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a S3 Lec 7: Anti-Diabetics by Dr. Marita Fuentes December 7, 2010
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5. Gliclazide (Diamicron)
vs
6. Glimeperide (Solosa)
DIABETES MELLITUS TYPE 2
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characterized by:
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 Increase insulin secretion for the pancreas
variable degrees of insulin resistance
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  SE: hypoglycemia, weight gain
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 impaired insulin secretion  Available preparation as monotherapy or with
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F.  increased glucose production combination with other antidiabetic drugs, e.g.
co SU + Metf, SU + TZD
Ri Diabetes Pharmacology – Oral Agents and
F. Insulin
ul Insulin Insulin Hepati High
Pa Secreti Resistan c Sensiti Sulfonylureas (Chlorpropamide, Glyburide,
vs on ce Glucos vity to Glipizide)
Vi Fails Persists e dietary  They are not effective for DM1 because they
Output CHO require some endogenous insulin secretion.
Increas
ne
le es  Newer agents have larger, less polar side
Ar Insulin X groups on the sulfonylurea backbone, which
a Secretago boosts potency.
ň gues  Chlorpropamide is excreted without
Ni Insulin X metabolism, so it should be avoided in renal
g Sensitizers disease. Chlorpropamide is the longest-acting
HGO X
an sulfonylurea.
inhibitors
ad
CHO X  Glipizide is metabolized in the liver, so it should
D Absorption be avoided in liver disease. Glipizide is the
er Inhibitors shortest-acting sulfonylurea.
h
Oral Hypoglycemic Agents
 Toxicities: hypoglycemia, hepatotoxicity,
allergic reaction
ac
e
• Used to stimulate insulin secretion from the
First Generation vs Second Generation
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pancreas in patients with NIDDM
1st Gen sulfonylureas
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• Four Pharmacological Classes
 longer half-life
be
co A. 1. Sulfonylureas
 greater incidence of hypoglycemia
Ri 2. Metiglinides
ie B. Biguanides  more frequent drug interactions.
ck C. Alpha-glucosidase inhibitors 2nd Gen sulfonylureas
Ni D. Thiazolidinediones  more rapid onset of action
ad E. Incretins  generally preferred
Gl - GLP1 analogue (Exenetide)
Je - DPP4 inhibitor (Sitagliptin, Vidagliptin, • First-Generation
nz Saxagliptin) 1. Tolbutamide
Ay  short half-life
h A. 1. Sulfonylureas  safest sulfonylurea for elderly diabetics  rare
at incidence of hypoglycemia
K  **Sulfonylureas stimulate basal and glucose-
o mediated insulin secretion. 2. Chlorpropamide
Jh  They are “secretagogues.”  half-life of 32 hours
First class of oral hypoglycemics
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  average maintenance dosage- 250 mg daily,
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 Drugs include: given as a single dose in the morning
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1. Tolbutamide (Orinase)  contraindicated in patients with hepatic or
e
2. Chlorpropamide (Diabinese) renal insufficiency
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3. Glipizide (Miinidiab)
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4. Glyburide (Euglocon)
 Prolonged hypoglycemic reactions  in elderly
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ce
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be
z
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k
ar  Does not stimulate release of insulin
M • Second Generation  SE: nausea, vomiting, decreased appetite
el 1. Glyburide
h  very low hypoglycemic activity Biguanide (Metformin Glucophage)
ac  usual starting dosage is 2.5 mg/d or less  Biguanides sensitize the liver to insulin, which
R  few adverse effects decreases hepatic glucose output.
”  Metformin (Glucophage) will not cause
“G 2. Glipizide hypoglycemia, and often leads to mild weight
n  shortest half-life (2–4 hours) loss.
h
 taken 30 min before breakfast  food delays  Metformin is used for DM2
 Toxicities: lactic acidosis, so Metformin is CI for
Jo
absorption
renal insufficiency, post-surgery, binge
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 starting dosage is 5 mg/d, up to 15 mg/d given
drinking, and CHF. Some people also
Ia
as a single dose
experience GI symptoms
a
n  contraindicated in hepatic or renal impairment
pt
•Action
Ni

