Pharmacology of Antidiabetic Agents

dr. Tri Widyawati, M.Si, Ph.D

BLOK 7, 27 April 2020, FKG

 Diabetes Mellitus
a common group of metabolic disorders that is
characterized by hyperglycaemia resulting from
relative insulin deficiency or insulin resistance or
both (ADA, 2010; Innes, 2009; Lenzen, 2008).
Criteria for the diagnosis of diabetes

ADA, 2019
Development and Progression of Type 2 Diabetes
Progression of Disease
Insulin resistance

Hepatic glucose
production
Insulin level

β-cell function

4–7 years Postprandial

glucose
Fasting glucose

Impaired Glucose Frank Diabetes

Tolerance
Diabetes Diagnosis
Insulin
Secretion
(GIT: Gastrointestinal tract, ATP: Adenosine triphosphates, PPAR: Peroxisome proliferator-activated receptor
;
GLP-1R: Glucagon-like peptide-1 receptor; DPP-IV: dipeptidyl-peptidase-IV; Glucose; Insulin
http://www.medscape.org/viewarticle/412864_3
http://watcut.uwaterloo.ca/webnotes/Metabolism/diabetesHbA1c.htm
 Management of Diabetes


Approaches to Glycemic Treatment
Pharmacological
Therapy for Type
1 Diabetes
*Virtually no insulin secretion
*Depends on administration
of exogenous insulin
OAD
Pharmacological Therapy
for Type 2 Diabetes
*Most type 2 diabetics do not require
exogenous insulin for survival, but many
need exogenous supplementation of
their endogenous secretion to achieve
optimum health
-*20%  taking insulin
Bariatric Surgery
*Surgery on the stomach
and/or intestines to help a
person with extreme obesity
lose weight.
*An option for people who
have a body mass index (BMI)
above 40; or between 35 and
40 who have health problems
like type 2 diabetes or heart
disease.
Insulin Preparation & Chemistry
Steps in Insulin Absorption

http://www.medscape.org/viewarticle/412864
Currently Available Insulin Preparations

http://www.ncbi.nlm.nih.gov/books/NBK279114/?
 Currently Available Insulin Preparations

Portable
Pen Injector

Insulin Inhalers: Orally Absorbed Insulin

Exubera (removed) (Oral-Lyn)
Afrezza

Continuous Subcutaneous
Standard delivery Insulin Infusion Devices
needle and syringe (CSII, insulin pumps
https://www.accu-chek.co.uk/gb/pumptherapy/subcutaneous-insulin-
 Complications of Insulin Therapy
1. Hypoglycemia

- Delay in taking a meal

caus es
- Inadequate carbohydrate consumed
- Physical over exertion
- Dose of insulin  too large for immediate needs

- Autonomic hyperactivity :
signs
• Sympathetic : tachycardia, palpitations, sweating, tremulousness
• Parasympathetic : nausea, hunger
- Convulsions
- Coma
Shu and Myers, 2004 17
 Complications of Insulin Therapy
1. Hypoglycemia treatment
- Mild hypoglycemia : conscious and able to swallow :
• Orange juice
• Glucose gel
• Any sugar containing beverage/food
- Severe hypoglycemia : unconsciousness/stupor :
• 20-50 ml of 50% glucose solution (IV infusion over 2-3 minutes)
• 1 mg glucagon : IM/SC
• small amounts of honey or syrup : buccal pouch
Contraindication : oral feeding

Shu and Myers, 2004 18

 Complications of Insulin Therapy
2. Immunopathology of Insulin Therapy
- Insulin allergy :
• Rare condition
treatment
• Urticaria
• Anaphylaxis
• Highly purified and human insulins :  insulin allergy
- Immune insulin resistance :
• A low titer of circulating IgG anti-insulin antibodies that neutralize the action of
insulin to a negligable extent develops in most insulin-treated patients.
• Rarely, the titer of insulin antibodies will lead to insulin resistance and may be
associated with other systemic autoimmune processes such as lupus
erythematosus

