IB - Inflammation Pharmacology Flashcards Preview

Pharmacology > IB - Inflammation Pharmacology > Flashcards

Flashcards in IB - Inflammation Pharmacology Deck (35):
1

Mechanism of acute inflammation?

1. Tissue damage

2. Synthesis and release of mediators

  • Histamine - vasodilation, bronchoconstriction, spasm, lots of local effects
  • Bradykinin/Nitric oxide - vasodilation, increase vascular permeability, pain
  • Prostaglandins - vasodilation, pain fever
  • Leukotrienes - bronchochonstriction, increase vascular permeability, chemotaxis 

3. Recruitment of immune cells 

  • monocytes/macrophages
  • phagocytes
  • mast cells - contain histamine in granules
  • lymphocytes - T cells (more likely)/B cells

2

What are the signs of acute inflammation?

  • heat
  • redness
  • pain
  • swelling
  • loss of funtion

3

What are the inflammatory mediators involve in acute inflammation?

Microbial Infection

  1. Exogenous chemoattractants (microbial peptides and endotoxins)
  2. Leads to complete phagocytosis by neutrophils

Surgical Trauma + Hypoxia or Repurfusion Injury

  1. Endogenous chemical mediators (leukotriene B4, prostaglandin E2, C5a)
  2. Leads to incomplete phagocytosis by ROS and hydrolytic enzymes

Both lead to acute inflammation...

  • 5 signs of acute inflammation
    • pain - prostaglandins
    • heat
    • redness - histamine
    • swelling - histamine
    • loss of function
  • vasoconstriction
  • vasodilation - prostaglandins, histamine
  • increased vascular permeability - leukotrienes
  • chemotaxis, adhesion - leukotrienes
  • fever - prostaglandins 

which can then lead to...

  • chronic inflammation​ --> fibrosis
  • resolution

4

Production of prastaglandins?

The Arachidonic Acid Pathway

 

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5

Function of prostaglandins?

  • vasodilation
  • pain 
  • fever

6

What are the individual synthase enzymes which make the individidual prostaglandins?

  • prostaglandin D2 - PGD synthase
  • prostaglandin E2 - PGE synthase
  • prostaglandin I2 - prostacyclin synthase
  • prostaglandin F2 - PGF synthase
  • thromboxane A2 - thromboxane synthase

7

Isoforms of COX?

Cyclooxygenase 1 (COX1)

  • constitutive, widespread
  • functions are homeostatic
  • manages central functions...
    • produces PGE2 in stomach - protective mucosal layer
    • produces TXA2 in platelets (subtype) - clotting and platelet aggregation
  • active site is a small hydrophobic channel - inhibited by small molecules

Cyclooxygenase 2 (COX2)

  • inducible - synthesis of enzyme increased by cytokines (when you injure yourself)
  • manages inflammatory response...
    • produces high levels of PG in areas of inflammation
    • produces PGI2 in endothelial cells and CNS - prevent aggregation
  • greater rate of reaction so greater rate of production
  • active site is a larger channel - inhibited by drugs with buly side groups which cannot enter COX1

8

Receptors of the prostaglandins?

Vast number of different receptors...

  • Gαs coupled = stimulate production of cAMP
    • IP receptor - PGI2
    • DP1 receptor - PGD2
    • EP4 receptor - PGE2
    • EP2 receptor - PGE2
  • Gαq coupled = increase calcium by regulation of phospholipase Cβ
    • EP1 receptor - PGE2
    • FP receptor - PGF2
  • Gα​/s/q coupled = increase calcium by regulation of phospholipase Cβ + stimulate/inhibit production of cAMP
    • EP3 receptor - PGE2
    • TP receptor - TXA2
  • Gal coupled = decrease production of cAMP + increased calcium by regulation of phospholipase Cβ
    • DP2 receptor - PGD2

 

9

Drugs that effect COX1/COX2?

NSAID = non-steroidal anti-inflammatory drugs

Non-competitive irrversible antagonists of COX enzyme...

  • non selective (weakly selective COX1)
    • e.g. aspirin - irreversible covalent modification
    • e.g. ibuprogen - reversible covalent modification
  • COX1 selective
    • e.g. ketorolac
    • e.g. flurbiprofen
  • COX2 selective​
    • generally reversible
    • celecoxib
    • rofecoxib

Side effects:

  • GI bleeding
  • possibly increased cardiovascular risk

Antipyretic Analgesic 

e.g. Paracetomal

 

10

Features of antipyretic analgesics (paracetamol)?

