Drugs Used to Treat Inflammation Research Paper.

Drugs Used to Treat Inflammation Research Paper.

Drugs Used to Treat Inflammation Research Paper.

  • Inflammation is the active response of tissues to injury -> can be beneficial/ protective or harmful
    • Elimination of injurious stimuli such as bacteria, chemicals or irritants, and containment of damage, removal of necrotic cells, and stimulation of repair and regeneration
    • Local response à occurs at the site of injury but systemic consequences may be observed
      • Involves an immune response, the coagulation cascade and regeneration/repair processes. Drugs Used to Treat Inflammation Research Paper.
    • Exaggerated à causes harm à allergic reactions, autoimmune reactions and spinal cord trauma to name a few
    • Untreated chronic inflammation can cause stimulate fibrosis or scarring à damage is dependent on the site that is targets à impaired vision, seizures, arrhythmias
    • Need to know if the goal is to manage inflammation or manage the initiating cause that resulted in inflammation – you should NOT suppress the immune system if an infection is present

Permalink: 

  • Inflammation is characterized by: Rubor (redness), calor (heat), tumor (swelling), dolor (pain), and functiolaesa (loss of function)
  • Three major changes that occur:
    • Blood vessels dilate
    • Blood vessels become leaky à edema
    • White blood cells enter inflamed tissue
  • Mediators of inflammation may exist pre-formed inside cells = histamine or they may be synthesized at the site of inflammation (eicosanoids – signaling molecules
  • The two most important classes of pro-inflammatory mediators = prostaglandins and leukotrienes (family of eicosanoid mediators) à Anti-inflammatory drugs inhibit these mediators

 

Struggling to meet your deadline ?

Get assistance on

Drugs Used to Treat Inflammation Research Paper.

done on time by medical experts. Don’t wait – ORDER NOW!

Synthesis of Inflammatory Mediators

 

  • 1st Step: Stimulus that results in a phospholipid release
    • Stimuli examples include: hormones, immunoglobulins, microbial products, lectins, phagocytosis, physical trauma and thrombin
  • 2nd Step: The enzyme phospholipase, which hydrolyzes phospholipids, will be activated à specifically phospholipase A2, which cleaves the FA at the site that releases arachidonic acid
    • Arachidonic acid serves as a precursor in the production of eicosanoids that play a role in inflammation
  • 3rd Step: Enzymes cyclooxygenase (COX) and lipoxygenases (LOX) become activated, prostaglandins and leukotrienes are synthesized respectively

 

Cyclooxygenases Pathway

 

  • Two isoforms: COX-1 and COX-2, metabolize arachidonic acid to prostaglandin H2 (PGH2) which is a common substrate for thromboxane A2 (TXA2), prostacyclin (PGI2) and prostaglandin E2 (PGE2)
  • COX-1: maintains homeostasis – expressed in many tissues
  • COX-2: also required for homeostasis but expressed in the kidney and GI epithelium
  • TXA2 is produced by platelets –> it stimulated platelet aggregation
  • Stimulation of PGE2 increases renal blood flow and gastric mucus production while PGI2 decreases gastric acid production and platelet aggregation

 

  • Following an inflammatory stimulus (heat, mechanical/chemical damage, infection) arachidonic acids will be produced and converted to COX-2 from PGH2
  • COX-2 will be induced in cells at the site of insult à elevated local prostaglandin levels at the site of injury à inflammation will result due to the dilation of blood vessels, WBC recruitment and edema
  • Prostaglandins are a large family of structurally similar compounds that each has potent and specific biological action
    • All share a chemical structure à prostanoid à 20 carbon carboxylic acid characterized by a cyclopentane ring and 15-hydroxyl group
    • PGE2 and PGI2 are the main prostanoids associated with inflammation – they sensitize pain receptors along with bradykinin à producing fever à results in redness and increase vascular permeability with histamine à causes swelling

 

Lipoxygenase Pathway

 

  • The other major fate of arachidonic acid = leads to the formation of leukotrienes
  • Lipoxygenases are enzymes that catalyze the insertion of molecular oxygen into arachidonic acid
    • The three major LOX à 5-lipoxygenase (5-LOX), 12-lipoxygenase (12-LOX) and 15-lipoxygenase (15-LOX)
    • The immediate products = HPETEs à further reduced (Ex. 5-HPETE is formed by 5-LOX & is the precursor to leukotriene A4 (LTA4) (also a precursor)

 