3. Glimepiride
 once-daily use as monotherapy or in  Reduces insulin resistance without increasing
combination with insulin insulin secretion
 long duration of effect with a half-life of 5 hours  Decreases hyperglycemia in type 2 DM patient
 allows once-daily dosing, thereby improving  Hypoglycemia very rare
compliance  Needs endogenous insulin
 No weight gain
 Improvement in lipid profile
 Improves vascular risk factors (increases
fibrinolysis)
A. 2. Metiglinides
Repaglinide/Nateglinide •Mechanisms
- Short-acting, non-sulfonylurea secretagogues that are  Suppresses hepatic glucose production
used only pre-prandially - - decreases HLP  inhibition of gluconeogenesis
1. Repaglinide and glycogenolysis
 very fast onset of action  peak effect within 1
hour and duration is 5-9 hrs  Increases insulin-mediated muscle glucose
 indicated for use in controlling postprandial uptake
glucose excursions - - translocation of Glut4 and glycogen synthesis
 taken just before each meal in doses of 0.25–4
mg  Decreases fatty acid oxidation
 hypoglycemia  if meal is delayed or skipped - - inhibits hepatic and adipose tissue lipolysis

2. Nateglinide  Decreases intestinal glucose absorption


 a D-phenylalanine derivative
Other Effects of Metformin
 Faster onset, shorter duration
 Effects on weight:
 Peak effect < 1hr, Duration < 4hrs
- - produces weight loss in obese and non-obese
 Taken just before meals (60-120 mg)
- - promotes satiety
 Amplifies the insulin secretion, but diminished - - weight loss is due to loss of fat tissue
effect in the presence of normoglycemia  - - weight reduction can be sustained for 1 year
lowest incidence of hypoglycemia
 Safe to use in renal insufficiency Multiple Mechanisms for Vascular Protection with
Metformin
B. Biguanide
** Metformin addresses CV risk by a range of direct
• Metformin (Glucophage) and indirect mechanisms
 Decreases glucose synthesis and increases
glucose uptake IMPROVED REDUCED
Insulin Sensitivity Hypertriglycerdemia

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Fibrolysis AGE Formation
Nutritive Capillary Flow Cross Linked Fibrin
Hemorrheology Neovascularization Drugs Affecting the Pancreas
Post Ischemic Flow Oxidative Stress
Insulin Preparations

• Three Sources
1. Beef
Reduced Cardiovascular 2. Pork
3. Human
4. Insulin analogue
C. Alpha-glucosidase Inhibitors • Differ primarily in their onset and duration of
action and incidence of allergic reaction.
**Alpha-glucosidase inhibitors delay the digestion of • Preparations may be short-acting, intermediate-
carbohydrates by reversibly inhibiting pancreatic alpha acting, or long-acting
amylase and intestinal alpha-glucoside hydrolase. This
slows the rise of blood glucose post-prandially Insulin Types and Actions
- Drugs include:
1. Acarbose (Precose) • Generic name:
2. Miglitol (Glyset) Insulin
3. Voglibose (Basen)
• Brand names:
 Delay carbohydrate metabolism
Regular Insulin, Humulin 70/30, Humulin R,
 SE: flatulence, cramps, diarrhea, abdominal Apidra, Humalog
distention • Classification:
Anti-diabetic
Alpha-glucosidase Inhibitors (Acarbose, Miglatol)
 Endogenous insulin is anabolic in that it
 Toxicities: severe flatulence, often bad enough
promotes uptake of glucose, glycolysis,
that patients will not use alpha-glucosidase
glycogenesis, protein synthesis, and fat
inhibitors
storage.
 Low insulin causes hyperglycemia, and no
D. Thiazolidinediones (Rosiglitazone,
insulin at all causes ketoacidosis.
Pioglitazone)
 Exogenous insulin reduces hepatic glucose
output during fasting, which helps relieve
** Thiazolidinediones are potent peripheral insulin
hyperglycemic overstimulation of the pancreas.
sensitizers. They do not cause hypoglycemia.
It is measured in units, and all U.S. insulin
comes as “U-100.”
 Thiazolidinediones are used to treat DM2, and  Exogenous insulin is not very physiologic
act via the PPARγ nuclear receptos because it is given in an “open loop” fashion
 decrease insulin resistance (controlled by the patient, not by glucose
levels), and because it is delivered
 ligands of peroxisome proliferator-activated subcutaneously.
receptor-gamma (PPAR-gamma):
 Exogenous insulin is often combined with
sulfonylureas, Metformin, and
o receptors found in muscle, fat, and liver
thiazolidinediones.
o mediate differentiation of adipocytes  Insulin is given to all patients with DM1, some
patients with DM2 if required, and to pregnant
o ↑ lipogenesis, enhance uptake of glucose and FFA diabetic women (Gest Diabetes)
 Insulin is administered subcutaneously (SC)
because in the blood it has a half-life of
 Toxicities: fluid retention, weight gain; earlier minutes
thiazolidinediones caused fulminate liver  The main determinant of its absorption is the
failure extent of its dimer and hexamer formation.
 Troglitazone, Rosiglitazone was also banned  Toxicities: hypoglycemia, weight gain due to
because of increased risk of CV events and insulin’s lipogenic effects, insulin allergy (IgE-
fracture. mediated), lipoatrophy at the injection site

