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PHAR2005 Inflammation
Pharmacology of Inflammation
49
Pharmacology
Undergraduate 2
04/23/2014

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Term
What is inflammation initiated in response to? (4)
Definition
Microbial infection
Noxious exogenous chemical stimuli e.g. acid
Neoplasm (tumour)
Trauma
Term
What is the aim of the pathophysiological process of inflammatory response?
Definition
Attempts to destroy, dilute or wall off the inflammatory initiating agent, prepare to 'clean' the tissue for wound healing and/or educate/stimulate the adaptive immune system to produce an appropriate response to various exogenous antigens (except for autoimmune inflammation then it is endogenous antigens)
Term
Why is inflammation considered a complex process?
Definition
Because it is controlled by a variety of mediators, which are controlled by a myriad of inter-dependent cellular processes which are controlled by a host of extracellular inflammatory mediators and intracellular signalling metabolic pathways
Term
What are the 5 cardinal signs of inflammation?
Definition
Heat
Redness
Swelling
Pain
Loss of Function
Term
How is inflammation initiated?
Definition
Detection of a causative agent. This involves detection of a chemical/antigen by a SPECIFIC receptor e.g. Pathogen-associated-molecular-patterns (PAMPS) by pathogen recognition receptors (PRRs) [components of the innate immune system]
Term
What happens in the microcirculation stage of inflammation?
Definition
-Pathogen is recognised
-Resident macrophages activated
-Increased vasodilation (swelling)
-endothelial cells express cellular adhesion molecules(CAM)
-CAMs cause leukocytes to stick to the endothelium and migrate out of the vessel into the cell
Term
What happens during the first part of the cellular phase of inflammation?
Definition
-polymorphnuclear cells (PMNs) usually neutrophils first enter the cell. Phagocytocise microbial material
-they also release proteases which have anti-microbial activity
-release mediators which can recruit more leukocytes
Term
What happens to monocytes to in the cellular phase if inflammation
Definition
-monocytes differentiate into macrophages enter the site after neutrophils
-remove microbes by phagocytosis and release inflamm. meds. like reactive oxygen species, lipid mediators and cytokines which can regulate inflamm. response and produce their own inflamm. mediators
-Macrophages can also present antigens to lymphocytes
Term
What do inflamm. mediators do?
Definition
-regulate the inflamm response.
-will directly modulate 1 of 5 cardinal signs
-follow Henry Dale's criteria for a chemical mediator
-synergistic and inhibitory interactions, positive and negative feedback pathways/cascades
changes in the cellular and mediator composition of the inflamm lesion
Term
What are the physiological processes and mediators involved in causing redness and heat?
Definition
-Increased blood flow, increased local metabolism, local haemorrhage
-Histamine, 5-hydroxytryptamine (5-HT), platelet activating factor (PAF), Bradykinin, Nitric oxide, PGI2, PGE2
Term
What are physiological processes and mediators of swelling
Definition
-increases vascular permeability, exudates and cell infiltration
-anaphylatoxins C3a C5a, LTB4, TNFa, IL-1, VEGF, PGE2, PAF, Bradykinin
Term
What are the physiological processes of pain and what are the mediators?
Definition
-Sensory Neuron firing, PNS windup
-Subtance p, calcitonin, gene-related-peptide (CGRP), bradykinin, hear, protons, prostaglandins
Term
What are the physiological processes of 'Loss of Function' and what are the mediators?
Definition
Dysfunction, destruction of parenchyma and stroma tissue
-Lipases, proteases, free radicals, bradykinin, LTD4, LTC4, histamine
Term
What kinds of histamine receptor are there and how is histamine stimulated?
Definition
H1-4, H1 is the main target of anti-histamines
-released by mast cells or basophils or by a variety of stimuli
-IgE cross linking
-anaphylatoxins C5a & C3a
-morphine
-Substance P, VIP
-Tubocurarine
Term
How is histamine metabolised?
Definition
Oxidation, by Diamine oxidase
N-methylation by N-methyltransferase
Acetylation by gut flora
Term
What are H1 antagonists used for?
Definition
-drugs crossing blood brain barrier: diphenhydramine, chlopheniramine
Purpose: sedation, tratement of motion sickness, Allergies (e.g. hayfever) but not preferred because of drowsiness
drugs not entering CNS: ranitidine
Purpose: Surpression of gastric secretion leads to healing of duodenal ulcers
Term
How do antihistamine's work and what are their main targets
Definition
Insect bites, Allergic rhinitis, drug hypersensitivity, urticaria
-immediate or anaphylactic hypersensitivity
-Cross CNS causing dizziness, tinnitus and fatigue
-new h1 antihistamines do not cross CNS: astemizole, terfenadine, cetirizine
Term
What causes peptic ulcers and how are they treated?
