Pharmacology 6: Immunosuppression and RA, and pharmacology of airway control

Question 1

overall mechanism of action of corticosteroids?

Answer 1

inhibitors of gene expression: lipophilic so capable of crossing PM to bind to cytoplasmic receptor.
Forms a hormone-receptor complex which enters nucleus and binds to intra-nuclear receptor and interacts with specific regions of DNA to alter rate of transcription of specific genes.
inhibit all stages of T cell activation
prevent IL-1 and -6 production by macrophages
especially decrease TNF-alpha prod

Question 2

corticosteroid ADRs?

Answer 2

hypertension
oral candidiasis- increased infection risk as immunocompromised
osteoporosis- as increased osteoclast activity, so may give Vit D supplements
weight gain- moon shaped face and central obesity- Cushing’s syndrome
bruising, purple striae
hyperglycaemia, diabetes
growth suppression in children
gastric ulcers- as transrepression of COX-2 required for PG synthesis in stomach for alkali and mucus prod= protective

Question 3

mechanism of action of azathioprine (an immunosuppressant)?

Answer 3

cytotoxic antimetabolite that acts selectively on cells with a higher mitotic rate.
primary action= inhibition of purine metabolism, which reduces both DNA and RNA synthesis.
Pro-drug- activated to 6-Mercaptopurine (6-MP)

Question 4

active form of azathioprine?

Answer 4

6-Mercaptopurine (6-MP)

Question 5

which enzyme is required for elimination of 6-Mercaptopurine (6-MP)?

Answer 5

TPMT: thiopurine methyltransferase- subject to high rate of genetic polymorphism.

Question 6

how does expression of enzyme TPMT- thiopurine methyltransferase, affect tment with azathioprine and why?

Answer 6

drug elimination requires this enzyme.
So high levels of enzyme expression will allow rapid elimination, hence undertreatment.
low levels of expression will lead to increased toxicity.

Question 7

ADRs of azathioprine?

Answer 7

BM suppression, must monitor FBC
increased infection risk
emergence of malignant cell lines, espec increased risk in transplanted patients**
hypersensitivity reactions e.g. dizziness, vomiting, diarrhoea, rash
hepatitis- monitor LFTs

Question 8

how does cyclophosphamide act as an immunosuppressant?

Answer 8

prodrug activated by CYP450s to produce active alkylating electrophilic cytotoxic metabolites whihc cross link DNA, inhibiting its replication
selectively acts on cells with higher mitotic rate.
suppress both T and B cells

Question 9

ADRs of cyclophosphamide?

Answer 9

excreted by kidney- can induce bladder cancer due to concentration of acrolein metabolite in urine, acrolein= toxic to bladder epithelium, can cause haemorrhagic cystitis, can be prevented through use of aggressive hydration and/or Mesna, most adjust dose accordingly if renal impairment
lymphoma
leukaemia
infertility
teratogenesis

Question 10

agent of choice in transplant immunosuppression?

Answer 10

mycophenolate mofetil (MM)

Question 11

ADRs of mycophenolate mofetil?

Answer 11

leuko and neutropenia
myelosuppression
increased infection risk- espec. viral

Question 12

how does methotrexate work in malignant disease?

Answer 12

acts an an antifolate, with folate being necessary for synthesis of purines and thymidine= precursors to building blocks in DNA synthesis.
Binds to DHFR (dihydrofolatereductase) as competitive reversible inhibitor- which uses folate as a substrate.
folate= role in single carbon transfer reactions central to synthesis of purines and thymidine.
Action selective during S phase of cell cycle in cells with high mitotic activity, so greater toxic effect on rapidly dividing cells e.g. GI and oral mucosa- replicate DNA more frequently.

Question 13

ADRs of methotrexate?

Answer 13

GI effects as gut mucosa= high mitotic activity- diarrhoea, anorexia, dyspepsia, abdom discomfort, GI ulceration e.g. mouth
may also cause hair loss as hair follicle cells= rapidly dividing
hepatotoxicity, hepatitis- may appear jaundiced, cirrhosis
pulmonary fibrosis and interstitial pneumonitis- dyspnoea, cough, crackles- would show ground glass opacification on CT
BM suppression- may be fatigued, susceptible to infections

Question 14

monitoring required with methotrexate?

