MP322 - Management of GastroIntestinal and Endocrine systems Flashcards

Question

What is Inflammatory Bowel Disease?

Answer 1

This is a broad term consisting of 2 diseases - Ulcerative Colitis and Crohn's disease Both are characterised by inflammation, swelling, and ulceration of intestinal tissue - chronic periods of remission Symptoms include stomach pain, weight loss, diarrheoa (blood/ mucus), and tiredness Can also cause joint pain, inflamed eyes and rashes.

Answer 2

UC only affects the large bowel and inflammation is on the inner lining. Crohn's can affect any area of the GI system and all layers of tissue can be inflamed.

Answer 3

Symptoms presented in Primary care, Blood tests conducted for anaemia, vitamin deficiencies, and inflammatory markers Can also get an X-Ray or MRI Sigmoidoscopy and Colonoscopy For Chron's disease, small bowel enema and small capsule endoscopy can be used.

Answer 4

Genetics, Autoimmune Disease Environmental Previous infection

Answer 5

Most common in late teens or early 20's, more common with white ethnic folk, is slightly more common in women than men, can affect 1 in 350 in the UK.

Answer 6

Induce and maintain remission Reduce symptoms and improve quality of life Reduce inflammation - steroid, aminosalicylates, and cytokine modulators Reduce autoimmune response - immunosuppressant drugs

Answer 7

Administered Orally and rectally - should use GR/ MR forms or enemas and foams etc. Hydrocortisone Beclomethasone Budesonide Prednisolone

Answer 8

Reduce inflammatory mediators directly, and also have effects on expression of genes associated with inflammatory and anti-inflammatory proteins

Answer 9

Avoid in congestive heart failure, hypothyroidism, osteoprosis, and untreated infection

Answer 10

Insomnia, dyspepsia, Cushing's syndrome, impaired healing, adrenal suppression with long term use.

Answer 11

Grapefruit juice increases plasma concentration or oral budesonide, corticosteroids antagonise diuretic effect.

Answer 12

Administered orally or rectally - Can be MR tabs/ caps/ granules, suspensions, or foam, suppository, enema's Balsalazide Mesalazine Olsalazine Sulfalazine

Answer 13

Blood disorders - unexplained bleeding, brusing, purpura, sore throat, fever, or malaise during treatment? Renal function should be checked before starting oral therapy then 3 months later, then annually Salicylate sensitivity?

Answer 14

Aminosalicylates are likely to be recommended: - As an initial treatment for people who have mild to moderate flare-ups of Colitis. - To maintain a period of recovery (remission), and help prevent flare-ups of colitis in longer term

Answer 15

Aminosalicylates are not commonly prescribed unless: - To get your symptoms under control, if your symptoms are mild, and you cannot, or decide against usage of steroids - If it is not clear whether you have Crohn's or colitis? - To help maintain remission if you have had surgery for Crohn's

Answer 16

Urine and contact lenses are coloured orange - hence contact lenses may be discouraged Sulfasalazine decreases concentration of digoxin (moderate) and absorption of folates (moderate).

Answer 17

These are monoclonal antibodies which inhibit pro-inflammatory cytokine, tumour necrosis factor alpha (TNF-a) Administered subcutaneously Examples - infliximab, adalimumab, golimumab, vedolizumab These stop the expansion of activated T-cells by interrupting the calmodulin-calcineruin cascade.

Answer 18

Mainly T-cell effects, administered orally or by injection, care required when handling in pharmacy Azathioprine, Ciclosporin, mercaptopurine Methotrexate Anticancer drugs with blood toxicity and liver toxicity so require regular monitoring of blood counts and organ function for safe use

Answer 19

Weekly dosage, usually orally but can be done via subcutaneous and intramuscular injection 2.5mg tablets normally used Can get sore throats, bleeding, bruising, and mouth ulcers. Regular monitoring - FBC, renal and liver Keep safety card High risk drug for MCR

Answer 20

In mild cases of disease in rectum and rectosigmoid is treated via local steroid or aminosalicylate Diffuse or unresponsive IBD is treated orally as above Parenteral administration is used in severe cases (steroid, immunosuppression and antibody therapy)

Answer 21

Smoking cessation Attention to diet - low residue diet - trigger foods? Surgery - Stoma operations - resection operations

Answer 22

Peptac, gaviscon (rafting agents)

Answer 23

Co-magaldrox, magnesium trisilicate

Answer 24

Omeprazole - 10, 20, 40mg Lansoprazole - 15, 30mg Esomeprazole - 20, 40 mg Rabeprazole - 10, 20mg

Answer 25

Tabs, caps, granules - gastro-resistant Dispersible, oro-dispersible tabs Oral Liquids/ suspensions from specials Injections

Answer 26

Increased risk of bone fracture on prolonged use in susceptible patients Increase of C.dif infection Masks symptoms of cancer Rebound hyper secretion of acid on cessation

Answer 27

Esomeprazole and Omeprazole reduce the antiplatlet effect of clopidigrel Pantoprazole may increase anticoagulant effect of warfarin.

Answer 28

Abdominal Pain, headaches - common Arthralgia, parasthesia - uncommon Confusion, gynaecomastia - Rare

Answer 29

Ranitidine (150, 300mg) Cimetidine (200, 400, 800mg) Famotidine (20mg, 40mg) Nizatidine (150, 300mg)

Answer 30

1. Masks symptoms of cancer 2. Diarrheoa, dizziness (common) 3. erythema - multiform (uncommon) 4. Hepatitis, confusion (rare).

Answer 31

Cimetidine increases blood conc of erythromycin Famotine and ranitidine reduce plasma conc or atazanavir

Answer 32

Chelates and complexes: Sucralfate - 1000mg Tripotassium dicitratobismuthate (120mg) Prostaglandin analogue: Misoprostol (200 mcg) Pro-kinetic drugs: Domperidone, metoclopramide

Answer 33

Should use lowest effective dose for shortest period, move from treatment doses to maintenance dose after period of time dependent upon the indication Can be used in combination with antibacterials for H.Pylori eradication

Answer 34

Omeprazole is usually in gastro-resistant form when administered - hence, it passes the stomach and evades being ionised at this point - it enters the bloodstream once absorbed in the small intestine, and then, once going through the bloodstream, it reaches the parietal cells and diffuses through the fatty secretory canals of the parietal cells. The pH of the parietal cells is very low (approx 1) Because of this, and the presence of the pyridinic groups, becomes ionised, and is thereafter trapped in the parietal cells as it cannot diffuse back out This results in a build up of omeprazole and causes chemical conversion Omeprazole converts to sulphenic acid and then sulphenamide (Which is omeprazole's active form). There is maximal conversion to sulphenamide due to steep proton gradient due to the proton pump enzyme Omeprazole and Sulphenamide are ion-trapped (sulphenamide is a permanently charged quarternary ammonium salt Sulphenamide reacts with thiol groups in the proton pump enzyme, which forms a stable disulphide complex. No more acid is produced until new enzyme is made, which results in long term inhibition of gastric acid production.

Answer 35

- formulated in hard gelatine capsules - prevents conversion to sulphenamide in stomach -if sulphenamide was formed, it would react with thiols in food and gastric mucus and be charged, rendering it unavailable.

Answer 36

High doses (80mg) are able to eliminate gastric acid production for atleast 4 hours Single 40mg does can still affect acid secretion 72 hours later with effects taking 3-5 days to disappear. Patients are given 20mg doses daily for 2-4 weeks (duodenal ulcer) or upto 8 weeks (gastric ulcer)

Answer 37

Improvement was sought but omeprazole is effective as a chiral molecule R-enantiomer was noted to give 15% gastric acid inhibition whereas the S-enantiomer gives 90% inhibition. Hence, Esomeprazole is now manufactured which is simply omeprazole but only the s-enantiomer form.

Answer 38

Ranitidine has a tertiary aliphatic amine, and 2 x Secondary alipathic amine, a thio-ether and nitro group. The sulfur can be converted to suloxides etc. There is likely complementary binding with the receptor and the antagonists, preventing the binding of other agonists etc. and therefore, inhibiting the activation of H2 receptors.

