Pharm Insulin And Oral Hypoglycemics

Front 1

prototype for insulin

Back 1

human regular insulin

Front 2

prototype for sulfonylurea

Back 2

glyburide

Front 3

prototype meglitinides

Back 3

rapaglinide

Front 4

prototype biguanide

Back 4

metformin

Front 5

prototype thiazolidinedoione

Back 5

rosaglitazone

Front 6

prototype alpha glucosidase inhibitor

Back 6

acarbose

Front 7

prototype dipeptidyl peptidase-4 inhibitor

Back 7

sitagliptin

Front 8

prototype incretin mimetic

Back 8

exenatide

Front 9

prototype amylin mimetic

Back 9

pramlintide

Front 10

where does insulin come from?

Back 10

Human: recombinant DNA (E coli or yeast), more pure, less immunogenic and antigenic

analogue insulin: biochem modification of human Regular insulin

previously from beef/pork mix now obsolete

Front 11

how is insulin administered?

Back 11

iv: regular or lispro
im: faster than sc
sc: all types; fastest from abd, affected by BF. don't rotate
inhaled: for prandial control
insulin pump

Front 12

what are some typical regimens of taking insulin?

Back 12

1. NPH and Regular/Lispro before breakfast and evening meal
2. Regular/Lispro before meals and NPH before bedtime (and breakfast)
3. Glargine (or Detemir) once per day with Regular/Lispro before meals (basal-bolus regimen)

Front 13

adverse effects of insulin?

Back 13

1. Hypoglycemia
2. local allergy and lipodystrophy (rare w/ human form)
3. edema

Front 14

how long does insulin act?

Back 14

depends on preparation:
rapid: onset 5-15 mins, pk 1 hr, lasts 2.4 hrs
short: 30-60, 2-3, 3-6
Interm: 2-4, 4-8, 10-16
Basal: 1-2, no pk, 12-24

Front 15

how do sulfonylureas work?

Back 15

glyburide:
stim 2nd phase insulin secretion by binding S.U. R's on β-cell

extra-pancreatic fx--small incr # insulin R's; gluconeogenesis inhibition and incr glucose uptake by musc and fat

Front 16

how do 1st gen sulfonylureas compare to 2nd generation?

Back 16

1st: extensively protein bound, less potent

2nd: don't bind plasma prots, less drug-drug interxn, all equally effective

both: T1/2 in tissue > plasma

Front 17

metabolism of S.U.s?

Back 17

differences in absorption, metab, elim
t1/2 in tissue > plasma
metab in liver, excrete in urine
some active metabolites

Front 18

adverse effects of SU's?

Back 18

more w/ 1st gen (2nd gen more commonly used clinically)
HYPOglycemia (~5%): incr in elderly, renal failure, w/ EtOH, poor nutrition
skin rash(rare)
nausea/vomit (mild)

Front 19

drug interxns w/ SUs?

Back 19

more w/ 1st gen (more binding to plasma prot):
displaced from albumin by ASA and sulpha drugs
potentiate hypoglycemia w/ EtOH
displace warfarin from album (prolong PT)

Front 20

contraindications of SUs?

Back 20

pregnancy (investigating for gestational DM use)
type 1 DM

Front 21

what are SUs used for?

Back 21

type 2 DM

Front 22

what's the efficacy of sulfonylureas?

Back 22

glyburide:
85% pts initially respond;
(25% have secondary failure)
decrease A1c by 1-2%

Front 23

meglitinides: prototype?

class effects?

Back 23

repaglinide: new class insulinotropic agents (secretagogues)
affect prandial glucose load

Front 24

mech of melitinides?

Back 24

repalinide:
binds R in ß-cell membrane, ATP-dependent K+-chs close, depol of ß-cell memb:
leads to Ca++ influx, incr intracell Ca++ and stim insulin secretion

Front 25

PK of meglitinides:
1. absorption
2. metab
3. elim

Back 25

repaglinide:
1. rapid (pk~1hr); 98% bound to plasma album
2. CYP450 (3A4)
3. feces

Front 26

adverse fx of meglitinides?

Back 26

repaglinide:
HYPOglycemia

rare (<1%): leukopenia, thrombocytopenia, elev liver, anaphylaxis

Front 27

drug interxns w/ meglitinides?