Shu and Myers, 2004 19

 Complications of Insulin Therapy

3. Lipodystrophy at injection sites

- Atrophy
- Hyperthrophy

Corrected by :
- avoidance of that spesific injection
- liposuction

Shu and Myers, 2004 20

Oral Anti-diabetic
Agents
(GIT: Gastrointestinal tract, ATP: Adenosine triphosphates, PPAR: Peroxisome proliferator-activated receptor
;
GLP-1R: Glucagon-like peptide-1 receptor; DPP-IV: dipeptidyl-peptidase-IV; Glucose; Insulin
Sulphonylureas: Mechanism of Action
 Sulphonylureas
 Mechanisms of action
• Stimulates Insulin release from β- cells
• Inhibits SUR-1 receptors present on ATP sensitive K+ Channels →
depolarizationfollowed by Ca+ eŶtry → iŶsuliŶ release
• Glucagon levels are suppressed
 Pharmacokinetics
• well absorbed
• PPB is high
• Metabolized in liver or kidney and excreted in urine
 Adverse effects
• Hypoglycemia
• Weight gain
• Cross placental barrier – fetal hypoglycemia (avoid in gestational DM)
 Sulphonylureas
Drug interactions
•Ketocanazole, chloramphenicol and anticoagulants- inhibit their
metabolism  hypoglycaemia
•Sulfonamides, salicylates etc- protein binding displacement
•Propranolol masks the symptoms of hypoglycemia
 Sulphonylureas
 First
Generation
Tolbutamide
• Onset of action is within one hour & lasts for 6-12
Hrs
• It is weaker, short acting, less likely to cause
hypoglycemia
Chlorpropamide
• Onset of action is within one hour & lasts for 24-60 Hrs
• It is more potent, long lasting, risk of prolonged
hypoglycemia
• Potentiates ADH
action
 Sulphonylureas
 Second Generation
Glibenclamide (glyburide)
• Onset of action is within 1-4 hours & lasts for 10-24 Hrs
• It is more potent than tolbutamide, risk of severe hypoglycaemia.
Glipizide
• Onset of action is within 1-3 hours & lasts for 10-24 Hrs
• Less potent than glibenclamide but more potent than
tolbutamide
• Risk of prolonged hypoglycemia
Gliclazide
• Onset of action & duration of action, same as glipizide
• More potent than tolbutamide
• Has an antioxidant and antiplatelet action
• Less weight gain
Glimepiride:
• Same as glipizide
 Meglitinide Analogues
Mechanism of action
•These act, like the sulfonylureas, but they don͛t have sulfonylureas moiety
•Short duration of action
•A low risk of hypoglycemia
•Rapidly metabolized by liver

*Repaglinide
•Onset of action is within one hour & lasts for 4-5 hrs
•Dose 0.25-4 mg before each meal

*Nateglinide
•Onset of action & duration of action, same as repaglinide
•Dose 60-120 mg before each meal
•Hypoglycemic risk is low
Meglitinides
 Advantages of Nateglinide/Repaglinide
• Flexibility in mealtime dosing –
• No significant increase in bodyweight

• Can be utillised in mild to moderate renal failure

• Nateglinide: approved in hepatic failure

Useful Situations
• Elderly patients in whom hypoglycaemia is a concern
• Patients with kidney failure or mild hepatic impairment
• Patients taking low-dose sulphonylureas who encounter
problems with hypoglycaemia
• Patients with irregular meal patterns
Int J Clin Pract. 2003 Jul-Aug;57(6):535-41.
Insulin actions at the target cells
 Biguanide: Metformin
• The primary drug of choice for diabetes by ADA
guidelines.
• Does not stimulate insulin release

• Not dependent on functional β- cells for its action

• Does not lower blood glucose in normal
No weight gain
subjects

• •As monotherapy, rarely causes

hypoglycemia
 Pharmacokinetic
• No PPB, Plasma t1/2 2-3 hours
• Excreted unchanged by
kidneys
Dose:

500 mg twice a day after meals

Biguanides
 Biguanides

Slowing of glucose absorption from GIT

www.diabeticretinopathy.org.u
k
 Biguanides
Advantages:
• Perpetuates weight loss
• Can be combined with insulin to reduce insulin
requirements
• Decreases risk of macro & microvascular disease
Adverse Effects:
Nausea, vomiting and diarrhea (5%), Vitamin B12
• Deficiency (0.5%), metallic taste, anorexia

 Phenformin
• Its use has been discontinued because of
lacticacidosis
 Thiazolidinediones (Glitazones)
 New class of drugs – acts as agonist to nuclear
receptor PPAR-Ƴ in adipose tissue, skeletal muscle and
liver.
Pioglitazone
• Duration of action more than 24hrs
• 10-45 mg OD
Rosiglitazone (withdrawn from the market in Oct. 2010 b/o risk of Heart failure
and MI)
• Duration of action same as pioglitazone
• Dose 4-8mg OD
Thiazolidinediones
Thiazolidinediones
 Glitazones
 Mechanism of action
Stimulates (nuclear receptor) i.e. Peroxisome Proliferator Activated Receptor-
gamma (PPAR-Ƴ) → promotes transcription of insulin responsive genes which
control glucose & lipid metabolism → ↑ insulin sensitivity & ↓ insulin resistance
Promotes uptake and utilization of glucose by increasing the GLUT-4 transpotors
Decrease glucose output by inhibiting gluconeogenesis

Adverse Effects
Weight gain, hepatotoxicity is rare, yet LFT are advisable
Contra Indication
Hepatic failure, pregnancy, lactating mother, children and heart failure
GIT as a site of target

Alpha glucosidase enzyme facilitates

digestion of complex starches,
oligosaccharides and disaccharides
into monosaccharides so that these
are absorbed from the small intestine.
The digestion is also facilitated by
pancreatic alpha amylase.
 GIT as a site of target