Answer 39

Aminosalicylates

Answer 40

Mesalazine

Answer 41

Typically formulated as sodium salts due to the presence of carboxylic acids - the di-sodium salt makes the molecule more water soluble for formulation

Answer 42

It is a pro-drug, which is responsible for breaking down to the active 5-aminosalisilic acid (Mesalazine)

Answer 43

Not completely clear but believed to inhibit prostaglandin and leukotriene biosynthesis amongst others.

Answer 44

Broken due to bacterial cleavage. The resulting sulfapyridine has no anti-inflammatory effect but can possibly give side effects hence balsalazide and olsalazine are designed.

Answer 45

Colonic microflora contains many species of bacteria It is low in oxygen and pH is between 6-7 Gives rise to reductive environment Hence bacterial azo-reductases cleave the sulfalzaine azo bond

Answer 46

They typically are formed as oral coated tablets which disintegrate at pH 7 in the intestine or suspension Administered by the rectum in suppository and enemae form

Answer 47

1/(1+10^Ph-pka)

Answer 48

1/(1+10^pka-ph)

Answer 49

Carboxylic acid has pka 2.5 Aromatic hydroxyl (phenol) has pka 11.5 and is acidic. Azo group acts fairly neutral in all circumstances Sulphonamide group has pka 6.5 and is also acidic Pyridine has pka of 4 and is basic so will be ionised. Because pH of stomach is roughly 2, carboxylic acid, phenol and sulphonamide will remain unionised. But pyridine will be fully ionised hence wouldn't absorb across stomach membrane. Log D = 0

Answer 50

In ileum, pH is roughly 7-8. Pyridine won't be ionised as it's pka is 4 and it's a base Sulphonamide will be dissociated as it has a pka of 6.5 Carboxylic acid will be ionised fully (pka 2.5) Phenol not ionised as it acts as acid and pka is 11.5. Furthermore, due to molecule size, it's able to pass through to colon where it is cleaved to 5-ASA

Answer 51

Carboxylic acid will be ionised fully (pka 2.5) and therefore can't passively absorb. Sulphonamide will be dissociated as it has a pka of 6.5 and therefore not fully ionised. Pyridine also may be partially ionised as it's pka is 4. Phenol not ionised as it acts as acid and pka is 11.5. Hence still has inability to passively be absorbed. BUT, is broken down to 5-ASA

Answer 52

With 5-ASA, the carboxylic acid is still fully ionised, and Aromatic amine and hydroxyl are not ionised, hence would still not passively absorb, but, because of the size of molecule being smaller, it is able to absorb through aqeuous gaps in between epithelial cells as it is a small molecule.

Answer 53

It does cleave but does not cause sulfa pyridyl toxicity.

Answer 54

Bioavailability Settling rate Possibility of obtaining homogenous mixtrues (and maintaining it) Flowability Other properties important for transformation of powders into tablets, capsules

Answer 55

Granulation

Answer 56

Milling Attrition

Answer 57

Pin and ball mills - combined impact and attrition methods vibration mills and hammer mills - Impact methods End runners mills roller mills - compression methods

Answer 58

Cutter mill can be used so the material is cut by one or more blade

Answer 59

Designed to apply pressure - can use Mortar and Pestle or use Roller mills

Answer 60

designed to cause particles to be hit by a moving surface and Moving particles to hit a surface

Answer 61

pressure and fiction principle can use Roller mills, but ones which rotate at different speeds.

Answer 62

The speed of rotation Need to use 2/3 of the angular velocity where centrifugal force occurs to ensure that the balls are lifted on the rising side of the drum, until their dynamic angel of repose is exceeded. At this point, they fall back or roll back and cascade back to base of drum - rendering most effective size reduction

Answer 63

consider Particle size to obtain Consider characteristics of the material: 1 - Cutter mills for elastic, fibrous, materials like roots and woods. 2 - Attrition methods are used for ointments, solid in suspensions and pastes 3. impact methods used for brittle materials Other factors such as cost,time, product stability should be considered.

Answer 64

The diameter of the area of space taken by particle surface, assuming it is fully circular

Answer 65

The diameter of of the complete area of space taken by particle, regardless of circularity or lack thereof.

Answer 66

The mean distance between 2 parallel tangents of the projected outline of a particle

Answer 67

Direct methods are sieving and microscopy Indirect methods include sedimentation rate and permeability

Answer 68

1-1000 micrometers for particles - provides 2D images and very diluted suspension used.

Answer 69

Size as low as 0.001 micrometers Can give 3D images, and info on shapes Disadvantages would be - expensive, high level of operator exercise.

Answer 70

Measure the volume of particles 0.1 to 1000 micrometres. The aperture creates a sensing zone. As the particle moves through the aperture there is a change in impedance and the change can be correlated to the volume of the particle.

Answer 71

Laser lights react with particles Light is diffracted by particles by an angle which is inversely proportional to the volume of the actual particle Detector analyses the radiation diffracted by the laser. He and Ne laser are more widely used laser.

Answer 72

Sieve's seaparate varying sizes of particles, they are classified based on the sieve aperture diameter (expressed in Micrometres). Sieve 1000 means the sieve aperture diameter is 1000 micrometer (1mm). Sieve aperture diameter - distance between 2 consecutive wires.

Answer 73

It is another method of particle seperation and the idea is the diameter of particles are estimated based on their sedimentation rate. Stokes equation is also used for this.

Answer 74

This is where particles suspended in medium are introduced at high fluid velocity. This results in vortex drawing them down due to fluid flow (gravity interactions are relatively minor). A tip of cyclone fluid flow is above the critical velocity where it can escape through narrow opening. This forms in inner vortex that travels up the cyclon and out of the outlet. coarser particles separate from fluid stream and fall out.

Answer 75

This is where fluid direction is opposite to sedimentation direction. Separatiom is dependent on veolcity of fluid flow Vectors are velocities If settling velocity is less than the fluid flow velocity particles get moved into direction of fluid flow.

Answer 76

Where two or more components are mixed together with the aim to obtain a homogenous distribution (without physical or chemical changes occurring).

Answer 77

Materials that mix sponteneously and irreversibly.

Answer 78

The components tend to separate

Answer 79

Components neither tend to separate nor mix.

Answer 80

Where the probability of selecting a particular type of particle is the same at all positions in the mix and is equal to the proportion of such particles in the total mix.

Answer 81

The more particles are present in a dose, ther more likely it is that the content will mirror the ratio in the mixture. Lower the proportion of a component in the mixture, the more difficult it is to achieve the same correct amount in each sample.

Answer 82

Particle size Shape Density Flowability Ratio between different components Mixing time Electrostatic interactions Total volume of powders being mixed Friability of material Humidity

Answer 83

The opposite process of mixing (i.e. de-mixing) Due to powders having different densities, shapes, and sizes

Answer 84

Tumbling mixers (mixing franuels and free flowing powders - at correct speed, tumbling action and powder bed dilates, resulting in shear mixing). Agitator mixers (motion of blade or paddle due to convection), mixer- granulators (impeller blade at high speed forces material up before it drops. Overall high shear forces and good mixing. Once mixed, granulation liquid can be added, chopper blade to break down products.

Answer 85

1. Initially mixing active ingredients with equal amount of diluent. Mix and then add more diluent 2. Not overflow mixing unit.

Answer 86

The process in which homogenous mixtures of primary powder particles form larger, still homogenous particles called granules.

Answer 87

Improve powder flow, Patient segregation improve compaction

Answer 88

The powders are mixed with granulating fluid, and the mass is then forced through a sieve.

Answer 89

1. adheshion and cohesion forces in immobile films 2. Interfacial forces in mobile liquid films. 3. Solid bridges (hardening binders or crystallization of dissolved substances). 4. Attractive forces between particles.

Answer 90

High speed mixer/ granulator - mixing, massing, and granulation all in one piece of equipment. OR fluidized - bed granulator - all granulation processes done in one equipment, but requires optimisation.

Answer 91

This is where a pressure is applied, intermediate product is broken, Sieving.

Answer 92

- use of attractive forces between solid particles - solid bridges (by partial melting) Granules formed via applied pressure, formation of sheet, milling and sieving etc.

Answer 93

Roller compaction.

