Pharmacology

Question 1

What is the mechanism of action of the sulfonylureas?

Answer 1

Act by displacing the binding of ADP-Mg2+ from the SUR1 subunit (thus closing the KATP channel and stimulating insulin release)

Question 2

Why would sulfonylureas not work in type 1 diabetes?

Answer 2

They increase insulin release from beta cells, in type 1 diabetes there are no functioning beta cells.

Question 3

Examples of sulfonylureas?

Answer 3

tolbutamide, gliclazide, glibenclamide, glipizide

Question 4

Tolbutamide, gliclazide, glibenclamide, glipizide are all examples of…

Answer 4

Sulfonylureas

Question 5

What drugs for T2DM can cause hypos?

Answer 5

Sulfonylureas, Glinides (less likely than SUs),

Question 6

Hypoglycaemia by excessive insulin secretion is a side effect of the sulfonylureas, who is more at risk of this side effect?

Answer 6

long acting agents (e.g. glibenclamide)
the elderly
patients with reduced hepatic/renal function, particularly chronic kidney disease (CKD)

Question 7

Explain how the sulfonyureas can cause weight gain?

Answer 7

anabolic effect of insulin increased
appetite increased
urinary loss of glucose decreased

Question 8

When are the sulfonyureas used?

Answer 8

first-line in patients intolerant of metformin, or with weight loss
second-line in conjunction with metformin
third line in conjunction with metformin and thiazolidinediones, or other drugs

Question 9

Mechanism of action of the glinides?

Answer 9

Almost the same as sulfonylureas but binding is slightly different

Question 10

Examples of the glinides?

Answer 10

Repaglinide and nateglinide

Question 11

Repaglinide is subject to mainly hepatic metabolism – thus safer than SUs in ______

Answer 11

chronic kidney disease

Question 12

Describe the incretin response, what two drugs for type 2 diabetes target this?

Answer 12

• Ingestion of food stimulates release of GLP-1 and IP from enteroendocrine cells in the small intestine (L cells in the ileum and K cells in the duodenum, respectively
• These enter the portal blood enhancing insulin release
• GLP-1 also decrease glucagon release
Hence blood glucose is decreased

The DPP-4 inhibitors and the incretin analogues

Question 13

Describe the mechanism of action of the DPP-4 inhibitors

Answer 13

• The incretin response is reduced in type 2 so this drug tries to restore it pharmacology
• Action of GLP 1 and GIP are very rapidly terminated by the enzyme DPP 4
The Gliptins competitively inhibit DPP-4 prolonging the actions of endogenous GLP-1 and GIP and increasing plasma insulin

Question 14

Repaglinide and nateglinide and examples of?

Answer 14

Glinides

Question 15

Why are drugs that target the incretin response only helpful in type 2 diabetes?

Answer 15

They target a response which helps with insulin secretion, if no insulin secretion in the first place this is not helpful.

Question 16

Examples of Gliptins/ DPP-4 inhibitors?

Answer 16

sitagliptin, saxagliptin, vildagliptin, linagliptin and alogliptin

Question 17

Sitagliptin, saxagliptin, vildagliptin, linagliptin and alogliptin are all examples of?

Answer 17

Gliptins/ DPP-4 inhibitors

Question 18

Main adverse effect of the gliptins?

Answer 18

Nausea

No hypos and weight neutral

Question 19

When are the gliptins usually used?

Answer 19

In combination with a SU, or metformin, but can be employed as monotherapy

Question 20

Describe the mechanism of action of incretin analogues?

Answer 20

peptides that mimic the action of GLP-1 but resist breakdown by DPP-4

Question 21

Do incretin analogues help lose weight? How?

Answer 21

Yes
suppress glucagon secretion
slow gastric emptying
decrease appetite (hypothalamic action)

Question 22

When are incretin analogues used?

Answer 22

Not first line, usually as an add on therapy particularly those with cardiovascular risk.

Question 23

Adverse effects of the incretin analogues?

