Pharmacology 4: Diabetes and obesity

Question 1

tment which must be given immediately for diabetic ketoacidosis?

Answer 1

insulin-IV at a fixed rate for DKA
rehydration- IV replacement fluids, with K+ in fluid as insulin drives K+ into cells via Na+/H+ exchange stimulation and subsequent increased Na+ pump activity, so patient would otherwise become hypokalaemic very quickly, putting them at risk of cardiac arrythmias.

Question 2

classes of oral hypoglycaemic drugs?

Answer 2

those which increase sensitivity to insulin (insulin sensitisers): biguanides e.g. metformin, thiazolineinediones (glitazones) e.g. pioglitazone.
those which stimulate insulin release: sulfonylureas e.g. tolbutamide and glipizide, and meglitinides e.g. nateglinide.
glucagon like peptide-1 analogues
dipeptidyl peptidase-4 (DPP4) inhibitors (gliptins)
alpha-Glucosidase inhibitors

Question 3

how do thiazolineinediones (glitazones) work?

Answer 3

agonsitically bind to peroxisome proliferator-activated receptor-gamma (PPAR-gamma)= transcription factor- regulates AT differentiation and role in lipid met., which binds with another nuclear receptor- retinoid X receptor, complex upregulates wide set of genes- in liver, SM and AT, with products important in insulin signalling and so increase insulin sensitivity in AT and muscle.
increase glucose uptake
reduce glucose synthesis in liver, muscle and AT
suppress hepatic gluconeogenesis, and so reduce hepatic glucose output

Question 4

how do sulfonylureas work?

Answer 4

antagonise beta cell K+/ATP channel activity, causing decrease in K+ current, which cause depolarisation, which then increases Ca2+ entry into cell, which governs fusion rate of insulin vesicles with beta cell membrane, and their release into circulation.
Meglitidines also work in this way.

Question 5

Orlistat is a drug used to treat obesity, how does it work?

Answer 5

gastric and pancreatic lipase inhibitor, so reduces dietary fat conversion to FA and glycerol for absorption.

Question 6

SEs of orlistat?

Answer 6

soft fatty stools, flatus, unpleasant faecal discharge or faecal incontinence

Question 7

Sibutramine is used to treat obesity, how does it work?

Answer 7

NA and serotonin (5-HT) reuptake inhibitor. Suppresses appetite anf some additional reduction in hyperglycaemia rate of glucose met, poss. due to increased thermogenesis.

Question 8

SEs of sibutramine

Answer 8

increase HR and BP- CVS risk factors present and being treated in obese diabetics

Question 9

example of drug used to delay carbohydrate absorption by gut?

Answer 9

alpha-glucosidase inhibitors e.g. acarbose- inhibits bdown of carbohydrates to glucose
SEs: runny stools, flatulence- as carbs fermented by gut bacteria, abdominal pain, diarrhoea

Question 10

effects of insulin in body, other than decreasing blood glucose levels?

Answer 10

STORAGE promotion hormone

• stimulates hepatic glycogen prod via increasing glucokinase activity, glycolysis, and inhibits glycogenolysis and gluconeogenesis
• stimulates hepatic FA synthesis-for transport as lipoproteins- increase circulating free FA, promote clearance of circulating free FA
• inhibition of fat b.down in hepatocytes (lipolysis)- lipase inhibition
• increase aa uptake by muscle

Question 11

3 modes of action of metformin?

Answer 11

increase sensitivity of cells to insulin, and so stimulates glucose uptake by AT and skeletal muscle
inhibits hepatic gluconeogenesis
reduced absorption of glucose from gut

Question 12

describe the process of insulin production

Answer 12

synthesised initially as preproinsulin- exported into ER where signal peptide cleaved by signal peptidase, to create proinsulin- folds via disulphide bond formation and is transported to secretory vesicles where cleavage via endopeptidase produces insulin (A and B peptides with 2 S-S bridges) and C peptide= released in endogenous amounts from secretory vesicle.