Answer 94

Increased liquidity of stool and/or Increased loose or liquid stool frequency (>3 times/day)

Answer 95

Acute (less than or around 14 days) Persistent (more than 14 days) Chronic (more than 30 days)

Answer 96

Inflammatory - Presence of inflammatory process - mucoid and bloody stool, tenesmus, fever, crampy abdominal pain - small, frequent bowel movements - Histology of GI tract - abnormal Non-inflammatory - watery, large-volume, frequent stool (>10-20/day) - volume depletion is possible due to high volume and frequency of bowel movements - no tenesmus, blood in stool, fever or faecal matter - histology of GI tract is normal

Answer 97

Osmotic diarrhoea: - presence of unabsorbed or poorly absorbed solute - stool volume is small -stops or improves with fasting - mainly occurs down to maldigestion or malabsorption Secretory Diarrhoea: - Altered transport of ions across the mucosa - Increased secretion and decreased absorption of fluids - doesn't improve by fasting

Answer 98

Most common cause is infectious diseases - Bacteria such as e.coli, campylobacter, salmonella, c.diff - Viruses such as Rotavirus, norovirus - Parasites/ protozoa such as Entamoeba histoltica, giardia lambia,

Answer 99

Most common cause is medications: 1. Cardiovascular drugs, such as digoxin, quinidine, propranolol, ACE inhibitors 2. GI drugs such as magnesium based antacids, laxatives, H2 Antagonists 3. Endocrine drugs such as Oral hypoglycaemic agents, thyroxine 4. Antibacterials such as amoxicillin, cephlasphorins, erythromycin

Answer 100

Water follows the movement of electrolytes and glucose

Answer 101

Normally absorbed passively and is secondary to the absorption of solutes

Answer 102

The secreted chloride comes from the Na/K/2Cl cotransporter This activity is driven by the low intracellular Na+ Once in the cells, chloride is secreted via chloride channels Na+ and water enter lumen by paracellular transport

Answer 103

The toxin from the cholerae enters the cell - activates the G protein, which activates adenylyl cyclase This causes increased intracellular cAMP and activation of protein kinase A (PKA) Leading to phosphorylation of chloride channels Hence causing increased efflux of Cl- (and water) and diarrhoeal like symptoms

Answer 104

Disruption of normal intestinal microflora Proliferation of opportunistic pathogens occurs (C.diff for example) Leading to impaired fermentation of poorly absorbed carbohydrate and/or reduced production of short chain fatty acids.

Answer 105

This occurs due to a reduction in intestinal transit time and will result in inadequate absorption - drugs with cholinergic activity - e.g. pilocarpine (for dry mouth) - drugs with anticholinesterase activity e.g. donepezil (for Alzheimer's disease)

Answer 106

Loperamide is an anti-motility drug, which aims to prolong intestinal transit - can be used in uncomplicated diarrhoea in adults?

Answer 107

Acts on Mu opioid receptors on neuronal varicosities - causes decreased acetylcholine release Causes the reduction of peristaltic activity and increase segmental contraction Diphenoxylate is usually provided as a combination with atropine - co-phenotrope Codeine also has similar mechanism of action

Answer 108

Rebound Constipation, higher doses can have CNS effects Prolonged use can lead to opioid dependence.

Answer 109

Causes the activation of delta opioid receptors, which decrease the cellular cAMP Leads to the decreased secretion of Chloride and water Note: Enkephalins are the endogenous activator of delta opioid receptors Racecadotril (pro- drug) is metabolised to thiorphan and thiorphan acts as an enkephalinase inhibitor (i.e. prevents the breakdown of enkephalins)

Answer 110

Heterogeneous disorder Patients typically report 3 or more: 1. fewer than 3 bowel movements a wee 2. straining 3. Lumpy/ hard stools 4. Sensation of anorectal obstruction 5. Sensation of incomplete defecation 6. Manual manoeuvring required to defecate

Answer 111

Level of stool liquidity - grade 1 being rock solid and grade 7 being pure liquid

Answer 112

Primary: 1. Normal transit 2. Slow transit 3. Pelvic floor dysfunction 4. IBS with constipation Secondary: 1. Medications 2. Metabolic disorders 3. Endocrine disorders 4. Psychiatric (anxiety, depression)

Answer 113

1. Anticholinergics - Antidepressants, antihistamines, antimuscarinics, antipsychotics, antiparkinsonian agents 2. Opioids 3. Drugs affecting electrolytes 4. Laxative misuse - leads to atonic colon

Answer 114

1. Osmotic 2. Stimulant 3. Bulk-forming 4. Faecal softeners Drug treatment: - Predominantly used in constipation associated with irritable bowel syndrome and chronic idiopathic constipation

Answer 115

Linaclotide is a 14 amino acid synthetic peptide Linaclotide activates Guanylate Cyclase C (GC-C) Increased cellular cGMP and activation of protein kinase G (PKG) Phosphorylation of Cl- channel Increased efflux of Cl- and water.

Answer 116

Member of a class of agents called prostones - derived from functional fatty acids that occur naturally

Answer 117

Lubiprostone acts directly on Cl- channels (CLC-2) This leads to efflux of Cl- (and water) MAY also restore mucosal barrier function

Answer 118

Whilst both tend to be well tolerated; 1. Diarrhoea 2. Nausea 3. Vomiting 4. Abdominal Pain

Answer 119

Steroids are hormones which control many biological events They are derived from lanosterol in animals Produced in human adrenal glands Glucocorticosteroids are important in controlling inflammation - ALL share same 4 membered ring backbone

Answer 120

Has primary aliphatic hydroxyls, ketones and methyl groups.

Answer 121

It has an extra double bond - which is useful in improving specificity Chlorine is also added in place of a hydrogen and this makes the molecule more lipophilic

Answer 122

They are very lipophilic, as the hydroxyl groups are aliphatic, meaning they are unlikely to unionise due to having a pka of 16, hence, the LogD will be equivalent to LogP and will be able to passively absorb. The hydrogen bonding exhibited should also aid in making it possible to passively absorb? Steroids exhibit complementary binding at their receptors

Answer 123

It is believed that orally absorbed molecules are likely to observe factors in multiples of 5 1. A molecular weight less than 500 da 2. No more than 5 hydrogen bond donors 3. No more than 10 hydrogen bond acceptors 4. Calculated logP value less than 5 These rules are not exclusive for all molecules e.g Some antibiotics/ TB drugs, ciclosporin breach this rule but acts as a good rule of thumb in understanding drug action and drug design

Answer 124

Administered orally or rectally GR/ MR formulations or enaemae and foams Due to chemical functionality i.e. non ionised and logP values between 0.5 and 1.2 Absorption therefore occurs in the stomach or colon

Answer 125

It causes bulking up and reduces water output which is the symptom of diarrheoa

Answer 126

Gets converted to Morphine via phase 1 metabolism via CYP450 2D6 -formulated as a phosphate when orally administered Once ingested and dissolved, should be ionised, but once it enters an area of higher pH, should be unionised, and therefore absorbed

Answer 127

Atropine inversely agonises the mAchR

Answer 128

This makes it easier to dissolve

Answer 129

Hydrolysis reactions via liver and plasma esterases

Answer 130

At the tertiary aliphatic amine located at the centre of the molecule

Answer 131

It must be via some form of active transport due to molecular size and polarity - it is a circular peptide. does not follow lipinski rule Can be given in hard capsules

Answer 132

It is a guanylate cyclase activator - which is responsible for increasing water and electrolyte secretion.

Answer 133

It is a CIC-2 calcium channel activator It increases water and electrolyte secretion.

Answer 134

Inadequate absorption of nutrients from the GI tract - most absorption occurs via the smal, intestine walls

Answer 135

Carbohydrates, fats and proteins

Answer 136

Vitamins, minerals etc.

Answer 137

Crohn's, Coeliac, and Surgery, which renders the intestine wall unable to absorb nutrients

Answer 138

Pancreatitits, Cystic Fibrosis, lactase deficiency - this is where macronutrients aren't broken down and hence nothing available for absorption.

Answer 139

Small Intestine bacterial overgrowth - this is where the damage to the mucosa as well as metabolism of bile salts via bacteria cause both forms of malabsorption

Answer 140

Deficiencies such as iron deficiency anaemia, B12/ folate deficiency, Vitamin D and calcium deficiency - N.B. Steroid usage in IBD cases can also cause additional issues.

