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MPharm Y3S1 > Inflammatory Pharmacology > Flashcards

Inflammatory Pharmacology Flashcards

1
Q

What 2 things can stem cells be differentiated to?

A

Common myeloid progenitor
Common lymphoid progenitor

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2
Q

What can common myeloid progenitor differentiate to?

A

Mageakaryocyte (thrombocytes)
Erythrocyte
Mast cell
Myeloblast (basophil, neutrophil, macrophages)

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3
Q

What can common lymphoid progenitor differentiate to?

A

Small lymphocyte (B and T cells)
Natural killer cells

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4
Q

What is autoimmunity?

A

Immune response against self (autologous) antigens therefore results from some failure of the house immune system to distinguish from self to non-self
Develops when multiple layers of self tolerance are dysfunctional

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5
Q

What are immunogens?

A

Substances that are capable of eliciting an immune response

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6
Q

What are tolerogens?

A

Antigens that induce tolerance rather than immune reactivity

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7
Q

Why is there both central and peripheral tolerance?

A

Not all self antigens are expressed in central lymphoid organs where the negative selection occurs
There is a threshold requirement for affinity to self antigens before deletion is triggered

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8
Q

Describe central tolerance in T lymphocytes:

A

Immature T lymphocytes in thymus, exposure to self antigens during development
APC displays self antigen to T cell by MHC and a co-stimulatory receptor (either CD4 or CD8) is needed

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9
Q

What are the outcomes of central tolerance in T lymphocytes?

A

Binding is either-> results in
Strong-> negative selection/apoptosis
Intermediate (high affinity)-> T reg cell which enters peripheral tissue
Weak-> Positive selection
None-> apoptosis

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10
Q

What is the difference in purpose of central and peripheral tolerance?

A

Central is to train the immature lymphocytes and peripheral is to mature lymphocytes in case any were untrained from peripheral

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11
Q

Describe central tolerance in B lymphocytes:

A

Immature B lymphocytes in bone marrow, exposure to self antigens during development
B cell receptor exposed to self antigens from any other cell

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12
Q

What are the outcomes of central tolerance in B lymphocytes?

A

High avidity, receptor editing so B cell expresses a new light chain, and self antigen attaches again, if still high avidity then apopotisis
Low avidity, reduce receptor expression and becomes anergic, this means B cell will never react to self antigen again (unresponsive)

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13
Q

What is the purpose of receptor editing?

A

Changes the antigen binding site on the light chain so new antigens can bind

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14
Q

Describe peripheral tolerance in T lymphocytes:

A

T cell will bind to antigen on APC with co-stimulator receptor normally, but with self antigen no co-stimulator receptor interaction

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15
Q

What are the outcomes of peripheral tolerance in T lymphocytes?

A

Anergy- functional unresponsiveness without the necessary co-stim signals
Suppression- blocks activation by T-regs
Deletion- apoptosis

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16
Q

Describe peripheral tolerance in B lymphocytes:

A

B cell will bind to antigen and will activate a T helper cell response and produce antibodies normally, but with self antigen, it doesn’t activate a T helper cell response so no cytokine release (IL4/IL5) and therefore no antibody production

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17
Q

What are the outcomes of peripheral tolerance in B lymphocytes?

A

Without the activation of T cells:
-Becomes anergic (doesnt respond to self antigens)
-Apoptosis
-If activated it is suppressed by inhibitory receptors

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18
Q

Why is T cell tolerance important?

A

As maintaining T cell tolerance enforces B cell tolerance as T cells are needed for B cell activation

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19
Q

Name 6 different ways the body can undergo self tolerance:

A

Central tolerance
Peripheral anergy
Antigen segregation
Regulatory T cells
Cytokine deviation
Clonal deletion

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20
Q

Describe what is antigen segregation:

A

Physical barrier to self antigen access to lymphoid system, certain areas such as the eyes are never exposed to B and T cells
Occurs in peripheral organs e.g thyroid, pancreas

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21
Q

Describe how regulatory cells are involved in self tolerance:

A

Suppression by cytokines, intercellular signals in 2º lymphoid tissue and sites of inflammation

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22
Q

Describe cytokine deviation:

A

Differentiation to Th2 cells, limiting inflammatory cytokine secretion in 2º lymphoid tissue and sites of inflammation

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23
Q

Describe the epidemiology of autoimmune disease:

A

More frequent in women than men, possible due to oestrogen influencing IS to predispose to the disease
The presence of one autoimmune disease increases the chances of having another

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24
Q

Describe the genetic factors of AID:

A

There is a strong genetic component (increased prevalence in MZ twins)
Most AIDs are polygenic, inserting many polymorphisms
Strong association of MHC class II genes with disease

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25
Q

Describe the joint mechanism for autoimmunity:

A

Susceptibility genes lead to a failure in self tolerance and produce self reactive lymphocytes
During an infection/ inflammation in tissues, this leads to tissue APCs being activated so and influx of self-reactive lymphocytes into tissues and so an overload

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26
Q

How can infections possible prevent AID?

