Week 5: Diabetes (2) (pharmacology) Flashcards
Type 1 diabetes mellitus
Diagnosis
- Fasting glucose >6.9 mml/L or random plasma glucose >11 mmol/L
- Plasma or urine ketones
- HbA1C >48 mmol/mol
- A single raised plasma glucose without symptoms not sufficient for diagnosis ( would need several blood tests in the absence of symptoms)
- *Diagnostic factors**
- Rapid onset symptoms
- Polyuria (nocturia)
- Polydipsia (needing to wake at night for water)
- Weight loss
- Fatigue/lethargy
- Generalised weakness
- Blurred vision
Glucose vs HbA1c
- Glucose = an immediate measure of glucose levels in blood mmol/L
-
Haemoglobin A1c- glycated haemoglobin
- % of RBC with sugar coating
- Reflects average blood sugar over last 3 months (mmol or %)
Diabetic ketoacidosis (DKA) Biochemical triad of
- Hyperglycaemia
- Ketonemia
- Acidosis
DKA predominantley found in
- T1DM
- Common in children on diagnosis
When to suspect DKA
- Blood glucose >11 mmol AND
- Polydipsia
- Polyuria
- Abdominal pain
- Acetonic breath
- Confusion
- Lethargy
- Visual disturbances
- Symptoms of shock
precipitating factors for DKA
- Infection
- Trauma
- Non-adherence to insulin treatment
- DDIs
diagnosis of DKA
- Blood glucose >11mmol (may not always be present = euglycemia)
- Test for ketones in blood and urine
DKA treatment
- Initially i.v.i fluid (with potassium) and then i.v.i soluble insulin
Therapeutic insulins
- Historically bovine and porcine (immunogenicity concerns)
- Now use human insulin
- Recombinant DNA (bacteria/yeast)
- Protein therefore must given parenterally to avoid digestion
- Usually formulation in 100 units/mL
- Due to obesity and insulin resistance there are higher doses (300 and 500 units/mL(
- NEVER abbreviate units or international units → dangerous mistake could be made
Emerging therapeutics
- Immunotherapy- monoclonal antibodies for high risk group
- Delay progression
- Islet transplantation
- Islet cell regeneration
- Inhaled insulin
- Pharmaceutical challenge
- SGLT-2 inhibitors
- TI and TII DM and other CVDs
Pharmacokinetics of insulin therapy
- Routine delivery= subcutaneous injection in upper arm, thighs, buttocks, abdomen
- Emergency e.g. DKA= i.v.i (IV infusion)
Half life of insulin in plasma is short (5 mins) therefore we need to slow absorption via a few methods
Half life of insulin in plasma is short (5 mins) therefore we need to slow absorption via a few methods:
- For bovine and porcine insulins adding protamine and/or zin complex – used less now
- Delays dissolving
- Soluble (neutral) insulin forms hexamers
- Delaying absorption from site of injection
- [plasma] insulin will be highest after 2-3 hours (dosing 15-30 min prior to meals)
- Insulin analogues
- Recombinant modifications- a few amino acid changes
- Changes PK and not PD
Effects of different insulin available
prescribing insulin
Prescribing insulin
- Many preparations available
- Combinations often prescribed
- Short and long-acting mixtures
- May take them separately
- Basal bolus dosing- common
- Methods of injecting
- Syringes
- Pens
- Pumps
- Inhalers?
