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MODA MVST1b > Inflammation and Immunosuppression > Flashcards

Inflammation and Immunosuppression Flashcards

1
Q

Omalizumab

A

mAb against IgE, used to treat dermatographic urticarial and allergic asthma
Binds to Cepsilon3 region of IgE (heavy chain) so prevents IgE binding to FcepsilonRI
Built on an IgG framework so doesn’t activate FcepsilonRI itself
Injection every 2-4w

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2
Q

Sodium cromoglyate

A

Reduces Ca2+ influx into mast cells, prevents degranulation. In eye drops for hayfever and used for mastocytosis, and occasionally asthma

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3
Q

Salbutamol

A

Short-acting beta2 adrenoceptor agonist, used as needed in treatment of asthma
Maximum effect in 30min
Duration of action 3-5hrs

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4
Q

Formoterol

A

Long-acting beta2 adrenoceptor agonist, prophylactic use in the treatment of asthma
Duration of action 8-12 hours
Long lipophilic tail enables it to be incorporated into the plasma membrane, which acts as a drug reservoir, and also the long tail binds to an extra binding site on the beta2 aidrenoceptor itself

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5
Q

Theophylline

A

PDE inhibitor producing increased cAMP, used prophylactically in treatment of asthma/COPD

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6
Q

Mepyramine

A

1st generation H1 receptor antagonist, crosses BBB causes drowsiness, used topically to treat insect bites.

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7
Q

Terfenadine

A

2nd gen H1 antagonist, inhibited hERG causing long QT syndrome and so no longer used. Prodrug metabolised by Cytochrome p450 3A4 to fexofenadine (the active compound).

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8
Q

Fexofenadine

A

3rd gen anti-histamine. Non-drowsy, no cardiac side effects. Used to treat hayfever and urticaria.

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9
Q

Loratidine

A

3rd gen anti-histamine, non-drowsy, used to treat hayfever and urticaria.

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10
Q

Adrenaline

A

Used to treat anaphylactic shock

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11
Q

Hydrocortisone

A

Corticosteroid used as anti-inflammatory. Short t1/2 <24h

Inhibits neutrophil degranulation

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12
Q

Imatinib

A

RTK inhibitor used in treatment of human mastocytosis. Ineffective in treatment of people with common D816V c-kit mutation.

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13
Q

Oclacitinib

A

Treatment of atopic dermatitis in dogs. Inhibits JAK, greatest specificity for JAK1, which is common to many signalling pathways associated with allergic skin diseases - so lowers proinflammatory signalling.

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14
Q

Proglumide

A

CCK2 receptor antagonist that produces an inhibition of histamine release from ECL cells

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15
Q

Cimetidine

A

H2 receptor antagonist, inhibits cytochrome p450, replaced by ranitidine

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16
Q

Ranitidine

A

H2 receptor antagonist, used in treatment of peptic ulcers

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17
Q

Omeprazole

A

PPI used in treatment of peptic ulcers.

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18
Q

Clarithromycin

A

Macrolide antibiotic used to eradicate H. pylori

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19
Q

Misoprostol

A

Synthetic PGE1 analogue acts to decrease ECL histamine release in treating peptic ulcers.

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20
Q

Arthrotec

A

Combination of misoprostol and diclofenac, used in chronic treatment of rheumatoid arthritis to prevent peptic ulcer formation. Misoprostol acts as a prophylactic agent against NSAID-induced ulceration.

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21
Q

Diclofenac

A

NSAID used in treating chronic inflammation

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22
Q

Ecallantide

A

Kallikrein inhibitor used in the treatment of HAE.

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23
Q

Tanezumab

A

Anti-NGF antibody, in clinical trials for treating OA

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24
Q

Bufexamac

A

LTA4 hydrolase inhibitor, can be used as an anti-inflammatory agent

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25
Q

Montelukast

A

CysLT1 receptor antagonist, used in treatment of asthma

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26
Q

Ibuprofen

A

Non-selective COX inhibitor, used as analgaesic, anti-pyretic and anti-inflammatory.

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27
Q

Etoricoxib

A

COX2 selective inhibitor, reserved for chronic inflammation in patients thought not to have substantial cardiovascular risk

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28
Q

Aspirin

A

Irreversible NSAID (acetylates ser530) that is used additionally to lower the risk of platelet aggregation.

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29
Q

Naproxen

A

NSAID

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30
Q

Paracetamol

A

Analgesic/anti-pyretic COX inhibitor that doesn’t cause the anti-inflammatory actions of classical NSAIDs.

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31
Q

Acetylcysteine

A

Increases hepatic glutathione production following paracetamol OD

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32
Q

Phenylbutazone

A

NSAID used mainly in horses, many side effects in humans

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33
Q

Robenacoxib

A

COX2 selective inhibitor used in cats and dogs

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34
Q

Firocoxib

A

COX2 selective inhibitor used in dogs and horses

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35
Q

Ondansetron

A

5-HT3 receptor antagonist used to prevent and treat vomiting

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36
Q

Cyclizine

A

H1 receptor antagonist used as an antiemetic

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37
Q

Scopolamine

A

Non-specific muscarinic receptor antagonist, acts via M1 to inhibit nausea and vomiting

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38
Q

Domperidone

A

D2 receptor antagonist, anti-emetic. More peripherally selective than metoclopramide, so produces acute dystonia less frequently

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39
Q

Metoclopramide

A

D2 receptor antagonist, used to treat nausea/vomiting. Can cause acute dystonia

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40
Q

Sumatriptan

A

5-HT1B/D/F agonist used in treatment of migraine
Side effect of peripheral vascular vasoconstriction, so contraindicated in coronary disease
Poorly absorbed when taken orally
Doesn’t cross BBB
Short duration of action
Available in nasal spray and subcutaneous injection

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41
Q

Lasmiditan

A

5-HT1F agonist being developed for potential use in treatment of migraine

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42
Q

Naratriptan

A

5-HT1B/D/F agonist used in treatment of migraine
Longer duration of action
Can cross BBB
Fewer cardiac side effects

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43
Q

Propanolol

A

Non-selective beta-adrenoceptor antagonist used prophylactically in migraine

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44
Q

Amytripyline

A

Antidepressant used, at lower concs, as a migraine preventative (inhibition of VGSC and inhibition of NET/SERT), also sedative and dry mouth due to anticholinergic action

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45
Q

Topirimate

A

Anti-epileptic, also used prophylactically in migraine, acts on numerous ion channels including inhibiting VGSC and facilitating GABAA
Side effects tingling in hands and feet

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46
Q

Pizotifen

A

serotonin antagonist that blocks 5-HT2A and 2B receptors, used in migraine prevention

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47
Q

Botulinum toxin A

A

Disrupts synaptic vesicle release by cleaving SNAREs, used prophylactically in migraine

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48
Q

Erunumab

A

mAb against CGRP, in development for use against migraine

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49
Q

Prednisolone

A

Corticosteroid - binds to glucocorticoid receptors, used as anti-inflammatory and immunosuppression.