Answer 14

FBC- as BM suppression risk
LFTs- as risk of hepatotoxicity
Us and Es-as mainly eliminated via kidneys
monitor resp symptoms at each visit e..g. dyspnoea and cough, stop tment if pneumonitis supected
dose monitoring if combined with aspirin or other NSAIDs- NSAIDs displace drug from plasma proteins- MTX has 50% protein binding

Question 15

name 2 diseases sulfasalazine is used in the tment of?

Answer 15

RA

IBD

Question 16

ADRs of sulfasalazine?

Answer 16

nausea
abdom pain
diarrhoea
vomiting, nausea
fatigue
headache
myelosuppression
hepatitis
allergic rash- anaphylaxis
so must do LFTs and FBC regularly

Question 17

ADRs of B2 agonists used as relievers in asthma?

Answer 17

skeletal muscle tremor
tachycardia
dysrhythmia
palpitations
headache

Question 18

features of temporal (giant cell) arteritis?

Answer 18

malaise
jaw claudication
severe peri-orbital headache

giant cell arteritis can affect other arteries of head and neck,large vessel vasculitis, no infection

=inflammation of temporal arteries= terminal branches of ECA, chronic inflammatory process,severe pain if patient tries to brush their hair, medical emergency as inflammation can spread to involve ICA- opthalmic artery- central artery of retina- sudden blindness

Question 19

why is azathioprine associated with increased risk of skin cancer?

Answer 19

causes accumulation of 6-thioguanine in patient’s DNA, which might trigger cancer on exposure of patient to UV light

Question 20

people giant cell arteritis is most common in?

Answer 20

women

aged >35

Question 21

what is given to all patients prescribed steroids for >3wks in case patient requires tment in an emergency?

Answer 21

blue steroid card- patients may enter an addisonian crisis if suddenly stop their steroid medication as steroids will have been suppressing release of ACTH from anterior pituitary that normally stimulates steroid release from adrenals, so HPA axis suppression, so on stopping steroids, endogenous prod of steroids may be so low with adrenal insufficiency that an addisonian crisis results= patient may be very confused, hypotensive, nausea, vomiting, severe abdominal pain, seizures

Question 22

most common cause of an addisonian crisis?

Answer 22

abrupt withdrawl of steroid medication

Question 23

how is giant cell arteritis treated?

Answer 23

initial dose of prednisolone= 40–60 mg daily (the higher dose being used if visual symptoms occur). Treatment should be continued until remission of disease activity and doses are then reduced gradually to about 7.5 –10 mg daily for maintenance. Relapse is common if therapy is stopped prematurely. Many patients require treatment for at least 2 years and in some patients it may be necessary to continue long-term low-dose corticosteroid treatment.

Question 24

indications for methotrexate?

Answer 24

RA- used in combination with other DMARDs to provide best outcome, and with biologics e.g. etanercept and infliximab.
malignancy
Crohn’s
Psoriasis
unlicensed roles= maintenance therapy in vasculitis

Question 25

how is methotrexate thought to work in tment of inflammatory diseases e.g. RA?

Answer 25

increases adenosine, through inhibition of enzymes involved in purine metabolism, which is a potent, endogenous anti-inflammatory mediator that inhibits neutrophil adhesion, phagocytosis, and superoxide generation. MTX also causes apoptosis of activated CD4 and CD8 T cells, but not of resting T cells.

Question 26

when might adenosine be given IV to treat a patient?

Answer 26

for arrhythmias e.g. re-entry, as short t1/2 <10s, acts on alpha 1 adrenoceptors at AV node, and enhances K+ conductance, hyperpolarising cells so conduction at AV node slowed/prevented.

Question 27

how often is methotrexate given and why?

Answer 27

once weekly as metabolites (polyglutamates) are long lived- long t1/2s 2.5 mg tablets, may take up to 8 for tment of moderate to severe active RA= max wkly dose 20mg

Question 28

if a patient is take methotrexate once weekly, what else must they also take once weekly?

Answer 28

folic acid= as MTX antagonises folate action in body, so taken NOT on same day as MTX as folate would then be ineffective folate required for DNA synthesis and repair, and for rbc synthesis to prevent anaemia.

Question 29

what is it important to note if thinking of commencing a young woman on methotrexate?