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Type Preparatio Onse Peak Duration  Glargine insulin cannot be mixed with other
n t insulins because of its acid pK
 Detemir insulin is an insulin analog that bind
Rapid Insulin 5-15 1-2 2-4 hrs
free fatty acids and albumin to slow absorption
Acting Lispro min hrs
 UltraLente insulin has very large insulin
10-20 crystals and high zinc concentration
min 3-5 hrs
Insulin 1 hr INSULIN
Aspart
 Protein secreted by beta cells of islets of
Short Regular 30-60 2-3 5-7 hrs langerhans
Acting min hrs  Responsible for promoting the uptake of
Prompt glucose by the cells (muscle, cardiac, CNS and
Insulin Zinc all other tissue)
(Semilente)
 Necessary for carbohydrate, fat, and protein
Intermedi Isophane 1-2 5-7 13-18 hrs metabolism
ate Insulin hrs hrs  Converts glycogen to fat
Suspension
(NPH) ACTIONS
 Allows glucose storage in the liver
Insulin Zinc
Suspension 13-20 hrs  Promotes fat and protein synthesis while
(Lente) 1-3 4-8 antagonizing fat breakdown
hrs hrs  Produces intracellular shift of potassium and
magnesium to reduce elevated serum levels of
Long Extended 2-4 8-14 18-36 hrs
those electrolytes
Acting Zinc hrs hrs
Suspension
(Ultralente) INDICATIONS
Up to 25  Rarely used in the field – blood glucose levels
Insulin 2-4 None hrs are necessary before administering in an
Glargine hrs
emergency situation
 In hospital use: diabetic ketoacidosis or other
hyperglycemic state
• Short-acting Insulin  Hyperkalemia
Regular insulin is used to cover meals.
CONTRAINDICATIONS
 - - Lispro insulin reduces hexamers and
 Hypoglycemia
promotes insulin monomers so it is very fast-
 Hypokalemia
acting.
 - - Aspart insulin reduces hexamers and INCOMPATIBLE/REACTIONS
promotes insulin monomers so it is very fast-
 Incompatible in solution with all other drugs
acting.
 Antagonized actions of epinephrine, steroids,
 Intermediate-acting Insulin (modifications estrogens, thyroid hormones, diazoxide,
of the solution, not of insulin itself) dilantin
 - - Neutral Protamine Hagedorn (NPH)
insulin uses protamine to form a less soluble Insulin notes
suspension of insulin.  Usually refrigerated
 - - Lente insulin has relatively large insulin  Oral hypoglycemic, such as Glibenclamide,
crystals and high zinc concentration in solution. Gliclazide, Glipizide, are not substitutes for
insulin, they stimulate the release of insulin
• Long-acting Insulins from a “sluggish” pancreas
 Glargine insulin is an insulin analog with acid
pK, which allows the insulin to remain soluble Insulin preparations
in acid solution but precipitate in the  Modified insulin preparations include:
subcutaneous space, prolonging absorption. o Neutral protamine hagedorn (regular
This delivers a basal insulin dose over 24 insulin attached to a protein to delay
hours. absorption)
o Lente (attached to zinc)

