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MODA Inflammation and immunosuppression > Lecture 5 > Flashcards

Lecture 5 Flashcards

1
Q

Pathology of rheumatoid arthritis

A
  • Joint damage driven by Th1 cells
  • Macrophages release IL-1 and TNFa causing release of metalloproteases from osteoclasts and fibroblasts leading to bone and cartilage destruction
  • Exacerbation by infiltrated leukocytes e.g. neutrophils which release proteases and ROS causing further damage
  • Hyperplasia of the synovium also occurs leading to pannus formation as fibroblast like synoviocytes proliferate and invade the joint and release proinflammatory cytokines and proteases
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2
Q

NSAIDs in rheumatoid arthritis

A

Symptom management

Relieve pain and reduce inflammation but do not alter underlying disease

Diclofenac/arthrotec largely superseded by NAPROXEN due to apparent reduction in cardiovascular risk

COX2 selective NSAIDs e.g. etoricoxib may also be used to reduce GI risk

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3
Q

Corticosteroids in rheumatoid arthritis treatment

A

E.g. oral prednisolone

Symptomatic relief and suppress disease activity

Reduced transcription of IL-1, TNFa and IL-2 (important for driving Th proliferation)

Due to side effects of systemic chronic use, they are only used for treating flare ups or as a bridging treatment when waiting for DMARDs to take effect

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4
Q

What does DMARD stand for?

A

Disease Modifying Antirheumatic drugs

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5
Q

Methotrexate

A

Mainstay for RA management. Used alone or in combo

  • folic acid antagonist, inhibits DHFR and competes with folic acid for transport into cells
  • reduced tetrahydrofolate for purine synthesis and thymidylate synthesis therefore antiproliferative and reduces the immune response

Effects seen after 3-12 weeks. Given orally once a week (or by sc injection) with folic acid supplement not taken daily to reduce risk of side effects.

Side effects: bone marrow suppression and GI disturbance

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6
Q

Sulfasalazine

A

Popular first choice DMARD also used in inflammatory bowel disease

MODA unclear> Administered orally and broken down by colonic bacteria to produce sulfapyridine and 5-aminosalicylic acid. 5-aminosalicylic acid may scavenge ROS released from neutrophils

Daily tablet, effects observed after 3 months
Side effects: bone marrow suppression, GI disturbance, hepatotoxicity. Tears in contact lenses may appear yellow, urine may appear orange.

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7
Q

Hydroxychloroquine

A

Developed as an antimalarial but is now also used in RA to treat patients refractory to other DMARDs.

MODA unclear. Lipophilic base therefore accumulates in the cytoplasmic acid vesicles which can reduce AG presentation by macrophages and ROS generation in neutrophils

Side effects: GI disturbance, ocular toxicity, skin reactions, myopathy, seizures and psychiatric disturbance

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8
Q

Leflunomide

A

Inhibits dihydroorotate dehydrogenase which is required for pyrimidine synthesis, therefore inhibits DNA synthesis. Main effect on rapidly dividing cells e.g. T/B cells

Side effects: GI disturbance, bone marrow suppression and hepatotoxicity

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9
Q

Name 4 conventional DMARDs

A

Methotrexate

Sulfasalazine

Hydroxychloroquine

Leflunomide

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10
Q

When are biological DMARDs prescribed and how are they given?

A

Reserved for patients who have failed conventional DMARD therapy

Given as an injection (iv or sc). More effective when given with methotrexate (can also reduce risk of developing neutralising antibodies)

Each class has similar efficacy but failure to respond to one class does not determine response to another class

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11
Q

Anti TNFa therapies

A

ETANERCEPT = fusion protein of soluble TNFa receptor and Fc portion of IgG1, therefore mops up high levels of TNFa characteristic of RA

-infliximab and adalimumab are chimeric/human mABs respectively. Also sequester TNFa

Side effects: bone marrow suppression, allergic reactions, susceptibility to infections (esp TB and HepB), cases of MS reported

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12
Q

Anti IL-6 therapy

A

TOCILIZUMAB = mAB targeting the IL-6 receptor (IL-6 is upregulated in RA)

Targeted towards patients with elevated CRP

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13
Q

Anti B cell therapy

A

RITAXIMAB is a mAB targeting CD20 that is primarily expressed in B cells therefore can induce B cell destruction

