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CAM202 Pharmacology > Diabetes Extra Flashcards > Flashcards

Diabetes Extra Flashcards

1
Q

Who are sulfanureas not use in and why?

A

The elderly because they are long acting.

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2
Q

What theoretical side effect is there for sulphonylureas?

A

May increase cardiovascular mortality in Type II, possibly as a result
of inhibition of ATP-sensitive K+ channels in the heart – not conclusively proven

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3
Q

Acarbose dosage

A

monotherapy in combination with diet control in the early stages of type II diabetes,or dual therapy with sulphonureas, in patients that do not tolerate metformin.

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4
Q

Why are glitazones not generally used?

A

Hepatotoxicity - liver function tests are recommended at least every 2 months for patients taking glitazones.

Weight gain up to 5kg, due to:
increased fat deposition (subcutaneous, not visceral).
increased fluid retention, (increased plasma and extracellular volume) Ø dilution anaemia

Can precipitate or worsen heart failure
Contraindicated in HF

Recent meta analysis show an increased risk of death from cardiovascular causes - more with rosiglitazone than pioglitazone and the reason for the difference is unknown

Increased risk of MI with rosiglitazone

Increased risk of peripheral fractures esp. women

Rosiglitazone C/I with insulin because of risk of myocardial ischaemia.

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5
Q

What are incretins?

A

oral glucose causes a greater insulin response than IV glucose the difference is the incretin effect.

The incretin effect:

  1. provide tight control of postprandial glucose Ø Act on pancreas, gut and brain
  2. Increase the secretion of insulin in a glucose dependent manner
  3. Delay gastric emptying
  4. Suppress appetite

Other potential pancreatic specific actions

  1. Improve ß-cell sensitivity
  2. Promote ß-cell proliferation
  3. Reduce ß-cell apoptosis
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6
Q

What is the incretin response to glucose?

A

Incretins are secreted from the GI into circulation within minutes of food entering the GIT

  1. GLP-1 secreted by L cells in ileum and colon
  2. GIP secreted by K cells in duodenum Ø G-protein coupled receptor distribution

GLP-1R is expressed in the heart, CNS, kidney, lung, GIT and pancreatic islet α and ß cells. In the CNS they are found in the Nucleus Accumbens – an area associated with reward and addiction. GIPR is expressed predominantly in the pancreatic islet ß cells, less so in the CNS and adipose tissue.

Incretin response to a meal lasts 2-3 hrs
Incretin t1/2 is 1-2 mins
Continually secreted while nutrients are in the GIT

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7
Q

What happens to the incretin effect in diabetes?

A

There is no GLP-1 response
This causes a reduction in postprandial insulin response, lack of appetite suppression and hyperglycaemia.

GIP levels are near normal - effect on insulin secretion is diminished

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8
Q

What are the two potential pharmacological therapies that act on the incretin pathway?

A

Incretin enhancers: prevent incretin metabolism by blocking the dipeptidyl peptidase-4 (DPP4). This increases concentration of circulating incretins.

Incretin mimetics: incretin analogues resistant to degradation by DPP4

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9
Q

Name the incretin mimetics

A
  1. Exendin (now available as exenatide). This is a peptide 50% homologous to GLP-1. It is a potent activator of the GLP-1R. Resistant to cleavage by DPP4. Long circulating t1/2 , SC administration
  2. Liraglutide. Maintains normal activity of the GLP-1R. Also resistant to DPP4 cleavage. Long circulating t1/2, SC administration. Favoured for once daily dosing
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10
Q

Side effects of GLP-1R agonists

A

No hypoglycaemia because incretin effect on insulin is only in the presence of hyperglycaemia.
Weight loss (delayed gastric emptying, reduced appetite) - up to 3kg in clinical trials
Anorexia, nausea and vomiting
Long term effects? unknown

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11
Q

What is important when inhibiting DPP4

A

Specificity is crucial: DPP8 and DPP9 inhibition causes renal and skin toxicity

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12
Q

Sitagliptin and Vildagliptin effects

A

Highly specific for DPP4

  • Long half-lives, allow once daily oral therapy Ø 2 hrs after one dose
  • Almost complete inhibition of DPP4 Ø 85% inhibition after 24 hrs

