Lesson 1: Anti-inflammatory Drugs

inflammation

complex dynamic tissue response to damaging stimuli

pressure, heat, ionizing radiation, ultraviolet rays

types of physical stimuli

bacteria, virus, fungi

biological class of inflammatory stimuli

toxins, venoms, plant poisons, pollen

types of biological/chemical stimuli

organic, inorganic chemicals

types of chemical stimuli

acute inflammation

comprises interrelated vascular and cellular changes in affected tissues as a response to noxious stimuli

tissue-resident immune cells

in the inflammatory response, the tissue damage and/or microbial infection can be recognized by?

vasodilation

inflammatory mediators act on smooth muscle cells to induce?

vascular permeability

nitric oxide and other mediators will increase _____ ________ and fluid is exchanged

acute inflammation

- it is necessary for survival and protection of affected individuals

- inflammation may be brought inappropriately against harmless substances or against normal body tissues somehow recognized as foreign

redness, heat, swelling, pain, altered function

signs of acute inflammation

redness (rubor)

cardinal sign of inflammation wc occurs due to transient hyperemia

heat (calor)

cardinal sign of inflammation wc occurs due to increased blood flow

swelling (tumor)

cardinal sign of inflammation wc occurs due to increased vascular permeability

pain (dolor)

cardinal sign of inflammation wc occurs due to stimulation of pain local receptors

altered function

cardinal sign of inflammation wc is usually manifested as reduced or loss of activity

innate non-immunological response, acquired specific immune response

2 main components of acute inflammatory reaction

vascular events, cellular events

components of innate non-immunological response

fluid, fibrin, neutrophils, macrophages

components of exudates

serous, fibrinous, purulent

types of inflammatory exudates

serous exudate

type of exudate wc have fluid containing salts and high concentration of proteins including immunoglobulins

fibrinous exudate

type of exudate wc contains fibrin, a high molecular weight filamentous insoluble protein

purulent exudate

type of exudate wc contains many neutrophils from WBC population, a few macrophages and a few lymphocytes

fluids and salts

the fluid in the acute inflammatory exudates contain nutrients, mediators, and igs. what are used for buffering and diluting locally produced toxins?

glucose and oxygen

the fluid in the acute inflammatory exudates contain these wc are used for nutrition of macrophage

immunoglobulins

the fluid in the acute inflammatory exudates that acts as opsonins, making antigens "palatable"

neutrophils, eosinophils, basophils

the initial predominant cell types infiltrating damaged tissues

chemotaxis

the act of migration of neutrophils are also called?

monocytes, lymphocytes

after short-lived PMNs (neutrophils) die, these cells replace them as the predominant cell type

dilute the offending noxious stimuli, eliminate damaging agents, removal of inflammatory tissue debris

aims of early inflammatory responses

vascular endothelial cells, mast cells, tissue macrophages

during cellular events, these cells are involved in inflammation that is present in tissues

platelets, polymorphonuclear cells (neutrophils, basophils, eosinophils), mononuclear cells (lymphocytes, monocytes)

during cellular events, these are cells from the blood that gain access to the tissues

vascular endothelial cells

during inflammation, these cells of the small arterioles are activated to secrete chemical mediators

nitric oxide, prostacyclin

secreted by endothelial cells to induce vascular relaxation and inhibit platelet aggregation

endothelin, plasminogen activator, platelet-activating factor

secreted by endothelial cells wc cause vasoconstriction

intercellular adhesion molecules

secreted by endothelial cells wc mediate cellular adhesions to vascular wall or other tissue components

receptors (histamine, acetylcholine, IL-1)

secreted by endothelial cells wc binds w local hormones or autacoids to cs modification of cell fx

mast cells

- morphologically similar to basophils; found in tissue rather than circulating blood

- secretes histamine and other inflammatory mediators

mast cells

this cell's membrane contains surface receptors for IgE and complement components C3a and C5a

langerhans cells

tissue macrophage of skin

histiocytes

tissue macrophage of connective tissue

microglial cells

tissue macrophage of brain

kupffer cells

tissue macrophage of liver

osteoclast

tissue macrophage of bone

alveolar macrophage

tissue macrophage of lungs

platelet

- primary role is for blood coagulation

- generates thromboxane A2, platelet-activating factor, free radicals

platelet-derived growth factor

contributes to the repair processes ff tissue damage

neutrophils, basophils, eosinophils

polymorphonuclear cells

neutrophils

this PMN's have the ability to move actively (chemotaxis) from vessel to damaged tissue, phagocytose, and form inflammatory mediators

neutrophils

the first leukocytes to enter the area of inflamm

- normally inactive and have to be activated

eosinophils

these PMN's have capacities similar w/ neutrophils; release a no. of potent granules that can damage multicellular parasites

basophils

similar w/ mast cells; secretes inflammatory mediators

monocytes/macrophages

adhere to endothelium and migrate into damages tissue in response to chemokines

cytokines

binding of macrophage to bacterial LPS generate and release this substance that act on vascular endothelial cells

type c, a-delta

what types of neurons in inflamed areas release inflammatory neuropeptides?

