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Pharmacology > Pharmacological Management of Diabetes > Flashcards

Pharmacological Management of Diabetes Flashcards

1
Q

Which organ monitors blood glucose?

A

Pancreas

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2
Q

What happens in the event of low blood glucose?

A

Glucagon is released from α-cells and the upper GI tract to stimulate glycogen breakdown and gluconeogenesis in the liver.

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3
Q

What happens in the event of high blood glucose?

A

Insulin is released from β-cells to stimulate muscle and adipose tissue to uptake glucose redistributing Glut4 to the cell membrane.

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4
Q

How does the liver act to control glucose levels?

A

By gluconeogenesis and glycogen synthesis

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5
Q

Give a diagramatic representation of how blood glucose is controlled.

A
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6
Q

Describe type 1 diabetes mellitus.

A
  • Genetic predisposition and exposure to environmental triggers such as viral infections, diet and vitamin D deficiency.
  • Pancreatic β-cell destruction, leading to impairment of insulin secretion and deficiency.
  • Clinical T1DM does not present util >80% of β-cells have been destroyed.
  • Clinical course of T1DM is characterised by the rapid onset of osmotic symptoms, including polyuria, polydipsia, weight loss and fatigue along with hypoglycaemia.
  • ~67% of patients present with life-threatening diabetic ketoacidosis at diagnosis (DKA).
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7
Q

Describe type 2 diabetes mellitus.

A
  • Genetic predisposition and progressive loss of insulin sensitivity and defective insulin receptor signalling.
  • Often due to impaired insulin receptor signalling leading to insufficient transport of glucose into tissues.
  • Often associated with metabolic syndrome, which starts with energy imbalance, high food consumption along with low energy expenditure.
  • Fatty deposits in visceral organs leads to altered insulin signalling, insulin resistance and β-cell damage.
  • T2DM progresses when ~80-90% of β-cells fail.
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8
Q

Describe the progression from prediabetes to type 2 diabetes.

A
  • There is a natural progression from prediabetes to diabetes.
  • Due to disruption of an individual’s ability to metabolise glucose.
  • Individuals with prediabetes have lower insulin sensitivity which results in hyperinsulinaemia.
  • Diabetes progresses when the β-cells are failing, resulting in low insulin secretion in combination with low insulin sensitivity.
  • >7mM fasting plasma glucose = diabetes.
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9
Q

At what level of fasting plasma glucose is diabetes indicated?

A

>7mM

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10
Q

How is effective T1DM usually measured?

A
  • Effective diabetes management is usually measured by self-monitoring of blood glucose (SMBG) - sampling capillary blood after a finger prick.
  • NICE guidelines:
    • Fasting glucose levels above 7mM indicative of diabetes.
    • OR random glucose measurement above 11.1mM.
  • HbA1C measurement is also used to diagnose diabetes and evaluate glucose levels over a longer time frame.
  • HbA1C provides an integrated measure of control over the lifespan of RBCs (~120 days) - levels above 7% indicate diabetes.
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11
Q

What fasting blood glucose level indicates diabetes?

A

>7.7mM

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12
Q

What random glucose measurement indicates diabetes?

A

>11.1mM

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13
Q

What HbA1C level indicates diabetes?

A

>7%

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14
Q

What is the aim of treatment for T1DM?

A

Replacement therapy to normalise glucose levels of 4-7mM (pre-prandial/fasting).

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15
Q

At which blood glucose level will the renal capacity be overloaded?

A

Blood glucose levels >10mM will overload the renal capacity and be detected in the urine.

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16
Q

Describe the different formulations of insulin.

A
  • Human insulin is made by recombinant DNA technology, which allows an identical pure preparation, limiting allergic reactions.
  • Designer human insulin analogues are modified insulins that produce either an extended duration of action or faster absorption.
  • Insulins may be pure preparation or complexed with proteins, salts or fatty acids to alter their duration of activity.
  • Durations of activity can be rapid-acting (within 15 minutes) to long-duration peakless forms (exceeding 24 hours).
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17
Q

Why is insulin administered parentally?

A

Because it is a protein that would be destroyed/digested by the gut if taken orally.

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18
Q

How is insulin administered?

A

For routine use it is given subcutaneously and by IV infusion in emergencies (only soluble forms).

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19
Q

Which formulations are rapid-acting soluble insulins?

A
  • Insulin lispro
  • Insulin aspart
  • Insulin glulisine
  • These are designer insulins that prevent dimer formation allowing more active monomers to be bioavailable.
  • Rapid onset (10-20 minutes)
  • Short duration (2-5 hours)
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20
Q

Describe isophane insulin (Neutral Protamine Hagerdorn; NPH).