Treatment for Inflammation

  • NSAIDs (non-steroidal anti-inflammatory drugs) à Ibuprofen
    • Group of drugs with antipyretic, analgesic, and anti-inflammatory properties
    • Inhibition of COX-1 (constitutive) and -2 (inducible – inflammatory cells, constitutive – kidney and GI mucosa) enzymes
    • SIDE EFFECTS: gastric ulceration and bleeding (following COX-1 inhibition) and hypertension and intravascular clotting à myocardial infarction (long-term selective COX-2 inhibition)
    • Aspirin – inhibition of prostaglandin synthesis – (inhibits COX enzymes – most NSAIDS inhibit both COX-1/2)
      • COX enzymes are responsible for catalyzing the formation of prostaglandins from arachidonic acids à NSAIDS inhibit COX-1/2 at this stage
      • It irreversibly inhibits COX-1 and -2, and provides anti-inflammatory, antipyretic and analgesic effects
      • Musculoskeletal or cutaneous pain à poor for visceral and internal organ pain. Drugs Used to Treat Inflammation Research Paper.
      • Due to aspirin’s platelet inhibition – it may cause bleeding even with normal doses – in rare cases Reye’s Syndrome may result
      • Hepatic necrosis may result in severe condition – often children – especially when viral infection and fever are present
    • Based on the fact that prostaglandins are cytoprotective, the adverse effects produced by NSAIDs are understandable.  In the stomach, prostaglandins (PGE2 and PGI2) reduce acid secretion by gastric parietal cells, dilate blood vessels in gastric mucosa and increase mucus and bicarbonate secretion by the gastric epithelium.  In the kidney, prostaglandins (PGE2) dilate blood vessels which increase perfusion of renal tissue.  Based on this information, a decrease in prostaglandins through COX-1 inhibition in the gastrointestinal tract will decrease blood flow and increase acid production (PGI2) and decrease gastric mucus (PGE2) which will result in gastric ulcers.  A decrease in PDE2 in the kidneys will decrease blood flow leading to impaired renal function and hypertension.  We also discussed platelets which contain only COX-1 and convert arachidonic acid to TXA2 which stimulates aggregation or clotting.  Blocking COX-1 with aspirin therefore helps reduce clotting and can prevent some myocardial infarctions.  In these patients, excessive reduction of TXA2 can result in bleeding.
    • Carprofenetodolacmeloxicam à have fewer GI tract adverse effects – better tolerated because they exhibit less gastric ulceration and bleeding – they preferentially inhibit COX-2
    • Rofecoxib (Vioxx) and celecoxib (Celebrax) – Even more selective for COX-2
      • Inhibition of COX-2 in the presence of gastric infection or inflammatory bowel disease may exacerbate mucosal damage – in which continued use can cause death
      • Therefore, COX-2 selective NSAIDS have fewer GI effects as long as the patients do not have GI disease
    • Ibuprofen – Advil – can cause gastric ulceration but less in comparison to aspirin
      • Often used in patients who require NSAIDS for chronic conditions (osteoarthritis)
      • Myocardial infarction may result follow chronic high doses
    • Celecoxib – approved for osteoarthritis in order to resolve inflammation in the joints
      • Very poor analgesic effects compared to other NSAIDS and no effects of platelets of bleeding (COX-2 is NOT involved in clotting)
      • Concerns = reduced bloof flow to the kidneys à reduced renal function à hypertension and intravascular blood clotting
      • Put patients at an increased risk of stroke and heart attack
    • Acetaminophen – inhibits prostaglandin synthesis in CNS – not a NSAID because it has little peripheral activity à poor anti-inflammatory effects and no effect on blood clotting. Drugs Used to Treat Inflammation Research Paper.

 

Glucocorticoids (non-endocrine applications)

 

  • Outer portion of the adrenal cortex produces steroid hormones à mineralocorticoids – aldosterone (sodium and water conservation), glucocorticoids – cortisol (increasing blood glucose levels), and sex steroids
  • Mineralocorticoids and glucocorticoids are synthesized from cholesterol à corticosteroids (conversion occurs in adrenal cortex)
    • is aldosterone – it regulates sodium/ water by increasing sodium, chloride and water OR decreasing potassium, phosphate, and calcium
    • Cortisol – increase blood glucose concentration (to regulate blood glucose levels) à has anti-inflammatory and immunosuppressive effects

Glucose indirectly inhibits phospholipase A2 that inhibits

prostaglandin and leukotriene production

 

Results in inhibition of immune/inflammatory function

 

Cortisol diffuses through the cell membrane and binds to a

cortisol receptor protein complex à the bound hormone

releases the protein and activates the receptor à activated

receptor binds to glucocorticoid response element in the

DNA causing gene activation (protein synthesis)

Physiological Effects

  • All cells have glucocorticoids receptors since 10-20% of genes are regulated by them
  • Catabolic effects can result in decrease muscle mass, skin thinning, osteoporosis, redistribution of fat, and antagonized effects of vitamin D on calcium absorption
  • Glucocorticoids stimulate hepatic glucose synthesis from amino acids and lipids as well as inhibit calcium absorption, bone formation, wound healing and immune function
    • Inhibit glucose uptake by muscle and adipose tissue while stimulating fat breakdown and the mobilization of amino acids from non-hepatic tissues

 

Glucocorticoids effects on the immune system

 

  • ADME of glucocorticoids: They can be administered and absorbed through oral, intramuscular, subcutaneous, intra-articular and topical methods.  Glucocorticoids are then carried in the blood bound to carrier proteins such as albumin and transcortin.  Some of the metabolites are activated in the liver such as cortisone to hydrocortisone and prednisone to prednisolone.  Lastly, the hormones are excreted in both the urine and the feces.
  • Adverse effects (seen after two weeks of continuous therapy) -> the risk is related to the duration of therapy and dose
    • Increase appetite and urination
    • Edema
    • Impaired wound healing
    • Hypetension
    • Negative Ca balance
    • Gastric ulcers
    • Psychoses or euphoria
    • Infection
  • Treatment is related to TOLERATION and not complete relief.  Drugs Used to Treat Inflammation Research Paper.

Struggling to meet your deadline ?

Get assistance on

Drugs Used to Treat Inflammation Research Paper.

done on time by medical experts. Don’t wait – ORDER NOW!

Open chat
WhatsApp chat +1 908-954-5454
We are online
Our papers are plagiarism-free, and our service is private and confidential. Do you need any writing help?