Drugs and Their Targets in T2DM Flashcards
(104 cards)
1
Q
If a drug is insulin dependent, what does this mean?
A
In order to have an effect, enough insulin must be present
2
Q
Which drugs can be described as insulin independent?
A
- α-glucosidase inhibitors
- SGLT2 inhibitors
3
Q
Name two drug classes involved in increasing insulins sensitivity
A
- Biguanides
- Thiazolidinediones (glitazones)
4
Q
As well as impacting insulin sensitivity, what other action do the biguanides and thiazolidinediones share?
A
Decrease hepatic gluconeogenesis
5
Q
Which drugs will increase insulin secretion?
A
- Sulphonylureas
- Incretin mimetics
- Glinides
- DPP-4 inhibitors
6
Q
Biguanides are insulin ____________
A
Biguanides are insulin dependent
7
Q
Glinides are insulin ___________
A
Glinides are insulin dependent
8
Q
α-glucosidase inhibitors are insulin ___________
A
α-glucosidase inhibitors are insulin independent
9
Q
SGLT2 inhibitors are insulin _____________
A
SGLT2 inhibitors are insulin independent
10
Q
DPP-4 inhibitors are insulin ______________
A
DPP-4 inhibitors are insulin dependent
11
Q
GLUT4 is a glucose transport protein associated with which tissues?
A
Target tissues
(e.g. adipose and skeletal muscle)
12
Q
Describe the process by which insulin is released
A
- Elevated BGL
- GLUT2 allows entry of glucose to cell cytoplasm
- Glucokinase converts glucose to glucose-6-phosphate
- Glucose-6-phosphate is converted to ATP
- ATP acts on KATP channel
- KATP channel closes and depolarisation of cell occurs
- Volages activated Ca2+ channels open
- Ca2+ influx triggers exocytosis of insulin storage granules
13
Q
Which drug class works by slowing glucose absorption from the GI tract?
A
α-glucosidase inhibitors
14
Q
During the insulin secretion mechanism, what exactly causes KATP channel to close?
A
The ratio of ATP:ADP
15
Q
How many subunits make up the KATP channel?
A
8
16
Q
Which two types of subunit are involved in the KATP channel?
A
- Kir6.2
- SUR1
17
Q
To which subunit will ATP bind to in order to close the KATP channel?
A
Kir6.2
18
Q
Which substance can bind to the KATP channel in order to keep it open and to which subunit will it bind?
A
ADP-Mg2+
SUR1
19
Q
To which subunit will the sulphonylurea drug class bind to in the KATP channel and what is the useful effect of this?
A
SUR1
This induces depolarisation leading to insulin release regardless of whether blood sugars are high or low
20
Q
In order for the sulphonylureas to be of use what is required?
A
Pancreatic β cells
(this is why this drug class is useless in T1DM)
21
Q
Why may the effect of the sulphonylureas decrease over time in a patient?
A
β cells decrease over time, even in T2DM
22
Q
Give 4 examples of sulphonylureas
A
- Tolbutamide (1st gen - rarely used)
- Glibenclamide
- Gliclazide
- Glipizide
23
Q
How do the sulphonylureas act?
A
Displacement of the ADP-Mg2+ from the SUR1 subunit causing closure of the KATP channel and subsequent depolarisation
24
Q
Which risk is associated with sulphonylureas since they act independently to BGLs?
A
Hypoglycaemia
(BGLs may already be low when administered for example, which would reduce them further)
25
How can the sulphonylureas be administered?
Orally
26
What is the duration of action of the different sulphonylureas?
1. Short acting - tolbutamide - 4-6 hours
2. Long acting - glibenclamide, glipizide, gliclazide - 16-48 hours
27
Which type(s) of vascular risks associated with diabetes do the sulphonylureas reduce?
**Microvascular** complications
28
In which patients is hypoglycaemia a particular risk when taking sulphonylureas?