Back 27

repaglinide:
highly prot bound (warfarin)--potentiate hypoglyc
also α-adrenergic blckrs potentiate hypogly

Front 28

contraindications for meglitinides?

use? what can it be combined w/?

Back 28

repaglinide:
type 1 DM
diabetic ketoacidosis

type 2 DM, may be used in combo w/ metformin

Front 29

efficacy of meglitinides

Back 29

repaglinide:
decr A1c ~1%

plasma insulin levels incr after meals and revert toward baseline before next meal

Front 30

mech of action for biguanides?

Back 30

metformin:
1. inhib gluconeogenesis/olysis
2. incr uptake glu sk musc
3. suppress appetite
4. NO effect on insulin secretion

Front 31

PK of biguanides?

Back 31

metformin:
1. 60% absorp by gut
2. t1/2: 1.5-4 hrs (kidney fxn)
3. excrete unchanged in urine
4. doesn't bind plas prot
5. extended release available

Front 32

efficacy of biguanides?

Back 32

metformin:
decr blood glu ~65 mg/dl
decr A1c by ~1.5%
wt loss 5-10 lbs
imprv lipid profile
glu lowering fx additive to SU
avail in combo w/ SU or TZD

Front 33

adverse fx of biguanides?

Back 33

metformin:
GI: abd cramp and diarrhea (30%) mild and usually transient
NO HYPOglycemia (doesn't effect insulin secr)
lactic acidosis (3:100.000)--incr risk w/ renal failure, CHF

Front 34

contraindications for biguanides?

Back 34

metformin:
pregnancy
type 1 DM
renal failure
conditions that incr lactate production (shock/trauma)
alcoholism

Front 35

mech of action of thiazolidinediones?

Back 35

rosi/pioglitazone:
incr insulin sensitivity:
1. activate PPARgamma (enhance insulin response elements like LPL and glut4)
2. red hepatic glu production
3. incr glu uptake by adipose

Front 36

pk of TZDs?

Back 36

rosi/pioglitazone:
metab in liver (P450)
fecal excretion

Front 37

efficacy of TZDs?

Back 37

rosi/pioglitazone:
1. decr glu by 30-35%
2. decr A1c by 0.8-2%
3. decr serum insulin up to 50%

Front 38

adverse fx of TZDs?

Back 38

rosi/pioglitazone:
1. liver fxn abnlities
2. hypoglycemia (usually due to combo w/ insulin)
3. fluid retention (exac CHF)
4. mild incr LDL

Front 39

contraindic of TZDs?

Back 39

pio/rosiglitazone:
pregnancy
type 1 DM
liver disorders
class III/IV CHF (caution w/ I and II)

Front 40

mech of acarbose

Back 40

competitive inhibition of intestinal alpha glucosidase enzymes (brk down carbs to glu causing delayed absorption)

Front 41

PK of acarbose

Back 41

drug not absorbed, metab in GIT by intestinal flora

Front 42

efficacy of acarbose

Back 42

greatest on post-prandial glu load
decr A1c by 0.5-0.75%

Front 43

adverse effects of acarbose

Back 43

GI: flatulence (40%), abd cramps (12%), diarrh (28%)
more delivery of glu to flora of LI

can cause hypoglycemia in combo w/ SU (reversed w/ lactose or dextrose)

Front 44

contraindications for acarbose?

Back 44

GI disorders: IBD, ulcerative colitis, gastroparesis
pregnancy
CRF
cirrhosis

Front 45

indication for acarbose?

Back 45

monotx in pts w/ mild incr glu

in combo w/ insulin or SU

Front 46

dipeptidyl peptidase-4 inhibitor

Back 46

sitagliptin:
selective oral inhib of DPP-4 (ubiquitous enzyme in plasma, ec's)
rapidly inactivate GLP-1 and GIP

GLP, GIP: incretin H's released at start of meal to mediate gluc-dependent insulin release and glucagon suppression

Front 47

how do DPP-4 inhibitors work?

Back 47

by inhib of DPP-4 (sitagliptin):
reduce inactivation of GLP-1 and GIP to incr insulin levels and reduce glucagon
improved glycemic control

Front 48

indication for DPP-4 inhibitor?

