Module 1C Flashcards
Abbreviations (IL, TNF, IFN, GF, GM_CSF, PRN, OTC, IBD, SC, COX,NK cells, VLA-4, VCAM-1)
- IL: interleukin
- TNF: tumour necrosis factor
- IFN: interferon
- TGF: transforming growth factor
- GM_CSF: granulocyte-macrophage colony-stimulating factor
- PRN: as needed
- OTC: over the counter
- IBD: inflammatory bowel disease
- SC: subcutaneous
- COX: cyclooxygenase
- NK cells: natural killer cells
- VLA-4: very late antigen 4
- VCAM-1: vascular adhesion molecule 1
CYP450: cytochrome P450 enzyme system
What is inflammation
- A physiological response to infection or tissue injury
-Can be acute or chronic(long)
Is inflammation present in almost all conditions or diseases
Yes
does inflammation= infection
no
What are the signs of inflammation
- Pain
- Heat
- Redness
- Swelling
Why does the acute inflammatory response happen
- Restricts damage to the localize site
- Recruits immune cells to kill pathogens
- Start wound repair
- Recruits immune cells to kill pathogens
How long does the acute inflammatory response last
- 24-48 hours
-Mild and localized
What happens within inflammation within minutes of injury
Plasma proteins are activated from clotting and kinin systems
What activates plasma proteins
Clotting and kinin systems
what is clotting
- The production of fibrin strands that accumulate to stop the spread of possible infection or bleeding to the outside
-Keeps everything local
What is a kinin:
Produced bradykinin which induces vasodilation and increases permeability
What is bradykinin
- Produced by kinin
- Increases permeability and vasodilation in blood vessels
- Allows for cells to go from blood to tissues easier
- Increases permeability and vasodilation in blood vessels
What do granulocytes contain
Contain substances that can kill a pathogen and enhance the inflammatory response
What do mast cells do within acute inflammation
- Degranulate
-This leads to a release of histamine and activates prostaglandins and leukotrienes
How does vasodilation aid in acute inflammation
- It increases blood flow to the affected area
- This leads to head, redness, and swelling (edema)
How does acute inflammation result in pain
- The swelling and activation of nociceptors result in pain
-It is a by product of the original injury from a nociceptor and swelling can cause pain also
What is diapedesis
The movement of leukocytes out of the blood into the site of infection or tissue damage
What are the 4 steps of diapedesis
- Chemoattraction
- Rolling adhesion
- Tight adhesion
- Transmigration
What is chemoattraction
- Various inflammation mediators are release earlier
Mast cells..
What is rolling adhesion
- Carbohydrate chains on the surface of the neutrophil cause leukocytes to roll on the edge of the blood vessel rather then the middle
What is tight adhesions
- Multiple cytokine and integrin receptors (depends on location)
What is transmigration
The leukocytes try to squeeze past the blood vessels
Where can leukocytes adhere to (undergo diapedesis)
Can only adhere to veins and not crawl through arteries
Different types of tissue injury
- Physical agent
- Chemical agent
- Pathogenic microorganisms
- Chemical agent
Mediators of Inflammation
- Capillary dilation->increased blood flow (Heat)
- Increased capillary permeability->extravasation of fluid (Redness)
- Attraction of leukocytes-> migration of white cells to site of injury (Swelling)
- Systematic response->fever and leukocytes (pain)
What happens after leukocytes are in the tissue
Leukocytes phagocytize the invading pathogens and release mediators
What mediators are released during acute inflammation
- Cytokines
- Histamine
- Prostaglandins
- Leukotrienes
- The mediators further contribute by recruiting and activating more cells, induces coagulation, further increase vascular permeability
What is chronic inflammatory response
- Continues after the acute response, cleans up debris, and facilitates healing process
- A result from continuous exposure to offender (pathogen persistence, autoimmune disease, cancers
What is chronic inflammatory response characterized by
- The accumulation and activation of macrophages and lymphocytes, as well as fibroblasts that replace the original, damaged or necrotic tissue
What is fibrosis
- An excessive deposition of fibrous connective tissue that interferes with normal tissue function (scaring)
- No function
How to deal with chronic inflammation
- The inflammation has now lost its helpfulness
- Need pharmacotherapy and involves anti inflammatory
- Want to reduce inflammatory trigger
When treating chronic inflammation do we want to stop all inflammation?
