the patient Flashcards

Question

Why is aldosterone important?

Answer 1

water retention

Answer 2

angiotensin 2

Answer 3

Hypothalamic, pituitary, adrenal axis

Answer 4

lack of available organs immune system - main

Answer 5

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

Answer 6

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!

Answer 7

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

Answer 8

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

Answer 9

Tissue transferred between genetically different members of the same species

Answer 10

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

Answer 11

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

Answer 12

when bone marrow is transplanted, the T cells in the transplant attack the bodys tissues. Transplantation of immunocompetent cells * GvHD can be lethal

Answer 13

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

Answer 14

second and subsequent infections with the same pathogen – Faster response – More specific response – Principle of vaccination last two, immunological memory

Answer 15

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

Answer 16

a more liekly graft rejection

Answer 17

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

Answer 18

T cells can respond to non-self peptides in non-self MHC Grafts with no lymphatic drainage tend to be more successful

Answer 19

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

Answer 20

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

Answer 21

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

Answer 22

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

Answer 23

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)

Answer 24

Graft injury disease drug toxicity

Answer 25

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

Answer 26

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

Answer 27

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

Answer 28

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

Answer 29

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

Answer 30

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

Answer 31

Incubate irradiated donor cells (yellow) with recipient lymphocytes (blue) This test indicates the presence of alloreactive T cells- acute/chronic rejection

Answer 32

– Corticosteroids – Cytotoxic compounds – T cell modifiers The majority of patients receive mismatched organs * We need to use drugs to suppress alloreactions and prevent rejection

Answer 33

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

Answer 34

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

Answer 35

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

Answer 36

minimise rejection

Answer 37

lifelong therapy on a cocktail of immunosuppressant drugs

Answer 38

too much Hyperthyroidism

Answer 39

hypothyroidism too little

Answer 40

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

Answer 41

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

Answer 42

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

Answer 43

Anti-thyroid drugs: ⇓ T3/4 secretion

Answer 44

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

Answer 45

* 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

Answer 46

– Thiocyanate – Perchlorate

Answer 47

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

Answer 48

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

Answer 49

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

Answer 50

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)

Answer 51

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

Answer 52

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

Answer 53

– 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.

Answer 54

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

Answer 55

– 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⇑)

Answer 56

* 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

Answer 57

* 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:

Answer 58

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

Answer 59

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

Answer 60

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

Answer 61

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

Answer 62

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

Answer 63

both decrease due to negative feedback

Answer 64

both still decrease

Answer 65

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

Answer 66

not commonly comissioned ££££ individual patient request black triangle drug Inhibits 11β-hydroxylation in the adrenal cortex Inhibition of cortisol production

Answer 67

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

Answer 68

Chronic adrenal insufficiency: effets men and women equally HYPOcorticolism – Insidious worsening of symptoms * Often undiagnosed, sometimes until an ADDISONIAN CRISIS occurs

Answer 69

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

Answer 70

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 !!!

Answer 71

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

Answer 72

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

Answer 73

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

Answer 74

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)

Answer 75

If the answer is NO: primary insufficiency most likely

Answer 76

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)

Answer 77

crushings disease

Answer 78

addisons disease

Answer 79

two tissues both of different origin

Answer 80

adrenal cortex adrenal medulla

Answer 81

Surrounds the medulla Three zones – secreting glucocorticoids and mineralocorticoids and androgens

Answer 82

Chromaffin tissue Secretes adrenaline and noradrenaline

Answer 83

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.

Answer 84

Produced by cells of zona fasciculata Controlled by pituitary ACTH in the adrenal cortex

Answer 85

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

Answer 86

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

Answer 87

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

Answer 88

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

Answer 89

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

Answer 90

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

Answer 91

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

Answer 92

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.

Answer 93

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.

Answer 94

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?