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50
Q

Betamethasone

A

Corticosteroid, used as anti-inflammatory

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51
Q

Dexamethasone

A

Corticosteroid, anti-inflammatory, binds to glucocorticoid receptors, used as an anti-inflammatory and in immunosuppression. Long lasting t 1/2 > 48h

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52
Q

Indacaterol

A

Ultra long acting beta2 adrenoceptor agonist, used in the treatment of COPDb

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53
Q

Beclomethasone

A

Corticosteroid, used as anti-inflammatory, commonly as an inhalable corticosteroid
Prophylactic treatment of asthma

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54
Q

Ipratropium

A

Non-selective muscarinic antagonist, used in treatment of asthma and COPD

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55
Q

Fluticasone

A

Corticosteroid, can be used as anti-inflammatory in cats/horses

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56
Q

Clenbutarol

A

Long acting beta2 adrenoceptor agonist used in treatment of recurrent airway obstruction in horses

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57
Q

Tiotropium

A

Long acting muscarinic antagonist used in the treatment of COPD

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58
Q

Roflumilast

A

Selective PDEIV inhibitor approved in treatment of COPD

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59
Q

Methotrexate

A

DHFR inhibitor used as a DMARD in rheumatoid arthritis

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60
Q

Sulfasalazine

A

DMARD
Administered orally, broken down by colonic bacteria to sulfapyridine and 5-amino salicylic acid
The acid scavenges ROS from nphils
Daily tablet
Don’t see therapeutic benefit for 3 months+
GI disturbances, skin rash, bone marrow suppression, hepatotoxicity, tears and contact lenses stained yellow, urine orange

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61
Q

Hydroxychloroquine

A

DMARD and anti-lupus drug
Weak base so accumulates in cytoplasmic acidic vesicles
Reduces Ag presentation by mphages and neutrophil ROS generation
Side effects ocular toxicity, GI upset, skin reactions, seizures, myopathy and psychiatric disturbance

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62
Q

Azathioprine

A

Prodrug for 6-mercaptopurine. Inhibits DNA synthesis in cells lacking a nucleotide salvage pathway (B and T cells) - used as an immunosuppressant
DMARD
Side effects: bone marrow suppression, hepatotoxicity, GI upset

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63
Q

Leflunomide

A

Inhibits dihydroorotate dehydrogenase and thus pyrimidine synthesis.
Main effect on rapidly dividing cells like B and T cells
used in RA
Adverse effects GI disturbance, bone marrow suppression, hepatotoxicity

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64
Q

Penicillamine

A

DMARD, may act by decreasing IL1 synthesis and collagen maturation
Rarely used for RA now
Has chelator properties so also sued following heavy metal poisoning and in Wilson’s disease
Side effects rashes, GI disturbance, bone marrow suppression, disturbances in taste

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65
Q

Auranofin

A

DMARD, unknown mechanism. Appears to inhibit IL1 and TNFalpha induction.
Side effects skin rashes, mouth ulcers, chrysiasis after long-term use (permanent grey/blue skin colouration)
Now rarely used as RA inhibitors

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66
Q

Etanercept

A

Fusion product of the soluble TNFalpha receptor and IgG1, used in RA

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67
Q

Infliximab

A

Chimeric anti-TNFalpha mAb, used in RA

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68
Q

Adalimumab

A

Human anti-TNFalpha mAb, used in RA

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69
Q

Tocilizumab

A

Anti IL6 receptor mAb, used in RA

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70
Q

Rituximab

A

Anti CD20 mAb, causes B cell destruction, used in RA

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71
Q

Abatacept

A

synthetic fusion protein of the costimulkatiory CTLA4 with an IgFc fragment. Interferes with T cell activation, so used in treatment of RA.

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72
Q

Anakira

A

Recombinant IL-1 receptor antagonist used in RA

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73
Q

Capsaicin

A

TRPV1 agonist used in osteoarthritis

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74
Q

IRAP

A

IL1 receptor antagonist protein, used to treat osteoarthritis in horses

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75
Q

Insulin lispro

A

Fast acting insulin used to treat DM
Analogue swapping of lys and pro towards C terminus of B chain
Reduces dimer and hexamer formation so larger amounts of active monomeric insulin are available after injection
Onset 5-15mins, duration 4-6h

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76
Q

Insulin actrapid

A

Short acting insulin, used to treat DM

Onset 30-60 mins, duration 8-10h

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77
Q

NPH insulin

A

Intermediate acting insulin used to treat DM
Neutral protamine hagedorn
Suspension of protamine polypeptide and insulin that forms relatively insoluble crystals, thus slowing absorption
Onset 2-4h, duration 12-18h

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78
Q

Glargine

A

Long acting insulin used to treat DM
AA changes to A and B chains change isoelectric point to more neutral
When injected subcutaneously, forms a microprecipitate of stable hexamers and higher aggregates, which retard and prolong absorption
Onset 2-4h, duration 20-24h

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79
Q

Metformin

A

Numerous beneficial effects in treating Type 2 DM, many involving activation of AMPK, the cellular energy sensor.
Decreased hepatic gluconeogenesis
Increased glucose uptake skeletal muscle
Decreased intestinal carbohydrate absorption
Decreased circulating levels VLDL and LDL
Decrease appetite

side effects: NOT hypoglycaemia: GI disturbances, lactic acidosis as inhibits hepatic lactate uptake, so alcoholics or people with renal dysfunction shouldn’t take metformin

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80
Q

Glibenclamide

A

Sulfonylurea used to inhibit KATP to enhance insulin release. Used in treatment of Type 2 DM.
Bind to SUR1 subunit of KATP channels, causes closure, triggering dep, Ca2+ influx and insulin release
Significant conversion to active products in the liver before urinary excretions, so action potentiated in people with renal inefficiency
Can cross placenta so contraindicated in pregnancy and breastfeeding
Possible interaction with SUR2A in heart

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81
Q

Glipizide

A

Sulfonylurea used to inhibit KATP to enhance insulin release. Used in treatment of Type 2 DM.
Bind to SUR1 subunit of KATP channels, causes closure, triggering dep, Ca2+ influx and insulin release
Mainly metabolised in liver to inactive products and excreted in urine
Can cross placenta so contraindicated in pregnancy and breastfeeding

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82
Q

Repaglinide

A

Meglitinide compound, inhibits KATP enhancing insulin release, used to treat type 2 DM.
Also binds to SUR1
Lower risk of hypoglycaemia
Faster onset and offset kinetics than sulfonylureas

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83
Q

Exenatide

A

Mimics effect of GLP-1 but longer acting, to stimulate insulin release/inhibit glucagon release. Used to treat type 2 DM.

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84
Q

Sitagliptin

A

Inhibits DPP-4 and thus slows GLP1/GIP breakdown. Used to treat Type 2 DM.

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85
Q

Dapagliflozin

A

SGLT2 inhibitor (the kidney PCT one), used to treat Type 2 DM.

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86
Q

Pioglitazone

A 
Activates PPARgamma TF in adipose tissue/liver/muscle 
Increased lipogenesis
Glucose/fatty acid uptake
Increased transcription GLUT4
Treatment type 2 DM
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87
Q

Acarbose

A

alpha-glucosidase inhibitor used in treatment of type 2 DM.
Slows the breakdown of starch/disaccharides into glucose in the GI tract
Reduce the amount of glucose entering the bloodstream

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88
Q

Belimumab

A

Anti-BLyS mAb used in SLE.

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89
Q

Mycophenolic acid

A

Inhibits IMPDH, crucial for guanosine synthesis, used as an immunosuppressant

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90
Q

Cyclophosphamide

A

Alkylating agent, kills dividing T and B cells, used as an immunosuppressive
Prodrug for phosphoromide mustard

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91
Q

Ciclosporin A

A

Drug binds to cyclophilin CpN which forms a CsA-CpN complex
CsA-CpN complex binds to and inhibits CaN
Prevents NF-AT dephosphorylation, retained in cytoplasm
IL2 depressed
Used as immunosuppressant suppressing rejection of transplanted organs

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92
Q

Tacrolimus

A

Macrolide antibiotic
Binds to FKBP, binds to and inhibits CaN, retains NF-AT in cytoplasm, inhibits IL2 transcription, can be used as an immunosuppressant in organ transplantation

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93
Q

Basiliximab

A

mAb against CD25 alpha subunit of the IL2 receptor, used as an immunosuppressant
IL2R found on activated T and B cells

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94
Q

Belatacept

A

Fusion protein of CTLA4 (which binds to CD80/86 and sends an inhibitory signal to the T cell) and IgG1.
Used as immunosuppressant

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95
Q

Sirolimus

A

Binds to FKBP, inhibits mTOR
mTOR is a ser/thr kinase involved in cell cycle progression and protein synthesis
Results in decreased T cell activation and proliferation and a decreased immune response
decreased T cell activation/proliferation, used as immunosuppressant
Coating of coronary stents to prevent restenosis
= Rapamycin

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96
Q

Muromonab-CD3

A

Anti-CD3 mAb, used to reduce acute transplant rejection

Murine

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97
Q

Alemtuzumab

A

mAb, binds to CD52 (on mature lymphocytes but not the stem cells they came from), used in treating chronic lymphocytic leukaemia, cutaneous T-cell lymphoma and T-cell lymphoma

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98
Q

Catumaxomab

A

Bifunctional mAb, anti-epCAM on cancer cells and anti-CD3 on T cells, used to treat acites in cancer patients

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99
Q

Trastuzumab

A

anti-HER2 mAb, used to treat HER2 positive breast cancers

Disruption of HER2 signalling and targeting tumour cells for ADCC

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100
Q

Trastuzumab emtansine (T-DM1)

A

anti-HER2 mAb coupled to antimicrotubule compound maytansine (DM1), used to treat HER2 positive breast cancers
Binding of T-DM1 to HER2 –> internalisation, lysosomal degradation –> release of DM1- -> bind to tubulin and prevent polymerisation causing cytotoxicity
Also just trastuzumab actions: disruption of HER2 signalling and targeting tumour cells for ADCC

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101
Q

What are the four signs of inflammation?