- No we don’t
When and how are inflammatory mediators released
- Released and generated during immune responses to coordinate and regulate immune cell activities
- They are in a preformed state in granules (like granulocytes) or synthesized at time of cellular activation
What can inflammatory mediators all do?
- Have antiviral, pro inflammatory or anti inflammatory activities
- Regulate processes
- Self regulate
- Can act both locally or systemically
- They guide other cells where to go (chemoattraction in diapedesis)
What are the four inflammatory mediators (not all of them)
- Cytokines
- Histamine
- Prostaglandins
- Leukotrienes
What are cytokines
- Soluble factors secreted by immune cells that are activated
-Can be organized based on there activities
Four groupings of cytokines and there activities
- 1: promote inflammation and mediate natural immunity (recruit more cells to area, so can inhibit this group to stop some inflammation)
IL-1, IL-6, IL-8, TNF, IFN-a- 2: support allergic inflammation
IL-4, IL-5, IL-13 - 3: Immunoregulatory activity (slow it all down, recruited late on and clean everything up after its all done, if we want to reduce inflammation we can try to boost these cells)
IL-10, IL-12, TGF-B, IFN-y - 4: act as hematopoietic growth factors (tell us to get more cells, drugs can be used to affect this so it increase the amount of cells generated)
IL-3, IL-7, GM-CSF
- 2: support allergic inflammation
What are biologics
- Drugs that are produced by using biological processes
- Complex large molecules
- Examples are hormones, vaccines, interferon
How do we use antibodies to target
- Monoclonal antibodies can use antibodies to targe specific receptors or pathogens
- Can attach a drug to an antibody which allows the antibody to only target specific cells and thus the drug only targets those specific cells
- This can make therapy more effective and minimize adverse effects
What is a way that IBD is treated
- Inflammatory bowel disease
- Infliximab (Remicade): tumour necrosis factor (TNF)- a inhibitor
- The TNF-a inhibitor is involved in inflammation and immune responses and is in very high levels in IBD
- Biologics have many indications and target TNF to reduce the active amounts
What is multiple sclerosis and how is it treated
- It is when immune cells destroy the myelin sheath which surrounds the axon of neurons
- Natalizumab is a monoclonal antibody which binds to and blocks a4 integrin
- It inhibits rolling adhesion so white blood cells are unable to get through the blood vessel and attack the neuron causing damage
What are Histamines
- A bioactive amine which is packaged into dense intracellular granules
- Mast cells are famous for releasing it
- When histamine is released it binds to histamine receptors
Types of histamine receptors and there uses (what happens when you block these)
- H1: within smooth muscle of the vascular system, bronchial tree, digestive track and nasal glands
Causes allergies, allergic reactions
Blocking H1 receptors helps with allergic rhinitis symptoms- H2: lining of stomach and produces gastric acid
Blocking these reduced the amount of acidity within the stomach - H3: within the CNS and involved in releasing neurotransmitters such as dopamine, GABA, acetylcholine, noradrenaline, serotonin
There is no way of blocking these as of now
- H2: lining of stomach and produces gastric acid
1st and 2nd generation antihistamines
- 1st: block H1 receptors, shorter acting, cause drowsiness, work faster, usually used to treat allergic response
- 2nd: longer acting, less sedating, take longer to start working, can be used everyday
What does arachidonic acid do and where is it released from
- It is released from immune cell membranes
- It is metabolized in two different ways to generate prostaglandins/ thromboxane or leukotrienes
What is the pathways that generate prostaglandins/ thromboxane’s vs leukotrienes
- Prostaglandins= cyclooxygenase pathway
- Leukotrienes= lipoxygenase pathway
What are prostaglandins
- Generated from arachidonic acid through the cyclooxygenase pathway