A

Possible if exposed to more antibodies our body is better capable of differentiating between self and non self

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27
Q

How can the induction of co-stimulators cause autoimmunity?

A

If a microbe attacks an APC with a self antigen, this will cause activation of the APC and express a co-stim molecule and the self antigen to the T cell, therefore fully activating a self reactive T cell and attacks self tissue

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28
Q

How can molecular mimicry cause autoimmunity?

A

Microbe infects an APC with a microbe antigen, this looks very similar to an APC expressing a self antigen
It then expresses antigen to T cell so causes activation of self reactive T cell

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29
Q

What are 2 factors that contribute to autoimmune damage?

A

Circulating autoantibodies
T lymphocytes

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30
Q

Describe ways how circulating antibodies cause autoimmune damage:

A

Complement lysis
Interaction with cell receptors
Toxic immune complexes
Ab dependent cellular cytotoxicity
Penetration into living cells

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31
Q

Describe ways how T lymphocytes cause autoimmune damage:

A

CD4 cells polaries towards Th1 responses via cytokines (rheumatoid arthritis, multiple sclerosis, T1D)
CD8 cells activated to become cytotoxic T cells and cause direct cytolysis

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32
Q

Describe other non specific ways of autoimmune damage:

A

Recruitment of inflammatory leucocytes into AI lesions

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33
Q

Name an example of systemic autoimmune diseases:

A

Rheumatoid arthritis

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34
Q

Name examples of organ specific autoimmune diseases:

A

Myasthenia gravis
Graves disease
T1D

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35
Q

How can corticosteroids act as anti-inflammatory agents?

A

Can block TNF and IL1 production

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36
Q

Describe non specific control of autoantibodies:

A

Infusion of IV immunoglobulin of multiple specificity from a group of healthy donors
Plasmapheresis- remove circulating antibodies, for short term treatment

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37
Q

Describe how a fever can occur:

A

Macrophage engulfs bacterium by endocytosis which releases endotoxin so macrophage release IL1 in return into the blood stream, which is sent to the hypothalamus which produces prostaglandin, which resets the body thermostat to a higher temperature

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38
Q

Describe the sequence of the acute phase inflammatory response:

A
  • Insult by trauma or pathogen causes acute phase reaction
  • Platelet adhesion, transient vasoconstriction of efferent vessels
  • Cytokine-induced vasodilation of afferent vessels (increased heat /blood flow to area)
  • Activation of complement, coagulation, fibrinolytic and kinin system
  • Leukocyte adhesion
  • Increase vascular permeability and extravasation of serum proteins (exudate) and leukocytes (→ neutrophils → macrophages → lymphocytes) with resultant tissue swelling
  • Phagocytosis of foreign material with pus formation
  • Wound healing and remodelling
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39
Q

What cytokines do macrophages release in acute phase reaction?

A

TNFa
IL1
IL6

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40
Q

Describe the first phase of inflammation:

A
  1. Vasodilation, triggered by cell parts, histamine, kinin, prostaglandin and leukotrienes
  2. Migration and margination= binding of phagocytes to the BV which they then force themselves between the endothelium cells of the BV and migrate into the tissues
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41
Q

How are cytokines involved in promoting inflammation?

A

Activate immune and other cells in local environment
Recruit immune cells to environment
GFs stimulate immune and non-immune cell growth
Acts as endogenous pyrogens (drive immune response and change overall temp)
Induce acute phase proteins in liver

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42
Q

What are acute phase proteins?

A

Fluctuate in response to tissue injury and infections
Usually made by hepatocytes
Synthesized in response to pro-inflammatory cytokines

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43
Q

Name 5 acute phase proteins:

A

C reative protein
Fibrinogen
Serum Amyloid A
Complement factors
Hapatoglobin and ferritin

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44
Q

What is the function of C reactive protein?

A

Opsonin- labeling pathogens so easier identification

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45
Q

What is the function of Fibrinogen?