Answer 95

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

Answer 96

cyclooxygenase enzymes

Answer 97

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

Answer 98

GI protection platelet aggregation vascular resistance renal blood flow chronic inflammation chronic pain raised blood pressure

Answer 99

renal homeostasis tissue repair and healing reproduction inhibition of platelet aggregation chronic inflammation chronic pain fever blood vessel permeability tumour cell growth

Answer 100

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

Answer 101

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

Answer 102

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

Answer 103

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

Answer 104

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

Answer 105

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)

Answer 106

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

Answer 107

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

Answer 108

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

Answer 109

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

Answer 110

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

Answer 111

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

Answer 112

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

Answer 113

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

Answer 114

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

Answer 115

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).

Answer 116

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

Answer 117

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

Answer 118

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

Answer 119

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

Answer 120

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

Answer 121

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

Answer 122

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

Answer 123

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

Answer 124

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

Answer 125

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]

Answer 126

antimalarial chloroquine

Answer 127

methotrexate

Answer 128

penicillamine leflunomide azathuoprine cyclosporin

Answer 129

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)

Answer 130

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

Answer 131

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

Answer 132

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

Answer 133

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

Answer 134

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)

Answer 135

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

Answer 136

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

Answer 137

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)

Answer 138

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

Answer 139

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).

Answer 140

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.

Answer 141

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

Answer 142

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

Answer 143

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

Answer 144

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

Answer 145

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

Answer 146

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

Answer 147

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

Answer 148

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.

Answer 149

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

Answer 150

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

Answer 151

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

Answer 152

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.

Answer 153

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

Answer 154

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

Answer 155

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

Answer 156

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

Answer 157

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

Answer 158

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

Answer 159

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.

Answer 160

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.

Answer 161

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

Answer 162

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

Answer 163

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.

Answer 164

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.

Answer 165

Deiodination Deamination Conjugation with glucuronic and sulfuric acids

Answer 166

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.

Answer 167

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.

Answer 168

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.

Answer 169

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

Answer 170

hyperthyroidism

Answer 171

hypothyroidism

Answer 172

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

Answer 173

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

Answer 174

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

Answer 175

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

Answer 176

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

Answer 177

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!

Answer 178

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

Answer 179

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!

Answer 180

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!

Answer 181

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

Answer 182

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.

Answer 183

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

Answer 184

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

Answer 185

hypothyroidism...

Answer 186

Syndrome caused by deficiency of thyroid hormones

Answer 187

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

Answer 188

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

Answer 189

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⇑)

Answer 190

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

Answer 191

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)

Answer 192

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

Answer 193

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

Answer 194

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)

Answer 195

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.

Answer 196

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

Answer 197

immune system

Answer 198

1906 1954 kidney transplant in boston - identical twins , synergic

Answer 199

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!

Answer 200

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

Answer 201

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

Answer 202

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

Answer 203

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

Answer 204

often rejected Tissue transferred between genetically different members of the same species

Answer 205

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

Answer 206

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

Answer 207

when a kidney is transplanted the recipients T cells attack the transplant an immune response

Answer 208

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

Answer 209

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

Answer 210

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

Answer 211

first encounter with a pathogen Longer lag time Less specific response

Answer 212

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

Answer 213

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

Answer 214

graft tolerated

Answer 215

graft is rejected rapidly first set rejection

Answer 216

graft shows accellerated second set rejection

Answer 217

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

Answer 218

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

Answer 219

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

Answer 220

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

Answer 221

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

Answer 222

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.

Answer 223

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

Answer 224

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)

Answer 225

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

Answer 226

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

Answer 227

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

Answer 228

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

Answer 229

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

Answer 230

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)

Answer 231

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

Answer 232

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

Answer 233

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

Answer 234

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

Answer 235

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

Answer 236

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.

Answer 237

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

Answer 238

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

Answer 239

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

Answer 240

Corticosteroids Cytotoxic compounds T cell modifiers

Answer 241

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

Answer 242

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

Answer 243

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

Answer 244

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

Answer 245

transplantations

Answer 246

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.

Answer 247

Successful transplantation requires lifelong therapy on a cocktail of immunosuppressant drugs