Answer 29

it is teratogenic as inhibits folate action, so can cause neural tube defects hence pregnancy should be avoided until at least 3mnths post stopping of MTX tment

Question 30

indications for sulphasalazine?

Answer 30

RA | inflammatory bowel disease

Question 31

immunological effects of sulphasalazine?

Answer 31

T cells- inhibit proliferation possible result in apoptosis inhibition of IL-2 production neutrophils- reduced chemotaxis and degranulation

Question 32

drug class for sulphasalazine?

Answer 32

aminosalicyclate combination of 5-aminosalicylic acid (‘5-ASA’) and sulfapyridine; sulfapyridine acts only as a carrier to the colonic site of action in treating IBD but still causes side-effects. sulfapyridine important in RA as absorbed into blood so can have sytemic effects.

Question 33

other drugs apart from sulphasalazine that are aminosalicylates?

Answer 33

balsalazide olsalazine sulphasalazine has sulphonomide component= sulfapyridine- absent from other drugs

Question 34

indications for azathioprine?

Answer 34

IBD SLE vasculitis- maintenance therapy here and in SLE RA

Question 35

what must be monitored if patient on azathioprine?

Answer 35

FBC

Question 36

factors limiting use of biologics in RA?

Answer 36

expense | profile of ADRs e.g. ...

Question 37

important drug-drug interactions of aspirin, in terms of treating a patient with RA?

Answer 37

``` corticosteroids= PDs, both drugs increase risk of gastric ulcer formation as inhibit PG production in stomach necessary for mucus and alkali production, aspirin= inhibits COX, and corticosteroids= transrepression of COX-2. methotrexate= PKs, aspirin reduces excretion of MTX NSAIDs= increase SEs as both inhibit COX in stomach. ```

Question 38

X-ray changes with RA?

Answer 38

bony erosions joint subluxation following tendon rupture due to inflammation osteopenia

Question 39

overall summary of RA pathophysiology?

Answer 39

AI- auto-antibodies targeted against synovium systemic- extra-articular manifestations e.g. CVD inbalance between pro- and anti-inflammtory cytokines, pro- dominate Cellular and humoral immune response, cellular= type IV hypersensitivity, cytokine prod by T helper cells, TNF-alpha fundamental in producing joint damage. Humoral= autoantibodies e.g. RF, form immune complexes- activate complement- inflammatory cell recruitment. Pannus= abnormal fibrovascular tissue resulting from misshapen growth of inflamed synovium, promotes bone destruction, prevents cartilage nutrition and produces subluxation.

Question 40

overall summary of SLE pathophysiology?

Answer 40

type III hypersensitivity reaction, AI chronic disease non-organ specific, circulating immune complexes, anti-dsDNA and anti-nuclear antibodies joint arthritis, butterfly/malar rash- skin, kidneys- hypertension, renal failure, CNS and PNS- seizures, fever

Question 41

Raynaud's phenomenon may occur secondary to both RA and SLE, what is it?

Answer 41

blood supply affected to certain parts of body, commonly fingers and toes. blood vessels go into a temporary spasm which blocks the flow of blood. This causes the affected area to change colour to white, then blue and then red as the blood flow returns.

Question 42

function of DMARDs and examples?

Answer 42

``` e.g. in RA- suppress disease process and hence halt progression, limiting damage, and can actually lead to clinical improvement in underlying condition. azathioprine sulphasalazine methotrexate biologics e.g. etanercept and infliximab ```

Question 43

what must be tested in patients before prescribing azathioprine?

Answer 43

thiopurinemethyltransferase activity as gene highly polymorphic

Question 44

what are calcineurin inhibitors and when are they used?

Answer 44

e.g. ciclosporin and tacrolimus bind to particular proteins (ciclosporin to cyclophillin and Tacrolimus binds to tacrolimus-binding protein ) and these complexes then bind to calcineurin which is an important factor in T cell activity as normally exerts phosphatase activity on the nuclear factor of activated T cells and this factor then migrates to the nucleus to start IL-2 transcription, so active against helper T cells, preventing production of IL-2 via calcineurin inhibition. widely used in transplantation, and in psoriasis and atopic dermatitis • Calcineurin normally exerts phosphatase activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription

Question 45

what must be checked regularly if patient on a calcineurin inhibitor e.g. transplant patient, and why?

