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Year 2 Pharmacology > Drugs and Their Targets in T2DM > Flashcards

Drugs and Their Targets in T2DM Flashcards

1
Q

Mechanisms of actions of T2DM therapies?

A
  1. Increase secretion of insulin (insulin DEPENDENT action):
    • Sulphonylureas
    • Incretin mimetics (AKA megaglitinides)
    • DDP-4 inhibitors
  2. Decreasing insulin resistance and reducing hepatic glucose output (insulin DEPENDENT action):
    • Biguanides
    • Thiazolidinediones (AKA glitazones)
  3. Slowing glucose absorption from GI tract (insulin INDEPENDENT action):
    • α-glucosidase inhibitors
  4. Enhancing glucose excretion by the kidney (insulin INDEPENDENT action):
    • SGLT2 (sodium glucose type-2) inhibitors
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2
Q

What is cellular energy status linked to?

A

Linked to insulin secretion in the pancreatic β-cell

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3
Q

Mechanism of insulin secretion?

A
  1. Elevation of BG conc.
  2. Increased diffusion of glutamate into the β-cell by facilitated transport (GLUT2)
  3. Phosphorylation of glucose by glucokinase
  4. Glycolysis of glucose-6-phosphate in mitochondria yielding ATP
  5. Increased ATP/ATP ratio within cell closes ATP-sensitive K+ channels (KATP) channels causing membrane depolarisation
  6. Opening of voltage-activated Ca2+ channels increases intracellular Ca2+ (triggers insulin secretion)
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4
Q

Structure of the KATP channel?

A

Octomeric complex of:
• 4 potassium inward rectifier 6.2 subunits (Kir6.2)
• 4 sulphonylurea receptor 1 subunits (SUR1)

Tetramer of Kir6.2 subunits form a potassium selective ion channel

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5
Q

Regular of the KATP channel?

A

SUR1 subunits regulate potassium channel activity

ATP binding to each of the Kir6.2 subunits CLOSES the channel causing depolarisation of the β-cell and insulin release (when extracellular glucose is high)

ADP-Mg2+ binding to the SUR1 subunits OPENS the channel maintain the resting potential of the β-cell and inhibits insulin secretion (when extracellular glucose is low)

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6
Q

Mechanism of action of sulphonylureas (SUs)?

A

Used in T2DM

  1. Seem to act by displacing binding of ADP-Mg2+ from the SUR1 subunit
  2. Bind to SUR1 and CLOSE the channel; this causes depolarisation and insulin release INDEPENDENT of plasma glucose conc.

This means that insulin release is essentially uncoupled from glucose conc. which explains why these drugs can cause hypoglycaemia

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7
Q

Examples of sulfonylureas?

A

First generation:
• Tolbutamide

Second generation:
• Glibenclamide (AKA glyburide)
• Glipizide

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8
Q

Which of the SUs are longer-acting?

A

Glibenclamide and Glipazide are more potent and longer-acting; this is likely to have no significant clinical advantage and may in fact cause hypoglycaemia more easily

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9
Q

At risk patients with SUs?

A

Risk of hypoglycaemia due to excessive insulin secretion; there is a greater risk with:
• Longer-acting agents
• In the elderly
• In patients with reduced hepatic/renal function

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10
Q

Which drugs can SUs be combined with?

A

Metformin

Thiazolidinediones

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11
Q

Adverse effects of SUs?

A

Undesirable weight gain

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12
Q

Mechanism of action of Glinides?

A

Similar to SUs as they bind to SUR1 (at a separate site) to close the KATP channel

Triggers insulin release

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13
Q

Examples of Glinides?

A

Repaglinide

Nateglinide

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14
Q

Advantage of Glinides over SUs?

A

Rapid onset/offset kinetics and so are less likely to cause hypoglycaemic

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15
Q

Administration of Glinides?

A

Active orally and are taken before meals to reduce post-prandial rise in BG

They can be used in conjunction:
• Metformin
• Thiazolidinediones

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16
Q

Describe the incretin effect

A

Ingestion of food stimulates release of the following from enteroendocrine cells in the SI:
• Glucagon-like 1 (GLP-1) from L-cells in the ileum and colon
• Glucose dependent insulinotropic peptide (GIP) from K-cells in the jejunum/duodenum

These enter the portal blood and cause decreased BG by:
• GLP-1 and GIP enhance (INCREMENT) insulin release from pancreatic β-cells and decrease gastric emptying; there is enhanced glucose uptake and utilisation
• GLP-1 decreases glucagon release from pancreatic α-cells; there is decreased glucose production

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17
Q

Mechanism of action of incretin analogues?

A

Mimic action of GLP-1 but are longer lasting

Binds to GPCR GLP-1 receptors, which increase intracellular cAMP conc.

Increase insulin secretion, suppresses glucagon secretion, slows gastric emptying and reduces appetite

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18
Q

Examples of incretin analogues?