- they also generate kinins and serotonin w/c stimulate the release of neuropeptides

- these substances mediate pain sensation

neurokinin, substance p

substances of neuropeptides that mediate pain sensation

natural killer cells

- specialized lymphocytes active in non-immunological reactions

- kills virus infected cells and cancer cells, both lacking MHC molecules

pus

as pmn's die, the content of the lysed cells accumulate to form?

b cells, t cells, natural killer cells

main groups of lymphocytes

b cells

responsible for antibody production - the humoral immune response

t cells

responsible for cell-mediated immune reactions

natural killer cells

specialized non-t and non-b lymphoid cells that are active in non-immune innate response

autacoids

local hormones; substances present in the body and act near the sites of their synthesis

histamine

is implicated in most allergic reactions

mast cells

histamine is synthesized, stored, and released mainly by?

histaminocytes

non-mast cell histamine is secreted by these cells in the stomach

histaminergic neurons

non-mast cell histamine is secreted by these in the brain

H1 receptors

pruritus and axon flare are mediated by what type of histamine receptor?

H2 receptors

by acting on this histamine receptor on mast cells and basophils, histamine prevents further histamine release by negative feedback

H1 receptors

histamine receptor that mediates most inflammatory reactions and are antagonized by the classical antihistamines

H2 receptors

histamine receptors that has a role in gastric acid secretion

H3 receptors

histamine receptors wherein description is still incomplete

mepyramine

antagonist of h1 receptor

cimetidine

antagonist of h2 receptor

thioperamidine

antagonist of h3 receptor

epinephrine, theophylline, cromolyn sodium

prevent release of histamine by inhibiting the responses of sensitized mast cells and basophils to specific antigens

epinephrine, theophylline, aminophylline

physiologically antagonize histamine effects

cromolyn sodium, nedocromyl, theophylline, aminophylline

block h1 receptors of histamine

epinephrine

by acting on specific adrenergic receptors, this causes peripheral vasoconstriction, bronchodilation, and cardiac stimulation

classical (h1) antihistamines

- not as widely used in animals (varying effectiveness)

- used in dogs and cats w chronic pruritus

- those w short-term pruritus do not tolerate glucocorticoids

red spot

a few mm around the site of injection is due to immediate direct vasodilator effect of histamine

flare

a bright red irregular outline from the original red spot due to reflex dilatation of the adjacent small vessels

wheal

a localized oedema due to leakage of plasma fluid through the abnormally permeable walls of the small blood vessels

red spot, flare, wheal

triple response to histamine by lewis

eicosanoids

includes the prostaglandins, prostacyclins, thromboxanes, and leukotrienes

- derived from arachidonic acid

arachidonic acid

impt precursor of eicosanoids; a pro-inflammatory substance

prostaglandins

these are not stored in tissues, but are rapidly formed and released when tissue is damaged

phospholipase A2

involved in the regulation of biosynthesis of prostaglandins by causing the release of the precursor arachidonic acid

cyclooxygenase, lipoxygenase

two major enzyme systems wc use arachidonic acid as substrate

cox-1

constitutive enzyme

cox-2

inducible enzyme

cox-1

inhibition of this cyclooxygenase isoenzyme is believed to underlie the most significant "side effects" of NSAIDs

cox-2

this cyclooxygenase isoenzyme is induced only during inflammation, and its inhibition accounts for therapeutic action of NSAIDs

5-HPETE

serves as a substrate for the enzyme leukotriene synthase, and is further transformed into various leukotrienes

leukotriene synthase

5-HPETE serves as a substrate for the enzyme?

PGE

prostaglandin that is chemotactic for leukocytes released during fever and may produce fever themselves

prostaglandin dehydrogenase

pge and pgf are rapidly metabolized in the lungs by?

platelet activating factor

polar lipid released from leukocytes and causes platelets to aggregate

prostaglandins, prostacyclin, thromboxane, leukotrienes

eicosanoids derived from arachidonic acid

aspirin/acetylsalicylic acid

- usually administered PO; converted to salicylic acid within a few minutes

- elimination is most rapid in herbivores, slower in carnivores, intermediate in omnivores

- cats cannot metabolize

- does not relieve excruciating pain