A

Coagulation factors

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46
Q

What is the function of serum amyloid A?

A

Cell recruitment and MMP inducer

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47
Q

What is the function of complement factors?

A

Opsonin, lysis, clumping and chemotaxis

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48
Q

Name 5 major pro-inflammatory cytokines:

A

IL-1
TNFa
IL-12
IL-6
IFN-a/B

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49
Q

What is the function of IL-1?

A

Vasculature (inflammation)
Hypothalamus (fever)
Liver (induces APP)

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50
Q

What is the function of TNFa?

A

Vasculature (inflammation)
Liver (induces APP)
Induction of cell death
Neutrophil activation
Cachexia

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51
Q

What is the function of IL-12?

A

NK cells
Promotes Th1 subset of T cells

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52
Q

What is the function of IL-6?

A

Liver (induces APP)
Influences adaptive immunity (proliferation and Ab secretion by B cells)

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53
Q

What is the function of IFN a/B?

A

Induces antiviral state
Activates NK cells

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54
Q

What are the four different families of chemokines?

A

CC
CXCRs
XCR1
CXXXC

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55
Q

Where do chemokines bind to?

A

GPCRs

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56
Q

What are the functions of chemokines and give examples:

A

They are chemotactic (attract cells)
IL-8 (CXCL8) attracts neutrophils
Monocyte Chemotactic Protein 1 (MCP1/CCL2) attracts monocytes
Eotaxin (CCL11) attracts eosinophils

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57
Q

What are adhesion molecules?

A

Transmembrane receptors that bind either to other cells or the extra cellular membrane
Allow leucocytes to attach and migrate on endothelial cell layer

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58
Q

What are the four main classes of adhesion molecules and give functions:

A

Ig superfamily (VCAM-1, ICAM-1, LFA-2)
Cadherins (E,P,N) cell to cell adhesion
Selectins (E,P,L) recognise carbs
Intergrins (8 sub-families e.g a4B1) ECM to cell

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59
Q

What are mettaloproteinases?

A

Proteases whose catalectic function requires metal, usually zinc

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60
Q

What are the three main families of metalloproteinases and give functions:

A

MMPs- degrade + remodel ECM, create chemokine gradient
ADAMS- cleave cytokine and adhesion molecule receptors from cell surface
ADAMTS- cleave receptors also, degrade proteoglycans

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61
Q

Name a different types of ECM proteins and their function:

A

Collagen I,II,III- fibrillar found in bone, skin, cartilage
Collagen IV- basement membrane
Laminin, Elastin, Proteoglycans, Fibronectin- provides layer on top of cells and allows cells to interact with each other

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62
Q

What is the function of NF-kB?

A

Family of transcription factors that regulate hundreds of pro-inflammatory mediators including cytokines, chemokines, MMPs etc

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63
Q

How does NF-kB become activated?

A

NFkB is bound to IkB (inhibitor of NFkB), it needs to be phosphorylated so NFkB can carry out its action
When DNA damaging agents are present, IkB kinase which are proteins that can phosphorylate IkB, degrade it so NFkB is released and can migrate to the nucleus
It binds to promotor sequences of transcription so drives some pro-inflammatory cytokines

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64
Q

Describe the second phase of inflammation:

A
  1. Phagocytes are attracted via chemokines/cytokines
    Phagocytes destroy MO and dead/mutated cells
  2. Tissue repair
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65
Q

Name 6 anti-inflammatory mediators produced by the body:

A

Anti-inflammatory cytokines e.g IL-10
Soluble adhesion molecules
TIMPs- inhibit MMPs
Plasmin activation system- clot recedes
Opioid peptides- counteract pain
Resolvins/ protectins- anti-inflammatory lipid mediators

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66
Q

What are the two types of inflammation?

A

Acute
Chronic

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67
Q

What does DMARDs stand for?

A

Disease Modifying Anti Rheumatic Drugs

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68
Q

Give examples of some DMARDs:

A

Methotrexate
Sulfasalazine
Gold compounds
Penicillamine
Chloroquine

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69
Q

What is the benefit of using DMARDS over NSAIDS?

A

NSAIDS only reduce the symptoms, but DMARDs aim to halt or reverse the underlying disease

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70
Q

Describe the brief way how methotrexate works:

A

A folic acid antagonist with cytotoxic and immunosuppressant activity

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71
Q

Why does methotrexate need to be monitored closely?

A

Bone marrow depression
Drop in white cell and platelet counts (fatal)
Liver cirrhosis

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72
Q

What are folates essential for in the body?

