Diabetes Drugs (M2 11/12) Flashcards
1
Q
LO’s
A
- Describe the mechanism of action and clinical use of drugs used in diabetes, including classes and duration of action of insulins
- Describe the major pharmacokinetic characteristics which affect the clinical use of drugs used in diabetes
- Describe the major side effects of drugs used in diabetes
2
Q
Why Do We Need Drugs To Treat Diabetes?
A
DM1: Total absence of insulin means the only treatment is to replace with exogenous insulin
DM2:
- In early stages lifestyle changes should be the foremost treatment
- When some insulin is present drugs will enhance the release of insulin and enhance the cell’s response to the insulin present.
3
Q
Where can we get insulin from?
A
- Animals like pigs and cows.
- From E.Coli and yeast genetically altered by recombinant DNA technology to contain the insulin gene.
4
Q
Describe how insulin exists in the beta cell.
A
- Is a peptide hormone
- Secreted by the beta-cells o the pancreas.
- In the beta cell, insulin exists as an inactive hexamer.
- Insulin is produced and stored in the body as a hexamer (a unit of six insulin molecules): an inactive form with long-term stability
- The hexamer formation keeps the highly reactive insulin protected, yet readily available for use by the cells in the active form which is the monomer
- The hexamer to monomer conversion is one of the central aspects of insulin formulations for injection. For example rapid acting insulins such as insulin lispro and aspart have been genetically engineered to not form insulin hexamers and to stay I the monomer format. The addition of Zinc to insulin aggregates further stabilises the insulin hexamer making it less soluble and more difficult to convert to the monomer format this is useful for a longer acting insulin.
5
Q
How do high glucose levels cause insulin release? Draw the steps.
A
- Glucose enters β-cells via the GLUT2 transporter
- Glycolysis happens via Glucokinase, even though most cells use hexokinase, because glucokinase binds to glucose weakly, so it has more ‘off’ time than ‘on’ time so can act as a glucose level sensor, as opposed to always being attatched to glucose like a high-afffinity binder. Also glucokinase is not inhibited by high glucose 6 phosphate. This means with glucokinase, Glucose 6 Phosphate will reflect blood glucose levels.
- Enters Kreb’s cycle and OP occurs
- ATP levels rise intracellularly
- ATP inhibits the ATP sensitive K+ pump preventing K+ from leaving the cell
- As a result membrane depolarizes and extracellular Ca2+ enters the cell via a voltage gated channel
- Finally rising levels of Ca2+ promotes fusion of storage vesicles with plasma membrane and release of insulin
- Insulin results in the upregulation of the GLUT4 glucose transporter in other cells
•As we will see later sulfonylureas affect this process
6
Q
Why is insulin not given orally, but as an injection?
A
Because insulin is a polypeptide it is degraded in the gastrointestinal tract and therefore cannot be administered orally. Generally insulin is administered via subcutaneous injection.
7
Q
Give examples of the four types of insulin injections
A
- Rapid acting: aspart, lispro and glulisine. Get peak insulin levels 30-90 mins after injection. Taken with meals.
- Short acting: soluble insulin (aka regular insulin). Taken with meals. Peak insulin levels 50-120 mins after injection.
- Intermediate acting: isophane insulin (aka NPH-Neutral Protamine Hagedorn). Taken with meals and with bedtime. Pek insulin level 5 hours after administration.
- Long lasting: glargine and detemir. Taken at bedtime, have no insulin peak.
8
Q
Describe the two dosing regimens for insulin
A
The standard dosing regime involves injection twice a day. The injection is usually premixed combination of insulin isophane and regular insulin in a 70/30 mix.
In contrast the intensive insulin regime is a series of more frequent injections that are given with meals and a longer acting insulin in the background or overnight. On the intensive program patients have to monitor their blood glucose more often before they administer the insulin.
9
Q
Adverse reactions to insulin
A
- Hypoglyceamia: headache, anxiety, dizziness, tachycardia, confusion and sweating.
- Weight gain.