Answer 45

eGFR and BP as causes renal toxicity

Question 46

why are multiple DDIs possible with calcneurin inhibitors e.g. ciclosporin, used in atopic dermatitis, psoriasis and transplant patients?

Answer 46

met via CYP450 system of enzymes in liver

Question 47

give 2 indications for myocphenolate mofetil?

Answer 47

transplant patients | induction and maintenance in lupus nephritis

Question 48

active metabolite of mycophenolate mofetil which can be monitored in transplant patients given the drug?

Answer 48

mycophenolic acid

Question 49

mechanism of action of mycophenolate mofetil?

Answer 49

Is a prodrug derived from fungus Penicillium stoloniferum Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis) impairs B- and T-cell proliferation spares other rapidly dividing cells (due to guanosine salvage pathways in other cells)

Question 50

indication of neutropenia on examination of a patient being treated with mycophenolate mofetil?

Answer 50

mouth ulcers

Question 51

indications for cyclophosphamide?

Answer 51

lymphoma leukaemia lupus nephritis wegener's granulomatosis (ANCA vasculitis)

Question 52

main active metabolite of cyclophosphamide?

Answer 52

4-hydroxycyclophosphamide

Question 53

action of dihydrofolate reductase?

Answer 53

catalyses the conversion of dihydrofolate | to the active tetrahydrofolate- the key carrier of one-carbon units in purine and thymidine synthesis

Question 54

how may methotrexate administration be altered if currently given orally but partial response or nausea occurring?

Answer 54

give subcutaneously

Question 55

where is sulfasalazine cleaved into its constituent parts?

Answer 55

large bowel 5-ASA= largely unabsorbed or EH circulation sulfapyridine= absorbed, and highly protein-bound

Question 56

factors favouring sulfasalzaine use in practice?

Answer 56

``` safe in pregnancy (contrast to MTX) long term blood monitoring not always needed effective few DDIs no carcinogenic potential* ```

Question 57

TNFalpha inhibitors that can be used in RA?

Answer 57

etanercept- fusion protein adalimumab golimumab infliximab= all monoclonal antibodies- made specifically to block any given substance in the body, or to target any specific cell type

Question 58

biologic that can be used in treating lymphoma?

Answer 58

rituximab= monoclonal Ab= depletes B cells

Question 59

biologics for RA that don't act to inhibit TNF-alpha?

Answer 59

rituximab tocilizumab- monoclonal Abs abatacept- fusion protein- usually based on naturally occurring receptor

Question 60

what must be screened for before commencing anti-TNF tment and why?

Answer 60

TB tment may cause reactivation of latent TB as TNF-alpha produced by macrophages in response to M.TB infection, and is essential for development and maintenance of granuloma

Question 61

effects of blocking TNF-alpha

Answer 61

reduce inflammation, cytokine cascade, leukocyte recrutiment to joint reduce angiogenesis- VEGF levels reduce joint destruction- MMPs, bone resoprtion and erosion, and cartilage bdown

Question 62

how does rituximab work?

Answer 62

binds to CD20 found on a subset of B cells- B cells presnt antigen to T cells, and produce cytokines and antibodies causes B cell apoptosis

Question 63

example of class of drugs that may be used in RA in the future?

Answer 63

JAK inhibitors- janus kinase inhibitors, JAK= intracellular enzymes important in cell signalling

Question 64

ADRs of cytokine modulators- biologics?

Answer 64

associated with infections, sometimes severe, including tuberculosis, septicaemia, and hepatitis B reactivation. Other side-effects include nausea, abdominal pain, worsening heart failure, hypersensitivity reactions, fever, headache, depression, antibody formation (including lupus erythematosus-like syndrome), pruritus, injection-site reactions, and blood disorders (including anaemia, leucopenia, thrombocytopenia, pancytopenia, and aplastic anaemia).

Question 65

what remodelling of the airways takes place in LT and poorly controlled asthma?

Answer 65

basement membrane thickening smooth muscle hypertrophy and hyperplasia mucous gland hypertrophy

Question 66

5 defining characteristics of asthma?

Answer 66

``` chronic inflammatory process airway hyperesponsiveness variable and widespread airflow obstruction susceptibility reversibility ```

Question 67

5 factors that contribute to airway narrowing in asthma?

