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week 19 (Y2) > the patient > Flashcards

the patient Flashcards

1
Q

where is the thyroid gland located

A

lower part of the neck

in front of the trachea

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2
Q

what is the lumen full of

A

colloid
( glue like )

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3
Q

what cells surround the lumen

A

thyroid follicular cells

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4
Q

what do they thyroid follicle cells produce

A

thyroglobulin protein by exocytosis into the lumen

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5
Q

what does the NIS transporter do and pendrin do?

A

transports iodide ions from follicular cells into lumen

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6
Q

what does thyroperoxidase do

A

converts iodide ions to atomic iodine

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7
Q

what is MIT

A

where 1 iodine is attached to a tyrosine ring on thyroglobulin

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8
Q

what is DIT

A

two iodines attached to tyrosine on thyroglobulin

di iodo tyrosine

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9
Q

what does DIT + DIT give?

A

T4

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10
Q

what does MIT + DIT give?

A

T3

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11
Q

what is T4

A

thyroxine
tetra iodo thyronine

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12
Q

what do T3 and T4 control

A

TRH and TSH by negative feedback

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13
Q

what does TRH stimulate the release of

A

TSH

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14
Q

what does TSH do

A

Travels to the thyroid gland

stimulating the synthesis and release of thyroid hormones

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15
Q

what do T3 and T4 do

A

control the secretion if TRH and TSH

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16
Q

where are the adrenal glands

A

top of the kidney like hats

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17
Q

what are the tree layers of the adrenal glands out to in

makes up the cortex

A

zona glomerulosa
zona fasciculata
zona reticularis

medulla = middle

remember via GFR

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18
Q

what does the outermost layer produce

A

aldosterone

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19
Q

what does the fasciculata produce

A

cortisol

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20
Q

what does the reticularis produce

A

sex steroids

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21
Q

what does the medulla produce

A

epinephrine
norepinephrine

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22
Q

what does the medulla do

A

flight or flight response

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23
Q

what is cortisol

A

stress signal

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24
Q

why are sex steroids important

A

reproduction

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25
Q

Why is aldosterone important?

A

water retention

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26
Q

what caused the release of aldosterone

A

angiotensin 2

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27
Q

what is the HPA

A

Hypothalamic, pituitary, adrenal axis

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28
Q

what is a serious issue with transplantation

A

lack of available organs
immune system - main

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29
Q

when was the first sucessful transplant

A

1906

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30
Q

when was the opt out scheme introduced

A

2018

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31
Q

what does rate of rejection depend on 3

A
  1. tissue type
    Skin rejected faster than kidney, liver well tolerated
  2. number of transplants
    Second grafts rejected faster
  3. rejection mechanism
    Antibody-mediated rejection can be instant
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32
Q

what are most transplants anf the sources of most transplant

A

Most transplants are cadaveric (dead donors)
Disadvantage: Long waiting list

Increases in living donor transplants
In the UK- 1 in 4 kidney transplants are now from living
donors
For either source of donated organ, still high risk of rejection
The immune system is just doing its job!

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33
Q

what is an AUTOGRAFT
(generally accepted)

A

Self-tissue transferred from one body site
to another in the same individual

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34
Q

what is an ISOGRAFT
(generally accepted)

A

Tissue transferred between genetically
identical individuals (inbred mice or
identical twins)

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35
Q

what is an ALLOGRAFT
(often rejected)

A

Tissue transferred between genetically
different members of the same species

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36
Q

what is an XENOGRAFT
(vigorously rejected)

A

Tissue transferred between different
species (e.g. baboon heart into human
recipient)

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37
Q

describe a transplant rejection

A

when a kidney is gransplanted the recipients T cells attack the transplant

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38
Q

describe graft vs host disease rejection
GvHD

A

when bone marrow is transplanted, the T cells in the transplant attack the bodys tissues.

Transplantation of immunocompetent
cells
* GvHD can be lethal

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39
Q

describe the Primary immune response

A

first encounter with
a pathogen
– Longer lag time
– Less specific response

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40
Q

describe the secondary immune response

A

second and
subsequent infections with the same pathogen
– Faster response
– More specific response
– Principle of vaccination

last two, immunological memory

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41
Q

what does immunological memory lead to

A

immunological memory results in the more rapid elimination
of pathogens, and more rapid destruction of a second graft

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42
Q

what does the second graft lead to sometimes

A

a more liekly graft rejection

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43
Q

what is indirect allorecognition

A

T cells can respond to non-self peptides in self
MHC

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44
Q

what is direct allorecognition

A

T cells can respond to non-self peptides in non-self MHC

Grafts with no lymphatic
drainage tend to be more
successful

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45
Q

what are the 3 rejection mechanisms

A

Hyper-acute - antibody mediated
* Acute - T cell mediated
* Chronic - Multiple mechanisms

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46
Q

tell me more about Hyper-acute - antibody mediated

A

Pre-existing recipient alloantibodies
– sensitised to donor MHC -previous
transplants, blood transfusion
* Rejection occurs in minutes
* Abs bind Ags on graft endothelial cells

Classical complement cascade activated

Neutrophils attracted to site

Blood clotting cascade initiated

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47
Q

Hyper-acute - antibody mediated tell me more about it

A

Type IV hypersensitivity
* Mediated by activated allospecific effector T cells
* Donor leukocyte involvement -direct allorecognition-
non-self peptide in non-self MHC of donor APC
* This stimulates a strong immune response

In the presence of alloreactive memory T cells
(previous transplants) - much more rapid rejection

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48
Q

tell me more about Chronic graft rejection

A

Occurs months to years after transplantation
* Gradual reduced blood supply to the graft- loss of function
* This causes failure of over half kidney/heart grafts within
10years

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49
Q

what does Indirect allorecognition drive?

A

chronic rejection

Indirect allorecognition of transplanted
tissue
* Allogeneic (non-self) HLA Class I are
processed and presented by self APC
* This activates self TH
* These will help activate naïve B cells –
release of anti-alloHLA alloantibodies
* Endothelial cells in the graft express
alloHLA antigens
* Binding of the anti-alloHLA antibodies
to the alloHLA antigens results in
impairment of function (autoimmune
mechanisms)

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50
Q

Also- Non-immunological rejection processes

A

Graft injury
disease
drug toxicity

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51
Q

what is graft injury chronic graft rejection

A

at time of transplantation or during
transit from donor to recipient
e.g. ischaemia-reperfusion injury

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52
Q

what is disease chronic graft rejection

A

Recurrence of the problem that
necessitated the transplant
e.g. lung infection in CF

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53
Q

what is drug toxicity chronic graft rejection

A

immunosuppressants can be
damaging
e.g. cyclosporin A is toxic to kidneys

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54
Q

The options to minimise rejection of allogeneic grafts are:

A
  1. HLA matching (tissue typing)
  2. Immunosuppressant therapy
  3. Induce tolerance (experimental)
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55
Q

ABO and Rh antigen matching prevents type
II hypersensitivity in blood transfusions testing

A

Cross match testing of matched blood prior to transfusion
will then reveal whether any other antibodies in the patient
serum react with the donor red cells

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56
Q

what is HLA expression analysis

A

Mix blood with a panel of antibodies to different HLA
antigens
Agglutination reaction (blue) indicates antigen expression

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57
Q

what is The mixed lymphocyte reaction that measures T cell responses

A

Incubate irradiated donor
cells (yellow) with recipient
lymphocytes (blue)

This test indicates the
presence of alloreactive T
cells- acute/chronic rejection

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58
Q

Three kinds of immunosuppressant:

A

– Corticosteroids
– Cytotoxic compounds
– T cell modifiers

The majority of patients receive mismatched organs
* We need to use drugs to suppress alloreactions and
prevent rejection

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59
Q

Corticosteroids

A

Steroids have many adverse side effects
– Use acutely, not long-term

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60
Q

Cytotoxic drugs 3

A

Azathioprine- pro-drug
* Inhibits DNA replication
* Prevents replication of
alloantigen-stimulated T
cells

Cyclophosphamide-
chemical weapon from WWI-
many toxic effects!

Methotrexate – inhibits
replication, useful in
inhibiting GVHD in bone
marrow transplants

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61
Q

what are T cell modifiers

A

Inhibit T cell activation but also
suppress B cell/granulocyte
activation

No effects on proliferating cells
(good news for the intestines)
BUT fairly toxic to the kidneys
* COMBINATION THERAPY

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62
Q

what can HLA do

A

minimise rejection

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63
Q

what does sucessful transplantation require

A

lifelong therapy on a cocktail of
immunosuppressant drugs

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64
Q

what is HYPERSECRETION

A

too much
Hyperthyroidism

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65
Q

what is HYPOSECRETION

A

hypothyroidism
too little

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66
Q

what is graves disease

A

Hyperthyroidism (Graves disease)
more common in men
Autoimmune disease
Causes overproduction of thyroid hormones

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67
Q

Result from generalised over activity of thyroid gland:

A

– Hot, flushed, heat intolerant
– Enlarged thyroid gland (goitre)
– Exopthalmos
– Weight loss
– Muscle weakness, tremor
– Pulse rate ⇑, palpitations, sweating
– Hair loss, menstrual changes

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68
Q

diagnosis for hyperthyroidism

A
  • Physical examination
  • Family history
  • Blood tests
    – Thyroid hormones (T3, T4 ⇑)
    – TSH levels (⇓)
    – Thyroid antibodies
  • Thyroid scan (iodine uptake)
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69
Q

Hyperthyroidism: Drug Treatment

A

Anti-thyroid drugs: ⇓ T3/4 secretion

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70
Q

Anti-thyroid Drugs
Drugs which inhibit organic binding of iodine:

A

Carbimazole
* FIRST LINE IN UK
* Thought to act by inhibiting the thyroperoxidase enzyme

Propylthiouracil
T4 pro-hormone, less active, more abundant)
* In UK kept for people unable to take carbimazole

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71
Q

prescribing carbimazole

A
  • Give in high doses unitl euthyroid
  • Reduce to maintenance dose
  • Withdraw after 1-2 years and monitor
    Clinical effect note:
    Rapid action to inhibit organic binding BUT large stores of T3 and T4 must be
    “used up” before therapeutic effect
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72
Q

Drugs which reduce the uptake of iodine:

A

– Thiocyanate
– Perchlorate

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73
Q

hyperthyroidism symptom relief drug

A

propanolol

B blocker

Used to reduce symptoms of over activity of the sympathTaken up by active transport &
concentrated in gland

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74
Q

how to track radioactive iodine

A

Taken up by active transport &
concentrated in gland
* Local tissue destruction by x ray &
β-particle emission

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75
Q

tell me more about radioactive iodine

A

may produce
hypothyroidism (need
replacement therapy).
* First line treatment
* sometimes
* OR after failure of anti
thyroid drugs
* OR after failure of
thyroidectomy
* OR as standard
procedure for some
thyroid cancers

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76
Q

what is Thyroidectomy

A

surgery

For patients where 131I and drugs have failed
– Patients with large goitre: cosmetic effects, swallowing or breathing
difficulties
* Ideally: sub-total thyroidectomy leaving patient with enough gland to
be euthyroid
– BUT possibility of recurrent thyrotoxicosis or developing hypothyroidism is a
risk
* Hypothyroidism: need thyroid replacement therapy (see later)

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77
Q

what is Hypothyroidism

A

Syndrome caused by deficiency of thyroid hormones
* Possible causes
* Congenital
* Autoimmune disease: Abs to thyroglobulin
* Inflammation of thyroid (Hashimotos thyroiditis)
* Dietary iodine deficiency

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78
Q

Hashimotos thyroiditis what is it
hypothyroidism

A

Inflammation, fibrosis and decreased function of thyroid gland. Goitre evident.

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79
Q

what is Myxoedema
hypothyroidism

A

– Hypothyroidism developing in adult life
– Adult onset slow and insidious, confused with normal aging process. ⇑ women
– In rare cases, becomes medical emergency, requires treatment by T3.

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80
Q

Cretinism: affects children from birth what is it
hypothyroidism

A

– Poor mental development, pot belly, dwarfism
– Prevented by RAPID treatment with T4 at birth
* Maternal iodine deficiency
* Congenital dysfunction in hormone biosynthesis

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81
Q

clinical features / symptoms of hypothyroidism

A

– Weakness, fatigue
– Cold intolerance
– Weight gain (but may have decreased appetite)
– Constipation
– Dry skin, thickened skin
– Brittle hair, alopecia
– Intellectual deterioration, mental and physical lethargy
– Goitre (TSH⇑)

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82
Q

diagnosis for hypothyroidism

A
  • Physical examination
  • Family history
  • Blood tests
    – Thyroid hormones (T4 ⇓)
    – TSH levels (⇑)
  • Overt hypothyroidism
    – TSH > 10mU/L and FT4 below reference range
  • Consider subclinical hypothyroidism
    – TSH is raised but FT4 within reference range
  • Consider secondary hypothyroidism
    – T4 is low without raised TSH and clinical features
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83
Q

Thyroid Replacement Therapy
hypothyroidism

A
  • Thyroxine (T4) used to replace deficiency
  • Aim of therapy:
    – Replace thyroid hormone function
    – ⇒ normal physical & mental development
    – Reduce goitre (suppress raised TSH levels)
  • Optimum dose determined individually
    – Single dose, before breakfast
    – Important counselling points!

Life-long therapy, monitor effect
Non-compliance leading to increased doses:

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84
Q

Drugs for Thyroid Replacement Therapy

A

Levothyroxine sodium
– Synthetic T4
– Treatment of choice for
maintenance
– Once daily dose
possible
* Liothyronine sodium
– Similar action but more rapidly
metabolised
– May be used in severe
hypothyroid states
– Used IV as part of supportive
treatment of thyroid coma

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85
Q

Monitor TSH levels when…

A

– Within 8 weeks of starting levothyroxine
– After a dose change
– Annually once established
Monitoring of Replacement Therapy

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86
Q

what is Cushing’s syndrome

A

which is a disorder caused by prolonged exposure to high levels of cortisol, a hormone produced by the adrenal glands

-Pituitary adenoma
Secretes excess ACTH
Benign (mainly), women 5:1 men

Ectopic ACTH tumour
– Malignant or benign, men 3:1 women
* Adrenal tumours
– Secrete excess cortisol & other adrenal hormones
– Non-malignant adenomas, onset>40 years, uncommon, rapid onset of symptoms:
women>men

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87
Q

Clinical Features / symptoms of crushings syndrome

A

Weight gain
– Increase in body fat
– Rounded face, flushed, prominent cheeks
* Easily bruised skin
* Violaceous striae
* Hypertension
* Glucose intolerance
* Depression or psychosis
* Osteoporosis

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88
Q

diagnosis of crushing syndrome

A

Patient history, physical examination, biochemical tests, scan for tumours
* Saliva cortisol test
* 24 hour free cortisol in the urine

Dexamethasone (steroid) suppression test (DST) – blood
– Low dose – presence of Cushing’s
– High dose - distinguishes between pituitary and ectopic ACTH-secreting
tumours
– Only PITUITARY ACTH suppressed by dexamethasone

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89
Q

with a normal pituitary, normal cortisol levels,

when you introduce dexamethaone what happens to ACTH and Cortisol

A

both decrease due to negative feedback

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90
Q

in pituitary adenoma
high cortisol and high ACTH
what happens when you introduce dexamethasone

A

both still decrease

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91
Q

describe the mngement of crushings syndrome

A

HPA axis is used to having high levels of steroids, you need to ween the patient off this.

normalisation of cortisol levels or actions

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92
Q

tell me about Metyrapone

A

not commonly comissioned

££££

individual patient request

black triangle drug

Inhibits 11β-hydroxylation in the adrenal cortex

Inhibition of cortisol production

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93
Q

what is Osilodrostat

A

Licensed for endogenous Cushing’s syndrome
– Steroidogenesis inhibitor that inhibits 11-beta-hydroxylase
– Not routinely commissioned by NHS England

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94
Q

what is addisons disease

A

Chronic adrenal insufficiency:
effets men and women equally

HYPOcorticolism
– Insidious worsening of symptoms
* Often undiagnosed, sometimes until an ADDISONIAN CRISIS
occurs

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95
Q

primary causes of addisons disease

A

Destruction of the adrenal cortex
* Cortisol AND aldosterone levels⇓⇓⇓
– Immune mediated, strong link with TB
– Adrenal insufficiency when 90%+ cortex destroyed
– Also associated with fungal infections, metastasis, amyloid and
surgical removal of adrenals

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96
Q

secondary causes of addisons disease

A

due to lack of ACTH
– Pituitary or hypothalamic in origin
– ACTH stimulation⇓ therefore Cortisol ⇓

Temporary
– Due to sudden stoppage of chronic exogenous glucocorticoid therapy

Permanent
– Surgical removal of ACTH-secreting tumours of pituitary (causing
Cushing’s)
– Piuitary atrophy, or lack of ACTH production (tumours, infections, radiation,
other damage)

aldosterone levels are normal due to asrenal cortex being normal !!!

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97
Q

Temporary Drug Induced Addison’s Disease

A

HPA takes a long time to reset after prolonged suppression with steroids
* Therefore, when chronic exogenous glucocorticoid therapy is stopped, the body
will no longer have sufficient endogenous cortisol secretion to respond to any
stress

eg COPD patients, have to be weened off steroids

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98
Q

clinical features of addisons disease

A

Anorexia
* Weight loss
* Weakness and fatigue
* GI disturbances
* Hypotension
* Salt cravings
* Increased thirst
* Postural dizziness
* Muscle or joint pain
* Skin hyperpigmentation

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99
Q

what is Addisonian Crisis, medical emergency

A

Acute response to stress in a compromised patient
– Sudden penetrating pain in lower back, abdomen or legs
– Severe vomiting, diarrhoea, dehydration
– Blood pressure decreases, loss of consciousness
– FATAL if untreated
Caused by body’s inability to respond to stress because of adrenal insufficiency.

treatment: steroid we can give via IV, emergency, eg hydrocortisone

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100
Q

how to diagnose addisons disease

A

Morning serum cortisol taken (exclusion test)

Synacthen test (ACTH stimulation test)
– Serum cortisol levels checked before and 30 mins after giving synthetic
analogue of ACTH (tetracosactide)

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101
Q

Does the adrenal gland respond to ACTH?

A

If the answer is NO: primary insufficiency most likely

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102
Q

Treatment of Addison’s Disease

A

Replacement of glucocorticoid and mineralocorticoid
* Glucocorticoid
– Usually hydrocortisone
* Mineralocorticoid
– Fludrocortisone

Sick day rules
* Emergency treatment pack
– IM hydrocortisone for self administration

(emergency, vomiting or diahorrea, cannot absorb steroid orally, switch to IV/IM hydrocortisone)

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103
Q

what is hypercorticolism

A

crushings disease

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104
Q

what is hypocorticolism

A

addisons disease

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105
Q

what is the adrenal glad composed of

A

two tissues
both of different origin

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106
Q

what two tissues are the adrenal cortex’ made up of

A

adrenal cortex
adrenal medulla

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107
Q

what is the adrenal cortex

A

Surrounds the medulla

Three zones – secreting glucocorticoids and mineralocorticoids and
androgens

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108
Q

what is the adrenal medulla

A

Chromaffin tissue

Secretes adrenaline and noradrenaline

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109
Q

what are glucocorticoids

A

Glucocorticoids are a class of steroid hormones produced by the adrenal cortex, specifically by the zona fasciculata. They play a crucial role in regulating various physiological processes in the body, including metabolism, immune response, and stress response. The primary glucocorticoid in humans is cortisol, also known as hydrocortisone.

