Download Insulin and Hypoglycemic Drugs

Insulin and Oral Hypoglycemic Drugs
Drug
Regular Insulin
 short-acting
 soluble Zn crystalline
insulin
 only form that
injectable IV or
infusion pumps
NPH Insulin
 neutral protamine
Hagedon
 intermediate-acting
 contains protamine
and insulin so neither
is uncomplexed
 insulin complexed to
protamine to prolong
its action
Ultralente
 long-acting
 poorly soluble
crystals from Zn and
bovine insulin
Lente
 intermediate-acting
30% semi/70% ultra
Semilente
 fast-acting
 amorphous ppt. of Zn
and insulin
Pharmacokinetics
 normally secreted by
beta cells of the pancreas
at the rate of 30-50 units
per day
 glucose is the primary
secretogogue
 rapidly metablized by
reduction of the disulfide
binds to A and B chains
followed by proteolysis
of the peptide chains in
the liver and kidney;
peripheral tissues (e.g.
fat) may also degrade
insulin
 t ½ 5-15 min
MOA
Effects on liver:
 reversal of catabolic features of
insulin delivery
 inhibits glycogenolysis
 inhibits FA and aa  keto acid
formation
 inhibits aa  glucose
Anabolic Action:
 promotes glucose storage as
glygogen
 inc. TG synth. and VLDL synth.
Inc. Glycogen synth.:
 inc. glucose transport
 induces glycogen synthase and
inhibits phosphorylase
Effect on adipose tissue:
 inc. TG storage
 LPL induced and activated to
hydrolyze TG from lipoprotein
 intracellular lipase is inhibited by
insulin
SE
 hypoglycemic rxns
 allergic rxns/anaphylaxis
 lipodystrophy (at site of
injection)
 hypokalemia (due to insulin
stim. of K+ uptake by
activation of Na+/K+
ATPase
 drug interactions
Use
DM
Sulfonureas
Tolbutamide
Chlorpropamide
Tolazamide
Acetohexamide
Glyburide
Glipizide
Tolbutamide:
 t ½ 4-6 hrs.
 given 2-3 times/day
Chlorpropamide:
 t ½ 60 hrs.
 given once/day
Others:
 t ½ 12-24 hrs.
 given 1-2 times/day
All:
 hepatic metabolism
 highly bound to albumin
 renal excretion
Pancreatic Effects:*
 stim. rapid secretion of preformed
insulin by beta cells
 potentiate the stim. effect of
glucose on insulin secretion
(maybe synthesis, too)
 drug effect related to glucose
concentration
 may stim. regeneration of beta
cell
Extra-pancreatic Effects:
 potentiate ability of insulin to
stim. glucose transport into
muscle, fat
 reduce hepatic glucose output
(inhibit glycogenolysis and
gluconeogenesis)
 stim. hepatic glycolysis
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*pancreatic betas cells have specific K+ channels which extrude K+ from the cell to maintain resting potential
various stimuli (esp. glucose) inhibits the channels, to decrease K+ extrusion
causes Mb depolarization
opens specific Ca2+ channel allow Ca2+ influx
increased Ca2+ stim. the movement of insulin granules to surface of the beta cell and extrusion of insulin
sulfonureas bind to a receptor on the beta cell Mb, to inhibit K+ channels, and stim. insulin secretion
may decrease secretion of glucagon in response to secretory stim.
hypoglycemia (esp. elderly)
GI complaints, skin rashes,
bone marrow depression,
hepatotoxic effects, goiter
hyponatremia (inapprop.
ADH secretion & action on
tubules)
possible inotropic and
chronotropic effects in the
heart
pharm-kinetic SE: due to inc.
binding to plasma proteins;
drugs that induce hep.
metabolism (like phenobarb.)
may antagonize effects; drugs
that inhibit hepatic met. or
compete for renal secretion
may enhance hypoglycemic
effects
pharm-dynamic SE: may
occur with drugs that alter
insulin secretion and exert
met. effects (e.g.
glucocorticoids)
NIDDM
those who fail
control by diet
and weight
reduction; or
who are
unwilling to take
insulin
Biguanides
Metformin




Thiazolidinediones
Troglitazone
Pioglitazone
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
a-Glucosidase Inhibitors
Acarbose
absorbed from SI
does not bind plasma
proteins
excreted unchanged in
urine
plasma t ½ is 1.3-4.5 hrs.
rapid absorption from GI
tract
peak blood levels in 2-3
hrs
food increases absorption
by 30-85%
hepatic metabolism
elim. in feces
steady-state within 3-5
days
poorly absorbed

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
dec. liver gluconeogenesis and
increases glucose uptake by
increasing insulin action in
peripheral tissues
NO effect on pancreatic insulin
secretion
REQUIRES presence of insulin to be
effective

dec. blood glucose by improving
insulin sensitivity in muscle and
adipose and by directly inhibiting
hepatic gluconeogenesis
do not stim. insulin secretion by
pancreas
lowers TG levels by 20% and may
inc. HDL

reduce intestinal absorption of starch,
dextrin, and disacchs. by inhibiting action
of intestinal brush border a-glucosidase
slowing the absorption dec. post-prandial
rise in plasma glucose



lactic acidosis – by inhibiting
lactate metabolism (esp.
associated with renal
impairment, high EtOH
intake, hypoxia, shock,
hepatic failure)
SE: metallic taste, diarrhea,
N, V, anorexia
also inhibits absorption of
vit. B12 and folic acid
may induce drug metabolism
by CYP3A4 (to dec. plasma
concentrations of terfenadine,
cyclosporine, tacrolimus,
OCs, and some HMG-CoA
reductase inhibitors)
may increase plasma volume
by 6-8 %
malabsorption, flatulence, and
abdominal bloating
NIDDM


insulin
resistance
impaired
glucose
tolerance