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SYSTEMIC PHARMACOLOGY > Diabetes > Flashcards

Diabetes Flashcards

1
Q

insulin synthesis

A
  • cleave the C-peptide off proinsulin (presence of C-peptide indicates endogenous synthesis of insulin)
  • stimulated by presence of glucose & amino acids (leucine, arginine) & acetylcholine -> acts on phospholipase C-IP3 pathway -> increase intracellular Ca2+
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2
Q

insulin receptor

A
  1. insulin binds to the alpha receptor -> autophosphorylation and activation of tyrosine kinase in beta subunit
  2. phosphorylates IRS-1 protein
  3. activates PI3-kinase: PIP2 -> PIP3
  4. PIP3 binds to Akt -> recruitment of GLUT4
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3
Q

insulin fn

A 
maintains normal blood glucose levels
- facilitate glucose uptake in cells
- regulate carbs. lipid, protein metab
increase glycolysis, decrease lipolysis, increase protein synthesis in muscle
- promote cell division and growth
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4
Q

insulin clearance

A

kidney: GFR and proximal tubular reabsorption

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5
Q

types of DM

A
  1. type 1 DM: absolute insulin def - immune mediated beta-cell destruction so cannot produce insulin
  2. type 2 DM: insulin resistance
  3. gestational DM - glucose intolerance during pregnancy
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6
Q

type 1 DM treatment

A

daily insulin injections

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7
Q

type 2 DM treatment

A

lifestyle modification (diet, exercise)

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8
Q

insulin therapy indications

A

type 1 DM

type 2 DM: only in severe hyperglycemia / OHAs not useful

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9
Q

insulin therapy drugs

A

mimicks normal pancreatic insulin secretion

  • basal insulin: suppresses hepatic production of glucose
  • prandial: provides insulin to remove excess serum glucose after eating
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10
Q

5 groups of insulin

A
  • rapid-acting insulins
  • short-acting insulins
  • intermediate-acting
  • long-acting
  • premixed
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11
Q

rapid acting insulin drugs

A

insulin analogues (has the letter s in it)

  • lispro
  • aspart
  • glulisine
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12
Q

rapid acting insulin analogues MOA

A

change to charge and conformation of the insulin molecule
reduce repulsion -> more rapid absorption = shorter duration of action
injected just before meals

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13
Q

short acting insulin MOA

A

similar to regular human insulin - crystalline zinc insulin
injected 20-30min before meals
clear appearance

greater hypoglycemia risk than rapid acting insulin

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14
Q

intermediate acting insulin drug

A

neutral protamine hagedorn (NPH)

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15
Q

NPH MOA

A

protamine + human insulin
precipitated crystals of NPH insulin releases slowly -> slower onset
- high risk of hypoglycemia cause of the variability from the long onset of action
so must eat after medication
cloudy appearance

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16
Q

long acting insulin drugs (2)

A
  • glargine
  • detemir - binds insulin to albumin: prolongs insulin action
    acts for 18-24hrs
    clear appearance
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17
Q

insulin degludec

A

ultra long acting (U-LA) insulin - slow release of insulin
42hrs duration of action

because of the long duration, adjustments not easy -> esp for those that need dosage adjustment cause of renal/hepatic failure

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18
Q

insulins that should NOT be mixed

A
  • glargine (LA) -> incompatible pH
  • detemir (LA)
  • glulisine (RA) - exc that it can be mixed w/ NPH
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19
Q

insulins that can be mixed

A
  • most insulins can be mixed w/ NPH

- aspart (RA) + degludec (U-LA)

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20
Q

factors affecting pk of insulin

A
  • faster absorption through abdomen injection
  • inject into muscles
  • exercise increase rate of absorption
  • heat
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21
Q

DM caused by drugs

A

steroids: hyperglycemia

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22
Q

ADR caused by insulin therapy

A
  • risk of hypoglycemia if too much insulin is given
    dizziness, tremor, weakness, hunger
    esp in renal impaired pts/ elderly
  • lipodystrophy (abnormal fat distribution)
    lipoatrophy: loss of fat at the site of the injection
    lipohypertrophy: accumulation of fat due to repeated injections at the same - lipogenic effect of insulin
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23
Q

methods to monitor blood glucose

A
  • casual plasma glucose (>11.1mmol/l)
  • fasting plasma glucose (>7mmol/l)
  • 2 hour post challenge plasma glucose
  • HbA1c - glycated haemoglobin (reflects 2-3mths blood glucose lvls)
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24
Q

drugs to help maintain blood glucose levels in type 2 DM (insulin resistance) - MOA