Answer 141

It is an autoimmune condition - whereby gluten activates an abnormal mucosal response - causing chronic inflammation and damage to the small intestine mucosa - villous atrophy Symptoms include fatigue, GI symptoms, weight loss. Diagnosed by serological testing. Has to be treated via elimination of gluten.

Answer 142

This is usually secondary to surgery but can be congenital May require parenteral nutrition - as less surface area available for absorption - Osteoporosis and vitamin deficiencies are potential risks

Answer 143

Levothyroxine, warfarin, oral contraceptives, digoxin

Answer 144

This is where chronic inflammation of pancreas leads to impaired function - less pancreatic enzymes Affects men more than women and can happen at any age. Strongly associated with alcohol consumption. Test includes faecal elastase - and also tests for fat-soluble vitamin deficiencies.

Answer 145

It is an inherited genetic condition - causes decreased chloride secretion - and increased sodium absorption = thick mucus. It is also strongly linked to pancreatic insufficiency (>85%). Symptoms include Steatorrhoea, Osteoporosis, and Malnutrition, weight loss etc.

Answer 146

Primary Secondary Congenital (Extremely rare) Developmental (for premature babies but improves with age).

Answer 147

Reduce or eliminate dietary lactose intake Alternative calcium source required

Answer 148

Chronic Pancreatitis, motility disorders, surgery - most common causes - as it slows the passage of food and waste products in the digestive tract Reduced gastric acid - restricts digestion: atrophic gastritis, drugs? Impaired motility - diabetes, radiation enteritis, drugs, post surgery -loops?

Answer 149

Problem with digestion, insufficient enzymes, or absorption Malabsorption more common in Coeliac, Crohn's Results in deficiencies of fat-soluble vitamins (A,D, E, K) Symptom - steatorrhoea - fat in stools

Answer 150

Meat, fish and dairy products.

Answer 151

1-2.5 mcg/ day

Answer 152

2 Mechanisms: 1. Passive absorption - Through buccal, duodenal and ileal mucosa - Rapid but extremely inefficient - less than 1% oral dose is absorbed. 2. Active transport - Normal physiological mechanism is active transport - occurs through the ileum - mediated by gastric intrinsic factor - around 70% of ingested amount is absorbed

Answer 153

Vitamin B12 is released from food and bound to haptocorrin (transcobalamin I), Intrinsic factor is secreted by parietal cells - on reaching the duodenum, haptocorrin is degraded by releasing vitamin B12. Vitamin B12 is then captured by intrinsic factor, which then passes along intestine. In the terminal ileum, intrinsic factor-bound Vitamin B12 is endocytosed by cubam. Inside the enterocyte, intrinsic factor is degraded, releasing Vitamin B12 An ABC transporter releases Vitamin B12 in the blood - and is then bound to transcobalamin II although can be bound to I, II AND III, but II is most important for cellular uptake. Internalisation occurs in complex with transcobalamin receptor CD320 via endocytosis. Transcobalamin is degraded, yielding Vitamin B12. Excess Vitamin B12 is sent to liver for storage.

Answer 154

It is an essential co-enzyme for 2 enzymes in the body: It aids in the converstion of Homocysteine into Methionine It also aids in the conversion of Methylmalonyl-CoA to Succinyl-CoA

Answer 155

Intrinsic factor is produced in the parietal cells and its secretion parrallels that of acid In absence of intrinsic factor, inadequate amounts of Vitamin B12 are absorbed. Causing megaloblastic anaemia - normal size of blood cells are 10 microns - megaloblastic means will be larger than this. When it is due to absence of intrinsic factor, it is known as pernicious anaemia.

Answer 156

It is known as autoimmune atrophic gastritis. Causes destruction of parietal cells and associated lack of intrinsic factor. Immune response directed against H+/K+/ ATPase Also causes achlorhydria (low or no gastric acid production) Can also be caused by antibodies directed against intrinsic factor.

Answer 157

Inadequate dietary intake (rare) Loss of gastric parietal cells or intrinsic factor Functionally abnormal intrinsic factor. Bacterial overgrowth in intesine Disorders of ileal mucosa Disorders of plasma transport Dynfunctional uptake and use of Vitamin B12 by cells

Answer 158

1. Proton pump inhibitors/ H2A's - reduction in stomach 2. Oral contraceptive and hormone replacement therapy - believed to reduce levels of transcobalamin 3. Metformin - reduces vitamin B12 absorption 4. Colchicine - impairs or inhibits receptors in the terminal ileum.

Answer 159

115-1000 pmol/L

Answer 160

Leucopaenia, thrombocytopaenia, hypersegmented neutrophils.

Answer 161

Neurological - Pins and needles in hands and feet Sensory loss Gait ataxia Weakness in legs Subacute combined degeneration of the spinal cord (also affects brain and peripheral nerves). Can also get digestive effects such as Hunter's glossitis Can also get cardiovascular effects such as angina, Venous thromboembolic disease Gynaecological effects such as infertility.

Answer 162

0-10% cyanocobalamin 8-15% hydroxycobalamin 22-39% Deoxyadenosylcobalamin 36-62% Methylcobalamin

Answer 163

Deoxyadenosylcobalamin and Methylcobalamin

Answer 164

200 mcg/ day 400 mcg/ day in pregnancy

Answer 165

Natural folates are conjugated to a polyglutamyl chain - folates are absorbed in monoglutamate form Hydrolysed by folypoly-y-glutamate carboxypeptidase 5-MTHF is main form of dietary folate

Answer 166

Most absorption occurs in proximal small intestine (duodenum, jejunum) - some can happen in colon. Folate absorbed from lumen by proton coupled folate transporter. Absorption also occurs via redued folate carrier (RFC), with folate being exchanged for organic phosphate.

Answer 167

Enterocytes also have folate receptors (binds folate and internalises it by receptor mediated endocytosis). Folate can be exported without further metabolism - or reduced to 5-MTHF. Both forms of folate are exported from enterocyte by an organic anion transporter.

Answer 168

Most is transported as mono-glutamyl derivative - most folate circulates free in the blood - some is bound to albumin Plasma conc is 10-30 nmol/l In terms of cellular uptake, this is done by the same mechanisms as for enterocytes - PCFT, RFC, and folate receptor

Answer 169

75% exists as polyglutamate conjugates.

Answer 170

The transfer on one-carbon units to amino acids, nucleotides, and other biomolecules.

Answer 171

Inadequate dietary intake Congenital defects in uptake systems Intestinal disease Drug interaction - cholestyramine, sulfasalazine, trimethoprim, methotrexate, metformin Chronic alcohol use Increased cellular requirement.

Answer 172

Sore tongue, pain upon swallowing, GI symptoms, Neurologic, and when severe, results in megaloblastic anaemia

Answer 173

Neural tube defects

Answer 174

Oral folic acid - 1-4 months Oral route sufficient even in malabsorption Treated until haematological recovery occurs.

Answer 175

This is where there is either an insufficiency in the production or action of the pancreatic hormone insulin. By far most common endocrine disorder.

Answer 176

Type 1 - loss of insulin production Type 2 - Insulin resistance, insufficient secretion of insulin

Answer 177

Abnormal fuel metabolism is noted - which results most notably in hyperglycaemia and dyslipidaemia, due to defects in insulin production/ secretion, insulin action, or both.

Answer 178

Referred to as insulin- dependent diabetes only 5-10% people with diabetes have type 1 peak age of diagnosis is 10-14 pancreas produces little to no insulin - autoimmune reasons?

Answer 179

Occurs when the body is in an insulin-resistant state and pancreatic beta cells cannot release sufficient insulin to compensate Most common form of diabetes Diagnosed later on in life Lifestyle causes - primary reason

Answer 180

600 calorie diet

Answer 181

Can affect up to 25% women during preganancy Usually develops in 2nd trimester and disappears after child is born. Cause not clear, but thought to be due to hormonal changes that occur during pregnancy, many of which can block the action of insulin

Answer 182

There are 3 main tests conducted? 1. Fasting glucose and random glucose 2. Glucose tolerance test 3. Hba1c

Answer 183

No food or drinks to be consumed for 8-10 hrs Normal: 3.9 to 5.4 mmol/l Prediabetes or impaired glucose tolerance: 5.5 to 6.9 mmol/l Diabetic: >7 mmol/l

Answer 184

Regardless of when person ate, random plasma glucose value of > 11.1 mmol/l

Answer 185

Subject must fast for atleast 8 hours - plasma glucose measured immediately before and 2 hours after giving 75g glucose dissolved in water. Plasma glucose two hours after glucose administration: >11.1 mmol/l indicates diabetes 7.9 - 11.1 mmol/l indicates impaired glucose tolerance

Answer 186

A measure of the average blood glucose levels over the previous 3-4 months.

