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Endocrine > Pharmacology: Diabetes Treatments > Flashcards

Pharmacology: Diabetes Treatments Flashcards

(41 cards)

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1
Q

Metformin

A

Lowers glucose production and increases glucose utilisation
First line therapy for T2DM
It is a biguanide

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2
Q

Metformin molecular mechanism

A

Weak cellular poison

  1. Inhibition of complex 1 of the mitochondrial respiratory train
  2. Fall in cellular ATP (rise in ADP/ ATP ratio)
  3. Many consequences
    - Rise in AMP: ATP ratio
    - Activation of AMPK
    - Reduction in gluconeogenesi
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3
Q

Metformin Site of action

A

Hydrophilic- not readily taken up by cells.

Requires active transport by Organic Cation Transporters (OCT)
- Present in intestines, liver and kidney

Excreted unchanged in the urine (metformin is NOT metabolised)

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4
Q

Metformin physiological mechanisms (6)

A

Lowers hepatic glucose production

Increases gut glucose utilisation and metabolism

Increases intestinal GLP-1 secretion

Altered gut microbiome

Decrease lipogenesis

Reduced inflammation

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5
Q

Metformin clinical use

A

Potent glucose lowering (HbA1c ~18mmol/L)

Weight neutral or negative

Usual dose 500mg bd

Cheap

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6
Q

Metformin side effects

A

GI Intolerance

  • Diarrhoea, bloating, abode pain, metallic taste, dyspepsia
  • To reduce side effects initiate slowly or use modified release formulation

Metformin Associated Lactic Acidosis (MALA)

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7
Q

Metformin Associated Lactic Acidosis

A

Metformin increases lactate production (especially by gut and liver)

Lactate is normally cleared by liver and kidneys

In Acute Kidney Injury, metformin is associated with greater risk of lactic acidosis.

metformin dose should be decreased as renal function falls

  • Max dose 1g daily if eGFR <45ml/min
  • Contraindicated if eGFr <30ml/min
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8
Q

Sulphonylureas

A

Act directly on pancreatic beta-cells to increase insulin secretion
–> insulin secretagogues

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9
Q

Sulphonylurea Generation Examples

A

1st Generation (very limited use)

  • Tolbutamide
  • Chloropropamide

2nd Generation

  • Gliclazide
  • Glipizide
  • Glimepiride
  • Glibenclamide
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10
Q

Sulphonylurea Stimulated insulin secretion (4)

A

Glucose independent insulin secretion

  1. SUs bind to SUR1
  2. Closure of Katp
  3. Rise in membrane potential triggers voltage gated calcium channel
  4. Calcium influx leads to insulin exocytosis
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11
Q

Sulphonylurea Clinical use

A

Potent glucose lowering (HbA1c ~18mmol/L)

increase weight (1-2kg on average)

Risk of hypoglycaemia

Cheap

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12
Q

Sulphonylurea Hypoglycaemia risk

A

Risk of hypoglycaemia increased with:

  • Increased age
  • diabetes duration
  • creatinine
  • lower HbA1c (esp <50mmol/L)
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13
Q

Sulphonylurea Side Effects

A

Hypoglycaemia

Weight gain

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14
Q

Thiazolidinediones (TZDs)

A

PPAR(gamma) agonists

Net effect is to increase fat mass in subcutaneous depots and to ‘suck out’ fat from viscera (liver and pancreas) and muscle.

Also increased adiponectin and reduced inflammatory cytokines like TNF-alpha and IL-6

Work to increase fat mass and increase beneficial/ reduce harmful cytokines

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15
Q

TZDs molecular mechanism

A

PPAR(gamma) ligands

Ligand binding results in formation of a complex with a co-activator

increased transcriptional activation of PPAR(gamma) target genes

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16
Q

TZDs physiological mechanism (4)

A

Main effect is on adipocytes

  1. Increased differentiation from pre-adipoctyes to adipocytes
  2. Increase fat mass (subcutaneous)
  3. ‘lipid steal’- FFA uptake removes fat from liver and muscle which reduces lipotoxicity.
  4. Increases adiponectin which acts on insulin to increase insulin sensitivity.

net Result: increased insulin sensitivity

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17
Q

TZDs clinical use

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A 
Good efficacy (HbA1c reduction. 15-20mmol/l)
- Especially potent in obese women

increase in weight
- Increase in fat mass and fluid retention

Reduction in blood pressure

  • SBP: Reduced by 4.7
  • DBP: Reduced by 3.8
18
Q

TZDs side effects

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A

Weight gain

Fluid retention

  • resulting in peripheral oedema
  • doubles risk of hospitalisation for cardiac failure