Effectively restore

  • GLP-1 circulating concentrations
  • Postprandial response of GLP-1 to that of a non-diabetic
  • Fasting incretin levels remain low
  • Fasting blood glucose is low
  • ß-cell mass is preserved
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13
Q

Sodium-glucose co-transporter inhibitors mechanisms

A

SGLTs are responsible for glucose reabsorption in renal tubules approx. 180g/day – wt. loss of 2-3 kg in 6-12 months
SCGL2 has high capacity and reabsorbs about 90% of filtered glucose
Inhibiting transporter is dependent on glomerular filtration to deliver glucose to proximal tubule – can reduce HbA1c by (0.4-0.8%)
Inhibition occurs independently of BSL, insulin, or decrease in peripheral insulin resistance

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14
Q

Examples of sodium-glucose co-transporter inhibitors

A

Canagliflozin, Dapagliflozin

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15
Q

Sodium-glucose co-transport inhibitors systemic effects

A
  1. Reduce BSL without stimulating insulin
    Specificity for SGLT2/ SGLT1
  2. Weight loss – 2-3 kg more visceral fat
  3. BP reduction of 1-6mmHg, expected from weight loss,
    dehydration (haematocrit increases by 1-3%)
  4. Intravascular volume depletion
  5. Increase in LDL
  6. Renal function important for efficacy
  7. Dapagliflozin – excess cancer cases
  8. Increased calcium excretion, fracture risk
    10 Increase in non-recurrent UTIs
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16
Q

First line treatment of type II diabetes

A

After diet and lifestyle modifications…
Metformin OR sulphonylureas if metformin is not tolerated.

Reevaluate in 3-6 months - if target is not being reached then reevaluate.

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17
Q

Second line treatment of type II diabetes

A

Continue MS if tolerated and add in sulphonyruea (standard approach). Then add in:

  1. Thiozolidenedione
  2. DPP4 inhibitor
  3. Acarbose
  4. SGLT 2 inhibitor
  5. Insulin (injectible)
  6. GLP1 agonist (injectible)
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18
Q

Sulphonylureas positives and negatives

A

Pro: low cost
Neg: weight gain, higher hypo risk with some SUs

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19
Q

Thiozolidenedione positives and negatives

A

Pro: low hypo risk*
Neg: weight gain, HF, fracture risk and possible bladder cancer risk

20
Q

DPP4 inhibitors positive and negatives

A

Pro: low hypo risk, weight neutral
Neg: cost, renal impairment except linagliptin, hepatic enzyme increase (vildagliptin)

21
Q

Acarbose positives and negatives

A

Pro: low cost
Negative: increase risk of gastrointestinal side effects

22
Q

SGLT 2 inhibitors postives and negatives

A

Pro: good if hypo a concern, and if weight gain is a concern
Negative: cost, renal impairment and dehydration. Long term studies needed.

23
Q

GLP-1 agonist positives and negatives

A

Pro: low hypo risk, weight loss
Negatives: cost, injectible, increase risk of GIT side effects.

24
Q

Third line treatment for type II diabetes

A

Continue MS/SUs if tolerated and add or substitute with one of these drugs:

  1. Thiazolidenedione: if no CHF
  2. Acarbose
  3. DPP4 inhibitor: if weight gain a concern
  4. SGLT 2 inhibitor: f other drugs are contraindicated
  5. Insulin: basal insulin or premixed initially and then add prandial insulin with time if required.
  6. GLP-1 agonist: if desired to lose weight.
25
Q

What are the two phases of the insulin response?

A

Phase I: stored insulin release

Phase II: stored hormone and new hormone synthesis

26
Q

Insulin administration and use

A

Insulin is rapidly destroyed in the GIT.

Administered parenterally: subcutaneously, IV or intramuscular

Many schedules available, bid about 30 mins before breakfast and dinner is a common routine

IV infusions used in ketoacidosis emergencies

Intraperitoneal insulin used in diabetic patients with end-stage renal failure treated by ambulatory peritoneal dialysis

27
Q

Ultrashort acting (bolus insulins)

A

Lispro aspart, Novorapid

Amino acid substitutions make it easier for the insulin molecules to dissociate in the subcutaneous tissue, speeding absorption.

