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Clinical Pharmacology, Therapeutics & Intro to Prescribing > Lecture 10- Diabetes mellitus > Flashcards

Lecture 10- Diabetes mellitus Flashcards

1
Q

what sort of hormone is insulin

A

peptide

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2
Q

insulin is secreted by

A

Beta cells

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3
Q

beta cells secrete insulin in response to

A
  • Increase [glucose] in plasma
  • Incretins (GLP-1, GIP)- the incretin effect
  • Parasympathetic activity (M3)
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4
Q

insulin secretion is inhibited by

A
  • Low glucose
  • Cortisol
  • Sympathetic activity (alpha2)
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5
Q

insulin half life

A

5 mins in plasma

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6
Q

Function of insulin

A
  • Decrease hepatic glucose output of gluconeogenesis and glycogenolysis- overall increasing glycogen stores
  • Promotes uptake of glucose into tissues- muscles and adipose esp.
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7
Q

why is insulin secreted in the blood even during fasting

A

prevents insulin receptor down regulation

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8
Q

what sort of pattern is insulin released

A

biphasic

  • Shortly after elevation of glucose conc,a transient stimulation of insulin secretion is observed ‘first phase secretion’
  • This is later followed by gradually developing secondary stimulation ‘second phase secretion
    • Spike in insulin conc
    • Then second lower spike
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9
Q

Type 1 diabetic 7 day overlay- being treated

A
  • Continual glucose monitoring (CGM)
  • Erratic
  • Even if being treated with insulin
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10
Q
A
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11
Q

Type 1 diabetes mellitus Diagnosis

A
  • 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)
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12
Q

symptoms of Type 1 diabetes

A
  • Rapid onset symptoms
  • Polyuria (nocturia)
  • Polydipsia (needing to wake at night for water)
  • Weight loss
  • Fatigue/lethargy
  • Generalised weakness
  • Blurred vision
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13
Q

measuring glucos vs HbA1c

A
  • Glucose = an immediate measure of glucose levels in blood mmol/L
  • HbA1C
    • Haemoglobin A1c- glycated haemoglobin
    • % of RBC with sugar coating
    • Reflects average blood sugar over last 3 months (mmol or %)
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14
Q

what is the main treatment for T1DM

A

therapeutic insulin

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15
Q

therapeutic insulin types

A
  • Historically bovine and porcine (immunogenicity concerns)
  • Now use human insulin
    • Recombinant DNA (bacteria/yeast)
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16
Q

why is insulin given parenterally

A

protein - avoids digestions

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17
Q

usual formation of insulins

A
  • Due to obesity and insulin resistance there are higher doses (300 and 500 units/mL(
  • NEVER abbreviate units or international units à dangerous mistake could be made
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18
Q

diabetic ketoacidosis is a biochemical triad of

A
  • Hyperglycaemia
  • Ketonemia
  • Acidosis
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19
Q

who is DKA predominately found in

A
  • T1DM
  • Common in children on diagnosis
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20
Q

When to suspect DKA

A
  • Blood glucose >11 mmol AND
  • Polydipsia
  • Polyuria
  • Abdominal pain
  • Acetonic breath
  • Confusion
  • Lethargy
  • Visual disturbances
  • Symptoms of shock
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21
Q

DKA- precipitating factors

A
  • Infection
  • Trauma
  • Non-adherence to insulin treatment
  • DDIs
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22
Q

Diagnosis of DKA

A
  • Blood glucose >11mmol (may not always be present = euglycemia)
  • Test for ketones in blood and urine
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23
Q

treatment of DKA (2 steps)

A

initial treatment- i.v.i (intravenous influsion) fluid with potassium

following initial treatment - i.v.i soluble insulin (fixed rate insulin)

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24
Q

delivery of insulin therapy

A
  • Routine delivery= subcutaneous injection in upper arm, thighs, buttocks, abdomen
  • Emergency e.g. DKA= i.v.i (IV infusion)
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25
Q

half life of insulin is only 5 minutes therefore we need to

A

slow absorption

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26
Q

how is absorption of insulin slowed

A
  • For bovine and porcine insulins adding protamine and/or zin complex – used less now
  • Soluble (neutral) insulin forms hexamers
  • Insulin analogues
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27
Q

How does adding protamine/ or zince complex to bovine and porcine insulins slow absorption of insulin

A
  • Delays dissolving
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28
Q

how does hexamer formation of soluble insulin delay aborption

A
  • Delaying absorption from site of injection
  • [plasma] insulin will be highest after 2-3 hours (dosing 15-30 min prior to meals)
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29
Q

Insulin analogues and slowing absorption

A
  • Recombinant modifications- a few amino acid changes
  • Changes PK and not PD
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30
Q