Fracture risk

  • fat accumulation in bone marrow
  • reduction in bone density
19
Q

TZDs uses

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A

Due to side effects they are normally used only in

obese, young, insulin resistant patients

20
Q

TZD example

21
Q

Incretin Drug Types (2)

Study These Flashcards
A

DPP4 Inhibitors

GLP-1 Receptor Agonists

22
Q

Incretins

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A

Intestinal secretion of insulin
Secreted in response to nutrient stimuli

GIP from K cells
GLP-1 from L cells

23
Q

Incretin MOA

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A

Act via amplifying pathway (of beta cells)

Act via GLP-1/ GIP receptor. G-protein coupled.

Results in increase cAMP

  • Closes Katy channel
  • Modulate calcium currents
  • Directly acts on insulin secretory mechanism

net Result: Augmentation of insulin secretion when the pathway is triggered (by glucose or sulphonylurea)

24
Q

DPP4 inhibitor examples

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A

Dipeptidyl Peptidase 4 Inhibitors

Commonly used DPP4i

  • Sitagliptin
  • Alogliptin
  • Saxagliptin
25
DPP4 inhibitors mechanism
Inhibit breakdown of GLP-1 and GIP Augments insulin secretion Incretin action is glucose dependent and therefore does NOT cause hypoglycaemia
26
DPP4 inhibitors clinical use
Weak glucose lower (HbA1c reduction ~5-8mmol/L) Weight neutral
27
DPP4 inhibitor side effects
Minimal Possible increased risk of pancreatitis
28
GLP-1 Receptor Agonists
Potent injectable treatments that promote incretin mediated insulin secretion
29
GLP-1 Receptor Agonist mechanism
GLP-1 molecule modified to avoid breakdown by DPP4. Different modifications or attachment alter half life Act-directly on GLP-1 receptor Act to promote insulin secretion in a glucose dependent mechanism Also lower glucagon
30
GLP-1 receptor agonist action in other tissues (2)
Act in the hypothalamus to reduce hunger Act in the intestines to reduce gastric emptying
31
GLP-1 receptor agonist clinical use
Potent(HbA1c reduction ~11-15mmol/L) Weight loss (2-3 kg on average) Blood Pressure - SBP: 2-5mmHg reduction Heart rate increase by 3-10bpm
32
GLP-1 Receptor agonist examples
Liraglutide | Semaglutide
33
GLP-1 Receptor Agonists Side Effects
nausea and vomiting - often improves after ~6 weeks Gallstones (small increase) CV and renal benefit
34
SGLT2 Inhibitors
Specific inhibitors of renal sodium glucose transporter 2 Increased renal glucose losses results in lowering of blood glucose and loss of calories --> results in weight looss
35
SGLT2 Inhibitors Physiology Direct Effects
Glucose loss results in osmotic diuresis. Inhibition of SGLT2 reduces Na reabsorption -- Mild diuretic action urate excretion is increased - reduction in plasma urate concentration
36
SGLT2 Inhibitors Renal Protection (4)
1. Increased sodium delivery to distal convoluted tubule 2. Increased Na uptake by Na/K/Cl transporter at macula densa 3. Increase in adenosine secretion 4. Reduction in renal afferent vasodilation --> reduced filtration pressure
37
SGLT2 Inhibitors Indirect Effect
Glucose Reduction - Reduction in insulin - Increased in glucagon Increase in lipolyisis - Increase in FFA results in increased ketone body production FFA and ketones are a fuel to cardiac monocytes --> Cardiac benefit
38
SGLT2 Inhibitor Clinical Use
moderate Efficacy (HbA1c ~11mmol/L) Glucose lowering relies on renal glucose filtration - No glucose benefit if eGFR <45ml/min Blood Pressure - SBP reduction by 3-6 mmHg - DBP reduction by 2-3mmHg Lipids: Slight increase in LDL and HDL cholesterol
39
SGLT 2 Inhibitor Examples
Empagliflozin Dapagliflozin Canagliflozin
40
SGLT2 Inhibitor Side Effects
Genetic mycotic infections (thrush) - secondary to glycosuria - usually mild and readily treatable Fournier Gangrene -rare but severe Hypovolaemia and hypotension -due to diuretic effect Diabetic ketooacidosis - due to increased ketone body production
41
SGLT2 Inhibitor contraindications
Prolonged fasting | Acute Illness

Endocrine (25 decks)

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