Diabetic drugs Flashcards
What stimulates the release of insulin?
- Secreted by B cells in response to:
1. Increase in glucose
2. Incretins
3. Parasympathetic activity
What is the half life of insulin?
- ~5 minutes in plasma
What inhibits the release of insulin?
- Decreased glucose concentration
- Cortisol
- Sympathetic activity
What is the role of insulin?
- Decreases hepatic glucose output via inhibition of gluconeogenesis and glycogenolysis
- Increases glycogen stores
- Promote uptake of glucose into tissues - muscle and adipose especially
How is insulin in the body regulated?
- Secreted into blood even during fasting - prevents receptor downregulation
- Rate and extent of glucose concentration change leads to biphasic pattern of insulin release
What are the symptoms of type 1 diabetes mellitus?
- Typically present in children and young adults
- Polyuria
- Polydipsia
- Weight loss
- Fatigue/lethargy
- Generalised weakness
- Blurred vision
How is type 1 diabetes diagnosed?
- Hyperglycaemia
- Fasting glucose >6.9 mmol/L
- Or random plasma glucose >11 mmol/L
- Plasma or urine ketones in presence of hyperglycaemia
- HbA1c >48 mmol/mol (>6.5%)
- Single raised plasma glucose without symptoms not sufficient for diagnosis
Compare plasma glucose with HbA1c
- Glucose - immediate measure of glucose levels in blood mmol/L
- HbA1c - measures percentage of red blood cells with a sugar coating (glycated haemoglobin)
- HbA1c reflects average blood sugar over last 10-12 weeks
What is the biochemical triad of diabetic ketoacidosis?
- Hyperglycaemia
- Ketonaemia
- Acidosis
- Predominantly in type 1 diabetes mellitus
- Particularly common in children on diagnosis
When do we suspect diabetic ketoacidosis?
- Blood glucose >11 mmol/L
- Polydipsia
- Polyuria
- Abdominal pain
- Vomiting and diarrhoea
- Lethargy
- Confusion
- Visual disturbance
- Acetonic breath
- Symptoms of shock
What do we test for when we suspect diabetic ketoacidosis?
- Ketones
- Urine or blood
- Venous pH <7.3
- Or HCO3- <15 mmol/L
What are the precipitating factors for diabetic ketoacidosis?
- Infection
- Trauma
- Non adherence to insulin treatment
- DDIs
How must insulin treatment be given?
- Parenterally to avoid digestion in the gut
- Because insulin is a protein
How is insulin formulated?
- In 100 units/mL
- 300 and 500 units/mL available to reduce volume
- Be careful when measuring dose
- Ensure you’re using correct vial so that you don’t prescribe an overdose
What is the routine delivery of insulin?
- Subcutaneous injection
- Upper arms, thighs, buttocks, abdomen
- I.V.I used for emergency treatment
- Rotate site of administration to limit lipodystrophy
How do we slow insulin absorption?
- Protamine and/or zinc complexes added to natural insulins (used less now)
- Causes soluble insulin to form hexamers - delays absorption from site of injection
- [plasma] is greatest after 2-3hours
- Dosing 15-30 minutes prior to meals
- Insulin analogues also used - a few amino acid changes
Which insulin types are fast acting?
- Insulin aspart - rapid acting
- Soluble insulin (Humulin S, Actrapid) - short acting
Which insulin types are longer acting?
- Isophane insulin (NPH) - intermediate
- Insulin glargine - long
What things do we need to consider when prescribing insulin?
- Combinations often prescribed - by brand name
- Short and long-acting mixtures
- May take them separately
- Basal-bolus dosing is common
- Other dosing regimens can be used - patient centred
- Syringes, pens, pumps, inhalers
What are the adverse side effects of insulin treatment?
- Hypoglycaemia
- Lipodystrophy
- Lipohypertrophy or lipoatrophy
What are the contraindications for insulin treatment?
- Renal impairment
- Hypoglycaemia risk
What are the DDIs for insulin treatment?
- Dose needs increasing with systemic steroids
- Caution with other hypoglycaemic agents
What is basal-bolus dosing?
- Given rapid acting insulin - bolus e.g. aspart
- Patient generally takes this before a meal
- Given long acting insulin - basal e.g. glargine
- Commonly used for young active T1DM patients
- Allows flexibility if adherence is good
What is diabulimia?
- When a type 1 diabetic stops or reduces their insulin to control their weight
Give an overview of type 2 diabetes mellitus?
- Slow progression of disease over many years
- Many people are asymptomatic early on
- Vast majority of T2DM patients are overweight or obese
- Age profile of T2DM has decreased
- Insulin into cells reduced due to cellular resistance associated with obesity
Outline the pathophysiology of insulin resistance
- Insulin resistance initially overcome by increased pancreatic insulin secretion
- Decreased insulin receptors
- Decreased GLP 1 secretion in response to oral glucose
- Response reduced at B cells
- Eventually insulin production reduced
Why is type 2 diabetes mellitus diagnosed later in life?
- Blood sugar rise typically slower than type 1 DM
- Symptoms are variable
- Often diagnosed through midlife MOT
How is type 2 diabetes managed?