Definition
Ulcers are x4 more common in the duodenum than the stomach
-use of NSAIDS blocks function of cycloxegenase and increases risk of gastric ulcers
-H2 antagonists used to treat ulcers
Term
How are kinins formed and what is their half-life?
Definition
Bradykinin and kallidin.
Kinins are formed from kininogens by enzymes (plasma and tissue kallikreins which split the active kinins from the precursors.
-metabolised by carboxypeptidase N and angiotensin converting enzyme
-20min half life
Term
What are the function of kinins?
Definition
vasodilators, increase venular permeability
-cause pain
-contract smooth muscle
-actions mediated by B2 receptors but B1 receptors also used.
-some actions indirectly mediated by histamine or prostaglandin release
-Icatibant is a B2 antagonist
Term
What is Arachidonic acid a precursor for? How are the subsequent fatty acids named?
Definition
eicosatetraeonic acid (ETE), Prostaglandin (PG), Thromboxane (TX), Leukotriene, Hydroxyeicosatetraeonic acid (HETE) Hydroperoxy ETE (HPETE)
-the letter following the prefix denotes what stage of metabolic process
-number indicates parent fatty acid
Term
How are Prostaglandins made and what is their structure?
Definition
Involves two enzymes from arachidonic acid to prostanoid cyclooxygenase (Prostaglandin H syntase) and the relevant synthase
-20 carbon molecules with an OH group at C15 which is essential for activity.
-Very potent at low nanomolar-high picomolar levels
-rapidly metabolised
Term
What are the receptors for prostanoids?
Definition
-Lack of selective antagonists makes classification difficult
-Agonist activity used for classification
-All are GPCR
Term
What are the Prostanoid inflamm mediators?
Definition
-Prostaglandin E2
-Prostaglandin I2
-Prostaglandin D2
-Thromboxane A2
-Prostaglandin F2a
Term
What do the 4 types of PGE2 do?
Definition
EP1-contraction of bronchial and GI smooth muscle
EP2-Bronchodilation, vasodilation (mainly in arterioles) stimulation of intestinal fluid secretion and GI smooth muscle contraction
EP3-COntraction of Gi smooth muscle, inhibits GI acid section, inhibition of lypolysis, inhibition of autonomic NT release, contraction of pregnant uterus
EP4-Contraction of bronchial and vasodilation
Term
what do
a) IP receptors do
b)DP receptors
c)TP receptors
d)FP receptors do
Definition
a) PGI2-vasodilation, inhib platelet aggregation, renin release
b) PGD2-Vasodilation, ",Relax GI and uterine muscle
c) Bronchoconstrictor with PGD2, vasoconstriction, platelet aggregation with TXA2
d)PGF2-Myometrium contraction (midlayer of uterine wall)
Term
What are the vascular effects of prostaglandins?
Definition
PGE2 is a vasodilator of arterioles.It produces little increase in vascular (postcapillay vanules) permeability but promotes increases in permeability produced by other agents eg histamine by increasing flow into permeabilized vessel
Term
What are the leukocyte effects of PGs?
Definition
PGE2 can also inhibit monocyte activation and suppress T cell activation. PGD2 appears to be an important regulator of (T helper) TH2 lymphocytes.
The leukotriennes, particularly LTB4 cause leukocyte chemotaxis and represent important targets in asthma
Term
How are PGs produced in Fever?
Definition
-hypothalamus produces PGE2 in response to interleukin 1 which is generated by bacteria interact with leucocytes
Term
Where do bacteria act to cause temperature rise in fever?
Definition
-PGE2 into ventricles causes temperature to rise when bacteria are injected
-Injecting PGE2 into ant hypothalamus causes temp to rise
-no other PG active
-PGE mediates rise in temp in response to pyrogens in circulation
Term
What role do PGs play in pain?
Definition
PGE2 causes the sensitization of sensory neurones, enhancing the generator current (eg via TRPV1) and increasing the likelihood of the neuron eliciting an action potential
Term
What effects do Non steroidal anti inflammatory drugs (NSAIDS) have?
Definition
-ANalgesic
-Anti-inflammatory
-Anti-pyretic (stop temp increase by over-riding an interleukin based increase in temp controlled by hypothalamus)
Term
What is the mechanism of NSAID action and how has it changed over the years?
Definition
-Inhibit COX.
-COX-1 is a constituitive enzyme (produced constantly by the cell
-COX-2 is induced at site of inflammation
-Most old NSAIDS are unselevtive for COX 1/2 or act mainly on COX1
-NSAID toxicity thought to be assc. with COX1 inhib., COX2 does appear to have a protective role in the CV system
-Newer NSAIDS may have reduced toxicity on GI tract but CV side effects are a prob
Term
What are the anti-pyretic effects of NSAIDs?