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110
Q

where are glucocorticoids produced

A

Produced by cells of zona fasciculata

Controlled by pituitary ACTH

in the adrenal cortex

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111
Q

roles of glucocorticoids

A

Intermediary metabolism: carbohydrate, lipid and protein
* Anabolic effects on liver, catabolic effects on skeletal muscle and adipose tissue

Permissive actions
* Required for functioning of sympathoadrenal system
* Necessary for catecholamine synthesis and uptake and action

Enable body to respond to stress

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112
Q

describe the HPA axis

A

hypothalamus
pituitary
adrenal

hypothalamus reacts to stess via adrenaline
releases CRH (corticotropin releasing hormone)
Anterior pituitary recats to this
releases ACTH (adrenocorticotropic hormone)
interpreted by adrenal cortex
releases cortisol

this is a negative feedback loop

hypothalamus detects increase in cortsol and stops the release of CRH

113
Q

What do endogenous glucocorticoids do?

A

Permissive actions”, usually when organism in resting state
– They permit or help (facilitate) action of other hormones.
* Enable body to RESPOND to threats
* Need at rest and in stress

114
Q

What do glucocorticoids do?

A

Enable body to respond to stress
– direct effects and permissive effects are both important.
* Metabolic actions
– Increased availability of glucose (energy)
* increased lipolysis, proteolysis, gluconeogenesis

Regulatory actions
– Negative feedback on HPA
– Reduce vasodilation, reduce fluid exudation
– Effect on cells of immune system to reduce inflammatory response and
immune response
* Reduces unwanted inflammation
* Reduces body’s ability to heal
* Reduces body’s ability to respond to infections

115
Q

How do glucocorticoids act?

A

In most target tissues:
– bind to specific cytoplasmic receptors
– Translocation of bound complex to nucleus
– Bind to steroid response elements on DNA
– Either REPRESS or INDUCE transcription of specific genes (depends on tissue)
* Therefore:
– Some actions of glucocorticoids take time to develop as rely on gene transcription

116
Q

what is the theraputic benefit of NSAIDs related to

A

The therapeutic benefit of prescribing nonsteroidal anti-inflammatory drugs
(NSAIDs) is heavily related to arachidonic acid and eicosanoid synthesis
* Conversely, the ADRs stem from this signalling pathway too

117
Q

Arachidonic acid derived from?

A

derived primarily from dietary linoleic acid – vegetable oils
converted hepatically to arachidonic acid and incorporated into phospholipids
* Found throughout the body – particularly in muscle, brain and liver
* Release from phospholipids by phospholipase A2 – rate limiting step in
eicosanoid generation

118
Q

Arachidonic acid and eicosanoids what are they, in relation to NSAIDs

A

Arachidonic acid is a fatty acid found in cell membranes that serves as a precursor for the synthesis of various signaling molecules known as eicosanoids. Eicosanoids are potent lipid mediators involved in regulating inflammation, immune responses, and other physiological processes.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of medications that inhibit the activity of cyclooxygenase (COX) enzymes, which are responsible for converting arachidonic acid into pro-inflammatory prostaglandins and thromboxanes. By blocking COX enzymes, NSAIDs reduce the production of these inflammatory mediators, thereby exerting anti-inflammatory, analgesic (pain-relieving), and antipyretic (fever-reducing) effects.

119
Q

what are prostanoids?

A

Prostanoids are a group of bioactive lipid compounds derived from arachidonic acid metabolism that includes prostaglandins, thromboxanes, and prostacyclins. They play diverse roles in regulating numerous physiological processes in the body, including inflammation, immune response, vascular tone, and platelet aggregation.

120
Q

what do prostanoids do?

A

PGE2, PGF2α, PGD2 PGI2 (prostacyclin) and TXA2 (thromboxane)
* Action locally at a number of GPCRs specific action depends on receptor
subtype and location
* Often action is enhanced by local autacoids including bradykinin and
histamine
* TXA2 and PGI2 have apposing vascular effects fine balance between them
crucial – haemodynamic and thrombogenic control
* Imbalance plays significant role in hypertension MI and stroke
* Diet rich in fish oils – northern latitudes – EPA and DHA (omega-3
polyunsaturated fatty acids) conversion to TXA3 and PGE3 – balance shifted
towards prostacyclin activity – lower incidence of CVD?

121
Q

MOA NSAIDs

A

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their effects primarily by inhibiting the activity of enzymes called cyclooxygenases (COX), which are involved in the synthesis of pro-inflammatory prostaglandins from arachidonic acid

Inhibition of COX Enzymes: NSAIDs inhibit COX enzymes, reducing prostaglandin synthesis.
Reduction of Prostaglandin Synthesis: This decreases inflammation, pain, and fever.
Anti-inflammatory Effects: NSAIDs attenuate the inflammatory response.
Analgesic Effects: They relieve pain by reducing pain receptor sensitization.
Antipyretic Effects: NSAIDs help normalize body temperature by acting on the hypothalamus.
Adverse Effects: NSAIDs can cause gastrointestinal and cardiovascular side effects, especially with long-term use.

MOA- inhibition of COX enzymes and subsequent reduction in prostanoid synthesis

122
Q

what are COX-1 AND COX-2

A

cyclooxygenase enzymes

123
Q

what are the two functional cyclooxygenase enzymes

A

two functional isoforms: (could be others)
COX-1 constitutively active across most tissues
COX-2 inducible – mostly – typically in active/inflamed tissues

124
Q

decsribe features of COX-1

A

GI protection
platelet aggregation
vascular resistance
renal blood flow

chronic inflammation
chronic pain
raised blood pressure

125
Q

describe features of COX-2

A

renal homeostasis
tissue repair and healing
reproduction
inhibition of platelet aggregation

chronic inflammation
chronic pain
fever
blood vessel permeability
tumour cell growth

126
Q

Nonsteroidal anti-inflammatory drugs (NSAIDs), tell me about them

A

Widely prescribed drug class – predominantly used for their analgesic and anti-
inflammatory effects
* 10% UK population prescribed an NSAID in any given year
* Chemically dissimilar resulting in varying antipyretic, analgesic and anti-inflammatory
properties
* Single common mode of action – inhibition of COX → ↓prostaglandin, prostacyclin
and thromboxane synthesis (which is good and bad)
* Compete with arachidonic acid for hydrophobic site of COX enzyme
* Aspirin moderate dose – NSAID – the original - relegated to use as antiplatelet – low
dose – irreversible COX inhibitor (remember platelets non nuclear – new platelets
needed) – anti-inflammatory at high doses

127
Q

NSAID Properties

A

Functionally acidic (pka 3-6)-
inflamed sites are acidic
pH 6-6.5.
* Absorption occurs throughout
the gastrointestinal tract, but
particularly in the stomach
(acidic environment).
* 2 or more aromatic groups
(except aspirin)-Lipophilic-pass
through membranes
* Pharmacokinetics-drugs must
accumulate at inflammatory
site- paracetamol is ineffective
anti-inflammatory agent but is
analgesic

128
Q

Aspirin Pharmacology

A

Irreversible inactivation of cyclooxygenase (COX) enzyme e.g. acetylation of
the active site of the enzyme by aspirin
▪ Antiplatelet: TXA2 enhances platelet aggregation, while PGI2 decreases it.
Aspirin (75mg) in low doses irreversibly block the formation of TXA2 in
platelets without markedly affecting TXA2 production in endothelial cells of
blood vessels.
▪ The effects of Aspirin persist for a period of 3-7 days, which is the life cycle of
platelets.
▪ Decrease of TXA2 will decrease platelet aggregation.
▪ Only NSAID with anti-thrombotic properties

129
Q

Anti-inflammatory effects

A

Most commonly used NSAIDs block COX-1 and COX-2
 Anti-inflammatory effects due to inhibition of COX-2
 Inhibition of COX enzyme- therefore main effects on pain (via bradykinin (BK)).
Vasodilatation (by reducing the synthesis of vasodilator prostaglandins
Oedema (by an indirect action: the vasodilatation facilitates and potentiates
the action of mediators such as histamine)
 Ibuprofen in the short-term. For chronic conditions, drugs which interfere with
the disease process

130
Q

analgesia effects

A

PGs sensitise nerve endings to BK
* Inhibition of PGE synthesis by NSAIDs prevents nerve ending sensitisation
* NSAIDs effective in modulating inflammatory pain-RA, toothache
* Relieve headache by inhibiting PG mediated vasodilation in vasculature
* NSAIDs in spinal column can inhibit pain
* Aspirin, paracetamol, ibuprofen for short term analgesia; Piroxicam for
chronic inflammatory pain

131
Q

antipyretic effects

A

Interlukin-1 (IL-1) endogenous pyrogen released from macrophages
* IL-1 stimulates PGE production in the hypothalamus
* PGE disturbs hypothalamic thermostat- FEVER
* NSAIDs decreases PGE=antipyretic
Paracetamol preferred-lower GI side effect profile and without risk of Reye’s
syndrome in children (particularly with the use of Aspirin)

