DIABETIC DRUG THERAPY

Question 1

MoA of gliclazide

Answer 1

Promotes insulin secretion from pancreatic beta cells by binding to sulfonylurea receptor SUR1 which then blocks KATP channels - so reduced efflux of potassium which results in depolarisation of beta cells - stimulates calmodulin to release insulin containing secretory granules

Question 2

What are sulfonylureas?

Answer 2

Insulin secretagogues that stimulate insulin release from pancreas to restore early phase insulin release - can get short acting e.g. gliclazide / tolbutamide or long acting e.g. glibenlamide

Question 3

Side effects of sulfonylureas

Answer 3

weight gain - not in overweight pts

risk of hypoglycaemia

Question 4

How much do sulfonylureas reduce HbA1c by?

Answer 4

1.5-2%

Question 5

when are meglitanides used i.e licensing?

Answer 5

Only licensed for use with metformin

Question 6

MoA of meglitanides e.g. repaglinide and netaglinide?

Answer 6

Increase insulin release (early phase response) by binding to a different . but closely related receptor recognised by sulfonylurea - mechanism same - closes k ATP channels

Question 7

Are the side effects less marked in meglitanides?

Answer 7

Yes - less weight gain compared to other short acting ones, reduced risk of hypoglycaemia due to action being dependent . on the presence of glucose

Question 8

What are short acting sulfonylureas?

Answer 8

Gliclazide

Question 9

What drug classes come under the umbrella term insulin secretagogues?

Answer 9

Sulfonylureas e.g gliclazide

meglitanides e.g repaglinide and nateglinide

Question 10

what drugs work on the . liver?

Answer 10

Biguanides and thiazolidinediones - reduce glucose production

Question 11

What drugs work on the pancreas?

Answer 11

• insulin secretagogues . - sulfonylureas and meglitinides

- GLP-1 incretins improve response to glucose level

Question 12

What drugs work on skeletal muscle / adipose tissue?

Answer 12

thiazolidinediones and biguanides also work on here to reduce insulin resistance

Question 13

What drugs work on small intestine?

Answer 13

Alpha- glucosidase inhibitors e.g. ascarbose to slow absorption of sucrose and starch

Question 14

what are insulin sensitisers?

Answer 14

Require some residual beta cell capacity - enhance the effect of endogenous circulating insulin to reduce insulin resistance and decrease hepatic glucose production
e.g biguanides and thiazo

Question 15

1st line drug in type 2 diabetes?

Answer 15

Metformin - a biguanide

Question 16

Why is metformin particularly good? / used in overweight too?

Answer 16

• suppresses appetite . so weight loss i.e doesnt get as much weight gain as others
• reduced risk of hypo
• cardioprotective

Question 17

What are the s/e of metformin and how can they be overcome?

Answer 17

GI side effect - but can be overcome by gradually . increasing the dose to therapeutic levels or using modified release forms
- also risk of lactic acidosis

Question 18

when is metformin contra-indicated?

Answer 18

renal, cardiac, liver . impairment due to inhibition of pyruvate metabolism leading to increased lactic acid build up - if renally impaired for example - cannot excrete the LA

Question 19

MoA of metformin?

Answer 19

Reduce glucose production in liver, increases glucose utilisation and uptake in periphery, decreases glucose absorption - via activation of AMPK in liver and skeletal muscle

Question 20

Example of a thiazolidinedione?

Answer 20

Pioglitazone

Question 21

MoA of pioglitazone?

Answer 21

Reduces peripheral insulin resistance and hepatic . glucose production by stimulating PPAR-gamma (peroxisome proliferator activated receptor gamma) - this modulates the expression of insulin-sensitive genes which control glucose production /transport/utilisation in adipose/muscle/liver

Question 22

What are . the risks of pioglitazone?

Answer 22

Can increase risk of heart failure (fluid retention) thus C/I in at risk pts
also small increased risk of bladder cancer so caution in elderly and at risk pts .

Question 23

How long does pioglitazone take to work and why?