A

The synthesis of purine nucleotides and thymidylate, which in turn are essential for DNA synthesis and cell division

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73
Q

How do folate antagonists work?

A

Interfere with thymidylate synthesis
Methotrexate does this

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74
Q

What are the three structural elements of folates?

A

A pteridine ring
A p-aminobenzoic acid
Glutamic acid
Methotrexate is structurally similar

75
Q

Describe the uptake and metabolism of methotrexate:

A

It has a low lipid solubility so doesn’t readily cross the BBB
Actively taken up into cells by the folate transport system and metabolised by polyglutamate derivatives, which are retained in the cell for weeks even with the absence of the drug

76
Q

How does methotrexate work?

A

Blocks dihydrofolate reductase and there prevents nucleotide production

77
Q

Describe the structure of Ciclosporin:

A

Fungal metabolite
A and B, found that A more active so used
Cyclic peptide of 11 amino acid residues
Doesn’t follow Lipinskis rule but orally bioavailable as balance of hydrophobicity and hydrophilicity is sufficient to cross gut membrane

78
Q

What are the immunosuppressive functions of Ciclosporin?

A

Potent immunosuppressive but no effect on the acute inflammatory reaction, doesn’t entail cytotoxicity:
- Decrease clonal proliferation of T cells by inhibiting IL-2 synthesis and decreasing expression of IL-2r
- Decrease induction and clonal proliferation of cytotoxic T cells from CD8+ precursor T cells
- Reduced function of the effector T cells responsible for cell mediated response (decrease in delayed hypersensitivity)
- Reduction of T cell dependent B cell responses

79
Q

Describe the uptake of Ciclosporin:

A

After oral admin peak plasma conc are at 3-4 hrs and half life is 24 hrs
Accumulates in most tissue 3-4x more than in plasma

80
Q

State and describe the most common side effects of Ciclosporin:

A

Nephrotoxicity- unconnected with calcinerurin inhibition
Hepatoxicity and hypertension can also occur
No depressant affect on bone marrow

81
Q

What is the indication for Leflunamide?

A

Mainly to treat RA and occasionally to prevent transplant rejection

82
Q

What is the MoA of Leflunamide?

A

Has a really specific inhibitory effect on activated T cells
It is transformed to be a metabolite that inhibits de novo synthesis of pyrimidines by inhibiting dihydro-orotate dehydrogenase

83
Q

Describe the uptake of Leflunamide:

A

Orally active and well absorbed from the GI tract
Has a long t1/2, which leads to a risk fo cumulative toxicity
The active metabolite undergoes enterohepatic circulation

84
Q

What are some unwanted side effects of Leflunamide?

A

Diarrhoea
Alopecia
Raised liver enzymes and a risk of hepatic failure

85
Q

Describe the general mechanism of how DMARDs work:

A

Anti IL-2 agents, so decrease in IL-2 so no CD4 T cells, no Th1, so little activation of fibroblasts and osteoclasts so limit erosion of cartilage and bone as decrease in MMPs

86
Q

Name the different classes of anti-inflammatory agents:

A

COX inhibitors
Antirheumatic drugs (DMARDS)
Glucocorticoids
Anticytokines and other biopharmaceutical agents
Antihistamines
Drugs to specifically control gout

87
Q

What are lipooxygenases?

A

Several subtypes
Work sequentially to synthesise leukotrienes, lipoxins and other compounds

88
Q

How are prostaglandins made?

A

Stimulus activates phospholipase A2 to turn phospholipids into arachidonic acid
Which either go to lipooxygenases or prostaglandins by COX 1 and 2

89
Q

When is COX 1 present?

A

Present in most cells as a constitutive enzyme
It produces prostanoids that act mainly as homeostatic regs

90
Q

When is COX 2 present?

A

Isn’t normally present but is strongly induced by inflammatory stimuli- believed to be more relevant for AI drug
Exception in CNS and renal tissue as its always expressed in kidney as prostacyclin

91
Q

Describe how COX transforms archiadonic acid into prostaglandins:

A

Catalyse 2 molecules of oxygen with two of the unsaturated double bonds in each archidonate molecule, forming the highly unstable endoperoxides prostaglandin
PGG2 and PGH2 are rapidly transformed in a tissue specific manner by endoperoxide isomerase or synthase enzymes to PGE2, PGI2, PGD2 which are end products

92
Q

What are the actions of PGD2?

