Transcript B. Oral hypoglycemic drugs

Pancreatic hormones &
antidiabetic drugs
Huifang Tang
Department of pharmacology
Email: [email protected]
History of Diabetes
1869
Paul Langerhans discovers islet cells in the
pancreas.
1889
Mehring and Minkowski produce DM in dogs by
removing the pancreas.
1921
Banting and Best find a pancreatic extract that
lowers blood glucose in pancreatectomized dogs.
VOL 101 / NO 4 / APRIL 1997 / POSTGRADUATE MEDICINE
Dr. F.G. Banting, Mr. C.H. Best, Mr. J.B. Collip and Prof. J.J.R.
MacLeod discovered insulin in 1921 at the University of Toronto.
Overview of Glucose Regulation
Alpha glucosidase inhibitors
Glucose
Sulfonylureas
Meglitinides
Defective insulin
secretion
b-cell insulin
secretion
Persistent Hepatic
Glucose Output
Incretin analogs
DPP-IV Inhibitors
Metformin
Amylin analogs
Thiazolidinediones
Insulin action
Amended from Dinneen SF. Diabetes Med. 1997;14(suppl 3):S19-24.
Resistance to
insulin action
Different forms of diabetes mellitus
Complications of diabetes mellitus


Acute complications
Diabetic ketoacidosis (酮症酸中毒)
Hyperosmotic nonketotic coma(高渗性非酮症性昏迷）
Chronic complications
Cardiovascular diseases
Renal damage
Retinal damage
Nerve degeneration
Infection
Myopathy
etc.
Pharmacological therapy

Insulin.

Oral hypoglycemic drugs
Insulin sensitizers
Insulin secretagogues
α-glucosidase inhibitors
A. Insulin
A. Insulin
Insulin
1. Pharmacological effects
(1)
Carbohydrate
metabolism:
reducing blood
glucose levels by gycogenolysis , glycogen synthesis ,
gluconeogenesis  (ketone badies )
(2) lipid metabolism: fat synthesis , lipolysis ,
plasma free fatty acids 
(3) Protein metabolism: active transport of amino
acids , incorporation of amino acids into protein ,
protein catabolism 
(4) Mechanism of insulin actions
Interacting with insulin receptor
Interaction
between insulin
and its
receptor
IRS: insulin receptor
substrate
tyr: tyrosine
P: phosphate
Insulin promotes the
translocation of
glucose transporters
into the membrane
A. Insulin
2. Clinical uses
(1) Insulin-dependent patients with diabetes
mellitus (type 1 diabetes mellitus)
(2) Insulin-independent patients: failure to other
drugs
(3) Diabetic complications: diabetic ketoacidosis
(酮症酸中毒), hyperosmotic nonketotic coma（高渗性非
酮症性昏迷）
(4) Critical situations of diabetic patients:
fever, severe infection, pregnancy, trauma, operation
(5) Others: promotion of K+ uptake into the cells,
pshychiatric disorders
A. Insulin
3. Preparations
Approximate Pharmacokinetic Profiles of
Insulins and Insulin Analogues
Human
Hirsch. NEJM. 2005; 352:174-83
A. Insulin
4. Adverse effects
(1) Hypersensitivity: treated with H1 receptor
antagonist, glucocorticoids
(2) Hypoglycemia: adrenaline secretion (sweeting,
hunger, weakenss, tachycardia, blurred vision,
headache, etc.), treated with 50% glucose
(3) Insulin resistance:
Acute: stress induced, need large dose of insulin
Chronic: need >200U/d and no complication
(4) Lipoatrophy: localized in injection sites
B. Oral hypoglycemic drugs
History





In 1942, Janbon and colleagues noted that some sulfonamides (磺胺
类)caused hypoglycemia in experiment animal.---Carbutamide （氨磺丁
脲）became the first clinically useful sulfonylurea （磺酰脲类）for
treatment of diabets.
In the early 1950s, Clinical trials of tolbutamide（甲苯磺丁脲）, the
first widely used member of this group, were instituted in type 2 DM
patients.
During the 1920s, biguanides were investigated for use in diabets,
but they are overshadowed by the discovery of insulin.
In 1997, the first member of a new class of oral insulin
secretagogues called meglitinide(美格替奈) was approved for clinical
use.
In 1997, Thiazolidinediones were introduced as the second major
class of insulin sensitizers.In 2000, the first of these agents,
troglitazone was withdrawn from use in the United Stats.
B. Oral hypoglycemic drugs
Insulin secretagogues(促胰岛素分泌剂):
Sulfonylureas(磺酰脲类)
Repaglinide (瑞格列奈)
GLP-1 receptor agonist
DPP-4 inhibitor
Insulin sensitizers （胰岛素增敏剂）:
Thiazolidinediones (TDs)
Biguanides
α-glucosidase inhibitors
B. Oral hypoglycemic drugs -1
1. Sulfonylureas
Tolbutamide (D860) 甲苯磺丁脲
Chlorpropamide 氯磺丙脲
Glibenclamide 格列本脲 (优降糖)
Glipizide 格列吡嗪
Gliclazide
格列齐特 (达美康)
甲苯磺丁脲
氯磺丙脲
格列本脲 (优降糖)
格列吡嗪
格列齐特 (达美康)
格列美脲
Mechanisms of Action of sulfonylureas
B. Oral hypoglycemic drugs -1
Sulfonylureas
1. Pharmacological effects
Act by binding to specific receptors (SUR1) on
the beta cells and promoting insulin secretion.
Blocking K+ channel: Ca2+ inflow , insulin release ,
Stimulating insulin secretion
Increasing insulin sensitivity (long-term use)
1st generation agents (tolbutamide, tolazemide,
chlorpropamide) rarely used today
2nd generation agents (glyburide, glipizide and
glimeperide) are more potent and all ~equally
effective in maximal dose.
B. Oral hypoglycemic drugs -1
Sulfonylureas – Caveats in Use

