Inflammation and Anti-Inflammatory Drugs Flashcards
Inflammation
SHaRP
- Swelling
- Heat
- Redness
- Pain
and loss of function
Inflammation trigers
vasodilation
- more blood flows to the area making it red, warm, and swollen
- pressure causes pain
3 Key Processes in the Inflammatory Response
1) Vasodilation: resulting in increased blood flow
2) Increased Vascular Permeability: plasma leaks from blood vessels into the damaged area
3) migration of neutrophils and other leucocytes from blood into damaged area
Purpose of Inflammatory Response
- prevent the spread of pathogens
- minimize further damage to tissues
- promote repair and healing
Neutrophils
- first WBCs to arrive at injury site
- infiltrates injured tissues
- remove pathogens and damaged tissue through phagocytosis
Macrophages
- more long lived than neutrophils
- phagocytose pathogens and cellular debris
- engulf neutrophils during resolution of inflammation
Mast Cells
- part of immune system
- mediate wound healing and defense against pathogens
- release HISTAMINE, a MAJOR vasodilator (helps make gaps for passage)
- major role in allergy, eczema, and anaphylaxis
Inflammatory Response Order
1) Neutrophils 2) Macrophages
- BV dilates
- packed endothelial cells become leaky
- – this allows WBCs to reach the damaged area
Kinin Cascade
Bradykinin (and other kinins):
- cause vasodilation
- increase permeability of BV
- lowers BP
- stimulates pain receptors
PGE2
PGE2=inflammatory prostaglandin
- released by macrophages and mast cells in the injured region to enhance the action of bradykinin
Prostaglandins
ALL come from ARACHIDONIC acid
- found in all tissues of the body
- belong to the EICOSANOID family
- – includes: prostaglandins, thromboxanes, and leukotrienes
Prostanoids
prostaglandins + thromboxanes
Eicosanoid Family
- prostaglandins
- thromboxanes
- leukotrienes
Prostaglandin E2
- signals creation of mucus to protect stomach lining
Prostaglandin I2
- in BV
- inhibits platelet aggregation/blood clotting
- promotes vasodilation
Thromboxane A2
- in platelets
- promotes platelet aggregation in the clotting process
- vasoconstriction
PGI2 and TXA2
COUNTERBALANCE eachother = homeostasis
Prostaglandin E2 results in
PGE2
- vasodilation
- increased vascular permeability
- increased sensitivity of pain receptors to bradykinin
- pain neuromodulation in dorsal horn of spinal cord
- pyresis (fever)
Prosanoids in Inflammation
- mast cells and macrophages produce large amounts of PGE2 that is released in the inflamed region of the body
- Arachidonic acid released from cell membrane loses P group and becomes acting -> interacts with COX2 => PGE2
Arachidonic Acid
substrate for ALL PROSTANOIDS
- prostaglandins and thromboxanes
COX1 vs COX2
COX1: housekeeping; always on
COX2: inflammation
Prostaglandin Synthesis
membrane phospholipid -1-> arachidonic acid (FA) -2-> cyclic endoperoxides -3-> prostaglandins
1) Phospholipase A2
2) Cyclo-oxygenase (COX)
3) Prostaglandin synthases
- can technically bind COX1&2 but binds COX2 preferentially during times of inflammation because more COX2 is present
Prostaglandin COX Binding
- can technically bind COX1&2 but binds COX2 preferentially during times of inflammation because more COX2 is present
Inflammatory Prostaglandin Synthesis
membrane phospholipid -1-> arachidonic acid (FA) -2-> cyclic endoperoxides -3-> prostaglandins
1) Phospholipase A2
2) Cyclo-oxygenase (COX2)
3) Prostaglandin synthases
Produced at site of injury
The precise biological action of a given Prostaglandin is ______________
Tissue Dependent
PGE2 stomach
PGE2 Injury site
stomach: protects stomach linin from erosion
injury site: plays central role in inflammation at the site of injury
How does Prostaglandin act differently at different sites
TISSUE DEPENDENT
- binds different prostaglandin receptors
- dependent on the receptor type they interact with
NSAIDS
Non-Steroidal Anti-Inflammatory Drugs
- provide analgesic, antipyretic, and anti-inflammatory effects
OTC NSAIDS include: Aspirin, ibuprofen, naproxen, diclofenac
Aspirin
NSAID
Ibuprofen
NSAID
Naproxen
NSAID
Diclofenac
NSAID
TOPICAL CREAM
NSAIDs Effects
- reduce the production of inflammatory grostaglandin E2 (PGE2) and so they attenuate inflammatory effects
- reduce swelling
- attenuate bradykinin-induced pain
- reduce allodynia (tenderness of skin)
- reduce fever
NSAIDs Side Effects
- due to binding COX1 instead of COX2 (bind both equally)
- Inflammatory PGE2 levels reduced (good); housekeeping PGEs produced by COX1 also reduced (bad)
- – stomach issues
NSAIDs action
- all similar actions: inhibit COX2
COX1
housekeeping
COX2
inflammatory
NSAID side effects
- reduction COX1
- GI discomfort
NSAIDS contraindicated for
patients with:
- peptic ulcers
- aspirin hypersensitivity
- coagulation defects
- congestive heart failure
- etc
NSAIDS NOT recommended for people with
- congestive heart failure
- kidney problems
NSAIDs may induce
Asthma Attacks!