A

Redness
Swelling
Heat
Pain

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102
Q

What causes inflammation?

A
  1. Noxious stimulation
  2. Bacterial/viral/fungal infection
  3. Autoimmune reactions
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103
Q

What is the triple response of Lewis?

A
  1. Flush - due to local release of vasodilator substances such as histamine
  2. Flare - 30-60s post inflammation redness spreads to surrounding area because of neurogenic inflammation
  3. Wheal - localised swelling due to histamine causing increased vascular permeability
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104
Q

Define neurogenic inflammation

A

Stimulated branch of a sensory nerve will send an action potential to the branching point, which travels both orthodromically to the spinal cord –> pain and antidromically —> collateral branches to result in the release of CGRP and substance P –> directly cause vasodilation, and substance P is also a potent activator of mast cell degranulation –> local production of histamine –> vasodilationa nd increased vascular permeability

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105
Q

Why does increased vascular permeability cause swelling?

A
  1. Plasma leaks into extracellular space

2. Plasma has higher tonicity compared to ECF so pulls water out of cells

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106
Q

What receptor mediates inflammation?

A

H1

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107
Q

What is dermatographic urticarial?

A

Condition where the triple response is exaggerated
Idiopathic
Treat with H1 receptor antagonists, and omalizumab MAb against IgE, decreases mast cell activation

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108
Q

Discuss the toxin alpha haemolysin

A

UPEC
Ca2+ oscillations in cells –> induce synthesis of proinflammatory cytokines IL6 IL8
Lyses host cells
Activate innate and adaptive immune system

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109
Q

Give a theory of why autoimmune reactions occur

A

Pathogen with an Ag similar to a protein expressed by the host triggers an immune attack, initially against the pathogen, but then continues to attack host tissues after the pathogen has been destroyed

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110
Q

What does TLR stim by PAMPS cause sentinel cells to release?

A

Proinflammatory mediators:
Prostaglandins PGE2/PGI2 - vasodil
Histamine - vasodil vascular perm
TNFalpha, IL-1 - produce further cytokines, vasc perm and expression of adhesion molecules on the intimal surface of postcapillary venules

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111
Q

What are the 4 proteolytic systems in exudate?

A
  1. Coagulation
  2. Fibrinolysis
  3. Kinin
  4. Complement
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112
Q

What does bradykinin do?

A 
Vasodilator
Increases vascular permeability
Spasmogen
Causes pain
Generates eicosanoids
Stim endothelial NO synthesis
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113
Q

What does C3a do?

A

Releases histamine from mast cells

Spasmogen

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114
Q

What does C5a do?

A

Chemotaxin + activates WBCs
Activates phagocytic cells
Releases histamine from mast cells

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115
Q

What triggers C3 –> C3b?

A
  1. Classical/Lectin pathway C1 C4 C2
  2. Alternative pathway Spontaneous
  3. Thrombin
  4. Plasmin
  5. Neutral proteases from phagocytic cells
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116
Q

What activates factor XII?

A

Contacting negatively charged substances like collagen

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117
Q

What makes up the MAC?

A

1 x C5b, C6, C7, C8

12-18 x C9

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118
Q

How do neutrophils get to a bacterium in the extracellular space?

A
  1. Capture Sialyl Lewis X and PSGL1 to P selectin
  2. Tight adhesion LFA-1 to ICAM-1
  3. Extravasation PECAM1 + integrins
  4. Chemotaxis C5a fMLF
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119
Q

How is histamine made?

A

Histidine - histidine decarboxylase

4 cells: mast cells, basophils, ECL in gut and histaminergic neurons in the brain

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120
Q

How is histamine packaged in basophils?

A

Acidic granules with HMW heparin called macroheparin

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121
Q

How is histamine released?

A

Ca2+ i increase leads to exocytosis

  1. C3a/C5a –>Gi –> betagamma –> PLCbeta –> IP3 –> increase Ca2+i
  2. Substance P –> Mas-related gene X2 MrgX2 receptors –> Gq –> PLCbeta –> IP3 –> increase Ca2+i
  3. IgE cross linking with FCepsilonRI due to allergens –> phos of LAT adaptor protein linker for activation of t cells –> PLCgamma –> IP3 –> Ca2+ release
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122
Q

What are the four Histamine receptors and what is their coupling?

A

H1 Gq/11 so PLCbeta IP3 DAG/PKC - inflammation
H2 Gs AC increase cAMP/PKA increase - gastric acid secretion
H3 Gi AC decrease cAMP/PKA decrease - inhibitory autoreceptor in CNS
H4 Gi AC decrease cAMP/PKA decrease - chemotaxis/cytokine release

123
Q

Which histamine receptor mediates smooth muscle contraction in the ileum, bronchioles and uterus?

124
Q

What are the itching receptors called?

A

Prutritoceptors H1

125
Q

Which histamine receptor is on the heart, causing increased HR?

126
Q

How is histamine metabolised?

A

Histaminase –> imidazole acetaldehyde

Histamine N-methyltransferase –> transfer of methyl group to nitrogen of imidazole ring to produce NT-methylhistamine

127
Q

What is allergic rhinitis?

128
Q

What is mastocytosis?

A

Too many mast cells present, excessive allergic-type reactions
Often due to C-Kit gain of function mutation
Dark skin
Test = for elevated serum tryptase

129
Q

How do you treat H1 histamine pathology?

A
  1. Sodium cromoglycate
  2. Beta2 agonist salbutamol, formoterol
  3. ACE inhibitor theophylline
  4. Antihistamine 1st gen mepyramine, 2nd gen terfenadine , 3rd gen fexofenadine, loratidine
  5. Adrenaline
  6. Hydrocortisone
  7. RTK inhibitors imatinib (ckit inhibitor)
  8. JAK1 inhibitor oclacitinib
130
Q

Which two cell types are involved in gastric ulcer formation?

A
  1. Parietal cells - secrete HCl into the stomach
  2. Mucus-secreting cells: secrete bicarbonate ions into mucus to create a protective pH 6-7 barrier at the mucosal surface
131
Q

What is the histamine H2 pathway from stim of synthesis to effect?

A

G cells –> gastrin –> CCK2R –> ECL cell –> histamine –> H2R–> parietal cell –> more H+/K+ antiporters

132
Q

What is the histamine H2 pathway from stim of synthesis to effect? Draw it

A

G cells –> gastrin –> CCK2R –> ECL cell –> histamine –> H2R–> parietal cell –> more H+/K+ antiporters

133
Q

What is the coupling of M3?

134
Q

How do NSAIDs act on ECL cells?

A

Inhibit AA –> PGE2
PGE2 normally acts on: EP2/3R to inhibit gastric acid secretion (histamine release?), EP4R to enhance mucin secretion, EP1/2R to enhance HCO3- secretion

135
Q

How do drugs inhibit gastric acid secretion?

A
  1. H2 receptor antagonists
  2. PPI omeprazole
  3. Stop using NSAIDs!
  4. Synthetic PGE1 Misoprostol
  5. Clarythromycin - treat H pylori
  6. Vagotomy/Atropine - M3R inhibition
  7. Antacids gaviscon
  8. Proglumide inhibit CCK2R on ECL (how gastrin acts)
136
Q

Draw the synthesis pathway of bradykinin

A

XII –> XIIa
Prekallikrein –> plasma kallikrein
HMW kininogen –> bradykinin
Metabolised to des-Arg-bradykinin by kininase I
Broken down by kininase II/ACE to inactive peptides
NB tissue kallikreins mainly produce kallidin

137
Q

What are the effects of further clipping of bradykinin?