Associated with increased risk of fatal brain injury called multifocal leukoencephalopathy which is caused by reactivation of the John Cunningham (JC) virus

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14
Q

Anti T cell therapy

A

ABATACEPT = fusion protein of cytotoxic T-lymphocyte protein 4 (CTLA-4) and the Fc fragment of human IgG1. This binds CD80 and CD86 on T cells so interferes with the ability of AG presenting cells to activate T cells

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15
Q

Anti IL-1 therapy

A

ANAKINRA = recombinant version of IL-1 receptor antagonist. Binds IL-1R with higher affinity than IL-1 itself but does not initiate receptor signalling

  • given by injection, response in 2-12 weeks
  • increased susceptibility to infections
  • not recommended for treatment in the UK (benefit vs cost)
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16
Q

OA risk factors

A
  • Age
  • More common in women
  • Obesity (more pressure on knee)
  • Joint injury/abnormality
  • Sometimes occurs as a consequence of RA
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17
Q

Characteristics of OA

A

Disruption in the equilibrium between cartilage breakdown and repair resulting in a net loss of articular chondrocytes

Early stage is associated with thinning of the subchondral plate

Late stage associated with reduced bone resorption but no reduction in bone formation leading to the development of subchondral sclerosis (increased bone density) and bony outgrowths at the joint margins called osteophytes

Synovitis (inflammation of the synovium) often occurs in early and late stages

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18
Q

3 drugs in OA treatment

A

NSAIDs

Capsaicin

Tanezumab

19
Q

NSAIDs in OA treatment

A

Diclofenac and etoricoxib commonly used for pain control (plus opioids if needed)

20
Q

Capsaicin in OA treatment

A

Applied topically as a cream 3/4 times per day.
Activates TrpV1 on nociceptors. Constant presence of agonist after an initial warming sensation leads to depolarising block of nociceptors as well as nociceptor degeneration

21
Q

Tanezumab

A

anti-NGF mAB

Increased NGF levels in the synovial fluid of OA patients (NGF causes pain)

22
Q

Other options for OA treatment

A

Autologous chondrocyte implantation/transplantation. remove healthy cartilage, isolate chondrocytes and implant in damaged areas

Injection of mesenchymal/bone marrow derived stem cells

23
Q

Why is insulin not given orally?

A

Low bioavailability

24
Q

What happens structurally when insulin is injected?

A

It forms hexamers which then dissociate to be absorbed into the blood stream

25
Q

Fast acting insulin

A

INSULIN LISPRO

An analogue swapping of a lys and pro residue towards the end of the C terminus of the b chain. Reduces dimer and hexamer formation, therefore more monomeric insulin is available after injection

Onset within 5-15mins. Duration 4-6 hours

26
Q

Short acting insulin

A

INSULIN ACTRAPID

Human sequence.

Onset within 30-60min, duration 8-10 hours

27
Q

Intermediate acting insulin

A

NEUTRAL PROTAMINE HAGEDORN (NPH) INSULIN

A suspension of protamine polypeptide and insulin which forms relatively insoluble crystals thus slowing absorption

Onset within 2-4 hours. Duration 12-18hrs

28
Q

Long acting insulin

A

GLARGINE

Insulin analogue with amino acid changes to the A and B chains change the molecule’s isoelectric point (pH at which there is no electrical charge) to a more neutral pH. When injected glargine forms a microprecipitate of stable hexamers and higher aggregates which retard and prolong absorption

Onset 2-4hrs. Duration 20-24 hrs

29
Q

Example of insulin dose regime

A

Once daily injection of long-acting insulin at night and multiple injections of fast-acting before eating
(or injection of a fast acting and an intermediate twice daily)

Insulin pumps that continuously infuse fast acting insulin into subcutaneous tissues are increasingly used

30
Q

Side effects of insulin

A

Hypoglycaemia - trembling and sweating followed by confusion and irritability. Can potentially result in drowsiness and coma
-best countered by ingestion something sugary

Lipodystrophy at site of injection. May be lipohypertrophy (fat build up due to local anabolic action of insulin) or lipoatrophy (fat loss likely from immune response)

Allergic reaction

31
Q

How does exercise increase insulin sensitivity?

