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Pharmacology 3 > L13: Inflammation > Flashcards

L13: Inflammation Flashcards

1
Q

What is inflammation?

A

Complex biological response to harmful stimuli (e.g. bacterial, fungal, parasitic infections, burns, cuts, cold, heat)

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2
Q

What are the components of inflammation?

A

Vasodilation, oedema formation, leukocyte accumulation, pain

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3
Q

What is the function of inflammation?

A

To destroy, dilute and partition off the injurious insult, host defence, tissue repair, tumour rejection

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4
Q

What are inflammatory mediators?

A

Chemicals released in and around the affected tissue that mediate inflammatory changes (e.g. arachidonic acid metabolites, cytokines, histamine, NO)

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5
Q

What are inflammatory diseases?

A

Inappropriate response leading to diseases such as allergic rhinitis, asthma, emphysema, rheumatoid arthritis, Alzheimer’s

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6
Q

What are the beneficial effects of Inflammation?

A
  • Stimulation of immune response. Inflammatory cell recruitment, drainage of inflammatory exudate into the lymphatics alllows particulate and soluble antigens to reach the local lymph nodes; dilutes bacterial toxins.
  • Entry of antibodies/complement components. Increased vascular permeability - plasma proteins enter extravascular space - opsonisation of microorganisms leading to their lysis or phagocytosis. Antibodies important for recognition of a foreign target (antigen).
  • Delivery of nutrients and oxygen. Delivery of nutrients (e.g. glucose) and oxygen is aided by increased fluid flow through the area)
  • Fibrin formation (clotting system). Fibrinogen in the exudate can form a fibrin ‘mesh’ impeding movement of microorganisms, trapping microorganisms and facilitating phagocytosis.
  • Mediator (and drug) transport. The fluid carries with it mediators (and therapeutic drugs such as antibiotics) to the site where bacteria are multiplying.
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7
Q

What are the detrimental effects of Inflammation?

A
  • Digestion of normal tissues. Collagenases and other proteases digest and destroy normal tissues. Leads to tissue damage and destruction (rheumatoid arthritis), also vascular damage, e.g. type III hypersensitivity reactions & glomerulonephritis.
  • Swelling. This protective response may also be harmful: Inflammatory swelling - serious in an enclosed space e.g. the cranial cavity raised intracranial pressure in acute meningitis or a cerebral abscess may impede blood flow into the brain resulting is ischaemic damage. Swelling of the epiglottis in children due to Haemophilus influenzae infection may obstruct the airways.
  • Inappropriate or prolonged inflammatory response Acute inflammatory responses occur where the provoking environmental stimulus (e.g. pollen) poses no threat to the individual (type I hypersensitivity reactions (e.g. hay fever). Allergic inflammatory responses may be life-threatening e.g. asthma.
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8
Q

What are the inflammatory cells and their mediators?

A

Inflammatory cells -> inflammatory mediators:
- neutrohils -> cytokines
- eosinophils -> chemokines
- monocytes/macrophages -> histamine
- lymphocytes -> prostaglandins
- mast cells -> leukotrienes
- basophils -> platelet-activating factor
- epithelial cells -> bradykinin
- endothelial cells -> complement factors
- fibroblasts -> reactive oxygen species

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9
Q

What are the stages of inflammatory response?

A
  1. sequestration, adhesion
  2. diapedesis, microvessel, transmigration
  3. granulocyte, chemotaxis
  4. phagocytosis, oxygen burst, degranulation
  5. apoptosis leading to necrosis or macrophage ingestion
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10
Q

What are the stages of Leukocyte-Vessel wall interactions?

A
  1. slow rolling (P-selectin, E-selectin)
  2. arrest
  3. adhesion, strengthening, spreading
  4. crawling
  5. scanning and protrusion (Integrin cluster and CAM cluster)
  6. transmigration (para - inbetween cells, trans - through the cell)
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11
Q

What are the effector cells? Describe and give examples

A

Neutrophil, eosinophil, macrophage.
Produce a variety of agents that can kill/supress microbial growth. Uncontrolled release can damage tissue.

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12
Q

What’s the mechanism of neutrophil maturation? What is its half-life and fate?

A

Mechanism: Bone Marrow/Stem cell -> (myeloblasts, promyelocyte, metamyelocyte) -> mature neutrophil -> peripheral blood
Half-life - 6 hr,
fate - liver, spleen, bone marrow, tissues
CHECK L13(1), slide 19

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13
Q

What’s the primary function of neutrophils? What are the features of neutrophils to fullfil this function?

A

Host defence (phagocytosis and destruction of invading organisms). In order to do this the neutrophil has to:
- recognise and respond to chemical signals generated in the inflamed tissue
- adhere to activated endothelium
- migrate to the site of infection
- recognise the invading organism
- phagocytose and/or destroy the organism

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14
Q

What are the defence mechanisms of neutrophils?

A
  • Phagocytosis of invading organisms
  • reactive oxygen species generation (NADPH oxidase - O2)
  • release of granule enzymes (elastases, collagenase, myeloperoxidase, lysozyme) into the phagolysosome and surrounding environment
  • generation of neutrophil extracellular traps (NETs)
  • release of infammatory mediators
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15
Q

How are neutrophils differentiated?