Answer 23

up to 3 months . due to indirect effect on blood glucose

Question 24

Side effects of pioglitazone

Answer 24

• fluid retention
• weight gain but note . that it is a less . risk of distiribution (hips and thighs)
• anaemia . and . GI effects

Question 25

Positive point about pioglitazone?

Answer 25

can improve . diabetic dyslipidaemia

Question 26

What is an example of a class and . drug that has inhibiting effects on GI glucose . absorption?

Answer 26

Alpha glucosidase inhibitors such as ascarbose

Question 27

MoA of ascarbose

Answer 27

Binds to alpha glucosidase with . higher affinity than dietary starch/sucrose - so breakdown of carbs inhibited/ Slows digestion and absorption of carbs post meals - reduces post prandial peak in blood glucose . so stabilises levels. Not as good at reducing hba1c than metformin and still has GI disturbances e.g. flatulence/diarrhoea

Question 28

what therapies are based on glucagon like peptide?

Answer 28

- dipeptidyl peptidase 4 inhibitors (DPP4) | - GLP-1 analogues

Question 29

What are DPP-4 inhibitors?

Answer 29

Gliptins --> They inhibit the enzyme DPP4 which usually breaks down GLP-1 - this means that GLP is free to act (not degraded)and stimulate insulin secretion, and decrease glucagon secretion. Also decreases appetite so good for weight loss

Question 30

Licensing for DPP4 inhibitors and guidance?

Answer 30

In combination with either metformin / sulfonylurea / pioglitazone (or sitagliptin also monotherapy with insulin) Also NICE --> only continue after 6 months if hbA1c reduced by at least 0.5%

Question 31

what drugs are GLP-1 analogues?

Answer 31

Exenatide and liraglutide - subcutaenous admin

Question 32

What are GLP-1 analogues?

Answer 32

DPP-4 resistant analgoues of GLp1 that bind to and activate GLP-1 receptor so then get the actions of GLP-1, stimulating insulin secretion, reducing glucagon secretion, reducing gastric emptying so weight loss (suppress appetite). Used in combo again

Question 33

What is the guidance on GLP-analogues e.g exenatide or liraglutide?

Answer 33

Only continue after 6 months if hba1c reduction of 1% and weight loss of 3%

Question 34

When are sodium-glucose co transporter inhibitors (gliflozins) used? canagliflozin etc

Answer 34

used as monotherapy if diet fails and metformin is inappropriate/contraindicated Also as an add on therapy with other medicines

Question 35

MoA of sodium-glucose co transpoter inhibitors?

Answer 35

Independent of insulin mediated glucose control pathways - actually act on nephron in tubules to block reabsorption of glucose in kidney and promote urinary excretion of it

Question 36

treatment of hypoglycaemia episodes?

Answer 36

oral glucose 10-20 g if conscious / swallow IM/SC glucagon or IV glucose if unconscious or cannot swallow Once episode is over - give longer acting carbs because glucagon mobilises the glycogen stores and must replenish these using the carbs

Question 37

Common complication in type 1 diabetics?

Answer 37

Diabetic ketoacidosis - chronic uncontrolled hyperglycaemia and ketones are due to a build up of free fatty acids due to mobilisation of the other stores. treat with IV rehydration 0.9% saline, insulin infusion and . careful correction of electrolyte . balance

Question 38

What is a common issue with diabetics when they are ill?

Answer 38

They . stop taking . insulin . if they feel . unwell and lose their . appetite as . they think it will cause hyperglycaemia. But . in fact - infections increase insulin . requirements

Question 39

Common complication in type 2 diabetics?

Answer 39

Hyperglycaemic hyperosmolar state Medical emergency, very high blood glucose >30mmol/L and hyperosmolality >320 mOsm/L. Due to illness and severe dehydration .

Question 40

Treatment for HHS

Answer 40

IV fluids Normalise blood glucose with low dose IV insulin LMWH prophylaxis Prevention of foot ulcers