A

Exenatide

Liraglutide (longer-acting agent)

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19
Q

Benefits of incretin analogues?

A

Modest weight loss

Reduce hepatic fat accumulation

20
Q

Adverse effects of incretin analogues?

A

Nausea

Hypoglycaemic

Pancreatits (very rarely)

21
Q

Administration of Liraglutide?

A

Once daily subcutaneous injection

22
Q

Function of DPP-4 enzyme?

A

AKA dipeptidyl peptidase-4 (DPP-4)

Rapidly terminates actions of GLP-1 and GIP

23
Q

Mechanism of action of DPP-4 inhibitors (AKA Gliptins)

A

Competitively inhibit DPP-4 and thus prolong the actions of GLP-1 and GIP

24
Q

Examples of Gliptins?

A

Sitagliptin

Saxigliptin

Vildagliptin

25
Q

Administration of Gliptins?

A

Usually combined with thiazolidinediones or metformin; can be used as a monotherapy

Sitagliptin is orally administered once daily and is mostly well tolerated

26
Q

Benefits of Gliptins?

A

No hypoglycaemic (when used as a MONOTHERAPY)

Weight-neutral

27
Q

What is α-Glucosidase inhibitor?

A

Dietary carbohydrates require digestion to monosaccharides to be absorbed in the SI

It is a brush-border enzyme that breaks down starch and disaccharides to absorbable glucose

28
Q

Mechanism of action of α-Glucosidase inhibitors?

A

Delay absorption of glucose and so reduce post-prandial increase in BG

29
Q

Uses of α-Glucosidase inhibitors?

A

Used in T2DM patients who are inadequately controlled by lifestyle measures or other drugs

30
Q

Example of α-Glucosidase inhibitors?

A

Acarbose (only clinically relevant one)

31
Q

Adverse effects of α-Glucosidase inhibitors?

A 
Occur in the GI tract as the undigested carbohydrates are welcomed by the colonic bacteria:
• Flatulence
• Loose stools and diarrhoea
• Abdominal pain
• Bloating
32
Q

Benefit of α-Glucosidase inhibitors?

A

NO RISK OF HYPOGLYCAEMIA

33
Q

Examples of Biguanides?

A

METFORMIN - 1st line agent for T2DM (with normal hepatic and renal function)

34
Q

Mechanism of action of Metformin?

A

Reduce hepatic gluconeogenesis (by stimulating AMP-activated protein kinase (AMPK))

Increases glucose uptake and utilisation by skeletal muscle (increases insulin signalling)

Reduces carbohydrate absorption

Increases fatty acid oxidation

35
Q

Benefits of Metformin?

A

Suitable for oral administration

Prevent hyperglycaemic but does NOT cause hypoglycaemic

Cause WEIGHT LOSS (unlike insulin and agents that promote insulin release)

Can be combined with, e.g: insulin, TZDs, SUs

36
Q

Adverse effects of Metformin?

A

GI upsets (diarrhoea, nausea and anorexia)

Rarely, LACTIC ACIDOSIS (avoid routine use in patients with hepatic/renal disease)

37
Q

Main effect of TZDs?

A

Enhance the action of insulin at target tissues but do not directly affect insulin secretion

They reduce amount of insulin required to maintain a given BG

38
Q

Mechanism of action of TZDs (AKA Glitazones)

A

Exogenous agonists of PPARγ, which is mostly in adipose tissue, that assoc. with retinoid-receptor X (RXR)

Activated PPARγ-RXR complex acts as a transcription factor and binds to DNA to promote gene expression of proteins inv. with insulin signalling:
• Lipoprotein lipase
• Fatty acid transport protein
• GLUT4 (this is regulated by insulin)

39
Q

Benefits of TZDs?

A

Promote fatty acid uptake and storage in adipocytes, rather than in skeletal muscle and liver

Reduced hepatic glucose output

40
Q

Adverse effects of TZDs?

A

Weight gain

Fluid retention

Some of the drugs in this class can cause serious hepatotoxicity (they are not used anymore)
• Ciglitazone
• Troglitazone

Increased incidence of bone fractures

41
Q

Only TZDs still in use?

A

Pioglitazone

42
Q

Combination therapy with TZDs?

A

May be combined with either metformin or an SU, to achieve control of BG

43
Q

Mechanism of action of SGLT2 (Sodium-Glucose co-transporter 2) inhibitors?

A

Selectively block reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron to cause GLYCOURIA; this decreases BG

44
Q

Benefits of SGLT2 inhibitors?

A

Little risk of hypoglycaemia

Calorific loss, i.e: glucose voided, and water accompanying glucose, i.e: osmotic diuresis, contributes to weight loss

45
Q

Example of SGLT2 inhibitors?

A

Dapagliflozin

46
Q

Adverse effects of SGLT2 inhibitors?

A

Glycosuria increases risk of thrush and other urinary infections, etc

Year 2 Pharmacology (7 decks)

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