Insulin profile closer to the normal secretion pattern after eating, thus better control of postprandial hyperglycaemia and less risk of hypoglycaemia between meals. Must eat after the injection

28
Q

very long-basal insulin

A

insulin glargine

Change of amino acid composition reduces solubility in
subcutaneous tissue. It is soluble at acidic pH (in the vial) and insoluble at neutral pH, ie after injection, forms an insoluble crystal, which is absorbed very slowly

Produces a long flat, reproducible absorption profile.
There is a newer version currently being trialled that produces a more consistent profile…

29
Q

intermediate-long insulin

A

Insulin Detemir

Insulin fatty acid complex. Fatty acid causes the insulin to complex with albumin upon injection in the subcutaneous tissue and plasma. Insulin slowly dissociates from the albumin, and diffuses from the extracellular space into circulation.

30
Q

Side effects of insulin

A
  1. Excessive action can cause Hypoglycaemia
    » can result in brain damage (particularly in children)
    » Treatment: sweet drink, snack, IV glucose or intramuscular glucagon
  2. Rebound hyperglycaemia (Somogyi effect)
    » Follows insulin induced hypoglycaemia
    » usually during the night, or after excessive insulin dose
    » Compensatory hormone release
    » adrenaline, cortisol, glucagon causes hyperglycaemia
  3. Allergy
    » Local or systemic reactions
    » Severe reactions, with antibody formation is rare
31
Q

Severe side effects of not enough insulin

A

Diabetic ketoacidosis.

Symptoms: dehydration, hyperventilation ketotic breath disturbed conscious state and shock

32
Q

Guide to starting and adjusting insulin

A
  1. Select basal insulin and injecting device
  2. Start basal insulin 10 units morning OR bedtime. Continue OHAs.
    - Bedtime insulin dosing if FBG is high (pre-breakfast)
    - Morning insulin dosing if FBG is on target but pre-dinner BGL is high.
  3. Titration; fix the fasting first.
    Adjust basal insulin dose to reach target. Practitioner-led titration can achieve a target in a shorter period of time than patient-led titration.
33
Q

Actions insulin secretagogues

A

Insulin secretagogues mimic glucose to close adenosine triphosphate-sensitive potassium channels (kir6.2) and stimulate insulin secretion.

34
Q

Direct pharmaceutical actions of GLP-1R agonists

A

GLP-1R agonists act directly via the GLP-1R on pancreatic islets, heart, intestine, subpopulations of immune cells, kidney, and brain.

Pancreatic islets:

  • beta cells: increase insulin secretion, increase insulin biosynthesis, increase beta cell proliferation, decrease apoptosis
  • alpha cells: decrease glucagon secretion

Cardiovascular: increase glucose utilisation, decrease FA metabolism, increase cardiac function, increase cardioprotection, increase vasoprotection, decrease inflammation

Intestines: increase growth, decrease lipoprotein secretion

Immune cells: decrease inflammation

Kidney: Increase Na+ secretion

Brain: decrease food intake, increase neuroprotion, increase neurogenesis.

35
Q

Cellular mechanisms SGLT2

A

something.

36
Q

Targets for self-monitoring glycaemic control

A

Pre-prandial blood glucose: 6.0-8.0 (normoglycaemia), 6.1-8.0 (NHMRC values)

Post-prandial blood glucose: 6.0-10.0 (normoglycaemia), 8.0-10.0 (NHMRC values)

Normal blood glucose levels (normoglycaemia) is not always possible, especially in the elderly.
Biochemical ideals should be tempered by common sense and the need to remove symptoms and maintain or improve quality of life.Over-zealous management can result in severe hypoglycaemia and may be associated with increased mortality.

37
Q

Factors that insulin regimes depend on

A
  1. Age, e.g.
    - Elderly patients with a stable, sedentary life style may prefer the premixed
    - Younger patients with an active, variable lifestyle may prefer being able to better control their insulin
  2. Lifestyle
  3. Weight
  4. Disease state
38
Q

When does a type II diabetic patient normally move onto insulin?

