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Endocrinolgy > More Diabetes (Pharmacology) > Flashcards

More Diabetes (Pharmacology) Flashcards

1
Q

What are the treatments for type1 and type 2 diabetes?

A 
Type I (IDDM): Insulin
Type 2 (NIDDM):
- Biguanides
- Sulphonylureas 
- Meglitinides 
- Thiazolidinediones (Glitazones) 
- Incretins 
- Dipeptidyl peptidase 4 (DPP4) inhibitors 
- Alpha-Glucosidase inhibitors 
- Insulin
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2
Q

Where are biguanides (eg. Metformin) absorbed?
Are they bound to plasma protein?
Are they broken down in the body?

A

Small intestine
not bound to plasma protein
excreted unchanged in urine

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3
Q

How does metformin (a biguanide) decrease blood glucose?

A
  • decreased hepatic glucose production
  • potentiates insulin action on muscle and adipose tissue
  • stimulation of glycolysis in tissues, stimulates glucose uptake
  • decreases carbohydrate absorption
  • stimulates lactate production
  • inhibit expression of genes involved in gluconeogenesis
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4
Q

What effect does metformin have on lipids?

A
  • decreases LDL and VLDL
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5
Q

Why is it thought that metformin may influence gene expression?

A

It lowers the risk of some cancers?

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6
Q

What is it important to note that metformin does not affect?

A 
do not affect release of: 
insulin 
glucagon 
growth hormone (GH) 
cortisol 
somatostatin
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7
Q

What 3 side effects associated with some other diabetes drugs does metformin not cause?

A

hypoglycaemia
stimulation of appetite
weight gain

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8
Q

What are the side effects of metformin?

A

diarrhoea
nausea
metallic taste
rare - lactate acidosis

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9
Q

What effect does metformin have on the absorption of ate and vitamin B12?

A

decreases intestinal absorption of folate and vitamin B12

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10
Q

When is Metformin implemented in type 2 diabetes and in combination with what?
What effect does it have on microvascular complications?

A

Drug of choice in obese patients who fail with diet alone
Given with sulphonylureas, thiazolidenediones and/or insulin
Reduces microvascular complications

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11
Q

What makes metformin pills difficult to take?

A

Their size

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12
Q

What is the half-life of metformin?

A

3 hours

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13
Q

What are the 5 drugs in the second generation of sulphonlyureas? (5 G’s)

A 
Glibenclamide 
Gliclazide 
Glimepiride 
Glipizide 
Gliquidone
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14
Q

What are the 2 drugs in the first generation of sulphonlyureas?

A

tolbutamide - devoid of antibacterial activity chlorpropamide chlorpropamide

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15
Q

Where to sulphonylureas bind?

A

Bind to sulphynylurea binding site which is associated with the K-ATP gate
Work from outside the cell

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16
Q

What are the acute effects of sulphylnylureas?

A

Increase insulin release
Increase plasma insulin concentration
Decrease hepatic clearance of insulin

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17
Q

What are the effects on effeicacy of chronic use of sulphylnylureas?

A

No acute increase in insulin release BUT decreased plasma glucose concentration still remains
Chronic hyperglycaemia per se decreases insulin release
Down regulation of sulphonylurea receptor

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18
Q

What is a significance consequence of sulphynylureas being largely protein bound (90-99%)?

A

drug interactions:

NSAIDs, MAO inhibitors, some antibiotics etc

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19
Q

In what way is sulphynylurea activity affected in the elderly and those with renal disease?

A

excreted in urine, enhanced effect in elderly & renal disease

20
Q

How do first and second generation sulphynylureas differ in terms of half life, potency and drug interactions?

A

1st generation long:
half life (>24 hours)
2nd generation:
short half life (7-10 hours)
100x more potent
last for 16-24 hours - can take once daily
less interactions (using smaller concentrations)

21
Q

What are the adverse effects of sulphynylureas?

A

Main adverse effect is hypoglycaemia
Neuroglycopenia - lack of glucose supply top brain
Confusion and coma

22
Q

How are the adverse effects of sulphynylureas dealt with?

A

Take oral glucose

If severe give iv glucose, glucagon, adrenaline

23
Q

Name 2 MEGLITINIDES.

How do these differ from sulphynylureas in terms if half life, release, potency and risk of hypoglycaemia ?

A 
Repaglinide (1998) Nateglinide  (2000) 
T1/2: 1 hour - more rapid (cf. 7-10 hours)
less sustained release
less potent than sulphonylureas
less hypoglycaemia
24
Q

When are MEGLITINIDES taken?

A

Just before meals

Not a mono therapy

25
Q

How do Close K+ATP meglitinides act on beta cells?

A

Close K+ATP channels on B-cells
Share 2 binding sites with sulphonylureas but have their own distinct binding site
More selective for B cell than cardiac/vascular K+ ATP channels

26
Q

Phew many THIAZOLIDENEDIONES (GLITAZONES) are clinically available and what are they?

A

1

Pioglitazone - Actos® (introduced 1999)

27
Q

What are the two THIAZOLIDENEDIONES that were withdrawn from the market? Why?

A

Troglitazone -1997-2000 - liver toxicity

Rosiglitazone - Avandia® - 1999-2010 - cardiovascular problems

28
Q

What are THIAZOLIDENEDIONES (GLITAZONES)?

Which tissues do they act on?