A
  • Intermediate acting insulin that precipitates into suspensions which slowly dissolve.
  • Human insulin complexed with positively charged polypeptide (protamine) and zinc.
  • Onset 1-2 hours
  • Duration 12-20 hours
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21
Q

Describe insulin glargine.

A
  • Longer acting ‘peakless’ designer insulin which has decreased solubility at neutral pH - forms aggregates that slowly dissolve into active monomers (24-36 hours).
22
Q

Describe insulin detemir.

A

Long-acting ‘peakless’ designer insulin with a fatty acid - this confers albumin binding, which slowly dissociates prolonging circulation (24 hour duration of activity).

23
Q

Describe insulin degludec.

A

Ultralong-acting designer insulin with a fatty-acid - this results in multi-hexamer formation at injection site with slow release (>42 hours).

24
Q

Describe fixed dose insulin therapy.

A
  • The amount of insulin taken at each meal does not vary from day to day.
  • Can help to simplify understanding of blood glucose results but does not offer the flexibility of how muh carbohydrate patients choose to consume at each meal.
25
Q

Describe flexible insulin therapy.

A
  • Used for patients that really understand glucose metabolism and gives patients more control over what they eat and how they balance their blood glucose levels.
  • Will take time and commitment to learn how best to adjust insulin doses.
  • Patients choose how much insulin to inject at each meal and also allows doses to be varied in response to different carbohydrate quantities in meals.
26
Q

What is the main adverse effect of insulin therapy?

A

Hypoglycaemia

27
Q

How are patients who have difficulty achieving good glycaemic control managed?

A

These patients may have to use an insulin pump.

28
Q

Describe injection insulin therapy.

A
  • 1-3 injections per day.
  • Either in the morning or at meal times.
  • Suitable for T2D patients.
  • Formulations:
    • Rapid-acting OR
    • Short-acting insulin mixed with intermediate insulin
  • Meal time and content is fixed.
  • Basic level of understanding required by patient.
29
Q

Describe basal-bolus insulin therapy.

A
  • Multiple injections per day.
  • Injections spaced throughout the day.
  • Suitable to treat T1D patients, and some T2D patients.
  • Formulations:
    • Intermediate or long-acting with short acting formulation.
  • Meal time and content is flexible.
  • High level of patient understanding is required.
30
Q

Describe the use of oral hypoglycaemic agents.

A
  • Oral hypoglycaemic tablets are used to alter glucose metabolism in T2Ds.
  • The principal drug used is Metformin (a biguanide drug).
  • T2Ds have some residual insulin and insulin sensitivity.
  • Metformin can potentiate residual insulin by increasing insulin sensitivity.
  • Acts to reduce gluconeogenesis in the liver, which is markedly increased in T2D and opposes the action of glucagon.
  • Increases glucose uptake and utilisation in skeletal muscle.
  • Slightly delays carbohydrate absorption in the gut.
  • Increases fatty acid oxidation - reducing circulating LDL and VLDL, which can help in obesity assiciated diabetes and atherosclerosis development.
  • Can encourage weight loss by suppressing apetite but can cause anorexia in rare cases.
  • Can be combined with drugs that stimulate insulin release.
31
Q

Describe the mechanism of action of Metformin.

A
  • Metformin alters energy metabolism.
  • it acts on the mitochondria to change the ratio of AMP to ATP.
  • Increased AMP:ATP ratios activate AMP-activated protein kinases (cells metabolic master switch).
  • Inhibits glucagon signalling and gluconeogenic pathways.
  • AMPK increases transcription of genes important for glucose transport fatty oxidation and inhibits faty acid synthesis.
  • Takes time due to regulating gene networks.
32
Q

What are incretins?

A
  • Glucagon-like peptide-1 (GLP-1) is secreted by L-cells in the gut.
  • Gastric inhibitory peptide (GIP) is secreted by K-cells in the gut.
33
Q

Describe the role of incretins.

A
  • Incretins:
    • stimulate insulin biosynthesis / secretion
    • Inhibit glucagon secretion in the pancreas
    • Delay gastric emptying
    • Increase cardiac output
    • Increase brain satiety signals
  • Incretins also indirectly increase insulin sensitivity in the muscle and decrease gluconeogenesis in the liver.
  • Incretins are rapidly degraded by an enzyme called dipeptidyl peptidase-4 (DPP-4).
34
Q

Describe incretin analogs.

A
  • Incretin analogs lower blood glucose after a meal by increasing insulin secretion and suppressing glucagon secretion.
  • Used for T2D in addition of oral agents to improve control and aid weight loss.
  • Given subcutaneously as peptide analogs.
  • Can cause hypoglycaemia and a range of GI effects.
35
Q

Name the 3 incretin mimetics.