Answer 187

>48 mmol/mol (6.5%) indicates Type 2 diabetes 42-48 mmol/mol (6.0-6.4%) indicates risk of developing diabetes

Answer 188

diagnosis made by combination of symptoms and abnormal blood tests In patients without classic symptoms, diagnosis can be made by 2 abnormal blood tests. Type 2 can be diagnosed via opportunistic screening. Early diagnosis is important because diabetes will otherwise get progressively worse

Answer 189

Excess urination, thirst, dehydration, weight loss, blurry vision

Answer 190

Potentially life-threatening complication of type 1 diabetes Caused by lack of insulin limiting glucose usage Causing free fatty acids released from adipocytes FFA's converted to ketone bodies by liver, and said ketones cause pH of blood to become acidic. Liver at the same time continues to synthesise glucose - blood glucose rises High glucose in urine takes water and solutes such as potassium and sodium with it, resulting in dehydration.

Answer 191

Fluid replacement, insulin, mineral replacement

Answer 192

These develop gradually (over decades) Chronic complications occur due to vascular damage. This can be either: 1. Microvascular - damage to small blood vessels (capillaries) 2. Macrovascular - damage to larger blood vessels (arteries and veins) Hyperglycaemia associated with damage to blood vessels and atherosclerosis Diabetes - increased risk of developing high blood pressure.

Answer 193

This is where nerve damage or poor blood flow increases risk of various complications. Cuts and blisters become serious infections, which often heal poorly. Diabetes is most common cause of lower limb amputations.

Answer 194

People with diabetes are at 1.5-2.5 x greater risk of dementia. Mechanisms not yet understood.

Answer 195

Increased risk of miscarriage, still birth, and birth defects when diabetes are not well-controlled. For mother, diabetes increases risk of DKA, retinopathy, pregnancy-induced high blood pressure and pre-eclampsia.

Answer 196

The beta cells in the pancreas

Answer 197

An increased uptake and metabolism of glucose leads to an increase in ATP-ADP ratio Said increased ratio leads to closure of ATP-sensitive Potassium channels and causes membrane depolarisation Depolarisation leads to the opening of voltage gated of calcium channels Increase in intracellular calcium promotes secretion of insulin

Answer 198

Increase: - Glucose uptake - Glycogen synthesis - Fatty acid/ triglyceride synthesis Decrease: - Glycogen breakdown - Gluconeogenesis - Lipolysis

Answer 199

It is able to travel through the blood - can target any cell in ther body -Mainly targets, fats, liver, and skeletal muscle

Answer 200

1. Insulin binds to Insulin receptor - leads to receptor autophosphorylation 2. Phosphorylated residues on the IR acts as binding site for insulin receptor substrate proteins 3. IR phosphorylates 4 tyrosine residues in IRS proteins 4. Lipid kinase known as Phosphoinositide 3-kinase binds to phosphorylated residues on IRS proteins - and converts PIP 2 TO PIP 3. 5. Binding to PIP3 activates PDK1, which then phosphorylates and activates protein kinase B. 6. Activated PKB can then diffuse through the cell and activate processes such as glucose transport and glycogen synthesis. Glucose is then able to transport into adipocytes and skeletal muscle.

Answer 201

Glucose transporter GLUT4 is contained in the cell in storage vesicles Protein AS160 acts to hold these vesicles inside the cell PKB phosphorylates AS160 and inactivates it. This allows GLUT4 vesicles to fuse with the plasma membrane, leading to increased levels of the glucose transporter at the cell surface.

Answer 202

Fox01 is synthesised in the cytosol but is targeted to the nucleus, where it regulates expression of genes, that mediate gluconeogenesis. PKB phosphorylates Fox01, preventing it from entering the nucleus, leading to lack of expression of gluconeogenic genes, which leads to a loss of glucose production.

Answer 203

Loss of insulin secretion or resistance leads to hyperglycaemia due to: 1. Loss of insulin-stimulated glucose uptake into target cells 2. Loss of insulin-mediated repression of gluconeogenesis (and glycogen breakdown) in the liver.

Answer 204

Risk of T1D is 15x higher for first degree relatives of someone with the disease. The HLA - region of chromosone 6 is linked to susceptibility to developing T1D - This contains genes encoding components of major histocompatibility complex - key component of the immune system - Although HLA genes have strongest association with T1D, only 5% of people with disease- linked variants develop T1D.

Answer 205

Presence of Autoantibodies against beta cell antigens is a significant risk factor. Examples: 1. Glutamic acid decarboxylase-65 2. Insulin 3. IA-2 4. ZnT8 Upto 3-5% of the population may test positive for these or other antibodies against beta cell proteins - but only 20% will develop T1D. Presence of two different antibodies increase risk of developing T1D within next 10 years to 75%

Answer 206

This is difficult to identify as these triggers may occur years before onset of symptoms and there may be several events involved. Enteroviruses (esp. coxsackie) have been implicated - could be due to similarity with 2c protein of virus and GAD65, which may suggest molecular mimicry might be involved.

Answer 207

Each form of cell (alpha, beta, delta), secrete distinct hormones. Each cell expresses different tissue-specific proteins. In T1D, an effector T cell recognises peptides from a beta-cell specific protein and kills the beta cell. Hence no insulin is produced.

Answer 208

Protein Tyrosine Phosphatase 1B is able to dephosphorylate the Insulin receptor, leading to a loss of IRS binding. IRS proteins can also be inactivated by phosphorylation of Serine residues by PKC, which prevents IR from phosphorylating tyrosine residues on IRS.

Answer 209

It is possible the amount of triacylglycerols exceeds the storage capacity of adipose cells... as a result, fat starts to accumulate in other tissues such as liver and muscle. Also, excess fat leads to increased levels of the intracellular lipid signalling intermediates Diacylglycerol and Ceramide (a component of sphingolipids) in the cytoplasm of cells. Both are formed from fatty acids. These both cause the inhibition of PKB activation and phosphorylation of Serine residues on IRS. Leading to insulin resistance.

Answer 210

Obesity is a pro-inflammatory condition associated with increased circulating levels of pro-inflammatory cytokines Adipose tissue from lean individuals secrete anti-inflammatory and insulin- sensitising adipokines such as adiponectin. In obesity, more pro-inflammatory cytokines are released such as TNF-a and less adiponectin.

Answer 211

TNF-a has many different effects that may contribute to insulin resistance, including: Expression of PTP1B, which can dephosphorylate the insulin receptor.

Answer 212

Adiponectin is secreted from adipocytes and promotes insulin sensitivity. Insulin-sensitising effects of adiponectin are related to its effects on sphingolipid metabolism. Adiponectin secretion is decreased in obesity , which contributes to insulin resistance.

Answer 213

Beta cell destruction and loss of insulin secretory pathway also contribute to Type 2 diabetes. Dysregulation of insulin secretion is linked to accumulation of fat in pancreas.

Answer 214

Type 2 diabetes is a complex polygenic disorder (caused by lack of combination of genetic and lifestyle factors). Recent GWAS studies identified many gene polymorphisms that occur more frequently in Type 2 diabetes than in controls (>75 risk genetic loci have been identified)

Answer 215

Metformin - a biguanide - Rx'd to approx 80% of people with T2DM Doesn't cause weight gain. Does not cause hypoglycaemia. First used clinically 1953

Answer 216

Metformin's main effect is it reduces hepatic glucose production Mechanism of action is not clear, but metformin is known to affect multiple cellular processes... most widely accepted model is linked to inhibition of mitochondrial respiratory-chain complex 1. This chain complex is involved in oxidative phosphorylation.

Answer 217

Metformin entetrs via OCT1 Then binds and inhibits mitochondrial respiratory-chain complex 1 results in less ATP synthesis Increase in AMP Activation of AMPK Phosphorylation and inhibition of CRTC2 Inhibition of gluconeogenic gene expression.