- Lifestyle
- Education
- Weight loss (surgery in more and more instances)
- Initially non-insulin therapies
- Adherence is challenging in many patients
- Insulin forms part of treatment plan in poorly managed or later stage disease
- Treat co-morbidities
What are the different classes of hypoglycaemic agents?
- Sulphonylureas
- Biguanides
- Thiazolidinediones (glitazones)
- Dipeptidyl peptidase 4 inhibitors (gliptins)
- SGLT-2 inhibitors (gliflozins)
- GLP-1 receptor agonists
Give an example of a biguanide
- Metformin
What is the mechanism of action of biguanides?
- Decrease hepatic glucose production by inhibiting gluconeogenesis
- Some gluconeogenic activity remains so hypoglycaemia risk is reduced
- Supresses appetite so weight gain is limited
- Typically first drug offered
- Can be taken concomitantly with other hypoglycaemic agents
What are the adverse side effects of metformin?
- GI upset
- Nausea
- Vomiting
- Diarrhoea
What are the contraindications for metformin?
- Stop if eGFR ,30 mL/min
- Alcohol intoxication
What are the DDIs of metformin?
- Drugs that may impair renal function e.g. ACEi, diuretics, NSAIDs
- Drugs that increase glucose levels e.g. loop and thiazide like diuretics
Give an example of a sulfonylurea
- Gliclazide
What is the mechanism of action of sulfonylureas?
- Stimulate B cell pancreatic insulin secretion
- Blocks ATP-dependant K+ channels
- Need residual pancreatic function to work
- Weight gain through anabolic effects of insulin
- Typically taken in combination with other agents
What are the adverse side effects of sulfonylureas?
- Mild GI upset
- Nausea
- Vomiting
- Diarrhoea
- Hypoglycaemia
What are the contraindications of sulfonylureas?
- Hepatic and renal disease
What are the DDIs of sulfonylureas?
- Other hypoglycaemic agents
- Loop and thiazide like diuretics - increase glucose so reduce action of sulfonylureas
Give some examples of glitazones
- Pioglitazone
- Rosiglitazone
Outline the mechanism of action of glitazones
- Insulin sensitisation in muscle and adipose
- Decrease hepatic glucose output by activation of PPAR-g
- Gene transcription
- Weight gain because of fat cell differentiation
- Used much less frequently than other agents
What are the adverse side effects of glitazones?
- GI upset
- Fluid retention
- Fracture risk
- Bladder cancer
What are the contraindications of glitazones?
- Heart failure because of fluid retention
What are the DDIs of glitazones?
- Other hypoglycaemic agents
Give some examples of gliflozins
- dapagliflozin
- canagliflozin
What is the mechanism of action of gliflozins?
- Decreased glucose absorption from tubular filtrate
- Increased urinary glucose excretion
- Competitive reversible inhibition of SGLT-2 in PCT
- Modest weight loss, hypoglycaemic risk is low
- Add on therapy in T2DM
- Treats HFrEF
What are the adverse side effects of gliflozins?
- UTI
- Genital infection
- Thirst
- Polyuria
- Pancreatitis?
What are the contraindications of gliflozins?
- Hypovolaemia - possible hypotension
What are the DDIs of gliflozins?
- Antihypertensive and other hypoglycaemic agents
Diabetic drugs are GLP-1 agonists. What are the physiological effects of GLP-1?
- Increases insulin secretion and biosynthesis
- Decreases glucagon secretion
- Decreases food intake by increasing satiety
- Decrease glucose production by the liver
- Increase glucose uptake by muscles
- Decrease gastric emptying
Give some examples of DPP-4 inhibitors (gliptins)
- Sitagliptin
- Saxagliptin
Outline the mechanism of action of gliptins
- Prevent incretin degradation - increase incretin plasma concentration
- Glucose dependant so acts after patient eats
- Does not stimulate insulin secretion at normal blood glucose
- Lower hypoglycaemic risk
- Suppress appetite so they are weight neutral
What are the adverse side effects of gliptins?
- GI upset
- Small pancreatitis risk
What are the contraindications of gliptins?
- Avoid in pregnancy
- History of pancreatitis
What are the DDIs of gliptins?
- Other hypoglycaemics
- Drugs that increase glucose can oppose gliptin action e.g. loop and thiazide like diuretics
Give some examples of GLP-1 receptor agonists
- Exenatide
- Liraglutide
- Semaglutide
What is the mechanism of action of GLP-1 receptor agonists?
- Increase glucose dependant synthesis of insulin and secretion from B cells
- Activate GLP-1 receptor
- Resistant to degradation by DPP-4
- Given by subcutaneous injection
- Promote satiety
What are the adverse side effects of GLP-1 receptor agonists?
- GI upset
- Decreased appetite with weight loss
What are the contraindications of GLP-1 receptor agonists?
- Renal impairment
What are the DDIs of GLP-1 receptor agonists?
- Other hypoglycaemic agents
Which type 2 diabetes drugs are modified/extended release?
- Metformin
- Incretin mimetics
What are the advantages of modified/extended release preparation diabetic drugs?
- Overcome GI upset
- Less frequent dosing
- Slower release changes PK properties
- Improved adherence
- But more difficult to modify dose
Why swallow an extended release tablet whole?
- Modified release preparation coats tablet
- Crushing up tablets overrides effects