Question 13

how is insulin secretion by pancreatic beta cells stimulated by increased glucose?

Answer 13

glucose met. increases IC ATP/ADP ratio.
glucose enters beta cells via GLUT2 transporter- facilitated diffusion, enters glycolytic pathway after conversion to glucose 6-phosphate by hexokinase. increase ATP closes K+/ATP sensitive channel, causing cell depolarisation, Ca2+ influx and fusion of insulin vesicles with cell membrane.

Question 14

why is insulin secretion prevented by low blood glucose?

Answer 14

low ATP:ADP in pancreatic beta cells as low glucose met, which opens K+/ATP channel, maintaining cells in a hyperpolarised state that prevents Ca2+ influx.

Question 15

how does insulin act on it target tissues e.g. AT, muscle and liver?

Answer 15

via a tyrosine-kinase linked receptor: binds to EC domain and activates TK, causing autophosphorylation of tyrosine and phosphorylation of intracellular insulin receptor substrate proteins. These protiens recruit 2nd messenger proteins important for insulin action.

Question 16

how is glucose reabsorbed by the kidneys and how is the process affected in diabetes?

Answer 16

PCT: high-capacity, low-affinity Na+-glucose co-transporter= SGLT2 on apical membrane= secondary AT using Na+ gradient generated by Na+K+ATPase, generates conc gradient for glucose that allows facilitated diffusion across BL membrane via GLT2.
straight PT: high affinity, low-capacity 2Na+-glucose co-transporter (SGLT1), GLT1 on BL membrane.
diabetes= excess glucose filtered, renal threshold exceeded so excess glucose unable to be reabsorbed and is excreted in urine. Glucose increase osmolarity of filtrate, reducing H20 reabsorption- remains with glucose and is excreted.

Question 17

renal threshold for glucose?

Answer 17

200mg/100ml

Question 18

despite high glucose in type 1 diabetes, why do glycogenolysis and gluconeogenesis proceed unchecked?

Answer 18

unavailability of insulin to promote glucose uptake into tissues, coupled with unopposed actions of counter-regulatory hormones e.g. cortisol and glucagon- increase PEPCK and fructose 1,6-bisphosphatase activity, causing starvation like response.

Question 19

how does obesity link to insulin resistance?

Answer 19

insulin receptor desensitisation
ectopic accumulation of lipid into liver and muscle
obesity-induced inflammation

Question 20

how does insulin suppress appetite?

Answer 20

insulin and leptin stimulate the inhibitory primary neurone that releases POMC to inhibit appetite, and inhibit the stimulatory pathway where NPY and agouti-related peptide are released to stimulate appetite.

Question 21

only aspect of insulin functioning which differs depending on which insulin you give to a patient?

Answer 21

rate of insulin absorption into blood following SC injection, which depends on insulin solubility and local circulation
this is dependent on aa sequence
formulation of drug different, can use recombinant DNA technology

Question 22

why might insulin requirement in an individual need to be increasef?

Answer 22

stress
infection
trauma
during puberty

Question 23

what insulin regimen may be suitable for a patient who has 3 meals a day at fixed times/structured lifestyle?

Answer 23

a twice daily insulin regimen/conventional insulin therapy: you will inject twice a day, once before breakfast and once before dinner, a mixture of a shorter acting insulin and intermediate acting insulin, and the shorter acting may be either short acting insulin or a rapid acting insulin.

Question 24

what insulin regimen may be suitable for a patient who doesn’t have fixed meal times?

Answer 24

a basal-bolus regimen: involves taking a longer acting form of insulin once or twice daily to keep blood glucose levels stable through periods of fasting and separate injections of shorter acting insulin to prevent rises in blood glucose levels resulting from meals. so basal taken= long or intermediate acting insulin, and bolus with every meal- short or rapid acting insulin. Tries to replicate how a non-diabetic person’s body releases insulin, and involves number of insulin injection throughout day. Can eat when you want.