Methods of injecting insulin

A
  • Syringes
  • Pens
  • Pumps
  • Inhalers?
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31
Q

what class of drug is insulin

A

hormonal

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32
Q

uses of insulin

A
  • Type 1 Diabetes
  • Sometimes severe T2DM
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33
Q

Mode of action of insulin

A
  1. Insulin binds to insulin receptor
  2. Causes cascade of events which causes GLUT4 receptors to translocate from the cytoplasm to the membrane
  3. GLUT4 increases uptake of glucose into the cell lowering blood glucose
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34
Q

Adverse drug response: insulin

A
  • Hypoglycaemia
  • Lipodystrophy
    • Lipohypertrophy or
    • lipoatrophy
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35
Q

lipodystrophy

A

need to make sur einjection site is roated- otherwise will affect adherence

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36
Q

contraindications : insulin

A
  • renal impairment- hypoglycaemia risk
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37
Q

Drug-drug interaction: Insulin

A
  • dose needs increasing with systemic steroids
  • caution with other hypoglycaemic agents
38
Q

what is a common insulin dosing schedule for T1DM?

A

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
39
Q

emerging therapeutics for T1DM

A
  • 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
40
Q

what is diabulimia

A

When a type 1 diabetic stops or reduces their insulin to control weight

41
Q

name the oral hypoglycameic agents used to treat T2DM

A
42
Q

Type 2 diabetes

A
  • Slow progression of disease over many years
    • Many asymptomatic early on
  • Vast majority T2DM patients are overweight or obese
  • Age profile of T2DM has decreased
43
Q

Pathophysiology of T2DM

A
  • Insulin resistance
    • Initially insulin resistance overcome by increased pancreatic insulin secretion
    • However overtime there is a decrease in insulin receptor’s, and a decrease in GLP-1 secretion in response to oral glucose
    • Response reduced in B cells and eventually insulin production reduced
  • Lack of production of insulin
44
Q

diagnosis of T2DM

A

Blood sugars rise slower than T1DM so variable symptoms- often diagnosed through midlife `MOT’

45
Q

Management of T2DM

A
  • 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
46
Q

NICE guidelines on T2DM

A
47
Q

name a drug from the drug class Biguanides

A

Metformin

48
Q

metformin uses

A

T2DM

49
Q

Mode of action of metformin (biguanides)

A
  • Reduces hepatic glucose production by inhibiting gluconeogenesis
  • Some gluconegenic activity remains so hypoglycaemia risk reduced
  • Also: suppresses appetite to limit weight gain
50
Q

Adverse drug response: insulin

A

GI upset

  • Nausea
  • Vomiting
  • diarrhoea
51
Q

Contraindications: metformin

A
  • eGFR <30 mL/min
    • excreted unchanged by kidneys
  • alcohol intoxication
52
Q

Drug-drug interaction : metformin)

A
  • 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
53
Q

name a drug from the class Sulfonylureas

A

Gliclazide

54
Q

use of glicazide (sulfonylureas)

A
  • Typically in combination with other agents or a first line option if metformin contraindicated
55
Q

Mode of action: Gliclazide (Sulfonylureas)

A
  • Inhibit ATP-dependent K+ channels causing membrane depolarisation (consists of 4 sulfonylurea receptor 1 and 4 potassium channel)
  • Causes calcium influx into B cell
  • Stimulate insulin secretion
  • NEED PANCREATIC FUNCTION TO WORK
56
Q

Gliclazide (Sulfonylureas) affect on weight

A
  • Can cause weight gain through anabolic effects of insulin
57
Q

Adverse drug response: Glucazide (SU)

A
  • Mild GI upset
    • Nausea
    • Vomiting
    • Diarrhoea
  • Hypoglycaemia (works at low [glucose])
58
Q

Contraindications: Glucazide (SU)

A
  • Hepatic disease
  • Renal disease
  • Caution of those at risk of hypoglycaemia
59
Q

Drug-drug interaction: gliclazide (SU)

A
  • Other hypoglycaemic agents
  • Loop and thiazide like diuretics (increase glucose so can reduce SU action)
60
Q

name a drug which comes under the drug class Thiazolidinediones (glitazones)

A

Pioglitazones, rosiglitazone

61
Q

mode of action of pioglitazones and rosiglitazone

A
  • Insulin sensitisation in muscle and adipose
    • Decrease hepatic glucose output by activation of PPAR- Y –> gene transcription
    • stimulates glucose –> triglyceride
  • Half life not related to duration of action -6-8 weeks for benefit
62
Q

pioglitazons and rosiglitazones affect on weight

A
  • Can cause weight gain because of fat cell differentiation
  • Used much less frequently than other agents
63
Q