A

Ligands for transcription factors
Selective agonists for PPARgamma (nuclear Peroxisome Proliferator- Activated Receptor gamma) PPARgamma combines with RXR (retinoid X receptor)

found in adipose tissue, muscle and liver

29
Q

How does Pioglitazone (THIAZOLIDENEDIONES (GLITAZONES)) work/what does it do?

A

Activates insulin responsive genes that control carbohydrate and lipid metabolism
Needs insulin to be effective
Reduces insulin resistance in peripheral tissues
Reduces glucose production by liver
Increases glucose uptake in muscle and adipose tissue potentiates actions of insulin
increase adipocyte number & lipogensis

30
Q

What type if drug is Pioglitazone?

A

A THIAZOLIDENEDIONE (GLITAZONE)

31
Q

What is the half life of Pioglitazone?
How is it carried in the body?
How long does it take for its maximum effect in the body to develop?

A

T1/2 7 hours - T1/2 24 hours active metabolite
Bound
6-12 weeks

32
Q

Is Pioglitazone a montherapy?

A

No, Give with metformin, insulin or other hypoglycaemic drugs

33
Q

What are the side effects of Pioglitazone?

A

weight gain (1-4kg) due to increased differentiation of adipocytes, fluid retention by stimulating amiloride sensitive Na+ absorption

34
Q

What are incretins?

What 2 incretins in the human body do you know about and where are they produced?

A

INCRETIN - compound stimulates insulin release

  • GIP glucose-dependent insulinotrophic peptide or gastric inhibitory peptide - K cells in duodenum
  • GLP1 glucagon-like peptide 1 – L cells in distal ileum
35
Q

What is Exendin-4?

What is Exenatide?

A

Exendin-4 isolated from saliva of Glia monster 50% homology with GLP1

Exenatide - synthetic version of exendin-4 - Byetta FDA approved 2005

36
Q

What are the effects of Exenatide (a synthetic incretins)?

A 
Acts on incretin receptor (GLP-1 receptor) 
Stimulates insulin release 
Suppresses glucagon secretion 
Reduces appetite and body weight 
Slows gastric emptying 
Stimulated beta cell number
37
Q

Is Exenatide (a synthetic incretins) active orally?

A

No, peptides - not orally active

38
Q

What are Serine protease dipeptidyl peptidase 4 (DPP4) inhibitors and how do they work?
Name some

A

Serine protease dipeptidyl peptidase 4 (DPP4) breakdown incretins
inhibitors: Sitagliptin,Vildagliptin (Galvus), Saxagliptin (Onglyza), Sitagliptin + metformin (Janumet, USA) Vildagliptin + metformin (Eucreas, UK)

39
Q

How do Serine protease dipeptidyl peptidase 4 (DPP4) inhibitors affect weight?
Do they cause hypoglycaemia
Side effects?

A

no effect on weight, no hypoglycaemia

Possible side effect: increase in incidence of some cancers - incretins may be agents involved in cell growth etc.

40
Q

What are alpha-GLUCOSIDASE INHIBITORS?

Name 2

A

Inhibits intestinal brush border alpha-glucosidase

acarbose (1995) ) & miglitol (2000)

41
Q

What effect do alpha-glucosidase inhibitors have?

What type of diabetes are they effective in?

A

Inhibits carbohydrate breakdown and reduce postprandial increase in blood glucose levels

effective in Type I (IDDM) and Type 2 (NIDDM)

42
Q

Are alpha-glucosidase inhibitors well absorbed?
Do they cause hypoglycaemia?
Side effects?

A

Poorly adsorbed
Does not cause hypoglycaemia
Side effects: flatulence and diarrhoea

43
Q

What are amyloid analogues?

A

AMYLIN ANALOGUES

Amylin (37aa) main component of pancreatic amyloid related to calcitonin/CGRP

44
Q

What are the effects of amylin?

A

Decreases gastric emptying
Inhibits glucagon release
Promotes satiety
but - Related to Beta-amyloid and can form aggregates

45
Q

What is Pramlintide?
In what type of diabetes is it effective?
What are its effects?

A
  • analogue of human amylin with Pro replacement as in rat amylin, does not aggregate
  • Adjunct for both Type I (IDDM) and Type 2 (NIDDM)
  • Decreases gastric emptying
    Inhibits glucagon release
    Promotes satiety
46
Q

Future developments in diabetes drugs?

A

Improved insulin delivery nasal inhalation
Afresa® inhaler submitted 2009, re-submitted July, 2010
patches
liposomes
insulin pumps with glucose sensors insulin in biodegradable microspheres

Islet transplants
Sodium glucose transporter 2 inhibitor - In kidney - can block reabsorption of glucose by 10-20pc:
canagliflozin, dapagliflozin, ipragliflozin
alpha2 - antagonists alpha2 receptors block insulin release
Beta 3 - agonists increase lipolysis/thermogenesis in brown adipose tissue

47
Q

treatments for obesity?

A 
monoamine uptake inhibitor sibutramine (withdrawan)
cannabinoid CB1antagonist rimonabant (withdrawn)
lipase inhibitor orlistat
Approved FDA 
5HT2C agonist lorcaserin(APD-356) 
Qsymia phentermine/topiramate 
In development 
Neuropeptide Y (NPY) agonists PYY3-36
ghrelin antagonists
ghrelin vaccine
melanocortin receptor (MC4R) agonists
melanin-concentrating hormone antagonists

Endocrinolgy (8 decks)

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