A

Causes vasodilation in many vascular beds
Inhibition of platelet aggregation
Relaxation of GI and uterine muscle
May also activate chemoattractant on some leukocytes

93
Q

What are the actions of PGI2?

A

Prostacyclin
Causes vasodilation and inhibition of platelet aggregation

94
Q

What are the actions of TXA2?

A

Causes vasodilation and inhibition of platelet aggregation and bronchoconstriction

95
Q

What are the actions of PGE2?

A

EP1- contraction of bronchial and GI SM
EP2 and 4- bronchodilation, vasodilation, stim of intestinal fluid secretion
EP3- contraction of intestinal SM, inhibition of gastric acid

96
Q

How are prostaglandins involved in acute inflammation?

A

PGE2 and PGI2 are generated by local tissues and blood vessels, mast cells release mainly PGD2

97
Q

How are prostaglandins involved in chronic inflammation?

A

Cells of the monocyte/ macrophage series also release PGE2 and TXA2
Together the prostanoids excert a sort of yin-yang effect in inflammation, stimulating some responses and decreasing others

98
Q

How can the inhibition of COX2 have an anti-inflammatory effect?

A

Decrease in PGE2 and PGI2 so decreases vasodilation and indirectly oedema

99
Q

How can the inhibition of COX2 have an analgesic effect?

A

Decreases PG means less sensitisation of nociceptive nerve endings to inflammatory mediators such as Bradykinin and 5-hydroxy tryptamine
Relief of headache is probably due to PG-mediated vasodilation

100
Q

How can the inhibition of COX2 have an anti-pyretic effect?

A

IL-1 releases PG in CNS, where they elevate the hypothalamic set point for temp control, causing fever, NSAIDs block this

101
Q

What are some unwanted side effects of NSAIDS and why?

A

Due to the COX inhibitors also inhibiting COX1:
Dyspepsia, nausea, vomiting and other GI effects due to suppression of gastroprotective PG in the gastric mucosa
Adverse CV effects, hypertension, inhibition of COX 2 in kidney
Skin reactions (mainly in mefamic acid and sulindac)
Bronchospasm, seen in aspirin sensitive asthmatics, coxibs uncommon

102
Q

What protective effects does COX 1 have?

A

Gastric cytoprotective by PG inhibiting acid secretion and protecting mucosa
Platelet aggregation
Renal blood flow autoregulation

103
Q

What prophylactic can be given with diclofenac to protect stomach issues?

A

Misoprostol

104
Q

What is the other name for aspirin?

A

Acetyl salicylic acid

105
Q

What are the unwanted side effects of aspirin?

A

Therapeutic doses: GI symptoms
Larger doses: Diziness, deafness, tinnitus
Toxic doses: uncompensated metabolic acidosis, particularly in children

106
Q

Why is aspirin not prescribed in paediatrics?

A

Linked with a rare but viral post-viral encephalitis (Reye’s syndrome)

107
Q

What is the consequence of taking aspirin and warfarin together?

A

Can increase the risk of bleeding

108
Q

For paracetamol, where is the inhibition mainly?

A

In the CNS enzymes

109
Q

What is the cause and treatment of toxic doses of paracetamol?

A

Liver damage by saturating normal conjugated enzymes, so the drug is converted to N- acetyl benzoquinone imine.
Needs to be inactived by conjugation with glutathione
IV acetylcysteine or oral methionine increases glutathione

110
Q

What joints does RA affect?

A

Synovial joints:
Hands, feet, knee and hip

111
Q

What is the epidemiology of RA?

A

Affects 0.3-1.5% of population (1% UK)
Most sufferers between 25 and 50
Ratio of women:men = 2-3: 1
Not racial or geographically different

112
Q

What genetic factors could affect the predisposition of getting RA?

A

70% of people with RA display HLA-DR4 gene
Other genes are STAT 4, TRAF1/C5 and PTPN22
MHC allele HLA-DRB1

113
Q

What environmental factors could affect their predisposition of getting RA?

A

Tobacco smoke or air pollution
Female hormones (oestrogen)

114
Q

Describe the first step in RA pathophysiology:

A

Initiator phase- unknown
Injury, infection, exposure to toxic substances?
APCs and citrillination of proteins, now seen as non-self

115
Q

Describe the second step in RA pathophysiology:

A

Inflammation phase- self antigens (citrillinated proteins) present
Leads to immune reaction:
-clonal expansion of T and B cells
-insufficiently controlled by T regs

116
Q

Describe the third step in RA pathophysiology:

A

Self perpetuating phase- inflammatory damage in synovial causes self antigens ‘unseen’ by immune system to be exposed so, immune response against cartilage, infiltration of immune cells

117
Q

Describe the fourth step in RA pathophisiology:

A

Destruction phase- synovial fibroblasts and osteoclasts activated by cytokines (TNF, IL6) so leads to destruction of bone and cartilage

118
Q

How are B cells and macrophages involved in RA?

