of prostaglandins and thromboxane A2.

Pharmacological effects:

· Inhibits prostaglandin synthesis

· Blocks the action of kinins, which are mediated by the synthesis of prostaglandins.

· Inhibits adherence of granulocytes to damaged vasculature.

· Stabilizes lysosomes.

· Inhibits the migration of PMN leukocytes and macrophages to the site of inflammation.

Use:

1. Anti-aggregation: M imp

2. Analgesic

3. Anti-inflammatory

4. Antipyretic

Adverse effects:

• CNS: Headache, Tinnitus, dizziness, blurred vision, irritability, hyperventilation(salicylicism)

• Cardiovascular: fluid retention, HT, edema, CHF (rarely)

• GIT disorders: abdominal pain, nausea, vomiting, peptic ulcer and bleeding

• Hypersensitivity: bronchial asthma, angioedema and rashes,

Side effects of aspirin:

• Renal effects:

Inhibition of PGE2-mediated vasodilatation in response to ATII renal insufficiency, renal failure, hyperkalemia, proteinuria. Analgesic nephropathy with chronic use

• Hepatic:

Liver function abnormalities, rarely liver failure.

Aspirin overdose:

• Acid-base disorder.

• Respiratory alkalosis (400 500 micrograms/ml).

• Direct stimulation of the respiratory centers

• Metabolic acidosis (0.5 1 mg/ml)

• Medullary depression.

Propionic acid derivatives:

E.g., Ibuprofen, Naproxen, Fenoprofen

Ibuprofen:

Ibuprofen was the first member of this class, introduced in 1969 as a better tolerated alternative to aspirin.

Mechanism of action:

Ibuprofen is a non-selective COX inhibitor and therefore inhibits both COX-1 and COX-2 activity. Inhibition of COX-2 activity reduces the synthesis of prostaglandins involved in mediating inflammation, pain, fever, and swelling, while inhibition of COX-1 is thought to cause some of the side effects of ibuprofen, including GI ulceration.¹³

Use:

1) Simple analgesic and antipyretic

2) Effective in dysmenorrhea

3) It is widely used in rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders

Adverse effects:

Nephrotoxicity, jaundice, nausea, dyspepsia, edema, rash, pruritus, tinnitus. Interactions and contraindications: same as aspirin.

3) Arylacetic acid derivatives: Eg: Diclofenac, ketorolac

Diclofenac

Analgesic-antipyretic-anti-inflammatory drug with similar effectiveness to naproxen.¹⁴

Mechanism of action:

It inhibits PG synthesis and is somewhat selective for COX-2. The antiplatelet effect is not noticeable due to sparing of COX-1. It also does not block the cardioprotective effect of low-dose aspirin.

• Short half-life (1 2 hours), high 1st pass metab., accumulates in synovial fluid after oral administration.

Use:

1) Diclofenac is used for pain relief.

2) Relieves pain in conditions such as headache, mild migraine, muscle pain, toothache, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis or painful menstruation.

Adverse effect:

• GI S/E: approximately 20% points. Serious effects such as gastrointestinal distress, gastrointestinal bleeding, gastric ulceration less common than with other NSAIDs and similar to celecoxib.

• High doses impair kidney function. Increases liver enzymes.

• Children with CI, pregnant women and nursing mothers.

4) Preferential COX 2 inhibitors: eg: meloxicam, etodolac, nabumetonnimesulide nimesulide

Mechanism of action:

This NSAID is a relatively weak inhibitor of PG synthesis and moderately selective for COX-2. The anti-inflammatory effect can also be exerted by another mechanism, e.g. reduced superoxide formation by neutrophils, inhibition of PAF synthesis and release of TNFα by free radicals, inhibition of metalloproteinase activity in cartilage.

Rel weak inhibition of PG synth, 5 10 COX 2 sel.

Another moss – reduced SO prod, free radical scavenger, inhibition of PAF synth & metalloproteinase action in cartilage.

Use:

It is effective in relieving pain caused by headache, migraine, nerve pain, toothache, throat pain, period pain, arthritis and muscle pain.

Adverse effects:

• Diarrhea

• Vomiting

• Rash

• Itching

• Dizziness

• Bitterness in the mouth

4) Derivatives of anthranilic acid fenamates: eg: mefenamic acid and flufenamic acid.

Mefenamic acid:

Analgesic, antipyretic and weaker anti-inflammatory drug that inhibits the synthesis of PGs and at the same time antagonizes some of their actions. Mefenamic acid has both peripheral and central analgesic effects.

Mechanism of action:

Mefenamic acid binds to COX-1 and COX-2 prostaglandin synthetase receptors, thereby inhibiting the action of prostaglandin synthetase. Because these receptors play a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity, pain symptoms are temporarily reduced.^14,15,16

Adverse effects:

Diarrhea is the most important dose-related side effect. They complain of epigastric discomfort, but intestinal bleeding is not significant. Skin rashes, dizziness and other CNS symptoms appeared.