A
  • Exenatide
  • Exenatide LAR
  • Liraglutide
36
Q

Describe Exenatide

A
  • Analog of exendin-4/GLP-1
  • Given twice daily
  • Can cause nausea
37
Q

Describe Exenatide LAR

A
  • Analog of exendin-4/GLP-1
  • Long-acting release formulation that is administered weekly
  • Induces less nausea
38
Q

Describe Liraglutide

A
  • Analog of exendin-4/GLP-1
  • Has an additional fatty side-chain tht confers albumin binding and slows renal clearance.
39
Q

Give 2 examples of DPP-4 Inhibitors (Gliptins).

A
  • Sitagliptin
  • Vildagliptin
40
Q

Describe the function of DPP-4 Inhibitors (Gliptins).

A
  • Enhance endogenous incretin effects by blocking DPP-4.
  • Lowers blood glucose by increasing the first phase of insulin response after meals.
  • Used in T2D in addition to other oral hypoglycaemic drugs.
  • Sitagliptin is well tolerated and weight neutral.
  • Vildagliptin is not available in the USA - found associated with respiratory tract infections, headache and on occasions serious pancreatitis.
41
Q

Describe sulphonylureas.

A
  • Insulin secretagogues
  • An older class of orally-active hypoglycaemic drugs.
  • Sulphonylureas interfere with β-cell ion channels to potentiate insulin secretion.
  • Well tolerated but can lead to weight gain by stimulating apetite.
  • Used in early stages of T2D, as they require functional β-cells.
  • Can be combined with Metformin and Glitazones.
  • But can interact with other drugs to produce severe hypoglycaemia due to competition for metabolising enzymes, plasma binding proteins and excretory pathways.
  • Sulphonylureas:
    • Tolbutamide
    • Chlorpropamide
    • Gilbenclamide
    • Glipizide
42
Q

Describe meglitinides.

A
  • Insulin secretagogue
  • Next generation secretagogues with a similr mechanism of action (blocking KATP channels to increase insulin release) - short duration of activity leads to lower risk of hypoglycaemia.
  • Meglitinides:
    • Repaglinide
    • Nateglinide
43
Q

Describe the mechanism of action of sulphonylureas.

A
  • High affinity receptors for these drugs are present in β-cell membranes.
  • Block ATP-sensitive potassium channels in β-cells.
  • Causes β-cell depolarisation, which leads to insulin secretion.
  • Only work if β-cells of the pancreas are functional.
44
Q

Give examples of selective sodium glucose cotransporter 2 (SGLT2) inhibitors.

A
  • Canagliflozin
  • Dapagliflozin
  • Empagliflozin
45
Q

When are SGLT2 inhibitors used?

A

Used in T2D as monotherapy when diet and exercise alone is not adequate for whom metformin is contraindicated or inappropriate.

46
Q

Describe the mechanism of action of SGLT2 inhibitors.

A
  • Block glucose reabsorption by the proximal convoluted tubule leading to theraputic glucossuria.
  • Controls glycaemia independently of insulin pathways.
  • Lead to reduced HbA1C up to 1.17% compared to placebo.
  • Well tolerated.
  • Reduce weight.
  • Reduce systolic blood pressure.
  • Do not cause hypoglycaemia but associated with increased risk of urinary tract infections.
47
Q

What are thiazolidinediones (glitazones)?

A
  • Peroxisome proliferator activated receptor - ɣ (PPARɣ - a nuclear receptor) agonists.
  • PPARɣ expressed in adipose tissue, muscle and liver.
48
Q

What are the actions of Pioglitazone (a thiazolidinedione (glitaozone))?

A
  • Pioglitazone:
  • Increases insulin sensitivity and lowers blood glucose in T2Ds.
  • Reduces the amount of exogenous insulin needed by ~30%.
  • Increases glucose uptake into muscle in response to insulin.
  • Reduces blood glucose and free fatty acid concentrations.
  • Promote transcription of several genes with products that are important in insulin signalling but take months to work.
  • Can cause weight gain and fluid retention.
  • Has been linked to bladded cancer, heart failure and osteoporotic fractures - withdrawn from Germany, France and India.
49
Q

Describe the mechanism of action of Pioglitazone. What is it used for?

A
  • PPAR-ɣ ligands promote transcription of genes important in insulin signalling: lipoprotein lipase, fatty acid transporters, Glut-4 and others.
  • Pioglitazone is used in the clinic as an additive to other oral hypoglycaemic drugs such as Metformin and Sulphonylureas.
50
Q

Describe the function of an α-glucosidase inhibitor.

A
  • Acarbose - a saccharide that acts as a competitive inhibitor of intestinal α-glucosidase.
  • Delays carbohydrate absorption in the small intestine reducing the postprandial spike in glucose.
  • Used in T2D often in combination with other hypoglycaemics.
  • Side effects can include flatulence and diarrhoea.

Pharmacology (7 decks)

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