Question 25

when are sulfonylureas e.g. gliclazide considered in type II diabetic patients?

Answer 25

patients who are not overweight, and in whom metformin is contra-indicated e.g. resp disease, compromised HRH function, or not tolerated. (mainly met in liver so can be used in renal failure patients.) can be used if patient acutely unwell

Question 26

why should glibenclamide be avoided in the elderly?

Answer 26

long acting sulfonyurea- assoc with greater risk of hypoglycaemia (elderly- more at risk of this, eat less, and reduced drug met- PKs altered?)

Question 27

cautions with sulfonylurea administration?

Answer 27

elderly obese patients- metformin= drug of choice G6PDD patients- risk of excessive haemolysis

Question 28

ADRs with sulfonylureas?

Answer 28

``` hypoglycaemia weight gain GI disturbances: diarrhoea and constipation hyponatraemia hypersensitivity reactions ```

Question 29

when are glitazones used in type 2 DM?

Answer 29

NICE (May 2009) has recommended that, when glycaemic control is inadequate with existing treatment, pioglitazone can be added to: a sulfonylurea, if metformin is contra-indicated or not tolerated; metformin, if risks of hypoglycaemia with sulfonylurea are unacceptable or a sulfonylurea is contra-indicated or not tolerated; a combination of metformin and a sulfonylurea, if insulin is unacceptable because of lifestyle or other personal issues, or because the patient is obese.

Question 30

ADRs of glitazones?

Answer 30

weight gain oedema- so contraindicated in HF patients fractures in post-menopausal women, increased OP risk as inhibit bone formation risk of bladder cancer- so must check for haematuria increased LDLs and HDLs- rosiglitazone no longer used as led to CVD events *drugs also high cost

Question 31

3 main tissues insulin acts upon?

Answer 31

liver skeletal muscle adipose tissue

Question 32

describe why insulin given to diabetics is associated with weight gain?

Answer 32

in type 2 diabetics, insulin resistance typically more severe in muscle and liver compared with AT, so insulin preferentially deposits calories in AT, causing weight gain. AT: insulin causes increased glucose uptake, lipogenesis and esterification of FA, and increase lipoprotein lipase activity in capillary bed for FA uptake.

Question 33

why are drugs for diabetes characterised by having low therapeutic indexes (TD50/ED50)?

Answer 33

to keep balance between hyper and hypo glycaemia

Question 34

4 types of insulin available with recombinant DNA technology?

Answer 34

human short acting human rapid acting analogues isophane intermediate acting insulin long acting basal analogues aa structure modified to affect absorption

Question 35

adverse effects of insulin?

Answer 35

hypoglycaemia hyperglycaemia lipodystrophy- hypertrophy or atrophy at injection site** painful injections insulin allergies- type IV (delayed) hypersentivity reactions may occur, can change brand of insulin as will be a different formulation in terms of preservative used

Question 36

give 2 important factors as to why diabetics may not be compliant with treatment?

Answer 36

risk/perceived risk of hypoglycameia | weight gain/fear of weight gain

Question 37

general HbA1c target in all type 2 diabetics?

Answer 37

6.5-7.5 %

Question 38

despite insulin have the greatest potential for lowering HbA1c, what is its main limitation?

Answer 38

risk of hypoglycaemia

Question 39

advantages of using metformin in type 2 diabetes?

Answer 39

little weight gain, may even be weight loss reduces LDLs and VLDLs- reduces CVS events cheap- £8-10 annually doesn't induce hypoglycaemia can use slow release (extended absorption) to help cope with GI symptoms, but this is more expensive 1-2% HbA1c lowering potential can be used in stage III CKD, but stopped once eGFR<30ml/min, or significant comorbidities

Question 40

conditions other than type 2 diabetes in which metformin may be used?

Answer 40

PCOS- reduces insulin resistance, balances androgens and oestrogens anti-cancer- breast and bowel?

Question 41

advantages of using sulfonylureas?

Answer 41

1-2% HbA1c lowering potential cheap mainly metabolised via liver, so can be used in renal impairment can be used if patients acutely unwell

Question 42

ADRs of metformin?

Answer 42

lactic acidosis reduced vit B12 absorption GI disturbances: diarrhoea, abdominal pain taste disturbance

Question 43

ADRs of acarbose?

Answer 43