Glyburide(格列本脲)
Longer duration of action, active hepatic metabolites,
renally excreted
May want to avoid in adults >65 years old

Glipizide（格列吡嗪）
Shorter duration of action

Glimepiride（格列美脲）
Largely excreted in bile
All are hepatically metabolized and should be used
cautiously with advanced liver disease
 Start with lowest dose and titrate slowly

B. Oral hypoglycemic drugs -1
2. Clinical uses
(1) Insulin-indenpedent diabetic
(type 2): alone or combined with insulin
(2) Diabetes insipidus (尿崩症):
patients
Chlorpropamide (氯磺丙脲): antiuretic hormone (ADH)

B. Oral hypoglycemic drugs-1
3. Adverse effects
Major side effects
- weight gain
- hypoglycemia, especially in the elderly or
in patients with impaired renal function.
Major advantages
- low price (generic glip $10-20/month)
- long track record of safety.
Others: leukopenia, cholestatic jaundice(胆汁淤积
性黄疸), hepatic damage
B. Oral hypoglycemic drugs -1
4. Drug interactions
(1) Potentiation of hypoglycemic effects
replacement in plasma protein binding:
salicylic acid, sulfates, indomethacin, penicillin,
warfarin, etc.
inhibition of hepatic microsomal enzymes:
chloramphenicol, warfaren
(2) Attenuation of hypoglycemic effects
induction of hepatic microsomal enzymes:
phenytoin, phenobarbital, etc.
interactions in pharmacodynamics: glucagon,
thiazides, etc.
B. Oral hypoglycemic drugs -2
2.Meglitinides
(Non-SU Insulin Secretagogues)

Prandial glucose regulators (餐时血糖调节剂)

Act by binding to SUR1 on beta cells to promote insulin
secretion.
Repaglinide (Prandin，瑞格列奈) and Nateglinide (Starlix，
那格列奈) are current agents in class.
Major side effect is hypoglycemia.
Major advantage is rapid onset and offset

Efficacy for repaglinide appears to be similar to SU’s



Can dose just prior to meals with better post-prandial control
Fewer overnight lows
Ability to skip the dose if skip the meal.
Mechanism of action
B. Oral hypoglycemic drugs -3
3. GLP-1 （glucogen-like peptide1)receptor
agonist and DPP-4 inhibitor
B. Oral hypoglycemic drugs-3
GLP-1 receptor agonist and DPP-4 inhibitor
B. Oral hypoglycemic drugs
GLP-1 receptor agonist and DPP-4 inhibitor
GLP-1 （glucogen-like peptide1)receptor agonist
依克那肽
利拉鲁肽
B. Oral hypoglycemic drugs
GLP-1 （glucogen-like peptide1)receptor agonist
Exenatide(依克那肽)
Exenatide is a synthetic version of exendin-4, a
hormone found in the saliva of the Gila monster
that was first isolated by Dr. John Eng in 1992.
 a 39-amino-acid peptide, an insulin secretagogue,
with glucoregulatory effects
 Mechanism
of action : It displays biological
properties similar to human glucagon-like peptide-1
(GLP-1), a regulator of glucose metabolism and
insulin secretion

B. Oral hypoglycemic drugs
Exenatide(依克那肽)


Must be taken as a BID injection w/in 60 mins prior to
meal
Major side effects: nausea, vomiting, diarrhea.
Increases the risk of Acute pancreatitis.
Not recommended in severe renal impairment.
Not recommended as monotherapy


To be used as add on therapy with SU, metformin, or
TZD’s
Increases the risk of Hypoglycemia when added to SU
treatment.
Major advantage : weight loss (~5 kg) as well as
maintained effect (preserved beta cell function).
Efficacy: decreases A1C ~1.0%.
B. Oral hypoglycemic drugs
DPP-4 (dipeptidyl peptidase 4 enzyme) inhibitor
Sitagliptin phosphate(磷酸西列他汀）

Mechanism of action:
Acts to prevent breakdown of intrinsic GLP-1, thereby
increasing portal GLP-1 levels
Acts as an incretin enhances insulin secretion in response
to an oral glucose load.
Suppresses post-prandial glucagon secretion in a glucosedependent manner
Preserves beta cell mass by reducing apoptosis and
increased neogenesis (animal models).
B. Oral hypoglycemic drugs
Sitagliptin phosphate(磷酸西列他汀）

Sitagliptin (Januvia) is first DPP-IV inhibitor
on market.
Effective as monotherapy or when used in
conjunction with metformin or a
thiazolidinedione.
 Appears to maintain efficacy (preserved beta
cell fxn).