Not an anti-inflammatory drug

antipyretic = reduces fever

analgesic = reduces pain

Several proposed mechanism of actions:

  • COX3 in CNS - there is a 3rd form of COX called COX3 found exclusively in the CNS
  • decrease nitric ocide in spinal cord - gas which causes vasodilation + neurotransmitter in pain transudction in the spinal cord
  • paracetamol is metabolites into NAPQI - NAPQI inhibits neurotransmission so when found in neurones, this toxic metabolite will reduce the ability of those neurones to signal

Advanatges:

  • safe and well tolerated - given for a wide range of conditions

Disadvantages:

  • liver toxicity 
    • toxic dose = 8-12,000mg - will experience symptom toxicity 

11

Mechanism of NSAIDs on COX?

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12

Production of leukotrienes?

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13

Function of leukotrienes?

  • bronchoconstriction
  • increase vascular permeability
  • chemotaxis

14

What is bronchoconstriction?

= closure of airways

Protective mechansim - if you are xperiencing damage to pulmonary tissues due to atmospheric chemical, it is important to limit access

Short term - beneficial

Long term - unhelpful as run out oxygen

15

Receptors of leukotrienes?

BLT Receptor = receptors for leukotriene B4

  • BLT1
    • found on leucocytes - involved in chemotaxis
  • BLT2
    • found on ubiquitous cell types - every tissue is somehow responsive to leukotrienes

CysLT Receptor = receptors for cysteinyl leukotrienes

  • CysLT1
    • found on vascular and bronchiole smooth muscle - cause vaso- and broncho- constriction
    • found on macrophages and leucocytes - important for chemotaxis and activation 
  • CysLT2
    • found on macrophages, brain, adrenal gland

16

How is histamine manufactured, stored and released?

Manufactured from: histidine

Stored in specific immune cells:

  • mast cells 
  • basophils
  • neutrophils

Types of granule release:

  • exosome secretion
    • little histamine released at a time
    • localised effect
  • piecemeal degranulation
    • slightly larger amounts of histamine released, create a bigger reaction
    • localised effect
  • anaphylactic degranulation
    • large amounts released
    • mass, systemic effects - eventually can lead to stopped breathing/heart

17

Receptors for histamine?

All GPCRs

H1

Major tissue location: smooth muscle, endothelial cells

Intracellular mechanism: activates PLC, which activates PKC and Ca2+

Function: acute allergic response - bronchoconstriction, vasodilation, increase vascular permeability, stimulation of sensory nerves and release of peptides mediators in the periphery --> vasodilation, pain

H2

Major tissue location: gastric parietal cells

Intracellular mechanism: activates AC, which activates PKA

Function: 

  • increased gastric acid secretion
  • increased heart rate

H3

Major tissue location: CNS (presynaptic)

Intracellular mechanism: activates AC, which activates PKA

Function:

  • modulating neurotransmission

H4

Major tissue location: mast cell, eosinophils, t cells, dendritic cells

Intracellular mechanism: activates AC, which activates PKA

Function:

  • regulating immune responses

 

18

Function of histamine?

Local

  • itching
  • redness
  • swelling
  • oedema
  • headache
  • vasodilation
  • bronchoconstriction
  • vomiting 
  • diarrhoea

Systemic

  • huge vasodilation
  • bronchoconstriction
  • spasm = airways cannot open

19

Overview of an allergic reaction?

  1. B cell initial contact with allergen
  2. B cell differentiates into plasma cell
  3. plasma cell releases IgE antibodies
  4. mast cells have IgE receptors which bind IgE antibody
  5. subsequent contact with allergen
  6. histamine and other chemical release from mast cell

20

Drugs that effect histamine?

Antihistamines - H1 receptor antagonists 

Older H1 receptor antagonists

  • e.g. promethazine, chlorphenamine
  • also antagonise muscarinic acetylcholine receptors in the CNS - sedative effects

Newer H1 receptor antagonists

  • e.g. loaratadine, fexofenadine
  • reduced anti muscarin effects as cant pass the blood brain barrier - no sedative effects

Uses

  • anti-allergy
  • sedation
  • cough/cold remedies
  • anti-emetic = used for sickness and dizziness

Side effects:

  • dry mouth
  • blurred vision
  • sedation (due to anti-muscarinic effects)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      

Side Effects

21

What are glucocorticoids? 

Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones

e.g. prednisone, beclametasone

22

Receptors of glucocorticoids?

  • nuclear receptors

They retain in the cytoplasm bound to chaperone proteins - inactive

When drug/glucocorticoid binds to glucocorticoid receptor, it dissociates from chaperone proteins and undergoes nuclear translocation

Receptors dimerise forming homodimers (nuclear receptors bound together)

Receptrs bind to a response element which will regulate transcription of genes which contain response elements in promotor region

This either:

  • facilitates recruitment of RNA polymerase 
  • facilitates recruitment of genetic transcription factors
  • inhibits recruitment of RNA polymerase

Gene expression changes:

  • decrease phospholipase A2 (PLA2) activity
  • decrease cyclooxygenase (COX) and expression

23

Side effects of glucocorticoids?

  • diabetes
  • osteoporosis
  • peptic ulcers
  • immunosuppression - if long dose for a long time
  • adrenal suppression
  • altered appearance = gain weight in face/trunk, wasted limbs
  • mental disturbance
  • topical = skin atrophy, hair growth

24

What is Gout? Symptoms?

A form of arthritis caused by excessive uric acid in the bloodstream

Causes inflammation at joints due to deposition of uric-acid crystals inside and around joints

Symptoms:

  • 5 signs of inflammation (especially pain)

25

How is uric acid formed?

hypoxanthine --> xanthine --> uric acid

Uric acid can build up due to:

  • lack of water resulting in reduced clearance
  • alcohol
  • lack of good diet (eating lots of milk, meat, cheese, chocolate, marmite)

26

How is gout treated?

Acute attacks are treated with:

  • NSAIDS - not aspirin
  • antigout agents - colchicine = microtubule inhibitor (prevents immune cells from leaving the blood, preventing inflamation)

Long-term control:

  • uricosuric drugs = increase uric acid excretion
  • xanthine oxidase inhibitor drug = prevents formation of uric acid e.g. allopurinal 

27

Types of chronic inflammation?

  • alzheimers and neurodegeneration = increased activity of immun cells in the CNS
  • chrons = inflammation of colon and bowel
  • diabetes = immune system has destroyed beta-cells of pancreas (type 1), type 2 leads to inflammatory conditions
  • rheumatoid arthritis = immune system attacks joints
  • cardiovascular disease = fatty plagues consists of macrophages that have consumed excess lipoprotein and become foam cells which are inactive, reducing the ability of endothelial tissue to respond to change
  • cancer = Tumours which are succusful, develop evasion techniques so they become unresponsive to apoptosise, they secrete anti-inflammatory cytokines which switch off macrophages/B cells/T cells so immune cells are infected

28

What is rheumatoid arthritis?

autoimmune disease that causes inflammation in your joints

 

29

What happens in rheumatoid arthritis?

  • inflammed hyperplastic synovial lining as cells are swollen + may be more of them
  • increase in synovial membrane thickness due to leucocyte recruitment
  • inflammation as antigens are recognised in the synovial fluid/synoval membrane, chemotactic factors are secreted which draw immune cells to site of infection
  • break down of cartilage
  • synovial fluid and membrane breaks down
  • bone on bone contact leads to wear and tear
  • inflammatory mediators secreted by immune cells activate osteoclasts (collapse bone) which weakens bone either side of joint

30

Drugs that effect rheumatoid arthritis?

Disease Modifying Anti-Rheumatic Drugs (DMARDS)

  • immunosupressants = a drug that is used to suppress the immune system
    • e.g. azathiaprine -  inhibits purine synthesis necessary for the proliferation of cells, especially leukocytes and lymphocytes
    • e.g. methotrexate - folate antagonist, cytotoxic
    • e.g. cyclosporin - decreased lymphocyte proliferation (can result in kidney damage) = binds to the cyclophilin of lymphocytes, especially of T cells. Ciclosporin-cyclophilin complex inhibits calcineurin, which is normally responsible for activating the transcription of interleukin 2
  • cytokine modulators
    • mainly antibodies against TNFalpha, IL-1, immune cell receptors - an anitbody against the cytokines itself will inhibit cytokines, reducing immune response
    • very expensive, specialist use, not orally active

Negatives:

  • rashes
  • gut upset
  • bone marrow suppression
  • slow onset - months/years

 

31

What is asthma?

long-term inflammatory disease of the airways of the lungs

32

What happens in asthma?