Use:

1) Mefemic acid is mainly indicated as an analgesic for muscle, joint and soft tissue pain, where a strong anti-inflammatory effect is not required.

2) May be useful in some cases of rheumatoid arthritis and osteoarthritis bound in plasma and distributed evenly throughout the body.^{17,18,19,20,21}

REFERENCES:

1. Abbas A.B.; Lichtman A.H. Inflammation and Its Pharmacotherapy). "Ch.2 Innate Immunity". In Saunders (Elsevier). Basic Immunology. Functions and Disorders of the Immune System (3rd ed.).(2009)

2. Amanda Wages, Megan Troutman, Inflammation and Its Pharmacotherapy, Department of Pathology College of Veterinary Medicine The University of Georgia Athens, July 28, 2009 unit test3 pg. no 1-4, 6-7.

3. Ash ASF, Schild HO. Inflammation and Its Pharmacotherapy. Br J PharmacChemother 1966; 27:427-37.

4. Cotran; Kumar, Collins Inflammation and Its Pharmacotherapy Robbins Pathologic Basis of Disease. Philadelphia: W.B Saunders Company.(1998)

5. Dr.Junge C.M., Dr. Burande M.D. and Wadulkar R.D., Dr.poul B.N. Inflammation and Its Pharmacotherapy, Nirali publication page no.50-56

6. Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE; Nielsen; Andersen; Girardin Inflammation and Its Pharmacotherapy "Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1beta generation".(February 2007).Clin. Exp. Immunol. 147

7. Fields C, Drye L, m Vaidya V, Lyketsos C: Inflammation and Its Pharmacotherapy Celecoxib or naproxen treatment does not benefit depressive symptoms in persons age 70 and older: Findings from a randomized controlled trial. A M J Geriatr Psychiatry 2012; 20: 505-513.

8. Harsh Mohan. Inflammation and Its Pharmacotherapy. Sixth edition 2010, page no 130147.

9. Hashemian F, Majd M, Hosseini SM, Sharifi A, Panahi MVS, Bigdeli O: Inflammation and Its Pharmacotherapy A randomized, double-blind, placebo-controlled trial of celecoxib augmentation of sertraline in the treatment of a drug naive women with major depression. Klin Psikofarmakol Bul 2011; 21: S183-S184.

10. Jiang Z, Jiang JX, Zhang GX: Macrophages: Inflammation and Its Pharmacotherapy A double-edged sword in experimental autoimmune encephalomyelitis. Immunol Lett 2014; 160: 17-22.

11. K.D Tripathi, inflammation and its pharmacotherapy, Essentials of Medical Pharmacology, seventh edition, 2013, page no.192-209.

13. Kumar, Rukmini; Clermont, Gilles; Vodovotz, Yoram; Chow, Carson C. Inflammation and Its Pharmacotherapy). "The dynamics of acute inflammation". Journal of Theoretical Biology. 230(2): 145–155(2004-09-21)

14. Martha white, Inflammation and its pharmacotherapy, J allergy CLIN Imunolvolumn 103 Nov3 part 2 1999 page no 1-4

15. Metcalfe DD, Kaliner M, Donlon MA. Inflammation its Pharmacotherapy. CRC Crit Rev immunol 1981;3:23-74

16. Ole Köhlera, Jesper Kroghc, Ole Morsa, and Michael Erikson Benrosc, Inflammation and Its Pharmacotherapy Bentham Science Publishers Current Neuropharmacology, 2016, Vol. 14,pg no2-5

17. Porth, Carol Inflammation and Its Pharmacotherapy Essentials of pahtophysiology: concepts of altered health states. Hagerstown, MD: Lippincott Williams and Wilkins. p. 270. (2007).

18. Uher R, Tansey KE, Dew T, Maier W, Mors O, Hauser J, Dernovsek MZ, Henigsberg N, Souery D, Farmer Inflammation and Its Pharmacotherapy A, McGuffin P: An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. A M J Psychiatry 2014;

19. Uvnas B. Inflammation and its pharmacotherapy. Ann NY AcadSci 1964;116:880-890

20. Warner-Schmidt JL, Vanover KE, Chen EY, and Marshall JJ, Greengard P: Inflammation and Its Pharmacotherapy Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by anti-inflammatory drugs in mice and humans. Proc Natl AcadSci U S A 2011; 108: 9262- 9267.

21. Werner, Ruth. Inflammation and Its Pharmacotherapy A massage Therapist Guide to Pathology (4th ed.). Wolters Kluwer.(2009)

Received on 01.09.2022 Modified on 04.11.2022

Asian J. Pharm. Tech. 2023; 13(3):201-206.

DOI: 10.52711/2231-5713.2023.00036