A

B cells produce autoantibodies which can activate complement and also bind to activated macrophages in synovium
Activated macrophages perpetuate inflammation

119
Q

How are autoantibodies involved in RA?

A

Rheumatoid factor and anti-citrullinated peptides are directed against antigens commonly present outside the joint

120
Q

How are T cells involved in RA?

A

Activate macrophages and synoval fibroblast which produce TNFa, IL-1 and IL-6, which produce MMPs which degrade cartilage
Joint destruction may be caused by CD4 T cell cytokine, RANK ligand, this promotes osteoclasts

121
Q

Why is RA associated with co-morbidities?

A

Because IL-6 (iron redistribution in liver), TNAa, IL-1 (insulin resistance) etc are produced in joint, these release systemic cytokines

122
Q

When are ‘coxibs’ usually offered?

A

For patients for whom treatment with conventional NSAIDs would pose an increase probability of serious GI SEs even though they can still occur in ‘coxibs’

123
Q

What is a chimeric antibody?

A

The variable regions have been spliced out and a mouse variable region has been added

124
Q

What is a humanised antibody?

A

Splice in complementary determining regions, key sequences within that region which are responsible for antigen binding

125
Q

What are full human antibodies?

A

With no mouse sections

126
Q

What is true about the suffix of all monoclonal antibodies?

A

They have the suffix ‘mab’

127
Q

Name the cell origins a monoclonal antibody can have and how to know:

A

The suffix before the ‘mab’
-u- = human
-o- = mouse
-xi- = chimeric
-zu- = humanised
-xi-zu- = hybrid of chimeric and humanised

128
Q

Name the letters that can be included in the name of the monoclonal antibody to show the disease targets:

A

-im- = immune
-es- = infectious diseases
-vir- = viral
-mel- = melanoma
-col- = colon

129
Q

Name three biologics which block cytokine signalling:

A

Tocilizumab
Rituximab
Abatucept

130
Q

How does Tocilizumab work?

A

Anti IL-6
Binds to IL-6 receptor so IL-6 can’t bind to its receptors blocking response to IL-6

131
Q

How does Rituximab work?

A

Binds to an antigen present on the surface of pre and mature B lymphocytes (CD20), so leads to B cell depletion

132
Q

How does Abatacept work?

A

Fc region of an antibody on bottom but top part is of a recombinant protein (fusion)
Blocks the interaction between APC and T cell, inhibits co- stim signals (CD80/CD86) which are essential for T cell activation

133
Q

Where can TNF bind to?

A

TNFR1 and TNFR2

134
Q

What are some important roles of TNF?

A

Differentiation factor for monocytes to macrophages
Cytokine in inducing a difference for intracellular pathogens
GF for both T and B cells
Signals through TFs like NFkB, so can induce expressions of the other cytokines
Pro thrombotic action (increase platelet aggregation)
Increase adhesion of endothelial cells (ICAM/VCAM), so can interact with leukocytes

135
Q

Name 3 Anti-TNFa strategies:

A

Infliximab (IV)
Adalimumab (SC)
Entanercept (SC)- Fusion protein

136
Q

What are biosimilars?

A

A biological product that is highly similar and has no clinically meaningful differences from an existing FDA approved product

137
Q

What are the roles of adhesion molecules?

A

To stop macrophages, so they roll on the endothelial cell layer and enter the tissue

138
Q

What is the purpose of soluble adhesion molecules?

A

They can bind to adhesion molecules preventing cells from binding to them, causing them to be saturated

139
Q

Which bacteria is most likely to cause a fever and why?

A

Gram -ve
Lipopolysaccharides (endotoxins) on wall of bacteria are good at attracting and activating macrophages, so these endotoxins promote macrophage to release IL-1

140
Q

What is Myasthenia Gravis?

A

Characterised by the weakness of skeletal muscle

141
Q

What is the brief main MoA in Myasthenia Gravis?

A

Autoantibodies are made to the nicotinic acetylcholine receptor in skeletal muscle therefore transmission through the neuromuscular junction is decreased

142
Q

What is the epidemiology of Myasthenia Gravis?