drug class of insulin
hormonal drug
mOA of insulin
- Insulin binds to insulin receptor
- Causes cascade of events which causes GLUT4 receptors to translocate from the cytoplasm to the membrane
- GLUT4 increases uptake of glucose into the cell lowering blood glucose
ADR insulin
Adverse drug response
- Hypoglycaemia
- Lipodystrophy
- Lipohypertrophy or
- lipoatrophy
Basal bolus dosing
A common dosing schedule for young active TIDM patients which provides some flexibility if adherence is good
- Basal- long acting e.g. glargine
- Given once a day
- Bolus- rapid acting e.g. aspart
- Given before meals
management of T@DM
Management
- Lifestyle
- Education
- Weight loss
- Initially non-insulin therapies
- May form part of treatment plan in poorly managed or later stage disease
- Treatment with hypoglycaemic agents
- Can cause weight gain- makes adherence to sustained successful therapy a challenge
- Treatment of comorbidities
classes of glucose lowering drugs
sulphonylureas
biguanides
glitazones
dipeptidyl peptidase-4 DDP (gliptins)
SGLT-2 (gliflozins)
GLP-1 receptor agonists (incretin mimetics)
1
biguanides example
metformin
sulphonylureas example
glicazide
glitazone example
pioglitazone
DDP-4 inhibitor example
saxagliptin
sitagliptin
SGLT-2 inhibitors
canagliflozin
GLP-1 receptor agonist
exenatide
liraglutide
metformin
biguanide
- First line treatment for T2DM
metformin MOA
- Reduces hepatic glucose production by inhibiting gluconeogenesis
- Some gluconegenic activity remains so hypoglycaemia risk reduced
- Also: suppresses appetite to limit weight gain
ADR metformin
nausea
vomiting
diarrhoea
metformin contraindication
- eGFR <30 mL/min
- excreted unchanged by kidneys
- alcohol intoxication
metformin DDI
Drug-drug interaction
- ACEi (drugs which impair renal function)
- Diuretics (drugs which impair renal function)
- NSAIDs (drugs which impair renal function)
- Loop and thiazide like diuretics which increase glucose so can reduce metformin action
gliclazide
sulfonylureas
used
- Typically in combination with other agents or a first line option if metformin contraindicated
gliclazide MOA
- Inhibit ATP-dependent K+ channels causing membrane depolarisation
- Causes calcium into the cell
- Stimulate B cell pancreatic insulin secretion by blocking
- NEED PANCREATIC FUNCTION TO WORKA
- Can cause weight gain through anabolic effects of insulin
ADR glicazide (SU)
- Mild GI upset
- Nausea
- Vomiting
- Diarrhoea
- Hypoglycaemia (works at low [glucose])
contraindication gliclazide (SU)
- Hepatic disease
- Renal disease
- Caution of those at risk of hypoglycaemia
DDI gliclazide (SU)
- Other hypoglycaemic agents
- Loop and thiazide like diuretics (increase glucose so can reduce SU action)
dapagliflozin
SGLT-2 inhibitor
Uses
- adjunct to insulin in T1DM (high BMI)
- T2DM as an add on therapy
- Modest weight loss, hypoglycaemic risk is low
MOA of gliflozins
- Competitive reversible inhibition of SGLT-2 in PCT
- Decrease glucose absorption from tubular filtrate
- Increase glucose excretion
ADR gliflozins
- UTI (sugar urine)
- Genital infections
- Thirst
- Polyuria
contraindication gliflozins
- Risk of DKA in T1DM
- Possible hypotension
DDI gliflozins
- Antihypertensives
- Other Hypoglycaemic agents
Physiological effect of GLP-1 (incretin hormone)
-
In the pancreas
- Increases insulin secretion
- Decrease glucagon secretion
- Increase insulin biosynthesis
Drugs which target GLP-1 actions
- Dipeptidyl peptidase- 5 (DPP-4) inhibitors (Gliptins)
- Glucagon-like peptide-1 (GLP-1) receptor agonists (incretin mimetics)
sitagliptin
Dipeptidyl peptidase- 5 (DPP-4) inhibitors (Gliptins)
MOA of gliptins e.g. DPP-4 inhibits
- Prevent incretin (GLP-1) degradation – increasing plasma incretin levels
- Glucose dependent so postprandial action
- Will not stimulate insulin secretion at normal blood glucose- lower hypoglycaemic risk
- Supress appetite- due to GLP-1 action in satiety
- Weight neutral
- Given subcutaneously like insulin – protein therefore would be digested if given enterally
ADR gliptins
- GI upset
- Small pancreatitis risk
contraindications gliptins
- Avoid in pregnancy
- History of pancreatitis
DDI gliptins
- Other hypoglycaemic agents
- Drugs increase glucose can oppose gliptin action- thiazide like and loop diuretics
exenatide
GLP receptor agonist- incretin mimetic
mode of action of exenatide (GLP-1)
- Increase glucose dependent synthesis of insulin secretion from B cells by activating GLP-1 receptors (resistance to degradation by DPP-4)
- Subcutaneous injection
- Promotes satiety- possible weight loss
ADR exenatide
- GI upset
- Decreased appetite with weight loss
