Antiinflammatory Drugs

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      # Lab 4 #
• it is a biological response of vascular
  tissues to harmful stimuli, such as
  pathogens, damaged cells, or

• Inflammation may ends with either :
   Complete healing    Permanent destruction
      of tissues            of tissues
          Signs of inflammation
• Redness:
  Due to vasodilatation by effects of
 releasing of histamine, bradykinin
 and prostaglandin.

• Hotness:
 Due to increased blood flow.
          Signs of inflammation
• Swelling:
  due to increased vascular
 permeability by the released
 mediators and increased the exudate
 in the inflammed area

• Pain:
  due to irritation of nerve ending by
 inflammation and the pressure of the
 swelling on the nerve ending.
• Inflammatory mediators:

  – histamine
  – 5-HT (serotonin)
  – Bradykinin                  inflammatory
  – Prostaglandins (eg PGE2 )     mediator

  – Interleukines
  – Substance P
  – Nitrous oxide
                 Phases of

• Fluid phase (vascular phase):
  Increased vasodilatation leads to
 increased permeability of the vascular
 bed to plasma protein.
  - Increasing fluid will help in:
  1- dilution of the irritant
  2- increase conc. of antibodies from blood
 to inflamed area
  3- supply nutrients to the immune cells.
             Phases of
• Cellular phase (exudative
 Involves migration of tissue
 macrophages and
 polymorphonuclear leukocytes
 (PMNL) to the inflamed area.

• Fibrous phase (proliferative
 A new connective tissue (fibrous)
         Classification of the

• Non – immunological :
  Induced by chemical irritants such as formalin

• Immunological :
  Induced by infections such as bacterial infection

Steroidal              Non-steroidal
  - Cortisone        - Acetaminophen
  - Hydrocortisone   - Aspirin
Steroids (SAIDs)
- Containing steroid moiety in their sturcure
         Glucocorticoids (GC)

          Glucocorticoids (GC)

Natural                                  Synthetic

 - Cortisone          Fluorinated     - Betamethasone
 - Hydrocortisone   Glucocorticoids   - Dexamethasone
                                      - Predinsone
                                              Liver enzymes

               Glucocorticoids (GC)
Mechanism of Action :

- They act by indirect inhibition of the enzyme phospholipase A2
  which activate synthesis of arachidonic acid with subsequent
  formation of prostaglandins.

- They induce synthesis of a protein “lipocortin-1” which has
  the inhibitory effect on phospholipase A2.
            GC inhibition

phospholipase A2
                 Side Effects :
• Immunosuppression
• Hyperglycemia due to increased gluconeogensis, insulin resistance, and
  impaired glucose tolerance ("steroid diabetes");
• Steroid-induced osteoporosis: reduced bone density (osteoporosis,
• Osteoporosis , higher fracture risk, slower fracture repair)
• Redistribution of body fat: moon face, buffalo hump and truncal obesity.
• Adrenal insufficiency
• Muscle breakdown (proteolysis), weakness; reduced muscle mass and repair
• Anovulation, irregularity of menstrual periods
• Growth failure, pubertal delay
• Increased plasma amino acids, increased urea formation;
• Glaucoma due to increased cranial pressure
     Side Effects :

Moon face        buffalo hump
Non-Steroidal Anti-inflammatory Drugs

• They don’t contain steroid moiety

• They also have analgesic and antipyretic activity
      Mechanism of Action :

• NSAIDs inhibit synthesis of PGs which are the main factors
  Playing a role in the inflammaltion.

• Inhibit synthesis of PGs through inhibition of cyclooxygenase
  Enzymes which are responsible for production of PGs
            GC inhibition

phospholipase A2
Cyclooxygenese ( COX ) Isoforms :

  COX 1                                          COX 2

- Constitutive                        - inducible
- Many tissues ( blood vessels        -By inflammatory processes
  stomach and kidney )                  and mediators

  COX 3            has recently been described
Non-Steroidal Anti-inflammatory Drugs

 Non-selective             selective COX2
COX inhibitors                inhibitors
- Aspirin                  - Celecoxib
- Ibuprofen                - Rofecoxib
- Diclofenac
- Meloxicam
            Side Effects :
• Unwanted effects, owing largely to inhibtion of COX1
  Particularly in the elderly and include :

- Despepsia, nausea and vomiting , ulceration and gastric
  damage in chronic users, with risk of hemorrhage

- Reversible renal insufficiency

- Analgesic-associated nephropathy ( irreversible )

- Liver disorders, in high doses, e.g. acetaminophen
Measurement the activity
anti-inflammatory drugs

 - Method :     Paw Oedema Method

- Principle :   induction a chemical inflammation
                by injecting an irritant ( formalin ) into
                rat’s paw

- Objective :   measure the anti-inflammatory activity of
                diclofenac and hydrocortisone with
                different doses )
-Procedure :
1- select 5 rats
2- inject each rat 1 ml urethane for anesthesia.
3- select one as control and inject the rest of them intraperitoneal
 rat 1 >>> control
 rat 2 >>> 40 mg/kg diclofenac
 rat 3 >>> 80 mg/kg diclofenac
 rat 4 >>> 20 mg/kg hydrocortisone
 rat 5 >>> 40 mg/kg hydrocortisone
4- after 1 hr , inject 0.1 ml formalin in each rat ( 2 to 5 ) into
their paws >>> to induce inflammation.
5- after 1 hr , take the reading using the plythysmometer of each
rat paw ( right and left ).
6- calculate the inflammation and response % for each drug.
   Dose              RP           LP       inflammat Response
                                               ion      %
  control                                       C      ___
40 mg/kg vol.                                   T1
80 mg/kg vol.                                   T2
 20 mg/kg                                       T3
 40 Inflammation = RP - LP                      T4
                            C - T
    Response % = ‫ ــــــــــــــــــــــــــــــــــــــــ‬X 100

     Response % >>>> Anti-inflammatory activity

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