Answer 67

bronchial wall thickening with inflammatory cell infiltration smooth muscle contraction epithelial shedding mediated by eosinophils mucus over prod, abnormal mucus- forms plugs mucosal oedema

Question 68

5 steps in treating asthma?

Answer 68

``` 1= mild intermittent= inhaled short-acting beta 2 agonist e.g. salbutamol 2= regular preventor therapy= add inhaled steroid, dose appropriate for disease severity 3= initial add-on therapy= add inhaled long-acting beta 2 agonist e.g. salmeterol. Can increase inhaled steroid dose if benefit from long acting beta 2 agonist but control still inadequate. If long-acting no response, stop and increase inhaled steroid. If control still not good enough with last 2 options, trial other therapies e.g. leukotriene receptor antagonist OR methylxanthine e.g. theophylline. 4= persistent poor control= increase inhaled steroid, add 4th drug e.g. LKTRA, methyxanthine or beta 2 agonist tablet 5= use daily steroid tablet (oral), maintain high dose inhaled ```

Question 69

describe the early phase response in asthma

Answer 69

type I hypersensitivity reaction, immediate response which reaches maximum in 20 mins interaction of allergen and specific IgE antibodies produced by plasma cells, causing mast cell degranulation and release of histamine, PGD2 and leukotrienes, which causes bronchoconstricition.

Question 70

describe the late phase response in asthma

Answer 70

type IV (delayed) hypersensitivity, 3-12 hrs after exposure to antigen inflammation, mast cells and T helper 2 cells release cytokines e.g. IL-4 and 5, that attract eosinophils and neutrophils. eosinophils release leukotriene C4 and other mediators, some toxic to epithelial cells so cause shedding. eosinophils very sensitive to steroid therapy*

Question 71

why must short acting beta 2 agonists not be used regularly?

Answer 71

reduce asthma control | with regular use, mast cell degranulation in response to allergen increases

Question 72

why are short-acting beta 2 agonists used in asthma?

Answer 72

for mild/intermittent asthma reverse bronchoconstriction and prevent it on exercise use on an as-required basis

Question 73

examples of short-acting beta 2 agonists used in asthma

Answer 73

salbutamol | terbutaline

Question 74

what is formoterol?

Answer 74

beta 2 agonist used in asthma tment, can have fast onset and long duration if inhaled, or slow onset and short duration if given orally.

Question 75

when are inhaled corticosteroids required in asthma?

Answer 75

symptoms 3 or more times a week waking at least once a wk using a beta 2 agonist 3 or more times a wk exacerbation requiring oral steroids in the last 2 yrs

Question 76

describe the 2 mechanisms by which steroids act in the nucleus

Answer 76

transrepression and transactivation activate transcription of anti-inflammatory genes e.g. beta 2 adrenergic receptors- so can increase efficacy of beta 2 agonist when giving an inhaled corticosteroid, and annexin-1. inhibit pro-inflammatory pathways, prevent translation of pro-inflammatory proteins e.g. inhibit COX-2- so risk of gastric ulceration*

Question 77

a lipophilic side chain on D-ring of corticosteroids has what benefits?

Answer 77

very high affinity for glucocorticoid receptor increased uptake and dwell time in tissue on local application rapid inactivation by hepatic biotransformation following systemic absorption

Question 78

why does beclomethasone have good systemic absorption?

Answer 78

not subject to much 1st pass metabolism, absorbed through gut and lungs *contrast to budesonide and fluticasone which are subject to extensive 1st pass met.

Question 79

what must be done before initiating a new drug therapy at step 3 in treating asthma?

Answer 79

re-check med compliance check inhaler technique- right inhaler and being used correctly eliminate trigger factors

Question 80

why is a long acting beta 2 agonist e.g. salmeterol or formoterol, used instead of increasing the dose of inhaled corticosteroid at step 3 in asthma tment?

Answer 80

been shown in trials that this is more efficacious, probably as most of the action of corticosteroids is achieved at low doses- relatively flat dose-response curve.

Question 81

examples of combination inhlaers that can be used in asthmatic pateints requring step therapy?

Answer 81

``` symbicort= budesonide/formoterol seretide= fluticasone/salmeterol fostair= beclometasone/ formoterol ```

Question 82

why are combination inhalers used in step 3 of asthma tment?