Answer 218

GI side effects - Diarrheoa, nausea, vomiting, bloating, reduced appeptite. Leads to discontinuation in 5% of patients. Vitamin B12 deficiency - reduces intestinal absorption of vit. b12 in up to 30% of patients and lowers serum levels in a dose dependant manner in 5-10% of patients. Can lead to symptoms such as tiredness and tingling in hands and feet Can rarely cause lactic acidosis.

Answer 219

Examples include gliclazide or glipizide They stimulate insulin secretion from pancreatic beta cells via mimicking high glucose level conditions via closing the ATP sensitive potassium channels being closed.

Answer 220

These act on the proximal tubule in the kidneys. SGLT2 act as glucose transporters These inhibitors prevent glucose from being reabsorbed in the kidney, resulting in glucose secretion.

Answer 221

empagliflozin (Jardiance®) dapagliflozin (Forxiga®) canagliflozin (lnvokana®)

Answer 222

These act as incretin mimics which stimulate insulin secretion and inhibit glucagon release. Normally, GLP1 and GIP are released in response to an increased concentration of glucose in the digestive tract lumen. And DPP4 can degrade incretins.

Answer 223

Liraglutide, semgalutide, exanatide, dulaglutide

Answer 224

DPP-4 inhibitors prevent the degredation of incretin, which subsequently allows for insulin secretion and inhibit glucagon release.

Answer 225

Sitagliptin, saxagliptin, alogliptin, linagliptin, viladagliptin

Answer 226

Increases insulin sensitivity by stimulating expression of insulin- sensitising genes via acting on nuclear receptors such as PPARy - these

Answer 227

Pioglitazone is only drug in this class.

Answer 228

They have a similar action to sulphonylureas but have a rapid onset and short duration Should be taken before meals Repaglinide Nateglinide

Answer 229

Should follow healthy diet and regular exercise T2DM is progressive disorder, oral medications may be required. If glucose control not adequate, insulin may be prescribed.

Answer 230

Weight loss surgery can be effective in putting T2DM in remission in the long term. This involves bypassing or reducing the size of the stomach - people feel much fuller sooner, less calories consumed = weight loss. Bariatric surgery is a treatment for people with type 2 diabetes - it is a treatment irrespective of weight loss - blood sugar levels drop soon after surgery and diabetes medications can be stopped soon after NICE recommends all patients in the uk with BMI of more than 35 with recent onset T2DM should be assessed for surgery. Initial cost of weight loss surgery is £6000

Answer 231

YES - studies have shown maintaining a 600 calorie diet for 3/4 weeks can reverse T2DM - success was closely correlated with weight loss.

Answer 232

In general, you start with one agent unless very symptomatic If not controlled, other agents can be added in. It is not recommended stopping a treatment unless you are at triple therapy or an injectable has been added - unless intolerant or no change in HbA1c in 6 months.

Answer 233

Increase dosing gradually to minimise GI side effects Increase weekly by 500mg - aim to get 1-2g daily can make it bd, can increase to tds, do not do qds - better to do 2 bd. Take with food. Caution - renal impairment Side effects - diarrheoa, anorexia, n&v N.B. BNF may be contradictory to local guidelines - BNF says no more than 2g, but manufacturers can recommend more Also possible to get 850mg tabs.

Answer 234

Could try offering M/R version - may improve pt compliance.

Answer 235

Can reduce HbA1c by 1-2% Not associated with weight gain Not associated with hypoglycaemia when given alone. Beneficial effects on lipid profile No Blood glucose monitoring required. Good evidence base.

Answer 236

Gliclazide, Glimeprimide, Glipizide, Glibenclamide Decreases HbA1c by 1-2% First line if metofrmin intolerant. Advantages: -good evidence base -Inexpensive - Good to bring back glycaemic control within 2 weeks. - Good for helping fatigue symptoms of T2DM Disadvantages: - Weight gain - Increased risk of hypoglycaemia (1/100) - Glibenclamide - has too high half life

Answer 237

Decreases HbA1c by 1%, do cause sodium retention though, will increase urination a releasing more glucose via urine hence it may be problematic if prone to UTI's. Advantages: Useful in renal failure as substitute for Metformin Low risk of Hypo Disadvantages: Contraindicated in heart failure Fractures - can increase risk Haematuria

Answer 238

Can be used in mono, dual and triple therapy Not believed to cause weight gain and not potent either. Take time to exert effect (2 months). Less incidence of hypo compared to sulfonylureas Alternative to use in place of TZD's (such as Pioglitazone) if weight gain a problem or glitazone is contraindicated/ poorly tolerated. Reduce HbA1c by approx 0.7% Good to use if no renal function.

Answer 239

Can decrease HbA1c by 5mmol/mol Weight loss BP reduction No hypos BUT: Does however take time to observe effect (6 WEEKS) Polyurea Genital infections more likely (as peeing more) Care with hypovolemia/ loop diuretics Cannot be given to >85 years Can cause renal impairment

Answer 240

Not commonly used due to cost Can be used as mono or with metformin Disadvantage: - weight gain - increased risk of hypoglycaemia (but less than sulfonylureas) - expensive

Answer 241

Albiglutide, dulaglutide, Exanatide MR, semaglutide - weekly Exenatide, Liraglutide, Lixisenatide - daily or twice daily.

Answer 242

3rd line with Met and SU or TZD BMI >35 HbA1c > 58mmol/mol Diagnosis < 10 years OR BMI <35 but unable to tolerate insulin.

Answer 243

This is where blood glucose is 4 mmol/ symptoms: - Sweaty, hungry, cold, pounding heartbeat, tingling lips - Neuroglycopenic - can lose consciousness, dizzy, faint, tired, confused irritability.

Answer 244

Eat or drink something which has sugar - sweets, glucose tabs, sugar drink Followed up by longer acting CHO - sandwich, fruit, biscuits, milk Should feel better after 5-10 min Eat normal meal soon as possible.

Answer 245

Annual CV risk assessment unless literally no risk factors such as BP, Weight, smoking, lipid profile Foot care should be monitored - Abnormal ACR tests should warrant checks.

Answer 246

It should be avoided unless they have serious cardiovascular issues.

Answer 247

No energy, depressed/ low mood, dry skin, high TSH and low free T4 levels

Answer 248

Levothyroxine, and Liothyronine Increase dosing by 25mcg every 2-4 weeks, and monitor for symptom improvement. Is possible to take overdose if wrong strength is consumed? Pt should be advised to take in morning.

Answer 249

Should use Carbimazole and Propylthiouracil Mainly use carbimazole - but can add propranolol if they have palpitations. Side effect of carbimazole - agranulocytosis - must make sure to be aware of cold-like symptoms, sore throats, bruising.

Answer 250

Use antihistamine

Answer 251

Insulin is first formed as its pre-sequence form. This takes it to the endoplasmic reticulum - from where it is packaged into secretory vesicles. Signal sequence is cleaved off by a protease in the endoplasmic reticulum, generating pro-insulin. Then, disulphide bonds are formed between Chain A and B. Then, proteases cleave at either end of chain C. This gives Insulin and 'C peptide'.

Answer 252

Insulin is stored as an inactive hexamer - which has 6 subunits. Has 2 A and 2 B chains Has Zinc ion in the middle of the hexamer - stabilises hexamer.

Answer 253

It disassembles upon release to bloodstream.

Answer 254

1 - Animal - not widely used but some people find it works better for them. 2 - Human - synthetically made via recombinant DNA 3 - Analogues - Human insulin is altered to make it work quicker and longer.

Answer 255

Rapid acting - soluble insulin - e.g. insulin aspart, insulin glulisine, insulin lispro Intermediate action - isophane insulin. Long acting - insulin detemir and insulin glargine.

Answer 256

They are pre- mixed insulin preparations containing various combinations of short-acting insulin or rapid-acting insulin analogue together with an intermediate acting insulin % of short acting can vary from 10-50%

Answer 257

Insulin and it's analogues are injected subcutaneously, they have to diffuse across capillary walls to enter general circulation. Diffusion is limited by size of insulin - ie. monomer > dimer > hexamer/aggregates

Answer 258

Humulin S (soluble) is short acting. Humulin I (isophane) is medium- acting. These both have the same form of insulin but have different profiles due to the I version adding on protamine

Answer 259

Protamine causes clustering of insulin, limiting diffusion through capillary walls. Protamine is basic protein (+ve charge), which binds to negatively charged insulin and clusters insulin hexamers.