Answer 23

No hypos
May cause nausea
Very occasionally pancreatitis

Question 24

Mechanism of action of alpha glucosidase inhibitors?

Answer 24

Alpha- Glucosidase is a brush border enzyme that breaks down starch and disaccharides to absorbable glucose. Therefore Inhibitors of alpha-glucosidase (e.g. acarbose, miglitol, voglibose) taken with a meal delay absorption of glucose and reduce postprandial increase in blood glucose

Question 25

When are alpha glucosidase inhibitors used?

Answer 25

Used in 2TDM patients inadequately controlled by life style measures or other drugs (e.g. SUs)

Question 26

Adverse effects of alpha glucosidase inhibitors?

Answer 26

GI upset—> flatulence, loose stools, diarrhoea, abdominal pain, bloating
no hypos

Question 27

Are alpha glucosidase inhibitors used a lot?

Answer 27

NO

Although they pose no risk of hypos the glycemic control is modest

Question 28

Examples of alpha glucosidase inhibitors?

Answer 28

acarbose, miglitol, voglibose

Question 29

Acarbose, miglitol, voglibose are examples of?

Answer 29

alpha glucosidase inhibitors

Question 30

The only therapeutic agent in the biguanides is…

Answer 30

metformin

Question 31

What is the first line agent in treatment of type 2 diabetes?

Answer 31

Metformin

Question 32

Mechanism of metformin?

Answer 32

reduces hepatic gluoconeogenesis [by stimulating AMP-activated protein kinase (AMPK)]
increases glucose uptake and utilization by skeletal muscle (increases insulin signalling)
reduces carbohydrate absorption
increases fatty acid oxidation

Question 33

5 desirable effects of metformin?

Answer 33

reduces the microvascular complications
suitable for oral administration
prevents hyperglycaemia but does not cause hypoglycaemia
causes weight loss (unlike insulin and some agents that promote insulin release)
may be combined with other agents (e.g. insulin, thiazolidinediones, sulfonylureas)

Question 34

2 adverse effects of metformin?

Answer 34

gastrointestinal upsets (diarrhoea, nausea, anorexia)
rarely lactic acidosis (avoid routine use in patients with significant hepatic, or renal, disease). Excessive alcohol consumption may increase the incidence of lactic acidosis

Question 35

Mechanism of action of Thiazolidinediones?

Answer 35

exogenous agonists of the nuclear receptor peroxyisome profilerator-activated receptor- (PPAR) which associates with retinoid receptor X (RXR) - PPAR is largely confined to adipocytes
Activated PPAR-RXR complex acts as a transcription factor that promotes the expression of genes encoding several proteins involved in insulin signalling and lipid metabolism

Question 36

Pioglitazone, ciglitazone, troglitazone are all examples of?

Answer 36

Thiazolidinediones

Question 37

Explain if thiazolidinediones cause weight gain?

Answer 37

They do as they are promoting storage of fat in the adipocytes

Question 38

When are thiazolidinediones used?

Answer 38

in combination with either metformin, or SUs, to achieve adequate control of blood glucose

Question 39

Examples of thiazolidinediones?

Answer 39

Pioglitazone, ciglitazone, troglitazone

Question 40

Mechanism of SGLT2 inhibitors?

Answer 40

Act to selectively block the reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron to deliberately cause glucosuria
Cause a decrease in blood glucose with little risk of hypoglycaemia

Question 41

How do SGLT2 inhibitors cause weight loss?

Answer 41

Calorific loss (i.e. glucose voided) and water accompanying glucose (i.e. osmotic diuresis) contributes to weight loss

Question 42

Examples of SGLT2 inhibitors?

Answer 42

dapagliflozin, canagliflozin and empagliflozin

Question 43

Dapagliflozin, canagliflozin and empagliflozin are examples of?

Answer 43

SGLT2 inhibitors

Question 44

Does metformin help with microvascular complications?

Answer 44

YES! it reduces them :)