Adverse drug response: Pioglitazones and rosiglitazone

A
  • GI upset
  • Fluid retention
  • Fracture risk
  • Bladder cancer
64
Q

Contraindications: Pioglitazones and rosiglitazone

A

Heart failure because of fluid retention

65
Q

Drug-drug interaction: pioglitazones and rosiglitazone

A

Other hypoglycaemic agents

66
Q

name a drug which comes under the drug class Sodium-glucose co-transporter (SGLT 2) inhibitors (gliflozins)

A

Dapagliflozin, canagliflozin

67
Q

Uses of Sodium-glucose co-transporter (SGLT 2) inhibitors (gliflozins)

Drug name: Dapagliflozin, canagliflozin

A
  • adjunct to insulin in T1DM (high BMI)
  • T2DM as an add on therapy
68
Q

Sodium-glucose co-transporter (SGLT 2) inhibitors (gliflozins) and weight

A

Modest weight loss, hypoglycaemic risk is low

69
Q

Mode of action: SGLT inhibitors ( Dapagliflozin)

A
  • Competitive reversible inhibition of SGLT-2 in PCT
  • Decrease glucose absorption from tubular filtrate
  • Increase glucose excretion
70
Q

Adverse drug response: SGLT inhibitors

A
  • UTI (sugar urine)
  • Genital infections
  • Thirst
  • Polyuria
71
Q

Contraindications: SGLT inhibitors

A
  • Risk of DKA in T1DM
  • Possible hypotension
72
Q

drug-drug interaction: SGLT inhibitors

A
  • Antihypertensives
  • Other Hypoglycaemic agents
73
Q

Physiological effect of GLP-1 (incretin hormone)

A
  • In the pancreas
    • Increases insulin secretion
    • Decrease glucagon secretion
    • Increase insulin biosynthesis
74
Q

Drugs which target GLP-1 (incretins) actions

A
  • Dipeptidyl peptidase- 5 (DPP-4) inhibitors (Gliptins)
  • Glucagon-like peptide-1 (GLP-1) receptor agonists (incretin mimetics)
75
Q

name a drug which comes under the class Dipeptidyl peptidase- 5 (DPP-4) inhibitors (Gliptins)

A

Sitagliptin, Saxagliptin

76
Q

uses of Sitagliptin, Saxagliptin (DPP-4 inhibitor)

A

when insulin (biguandides) and gliclazide (SU) are contraindacted/ or as an add on

77
Q

Mode of action- gliptins (DDP-4i)

A
  • Prevent incretin (GLP-1) degradation by inhibiting dipeptidyl peptidase- 4 (which usually breaks down GLP1) increasing plasma incretin levels
  • Glucose dependent so postprandial action
    • Will not stimulate insulin secretion at normal blood glucose- lower hypoglycaemic risk
78
Q

DPP-4i (glipitins) affect on weight

A

Supress appetite- due to GLP-1 action in satiety

Weight neutral

79
Q

Adverse drug response: Gliptin

A
  • GI upset
  • Small pancreatitis risk
80
Q

Contraindications: gliptins

A
  • Avoid in pregnancy
  • History of pancreatitis
81
Q
A
82
Q

Drug-drug interaction : gliptins

A
  • Other hypoglycaemic agents
  • Drugs increase glucose can oppose gliptin action- thiazide like and loop diuretics
83
Q

name a drug which comes under the class Glucagon-like peptide-1 (GLP-1) receptor agonists (incretin mimetics)

A

Drug name: exenatide, liraglutide

84
Q

mode of action of GLP-1 receptor agonists (incretin memetics)

A
  • 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
85
Q

how are GLP-1 receptora gonists (incretin) delivered

A

subcutaenous injection (peptide so would be digested if taken enterally)

86
Q

GLP-1 receptor agonists (incretin mimetics) affect on weight

A
87
Q
A
88
Q

Adverse drug response: GLP1 receptor agonists

A
  • GI upset
  • Decreased appetite with weight loss
89
Q

Drug-drug interaction Glucagon-like peptide-1 (GLP-1) receptor agonists (incretin mimetics)

A

Other hypoglycaemic agents

90
Q

how can GI upset by hypoglycaemic agents be avoided

A
  • Modified/extended release (metformin, incretin mimetics) overcome GI upset, less frequent dosing
    • Slower release changes PK properties
91
Q

Why swallow extended-release tablet home (instead of chewing)?

A
  • Slows down absorption disrupting modified release
  • Improve adherence vis ease of dose modifications
  • Not great when we need to tweak doses
92
Q
A

Clinical Pharmacology, Therapeutics & Intro to Prescribing (39 decks)

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