Back 48

sitagliptin: Type 2 DM ONLY
1. adjunct to diet/exercise (monotx)
2. inadequate control on metformin or TZD
3. NOT w/ SU or insulin
4. NOT for Type 1 DM

Front 49

adverse effects of DPP-4 inhibitors

Back 49

sitagliptin:
nasopharyngitis
URI
headache

*no contraindications or known drug interxns

Front 50

efficacy of DPP-4 inhibitors?

Back 50

sitagliptin:
1. fasting glu red by 17 mg/dl at 24 wks
2. 2 hr post prand glu down by 47
3. HbA1c red by 0.8% at 24 wks
4. weight and appetite neutral

Front 51

incretin mimetics mech of action

Back 51

exanitide:
injectable mimetic of GLP-1
restores GLP-1 def seen in type 2 DM
GLP-1=incretin H (potent insulinotropic H) from intestinal L-cells during a meal:
slows gastric emptying, supress abnl elevated postprand glucagon in type 2, decr appetite/ incr satiety, stim prolif of beta cells in rodents

Front 52

exanatide

Back 52

synthetic form of GLP-1 from saliva of Gila monster (similar enough to human form that it binds our R's and mimics all the actions)
better than human form--its resistant to DPP-4 degradation

Front 53

actions of GLP-1?

Back 53

exanetide/incretin mimetic/ from L-cells at start of meal:
slow gastric emptying
suppresss abnl elev postprand glu in type 2 DM
decr appetite, incr satiety
rapidly degraded by DPP-1
stim prolif/neogen of beta cells in rodents

Front 54

indications for exanetide?

Back 54

1. adjunct tx at mealtime
2. type 2 DM inadequately controlled w/ metformin, SU, TZD or combo
3. not indicated for monotx or adjunct w/ insulin
4. not for type 1

Front 55

who should exenatide be avoided in?

Back 55

end-stage renal dz, severe GI dz or gastroparesis

its eliminate by glom filtration w/ subseq proteolytic degradation

Front 56

adverse effects of exenatide

drug interxns?

Back 56

GI: nausea, vomit, diarrhea, dyspepsia
hypoglycemia w/ SU (reduce SU dose)

since it slows gastric emptying, may reduce threshold conc of oral medications (take other meds >1 hr before injection)

Front 57

how is exenatide administered?

Back 57

sc injection (pks in 2.1 hrs)

Front 58

amylin mimetic=pramlintide

Back 58

injectable synthetic amylin analog
potency/solubility> than human form
restores amylin def in Type 1 (complete) and 2 (partial)

Front 59

what's amylin?

Back 59

37 AA neuroendocrine peptide co-localized and co-secreted w/ insulin from pancreatic beta cells

Front 60

when is an amylin mimetic indicated?

Back 60

pramlintide:
1. adjunct tx w/ meal to imprv postprand control
2. type 2 DM (+/- oral agents)
3. Type 1 DM (rapid-acting insulin)
4. not approved for use w/o insulin

Front 61

mechanism of amylin mimetic

Back 61

pramlintide:
1.complements insulin action
2.restores neuroendocrine action
3.slows gastric emptying
4.suppresses glucagon secretion
5.decreases appetite and enhances satiety
6.decreases postprandial plasma glucose 24 mg/dl (type 1) to 48, mg/dl (type 2)
7.decreases weight 6.6 lb (type 1) to 6.1 lb (type 2)

Front 62

PK of pramlintide

Back 62

amylin mimetic:
1. 30-40% bioavail
2.. 40% unbound in plasma
3. t1/2=48 mins
4. metab by kidneys

Front 63

adverse effects of pramlintide

Back 63

amylin mimetic:
hypoglycemia
nausea (type 1>2)
anorexia
vomit
fatigue
dizzy

Front 64

are there drug interxns w/ pramlintide?

Back 64

amylin mimetic:
1. slow gastric emptying (red thresh of other oral drugs--take 1 hr before)
2. anti-ACh agents
3. alpha-glucosidase inhibitors

Front 65

contraindications for giving pramlintide?

Back 65

amylin mimetic:
known hypersensitivity to pramlintide
gastroparesis
hypoglycemic unawareness
do not mix with insulin
do not administer if: low premeal blood glucose, meal omitted, meal contains <30 gram carbs

Front 66

efficacy of pramlintide

Back 66

amylin mimetic:
HbA1c red by 0.4% (type 1) to 0.6% (2)
2. weight reduced 4-6 lbs (6 mo)