``` runny, loose stools abdominal pain abdominal distension flatulence diarrhoea ```

Question 44

effects of glucagon like peptide-1 (GLP-1) in body?

Answer 44

released from intestinal L cells and it: increases is insulin secretion reduces glucagon secretion increases insulin biosynthesis increases satiety, so reduces food intake reduces gastric emptying increases glucose uptake in muscle and reduces glucose prod. by liver

Question 45

mechanism of action of gliptins (DPP-4 inhibitors) e.g. sitagliptin, saxagliptin?

Answer 45

inhibit breakdown of glucagon like peptide-1 so increase post-prandial concentrations of GLP-1, which increases insulin release and reduces glucagon release, so there is increased glucose uptake, and reduced glucose output from the liver.

Question 46

advantages of gliptin use?

Answer 46

weight neutral low risk of hypoglycaemia modest HbA1c reduction

Question 47

ADRs of gliptins?

Answer 47

``` GI disturbances peripheral oedema URTIs headache possible pancreatitis ```

Question 48

NICE guidelines on gliptins?

Answer 48

consider adding 2nd line to metformin or sulfonylurea with HbA1c >6.5% if: patient at significant risk of hypoglycaemia and its consequences e.g. elderly, living alone patient doesn't tolerate sulfonylurea, or CI can be used as triple therapy continue only if HbA1c reduction > or equal to 0.5% is achieved and maintained over 6 mnths

Question 49

ADRs of GLP-1 agonists e.g. exenatide?

Answer 49

GI symptoms- diarrhoea, nausea, loose stools GO reflux occasionally painful to inject ?pancreatitis but low risk of hypoglycaemia

Question 50

NICE guidelines on exenatide?

Answer 50

continue only if HbA1c reduction of 1% or more at 6 mnths | and weight loss of at least 3% at 6 mnths

Question 51

action of glifozins e.g. dapaglifozin?

Answer 51

insulin-independent approach to remove excess glucose | inhibit SGLT2 in PCT- so inhibit glucose reabsorption

Question 52

ADRs of glifozins?

Answer 52

increase risk of lower UT symptoms e.g. genital and UTIs polyuria hypoglycaemia BUT weight neutral, and may promote weight loss

Question 53

define hypoglycaemia and list its clinical signs

Answer 53

plasma glucose concentration of less than or equal to 3mmol/L similar signs to someone intoxicated with alcohol include slurring of speech, confusion, drowsiness, weakness, trembling, sweating, nausea, tingling around lips, palpitations, staggering walk

Question 54

general dietary advice for diabetic patients?

Answer 54

– include high-fibre, low-glycaemic- index sources of carbohydrate – include low-fat dairy products and oily fish – control the intake of foods containing saturated fats and trans fatty acids. -Limited substitution of sucrose- containing foods for other carbohydrate is allowable, but care should be taken to avoid excess energy intake. - Discourage use of foods marketed specifically for people with diabetes

Question 55

how should HbA1c be monitored in diabetics?

Answer 55

2-6mnthly until stable on unchanging therapy | then 6 mnthly when blood glucose levels and blood glucose lowering therapy stable

Question 56

when might a sulfonylurea be considered rather than metformin for type 2 DM tment?

Answer 56

metformin CI e.g. heptic, renal or CVS dysfunction, or resp disease patient not overweight rapid therapeutic response required due to hyperglycaemic symptoms