- Have many functions including constrict/ dilate vascular smooth muscle cells, cause aggregation/ disaggregation of platelets, induce labour, release during menstruation, play an important role in mucosal production in Gi tract, act on thermoregulatory centre to produce fever
What is cyclooxygenase (COX)
- Enzyme that converts arachidonic acid to prostaglandins
- COX-1: in all tissues and involved in platelet aggregation
- COX-2: more specific for inflamed tissue
Drugs that affect prostaglandins
NSAIDS (non steroidal anti inflammatory)
What do NDAIDs do
- Inhibit cyclooxygenase (COX)
- This reduces prostaglandin synthesis which then inhibits inflammation
- Have analgesic and antipyretic properties
- Can be used to treat mild to moderate inflammation, fever, dysmenorrhea (period cramps), platelet inhibition
What are classic NSAIDs vs COX-2 inhibitors
- Classic NSAIDs: inhibit both COX-1, and COX-2
Ibuprofen, naproxen- COX-2 inhibitors: more specific to inflamed tissue
Should we take NSAIDs before or after we get pain/inflammation
- Should take them before as they inhibit COX and this produces less prostaglandins
- If we take them after pain there is already prostaglandins that were produced from COX
What is Analgesic
Acting to relieve pain
What is antipyretic
Used to reduce fever
Adverse side effects of classic NSAID and COX-2 inhibitors
- Classic NSAID: nausea, dyspepsia, ulcer with long term use, anti platelet action, hypertension, increase risk of cardiac events
Can take with food and take on an as needed basis whenever possible to reduce side effects- COX-2 Inhibitor adverse effects: fewer GI issues but same in kidney and CV
What are leukotrienes
- Generated from arachidonic acid through the lipoxygenase pathway
- Mostly active in smooth muscle lining of the bronchioles
- Contribute significantly to the pathophysiology of asthma
How do leukotriene contribute to asthma
- Airflow obstruction
- Increased secretion of mucous
- Bronchoconstriction
- Infiltration of inflammatory cells in airway
What does Montelukast do
- A drug affecting leukotrienes
- Leukotriene receptor antagonists (LTRAs)
- Reduces inflammation by blocking leukotriene receptors
- Is preventative and doesn’t work fast enough for immediate relief
- Adverse effects include headache, cough GI upset
- Must be taken daily to work
All the drugs that affect inflammation 5 types
• Cytokines
- Biologics (immunosuppressant/stimulant, anti-inflammatory….
• Histamine
- Antihistamines (H1)
- H2- receptor antagonists (H2RAs)
• Prostaglandins
- Non steroidal anti inflammatory drugs (NSAIDs)
• Leukotrienes
- Leukotrienes receptor antagonists (LTRAs)
• Cortisol
- Corticosteroids
What is cortisol
- A hormone released in response to stress
- Job is to return body back to homeostasis
- Two main effects are anti inflammatory and immunosuppressive
Where does cortisol have receptors
- All over the body and in every situation there will be the indication for the drug and adverse effects
Explain cortisol’s anti-inflammatory MOA
- Decrease production of phospholipase A, this decreases production of prostaglandins, leukotrienes, thromboxane’s
- Decreased leukocytes means less recruitment of leukocytes to site of injury
- Decreased bactericidal activity of phagocytes and stabilizes mast cells
Explain cortisol’s immunosuppressant MOA
- Induce apoptosis of T cells
- This means less T cell recruitment to site of antigen
- This increases T cell redistribution to lymph nodes and there is no B cell effects from cortisol
What is corticosteroid and some uses
- It is a synthetic version of cortisol (mimic human endogenous cortisol)
- Has many different uses such as asthma or allergies
Three type of corticosteroids (not all of the drugs)
- Short acting: hydrocortisone, cortisone
- Intermediate acting corticosteroids: methylprednisolone, prednisone
- Long acting corticosteroids: betamethasone, budesonide
Different routes of administration for corticosteroids
- There are different ways to administrate to attempt to minimize adverse effects
- Always try to use the most local way
- Otoc (ear)
- Oral
- injectable
- Inhalation
- Topical
- Ophthalmic (eye)