Answer 260

Insulin aspart (Novorapid) has a proline to aspartate substitution in the B chain, which reduces the tendency to form hexamers. As a result, it is more rapidly transferred from the sub-cutaneous injection site to the bloodstream.

Answer 261

Insulin lispro has two substitutions in the B chain, which also diminish the tendency of insulin molecules to self - associate.

Answer 262

Insulin glulisine has two substitutions in the B chain - Asparagine is replaced with a lysine, and a lysine is replaced with a glutamic acid. These changes also reduce insulin self-association.

Answer 263

It contains an aspargine to glycine substitution in A chain and also has two arginines added to the carboxy terminal end of the B chain - these changes make insulin analogue less soluble at physiological pH, which limits absorption from the site of injection. Half life ~18-26 hrs

Answer 264

Insulin detemir has a covalently attached fatty acid (myristic acid) that causes the molecule to bind to albumin in the blood serum. Albumin competes with the insulin receptor for binding to insulin detemir, prolonging its action. Albumin binding also protects insulin detemir from circulating peptidases, increasing its stability. Half life ~18-26 hrs

Answer 265

It has a hexadecaneodioic acid group added to B chain - this mediates albumin binding but also causes formation of multi-hexamers when injected. Monomers are slowly released from these multi-hexamers, extending duration of action beyond 40 hours.

Answer 266

If orally administered, it would be degraded by proteases in the stomach and small intestine. Injection is sub-cutaneous. Once injected, insulin diffuses into small blood vessels and enters the bloodstream.

Answer 267

Injection site is typically the stomach, buttocks, or thighs. Rotated to avoid lipohypertrophy, accumulation of lumps under the skin. This can lead to problems with absorption of insulin.

Answer 268

Below 25 degrees celcius and ideally in the fridge.

Answer 269

Multiple daily injection basal-bolus insulin regimens. Injections of short action insulin analogue before meals, together with 1 or more separate daily injections of intermediate-acting insulin or long acting insulin analogue. Can use continuous subcutaneous insulin infusion; a programmable pump and insulin storage device that gives a regular or continuous amount of insulin (usually rapid acting insulin analogue or short acting insulin).

Answer 270

Insulin should be used in combination with oral-antidiabetic drugs Basal insulin is usually a suitable first step with once- or twice daily intermediate or long acting insulin. Biphasic insulin can be used if diabetic control is particularly poor. Basal-bolus regimen can be introduced if blood glucose remains inadequate.

Answer 271

It is a closed loop system that continuously monitors glucose levels and uses the information to adjust the levels of insulin being administered by an insulin pump

Answer 272

Islet cell transplantation takes the approach of implanting islet cells from a deceased donor or using stem cell-derived beta cells. Simple procedure where these are injected into the hepatic portal vein But body's immune system can attack these cells - need immunosuppressants Recently islet cells have been encapsulated in biocompatible material, which blocks the immune response to transplanted islet cells and negates the need for immunosuppressive drugs.

Answer 273

Beta cell regeneration - using chemical/genetic approaches that stimulate beta cell growth and regeneration and prevent immune system attack. Immunotherapy - these drugs are given to at-risk individuals and can delay the onset of T1D by up to 3 years. Hopes that similar drugs might reverse and permanently stop beta cell destruction. Also hoping to create insulin spray which is absorbed by mouth - attach insulin to carriers that protect from degredation and allow oral delivery. Non protein insulin subs that are able to bind to the insulin receptor and activate intracellular signalling pathways.

Answer 274

Log P are all negative, Pka's of 12 approx, likely due to resonance forms of biguanide which stabilise the conjugate acid. Hence will always be ionised in physiological pH. Therefore can never be passively absorbed.

Answer 275

Metformin does not get metabolised so is unchanged throughout the body.

Answer 276

Oldest form of oral hypoglycaemic agents. Pka's approx 5.4-5.9 Stimulate insulin secretion by binding to sulfonylurea receptor 1 subunit of ATP sensitive K-channels in the beta cell plasma membrane. Can be used with metformin if required.

Answer 277

Nateglinide has Log P 3.8, Pka of 3.6 (refers to carboxylic acid) Repaglinide has log P 5.2, Pka of 4.1 (aromatic carboxylic acid) and 6.0 (aromatic tertiary amine) These work similarly to sulfonylureas But has weaker binding and dissociation from the SUR-1 binding site of ATP sensitive potassium channel.

Answer 278

Possess the TDZ moiety Activates the gamma isoform of the peroxisome proliferator-activated receptor (PPAR-Gamma) Helps improve insulin sensitivity.

Answer 279

DPP4 normally acts on GLP1 AND GIP Released after food intake in the intestine and stimulate insulin production DPP-4 inactivates GLP-1 AND GIP so inhibition results in insulin stimulation.

Answer 280

Thyroid follicles have epithelial cells arranged in spheres Colloid - proteinaceous depot of thyroid hormone precursors. Iodine is brought into follicle cells via the Na/I co-transporters. Iodine then diffuses across and is transported to the colloid via pendrin transporters - oxidised, and attached to rings of tyrosines in thyroglobulin (forming MIT and DIT). The iodinated ring of one MIT or DIT is added to another DIT at another spot - giving t3 and t4 structures in thyroglobulin. This structure is endocytosed back into follicle cells. Lysosomal enzymes release t3 and t4 from their thyroglobulin structures. Then t3 and t4 are secreted.

Answer 281

T3 is the active one Most circulating t3 derived from t4 (via deiodination) T3 and T4 are extensively protein bound in the plasma. Bound to thyroxine- binding globulin (TBG) and Transthyretin thyroxine-binding prealbumin.

Answer 282

Hypothalamus releases TRH targeting the anterior pituitary. Anterior pituitary then releases TSH. TSH targets the thyroid gland - releases thyroid hormone - target cell response.

Answer 283

This is where thyroid secretion is normal.

Answer 284

Thyroid hormone secretion is subnormal (also known as myxoedema)

Answer 285

Thyroid hormone secretion is excessive (also referred to as thyrotoxicosis)

Answer 286

Increasing protein synthesis in follicular epithelial cells, increases DNA replication, and cell division Increases rough endoplasmic reticulum and cell machinery required for protein synthesis Thyroid will undergo hypertrophy if exposed to greater TSH concentration. Results in Goitre

Answer 287

Increased BMR Heat production Responsiveness to parasympathetic stimuli Permits normal growth and development Permits maintenance of normal activity.

Answer 288

1. Cretinism is the most extreme manifestation of iodine deficiency 2. Can cause mental retardation 3. Reduction in physical growth 4. Deaf-mutism 5. Can be caused by inadequate dietary iodine intake 6. Can also be due to maternal iodine deficiency during pregnancy Salt is now fortified with iodine

Answer 289

High T4, low TSH

Answer 290

High TSH, low T4

Answer 291

low TSH, low T4

Answer 292

1. Cold intolerance 2. Modest weight gain 3. Bradycardia 4. Unexplained tiredness 5. Constipation 6. Forgetfulness 7. Pale, coarse skin 8. Puffiness of face

Answer 293

Damage or loss of thyroid tissue But can also be due to low iodine consumption

Answer 294

Autoimmune condition whereby CD4 T cells recruit CD8 T cells and B cells. Antibodies to thyroid peroxidase and Cytotoxic T cells attack thyroid cells, leading to necrosis/ apoptosis of thyroid cells, resulting in hypothyroidism. Can also result in goitre.

Answer 295

Levothyroxine, which is the synthetic form of thyroxine (t4) Dose adjusted until TSH levels in mid range, patients should be monitored atleast annually, but more frequently for kids.

Answer 296

Monthly monitoring, and require 50-100% increase in normal dose Early treatment needed in neonates to prevent mental defect.

