Major anti inflammatory drug groups.

Aims of anti inflammatory medication

Pain, swelling, fever prevention.

Key inflammatory mediators?

• Histamines

• Prostaglandins

• Cytokines

Major anti inflammatory drug groups?

Anti histamines, glucocorticoids, non-steroidal anti-inflammatory drugs.

Where is histamine released? What is release triggered by?

mast cell. Stimulus triggers degranulation.

triggered by antigen/antibody complex binding to Fc receptor. Also triggered by other receptors e.g complement system

Example of a drug which directly displaces histamine from mast cells?

Morphine

What effects does a H1 antagonist have?

• Systemic vasodilation

• increased vascular permeability

• Itching

• Bronchodilation

• Ilium contraction

• Effects on neural firing

What effects do H2 (histamine) antagonist have?

• Stimulate gastric acid secretion

• Relax smooth muscle

• Increase HR

• Inhibit antibody + cytokine production

• Inhibit neutrophil activation

What effect do H3 antagonists have?

• - inhibit neurotransmitter release from neurones

What effects do H4 antagonists have?

• Mast cell chemotaxis

• Effects on WBC production + migration

Describe first generation antihistamines

side effects? why?

• anti allergy but:

• Causes sedation

• Relives dizziness, nausea and vomiting caused by motion sickness as it Crosses BBB - CNS effects.

• Shorter half life

Describe second generation antihistamines

when used?

• do not cross BBB

• Most useful in preventing allergies if administered before allergen exposure

• Less effective for on going inflammation

• Longer half life

When are protoglandins released and key ones?

Produced in cells in response to stimuli

• PGE2 and PGI2 have pro - inflammatory effects

how are protoglandins synthesised?

1. phosopholipids in plasma memrbane are converted to arachiodonic acid by phospholipase A2

   1. trigger by - bradykinin, antigen-antibody binding on mast cells, thrombin, complement 5a, cell damage

2. cyclooxygenase causes convertion to prostoglandins, thromboxanes and leukotrines

what triggers enzymes phospholipase A2 to convert phospholipids to arachidonic acid in the process of generating prostaglandin (inflammatory mediators)?

Bradykinin, antigen-antibody binding on mast cells, thrombin, complement 5a, cell damage

What does arachidonic acid convert into before PGI2 and PGE2?

PGG2 then PGH2

• these are unstable and have no inflammatory effects

How is COX-1 expressed?

Continually produced in most cells

How is COX-2 expressed?

Expressed by inflammatory factors, e.g. cytokines

What does PGE2 do?

Vasodilation
Pain - increases sensitivity of pain neurons
Fever - effects hypothalamus

What does PGI2 do?

Vasodilation
Pain - increases sensitivity of pain neurons

Which drugs interfere with prostaglandin function?

Glucocorticoids
NSAIDs
Prostaglandin receptor antagonists

What is the action of glucocorticoid?

• Glucocorticoids bind to receptor in cell cytoplasm

• Glucocorticoid/receptor complex moves to nucleus

• Increases or decreases gene transcription

where are glucocorticoids produced?

Adrenal glands (via pituitary gland hormones)
Corticosterone/cortisol (species dependent)

anti inflammatory effects of glucocorticoids?

Decrease COX-2 expression
Increase of lipocortin (suppress inflammation) , inhibits PLA2
Inhibits some cytokine production

Which delivery of glucocorticoids has the longest effect?

Which delivery of glucocorticoids has the longest effect?

Local injection (weeks) over oral (days)

What are the side effects of glucocorticoids?

Metabolic impact:
Decrease glucose uptake from blood
Increase gluconeogenesis
Increase protein catabolism
Decrease protein synthesis
Increase calcium excretion
Increased risk of infection
Decrease in wound healing rate

What syndrome is linked to excess corticosteroids?

Cushing's

what causes cushings?

Prolonged glucocorticoids administration
Excessive activity of adrenal glands

signs of cushings?

Increased, excessive appetite
Distended abdomen/pot belly
Coat problems - baldness, hair loss, hair thinning, discolouration
Polyuria/polydipsia
Muscle wastage

clinical uses of glucocorticoids?

Treatment of inflammatory, immune or tumour-related diseases
Emergency treatment of anaphylaxis, shock, asthma, CNS trauma

How can glucocorticoids be administered?

Topically
Orally
IV
IM
Intralesional

What are the most common uses of NSAIDs?

Non-infectious/non-allergic inflammation
Control inflammation and pain, e.g. post-surgery or osteoarthritis

actions of NSAIDs

reduce swelling, pain and fever

What is the role of COX-1?

Constitutively expressed
Housekeeping - Gastric protection
Housekeeping - Blood clotting
Housekeeping - Renal blood regulation
Not a main role in inflammation

What is the role of COX-2?

Inflammation response
Produce prostanoids mediating inflammation
Induced by inflammation

What is the benefit of the different binding pocket of COX-1 and COX-2?

Drugs can be designed to inhibit COX-2 and not COX-1
Reduce side effects of COX-1 inhibition

What is a -coxib drug?

COX-2 selective, e.g. celecoxib

Why does COX-1 inhibition lead to gastric ulceration?

Inhibits PGE2 and PGI2 used in gastric mucosa protection
Can cause direct cell lining damage
Inhibits platelet aggregation increasing bleeding

Why is asprin avoided in veterinary practice?

Irreversibly inhibits COX-1 and so platelet aggregation.

Which drug should not be used concurrently with NSAIDs? why?

Glucocorticoids

causes Dehydration, hypovolemic shock and disruption to gastric blood flow

What is Galliprant?

NSAID

An inhibitor of prostaglandin E2 receptor (EP4)
OA pain relief for canines

use of anti inflammatories?

reduce pain and inflammation

reduce animal suffering

• can mask other issues and do not remove cause