A

Terminally differentiated with distinctive multilobed nucleus and cytoplasmic granules

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16
Q

What’s the mechanism of eosinophil maturation? What is its half-life and fate?

A

Mechanism: Bone Marrow/Stem cell -> (myeloblasts, promyelocyte, metamyelocyte) -> mature eosinophil -> peripheral blood
Half-life - 18 hr,
fate - tissues, liver, spleen
CHECK L13(1), slide 22

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17
Q

How can eosinohpils be differentiated?

A

Bilobed nucleus with distinctive cytoplasmic granuls containing proteins such as eosinophil cationic protein, eosinophil peroxidase (EPO), major basic protein (MBP)

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18
Q

What’s the primary function of eosinophils?

A

Host defence. Destruction of invading parasites, involved in allergic disease of the lung, nose, skin, eye

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19
Q

What’s the destructive potential of eosinophils?

A

Granules can be released to destroy pathogens:
- Specific granules - major basic protein, eosinophil cationic protein, eosinophil peroxidase, eosinophil derived neurotoxin
- small granules - acid phosphatase, beta-glucuronidase

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20
Q

What’s the mechanism of action of mast cells? What does its granule contain?

A

Bind IgE via IgE receptor. This triggers rapid activation and release of granule contents (mediators e.g. histamine)

21
Q

What are the examples of chemical mediators released from cells?

A
  • histamine
  • serotonin (5-HT)
  • platelet-activating factor (PAF)
  • Prostaglandins (e.g. PGE2, PGI2)
  • Leukotrienes (LTB4, LTC4)
  • Cytokines and chemokines
22
Q

What are the examples of plasma factors of chemical mediators?

A

Complement factors, Kallikrienes (bradykinin), coagulation factors, fibrinolytic factors

23
Q

Where is histamine stored? How is itreleased? Which receptors does it interact with?

A
  • basic amine
  • stored in granules within mast cells and basophils bound to heparin or heparin like molecules
  • released upon stimulation by complement components C3a and C5a or when antigen interacts with cell fixed IgE
  • interacts with H1, H2 and H3 receptors

For histamine release mechanism CHECK L13(2), slide 4

24
Q

What are the main actions of histamine in humans?

A
  • stimulates gastric acid secretion (H2)
  • contract most smooth muscle (H1) (except blood vessels)
  • cardiac stimulation (H1)
  • vasodilatation (H1)
  • increased vascular permeability (H1)
25
Q

What are prostanoids?

A
  • long-chain fatty acids derived from arachidonic acid
  • COX acts on arachidonic acid in order to produce cyclic endoperoxides (prostanoids)
26
Q

What acts on arachidonic acid to produce cyclic endoperoxides (PGG2, PGH2)?

A

Cyclooxygenase (COX), two types:
- COX-1 (constitutive),
- COX-2 (induced by inflammatory mediators)

27
Q

What is PGI2 (prostanoid), from where it’s obtained, which receptors it acts on, what’s its effect?

A
  • PGI2 (prostacyclin)
  • from vascular endothelium
  • acts IP receptors
  • vasodilatation and inhibition of platelet aggregation (PGD2)
28
Q

What’s TXA2 (prostanoid), from where it’s obtained, what’s its effect?

A
  • TXA2
  • from platelets
  • platelet aggregation and vasoconstriction
29
Q

What’s PGE2 (prostanoid), from where it’s obtained, which receptors it acts on, what’s its effect?

A
  • mediator of fever and in inflammatory responses
  • EP1-receptors contraction of bronchial and GI tract smooth muscle
  • EP2-receptors relaxation of smooth muscle
  • EP3-receptors inhibits gastric acid secretion, increase gastric mucus secretion, contracts smooth muscle
  • EP4-receptors many inflammatory responses
30
Q

What’s PGF2-alpha (prostanoid), from where it’s obtained, which receptors it acts on, what’s its effect?

A
  • PGF2-alpha
  • FP-receptors
  • contracts uterus
31
Q

What/s PGD2 (prostanoid), from where it’s obtained, which receptors it acts on, what’s its effect?

A
  • PGD2
  • derived from mast cells
  • acts on DP receptors
  • vasodilatation and inhibition of platelet aggregation
32
Q

What are leukotrienes?

A
  • synthesised from arachidonic acid
  • 5-LO acts on AA to produce 5-HPETE
  • 5-HPETE is converted to LTA4
  • LTA4 is converted either to LTB4 or to series of cysteinyl-leukotrienes, LTC4, LTD4, LTE4
33
Q

What’s the function of LTB4 regarding leukotrienes? What receptors does it act upon?

A

LTB4 powerful leukocyte chemotactic agent and leukocyte activator, acts upon specific LTB4 receptors

34
Q

What’s the function of cysteinyl-leukotrienes? What receptors does it act upon?

A

Cysteinyl-leukotrienes cause contraction of bronchial muscle and causes vasodilatation in most cells by interacting with LTC receptors

35
Q

CHECK L13(2), slide 16 for acute inflammatory response diagramm!