A

Kininase I: cleaves C-terminal arg to form des-Arg-bradykinin. Agonist for bradykinin B1
Kininase II/ACE: inactivates kinins by removing 2 C-terminal aa

138
Q

Which receptors do kallidin/bradykinin/des-arg-bradykinin act on?

A

Des-arg-bradykinin: B1

B2: bradykinin and kallidin

139
Q

What is the coupling of B1 and B2 receptors?

140
Q

What is the mechanism of action of B1 and B2 receptors?

A

Gq –> PLCbeta IP3 –> Ca2+ up –> activates cPLA2 cytosolic phospholipase A2 –> PGI2 –> eNOS release –> NO production
NO and PGI2 diffuse into vascular smooth muscle layer
NO –> increase cGMP
PGI2 –> Gs coupled increase cAMP –> PKA –> MLCK relaxation

141
Q

What do ACE inhibitors do to cause vasodilation?

A

Reduce Ang II levels so reduce vasoconstriction

Increase bradykinin levels so enhance vasodilatation

142
Q

How does bradykinin activate nociceptors?

A 
Gq GPCR
PLC beta 
DAG
PKC
phos ion channels involved in sensitisation of pain
143
Q

What is hereditary angioedema?

A

Kallikrein inhibited by C1-esterase inhibitor C1-INH
HAE mutation in C1-INH
Excessive bradykinin
Patients have severe and painful swelling
Type I = HAE synth/secretion
Type II = mutations that allow C1-INH to be produced, but it is inactive

144
Q

How do you treat hereditary angioedema?

A

Ecallantide - kallikrein inhibitor

Recombinant C1-INH

145
Q

What are the four main groups of cytokines? Give examples

A 
1. Interleukins
Pro inflamm IL1, TNFalpha
Anti inflamm  IL10, IL-1ra (endogenous receptor antagonist)
2. Chemokines
CCL3
146
Q

What are the four main groups of cytokines? Give examples

A 
1. Interleukins
Pro inflamm IL1, TNFalpha
Anti inflamm  IL10, IL-1ra (endogenous receptor antagonist)
2. Chemokines
CCL3
3. Interferons:
Antiviral IFN alpha beta
Induction of Th1 response IFN gamma
4. Colony stimulating factors
- Nerve growth factor
147
Q

What are the different types of chemokine (discuss nomenclature)?

A

Related to N-terminal cysteines

  1. ALPHA CXC - single aa between two cys
  2. BETA CC to adjacent cysteines
  3. GAMMA C one cysteine
  4. DELTA CX3C - three aa between the two cy
148
Q

What types of receptors are cytokines coupled to?

A

Most RTK

Except chemokines GPCRs

149
Q

What does nerve growth factor do?

A

Released from macrophages and mast cells –> sensitising agent. Activates signalling pathways that result in a lesser stimulus causing pain e.g. following NGF injection, 5 degree lowering of temp required to generate pain in humans.
Mediated by TrkA high affinity NGF receptor tropomyosin-related kinase A
Blocked by tanezumab

150
Q

Which drugs interact with peptide mediators of inflammation?

A

Ecallantide, recombinant C1-INH inhibit kallikrein
ACE inhibitors inhibit kininase II so inhibit inactivation of bradykinin
Tanezumab MAb against Nerve growth factor

151
Q

List the peptide mediators of inflammation in categories

A
  1. Bradykinin
  2. Cytokines
  3. Peptides: Annexin A1
152
Q

What is annexin A1?

A

Protein produced by many cells that downregulates both inflammatory cell activation and mediator released via binding to GPCR FPR2

153
Q

What binds to FPR2?

A

Annexin A1

Lipoxin

154
Q

Name the lipid mediators of inflammation in categories

A

Leukotrienes
PAF
Prostanoids

155
Q

What are eicosanoids? Why are they called that?

A

Substances made from arachidonic acid

Eicosa = 20 C, tetraenoic = 2 double bonds

156
Q

What is the rate limiting step for eicosanoid synthesis?

A

Liberating arachidonic acid from membrane phospholipids

157
Q

What is the rate limiting step for eicosanoid synthesis?

A

Liberating arachidonic acid from membrane phospholipids, usually by PLA2
Cytosolic PLA2 activated by phosphorylation and Ca2+
So can be activated by bradykinin at B2 receptors, TNFalpha

158
Q

How does TNFalpha act?

A 
TNFR1
MAPK 
Phos cPLA2 at ser 505 and ser 727
Also TNFR2
Ca2+i up
159
Q

What does PLA2 do?

A

Produce arachidonic acid and lyso-PAF

160
Q

Discuss 12-HETE

A

Produced from arachidonic acid by 12 lipoxygenase
Leukotriene
Chemotaxin

161
Q

Discuss LTA4

A

Produced from arachidonic acid by 5 lipoxgenase –> 5-HPETE –> LTA4
Further converted in cells expressing LTA4 hydrolase to LTB4 or by LTC4 synthetase to LTC4/D4/E4 sequentially

162
Q

Discuss LTB4

A

Made from LTA4 by LTA4 hydrolase
Chemotaxin for neutrophilsa nd macrophages
Upreg neutrophil adhesion molecule expression
Promotes mphage cytokine release
Found in the inflammatory exudate in many conditions

163
Q

Discuss LTC/D/E4

A

Cysteinyl leukotrienes
Made sequentially from LTA4 by LTC4 synthase
Bronchoconstrictors, increase vascular permeability, mucus production
Released from mast cells and eosinophils

164
Q

What are leukotrienes coupled to?

A 
GPCR
LTB4 BLT1 and BLT2 receptor. Gq or Gi
CysLTs CysLT1 and CysLT2. Gq
CysLT1R LTD4>>LTC4>LTE4
CysLT2R LTC4=LTD4>LTE4
165
Q

What are the drugs involved in lipid mediators of inflammation?

A

Bufexamac inhibit LTA4 hydrolase

Montelukast inhibits CysLT1R

166
Q

What is LXA4?

167
Q

How is LXA4 made?

A

Either 15-lipoxygenase conversion of aa –> 15S-HETE, then 5-lipoxygenase conversion to LXA4
OR LTA4 conversion to LXA4 by 12-lipoxygenase

168
Q

What does 12 lipoxygenase do?

A

Convert aa to 12-HETE (chemotaxin)

Convert LTA4 to LXA4 (lipoxin)

169
Q

What does 5 lipoxygenase do?

A

Convert 15S-HETE to LXA4
Convert aa to 5-HPETE (to make LTA4)
Convert 15R-HETE (made by asprin acetylated COX2) to ATL asprin-triggered lipoxin, similar function to LXA4

170
Q

How does LXA4 act?

A

Binds to FPR2
Gi
Reduces neutrophil chemotaxis and degranulation
Antagonist of CysLT1 receptors

171
Q

Discuss PAF

A 
Made by acetyltransferase from lyso-PAF
Increases thromboxane production in platelets
Spasmogenic
Neutrophil chemotactic
activates PLA2
172
Q

How are COX enzymes expressed?

A

COX1 constitutively

COX2 induced in inflammation, but still some constitutive expression

173
Q

Which prostanoid receptors are Gs coupled?

A

DP1 EP2 EP4 IP

174
Q

Which prostanoid receptors are Gq coupled?

175
Q

Which prostanoid receptors are Gi coupled?

176
Q

Describe PGD2

A 
Mast cells
Vasodilation
Inhibition of platelet aggregation
Relaxation of GI smooth muscle (DP1, Gs)
Bronchoconstriction (TP Gq)
177
Q

Describe PGE2

A

Locally produced
Bronchial/GI smooth muscle contraction EP1 Gq
Bronchodilation
Vasodilation and relaxation GI smooth muscle EP2 Gs
Contraction GI/uterine smooth muscle and fever EP3 Gi
Sensitisation of nociceptors EP4 Gs

178
Q

Describe PGI2

A

Vasodilation and inhibition of platelet aggregation IP

Gs

179
Q

Describe TXA2

A

Vasoconstriction
Bronchoconstriction
Platelet aggregation
TP Gq

180
Q

Describe PGF2alpha

A

Uterine contraction in animals, bronchoconstriction in cats and dogs FP Gq

181
Q

What does the TP receptor do?