Efficacy: decreases A1C ~0.8%.
B. Oral hypoglycemic drugs-2
Insulin sensitizers
Biguanides
Metformin 二甲双胍
Phenformin 苯乙双胍
1. Pharmacological effects
increasing glucose uptake in fat tissues and anaerobic
glycolysis in skeletal muscles
decreasing glucose absorption in gut and glucagon release
2. Clinical uses
mild insulin-independent patients with obesity
3. Adverse effects
severe lactic acidosis, malabsorption of vitamin B12 and
folic acid
Mechanism of action
B. Oral hypoglycemic drugs -2
Biguanides
Mechanism of action not well understood, but
causes inhibition of hepatic glucose production.
 Metformin is only agent in this class available in
US.
 Major side effect

GI intolerance (20-30%): bloating, anorexia, diarrhea, and
flatulence. Lactic acidosis is rare, but may be severe.

Major advantages:
Lack of weight gain
Absence of hypoglycemia
Low cost with generic prep.
B. Oral hypoglycemic drugs-2
Thiazolidinediones (TZDs) 噻唑烷酮类化
合物
Rosiglitazone 罗格列酮
Pioglitazone 吡格列酮
Troglitazone 曲格列酮
B. Oral hypoglycemic drugs-2
Rosiglitazone
罗格列酮
Pioglitazone
吡格列酮
B. Oral hypoglycemic drugs -2
Insulin action enhancers
1. Pharmacological effects
Selective agonists for nuclear peroxisome
proliferator-activated receptor- (PPAR , 过氧化物
酶增殖体激活受体), by enhancing peripheral insulin
sensitivity, esp. at muscle and adipose tissue, via
activation of PPARγ, increasing glucose transport
into muscle and adipose tissue.
(1) Lowering insulin resistance
(2) Lipid metabolism regulation: TG, free fatty acid 
(3) Antihypertensive effects
Mechanism of action
B. Oral hypoglycemic drugs-2
2. Clinical uses
used for treatment of insulin-resistant
diabetic patients or type 2 patients
3. Adverse effects
Edema, headache, myalgia, GI reactions,
hepatic damage (troglitazone)
B. Oral hypoglycemic drugs -3
Alpha-Glucosidase inhibitors
Acarbose-Precose 阿卡波糖 1996
Miglitol-Glyset
米格列醇 1998
Voglibose
伏格列波糖
B. Oral hypoglycemic drugs -3
Acarbose 阿卡波糖
Reducing intestinal absorption of starch (淀粉), dextrin (糊精),
and disaccharides ( 二 糖 ) by inhibiting the action of alphaglucosidase enzymes in the brush border of the small intestines.
B. Oral hypoglycemic drugs-3
Mechanism of Acarbose
Alpha-Glucosidase Inhibitors
– Caveats in Use

Acarbose has minimal systemic absorption, but some
hepatic metabolism occurs.
Contraindicated with advanced liver disease


Miglitol has greater systemic absorption
Not metabolized by the liver
Renally excreted, and hence should not be used in renal
failure (creatinine >2)
Voglibose in contrast to acarbose, has less of GI
side effects. It is also more economical compared
to acarbose.
B. Oral hypoglycemic drugs -3
Alpha-Glucosidase inhibitors


Major side effect : GI intolerance, including
bloating, cramping, and flatulence, diarrhea…
need to titrate very slowly.
Major advantage: absence of hypoglycemia
when used as monotherapy.
Summary
Medication
Site of Action/Mechanism
Sulfonylurea (eg. glyburide)
Augments insulin secretion, Hypoglycemia, caution renal
binds SUR
insufficiency, elderly
Thiazolidinediones
rosiglitazone)
(eg. PPARg
receptor/increased Liver, LE edema, congestive
insulin sensitivity
heart failure, MI
Biguanide (metformin)
Reduced
gluconeogenesis
Glinides (repaglinide)
Bind SUR, short action
Alpha-glucosidase
(acarbose)
Side-Effects
inhibitors Inhibits
brush
enzyme/Reduce
absorption
hepatic GI upset, Lactic
(very rare), only
creatinine<1.5 mg/dl
acidosis
use if
Hypoglycemia, caution in renal
insufficiency
border Flatulence, diarrhea
glucose
Incretins/GLP-1 (exenatide)
Stimulates insulin, delays Nausea, vomiting (given by
gastric emptying, satiety
injection)
DPP4 Inhibitors (vildagliptin)
Inhibits GLP1 breakdown
GI side effects