1. Elderly (renal function decreases with age)
2. Reduced hepatic or renal function
3. Pregnant women
(N.b. **Long acting agents** pose a higher hypoglycaemic risk)
29
In a treatment algorithm, sulphonylureas will usually be _________ line therapy with \_\_\_\_\_\_\_\_\_\_
In a treatment algorithm, sulphonylureas will usually be **second** line therapy with **metformin**
(N.b **_Not_** in pregancy; they may also be used **3rd line** with TZDs and metformin)
30
Sulphonylureas cause weight \_\_\_\_\_\_\_\_
Sulphonylureas cause weight **gain**
31
What are the main reasons sulphonylureas can cause weight gain?
1. Increased appetite
2. Glucose is lost which induces calorific retention
3. Anabolic effect of insulin (glucose storage) is increased
32
Why are glinides less likely to cause hypoglycaemia when compared with sulphonylureas despite their mechansims being similar?
Action of the glinides increases with glycaemia
(sulphonylureas work the same regardless of glycaemic level)
33
Where do glinides bind and what is the result?
1. SUR1 at the benzamido site
2. KATP closes and depolarisation induced
3. Insulin released
34
Give two examples of glinides
1. Repaglinide
2. Nateglinide
35
How are glinides administered?
Orally
36
Why may the glinides be useful in lowering post-prandial glucose levels?
Thay have a rapid onset of action
37
Why is it that glinides are safer in CKD than sulphonylureas?
Glinides are metabolised by the liver
38
When is the use of glinides contraindicated?
1. Hepatic impairment
2. Pregnancy
3. Breast-feeding
39
Where are GLP-1 and GIP released from?
1. L cells in the ileum and colon
2. K cells in the duodenum and jejunum
40
What is the effect of the incretins?
1. Enhanced glucose uptake and utilisation (GLP-1 and GIP)
2. Decreased hepatic gluconeogenesis (GLP-1 only)
41
How do the incretins cause enhanced glucose uptake and utilisation?
1. Enhance insulin release
2. Delay gastric emptying
42
How do the incretins cause decreased glucose production from the liver?
Decrease glucagon release
43
Give an example of an incretin analogue
Extenatide
Liraglutide (long acting)
44
What are the main effects of extenatide?
1. Increase insulin secretion
2. Decrease glucagon secretion
3. Slow gastric emptying
45
Extenatide will cause weight _______ by ____________ appetite and increasing _________ by acting on the \_\_\_\_\_\_\_\_\_\_\_
Extenatide will cause weight **loss** by **decreasing** appetite and increasing **satiety** by acting on the **hypothalamus**
46
How are the incretin analogues administered?
Subcutaneous injection
47
What are the side effects of the incretin analogues?
1. Nausea
2. Hypoglycaemia
3. Pancreatitis (rare)
48
In which two ways can the incretin effect be maximised/maintained pharmacologically?
1. Reduce endogenous incretin breakdown (via DPP-4 inhibitors)
2. Exogenous incretin analogues
49
Why will more insulin be released if the same amount of glucose is taken orally versus by IV?
**Incretin effect**
Incretins (GLP-1 and GIP) increase insulin release
50
Which class of drugs can competitively inhibit the enzymatic breakdown of the incretins to maintain the incretin effect (and keep insulin levels higher)?
DPP-4 inhibitors (Gliptins)
51
Actions of GLP-1 and GIP are very rapidly terminated by which enzyme?
Dipeptidyl peptidase-4 (DPP-4)
52
Give an example of a DPP-4 inhibitor
1. **Sitagliptin**
2. Saxigliptin
3. Vildagliptin
53
What effect do DPP-4 inhibitors have on weight?
They are **weight neutral**
54
How are DPP-4 inhibitors administered?
Orally
55
What are the side effects of DPP-4 inhibitors?
Generally **well tolerated**
Nausea, yet **_NO_** hypoglycaemia (when used as a monotherapy)
56
As well as causing a mild weight loss, the actions of fat distribution are desirable in incretin analogue use, why?
Fat is redistributed from the liver to **subcutaneous tissue**
This reduces organ complications and is essentially healthier
57
What is α-glucosidase and what is its role?