A

Bronchoconstriction TXA2 PGD2

Vasoconstriction platelet aggregation TXA2

182
Q

What are some antiplatelet agents?

A 
Low dose aspirin
Fish oil (produces TXA3, less potent, PGI3, more potent, so overall tip towards anti-aggregation)
183
Q

What is the mechanism of action of NSAIDs?

A

Inhibit COX enzymes so inhibit pro-pain and pro-swelling prostanoids
Most inhibit COX by entering a hydrophobic channel on the enzyme and forming hydrogen bonds with arg120. Prevents entrance of fatty acids like aa into catalytic domain
Reversible
NOT MECHANISM OF ASPIRIN

184
Q

What is the difference between the shapes of COX1 and COX2 and what is the benefit of this?

A

COX1 has a narrow hydrophobic tunnel, COX2 wide
Need to enter this tunnel to get to arg120 to inhibit
Drugs with bulky sulphur containing side groups can selectively act on COX2 but not COX1 as cannot enter tunnel

185
Q

Name some COX inhibitors and define their selectivity

A

Ibuprofen non selective

Etoricoxib COX2

186
Q

What is the mechanism of action of aspirin?

A
  1. Acetylates ser530 in active site COX1 irreversibly
    Thus forms salicylate - reversible COX inhibitor (but concs unlikely to have a therapeutic effect)
    In endothelial cells which make PGI2, just make more COX1
    In platelets can’t synthesise more TXA2 or COX1
    Net switch to beneficial anti-thrombotic effects
  2. Also acetylates COX2, intermediates to make PG and TXA2 not produced but instead 15R-HETE (15S-HETE stereoisomer). 5-lipoxygenase then converts 15R-HETE to ATL aspirin triggered lipoxin, similar functions to anti-inflammatory LXA4
187
Q

Why are COX2 selective inhibitors not totally safe?

A

COX2 actually constitutively expressed in some endothelial and vascular smooth muscle cells, so inhibition –> decreased PGI2 –> increased platelet aggregation and vasoconstriction
Also raises endogenous inhibitors of eNOS –> decreased NO production, so some associated with myocardial risk increase

188
Q

When do the guidelines state COX2 inhibitors should be taken?

A

Chronic inflammation
Non substantial cardiovascular risk
When conventional NSAIDs thought to pose a high GI risk

189
Q

What are the predominant NSAID side effects?

A 
Gastric bleeding (PGs normally increase mucin secretion and inhibit gastric acid secretion by EP4R and EP2/3R respectively, EP1/2R to increase HCO3- secretion
Renal insufficiency and nephropathy (PGE2 and PGI2 involved in maintaining renal blood flow)
Stroke/MI (COX2 constitutively expressed in smooth muscle, inhibition decreased PGI2 which is vasodilatory)
Bronchospasm
190
Q

What are the side effects of aspirin?

A
  1. Reye’s syndrome

2. Salicylism

191
Q

What is Reye’s syndrome?

A

Children
Hepatic encephalopathy (altered level of consciousness as a result of liver failure)
Occurs when aspirin taken for treating viral symptoms

192
Q

What is Salicylism?

A 
Aspirin OD
Kreb's cycle inhibition and uncoupling ox phos in skeletal muscle, increased O2 consumption, increased CO2 production, stim peripheral and central chemoreceptors, increased ventilator rate, respiratory alkalosis, compensated for by increased renal bicarbonate excretion.
Larger doses suppress resp centres, CO2 accumulates, + reduced plasma bicarb --> resp acidosis, combines with metabolic acidosis due to accumulating acidic metabolites due to disrupted carbohydrate metabolism
Fever and repeated vomiting
Dehydration
Resp depression
Coma 
Death
193
Q

How do you treat salicylism?

A

Gastric lavage if <1h
Fluids
Bicarbonate –> alkalinise urine –> ion trapping
Activated charcoal given which adsorbs aspirin in GI tract
Haemodialysis

194
Q

How does paracetamol work?

A

COX1 and 2 inhibition with some COX2 selectivity (whereas aspirin COX1 selective weakly)
Reduces active site required to PGG2 –> PGH2
Anti-pyretic and analgaesic

195
Q

Why is paracetamol toxicity a problem?

A

Elimination of paracetamol:

  1. Mainly conjugation.
  2. When hepatic conjugation enzymes saturated, oxidases act to metabolise paracetamol to NAPQI
  3. NAPQI conjugated to glutathione
  4. During OD there is insufficient glutathione
  5. NAPQI oxidises the thiol groups of cellular proteins –> hepato and renal toxicity
196
Q

How do you treat paracetamol overdose?

A

If patient seen soon after ingestion, give acetylcysteine to increase hepatic glutathione production

197
Q

What conc paracetamol is needed to induce toxicity?

A

150mg/kg so 65kg adult = 9.75kg

198
Q

Why shouldn’t you drink on paracetamol?

A

Alocohol upregs Cyp2E1, which converts paracetamol to NAPQI

199
Q

Why is it a risk to take paracetamol while fasting?

A

Decreased hepatic glutathione levels (which conjugate NAPQI)

200
Q

Name drugs that interfere with lipid mediators of inflammation

A
  1. Montelukast CysLT1R inhibitor
  2. Bufexamac LTA4 hydrolase inhibitor
  3. Glucocorticoids PLA2 inhibitor
  4. Fish oil increases PGI3
  5. NSAIDs non-selective ibuprofen etoricoxib, aspirin weakly COX1 selective, paracetamol weakly COX2 selective. Aspirin also inhibit TXA2 production, and generation of 15R-HETE –> ATL
201
Q

What does ATL stand for?

A

Aspirin triggered lipoxin

202
Q

What does serotonin do?

A

Released from platelets, induces further platelet aggregation, and causes vasoconstriction in damaged blood vessels
Also in ECL and serotonergic neurons of enteric and CNS

203
Q

How is 5-HT synthesised?

A

Tryptophan –> tryptophan hydroxylase to 5-hydroxytryptophan –> DOPA decarboxylase –> 5-hydroxytryptamine/serotonin

204
Q

How is serotonin loaded into platelets?

A

SERT transporter

Load up as the platelets pass through the intestinal circulation

205
Q

How is serotonin degraded?

A

Oxidative deamination by MAO
Oxidation by aldehyde dehydrogenase
Produces 5-HIAA
Urine

206
Q

What are the 5-HT receptors?

A 
5-HT1ABD-F Gi
5-HT2A-C Gq
5-HT3 ionotropic receptor/ligand gated ion channel
1 is i
2 rhymes with q
3 is weird

also but less relevant as there are no selective drugs in clinical use
4 Gs
5A Gi
6 Gs
7Gs
207
Q

What governs emesis?

A

Medulla

Circulating chemicals –> chemoreceptor trigger zone 5-HT3–> vomiting centre –> emesis

208
Q

What governs emesis?

A

Vomiting centre in medulla integrates information from:

  1. Higher cortical centres (pain, repulsive sights/sells, emotional factors)
  2. Vestibular nuclei
  3. Vagal afferents
  4. Circulating emetic chemicals –> chemoreceptor trigger zone, also in medulla
209
Q

Describe anti-emetics

A
  1. Ondansetron - 5-HT3 receptor antagonist (these are in chemoreceptor trigger zone) - CTZ
  2. Cyclizine - H1 receptor antagonist, used against motion sickness - higher cortical centres
  3. Scopolamine - non-selective muscarinic antagonist anti vomiting via M1 - vestibular nuclei
  4. Domperidone, metoclopramide - Dopamine D2 receptor antagonists in chemoreceptor trigger zone (but also GI tract). Domperidone better as peripherally selective so less dystonia
210
Q

Define migraine

A

Severe headache either with or without aura

211
Q

What are the hypotheses for the cause of migraine?

A
  1. Vascular hypothesis: intracerebral vasoconstriction –> aura –> subsequent extracerebral vasodilatation –> headache. Studies showed headache begins during vasoconstriction, and not all stimuli that cause similar cerebral blood flow changes produce headache
  2. Brain hypothesis: wave of cortical spreading depression CSD spreads across the brain, associated with aura.
  3. Inflammation hypothesis - activation of trigeminal nociceptors that innervate the meninges and extracranial blood vessels is initial event in migraine –> pain and neurogenic inflammation
    Brain and inflammation hypotheses may not be mutually exclusive
212
Q

What is CSD and what is its speed?

A

Cortical spreading depression, results in silencing of neuronal electrical activity for several minutes
2-5mm/min
Can be triggered by elevated extracellular K+ e.g. after hyperactive neuronal firing
Also causes ionic imbalance
Release of mediators including H+, glu, NO, aa, 5-HT released

213
Q

What can be observed physiologically during migraine?

A
  1. Silence EEG
  2. Increase K+
  3. Decreased DC recording
  4. Mediators released
  5. Urine levels 5-HIAA rise, blood levels 5-HT drop
  6. CGRP conc in external jugular vein elevated
214
Q

How would mediators in blood vessels reach the meningeal nociceptors? What is the effect of this? Why would this cause nausea?

A

Disruption of BBB due to upregulation of matrix metalloproteinases
Release of CGRP, SP and neurokinin A –> further drive inflammatory pain.
Enhanced by activation of parasympathetic reflex involving activation of the SSN and SPG sphenopalatine ganglion –> release VIP NO ACh
Parasympathetic reflex links migraine to nausea and vomiting

215
Q

What is the evidence that 5-HT is involved in migraine?

A

Urine levels 5-HIAA rise, blood levels 5-HT drop

Drugs that target 5-HT function treat migraines

216
Q

What is the evidence that CGRP is involved in migraine?

A

CGRP conc in external jugular vein elevated in migraine

Injection of CGRP to external jugular induces headaches in migraineurs, but not non-migraineurs

217
Q

What is familial hemiplegic migraine?

A

Migraine and half body paralysis
Inherited through mutations in different genes:
CACNA1C encoding VGCC 1.2alpha subunit
Produce variable effects in channel function
May lead to lower threshold for CSD initiation

218
Q

Which gene mutation can cause migraines?

A

CACNA1C familial hemiplegic migraine
TRESK: TWIK-related spinal cord potassium channel. Involved in regulating resting membrane potential. Some dominant negative mutations in TRESK are associated with migraine.

219
Q

What are the treatments of migraine?

A 
Treatment ladder
1. NSAID +- emetic Ibuprofen + domperidone
2. Triptan: sumatriptan
NB non-triptan lasmiditan
3. Prophylactics
Propanolol
Amitryptiline
Topiramate
Pizotifen
Botulinum toxin
Erunumab
220
Q

What are the two stages of adaptive immunity?

A
  1. Induction

2. Effector

221
Q

How is IL2 relevant in T cells?

A

CD4+ acts in autocrine manner to induce production of Th0 cells
CD8+ acts in autocrine manner to induce production of cytotoxic T cells

222
Q

What do you treat graft rejection with?

A

Corticosteroids e.g prednisolone

223
Q

Draw the HPA for glucocorticoids

A

Hypothalamus –> CRF –> Ant pit –> ACTH –> adrenal cortex –> glucocorticoids
Long feedback loop on H and P glucocorticoids
Short feedback loop ACTH on hypo

224
Q

What are the metabolic actions of corticosteroids?

A 
Decreased uptake of glucose by muscle/fat
Increased gluconeogenesis
Increased protein catabolism
Decreased protein anabolism
Redistribution of fat
225
Q

What are the anti-inflammatory actions of corticosteroids?

A

Decrease influx of leukocytes
Decrease activity of monocytes
Decrease clonal expansion of T and B cells
Switch to Th2 response
Decrease proinflammatory cytokine production (IL1,2,5,TNFalpha)
Decrease eicosanoid production
Increased release of anti-inflammatory factors IL10, IL-1ra, lipocortin 1, annexin A1, IkappaB

226
Q

How do you interfere, pharmacologically, with the HPA for glucocorticoid production?

A
  1. Exogenous ACTH
  2. Drugs that inhibit ACTH triggering glucocorticoid release in the adrenal cortex: metyrapone, mitotane, trilostane
  3. Exogenous glucocorticoids e.g. prednisolone
227
Q

What do glucocorticoids bind to?

A

Glucocorticoid receptor GRalpha
Homomers in cytoplasm bound to HSP90
Binding of ligand triggers dissociation and enables formation of homodimers
Translocate to nucleus
Can either transactivate or transrepress a wide range of genes

228
Q

How can bound GRalpha regulate gene expression?

A
  1. Binds to a positive GRE (glucocorticoid response element) - bind to a promoter for a gene with low transcriptional activity and activate transcription machinery
  2. Negative GRE - bind to a promoter that is constitutively driven by TFs. Binding displaces TFs and represses the transcription machinery
  3. Fos/Jun - the transcription machinery is driven at a high level by Fos/Jun TFs binding to their AP-1 regulatory site. Effect reduced by GRalpha binding (repressive)
  4. P65 and P50 - TM driven by TFs P65 and P50 binding to the NFkappaB site, promoting the TM. These TFs are blocked from binding by prior GRalpha binding (repressive)
229
Q

What are the non-genomic actions of corticosteroids?

A

Hydrocortisone inhibits mast cell degranulation
IgE mediated mast cell degranulation also inhibited (non genomic as membrane impermeable versions have identical effects to membrane permeable versions)
Betamethasone reduced nasal itching within 10 mins for patients with allergic rhinitis - too fast to be genomic

230
Q

What are the side effects of corticosteroids?

A

Opportunistic infection due to suppressed immune system
Thinning of skin and impaired wound healing
Oral thrush - suppression of local anti-infective mechanisms when taken orally
Osteoporosis - reduced osteoblast increased osteoclast activity
Hyperglycaemia due to glucose metabolism effects
Muscle wasting
Stomach ulcer
Avascular necrosis of femoral head

231
Q

What is coprescribed with corticosteroids to reduce risk of side effects?

A

PPI to prevent ulcer

Bisphosphonate (bone protection)

232
Q

What is Cushing’s syndrome?

A

From long term corticosteroid treatment or from an ACTH secreting tumour

  • Pot bellied appearance
  • Hair loss
  • Polydipsia
  • Polyuria
  • Moon face
233
Q

What is the problem with stopping corticosteroids?

A

HPA suppressed

Sudden withdrawal can result in acute adrenal insufficiency

234
Q

Name a short and a long acting corticosteroid

A 
Short = hydrocortisone
Long = dexamethasone
235
Q

Why would you give corticosteroids?

A 
Asthma
Inflammatory skin conditions
Autoimmune conditions
Reduce cerebral oedema
Alos to replace physiological levels of endogenous steroids in Addison's
236
Q

What is asthma?

A
  1. Inflammation of airways
  2. Bronchial hyper-reactivity
  3. Reversible bronchoconstriction
237
Q

What are the key mediators of asthma?

238
Q

Draw the diagram of the pathogenesis of allergic asthma

A

APC CD4 Th0 Th2

  1. IL4 –> B –> P –> IgE (–> eosinophil and mast cell)
  2. IL4 IL5 IL13 –> eosinophil
239
Q

Describe the acute and delayed phases of the asthma attack

A
  1. Acute: allergen induced FcepsilonRI cross linking on mast cells, degranulation, release histamine and CysLTs, both powerful bronchoconstrictors and increase vascular permeability. Mast cells also release IL4/5/13 which recruit eosinophils and macrophages.
  2. Delayed: smooth muscle hypertrophy. Eosinophils recruited to mucosal surface release CysLTs and granule proteins such as eosinophil cationic protein and eosinophil major basic protein which both damage the epithelium. Results in airway hypersensitivity. Means that nociceptive C fibres are more accessible to irritant stimuli
240
Q

What is the treatment for asthma?

A
  1. Bronchodilation
    Short-acting inhaled beta2 agonist salbutamol 1
    Long-acting beta2 agonist LABA e.g. formoterol 3
    Leukotriene receptor antagonist e.g. montelukast 4
    Theophylline PDE inhibitor 5
    Oral LABA 6
  2. Anti-inflammatories
    Regular inhaled corticosteroid beclomethasone2
    Daily oral corticosteroids 7
    Numbers on right = order they give them
241
Q

What are the proteins released by eosinophils?