A

Incidence: 5.3 in every million/ year (how many ppl get it each year)
Prevalence: 77 in every million (how many ppl living with it)
Mortality 0.1-0.9 in every million per year
UK prevalence is 15 per million

143
Q

Why is the epidemiology of Myasthenia Gravis likely to be an underestimate?

A

Due to the lack of diagnosis in older patients as they can experience similar symptoms and be understood e.g stroke

144
Q

What is the aetiology of Myasthenia Gravis?

A

Causes/ risk factors:
Age: females peaks at 20-30 years
males peaks at 60-80 years
Risk is higher in young females than males
Causes is largely unknown

145
Q

What are the main symptoms of Myasthenia Gravis?

A

Usually patients present with ocular symptoms:
Drooping eyelids (ptosis)
Double vision (diplopia)
Restricted eye movements (worsen when tired)

146
Q

What are other non ocular symptoms of Myasthenia Gravis?

A

Lack of facial expression
Slurred speech
Difficulties chewing
Difficulties swallowing (dysphagia)
Weakness in arms/ legs/ neck

147
Q

What is Myasthenic crisis?

A

Affects 20% of patients at some point
Shortness of breath which can be severe
Needs mechanical ventilation- medical emergency
Acute respiratory failure- diaphragm is skeletal muscle, no transmission here through NMJ

148
Q

Why can it be difficult to diagnose MG?

A

Symptoms can fluctuate

149
Q

Name 5 tests for MG:

A

Ice test
Blood test for autoantibodies
Neurophysiology
Edrophonium test
CAT scan to rule out thymoma

150
Q

Describe the Ice test to test for MG:

A

Put ice on the muscles affected and this should improve symptoms
It is simple and cheap

151
Q

Describe neurophysiology tests to test for MG:

A

Electromyogram measures the muscle compound action potential in response to repeated stimulation
See a decrease in the size of the muscle response in MG

152
Q

Describe the Edrophonium test to test for MG:

A

Edrophonium is a short acting cholinesterase inhibitor
Injection of edrophonium causes increase in muscle strength (ptosis is reversed)
Rarely used due to SEs

153
Q

Describe where MG initiates and does it progress to different parts of the body?

A

Usually starts with ocular symptoms but then progresses to affect other muscles
80% of pts show progression
Progression can be rapid (weeks) or slow (years)

154
Q

Name and describe the treatments for MG:

A

First line- acetylcholinesterase inhibitors e.g Pyridostigmine
Can be given with immunosuppressive therapy:
-oral steroids -other immunosuppressants e.g azathioprine
IV Ig or plasma exchange:
-only for rapidly deteriorating MG or myasthenic crisis
Thymectomy

155
Q

Describe the events at the NMJ:

A

AP opens voltage gated Ca2+ channels, Ca2+ goes into the synaptic terminal therefore exocytosis of Ach which diffuses across the synaptic cleft and interacts with nicotinic Ach receptors
Opens ligand gated ion channels which allows Na into the muscle cell, then enters the action potential and contraction of muscle

156
Q

Which muscles are affected most in MG?

A

The muscles in most use
Giving lots of facial symptoms as has more than 40 different muscles

157
Q

Describe the function of Ach esterase at the NMJ:

A

AchE breaks down the Ach which is important in terminating the contraction therefore causing muscle to relax
It breaks it down into choline and acetate where the choline is taken back into the pre-synaptic terminal where it can be used again

158
Q

How is the thymus gland related to MG?

A

Disease is sometimes accompanied by a tumour of the thymus gland and removal of the thymus may improve motor symptoms

159
Q

How is Ach synthesised?

A

Choline acetyl transferase, choline into Ach and is stored in vesicles

160
Q

Name 4 AchE inhibitors and why would they work?

A

Inhibition of AchE causes an increase in Ach at the synaptic cleft prolonging its activity
Neostigmine, Pyridostigmine - MG
Malathion- insecticide (headline)
Donepezil - Alzheimers disease

161
Q

Name 2 different types of cholinesterases:

A

AchE
Butyrylcholinesterase (BuChE)

162
Q

Describe Acetylcholinesterase:

A

Can be membrane bound (synaptic cleft) or in soluble form (pre-synaptic terminal, cerebrospinal fluid)
Found at Ach synapses
Specific for Ach

163
Q

Describe BuChE:

A

Widespread distribution - plasma, liver, skin
Broader substrate specificity
Genetic variant for BuChE activity (reduced activity)

164
Q

What are the 3 main groups of cholinesterase inhibitors and give examples:

A

Short acting- edrophonium
*Medium acting- Neostigmine, pyridostigmine, donepezil
Irreversible- malathion, pyflos, Novichok

165
Q

What are irreversible cholinesterase inhibitors and why can one be used in treatment?