A
36
Q

What are the examples of anti-inflammatory drugs?

A
  • Non-steroidal-anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, indomethacin, etc)
  • Glucocorticoids (e.g., hydrocortisone, prednisolone, dexamethasone, etc)
  • Histamine H1 – receptor antagonists (mepyramine, loratadine, etc)
  • Leukotriene (LT) modifiers (montelukast, zafirlukast, zileuton)
  • Anti-TNF therapies (infliximab, etanercept, adalimumab)
  • IL-1 blocking agents (anakinra- IL-1 RA, etc)
  • DMARDs (Disease modifying anti-rheumatoid drugs) (e.g., methotrexate, sulfasalazine, gold compounds, penicillamine, chloroquine)
37
Q

What are non-steroidal anti-inflammatory drugs? Give examples, where it’s used, main effects and side effects.

A
  • Most widely used of all therapeutic agents worldwide
  • Examples aspirin, ibuprofen, indomethacin (> 50 e.g., )
  • Used mainly for inflammatory diseases, rheumatic complaints, minor aches and pains, etc.
  • Main effects: Anti-inflammatory effects; Analgesic effects; Anti pyretic effects
  • COX inhibitors
  • Side effects (e.g., gastro-intestinal problems, bleeding)
38
Q

What’s the mechanism of action of non-steroidal anti-inflammatory drugs?

A

Inhibition of arachidonic acid in inflammatory cells and the resultant decrease in PG synthesis
Check L13(3), slide 7 for diagramm

39
Q

What are the anti-inflammatory effects of non-steroidal anti-inflammatory drugs?

A

Decrease in vasodilator PGs results in less vasodilatation and oedema

40
Q

What are the analgesic effects of non-steroidal anti-inflammatory drugs?

A

decrease in PG generation - less sensitisation of nociceptive nerve endings to inflammatory mediators such as BK and 5HT. Relief of headachae is probaby a results of decreased PG - mediated vasodilatation

41
Q

What are the antipyretic effects of non-steroidal anti-inflammatory drugs?

A

this is partly due to decrease in PGs (generated in response to IL-1) that are responsible for elevating the hypothalamic set point for temperature control (fever)

42
Q

What are the unwanted effects of NSAIDs? Example of aspirin

A
  • COX-1 inhibition causes reduction in PGE2, resulting in local ischaemia, reduced mucus secretion - ulcers.
  • bleeding - inhibit thromboxane synthesis, platelet aggregation
  • in some - skin rashes, itching, photosensitivity
  • recued renal flow - can be toxic (nephritis)
  • Reye’s syndrome (encephalitis) in under 16s
43
Q

How do glucocorticoids work?

A

A variety of sensorineural inputs regulate the release of corticotropin releasing hormone (CRH) in the hypothalamus. CRH releases adrenocorticotropic hormone (ACTH). ACTH leads to cortisol production in the adrenal zona fasiculata. Cortisol can then exert many effects by interacting with specific receptors.

44
Q

What are the two main classes of steroid that adrenal cortex releases?

A
  • mineralcorticoids
  • glucocorticoids (cortisol) (synthesized in zona reticularis and zona fasciculata)
45
Q

What are the main effects of glucocorticoids?

A

Inhibit inflammatory cell infiltration into the airways and reduce oedema formation by acting on the vascular endothelium. Natural glucocorticoids (i.e., cortisol) are liberated from the adrenal cortex of the kidneys and have powerful effects on metabolism and inflammation).
* Induce the synthesis of mediators with anti-inflammatory potential (e.g., lipocortin 1, IL-1 receptor antagonist, IL-10, etc).
* Inhibit the synthesis of many pro-inflammatory mediators by preventing the action of key transcription factors (e.g., AP-1 and NF-kB).
* Can resolve established inflammatory responses (induce apoptosis of lymphocytes and augment efferocytosis (ability of macrophages to phagocytose dead apoptosed cells)).

46
Q

How do glucocorticoids mediate anti-infllammatory responses?

A

Glucorticoids regulate gene expression. By entering the cell, binding to glucorticoid receptor. GR homodimers bind to GRE in the promoter region of steroid-sensitive genes, which may encode anti-inflammatory proteins.

47
Q

What are leukotriene modifiers? How do they work? What is their effect?

A
  • Drugs that block the effects of leukotrienes are the newest drugs available for the treatment of asthma. Leukotrienes associated with an allergic response.
  • Interfere with LTs action by inhibiting their synthesis or blocking the receptors to which they bind.
  • Well tolerated, can affect liver, increase the risk of infection, cause and allergic reaction reffered to as Churg-Strauss syndrome, and cause muscle aches.
48
Q

What happens in joints affected by Rheumatoid Arthritis?

A
  • swollen joint capsule
  • inflamed synovium
  • bones loss/erosion
  • cartilage loss
49
Q

What drugs are used for Rheumatoid Arthritis?

A

Infliximab, Etanercept, Adalimumab, CDP870 (Anti-TNF therapies)
Anakinra, IL-1 trap (IL-1 blocking agents)

Pharmacology 3 (21 decks)

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