A

Eosinophil major basic protein

Eosinophil cationic protein

242
Q

What are the prophylactic drugs for asthma?

A 
Formoterol
Theophylline
Beclomethasone
Montelukast
Sodium cromoglycate
Omalizumab
243
Q

What are the acute drugs for asthma?

A

Salbutamol

Ipratropium

244
Q

What is COPD?

A

Chronic obstructive pulmonary disease

Chronic inflammation of the airways and lung tissue leading to narrowing of the airways and shortness of breath

245
Q

What is the difference between asthma and COPD?

A

Asthma: activated mast cells and eosinophils, epithelial loss. Reversible. Th2 type lymphocytes
COPD: neutrophils and macrophages, fibroblast proliferation leading to small airway peribronchiolar fibrosis, alveolar tissue destruction, epithelial proliferation. Irreversible. Th1 type lymphocytes and Tc1 type

246
Q

What is the treatment for COPD?

A
  1. LABAs like formoterol and indacaterol
  2. LAMAs long-acting muscarinic antagonists, tiotropium (long lasting)
  3. Theophylline: raise cAMP in neutrophils and other immune cells, decrease in chemotaxis and activation. PDEIV main in nphils, T cells, mphages, so specific PDEIV inhibitor rofulmilast used.
  4. Long term inhaled O2
    future
  5. Inhibitors of p38 MAPK and PI3K - both proinflammatory
  6. Modulators of neutrophil chemotaxis (e.g. CXCR2 antagonsits)
  7. Anti-fibrotic therapy
  8. Inhibition of elastase activity
247
Q

Why are short acting bronchodilators, corticosteroids not helpful for the treatment of COPD?

A

Bronchodilators: Irreversible fibrotic bronchoconstriction that affects tissue elasticity
Corticosteroids: not effective due to reduction in expression and activity of histone deacetylase 2: superoxide O2- and NO produced from cigarette smoke and activated immune cells –> peroxynitrite ONOO- which nitrates HDAC2 at the active site –> inactivated, ubiquinated. Thus increased acetylation of GRalpha, so prevents it from inhibiting NFkappaB driven inflammation.

248
Q

Describe the differing mechanisms of LABAs and LAMAs

A

LABAg: Gs AC cAMP PKA MLCK inactivation
LAMAnt: Gq PLC IP3 Ca2+ contraction - this is inhibited

249
Q

Are autoimmune diseases more prevalent in males or females?

250
Q

Give examples of the three types of autoimmune diseases?

A

Direct Ab: Goodpasture’s, myasthenia gravis, Graves, Hashimoto’s thyroiditis, primary biliary cirrhosis, autoimmune haemolytic anaemia
Ab-complexes: SLE vasculitis
T cell mediated: Type 1 DM, RA, MS

251
Q

Draw a diagram of the pathology of rheumatoid arthritis

A

PATHOLOGY
Th1 –> mphages –>IL1, TNFalpha –> osteoclasts and fibroblasts secrete metalloproteinases like collagenase –> cartilage and bone destruction
Mphage also releases other inflammatory cytokines and mediators –> recruit neutrophils and other inflammatory cells –> neutrophils release proteases and ROS that cause damaage
Hyperplasia of synovium –> pannus formation as fibroblast-like synoviocytes proliferate

252
Q

What are the drugs used to treat rheumatoid arthritis?

A

Symptom treatments:

  • NSAIDS
  • Corticosteroids

Reduce disease progression (DMARDS)
- Corticosteroids prednisolone. Decrease IL2 transcription, so decreased Th cell proliferation, also decrease IL1 and TNFalpha transcription
- Methotrexate: folic acid antagonist inhibition DHFR so antiproliferative i.e. inhibits proliferation of immune cells CD4 –> Th1. Weekly NOT daily administration
- Sulfasalazine: scavenges ROS from neutrophils
- Hydroxychloroquine: reduces antigen presentation by mphages and ROS production in neutrophils by accumulating in cytoplasmic acidic vesicles
- Azathioprine: prodrug 6 mercaptopurine. Inhibits B and T cell proliferation
- Leflunomide: inhibits dihydroorotate dehydrogenase (in pyrimidine synthesis, so inhibits B and T cells)
- Penicillamine: decrease IL1 synthesis, inhibit collagen generation
- Auranofin: inhibit IL1 and TFNalpha
Biological DMARDS
Anti TNFalpha
- Etanercept: mop up TNFalpha
- Infliximab/adalimumab: sequester TNFalpha
Anti IL6
- Tocalizumab: anti IL6 receptor
Anti B cell
- Rituximab: CD20 on B cells
Anti T:
- Abatacept: CD80 and CD86 on T so interferes with ability of antigen presenting cells to activate T cells
Anti IL1
- Anakinra: binds to IL-1 receptor but doesn’t initiate receptor signalling

253
Q

What does DMARD stand for?

A

disease modifying anti rheumatic drug

254
Q

In which RA patients to you use tocalizumab?

A

Patients with elevated CRP in blood as tocaliziumab = anti IL6R
IL6 drives production of CRP

255
Q

What can rituximab cause?

A

MAb against CD20 on B cells
Associated with increased risk of progressive multifocal leukoencephalopathy
Caused by reactivation of the John Cunningham virus

256
Q

What are the risk factors for OA?

A

Age +40
Gender women
Obesity
Joint injury/abnormality

257
Q

What are the stages of OA development?

A
  1. Bone remodelling: thinning of the subchondral plate
  2. Decrease in bone resorption but no decrease in bone formation –> subchondral sclerosis (increased bone density) and bony outgrowths at joint margins (osteophytes)
  3. Also cartilage damage all the way
  4. Synovium inflamed sometimes
258
Q

Why is OA defined as a non-inflammatory condition?

A

Leukocyte count in synovial fluid lower than that which defines an inflammatory condition

259
Q

Name some NSAIDs used to treat OA

A

Diclofenac

Etoricoxib

260
Q

How does capsaicin work?

A

Activates TRPV1 expressed by nociceptors and constant presence of the agonist causes depolarising block of nociceptors, as well as nociceptor degeneration

261
Q

How do you treat OA?

A 
NSAIDs
Corticosteroids
Capsaicin
Horses: IRAP
Tanezumab anti-NGF MAb

Non pharmacological
Autologous chondrocyte implantation/transplantation
Injection of mesenchymal stem cells
Arthroplasty
Potentially don’t do anything: glucosamine and chondroitin supplement

262
Q

What is the insulin receptor cascade?

A

Insulin receptor RTK
Tyrosine autophosphorylation
Binding via SH2 domains to IRS-1
IRS-1 phosphorylated
Interacts with SH2-domain containing proteins such as PI3K
Converts PIP2 to PIP3
- Increase glucose uptake by muscle/fat
- increased glycogenesis in muscle + liver
- Increased lipogenesis
- Decreased hepatic gluconeogenesis and glycogenolysis

263
Q

What causes insulin release?

A
  • Glut into beta cells via GLUT2
  • Metabolised to ATP
  • KATP close when ATP conc rise and binds to Kir6.2
  • Increases intracellular K+
  • Depolarisation activates VCGG
  • Ca2+ influx
  • Fusion of insulin containing vesicles
  • Insulin is released
264
Q

What is the structure of the KATP channel?

A

Octameric
4 IR K+ channel subunits, Kir6.2 - pore, where ATP binds
4 sulfonylurea receptor 1 SUR1 subunits

265
Q

What is the treatment for diabetes?

A 
Insulin: only treatment for type I
Fast acting insulin lispro, short acting insulin actrapid, intermediate acting NPH insulin, long acting glargine
Additional treatments for type II:
Metformin
Sulfonylureas: Glibenclamide, glipizide. 
Meglitinide: e.g. repaglinide
Exenatide
Sitagliptin
Dapaglifozin SGLT2 inhibitor
Thiazolidinediones e.g. pioglitazone
Acarbose
266
Q

What is the structure of insulin?

A

51 aa

2 chains A and B linked by S-S

267
Q

What happens when you inject insulin?

A

Forms hexamers

Then dissociate to be absorbed into the blood stream

268
Q

What is lipodystrophy?