A **brush border enzyme** in the small intestine
Breaks down CHOs to **monosaccharides**
58
Why are α-glucosidase inhibitors useful in T2DM?
Slow the breakdown of CHOs to monosaccharides
Reduces peak glucose levels in the blood
59
Name an α-glucosidase inhibitor
Acarbose
60
What are the adverse effects of α-glucosidase inhibitors?
1. Flatulence
2. Bloating
3. Abdominal pain
4. Diarrhoea
(occur as excess CHOs build up causing increased bacterial activity)
61
There is a risk of hypoglycaemia with α-glucosidase inhibitors
True or false?
False
62
What is the only therapeutic agent in the biguanide class of drugs?
Metformin
63
Generally metformin is considered the _______ line drug for T2DM
Generally metformin is considered the **first** line drug for T2DM
64
In which instances would metformin be contraindicated?
1. Hepatic dysfunction
2. CKD or reduced kidney function
65
What are the key effects of metformin?
1. Reduce hepatic gluconeogenesis
2. Increase glucose uptake and utilisation by skeletal muscle
3. Reduce CHO absorption
4. Increase fatty acid oxidation
66
Why is metformin a desirable drug for use in T2DM?
1. Reduces hyperlgycaemia
2. Do not cause hypoglycaemia
3. Can be used with other agents
4. Reduces micro and macrovascular complications of diabetes
5. Causes weight loss
6. Can be used in pregnancy
7. Can be taken orally
8. Minor BP reduction
9. Reduces triglycerides and LDL
67
What are the side effects of metformin?
1. GI side effects are most common - nausea, anorexia, diarrhoea
2. Metallic taste in the mouth
Generally these effects **subside with time**
**Lactic acidosis** (much more serious, yet rare) implicated in patients with hepatic or CKD. Alcohol excess may also induce this.
68
What dose is metformin
a) Generally started at
b) Rarely prescribed more than?
a) 500mg
b) 1g
(Metformin can be prescribed up to 3g/day yet there is not much added benefit of doing this vs 1g - adding another drug is more effective)
69
What is the main priciple behind the action of the thiazolidinediones (TZDs)?
Enhance the action of insulin
(this reduces the amount of insulin required to have an effect)
70
TZDs are agonists of _________ receptor \_\_\_\_\_\_\_\_-\_\_\_\_\_\_\_\_\_\_\_ ____________ \_
TZDs are agonists of **nuclear** receptor **proliferator-activated receptor γ**
(proliferator-activated receptor γ = PPARγ)
71
What occurs when TZDs bind to proliferator-activated receptor γ?
1. PPARγ which associates with retinoid receptor X (RXR)
2. Activated PPARγ-RXR complex acts as a transcription factor that binds to DNA
3. This promotes expression of genes encoding several proteins involved in insulin signalling etc.
Examples include:
* Lipoprotein lipase
* Fatty acid transport protein
* GLUT4
72
What are the desirable effects of the TZDs?
1. Promote **fatty acid uptake and storage in adipocytes**, rather than skeletal muscle and liver
2. Reduced **hepatic glucose output**
73
What is the only TZD still in use?
Pioglitazone
74
What are the adverse effects of pioglitazone?
1. Weight gain
2. Fluid retention (Na+ resorption by kidneys promoted)
3. Increased incidence of bone fractures
75
What are the only SGLT2 inhibitors currently licensed (2017)?
1. Dapagliflozin
2. Empagliflozin
76
What is the mode of action of the SGLT2 inhibitors?
1. Resorption of glucose is blocked in the proximal kidney tubule
2. Glucose is lost in the urine (glucosuria)
3. Blood glucose levels are reduced
77
What are the key benefits to Dapagliflozin and other SGLT2 inhibitors?
1. Weight loss (calorific loss)
2. Glucose lost in urine causing reduced BGLs
3. Osmotic diuresis (water follows glucose into urine ↑ weight loss)
4. Reduces CV risk
5. Reduces death by any cause
6. Benefits micro and macrovascular complications of diabetes
78
In which instances should metformin be avoided?