132
Q

Several classes of NSAIDs-vary in their potency, duration of action
and elimination

examples

A

Salicylic Acids-Aspirin-Cheap and effective. Can cause Reye’s syndrome in
children. Anti-thrombotic
* Propionic acids- Ibuprofen- Effective and better tolerated than most
NSAIDs. Half-Life=1-4hrs
* Phenylacetic acids- a diclofenac
* Fenamics Acid-mefenamic acid-menstrual pain
* Heterocyclic acetic acids- Indomethacin-one of the most potent NSAIDs in
vitro : Rheumatoid arthritis (RA)
* Oxicams –Piroxicam-Long half (45h) –given once per day
* Pyrazolones- phenylbutazone -v.potent and toxic. Used for ankylosing
spondylitis

133
Q

NSAID side effects

A

Gastric bleeds- Inhibit GI COX and decrease in platelet aggregation (risk
1.3% to 1.6% hospitalisation/death)
 Reversible renal insufficiency –PGE2 and PGI2 maintain renal blood supply=
lack of compensatory vasodilatation in response to angiotensin II
 Skin reactions – Urticaria
 In 3-5% asthmatics, aspirin can cause asthma to worsen, often in the form
of a severe and sudden attack
 Chronic Obstructive Pulmonary Disease (COPD) may be exacerbated by
NSAIDs as arachidonic is diverted away from the PG synthesis pathway
towards the Leukotriene synthesis
Leading cause of admissions to hospital in heart failure patients-due to
interference with ACE inhibitors/diuretics

134
Q

gastrointestinal ADRs due to NSAIDs

A

Probably the most common
Dyspepsia, nausea, peptic ulceration, bleeding and perforation
* Overall NSAID use 4X incidence of severe GI haemorrhage up to 2000 deaths
annually in UK
* ↓ mucus and bicarbonate secretion, ↑ acid secretion
* ↓ mucosal blood flow → enhanced cytotoxicity and hypoxia
* ↓ hydrophobicity of mucus layer due to acidic nature of NSAIDs locally
* Exacerbation of inflammatory bowel disease
* Local irritation and bleeding from rectal admin.
* Risk:
Age, prolonged use, glucocorticoid steroids, anticoagulants, smoking, alcohol,
history of peptic ulceration, helicobacter pylori

135
Q

risk factors for GI adverse effects in detail, NSAIDs

A

Age over 65
- History of GI bleed or ulcer
- Concurrent use of drugs that increase the risk of GI adverse events
- Heavy smoking or alcohol use
- Prolonged NSAID use
- Particular NSAID and high dose
- Serious co-morbidity

136
Q

Categories of Cox Inhibitors

A

COX-1 SPECIFIC = Low dose aspirin
* COX NON-SPECIFIC= All current NSAIDs
* COX-2 preferential= Some anti-inflammatory or analgesic activities that
inhibit COX-2, but no significant inhibition of COX-1
* COX-2 specific= causes no clinically significant inhibition of COX-1, even at
maximal dose

137
Q

efficacy of NSAIDs

A

About 60% of patients will respond to any NSAID.
*Those who do not respond to one may well respond to another.
*Pain relief starts from the first dose, with full analgesic effects obtained within
a week.
*Anti-inflammatory effects may not be achieved for up to three weeks

138
Q

Would a more selective COX – 2
Inhibitor reduce the side effects?

A

Selective COX-2 inhibitors were developed to reduce gastrointestinal side effects compared to nonselective NSAIDs, but they still carry increased cardiovascular risks. Their use requires careful consideration, especially in patients with cardiovascular risk factors, with adherence to recommended dosage and duration

139
Q

COX-2 inhibitors examples

A

Designed to block COX-2 (Inducible) inhibitor only e.g. Rofecoxib (Vioxx®),
Celecoxib (Celebrex®)
* Passed through clinical trials and used in practice widely.
* VIGOR (Vioxx ® GI Outcomes Research)- Rofecoxib vs. Naproxen (4 fold increase
of AMI)
* APPROVe study (2 fold increase in stroke and MI)
* Studies showed that Vioxx® may cause an increased risk in cardiovascular events
such as heart attacks and strokes during chronic use.
* Rofecoxib withdrawn in September 2004
* Pharmacology: Excess of thromboxane (THX) causing vasoconstriction, platelet
aggregation and thrombosis

140
Q

tell me about painkiller heart alert

A

A painkiller taken by millions can
increase the risk of heart attack and
stroke by 40 per cent, a study has
found.’

141
Q

MHRA January 2010
NSAIDs and CV risk in the general population

A

Two important studies since 2006 found a very small increase in the risk of
cardiovascular events. This may apply to all users of NSAIDs, not only those with
baseline cardiovascular risk factors after relatively short-term NSAID use (that may
increase with increasing duration of use).

142
Q

MHRA advice on cox-2 and non-selective NSAIDs

A

COX-2 inhibitors associated with 3 additional thrombotic events per year in
the general population
* Non-selective NSAIDs may also be associated with thrombotic risk
* Low dose ibuprofen <1200mg low risk
* Naproxen associated with lower thrombotic risk than coxibs (VIGOR)
* Diclofenac -risks similar to Etorcoxib
Additional 3 CV events per 1000 patients per year
* High doses and long term treatment more risky

143
Q

prescribing advice for NSAIDs

A

Lowest effective dose for shortest period
* Consider patient risk profile and profile of drug
* Do not switch without careful evaluation of risk
* Risk of GI problems greatly increased by addition of low dose aspirin
* Refer to MHRA safety update on NSAID

MHRA : Prescribers are reminded that for all NSAIDs (including COX-2
inhibitors), the lowest effective dose should be used, for the shortest
duration necessary

144
Q

Management of chronic inflammatory disease

NSAIDs

A

Aim to achieve remission
* Reduction in symptoms; decrease
in pain, decrease in swelling,
increase in mobility/function
* Achieved through NSAIDs (+/-)
Steriods (+/-) DMARDs (+/-)
Cytotoxics/immunosuppressants

145
Q

NSAIDs summary

A

NSAIDs effective and widely prescribed
* Inhibition of homeostatic prostaglandins contributes to extensive ADRs
* Many unnecessary cases of morbidity and mortality
* Risk benefit and minimum duration discussions should be had
* COX-2 selective have less GI ADRs
* CVS effects do not appear to be class specific
caution needed in patients with coronary and cerebrovascular disease
* Aspirin as an antiplatelet – low vs. moderate dose
* Paracetamol for mild-moderate pain and fever
toxicity is challenge due to change in pharmacokinetics

146
Q

DMARDs act to…

A

Ameliorate symptoms
* Slow progress of rheumatoid (RA) and other arthritic diseases including
psoriatic arthritis, juvenile arthritis etc..
* May be used for other chronic inflammatory conditions e.g. Ulcerative
Colitis, Crohns and Psoriasis
* Heterogeneous group of compounds

147
Q

DMARDs

Modification of disease process

A

Radiological evidence, symptoms and quality of life improvements support
early aggressive management of RA
* Slow onset-therapeutically active after 3-6 months, usually response within
6 months
* Frequently found by chance to be effective
* Mechanism of action poorly understood
* DMARD toxicity>NSAIDs
* Require haematological monitoring

148
Q

common MOA of DMARDs?

A

Mechanism of action are varied:
Decrease macrophage activity; Decrease T cell activation, Decrease
nucleotide synthesis, free radical scavenger
* No evidence for decrease in bone erosion, but decrease Rheumatoid
Factor

149
Q

therapy evidence found in DMARDs

A

Monotherapy with methotrexate effective-1st line treatment
* If methotrexate fails, other DMARDs less likely to work
* Combination therapy more effective
* Combinations tolerated as well as monotherapies
* Drug choice less important than speed and intensity of DMARDs
introduction
* Start within 3 months of symptoms

150
Q

what is a DMARD

A

DMARDs, or disease-modifying antirheumatic drugs, are a class of medications used to treat autoimmune and inflammatory conditions, particularly rheumatoid arthritis (RA) and other forms of inflammatory arthritis. These medications work by targeting the underlying disease processes rather than just providing symptomatic relief

151
Q

NICE GUIDANCE: Rheumatoid arthritis
The management of rheumatoid arthritis in adults

A

Conventional disease-modifying anti-rheumatic drugs
1.4.1 For adults with newly diagnosed active RA:
Offer first-line treatment with conventional disease-modifying anti-rheumatic drug (cDMARD)
monotherapy using oral methotrexate, leflunomide or sulfasalazine as soon as possible and
ideally within 3 months of onset of persistent symptoms.
Consider hydroxychloroquine for first-line treatment as an alternative to oral methotrexate,
leflunomide or sulfasalazine for mild or palindromic disease.
Escalate dose as tolerated. [2018)

1.4.2 Consider short-term bridging treatment with glucocorticoids (oral, intramuscular or intra-
articular) when starting a new cDMARD. [2018)

1.4.3 Offer additional cDMARDs (oral methotrexate, leflunomide, sulfasalazine or
hydroxychloroquine) in combination in a step-up strategy when the treatment target (remission
or low disease activity) has not been achieved despite dose escalation. [2018]

152
Q

what is availible for mild or active RA

A

antimalarial
chloroquine

153
Q

what is availible for moderate to severe RA

A

methotrexate

154
Q

what is availible for severe RA

A

penicillamine
leflunomide
azathuoprine
cyclosporin

155
Q

tell me about methotrexate DMARD

A

Most effective DMARD available
* Dihydrofolate reductase (DHFR) inhibitor: blocks folate synthesis; for
severe active RA. Its main therapeutic effect is inhibition of DNA synthesis
but is also impairs RNA and protein synthesis.
* Decrease the secretion of pro-inflammatory cytokines such as tumour
necrosis factor (TNF), while increasing the secretion of the inhibitory
cytokine interlukin-10 (IL-10)

156
Q

tell me about methotrexate MTX pathway

A

MTX- 50-90% Renally
Excreted and 6-7%
Hepatically Excreted
Remainder Travels to
Bone Marrow
Haematopoietic Pro-
Generator Cells

As MTX is an analogue of
Folate
Folate Pathway
Modified MTX by
Polyglutamation
Enhances the effect of
MTX on cell

Haematopoiesis
MTX Polyglutamate Effects
de-novo purine synthesis
Effects AICAR transformase
Effects GMP and AMP
Compromising DNA
synthesis
Reducing cell
proliferation:
Reduced titre of
leucocytes. Moving
to RA sites

157
Q

methotrexate applications DMARD

A

Once weekly dosage regimen-doses used in rheumatoid arthritis are lower
than those used in cancer chemotherapy
* Onset of action (6 weeks to 3 months )
* Started at a dose of 7.5mg orally once weekly and this is increased slowly
to a maximum of 25mg once weekly
* First-Line DMARD, especially if disease is severe, progressing quickly
and/or the patient cannot tolerate Sulphasalazine

158
Q

methotrexate side effects

A

Nausea and Stomatitis- successfully managed with folic acid
supplementation without the need for dosage reduction
There appears to be no clear guidance on the optimal dosage regimen of folic
acid. Some rheumatologists recommend a dose of 5mg daily, some use 5mg
once weekly (72 hours after the methotrexate) and others advocate 5mg
daily for six days each week, with the dose withheld on the day methotrexate
is taken.
* Hepatic and Pulmonary ADRs

Hepatic fibrosis or cirrhosis is rare in the absence of previously abnormal
liver function tests.
* The risk of hepatic toxicity is also greater if there is an excess alcohol intake
* Methotrexate is also teratogenic to ova and sperm
* Haematological
* Renal
* Other

159
Q

pulmonary side effects of methotrexate DMARD

A

Pulmonary complications in the form of pneumonitis (Inflammation of the
lung) are rare idiosyncratic reactions and are potentially lethal
* The classical presentation is with rapid onset dyspnoea (shortness of
breath) which may result in death after a few days
* Patients should be advised to stop methotrexate if the experience
dyspnoea or cough and to seek immediate attention

160
Q

methotrexate DMARD monitoring

A

Pre-treatment assessment: FBC, U&Es, creatinine, LFTs and chest x-rays
* Monitoring requirements: FBC and LFTs fortnightly until 6 weeks after last
dose increase, and monthly thereafter. U&Es 6-12monthly (more
frequently if there is any reason to suspect deteriorating renal function)

161
Q

tell me about hydroxychloroquine
antimalarial drug used in RA

A

An anti-malarial drug, which is also effective in rheumatoid arthritis and
systemic lupus erythematosus.
* Mode of action may be related to inhibition of cellular lysosomal enzymes
release and interference with intracellular function through inhibition of
Interlukin-1 (IL-1) release
* Drug Interactions: Antacids decrease absorption, cimetidine increases
drug levels. Hydroxychloroquine antagonises anti-convulsants

162
Q

hydroxychloroquine applications

A

May be prescribed with other DMARDs
* Typical dosage regimen: 200 to 400mg daily, aiming for a maintenance
dose of 3-5mg/kg/day, depending on response
* Base dose on ideal body weight-risk of toxicity in obese patients
* Time to response: Approximately 3-6months
* Lower toxicity than most DMARDs

163
Q

hydroxychloroquine side effects

A

5 people in every 100 have to stop taking the drug because of side effects
* Gastrointestinal: Nausea, diarrhoea, abdominal cramps (1 in 4)
* Mucocutaneous: Pruritic erythematous macular rash occurring soon after
treatment commenced, blue-black pigmentation of skin
* Ocular: irreversible retinopathy
* Myelosuppression (rarely)

164
Q

hydrocholorquine monitorning

A

Pre-treatment assessment: Visual acuity assessment, U&Es, LFTs
* Monitoring requirements: Yearly visual acuity assessments (Snellen test)
* Use with caution if patient has concurrent ophthalmological condition

165
Q

Sulphasalazine (Salazopyrin EN™) what is it

DMARD

A

Sulfasalazine, marketed under the brand name Salazopyrin EN™, is a disease-modifying antirheumatic drug (DMARD) used to treat inflammatory conditions such as rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease (e.g., ulcerative colitis and Crohn’s disease).

166
Q

Sulphasalazine (Salazopyrin EN™) indication

A

UC and RA

167
Q

Sulphasalazine (Salazopyrin EN™) MOA

A

Sulfasalazine exerts its therapeutic effects by inhibiting the production of inflammatory mediators, suppressing immune cell activity, and exerting antibacterial effects in the gastrointestinal tract.

Mechanism of action:
-Sulphasalazine and its metabolite are poorly absorbed into the bloodstream
-5-aminosalicyclic component not thought to be active as DMARD
-Due to sulfapyridine moiety inhibiting bacterial active component.

168
Q

Sulphasalazine:
Applications
DMARD

A

Good efficacy with moderate toxicity
* Time to response: Approximately 3 months
* Typical dosage regimen: 500mg/day increasing by 500mg/day/week, to a
maximum of 2.0-3.0g/day depending on efficacy and tolerability

169
Q

Sulphasalazine:
Side effects
DMARD

A

Haematological: Neutropenia, thrombocytopenia and rarely haemolytic or
aplastic anaemia
* Hepatic: Allergic hepatitis usually causes liver dysfunction early on i.e.
when dosage being increased
* Gastrointestinal: Mild nausea common early on, but severe nausea and
vomiting may preclude drug’s use
* Rashes, hypersensitivity to salicylates and sulphonamides
* Variable degree of reversible male infertility

170
Q

Sulphasalazine:
Monitoring
DMARD

A

Pre-treatment assessment: FBC,LFTs and baseline renal function
* Monitoring requirements: Fortnightly FBC and monthly LFTs for the
first 3 months, reducing to three monthly thereafter. Patients
should be asked about the presence of rash or oral ulceration at
each visit

171
Q

parenteral and oral gold definitions

A

Parenteral and oral gold, also known as gold salts, are medications used in the treatment of autoimmune and inflammatory conditions, particularly rheumatoid arthritis. Here’s a brief overview:

Parenteral Gold: Parenteral gold refers to gold compounds administered via injection, typically intramuscularly or intravenously. The most common parenteral gold compound used is aurothiomalate (Myochrysine™), which is administered as an intramuscular injection. Other parenteral gold compounds include auranofin (Ridaura™), which is taken orally but metabolized into gold compounds in the body.

Oral Gold: Oral gold refers to gold compounds administered in tablet form, which are taken orally. Auranofin is the primary oral gold compound used in the treatment of rheumatoid arthritis. Once ingested, auranofin is metabolized into active gold compounds in the body.

Oral- Auranofin (Ridaura™): Moderate efficacy: Low toxicity. No longer
available from the UK market
* Sodium Aurothiomalate (Myocrisin™): Good efficacy; moderate/high
toxicity
* Indications: Active RA
* Mechanism of action: Inhibits antigen processing within the lysosomes of
macrophages. Lymphocyte maturation and activation

172
Q

gold applications

A

Typical dosage regimen: 10mg test dose followed by observation (to
exclude drug sensitivity). Then commence weekly 50mg injections until
significant response occurs. Thereafter, 50mg fortnightly for three months,
then 50mg monthly.
* In responders, increase intervals between injections
* If after a total dose of 1000mg has been administered, no therapeutic has
occurred, the treatment should be stopped.
* Treatment is continued for up to 5 years after complete remission
* Only 20-25% of patients are still treatment after 2 years

173
Q

gold side effects

A

Mucocutaneous: Mild rashes but intensely itchy, rarely severe
erythematous rashes- but normally resolve rapidly on discontinuation.
* Haematological: Neutropenia, thrombocytopenia, eosinophilia
* Renal: Proteinuria
* Gastrointestinal: Nausea, reversible taste disturbance (metallic taste),
mouth ulcers, diarrhoea

174
Q

gold monitoring

A

Pre-treatment assessment: FBC, urinalysis, U&Es, creatinine, LFTs
* Monitoring requirements: FBC and urinalysis at the time of each
injection

175
Q

Penicillamine : (Distamine ™)
indications
DMARD

A

Indications: Non-responders to gold, active, progressive RA, vasculitis

Penicillamine is a disease-modifying antirheumatic drug (DMARD) used in the treatment of autoimmune and inflammatory conditions, particularly rheumatoid arthritis.

176
Q

Penicillamine : (Distamine ™)
MOA
DMARD

A

Mechanism of action: decrease macrophage activity; decrease DNA and
collagen synthesis; decrease Rheumatoid Factor; inhibit
polymorphonuclear leucocyte myeloperoxidase

177
Q

Penicillamine:
Applications
DMARD

A

Typical dosage regimen: Commence at 125mg/day, increasing by
125mg/day/month to 500mg/day. If no response after 3 months at this
dose, increase again by 125mg/day/month to 750mg/day. If no response
after 3 months increase by 125mg/day/month to a maximum of 1g daily. If
no response after 3 months on maximum dose, stop treatment.
* Time to response: Three to six months
* Drug Interactions: Antacids, and drugs containing calcium, iron and zinc

178
Q

Penicillamine:
Side effects
DMARD

A

Gastrointestinal: Nausea, taste alterations (metallic taste, usually settles
spontaneously).
* Mucocutaneous: Rashes, urticaria, oral ulceration. 40% of patients lost
through side effects
* Renal: Proteinuria
* Haematological: Neutropenia, thrombocytopenia and rarely aplastic or
haemolytic anaemias

179
Q

Penicillamine:
Monitoring
DMARD

A

Pre-treatment assessment: FBC, urinalysis, U&Es and creatinine
* Monitoring requirements: Fortnightly FBC and urinalysis until on stable
dose, then monthly thereafter. Patient should be asked about the
presence of rash or oral ulceration at each visit.