  1. APC e.g. macrophage/dendritic cell englufs allergn and presents it on MHC II
  2. CD4+ T cell recognises antigen and is activated
  3. CD4+ T cell differeniates TH1 (pro-inflammatory) and TH2
  4. TH2 activates B cells, which proliferate and terminally differenated into plasma cells which secrete IgE antibodies, which bind to eosinophils and mast cells
  5. TH2 release cytokines which activate eosinophils

Changes in bronchodiolar structure:

  • dilated blood vessels
  • eosinophil, mononuclear cell and mast cell infiltration
  • thickened basement membrane
  • mucus plug with eosinophils and desquamated epithelial cells 
  • oedema
  • hypertrophied smooth muscle 

33

Stages of asthma and mediators?

Immediate Phase

1. Eliciting agent (allergen on non-specific stimulus)

2. Infiltration of mast cells and mononuclear cells

3. Bronchospasm induced by spasmogens such as...

  • acetylcholine (M receptor)
  • histamine (H1 receptor)
  • prostaglandins (PGD2​ receptor)
  • leukotrienes (cysLT receptor)

4. Late phase induced by chemotaxins, and chemokines

Late Phase

1. Infiltration of cytokine-releasing TH2 cells, and monocutes and activation of inflammatory cells, such as eosinophils

2. Infiltration of mediators such as....

  • leukotrienes (cysLT)
  • neuropeptides
  • NO
  • adenosine

3. Eosinophil-granule major basic protein (EMBP) and eosinophil cationic protein (ESP) levels increase causing epithelial damage

4. Mediators and epithelial damage cause airway inflammation and airway hyper-reactivity

5. Bronchospasm, wheezing, coughing

A image thumb
34

Receptors and innervation of the bronchiolar smooth muscle?

Parasympathetic innervation...

  • sensory nerves stimulated --> parasympathetic reflex --> release of ACh
  • sensory nerves stimulated --> release of peptides --> bronchochonstriction

Little sympathetic innervation but lots of β​receptors

  • PAF (platelet-activating factor) - increase calcium concentration in cell leading to muscle contraction
  • H1 - increase calcium concentration in cell leading to muscle contraction
  • LT (leukotriene receptor) - increase calcium concentration in cell leading to muscle contraction
  • M (Muscarinic acetylcholine receptors) - increase calcium concentration in cell leading to muscle contraction
  • β2 - GPCR Gs coupled = convert ATP to cAMP, which increases AMP concentration and decreases calcium concentration in cell leading to bronchodilation

35

Drugs that effect asthma?

Bronchodilators

  • β2 agonists e.g. slabutamol, salmeterol
    • activate βreceptors
    • decrease mast cell release 
    • first choice drugs - inhalation + iv/oral
    • side effects: tremor, tachycardia (β1)
  • M antagonists e.g. ipratroprium
    • prevent activation of M receptor
    • inhalation
    • side effects: few
  • methylxanthines e.g. theophylline
    • inhibits phosphodiesterase, therefore increasing concentration of cAMP in the cell
    • oral
    • long action
    • side effects: nausea, heache, insomnia, arrythmia, convulsions in overdose
  • Leukotriene (LTC4/D4) antagonists e.g. montelukast
    • prevents activation of LT receptor
    • oral
    • weak inflammatory activity too
    • side effects: few 
  • Antihistamines - H1 antagonists
    • prevents activation of H1 receptor

Prophylactic Anti-Inflammatory Drugs

  • glucocorticoids e.g. beclometasone
    • first choice drugs
    • inhaled + oral
    • slow acting (3-7 days)
    • side effects: oral candidiasis, sore throat, hoarseness
  • mast cell stabilizers e.g. sodium cromoglicate 
    • mechanism unclear - mast cell stabiliser? decreases sensory nerve stimulation?
    • inhalation only - powder
    • weak, not effective in all patients
    • slow acting (several weeks)
    • side effects: none, cough from powder

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