Definition
Exogenous pyrogens eg bacteria are engulfed by macrophages
-macrophages make endogenous pyrogen (IL-1, TBFa)
-endogenous pyrogen causes PGE2 formation in hypothalamus
PGE resets the body's thermostat in the hypothalamus to a higher level
-Inhib, by NSAIDS, of PGE2 formation in the hypothalamus causes the thermostat to be set back to normal level
Term
What are the analgesic actions of NSAIDs?
Definition
-At the site of inflamm, PGE2 is formed
-PGE2 sensitizes sensory nerves, lowering pain threshold
-pain is increased
-NSAIDS reduce PGE2 formation, reducing the sensory neuronal sensitization and lowering pain.
There is also an effect on the CNS
Term
What anti-inflammatory actions do NSAIDs have?
Definition
PGE2, PGD2 and PGI2 are all vasodilators and promote oedema formation- the heat, redness and swelling of inflammation
NSAIDS inhibit the formation of these prostanoids and reduce the heat, redness and oedema of inflammation
Term
What are the main toxic effects of NSAIDs?
Definition
-particularly those that act on COX-2-damage to upper GI tract
-PGE2 from COX-1 in the stomach inhibits gastric acid secretion and promotes protective mucus formation and bicarbonates release
-Inhib. of COX1 increases acid secretion and reduces mucus and bicarb.
-mucosa ulcerates and bleeds
COX-2 selective drugs cause less intestinal damage
Term
What are the effects of asprin on the GI tract?
Definition
-In a 7 year period, aspirin caused 40 deaths from GI haemorrhage
-One asprin tablet increases GI bloodloss from 2ml to 12ml per day due to ulceration and bleeding
-Annual bloodloss caused by asprin is 20,000 gallons
Term
What is the naturally occuring glucocorticoid, what are sythenic alternatives and what do they do?
Definition
naturally occuring=hydrocortisone. It has roughly equal potency as an antiinflammatory and a mineral corticoid.
-Synthetic compounds offer a)improved potency and b)greater selectivity for anti-inflamm action over mineral corticoid action (action on salt and water balance)
e.g. prednisolene, betamethasone
Term
What is the inflamm actions do Glucocorticoids suppress?
Definition
a0anti-inflamm and b)immunosuppressive. Supress early events on inflammation- vasodilation, oedema, leucocyte infiltration and activation
later events of inflammation are also suppressed-cell proliferation, macrophage activity, fibroblast activity, angiogenesis
Term
What do glucocorticoids suppress the production of?
Definition
Some of the anti-inflamm effects are caused by suppression of the production of autocoids (mediators of inflamm) e.g. PGs, LTs TX PAF. Histamine release from basophils is also inhibited
Term
How do glucocorticoids get in to and administer their effects on the cell?
Definition
Glucocorticoids are lipid soluble so easily cross the cell membrane. Here, they bind the glucocorticoid receptor (gr). This results in the loss of hsp complex revealing a translocation and DNA binding region on GR. The receptor enters the nucleus
Term
What are the effects of activated GR on the cell nucleus?
Definition
1.binds glucocorticoid regulatory element (GRE) and activates gene transcription of anti-inflammatory proteins eg Lipocortin-1 (calcium regulated annexin IkB
2. Binds GRE which negatively regulate pro-inflammatory gene transcription eg IL-1
3. Transrepression of NFkB at DNA
4. Direct bind of soluble transcription factors or transactivators.
Term
What is the time scale for anti-inflammatory steroids?
Definition
synthesis of new protein or the suppression of protein synopsis are not immediate effects, the anti-inflamm effects of steroids do not manifest for several hours
Term
What COX and lip oxygenate products do anti inflamm steroids reduce?
Definition
Reduced COX products: PGE2 PGF2a PGI2 and PGD2 results in reduced oedema, reduced blood flow and reduced pain at site of inflamm
Red. Lipoxygenase products:LTB4 LTC4 LTD4 results in reduced leucocyte infiltration, reduced bronchoconstriction, oedema blood flow and pain
Term
Reduction of the expression of COX2, NOs, adhesion molecules and some cytokines results in:
Definition
Reduced cyclooxygenase products
Reduced blood flow
Reduced cellular infiltration (adhesion molecules IL5 IL8)
Reduced pro-inflammatory effects of cytokines IL1 and TNF
Term
What is TNF and what is its function
Definition
TNF a is a cut okie (trimmer made up of about 3x 17k. da peptide) which is a key regulatory in the inflammatory response
In particular it is associated with chronic inflammatory diseases
Term
What are the effects of TNF a?
Definition
Induces fever
Stimulates acute phase protein release
Cytotoxic/cytostatic for cells
Activates granulocytes and macrophages
Promotes bone resorption by osteoclasts
Inhibits collagen synthesis and promotes breakdown
Induces cytokines synthesis
Promotes fibroblast proliferation
Activates endothelial cells
Promotes angiogenesis
Term
What is the mode of Action against TNF?
Definition
Preventing it from binding to its receptor
Humanised TNF antibodies - infliximab, cdp571, adalimumab,
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