A
  1. Early in the condition when treatment is being started (the so-called ‘primary’ failure of oral hypoglycaemic agents that suggests the patient actually has type 1 diabetes)
  2. when the patient has later become refractory to oral hypoglycaemic agents (so-called ‘secondary’ failure consistent with the usual progression of type 2 diabetes).
39
Q

What indicated a type II diabetic should move onto insulin?

A
  1. If the patient is symptomatic then insulin is required.
  2. If there are no symptoms but fasting blood glucose levels are consistently >7.0 mmol/L, the decision is more difficult.
    - Initiation of treatment with insulin is regarded as a major step by most patients. They require encouragement and psychological support.
    - Insulin is not a substitute for healthy eating, activity and weight control in type 2 diabetes.
    - Inappropriate use of insulin produces weight gain and continuing poor control.
40
Q

What regime do you follow for moving a type II diabetic onto insulin?

A

Typical starting dose: 10 U of basal insulin before bedtime and as late as possible.

Early introduction of insulin in the young greatly reduces the risk of lifetime complications

If the patient is taking supra-max doses of oral-hypos., then reduce to manufacturers recommendations
If the patient is on triple therapy - cut out one
If the patient is suffering adverse effects from Metformin, reduce the dose until it can be tolerated

41
Q

What are the risks of initiating insulin therapy?

A
  1. Hypoglycemia

2. Inappropriate use of insulin produces weight gain and continuing poor control

42
Q

How do you minimise insulin resistance?

A

In the long term metformin can be continued or added to reduce insulin resistance (and dose) and to help reduce weight gain.

43
Q

What did the UK prospective Diabetes study (UKPDS trial) find?

A

There is a significant reduction in the risk of cardiovascular events if mean BP was reduced from 154/87 to 144/82.

Analysis of UKPSS suggested that for every 1% reduction in HbA1c

  • reduced the RR of any diabetes related death of any diabetes complications by 21%,
  • diabetes related complications by 21%,
  • diabetes death by 21%,
  • MI by 14%
  • microvascular complications by 37%.

The risk of diabetes related complications decreased as HbA1c because progressively lower, with the lowest rate of complications with an average of 6% HbA1c

UKPDS: post trial monitoring
Microvascular effects with SUs: A legacy effect in early glycaemic reductions persist over time, with macrovascular risk reductions that may take years to be seen.

44
Q

Hb1Ac reduction

A 
Metformin 1-2%
Sulfonylureas 1-2%
Insulin 1.5-3.5%
DPP-4 Inhibitors 0.5-0.8%
Thiazolidediones 0.5 - 1.4%
GLP-1 R agonists 0.5-1%
Alpha-glucosidase inhibitor 0.5-0.8%
SGLT2 Inhibitors 0.5 – 0.8%
45
Q

Initial management of HTN

A
  1. Confirm the patient has HTN and exclude all secondary causes.
  2. Recommend lifestyle modifications (SNAP: smoking, nutrition, alcohol and physical activity)
46
Q

Antihypertensives in diabetes

A
  1. ACEI
    First line hypotension, Decreased GFR, Hyperkalaemia,
    Persistent cough, Angioedema. Start with a low dose and check electrolytes a week later.
  2. ARBs
    Assumed to be as effective as ACEIs. However, based on
    surrogate endpoint data, ARBs might slow the progressive loss of renal function.
  3. Thiazides
    Low dose thiazides have minimal SEs and complement ACEI action, although there is a potential to exacerbate/cause diabetes.Check Electrolytes 1 week after commencing treatment
47
Q

Targets in managing diabetes

A
  1. BGL – 6-8 mmol/L fasting, 8-10 mmol/L postprandial
  2. HbA1c – Individualised but generally ≤53mmol/L (≤7% with range of 6.5– 7.5)
  3. Total cholesterol - <2.0 mmol/L
  4. BP 130/80mmHg

Reducing HbA1c levels too low may have adverse effects while conferring little benefit
Aggressively lowering BP or lipids may be of limited benefit and may increase the risk of adverse events.

CAM202 Pharmacology (6 decks)

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