1. CKD
2. Hepatic failure/cirrhosis
3. Alcoholism
4. CLD
5. Cardiac failure
6. Mitochondrial myopathy
7. Other serious illness
79
What are the main side effects of SGLT2 inhibitors?
1. UTI
2. Thrush
3. Polyuria
(due to increased glucose output in urine)
80
Due to osmotic diuresis, SGLT2 inhibitors may even reduce _______ \_\_\_\_\_\_\_\_
Due to osmotic diuresis, SGLT2 inhibitors may even reduce **blood pressure**
81
1/3rd of all T2DM patients will eventually require ________ as part of their treatment
1/3rd of all T2DM patients will eventually require **insulin** as part of their treatment
82
What is one key, unique benefit to insulin therapy?
There is no upper dose limit - it is used as much as required
83
What are the side effects of insulin treatment?
1. Hypoglycaemia
2. Hyperglycaemia
3. Local reactions at injection site
4. Loss of fatty tissue at injection site
5. Insulin resistance
84
What happens to the required insulin doses in renal failure and why is this?
Required dose **decreases**
Insulin is usually excreted by the kidneys, yet this process becomes ineffective
85
Why can insulin induce hyperglycaemia?
Somogyi effect
There is overcompensation for induced hypoglycaemia
86
Which pathway can regulate glucose levels in insulin independent tissues?
Poyol pathway
87
Why are insulin independent tissues such as nerves, retina and blood vessel walls more susceptible to the effects of raised blood glucose?
They cannot regulate blood glucose levels through uptake
88
How does the Poyol (aldose reductase) function?
1. When there is significant excess of glucose in the blood, **aldose reductase** activates
2. Glucose is converted mostly to **sorbitol** yet some is converted to methylglyoxal and acetol
3. Sorbitol exerts osmotic pressure on cells inducing damage
4. **Sorbitol dehydrogenase** converts sorbitol to **fructose** so it can **diffuse** out of the cell
5. Advanced glycation end products (AGEs) may also cause damage
6. Glycating sugars and excess glucose bind to proteins forming AGES
7. AGEs are less effective and HbA1c is an example
89
Why does aldose reductase only activate in significantly raised blood glucose?
It has a very high Km when compared with glucokinase
90
Why does metformin cause weight loss?
Suppresses appetite
91
Thiazolidinediones (TZDs) exert their effect in which tissues?
1. Adipose
2. Skeletal muscle
3. Liver
92
How are GLP-1 (incretin) analogues administered?
Injected subcutaneously twice daily
| (before first and last meals)
93
As well as T2DM, when else may metformin be used?
1. NAFLD
2. Polycystic ovary syndrome
94
Metformin may induce a deficiency in which 2 main things?
1. Vitamin B12
2. Folic acid
95
What is the normal dose range for glicazide, yet there is little therapeutic benefit above which dose?
40-160mg
80mg
96
Which sulphonylurea is preferentially used in pregnancy and why?
Glibenclamide
Does not cross placenta
(used at 5-15mg)
97
What is eGFR?
Estimated glomerular filtration rate (of kidneys)
98
At which eGFR levels will metformin doses need to be altered and in which way for each?
eGFR = 30-45ml/min, half dose given
eGFR \< 30ml/min (or serum creatinine \>150micromol/l), **_STOP_** medication
(eGFR should be \>/= 90ml/min in a healthy patient)
99
In terms of beta cell function, what is a potential concern with using sulphonylureas?
It has been suggested they may be implicated in increased beta cell decline
100
How do GLP-1 agonists cause weight loss?
Act on hypothalamus to increase satiety
| (suppress appetite)
101
What is the extent of weight loss in SGLT2 inhibitors?
3-5kg
| (weight loss plateaus after this)
102
Which drug is very useful for a type 2 diabetic patient with high CV risk?
1. Dapagliflozin
2. Empagliflozin
103
Dapagliflozin should not be used if a patient has an eGFR below which level?
eGFR \<60ml/min
104
Which drugs, when used with sulphonylureas may cause a reductive effect?
1. Corticosteroids
2. Thiazide diuretics
