Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Endocrine > Pharmacology: Diabetes Treatments > Flashcards

Pharmacology: Diabetes Treatments Flashcards

1
Q

Metformin

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Metformin clinical use

A

Potent glucose lowering (HbA1c ~18mmol/L)

Weight neutral or negative

Usual dose 500mg bd

Cheap

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Sulphonylureas

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Sulphonylurea Generation Examples

A

1st Generation (very limited use)

  • Tolbutamide
  • Chloropropamide

2nd Generation

  • Gliclazide
  • Glipizide
  • Glimepiride
  • Glibenclamide
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Sulphonylurea Clinical use

A

Potent glucose lowering (HbA1c ~18mmol/L)

increase weight (1-2kg on average)

Risk of hypoglycaemia

Cheap

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Sulphonylurea Hypoglycaemia risk

A

Risk of hypoglycaemia increased with:

  • Increased age
  • diabetes duration
  • creatinine
  • lower HbA1c (esp <50mmol/L)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Sulphonylurea Side Effects

A

Hypoglycaemia

Weight gain

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

TZDs clinical use

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

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

A

Due to side effects they are normally used only in

obese, young, insulin resistant patients

20
Q

TZD example

A

Pioglitazone

21
Q

Incretin Drug Types (2)

A

DPP4 Inhibitors

GLP-1 Receptor Agonists

22
Q

Incretins

A

Intestinal secretion of insulin
Secreted in response to nutrient stimuli

GIP from K cells
GLP-1 from L cells

23
Q

Incretin MOA

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

A

Dipeptidyl Peptidase 4 Inhibitors

Commonly used DPP4i

  • Sitagliptin
  • Alogliptin
  • Saxagliptin
25
Q

DPP4 inhibitors mechanism

A

Inhibit breakdown of GLP-1 and GIP

Augments insulin secretion

Incretin action is glucose dependent and therefore does NOT cause hypoglycaemia

26
Q

DPP4 inhibitors clinical use

A

Weak glucose lower (HbA1c reduction ~5-8mmol/L)

Weight neutral

27
Q

DPP4 inhibitor side effects

A

Minimal

Possible increased risk of pancreatitis

28
Q

GLP-1 Receptor Agonists

A

Potent injectable treatments that promote incretin mediated insulin secretion

29
Q

GLP-1 Receptor Agonist mechanism

A

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
Q

GLP-1 receptor agonist action in other tissues (2)

A

Act in the hypothalamus to reduce hunger

Act in the intestines to reduce gastric emptying

31
Q

GLP-1 receptor agonist clinical use

A

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
Q

GLP-1 Receptor agonist examples

A

Liraglutide

Semaglutide

33
Q

GLP-1 Receptor Agonists Side Effects

A

nausea and vomiting
- often improves after ~6 weeks

Gallstones (small increase)

CV and renal benefit

34
Q

SGLT2 Inhibitors

A

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
Q

SGLT2 Inhibitors Physiology Direct Effects

A

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
Q

SGLT2 Inhibitors Renal Protection (4)

A
  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
Q

SGLT2 Inhibitors Indirect Effect

A

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
Q

SGLT2 Inhibitor Clinical Use

A

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
Q

SGLT 2 Inhibitor Examples

A

Empagliflozin

Dapagliflozin
Canagliflozin

40
Q

SGLT2 Inhibitor Side Effects

A

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
Q

SGLT2 Inhibitor contraindications

A

Prolonged fasting

Acute Illness

Endocrine (25 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions