pharma lecture 10

What are the five macroscopic signs of inflammation?

Redness, pain, swelling, heat, loss of function

Is inflammation an adaptive (acquired) or non-adaptive (innate) immune response?

Non-adaptive (innate)

What type of immunity is the inflammatory response part of?

Innate immunity (non-adaptive)

What do macrophages release in inflammation?

PAMPs and cytokines (e.g., interleukins)

What do mast cells release in inflammation?

Histamine

What do polymorphonuclear leukocytes release in inflammation?

Reactive oxygen species (ROS) and cytokines

What do damaged local tissues produce in inflammation?

Eicosanoids and bradykinin

What do platelets release in inflammation?

Serotonin (5-HT)

What do nerves release in inflammation?

Substance P

What do vascular endothelial cells express in inflammation?

Adhesion molecules

What are the four actions of bradykinin in inflammation?

Vasodilator, spasmogen, nociceptive (pain-causing), increased vascular permeability

How is bradykinin produced?

From precursors via enzymatic cleavage (part of the kinin-kallikrein system)

What are the three clinical uses of antihistamines?

1) Allergy (hay fever, urticaria, insect bites), 2) Anti-emetic (motion sickness, vertigo), 3) Sedation

Name an antihistamine used for allergy.

Chlorphenamine

Name an antihistamine used as an anti-emetic.

Cyclizine

Name two antihistamines that cause sedation.

Chlorphenamine and promethazine

What condition is treated with cyclizine?

Motion sickness or vertigo (as an anti-emetic)

What is urticaria?

Hives – a skin rash typically caused by an allergic reaction

Name six NSAIDs.

Aspirin, ibuprofen, mefenamic acid, indomethacin, diclofenac, celecoxib

What is the mechanism of action of NSAIDs?

Reduce production of pro-inflammatory prostaglandins by blocking cyclo-oxygenase (COX)

What enzyme do NSAIDs inhibit?

Cyclo-oxygenase (COX)

What are the two isoforms of cyclo-oxygenase?

COX-1 and COX-2

What is the structure of the cyclo-oxygenase enzyme?

Two identical subunits with four active sites; located in the cell membrane

Which COX enzyme is constitutive (always expressed)?

COX-1

Which COX enzyme is inducible (expressed during inflammation)?

COX-2

What are the physiological functions of prostaglandins?

Housekeeping (gastric mucosal protection, renal blood flow, regulation of clotting) and pathological (fever, smooth muscle contraction, tumour progression, pro-inflammatory)

What accounts for the main side-effects of NSAIDs?

Inhibition of housekeeping functions of prostaglandins

What are the main side-effects of NSAIDs related to prostaglandin inhibition?

Gastric injury, renal toxicity, and (for COX-2 inhibitors) cardiotoxicity

Which prostaglandin is primarily involved in fever?

PGE₂

What is the role of PGE₂ in fever?

Acts on hypothalamus to raise body temperature

What is the role of prostacyclin (PGI₂)?

Vasodilation and inhibition of platelet aggregation

How does aspirin affect platelets?

Irreversibly inhibits COX-1 in platelets → prevents TXA₂ production → inhibits platelet aggregation and clotting

What does TXA₂ stand for and what does it do?

Thromboxane A₂ – causes platelet aggregation and vasoconstriction

What is the mechanism of action of celecoxib?

Selective COX-2 inhibitor

What is the advantage of celecoxib over non-selective NSAIDs?

Less GI irritation

What has happened to many other COX-2 inhibitors?

They have been withdrawn from use (due to cardiotoxicity concerns)

What is the pathway from membrane phospholipid to TXA₂?

Membrane phospholipid → (PLA₂) → arachidonic acid → (COX-1) → PGH₂ → (TX synthase) → TXA₂

What is the main side-effect associated with COX-2 selective inhibitors?

Cardiotoxicity

How are leukotrienes produced?

By lipoxygenases from arachidonic acid

What are the two main classes of leukotrienes?

LTB₄ and cysteinyl-leukotrienes (LTC₄, LTD₄, LTE₄)

In what inflammatory conditions are leukotrienes involved?

Psoriasis, ulcerative colitis (UC), rheumatoid arthritis (RA), asthma

What is the clinical use of leukotriene receptor antagonists?

Second-line agents in asthma

Name a leukotriene receptor antagonist.

Montelukast or zafirlukast (common examples, though not named in slides)

What are the three main therapeutic uses of glucocorticoids?

1) Replacement therapy (e.g., Addison's disease), 2) Anti-inflammatory therapy (asthma, IBD, arthritis), 3) Immunosuppressive therapy (leukaemia, Hodgkin's disease)

What is Addison's disease?

Adrenal insufficiency – reduced mineralocorticoids and glucocorticoids

What are the routes of administration for glucocorticoids?

Oral, IV, inhaler, infusion, topical

Name a low-potency glucocorticoid with high mineralocorticoid activity.

Hydrocortisone

What are the uses of hydrocortisone?

Replacement therapy, hypersensitivity, topical anti-inflammatory (1%)

Name two high-potency topical glucocorticoids.

Betamethasone 0.1% and clobetasol propionate 0.05%

What are the adverse effects of topical glucocorticoids?

Loss of pigmentation, skin atrophy, striae, systemic absorption

What is Cushing's syndrome?

The condition caused by excess glucocorticoids

Name a drug that blocks TNFα and what is it used for?

Adalimumab – used for severe arthritis and psoriasis

Name a drug that blocks IL-1 and what is it used for?

Anakinra – used for severe arthritis and psoriasis