Answer 82

makes taking tment easier improves adherence- can't use agonist without using steroid safety- as want them both together, using agonist without inhaled corticosteroid is potentially harmful potentially cheaper than 2 individual inhalers 1 versus 2 prescriptions to worry about

Question 83

when might leukotriene receptor antagonsits be used in treating asthma and why?

Answer 83

step 3/step 4 add-on therapy inhibit actions of leukotriene C4 released by mast cells and eosinophils which can induce bronchoconstriction, mucosal oedema and mucus secretion, and promote inflammatory cell recrutiment, and cause epithelial shedding.

Question 84

ADRs of leukotriene receptor antagonists?

Answer 84

``` fever dry mouth angioedema anaphylaxis arthralgia gastric disturbances ```

Question 85

action of methylxanthines?

Answer 85

antagonise adenosine receptors | previously thought to inhibit phosphodiesterase and increase cAMP

Question 86

what limits use of methylxanthines e.g. theophylline and aminophylline for asthma in practice?

Answer 86

often poorly efficacious narrow therapeutic window frequent SEs: nausea, headache, reflux AND potentially life-threatening toxic complications= tachycardia and arrhythmias and fits/ psychomotor agitation met. by CYP450 so important DDIs e.g. increased risk of toxicity with erythromycin and ciprofloxacin antibiotics as enzyme inhibitor so reduced xanthine metabolism.

Question 87

what else can be added other than a methylxanthine or leukotriene receptor antagonist as a step 3/step 4 add-on therapy?

Answer 87

anticholinergic e.g. tiotroprium bromide= long-acting, once daily licensed for COPD and severe asthma, reduces exacerbations

Question 88

ADRs of tiotropium bromide (anti-muscarinic) ?

Answer 88

dry mouth urinary retention glaucoma dizziness

Question 89

after oral steroids in step 5 of asthma tment, what else can be used?

Answer 89

anti-IgE= prevent IgE binding to mast cells and causeing their degranulation, but very expensive. May reduce exacerbation rates in those not controlled on oral steroids.

Question 90

what is recommended in terms of tment when asthma is well controlled?

Answer 90

stepping down if not, may be receiving higher dose than necessary, and pts should be maintained at lowest possible dose of inhaled corticosteroid.

Question 91

most effective size of particles in inhaler devices?

Answer 91

1-5 microns- settle in small airways if too big, can't reach small airways too small- not deposited in lungs, and taken into alveoli then breathed out

Question 92

features of patient with acute, severe asthma?

Answer 92

can't complete sentences pulse> or equal to 110 beats/min RR > or equal to 25/min PEFR between 33 and 50% of that predicted/best

Question 93

why is ipratropium not used straight away in acute severe asthma?

Answer 93

bronchodilation induced more slowly, and less intense

Question 94

features of life-threatening asthma?

Answer 94

same as acute severe, plus cyanosis PEFR <33% that predicted feeble resp effort

Question 95

tment of acute severe asthma?

Answer 95

Oxygen, high flow – aim to keep O2 94-98% sat Nebulised salbutamol – continuous if necessary, oxygen driven Oral prednisolone ~40 mg daily for 10-14 days - can be stopped without tailing down If moderate exacerbation not responding, or acute severe/life threatening, add nebulised ipratropium bromide Consider IV aminophylline if no improvement and life threatening features not responding to above treatment (BEWARE if taking oral theophylline ).

Question 96

if a patient is receiving IV cyclophosphamide, what might they be given to reduce their risk of bladder cancer?

Answer 96

mesna

Question 97

in what different ways does activation of beta 2 adrenoceptors cause bronchial smooth muscle relaxation?

Answer 97

beta 2= Gs GPCR= activation activates adenylate cyclase, which increases cAMP and PKA PKA reduces affinity of light chain myosin for Ca2+ PKA also reduces IC Ca2+ by increasing amount sequestered by SER and PKA phosphorylates K+ channels, causing increased K+ efflux so hyperpolarisation which reduces contractility and reduces actvity of voltage-activated Ca2+ currents, AND there may be additional hyperpolarisation due to Gs independent increase in Ca2+ activated K+ currents.