A

Insulin-stimulated PI3K activation is increased in human skeletal muscle which results in increased GLUT4 expression (transports glucose into skeletal muscle) thus facilitating insulin mediate glucose uptake

32
Q

Metformin

A

Most common first line T2DM treatment

MODA unclear but activation of AMPK, adenosine monophosphate activated protein kinase, may be involved (cellular energy sensory). AMPK decreases the expression of genes involved in hepatic gluconeogenesis

Many beneficial effects:

  • reduced hepatic gluconeogenesis
  • increased glucose uptake in skeletal musc
  • reduced intestinal carb abs
  • reduced circulating levels of VLDL & LDL
  • reduced appetite (many diabetics overweight)
33
Q

Sulphonylurea (SU) mechanism

A

SU compounds e.g. Glibenclamide and glipizide now being superseded by other compounds

Bind to the SUR1 subunit of K-ATP channels in pancreatic B cells causing closure of the channel, triggering depolarisation and Ca2+ influx and insulin release
(i.e. only beneficial when patient still has B cells)

SUs are well absorbed. Peak plasma conc reached within a few hours and duration of action = 24hrs

34
Q

Metabolism of SUs

A

GLIPIZIDE: mainly metabolised in the liver to inactive products and excreted in the urine

GLIBENCLAMIDE: shows significant conversion to active products in the liver before urinary excretion. Therefore in patients with renal insufficiency the action of glibenclamide is potentiated

35
Q

When are SUs contraindicated (not used)

A

During pregnancy and breastfeeding as they can cross the placenta and enter breast milk

36
Q

Side effects of SUs

A

Hypoglycaemia and weight gain

Blockade of cardiac K-atp not a huge problem since the SUR2A subunit, not SUR1 is expressed in the heart and SUs show greater affinity to SUR1

A recent study has shown that diabetics treated with Sus have a slightly higher cardiac risk however other studies have not found an association

37
Q

Meglitinides

A

e.g. REPAGLINIDE

Inhibit K-atp by binding to SUR1 but have faster onset and offset kinetics than SUs and are therefore often taken just before a meal and are less likely to cause hypoglycaemia

38
Q

What is an incretin?

Give examples

How are they broken down

A

A substance that reduces blood glucose

Glucagon-like insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) secreted by K and L cells respectively

Both act to stimulate insulin secretion and inhibit glucagon secretion as well as reducing gastric emptying thus slowing the rate of absorption.

GLP-1 also acts in the brain to reduce appetite

Both are broken down by dipeptidyl peptidase-4 (DPP4)

39
Q

Exenatide

A

A synthetic version of extendin 4 (a peptide found in the saliva of the glia monster) and mimic the effect of GLP-1 but is longer acting

s.c. injection. Administered twice daily but slow release version is also available for weekly injection

40
Q

Gliptins

A

A class of drugs that inhibit DPP-4 (which breaks down incretins)

e.g. sitagliptin

Taken orally and given in combo with other drugs

41
Q

Gliflozins

A

Inhibit SGLT2 (e.g. DAPAGLIFLOZIN) or combined SGLT1/2 inhibition

SGLT1 = active abs of glucose in the small bowel 
SGLT2 = reabsorption of glucose from kidney

Gliflozins increase urinary glucose loss (and also reduce GI abs) Efficacy is reduced if renal function is reduced .

Side effects = increased urinary and genital infections, increased frequency of urination and an increase in ketone production in the liver (unknown why)

42
Q

Thiazolidinediones

A

e.g. PIOGLITAZONE

Activate the peroxisome proliferator-activated receptor γ (PPARγ) a TF highly expressed in adipose tissue but also present in liver/muscle

PPARγ activation = lipogenesis, glucose uptake and increases transcription of numerous genes including GLUT4

Effects are not immediate and can be used as an add-on therapy

Side effects include weight gain and fluid retention due to enhancement of amiloride sensitive Na+ reabsorption

43
Q

α-glucosidase inhibitors

A

e.g. ABCAROSE

Slow the break down of starch/disaccharides into glucose and reduce the amount of glucose entering the blood stream (also aid weight loss)

Side effects = flatulence and diarrhoea

Rarely used. If used they are combined with other drugs

44
Q

NICE guideline NG28

A

Uses the HbA1c concentration (amount of glycated haemoglobin, higher in hyperglycaemia) to indicate the treatment someone with T2DM should have if diet and exercise are insufficient

Stage 1 = metformin alone
Stage 2 = metformin combined with a second drug
Stage 3 = adding a third compound or moving to insulin based treatment

MODA Inflammation and immunosuppression (6 decks)

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