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 Derived from beef or pork, lentes, may lead to  Side effect: local tissue necrosis if infiltration
allergic reactions. occurs
 Natural human insulin preparations do not
have allergic reactions
Dextrose 50%
Today’s Smart Pumps  Rapidly increases serum glucose levels
 Carb boluses  Provide short-term osmotic dieresis
o Personalized carb factors for different  Indications:
day o Coma of unknown origin
o Easy carb bolus calculations o Hypoglycemia
o Personalized carb database o Status epilepticus
 Correction boluses  Adverse reactions:
o Personalized collection factors for o Extravasation leads to tissue necrosis
different times  Dose:
o Easier and safer correction of high BGs o Adult: 25-50g IV bolus
o Reveal when correction bolus is high, ie o Pediatric: 25%, 2-4ml/kg IV bolus
>8% of TDD  Incompatible reactions
 Combined carb/correction boluses o Sodium bicarbonate
 Automatic bolus reduction for bolus on board o Coumadin
(BOB)  Onset: immediate
 Peak: variable
Bolus Concepts
 Duration: variable
 Basal insulin
o 50% of daily insulin need
Glucose
o Limits hyperglycemia after meals
 quickly absorb form of glucose to increase
o Suppresses glucose production
blood glucose levels
between meals and night
 indication
 Bolus insulin o hypoglycemia
o Limits hyperglycemia after meals
o conscious patients
o Immediate rise and sharp peak at 1
 precaution:
hour
o assure that the airway is patent
o 10% to 20% of total daily insulin
requirement for each meal
Glucagon
 protein secreted by the alpha cells of the
Hyperglycemic Agents
pancreas
 Glucagon
 causes a breakdown of stored glycogen to
 Diazoxide (proglycem)
glucose (glycogenesis); increases circulating
o Increase blood glucose levels
blood glucose
 IV glucose  unknown mechanism of stabilizing cardiac
rhythm in beta-blocker overdose
Glucose
 contraindication:
 Given IM if IV live is unobtainable o hyperglycemia
 Converts glycogen stores to glucose o known hypersensitivity
 Side effects: N/V, allergic reactions (rare)  precautions:
o caution with administration to patiens
Diazoxide
with a history of cardiovascular or renal
 Inhibits insulin release disease
 Typically used for patient with hyperinsulin  dose:
reaction in pancreatic tumors o adult: 0.5-1mg IV; repeat 1-2 times if
 Not indicated for treating diabetes-induced no response within 20 minutes
hypoglycemia o pediatric: not used
 incompatible/ reactions:
D50
o incompatible with solution with most
 Sugar solution given IV for acute hypoglycemia
other substances
 onset: 1 minute

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 peak: 30 minutes o Delirium tremens
 duration : variable o Other thiamine deficiency syndromes
 should always be used in conjuction with D5W
 must be reconstituted before administration.  Dose:
Must be used or refrigerated after o Adult: 100 mg
reconstitution o Pediatric: rarely used
 Incompatible/reactions:
Thiamine (Vitamin B1) o Alkaline solutions
 Brand name: Betalin o Barbiturates
 Required for carbohydrate metabolism o Bicarbonates
 Deficiency leads to anemia, polyneuritis, o Cephalosporin
Wernicke’s encephalopathy, cardiomyopathy o Other antibiotic
 Administration may reduce symptoms of  Onset: hours
deficiency, but effects are dependent upon  Peak: 3-5 days
duration of illness and severity of disease  Duration: variable
 Any comatose patient, especially those who
 Contraindication: are suspected to be alcoholic, should receive IV
o Known hypersensitivity thiamine prior to the administration of D50 or
 Indications: Narcan
o Coma of unknown origin, especially if
alcohol is involved

Oral Monotherapies
SUs Megliniti TZDs Metfor α- DPP-4
des min glucosidase inhibitors
inhibitors
Improves + + +
insulin
secretion
Improves + +
insulin
resistance
Lowers hepatic + + +
glucose
production

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