- Lipodystrophy: disorder of adipose tissue at the site of injection causing hypertrophy or atrophy.
- Irritation and even allergic reactions at the injection site.
10
Q
What are the three classifications of anti-diabetic drugs?
A
- Secretagogue therapy: Sulphonylureas, Meglitinides, Incretin analogues and DPP4 inhibitors. These enhance the production of insulin.
- Insulin sensitisers: Biguanides and Thiazolidinediones.
- Drug that modify glucose absorption: α- glucosidase inhibitors and sGLT 2 inhibitors
11
Q
Common drugs used in diabetes: Metformin
A
- Metformin is the only biguanide.
- It is the frontline drug, if 3/4 months of lifestyle changes fail in T2DM.
- How it works:
- Metformin inhibits oxidative phosphorylation, so ATP production is decreased and AMP production is increased. Build up of AMP activates AMPK.
- AMPK has an important role in insulin signalling, whole body energy balance, and the metabolism of glucose and fats
- AMP causes NADH buildup, used to convert pyruvate (a gluconeogenic precursor) to lactate.
- AMPK activation causes gluconeogenic genes to be switched off.
- So, overall AMPK activation causes increased glycolysis and reduced gluconeogenesis. This decreases hepatic/liver glucose production.
- Also, when AMPK is activated by metformin, GLUT4 is opened, so there is insulin independant glucose uptake in periphery.
- Also, it maintains energy levels, by preventing energy loss through anabolic processes like FA synthesis (through phosphorylation of Acetyl CoA Carboxylase) and cholesterol synthesis (through phosphorylation of of HMG-Reductase & SREBP1c).
- Metformin prevents the storage of energy as lipid and promotes the production of ATP via TCA/Kreb’s cycle.
- Typical reduction in glycated HbA1c for Metformin is 1.5–2.0%
12
Q
Common drugs used in diabetes: Thiazolidinediones
A
- Thiazolidinediones are steroid receptors.
- Go to nucleus and activate gene expression.
- Increase insulin sensitivity
- Cause inhibition of hepatic glucose production.
13
Q
Common drugs used in diabetes: Sulfonylureas
A
- Sulfonylureas are the most common Secretagogues.
- They work by increasing insulin secretion from functioning b-cells.
- Normally, high blood glucose causes insuling release by:
- Glucose enters beta-cell through GLUT2
- Respiration of glucose produces ATP
- ATP increase, causes ATP sensitive potassium channel to close
- Depolarisation since K can’t leave
- Calcium enters cell through voltage gated calcium channel
- Calcium causes insulin vesicles to bind to membrane and release insulin.
- Solfonylureas bind to the ATP sensitive pottasium channel (as it is a complex, and has a solfonylurea receptor) and inhibit the reopening of the potassium channel, allowing longer release of insulin.
14
Q
What are the advantages of using metformin?
A
- There is no weight gain, like other drugs that promote insulin levels, because insulin causes glycogenosis in the liver and fat storage, wheras metformin causes hepatic glucose levels to production to decrease and insulin independant glucose uptake by cells.
- Reduces CV incidences in DM II patients
- Evidence shows metformin slows/prevents the progression to DM II
- Safe to use during pregnancy (gestational diabetes)
15
Q
What are the side effects of using metformin?
A
- Gastrointestinal
- Most common when starting, so give low dose (1-1.7g/day) to begin. Main problems are severe discomfort, diarrhoea and nausea/vomiting
- Malabsorption of Vit. B12, can result in elevated levels of homocysteine, leads to inflammation in the blood vessels, which in turn may lead to atherogenesis
- Lactic acidosis: Rare, but can be serious if not life threatening. Lactate is normally taken up by liver for gluconeogenesis but this is inhibited by metformin. Clearance an issue with kidney damage/liver damage heart failure and respiratory disease.
- Overdose: GI issues, hypoglycaemia, abdominal pain- elderly more at risk. Extracorporeal treatment in severe overdoses (80-200 mg l-1).