180
Q

Leflunomide (Arava™)

what is it

DMARD

A

Leflunomide, marketed under the brand name Arava™, is a disease-modifying antirheumatic drug (DMARD) used in the treatment of autoimmune and inflammatory conditions, primarily rheumatoid arthritis

Inhibits de novo pyrimidine synthesis by blocking dehydrogenase
* Activated T cells very susceptible
* Inhibits TNFα mediated transcription factor activation
* Comparable to MTX in efficacy

181
Q

Leflunomide (Arava™)
applications and monitoring
DMARD

A

Considered a drug of second choice for aggressive RA in patients
intolerant to MTX
* Active metabolites have half-lives of up to 4 weeks
* Pre-treatment assessment: FBC,LFTs, U&Es and blood pressure
* Time for response: Begins after 4-6 weeks
* Monitoring requirements: FBC two weekly for the first 6 months, then two
monthly, LFTs/BP monthly for the first 6 months

182
Q

Leflunomide (Arava™)
side effects
DMARD

A

Mucocutaneous: Eczema, dry skin, itching, urticaria, oral ulceration and
alopecia
* Haematological: leucopenia, anaemia, mild thrombocytopenia,
eosinophilia and rarely agranulocytosis
* Gastrointestinal: Nausea, vomiting, anorexia, abdominal pain, taste
disturbance and diarrhoea
* Abnormal LFTs
* Teratogenic

183
Q

tell me about immunosurpressants DMARDs

A

DNA synthesis is inhibited by: azathioprine, through its active metabolite
mercaptopurine-antimetabolite (FBC/U&Es/Creatinine and LFTs)
* Ciclosporin, inhibits T-Cell activation, cytokine production
(FBC/U&Es/Creatinine/LFTs/Lipids/BP)
* Mycophenolate Mofetil, through inhibition of de novo purine synthesis

184
Q

what is the structure of the thyroid gland

A

The thyroid gland is a butterfly-shaped endocrine gland located in the front of the neck, just below the Adam’s apple (thyroid cartilage). It consists of two lobes, one on each side of the trachea (windpipe), connected by a narrow band of tissue called the isthmus

185
Q

what is the function of the thyroid gland

A

The thyroid gland plays a crucial role in regulating metabolism, growth, and development by producing and releasing thyroid hormones.

186
Q

what does the thyroid hormone secrete

A

The thyroid gland secretes two main hormones: thyroxine (T4) and triiodothyronine (T3). These hormones are synthesized and released by the thyroid follicular cells in response to stimulation by thyroid-stimulating hormone (TSH) from the pituitary gland.

187
Q

Iodination (organification) of tyrosine

A

tyrosine to thyroxine

Tyrosine Incorporation: Tyrosine is incorporated into thyroglobulin.

Iodination of Tyrosine: Iodide ions are oxidized by thyroid peroxidase. forming diidotyrosine

thyroid peroxidase enzyme acts again to form diidotyrosine to thyroxine.

188
Q

Essential Stages of T3 and T4 Secretion

A

Iodine uptake into cell
– Active transport by carrier
* Iodination of tyrosine residues on thyroglobulin (TG)
– by thyroperoxidase enzyme
– called organic binding
* Formation of T3 and T4 from MIT and DIT
* Endocytosis of TG, enzymatic release of T3 and T4, secretion

189
Q

Action of thyroid hormones: metabolism

A

Regulate metabolism in most tissues.
* Modulate effects of other hormones (e.g. glucagon)
* T3 more potent than T4
* Increase metabolism of carbohydrates, proteins and fat
* Increase oxygen use and heat production,
* Increased basal metabolic rate

190
Q

Action of Thyroid Hormones, general

A

Affecting growth and development
– Direct and indirect action on cells
* Potentiates secretion and effects of growth hormone
– Needed for normal skeletal development, and maturation of CNS.
– Act by entering cell nucleus, T3 binds to receptor and switches it off.
* Receptor normally STOPS transcription
* So, T3 causes increase mRNA and protein synthesis in cells.

191
Q

Transport and Action of Thyroid Hormones

A

T3 and T4 transported bound to a protein carrier, TBG, little free.
– TBG (thyroxine binding globulin)
* LARGE pool T4, less active and mainly in circulation
* SMALL pool of T3, mainly intracellular
– T4 converted to T3 in target tissues, T3 is the active form.

192
Q

metabolic processes involved in the regulation and elimination of thyroid hormones

3 steps

A

Deiodination

Deamination

Conjugation with glucuronic and sulfuric acids

193
Q

Deiodination:

A

Deiodination refers to the removal of iodine atoms from thyroid hormones, primarily thyroxine (T4) and triiodothyronine (T3). Deiodinase enzymes catalyze this reaction, converting T4 to the more biologically active T3 or to inactive metabolites such as reverse T3 (rT3). Deiodination occurs predominantly in peripheral tissues, allowing for local regulation of thyroid hormone activity and metabolism.

194
Q

Deamination:

A

Deamination involves the removal of an amino group from thyroid hormones, resulting in the formation of inactive metabolites. This process can occur during the metabolism of thyroid hormones in the liver and other tissues. Deamination contributes to the clearance of excess thyroid hormones from the bloodstream and helps maintain hormonal balance within the body.

195
Q

Conjugation with Glucuronic and Sulfuric Acids:

A

Conjugation with Glucuronic and Sulfuric Acids: Thyroid hormones, particularly T4 and T3, can undergo conjugation with glucuronic acid or sulfuric acid in the liver. This conjugation process involves attaching glucuronic acid or sulfuric acid molecules to thyroid hormones, facilitating their excretion from the body in urine or bile. Conjugation with glucuronic and sulfuric acids enhances the water solubility of thyroid hormones, making them more readily excreted by the kidneys or eliminated in bile.

196
Q

Control of Secretion – HPT Axis

A

hypothalamus
pituitary
thyroid

hypothalamus secretes TRH
detected by anterior pituitary
produces / stimulates TSH
thyroid gland recats and secretes thyroid hormone to target cells

negative feebcak loop and hypothalamus detects this

197
Q

what is hypersecretion of thyroid hormone

A

hyperthyroidism

198
Q

what is hyposecretion of thyroid hormone

A

hypothyroidism

199
Q

Hyperthyroidism graves disease, what is it

A

Graves’ disease is an autoimmune disorder causing hyperthyroidism. Symptoms include weight loss, palpitations, tremors, and anxiety. Diagnosis involves tests like thyroid function tests and imaging. Treatment options include antithyroid drugs, radioactive iodine therapy, or thyroidectomy. Prognosis is usually good with proper management.

Hyperthyroidism (Graves disease)
* Occurs in 2% of women, which is ten times incidence observed in
men
* Autoimmune disease
– antibodies directed against proteins on surface of follicular cells
* Causes overproduction of thyroid hormones
– Possible involvement of environmental or emotional trigger factors
– Medication

200
Q

hyperthyroidism clinical features

A

Result from generalised over activity of thyroid gland:
– Hot, flushed, heat intolerant
– Enlarged thyroid gland (goitre)
– Exopthalmos
– Weight loss
– Muscle weakness, tremor
– Pulse rate ⇑, palpitations, sweating
– Hair loss, menstrual changes

201
Q

what is a goitre

A

A goiter is an enlargement of the thyroid gland, resulting in a visible swelling or lump in the front of the neck. It can occur due to various factors, including iodine deficiency, autoimmune diseases (such as Hashimoto’s thyroiditis or Graves’ disease), thyroid nodules, or certain medications.

can be caused by hyper or hypothyroidism

202
Q

Exophthalmos, what is it

A

Exophthalmos, also known as proptosis or bulging eyes, is a condition characterized by abnormal protrusion of one or both eyeballs from the eye sockets. It is often associated with thyroid eye disease (TED), also known as Graves’ ophthalmopathy, which is an autoimmune condition commonly linked with Graves’ disease, a form of hyperthyroidism

203
Q

diagnosis of hyperthyroidism

A

Physical examination
* Family history
* Blood tests
– Thyroid hormones (T3, T4 ⇑)
– TSH levels (⇓)
– Thyroid antibodies
* Thyroid scan (iodine uptake)

204
Q

hyperthyroidism drug treatment overall

A

Anti-thyroid drugs: ⇓ T3/4 secretion
* Prompt control: AIM RELIEVE SYMPTOMS
* Mild hyperthyroidism
* Children or young adults
* Temporary treatment
– Treatment for 12-18 months
* Prolonged remission in 20-30% patients
– Allergic reactions 5%, rashes, fever, pains
– Neutrophils ⇓, infection risk
– Agranulocytosis: rare, possible fatal
* Important counselling points!

205
Q

examples of hyperthyroidism drugs

A

Drugs which inhibit organic binding of iodine:
* The thiourelynes (thionamides)
– Carbimazole precursor of methimazole which inhibits oxidation of iodide and coupling to
tyrosine
* FIRST LINE IN UK
* Thought to act by inhibiting the thyroperoxidase enzyme
– Propylthiouracil (PTU): ALSO inhibits peripheral de-iodination of T4 to T3
* T4 pro-hormone, less active, more abundant)
* In UK kept for people unable to take carbimazole

206
Q

tell me about carbimazole

A

Give in high doses unitl euthyroid
* Reduce to maintenance dose
* Withdraw after 1-2 years and monitor
Clinical effect note:
Rapid action to inhibit organic binding BUT large stores of T3 and T4 must be
“used up” before therapeutic effect!

207
Q

Drugs which reduce the uptake of iodine:
hyperthyroidism

A

Drugs which reduce the uptake of iodine:
– Thiocyanate
– Perchlorate
* Reduce uptake of iodide ion
– Seldom used today because of danger of aplastic anaemia
* Sensible drug target… but side effects mean not clinically useful!

208
Q

symptom relief drugs for hyperthyroidism

A

β-blocking drugs :
– propranolol (most common), nadolol
– Used to reduce symptoms of over activity of the sympathetic nervous system
* Reduces tremor, tachycardia, and the anxiety associated with the condition
* NOT anti-thyroid drugs
– Used in many patients prior to and during initiation of other treatments to reduce distress
while waiting for therapeutic effect
* NB contraindications in some patients

209
Q

why is radioactive iodine given as treatment for hyperthyroidism

A

Selective Uptake by Thyroid Tissue: The thyroid gland is unique in its ability to concentrate iodine from the bloodstream for the synthesis of thyroid hormones. Radioactive iodine (usually iodine-131) is taken up by the thyroid gland in the same way as stable iodine. Once inside the thyroid follicular cells, radioactive iodine emits beta radiation, damaging and eventually destroying the thyroid tissue.

Targeted Destruction of Thyroid Cells: Hyperfunctioning thyroid cells, such as those seen in Graves’ disease, take up more iodine compared to normal thyroid tissue due to their increased activity. As a result, these hyperactive cells absorb more radioactive iodine, making them preferential targets for destruction. The radiation emitted by radioactive iodine selectively destroys these overactive thyroid cells while sparing surrounding tissues.

210
Q

tell me more about radioactive iodine given in hyperthyroidism

A

131I given as aqueous solution or
capsules
* Taken up by active transport &
concentrated in gland
* Local tissue destruction by x ray &
β-particle emission

Slow, progressive effect,
difficult to control:
* may produce
hypothyroidism (need
replacement therapy).
* First line treatment
* sometimes
* OR after failure of anti
thyroid drugs
* OR after failure of
thyroidectomy
* OR as standard
procedure for some
thyroid cancers

211
Q

surgery in hyperthyroidism

A

Thyroidectomy
– For patients where 131I and drugs have failed
– Patients with large goitre: cosmetic effects, swallowing or breathing
difficulties
* Ideally: sub-total thyroidectomy leaving patient with enough gland to
be euthyroid
– BUT possibility of recurrent thyrotoxicosis or developing hypothyroidism is a
risk

212
Q

what can hyperthyroidism treatment cause

A

hypothyroidism…

213
Q

what is hypothyroidism

A

Syndrome caused by deficiency of thyroid hormones

214
Q

possible causes of hypothyroidism

A

Congenital
* Autoimmune disease: Abs to thyroglobulin
* Inflammation of thyroid (Hashimotos thyroiditis)
* Dietary iodine deficiency

215
Q

Types of Hypothyroidism

A

Hashimotos thyroiditis (auto-immune)
– Inflammation, fibrosis and decreased function of thyroid gland. Goitre evident.
* Myxoedema
– Hypothyroidism developing in adult life
– Adult onset slow and insidious, confused with normal aging process. ⇑ women
– In rare cases, becomes medical emergency, requires treatment by T3.
* Cretinism: affects children from birth
– Poor mental development, pot belly, dwarfism
– Prevented by RAPID treatment with T4 at birth
* Maternal iodine deficiency
* Congenital dysfunction in hormone biosynthesis

216
Q

clinical features of hypothyroidism

A

Weakness, fatigue
– Cold intolerance
– Weight gain (but may have decreased appetite)
– Constipation
– Dry skin, thickened skin
– Brittle hair, alopecia
– Intellectual deterioration, mental and physical lethargy
– Goitre (TSH⇑)

217
Q

diagnosis of hypothyroidism

A

Physical examination
* Family history
* Blood tests
– Thyroid hormones (T4 ⇓)
– TSH levels (⇑)
* Overt hypothyroidism
– TSH > 10mU/L and FT4 below reference range
* Consider subclinical hypothyroidism
– TSH is raised but FT4 within reference range
* Consider secondary hypothyroidism
– T4 is low without raised TSH and clinical features

218
Q

TRT thyroid replacement therapy in hypothyroidism

A

Thyroxine (T4) used to replace deficiency
* Aim of therapy:
– Replace thyroid hormone function
– ⇒ normal physical & mental development
– Reduce goitre (suppress raised TSH levels)
* Optimum dose determined individually
– Single dose, before breakfast
– Important counselling points!

Life-long therapy, monitor effect
– Signs of overdose - thyrotoxicosis
* Tremor, agitation, weakness
* Insomnia
* Flushing, sweating, weight loss
* Angina-type pain, arrhythmias
* Diarrhoea, vomiting
* Non-compliance leading to increased doses:
– Check TSH levels, if raised, then not taking the tablets
– (Why? HINT - HPT)

219
Q

Drugs for Thyroid Replacement Therapy

A

Levothyroxine sodium
– Synthetic T4
– Treatment of choice for
maintenance
– Once daily dose
possible

Liothyronine sodium
– Similar action but more rapidly
metabolised
– May be used in severe
hypothyroid states
– Used IV as part of supportive
treatment of thyroid coma

220
Q

Monitoring of Replacement Therapy
hypothyroidism

A

Monitor TSH levels
– Within 8 weeks of starting levothyroxine
– After a dose change
– Annually once established

221
Q

What is a thyroid storm?

A

A thyroid storm, also known as thyrotoxic crisis, is a rare but life-threatening complication of hyperthyroidism characterized by severe and sudden exacerbation of symptoms related to excessive thyroid hormone levels. It represents a state of severe thyrotoxicosis with multi-system involvement and can be considered a medical emergency requiring prompt diagnosis and treatment

Thyroid storm is characterized by a sudden and severe exacerbation of hyperthyroid symptoms, including:

High fever (often above 104°F or 40°C)
Profound tachycardia (rapid heartbeat)
Severe hypertension (high blood pressure)
Agitation, confusion, or delirium
Extreme weakness or fatigue
Nausea, vomiting, or diarrhea
Jaundice (yellowing of the skin or eyes)
Tremors or seizures
Coma (in severe cases)
222
Q

treatment for thyroid strom?

A

Thyroid storm requires immediate medical intervention in an intensive care setting. Treatment aims to rapidly reduce circulating thyroid hormone levels, stabilize cardiovascular function, and manage symptoms. Treatment modalities may include:

Intravenous administration of antithyroid medications such as methimazole or propylthiouracil to block thyroid hormone synthesis.
Administration of beta-blockers to control heart rate and reduce symptoms of sympathetic overactivity.
Supportive measures such as hydration, cooling measures for fever, and correction of electrolyte imbalances.
Potassium iodide or potassium perchlorate to inhibit thyroid hormone release.
Glucocorticoids to inhibit peripheral conversion of T4 to T3.
In severe cases, plasmapheresis or thyroidectomy may be considered.
223
Q

what is transplantation

A

Transplantation is the grafting of organs or tissues from one individual to another
This is the ONLY treatment for most end-stage organ failure

Lack of available organs is a serious issue but…

	…the major barrier is our IMMUNE SYSTEM
224
Q

what is the major barrier to transplantation

A

immune system

225
Q

when was the first successful transplant

A

1906
1954 kidney transplant in boston - identical twins , synergic

226
Q

Donor Sources

A

Most transplants are cadaveric (dead donors)
Disadvantage: Long waiting list

Increases in living donor transplants
In the UK- 1 in 4 kidney transplants are now from living donors

For either source of donated organ, still high risk of rejection
The immune system is just doing its job!

227
Q

Rejection
donor

A

Rate of rejection – depends on;

1. tissue type

Skin rejected faster than kidney, liver well tolerated

2. number of transplants
Second grafts rejected faster

3. rejection mechanism
Antibody-mediated rejection can be instant
228
Q

why are second grafts rejected faster

A

Second grafts are rejected faster in organ transplantation due to alloimmune memory, where the immune system remembers previous exposure to foreign antigens from the first graft

229
Q

what is an autograft

A

generally accepted

Self-tissue transferred from one body site to another in the same individual

230
Q

what is an isograft

A

generally accepted

Tissue transferred between genetically identical individuals (inbred mice or identical twins)

231
Q

what is an allograft

A

often rejected

Tissue transferred between genetically different members of the same species

232
Q

what is a xenograft

A

majorly rejected

Tissue transferred between different species (e.g. baboon heart into human recipient)

233
Q

what is graft vs host disease

A

when bone marrow is transplanted, the T cells in the transplant attack the recipients tissues

234
Q

what is transplant rejection

A

when a kidney is transplanted the recipients T cells attack the transplant

an immune response

235
Q

what does graft acceptance depend upon

A

depends on the recipient sharing the donor’s MHC
(self vs non-self)

236
Q

tell me about graft vs host disease
GvHD

A

allogeic bone marrow transplant creates mature memory T cells

T cells circulate in blood to secondary lymphoid tissues

alloreactive cells interact with dendritic cells and proliferate

effector CD4 AND CD8 T cells enter tissues inflammed by the conditioning regemin

cause further tissue damage

transplantation of immunocompetent cells

237
Q

What’s happening at the cellular level?