Answer 297

Hair loss first few months of treatment Headaches Insomnia Nervousness Fever, hot flashes and/or sweating Pounding heart beat or fluttering in chest Appetite changes

Answer 298

Liothyronine, is a synthetic form of T3, Controversy surrounds its use in treatment of hypothyroidism Not supported in Royal College of Physicians Risks from t3 therapy on bone, and heart

Answer 299

Levothyroxine: 1. Single dose, max effect in 10 days, passes off in 2-3 weeks 2. Half life is 7 days in euthyroid, 14 days in hypothyroidism Liothyronine: 1. 5 times as biologically potent as t4 2. Single dose reaches max effect in 24 hrs and passes off in 1 week 3. Half life is 2 days in euthyroid

Answer 300

This is uncommon, as it suggests that the pituitary does not produce TSH or the hypothalamus doesn't produce sufficient TRH (tertiary) Both t3, t4, and TSH are low, treatment similar to primary hypothyroidism

Answer 301

This is end result of untreated hypothyroidism Progessive weakness leading to unconsciousness Extreme hypothermia Areflexia, seizures, and respiratory depression Precipitating factors - illness, infection, trauma, drugs which suppress CNS Medical emergency requiring urgent treatment

Answer 302

Corticosteroids - Can decrease basal production of TRH and TSH, consequently decreasing thyroid hormone levels Lithium - inhibits release of thyroid hormone and interferes with their peripheral deiodination Amiodarone - Contains iodine and can cause both hypothyroidism and hyperthyroidism Cholestyramine - Reduces absorption of thyroxine

Answer 303

Heat intolerance Palpitations Weight loss - decreased appetite Restlessness and Nervousness Fatigue Increased sweating Frequent bowel movements Goitre may be present

Answer 304

Thyroid produces excess of t4 Reduction of TSH due to negative feedback loop T3 usually elevated as well.

Answer 305

Most common cause of hyperthyroidism Signs include goiter and Exopthalmos

Answer 306

This is also an autoimmune disease Caused by thyroid stimulating immunoglobulin (TSI) Activates TSH receptor on thyroid follicular cells Results in increased secretion of thyroid hormones

Answer 307

Surgery Radioactive iodine (131 iodine) Administered orally - solution or capsule Taken up by thyroid gland Emits gamma and beta radiation (half life 8.1 days) Treatment usually has its maximum effect around 3 months; but may be as long as 6 months.

Answer 308

Thioamides such as carbimazole , propylthiouracil Accumulated by thyroid Inhibit thyroid peroxidase, which is responsible for the iodination of tyrosine, and prevent hormone synthesis. Propylthiouracil also inhibits peripheral deiodination Effect is slow in onset - 4-6 weeks. Generally safe but may cause agranulocytosis, thereby increasing risk of infection.

Answer 309

Adrenocorticoids - such as: - mineralocorticoids - mainly aldosterone - released from zona glomerulosa - responsible for sodium resorption and potassium excretion in kidneys - glucocorticoids - mainly cortisol - released from zona fasciculata - regulate the body's response to stress. Sex hormones - androgens - released from zona reticularis - regulate reproductive function

Answer 310

Mainly catecholamines 80% adrenaline, 20% noradrenaline

Answer 311

Hypothalamus releases CRH Anterior pituitary then releases ACTH, which targets the adrenal cortex, which then causes the production of cortisol.

Answer 312

Cortisol shows daily fluctuation - spikes when time to get up, shows diurnal variation

Answer 313

Receptors for cortisol are found in many tissues Increases circulating glucose level Maintain normal responsiveness of blood vessels to vasoconstrictive stimuli Effects on immune system, nervous system, and kidneys

Answer 314

Inhibits glucose and amino acid uptake by many tissues Increases lipolysis of adipocytes Increases protein breakdown and reduced protein synthesis in muscle tissues etc. Increases gluconeogenesis in the liver.

Answer 315

Cortisol can easily pass the plasma membrane and does not require transporters etc. Alters gene expression - takes some time for proteins etc. to be formed or lack thereof.

Answer 316

This is due to dysfunction or destruction of the entire adrenal cortex Affects both glucocorticoid and mineralocorticoid function Onset of disease occurs when 90% or more of both adrenal cortices are destroyed. 40-60 cases per 1 mil population Most common in adults 30-50 years.

Answer 317

Darkened areas of skin Extreme fatigue Unintentional weight loss Low BP - light headedness and faintaing GI disturbance - nausea, vomiting Salt craving Low blood glucose (hypoglycaemia)

Answer 318

Primary adrenal insufficiency Autoimmune destruction of gland Can be triggered via infections - TB, HIV, sphilis, Cryptococci Invasion - neoplastic, fibrosis, sarcoidosis, amyloidosis Haemorrhage

Answer 319

Decreased cortisol due to lack of negative feedback Increased CRH and ACTH

Answer 320

Hydrocorisone, prednisolone, dexamethasone fludrocortisone (mineralocoritcoid) Daily adult dose HC is 15-30mg Given as divided dose e.g. 10mg waking, 5mg noon, 5mg evening Intercurrent illnesses might require increased glucocorticoid dose - life long treatment

Answer 321

Lack of ACTH secretion from pituitary Lack of CRH release from hypothalamus Patients don't typically show hyperpigmentation or have cravings for salt Can also be due to glucocorticoid drug therapy Can occur if glucocorticoid meds stopped abruptly. Treatment is glucocorticoid - mineralocorticoid is unnecessary

Answer 322

Bronchial asthma, anaphylaxsis and angioedema Acute fibrosing alveolitis Chronic inflammatoryn diseases such as IBD, chronic active hepatitis, glomerulonephritis, systemic lupus Neoplastic disease such as myeloma, lymphomas, lymphocytic leukaemias

Answer 323

Glucocorticoids suppress hypothalamus and anterior pituitary

Answer 324

No single regime as depends on patient response, disease being treated, and duration of treatment Short courses of less than 3 weeks can be stopped abruptly Gradual for: - those who received >3 weeks treatment - repeated courses - >40mg prednisolone daily for a week

Answer 325

This is where you have sudden, severe pain in the lower back, abdomen or legs Severe vomiting and diarrhoea, dehydration, low BP loss of consciousness Can result in death if not treated immediately.

Answer 326

-Hypersecretion of cortisol - linked to metabolic complications - T2DM, Dyslipidaemia, excessive bone resorption, hypertension

Answer 327

Pituitary tumour leading to excess secretion of ACTH - 65-70% of cases Adrenocorticol tumours - benign or malignant - or bilateral hyperplasia or dysplasia - 15-20% of cases Tumours external to HPA axis - 10-15% of cases.

Answer 328

ACTH dependant - body making too much ACTH - Due to pituitary or ectopic tumour ACTH independent - ACTH levels are low - adrenal glands making too much cortisol - adrenal tumour or hyperplasia.

Answer 329

Iatrogenic (drug related) Cushing Syndrome is commonly seen in clinical practice Glucocorticoid treatment e.g. prednisolone, dexamethasone, hydrocortisone, beclomethasone Occurs irrespective of route of admin If treatment is prolonged,and drug is potent, then Cushing's can occur

Answer 330

Glucocorticoids - metabolised by cyp p450 enzymes cyp3a4 important for metabolism Drugs which inhibit cyp p450 enzymes can prolong action of glucocorticoids - itraconazole, ritonavir, number of antidepressants.

Answer 331

Surgery - to remove pituitary gland or adrenal glands When drug induced - gradual withdrawal of the causative drug - aim to discontinue causative drug if possible Mifepristone - glucocorticoid receptor antagonist - Restore glucose tolerance and low blood pressure - doesn't reduce cortisol level

Answer 332

It is an 11B - hydroxylase inhibitor recent studies show effective for short and long term treatment of cushing's requires dose titration and careful clinical and biochemical monitoring

Answer 333

Blood bound to proteins - active in unbound form - have function in almost all cells

Answer 334

Log P 7.4 for levo and 6 for liothyronine and pka's of 10, 9, and 4 Halogens add more molecular weight and increase lipophilicity

Answer 335

Can simply be given orally but can be given by IM injection too.

Answer 336

It is a prodrug, which converts to methimazole - which inhibits thyroid peroxidases, preventing conversion of tyrosine into MIT and DIT, which means T3 and T4 won't absorb.

Answer 337

inhibits thyroid peroxidases, preventing conversion of tyrosine into MIT and DIT, which means T3 and T4 won't absorb. But also inhibits 5' deiodinase enzymes helping to stop T3 biosynthesis.

MP322 - Management of GastroIntestinal and Endocrine systems Flashcards

(365 cards)