A
  • increase sensitivity of tissues to insulin
  • reduce glucose release by liver
  • slow down carbs digestion in intestines
  • inhibit glucagon (glucagon inhibits insulin secretion)
  • stimulate insulin release
  • incretins ??
  • block glucose reabsorption at kidneys
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25
Q

groups of drugs to increase sensitivity of tissues to insulin (2)

A
  • biguanide

- thiazolidinediones

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26
Q

group of drugs to reduce glucose release by liver

A

biguanides

27
Q

group of drugs to slow down carbs digestion in intestines

A

a-glucosidase inhibitors

28
Q

groups of drugs to inhibit glucagon (2)

A
  • biguanide

- glucagon-like peptide-1 agonist

29
Q

groups of drugs to stimulate insulin release (3)

A
  • sulfonylureas
  • meglitinide
  • glucagon-like peptide-1 agonist
30
Q

groups of drugs to increase incretins

A
  • dipeptidyl peptidase-4 (DPP-4) inhibitor

- bile acid sequestrants

31
Q

groups of drugs to block glucose reabsorption at kidneys

A

SGLT2 inhibitors (sodium glucose co-transporter 2)

32
Q

biguanide drug + MOA

[insulin sensitizer]

A

metformin
- decreases hepatic glucose production
- increase sensitivity of insulin receptors by increasing density of insulin receptors at tissues
- decrease intestinal glucose absorption
- improve muscle glucose absorption
DOES NOT affect amount of insulin secreted
*first line T2DM treatment: does not cause hyperinsulinemia/ hypoglycemia

33
Q

metformin ADR + CI

A

GI: diarrhea, vomiting, indigestion, flatulence -> eat after meals
cause it affects glucose absorption in intestines -> may also cause vit B12 malabsorption
(CI/ just be cautious): renal problems; lactic acidosis

34
Q 
thiazolidinediones drugs (2) 
[insulin sensitizer]
A 
(-glitazone) 
- pioglitazone* 
oral, high absorption, hepatic metab
duration of action: 1 day 
fecal excretion
- rosiglitazone
35
Q

thiazolidinediones MOA

A
  • increase insulin-dependent glucose disposal
  • decrease insulin resistance in the periphery + liver
    activates PPAR-y (regulate glucose metab, adipogenesis + improve insulin sensitivity) -> increase production of GLUT1 &4
36
Q

pioglitazone ADR

A

fluid retention

  • weight gain
  • peripheral edema
  • increased risk of HF
  • bone fractures

induce CYP450 - increase metab of other drugs - careful of DDIs

37
Q

sulfonylureas drugs

[insulin secretagogues]

A

(-amide)

  • tolbutamide
  • gibenclamide: risk for hypoglycemia

(-zide/-ride)

  • glipizide
  • gliclazide* preferred
  • glimepiride
38
Q

sulfonylureas MOA

A

stimulate release of insulin from pancreas (beta cells in pancreatic islets)
- bind to sulfonylurea (SU) receptor proteins -> inhibit Katp channel mediated K+ efflux -> so Ca2+ exocytose instead -> exocytosis of insulin granules tgt

39
Q

recommended sulfonylurea drug

A

gliclazide: 80mg tablet, 0.5h before food

hepartic metab, excreted in urine

40
Q

sulfonylurea ADR + CI

A

weight gain
gibenclamide: risk for hypoglycemia (esp elderly, renal/hepatic impairment)

CI: allergy

41
Q

meglitinides drugs

A 
(-glinide)
- repaglinide
hepatic metab
half life: 1h
short duration of action
mainly excreted in feces 
- nateglinide
hepatic metab
half life: 1.5h
duration of action: 4h
mainly excreted in urine

both have rapid onset + short duration of action - good choice - take before meal

42
Q

meglitinides MOA

A

bind and close Katp channels - glucose dependent
since it is glucose dept, and original insulin lvls are supposed to be so, low risk of hypoglycemia - cause it will auto off when glucose levels are low

43
Q

meglitinides caution

A

caution in pts with hepatic impairment - hepatic metab

44
Q

a-glucosidase inhibitor drugs

A
  • acarbose*

- miglitol

45
Q

a-glucosidase inhibitor MOA

A

irreversibly inhibit a-glucosidase in brush border
slows down the increase in glucose lvls after a meal
to be taken with food

