HUF 2-82 Pharmacology of autacoids and anti-inflammatory drugs III

Question 1

Kinin-Kallikrein System

Answer 1

Kininogen LMWK (many tissues)
↓ (Tissue Kallikrein)
Kallidin
↓ (Aminopeptidase)
Bradykinin

Kininogen HMWK (liver → circulation)
↓ (Plasma Kallikrein)
Bradykinin

Plasma Kallikrein
- converted from inactive precursor prekallikrein by coagulation factor XII (blood coagulation cascade)

Question 2

Bradykinin

Answer 2

• pain/hyperalgesia (peripheral sensitisation of nociceptors)
• vasodilation (may ↓↓ BP)
• ↑ vascular permeability
• B1R: inducible w/i hours by inflammation & tissue damage
  ` agonist: bradykinin(1-8) by kininase I
  ` antagonist: [Leu8’-bradykinin(1-8), des-Arg10 Hoe140
• B2R: constitutively expressed in many tissues

Question 3

Roles of bradykinin in inflammation

Answer 3

1. B2R (acute phase of inflammation)
   => vasodilation, ↑ vascular permeability, edema, inflammatory pain
2. B1R (chronic phase of inflammation)
   => chemotaxis of leukocytes, hyperalgesia (immune cells, sensory n.)

Question 4

Chronic inflammations

Answer 4

• persistent infections
• persistent contact with irritant / toxic substances
• autoimmune diseases

Question 5

Simple outlines of glucocorticoid usage

Answer 5

1. Asthma
   - orally with inhaled / oral glucocorticoids
2. Rheumatoid arthritis
   - suppress self-immune attach to joints
   - used w/ DMARD

Question 6

Effects of glucocorticoids

Answer 6

1. Anti-inflammatory
   - inhibit PLA2 (via lipocortin-I)
   - inhibit COX2
   - inhibit proinflammatory mediators
   - stabilise lysosomal membrane
   - ↓ vascular permeability
2. Immunosuppresive
   - cell-mediated immunity
   - lympholysis

Question 7

Mechanisms of glucocorticoids

Answer 7

1. Genomic actions
   - intracellular receptors => gene transcription
   - activate anti-inflammatory genes
   (e. g. lipocortin-I, IL-1Ra)
   - repress pro-inflammatory genes
   (e. g. COX2, IL6, TNF-α)
2. Non-genomic action
   - direct release of lipocortin-I from leukocytes
   - inhibit PLA2, AA, PG…
   - inhibit leukocyte trafficking
   - other anti-inflammatory actions

Question 8

PK profile of glucocorticoids

Answer 8

• short t1/2 (~ 90 mins)
• plasma albumin / corticosteroid-binding globulin
  => biologically inactive
  => ↑ t1/2 (~ 8 hrs)
• diffusion → cells
• metabolised in liver
• excreted by kidney
• cortisone → hydrocortisone
• prednisone (prodrug) → prednisolone

Question 9

Other clinical uses of glucocorticoids

Answer 9

• prevention of tissue rejection in solid organ transplant recipient
  e. g. prednisone
• replacement therapy for adrenal insufficiency
  e. g. hydrocortisone
• functional test for hypothalamic-pituitiary-adrenal hormonal control axis
• anti-emetics during chemotherapy
  e. g. dexamethsone
• treatment for psoriasis & eczema
  e. g. topical corticosteriods

Question 10

Undesirable effects of long-term use of glucocorticoids

Answer 10

1. Suppression of hypothalamic-pituitary-adrenal axis
   - -ve. feedback to ACTH & cortisol
   - atrophy of zona fasciculata & reticularis
2. Response of endogenous glucocorticoid to stress is reduced or absent
   => takes long time to recover
   ∴ abrupt discont. => 2° adrenal insufficiency
   ∴ gradually temper withdrawal of exogenous glucocorticoid after chronic treatment (>2 weeks)
3. Iatrogenic Cushing’s syndrome

Question 11

Iatrogenic Cushing’s syndrome

Answer 11

1. Protein degradation
   - CT: thinning of skin, easy bruising, striae formation, poor wound healing
   - muscle: muscle wasting
   - children: stunted growth
2. Lipogenesis
   - truncal obesity, moon face, buffalo hump supraclavicular fat pad
3. Anti-insular effect
   - endocrine: insulin resistance => DM
   - ↑ BG & insulin levels
4. Renal & CNS effects
   - mineralocorticoid effect, hypokalaemia
   - hypertension
5. Side effects
   - bone: osteoporosis / osteopenia
   - immune system: ↑ susceptibility to infections
   - CNS: euphoria, irritability, depression, emotional lability

Question 12

Drugs for rheumatoid arthritis

Answer 12

1. NSAID
   - symptomatic relief, pain relief
2. Glucocorticoid
   - suppress immune actions against damaged joints
3. DMARD
   - various mechanisms
   - very slow onset of action
   - NSAID ‘cover’ in induction phase
   - successful => concomitant NSAID can be reduced
   e. g. methotrexate, sulphasalazine, chloroquine, immunosuppressive drugs, monoclonal Ab