Anaphylactic Shock
- b/c decrease in COX, arachidonic acid not converted into cyclic endoperoxides
- INSTEAD arachidonic acid is created into cysteinyl leukotrienes = bad
- – 5-lipoxygenase
Aspirin
NSAID
- Unique among NSAIDS, aspirin binds COVALENTLY (irreversibly) to the COX1&2 Enzymes
- net effect => anti-platelet drug
- – clot inhibitors
- binding of COX1 => GI effects
Selective COX2 Inhibitors
- highly selective COX2>COX1 = selectively inhibiting production of pro-inflammatory PGE2
- less risk of side-effects especially GI related
- cardivascular side effects
Celebrex
ONLY selective COX2 inhibitor on US market
Selective COX2 inhibitors increase risk of ____
Thrombosis (which can lead to myocardial infarction and stroke)
- increases thromboxanes which messes with equilibrium (TXA2>PGI2)
Aspirin can decrease _____ preventing _____
- decrease risk of thrombosis
- preventing coronary heart disease
BLOCKS COX1&2 equally (PGI2>TXA2)
Acetaminophen is not
NSAID!
Acetaminophen
- anti-pyretic and analgesic
- – NOT anti-inflammatory
- mechanism unknown
- narrow TI
Acetaminophen Adverse Effects
- most common cause of acute liver failure
- ** worse in alcoholics***
- causes NAPQI accumulation = toxic
Acetaminophen overdose antidote
- N-Acetylcysteine via IV
Steroidal Anti-inflammatory Drugs
Glucocorticoids
(e. g. cortisol)
- produced by adrenal cortex
- effects:
- – inflammatory response, stress response, immune response
- – carbohydrate, protein, fat distribution
- – behavior
Hydrocortisone
synthetic glucocorticoid
Prednisolone
synthetic glucocorticoid
Prednisone
synthetic glucocorticoid
Dexamethasone
synthetic glucocorticoid
Betamethason
synthetic glucocorticoid
Glucocorticoids Anti-inflammatory effects
- powerful anti-inflammatory effects by down-regulating the production of COX2 and inflammatory prostaglandin
Immunosuppressive Effects of Glucocorticoids
- reduce activity of immune cells including mast cells
- reduces the production of histamine and inflammatory activity, but also increases risk on infections
Glucocorticoids for the Suppression of Inflammatory Responses
indicated for disorders with an inflammatory component
- allergic reactions
- asthma
- arthritis
- bursitis
- cerebral edema
- SLE
- atopic dermatitis
Adverse Effects of Glucocorticoid Therapy
- NOT usually curative and can be dangerous
- USE AT MINIMALLY EFFECTIVE DOSES
Metabolic Complications of Glucocorticoid Therapy
Carbohydrates
- stimulate gluconeogenesis and inhibit glucose uptake by cells
Net effect: increase plasma glucose levels, hyperglycemia, weight gain, diabetes
Metabolic Complications of Glucocorticoid Therapy
Lipids
- stimulate hormone-sensitive lipase -> ipolysis
Net effect: increase fat redistribution to face, back of neck, etc.
CUSHINGS
Metabolic Complications of Glucocorticoid Therapy
Proteins
- reduce protein synthesis
Net effect: muscle wasting and osteoporosis (major limitation on long-term therapy)
Synthetic Glucocorticoid Drugs: Side Effects
adverse effects of steroids from immunosuppressive drugs that reduce protein synthesis:
- suppression of injury response
- suppression of response to infection
- suppression of endogenous corticosteroids
- muscle wasting
- osteoporosis
- bacterial and opportunistic infections
- fluid retention
- fat redistribution: CUSHINGOID symptoms: “moon facies”, buffalo hump
CUSHING’S Syndrome