A

Poisons, not used therapeutically
Malathion can be used as an insecticide due to low conc being used as insects are very sensitive to this without affecting humans

166
Q

What are the main systems in the body where cholinesterase has an affect on and therefore what does the inhibitor target?

A

Skeletal muscle in somatic efferent system
Salivary glands/smooth muscle/ heart/ other glands in parasympathetic system
Parasympathomimetic- selectivity for parasympathetic, mimicking what the ns normally does (rest and digest)

167
Q

How does neostigmine and pyridostigmine increase twitch tension?

A

As more Ach, due to less AchE, more muscle contraction

168
Q

What CV effects do cholinesterase inhibitors have?

A

Bradycardia (decrease HR)
Decrease cardiac output
Vasodilation of arterioles (release of NO) therefore decreases BP

169
Q

What smooth muscle effects do cholinesterase inhibitors have?

A

Contraction of SM (except vascularism)
Increase peristaltic activity (gut motility)
Increase contraction of bladder (emptying)
Contraction of bronchioles

170
Q

Why eye effects do cholinesterase inhibitors have?

A

Pupil constriction
Constriction of ciliary muscle (glaucoma)

171
Q

What gland effects do cholinesterase inhibitors have?

A

Increase secretion (salivation, lacrimation, bronchial secretion, digestive enzymes, sweating)

172
Q

How can cholinesterase inhibitors have central effects and why is this beneficial/ not?

A

They can cross the BBB
Increase cognition (therapeutic)- Alzheimers
Convulsions, unconsciousness, resp failure (toxic)

173
Q

What can be some triggers for MG?

A

Infection
Stress/trauma
Thyroid dysfunction
Withdrawl of AchE inhibitor
Rapid intro or increase corticosteroids
Anaemia
Electrolyte imbalances
Medicines

174
Q

What should be the measures taken with infection for someone who has MG?

A

They should have the annual flu and one off pneumococcal vaccination
Ensure the patient with the infection is receiving the correct drug and is working properly

175
Q

What should be the measures taken with thyroid function for someone who has MG?

A

See effects of drugs which could cause thyroid imbalances

176
Q

Name 2 oral acetylcholinerase inhibitors and which one is preferred and why?

A

Pyridostigmine
Neostigmine- used less due to shorter duration of action

177
Q

Describe the dosing of Pyridostigmine:

A

Starting at 15mg QDS with food
Assess cholinergic side effects
Typical maintenance at 60mg 4 to 6 times a day

178
Q

What are the adverse side effects of pyridostigmine?

A

Nicotinic and muscarinic effects which are dose dependent
Nicotinic- muscle and abdominal cramps
Muscarinic- gut hyper-mobility (cramps and diarrhoea), increase sweat/ salivations/ lacrimation, hypotension, bradycardia, mitosis (pupil constriction), urinary incontinence, tachypnea

179
Q

What is cholingergic crisis?

A

The result of excess AchE treatment
This causes weakness and is hard to distinguish from worsening MG
With the prescribed dose this is rarely seen if ever

180
Q

What would be the management options for the side effects of pyridostigmine?

A

Taking with food can mitigate GI SEs
Co-prescribing oral anti-cholinergic drugs (have no or little effect on nicotinic receptors but can decrease SEs e.g glycopyrrolate, propantheline)
Diarrhoea can be controlled by loperamide

181
Q

How does anti-costimulation e.g Abatacept work?

A

Recombinant fusion protein that inhibits co-stim T cell signals

182
Q

How do anti-CD20 biologics work?

A

Chimeric MAB that binds to the CD20 portion on B lymphocytes

183
Q

Name 2 JAK inhibitors:

A

Tofacitinib
Bariotinib

184
Q

Describe the STAT JAK signalling pathway:

A

Cytokine binds to receptor
Tyrosine kinase receptors undergo receptor dimerisation and are associated with JAK proteins, once receptors ligand binds the JAKs can phosphorylate the receptor
These phosphorylation sites can attract other proteins e.g STAT
The STAT dimer is formed which then travels to the nucleus and binds to DNA and activates gene transcription
These help relay the message to the nucleus to other cytokines

MPharm Y3S1 (13 decks)

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