A

The immune response to a graft is STRONGER than that to a pathogen…

238
Q

what does adaptive immunity improve with

A

age

239
Q

what is the primary immune response

A

first encounter with a pathogen
Longer lag time
Less specific response

240
Q

what is the secondary immune response

A

– second and subsequent infections with the same pathogen
Faster response
More specific response
Principle of vaccination (immunological memory)

241
Q

what does immunological memory result in

A

Immunological memory results in the more rapid elimination of pathogens, and more rapid destruction of a second graft

242
Q

graft to graft synergic recipient

A

graft tolerated

243
Q

skin graft to allogenic recipient

A

graft is rejected rapidly

first set rejection

244
Q

second skin graft from same donor to same recipient

A

graft shows accellerated second set rejection

245
Q

why is the immune response to a graft stronger than that to a pathogen?

A

Many T cells will recognise the graft as non-self
Viral infection: 1 in 100,000 T cells respond
Non-self (grafted) tissue: 1 in 100 T cells respond

T cells are MHC restricted… so
T cells can respond to non-self peptides in self MHC
this is called indirect allorecognition

246
Q

what is indirect allorecognition

A

T cells are MHC restricted… so
T cells can respond to non-self peptides in self MHC

247
Q

what is direct allorecognition

A

T cells can respond to non-self peptides in non-self MHC

248
Q

tell me about indirect allorecognition

A

Similar to normal T cell recognition
Non-self peptide: self MHC
Recipient host T cells recognise non-self, donor-derived antigen presented by host APC

what is indirect allorecognition important in?

in chronic graft rejection

249
Q

tell me about direct allorecognition

A

Donor APC migrate to draining lymph nodes
Interact with recipient host T cells- recognition of non-self peptide in non-self MHC
Depletion of grafted tissue APC promotes graft survival

Grafts with no lymphatic drainage tend to be more successful

250
Q

what is an MHC

A

MHC, or Major Histocompatibility Complex, are genes encoding proteins crucial for immune recognition. They present antigens to T cells, distinguishing between self and non-self. MHC class I presents intracellular antigens to CD8+ T cells, while MHC class II presents extracellular antigens to CD4+ T cells. MHC compatibility is crucial in transplantation to avoid rejection. Variations in MHC genes influence susceptibility to diseases. Overall, MHC molecules play pivotal roles in immune responses, disease susceptibility, and transplantation outcomes.

251
Q

what are the three rejection mechanisms

A

Hyper-acute - antibody mediated

Acute - T cell mediated

Chronic - Multiple mechanisms

252
Q

Hyper-acute graft rejection

A

Pre-existing recipient alloantibodies
sensitised to donor MHC -previous transplants, blood transfusion
Rejection occurs in minutes
Abs bind Ags on graft endothelial cells

Classical complement cascade activated
(inflammatory response = vascular leakage)
Neutrophils attracted to site
(release of lytic enzymes = cell damage)
Blood clotting cascade initiated
(blood coagulation = vessel blockage)

253
Q

Acute graft rejection

A

Type IV hypersensitivity
Mediated by activated allospecific effector T cells
Donor leukocyte involvement -direct allorecognition- non-self peptide in non-self MHC of donor APC
This stimulates a strong immune response

254
Q

give an example of acute graft rejection

A

kidney graft with dendritic cells

dendritic cells migrate to the spleen where they activate effector T cells

effector T cells migrate to graft via blood

graft destroyed by T cells

255
Q

when is acute graft rejection acellerated

A

In the presence of alloreactive memory T cells (previous transplants) - much more rapid rejection

256
Q

what is chronic graft rejection

A

Occurs months to years after transplantation
Gradual reduced blood supply to the graft- loss of function
This causes failure of over half kidney/heart grafts within 10years

257
Q

give an example of chronic graft rejection

A

alloantibodies recruit inflammatory cells to the blood vessel walls of the transplanted organ

increasing damage enables immune effectors to enter the tissue of the blood vessel wall and to inflict increasing damage

258
Q

what drives chronic rejection

A

Indirect allorecognition drives chronic rejection

Indirect allorecognition of transplanted tissue

Allogeneic (non-self) HLA Class I are processed and presented by self APC

This activates self TH

These will help activate naïve B cells – release of anti-alloHLA alloantibodies

Endothelial cells in the graft express alloHLA antigens

Binding of the anti-alloHLA antibodies to the alloHLA antigens results in impairment of function (autoimmune mechanisms)

259
Q

tell me abut non immunological rejction processes

A

Graft injury - at time of transplantation or during transit from donor to recipient
e.g. ischaemia-reperfusion injury
Disease - Recurrence of the problem that necessitated the transplant
e.g. lung infection in CF
Drug toxicity -immunosuppressants can be damaging
e.g. cyclosporin A is toxic to kidneys

260
Q

Matching donor and recipient HLA reduces rejection

A

We could just use syngeneic grafts- genetically identical, always accepted…
…but since we don’t all have an identical twin, there is a need to use non-identical (allogeneic) matches

261
Q

The options to minimise rejection of allogeneic grafts are:

A

HLA matching (tissue typing)
2. Immunosuppressant therapy
3. Induce tolerance (experimental)

262
Q

HLA matching/Tissue typing

A

ABO matching

HLA expression

Mixed lymphocyte reaction

HLA matching, also known as tissue typing, is a process used in organ transplantation to assess the compatibility between the human leukocyte antigens (HLA) of the donor organ and the recipient’s immune system

263
Q

ABO and Rh antigen matching prevents type II hypersensitivity in blood transfusions

A

Red blood cells- no class I MHC, no class II MHC expression

BUT red blood cells do express ABO and Rhesus alloantigens

Preformed antibodies in the transplant patient’s serum can bind surface antigens on the cells- red blood cell lysis

Histocompatibility matching prior to transplantation prevents this reaction

Cross match testing of matched blood prior to transfusion will then reveal whether any other antibodies in the patient serum react with the donor red cells

264
Q

what does ABO and Rh antigen matching prevent

A

type II hypersensitivity in blood transfusions

ABO and Rh antigen matching in blood transfusions are essential to prevent adverse reactions. ABO compatibility ensures that the donor’s blood type is compatible with the recipient’s, preventing acute hemolytic transfusion reactions. Rh compatibility prevents the formation of antibodies against Rh-positive RBCs in Rh-negative recipients, which can lead to hemolytic disease of the newborn or delayed hemolytic transfusion reactions. Compatibility testing involves crossmatching donor and recipient blood samples to ensure safe transfusions. Overall, ABO and Rh antigen matching are crucial for safe and effective blood transfusions, reducing the risk of complications and promoting patient safety.

265
Q

HLA expression analysis

A

Mix blood with a panel of antibodies to different HLA antigens
Agglutination reaction (blue) indicates antigen expression

266
Q

The mixed lymphocyte reaction measures T cell responses

A

Incubate irradiated donor cells (yellow) with recipient lymphocytes (blue)
If recipient cells recognise donor as non-self, they will respond by proliferation
(CD4:MHC class II mismatch) and cell death
(CD8:MHC Class I mismatch)

This test indicates the presence of alloreactive T cells- acute/chronic rejection

267
Q

Immunosuppressants permit successful allogeneic transplantation

A

The majority of patients receive mismatched organs
We need to use drugs to suppress alloreactions and prevent rejection

268
Q

Three kinds of immunosuppressant:

A

Corticosteroids
Cytotoxic compounds
T cell modifiers

269
Q

Corticosteroids for immunesupression

A

Prednisone- synthetic derivative of hydrocortisone
Requires enzymatic conversion in vivo to prednisolone
Global effects throughout the body
Steroids are Anti-inflammatory
Inhibition of NFB
Steroids are lymphocyte modifiers
Prevent homing to secondary lymphoid tissue
Steroids have many adverse side effects
Use acutely, not long-term

270
Q

Cytotoxic drugs for immunosupression

A

Azathioprine- pro-drug
Inhibits DNA replication
Prevents replication of alloantigen-stimulated T cells…
…and every other dividing cell (bone marrow, intestine)
Cyclophosphamide- chemical weapon from WWI- many toxic effects!
Methotrexate – inhibits replication, useful in inhibiting GVHD in bone marrow transplants

271
Q

T cell modifiers for immunosupression

(combination therapy)

A

Cyclosporin A- isolated from fungus
Tacrolimus (FK506)- isolated from bacteria
Rapamycin –isolated from bacteria on Easter Island
Inhibit T cell activation but also suppress B cell/granulocyte activation
No effects on proliferating cells (good news for the intestines) BUT fairly toxic to the kidneys
COMBINATION THERAPY

272
Q

Other potential therapies for transplant rejection

A

T cell specific antibodies can treat acute rejection
Anti-T cell antibodies that target the cell surface can bind to T cells and destroy them (C’fixation & phagocytosis)
Anti-T cell antibodies that target specific proteins (e.g. anti-CD3) interfere with function
Advances in humanising these antibodies reduce serum sickness
Daclizumab- binds a chain of IL2R
Reduces kidney rejection by 40%
Costs £720 per dose (equivalent to 1 year of tacrolimus)
Still need to be used in combination with corticosteroids/cytotoxic drugs

273
Q

what is the option for end stage organ failure

A

transplantations

274
Q

what is the barrier to successful transplantations

A

The barrier to successful transplantation is the difference in MHC between donor and recipient (self vs non-self )

The difference in MHC between donor and recipient poses a significant barrier to transplantation success. MHC molecules play a key role in immune recognition, and when a transplant expresses different MHC from the recipient, it triggers immune rejection. HLA matching helps reduce this risk.

275
Q

what does HLA matching reduce

A

rejection

276
Q

what does successful transplantation require

A

Successful transplantation requires lifelong therapy on a cocktail of immunosuppressant drugs

277
Q
A
278
Q
A

week 19 (Y2) (3 decks)

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