46
Q

acarbose

  • route
  • metabolism
  • half life
  • duration of action
  • excretion
A
  • route: oral
  • metabolism: by intestinal bacteria and digestive enzymes
  • half life: 2hrs
  • duration of action: 2-4hrs
  • excretion: fecal
47
Q

acarbose SEs + CIs

A

cause glucose is not absorbed -> more in colon
gaseous distention and flatulence (pass more gas)
poor tolerance -> not preferred
CI: pts w/ GI diseases (IBD)/ renal/hepatic disease

48
Q

incretin based therapy (IBT)

A
  • dipeptidyl peptidase 4 inhibitors

- GLP-1 receptor agonists

49
Q

IBT MOA

A

incretins (hormones) released augment secretion of insulin by b cells in pancreas
2 incretins:
GIP (glucose dependent insulinotrophic polypeptide);
GLP-1 (glucagon-like peptide-1)

50
Q

dipeptidyl peptidase (DPP-4) inhibitors MOA

A

DPP-4 degrades incretin

  • > inhibit DPP-4 will increase incretin lvls
  • > incretin stimulates insulin secretion in b-pancreatic cells + suppress a-cell mediated glucagon release & hepatic glucose production
51
Q

DPP-4 inhibitors drugs

A

(-gliptin)
- sitagliptin
- vildagliptin: hepatic metab - cannot be used in pts w/ hepatic impairment
- linagliptin*: fecal elimination (rest are renal) - no dose adjustment needed for renal impairment
oral

52
Q

DPP-4 inhibitors SEs

A 
GI: nausea, diarrhoea, stomach flu
Flu-like: headache, runny nose, sore throat
skin reactions
careful if pt has pancreatitis
expensive
53
Q

GLP-1 receptor agonists MOA

A

activates GLP-1 receptor (membrane bound receptor in pancreatic b-cells)

  • > increase insulin release when glucose conc increases [GLUCOSE DEPENDENT - WILL ONLY HAVE EFFECT IF IT IS IN THE ORIGINAL HYPERGLYCEMIC STATE]
  • > glucose-dept: no effect if glucose conc decreases and are normal
54
Q

GLP-1 receptor agonists drugs (2)

A
  • exenatide - does not metabolise, shorter half-life
  • liraglutide
    subcutaneous injection
55
Q

GLP-1 receptor agonists SEs

A

GI: nausea, vomiting, diarrhoea
exenatide CI: pancreatitis
VERY expensive

56
Q

GLP-1 receptor agonists clinical use

A
  • obesity

- reduce CVS diseases, + reduce hospitalisation for HF

57
Q

SGLT-2 inhibitors drugs (3)

A 
(-gliflozin)
- empagliflozin
- canagliflozin
- dapaglifozin
oral
58
Q

SGLT-2 inhibitors MOA

A

SGLT2: reabsorption of glucose from tubules

inhibit SGLT2 = decrease reabsorption - more glucose excreted

59
Q

SGLT2 inhibitors clinical use

A

atherosclerotic CHD
reduce hospitalisation for HF
reduce progression of renal disease

60
Q

SGLT2 inhibitors ADR

A 
UTI - glucose in urine = bacteria!
increased urination
genital mycotic (fungal) infection
diabetic ketoacidosis
canagliflozin: risk of LL amputation
61
Q

types of hypoglycemic drugs (5)

A
  • insulin sensitizers
  • insulin secretagogues
  • a-glucosidase inhibitors
  • sglt2 transporter inhibitor
  • incretin therapy
62
Q

chronic DM complications**

A
  • micro: retinopathy, neuropathy, nephropathy
  • macro: CVS related - atherosclerosis
  • decrease leukocyte function -> increased risk of infections
63
Q

prevent/minimise chronic DM complications**

A

retinopathy - laser treatment
nephropathy - renal transplant/ dialysis

atherosclerosis/thrombosis: aspirin

64
Q

classification of drugs

A
  • insulin sensitisers: biguanide (metformin), thiazoldinediones
  • insulin secretagogues: sulfonylureas, meglitinides
  • a-glucosidase inhibitors: acarbose
  • incretin based: DPP4 inhibitors, GLP1 agonist
  • SGLT2 inhibitors

SYSTEMIC PHARMACOLOGY (22 decks)

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