A

A side effect of insulin injection - lipohypertrophy (fat build up due to local anabolic action of insulin) or lipoatrophy (fat loss due to an immune reaction)

269
Q

How does exercise increase insulin sensitivity?

A

Insulin-stimulated PI3K activation increased in human skeletal muscle
Increased GLUT4 expression
More glucose uptake

270
Q

Why do sulfonylureas not cause heart issues?

A

SUR2A subunit, not SUR1 expressed in KATP in the heart

Sulfonylureas higher affinity and efficacy at SUR1

271
Q

What are two endogenous incretins?

A

GLP1 released by L cells
GIP released by K cells
gut

272
Q

What do incretins do?

A

Stimulate insulin sec
Inhibit glucagon set
Reduce gastric emptying so slow rate of food absorption
GLP1 also reduces appetite

273
Q

What metabolises incretins? What inhibits this?

A

DPP4 dipeptidyl peptidase 4

Sitagliptin

274
Q

What are the different SGLTs?

A

SGLT1: glucose AT in small bowel
SGLT2: glucose reabsorption in PCT

275
Q

What inhibits SGLTs?

A

Dapagliflozin inhibits SGLT2

Increases urinary glucose loss

276
Q

How do you measure blood glucose without measuring blood glucose?

A

Conc glycated haemoglobin HbA1c

Higher with hyperglycaemia

277
Q

What is lupus?

A

Autoimmune condition (immune complexes)

  1. Discoid which affects only skin
  2. Systemic lupus erythematosus skin and joints and freq also internal organs
278
Q

Which defects of the immune system is SLE associated with?

A

Defective clearance of apoptotic cells
Increased response to antigens containing nucleic acids
Decreased threshold for activation of autoantibody producing B cells
Impaired NET degradation
Increased levels of several cytokines: TNFalpha, IL6, interferons and B lymphocyte stimulator

279
Q

Give a theory of the pathophysiology of SLE

A

Defective clearance of apoptotic cells by mphage
APCs present apoptotic material as autoantigens
Antinuclear antibodies develop

280
Q

What are the diagnostic tests for SLE?

A

Physical examination

Blood tests against ANA and anti-dsDNA

281
Q

What is the treatment for SLE?

A 
NSAIDs e.g diclofenac
Hydroxychloroquine
Corticosteroids
Immunosuppressives like methotrexate and azathioprine
Rituixmab
Belimumab
282
Q

What is BLyS?

A

B lymphocyte stimulator
Important cytokine for B cell survival, differentiation and antibody production
MAb against it is belimumab

283
Q

Which drugs can induce lupus?

A

Etanercept
Infliximab
Both anti IL1s in rheumatoid arthritis

284
Q

List immunosuppressive drugs:

A 
1. Corticosteroids
Steroid sparing agents
2. Azathioprine
3. Methotrexate
4. Mycophenolic acid
5. Cyclophosphamide
6. Ciclosporin A
7. Tacrolimus
8. Basiliximab
9. Belatacept
10. Sirolimus/rapamycin
285
Q

Discuss the metabolism of azathioprine

A

Azathioprine
HPRT converts to TIMP
Converted by 2 different enzymes to produce 2 products with inhibitory effects upon DNA function:
TPMT converts to 6-methyl TIMP which inhibits de novo purine synthesis
IMPDH converts to 6-TGN, incorporated into cellular nucleic acids - inhibits nucleotide and protein synthesis
Inhibition of cellular proliferation especially in cells with no salvage pathway (lack ability to synth nt from intermediates of nt degradation)

286
Q

Discuss the link between azathioprine and hepatotoxicity

A

TPMT (TIMP –> 6 methyl TIMP) levels in 10% pop v low
In these 6-thioguanine intermediate accumulates
Toxicity
Check by checking TPMT levels, or close monitoring of blood counts/liver function on starting treatment

287
Q

Which drug inhbits IMPDH?

A

Mycophenolic acid

Enzyme crucial for de novo guanosine synthesis

288
Q

What are the uses and side effects of cyclophosphamide?

A 
Immunosuppressive
Anticancer
But 
Bone marrow depression
Potential infertility
Bladder irritation (Metabolite acrolein activates TRPA1 expressed by bladder innervating nociceptors)
Cancer
289
Q

What is the cyclophosphamide mechanism of action?

A

Prodrug
P450 to aldophosphamide then active phosphoramide mustard
1. Bischloroethylamine cyclises and releases Cl- to immonium cation
2. Immonium strained ring opens to form reactive carbonium
3. Carbonium reacts with guanine N7 to produce 7-alkylguanine
4. 7-alkylguanine pairs with T so GC to AT transition, can also cause guanine excision and chain breakage

290
Q

Discuss the attempt to develop an anti-CD28 Ab

A

Should have worked as activation of CD28 alone without TCR can cause activation and proliferation Treg
But a cytokine storm occurred in humans as activating effects non-selective (activated pro-inflammatory memory T as well as Treg).
In future maybe use at lower doses that enable selective activation of Treg

291
Q

What is the IL2 synthesis pathway?

A

Usually antigen interacts with T cell receptor, increase Ca2+i
Stim activity of ser-thr phosphatase calcineurin (CaN)
Dephosphorylates nuclear factor of activated T cells (NF-AT)
NF-AT can translocate to nucleus
Upreg IL-2

292
Q

How do you generate a polyclonal Ab?

A
  1. Inject an organism with Ag
  2. Extract serum which contains multiple Abs against the Ag from different plasma cells producing different Abs - polyclonal antibodies
293
Q

What is a hybridoma?

A

Fused mouse B cell with an immortalised tumour cell

Can grow indefinitely

294
Q

How do you make a MAb?

A
  1. Inject mice with Ag
  2. Isolate Ab producing B cells form the spleen
  3. Mix with myeloma cells (HPRT-ve, involved in purine salvage) in polyethylene glycol to produce hybridomas
  4. Grow in DHFR inhibitor to kill unfused myeloma cells (as don’t have HPRT), whereas hybridomas can create new nt from supplements in medium using B cell HPRT. Unfused B cells short life and die off
  5. ELISA screen for B cell specificity
  6. Use limiting dilution to clone individual cells
  7. Propagate
  8. MAb collected
295
Q

What was the problem with first generation MAb?

A

Relatively low circulatory half life
unable to activate human complement
immune response due to human-anti mouse Ab generation

296
Q

What is the difference between chimaeric and humanised MAb? Give examples

A 
Chimaeric = human Fc, mouse variable. E.g. infliximab
Humanised = all human except mouse CDR e.g. omalizumab, alemtuzumab, rituximab
297
Q

What does the suffix ximab mean?

298
Q

What does the suffix axomab mean?

A

Rat/mouse hybrid

299
Q

What does the suffix zumab mean?

300
Q

What does the suffic umab mean?

301
Q

How could we improve MAb?

A
  1. Bi-specific antibodies so one half binds target cell, other binds cytotoxic cell e.g. catumaxomab
  2. Engineered improvement of antibody-NK cell coupling e.g. afucosylate Ab so has higher affinity for FcgammaRIIIA, so outcompetes serum IgG, increasing the window of time for ADCC to occur
  3. Antibody drug conjugates: deliver cytotoxin chemical to target cell e.g. trastuzumab Herceptin
  4. Improved pharmacokinetics by mutation of Fc region - improve binding to FcRn at low pH so more is recycled out of cells and not broken down by intracellular degradation machinery
  5. Improve structure - shrink peptide scaffold that displays antigen binding loops (reduce diffusion time into tissues and more access to intracellular targets) or create bicyclic peptides that are more rigid and so can bind with higher affinity, and are more resistant to serum proteases
  6. Make nanobodies which are single domain only heavy chains - better tissue permeability and tissue penetration but lower half life
302
Q

What is a trifunctional Ab?

A

Fc portion binds Fc on macrophages
One variable region binds target cell
Other targets cytotoxic cell

303
Q

Why does fucosylation of Ab decrease ADCC?

A

Displacement of oligosaccharide tree connected to Asn162 FcgammaRIII
Increased distance of contact between Fc and FcgammaRIII
Reduced bond strength

MODA MVST1b (11 decks)

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