Alpha glucosidase enzyme facilitates digestion of complex starches, oligosaccharides and

disaccharides into monosaccharides so that these are absorbed from the small intestine.
The digestion is also facilitated by pancreatic alpha amylase.
 α-Glucosidase Inhibitors
Acarbose, Miglitol, Voglibose
Work on the brush border of the intestine cause
carbohydrate malabsorption
Reduce post meal hyperglycemia
Regular use tend to lower HbA1c, triglycerides and body
weight
Do not directly affect insulin secretion
No hypoglycemia
Dose: 50-100mg TDS
 α-Glycosidase Inhibitors
 Pharmacokinetic
Absorption of acarbose is minimal, but miglitol is absorbed well
A part of acarbose is excreted unchanged while a part is metabolized by
intestinal bacterial flora
 Advantages:
Selective for postprandial hyperglycaemia
No hypoglycaemic symptoms
 Disadvantages:
Abdominal distension and flatus
Only effective in mild hyperglycaemia
Dose:
Acarbose - 25 mg to 50mg TID
Miglitol - 25mg to 100mg TID
Voglibose - 0.2 to 0.3 mg TID
 What are Incretins?
 Is a group of hormones (GLP & GIP) – released after meals and
augment glucose-dependent insulin secretion
 GLP-1 (glucagon-like peptide 1) (*More Important)
• is a prominent insulinotrophic incretin.
• half life- 1-2 min.
• metabolized quickly by DPPIV enzyme.
 GIP: Glucose-dependent insulinotrophic polypeptide
Small effect in Type 2 diabetes.

  prandial insulin secretion

E
  glucagon secretion
F
F   Acid secretion and GI motility ( gastric emptying
E   satiety and  food intake
C • ? β cell protection
T • ? Cardiovascular effects
 Incretin concept
Insulin secretion dynamics is dependent on the method of
administration of glucose
Intravenous glucose gives a marked first and second phase
response
Oral glucose gives less marked first and second phase
insulin response, but a prolonged and higher insulin
concentration
tmedweb.tulane.edu
 Incretin-mimetics
Incretin–mimetics
Glucagon Like Peptide – 1 (GLP-1) → released after meals from the
upper & lower bowel → augment glucose dependent insulin
secretion, during the phase of nutrition absorption from GIT
t ½ GLP-1 – 1 to 2 min
Metabolized quickly by DPP-IV enzyme

Exenatide [incretin (GLP-1) agonist]

Obtained from salivary gland venom of Gila monster
Resistant to DPP-IV degradation
Potent agonist of GLP-1 receptor, Orally inactive
Given SC (5-10μg) twice daily, 30-60 min before meals
It reduces only post meal glucose rise
 Incretin-mimetics

Mechanism of action
Stimulates insulin secretion from β- cells
Decreases glucagon release
Adverse Effects
Diarrhea, nausea, anorexia
 GLP-1 Modes of Action in Humans

Upon ingestion of food… • Stimulates glucose-dependent

insulin secretion

• Suppresses glucagon secretion

• Slows gastric emptying

GLP-1 is secreted • Reduces food intake

from the L-cells
in the intestine

Long term effects

demonstrated in animals…
This in turn…
• Increases beta-cell mass and
maintains beta-cell efficiency
 GLP-1
DPP IV
7

His Ala Glu Gly Thr Phe Thr Ser Asp

Val

Ser

Lys Ala Ala Gln Gly Glu Leu Tyr Ser

Glu

Phe

Ile Ala Trp Leu Val Lys Gly Arg Gly

37
NH2

Native GLP-1 has short duration of action

(t½=2.6 minutes) when given intravenously
Native GLP-1 is rapidly degraded by DPP-IV

Human ileum,
GLP-1 producing
L-cells

Capillaries,
DiPeptidyl
Peptidase-IV
(DPP-IV)

Adapted from: Hansen et al. Endocrinology 1999:140(11):5356-

 DPP IV
7 DPP-IV (DPP4)
His Ala Glu Gly Thr inhibitors
Phe Thr Ser Asp
Val

Ser

Lys Ala Ala Gln Gly Glu Leu Tyr Ser

Glu

Phe

Ile Ala Trp Leu Val Lys Gly Arg Gly

37
NH2
 DPP-IV Inhibitors
DPP-IV Inhibitors

Sitagliptin, Vildagliptin, Saxagliptin, Septagliptin, Allogliptin

Orally active
Selective inhibitors of DPP-IV enzyme that deactivates GLP-1

Mechanism of action
Increase insulin secretion
Decrease glucagon release
Delay gastric emptying
Suppress appetite

Adverse Effects
Nasopharyngitis because substance P is also a substrate for DPP-IV, whose levels get
elevated, GIT distress and diarrhea
 Mechanism of Action of Sitagliptin

Glucose
dependent
 Insulin  Glucose
Ingestion (GLP-1 and uptake by
of food Pancreas GIP) peripheral
Release of tissues
active incretins β cells
GLP-1 and GIP α cells  Blood glucose
in fasting and
GI tract postprandial
states
Glucose-
X
DPP-4
Sitagliptin enzyme dependent
(DPP-4  Glucagon  Hepatic
inhibitor) (GLP-1) glucose
Inactive Inactive production
GLP-1 GIP

Incretin hormones GLP-1 and GIP are released by the intestine throughout the day,
and their levels increase in response to a meal.

Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and
prolonging the actions of these hormones.
30
 Amylin - mimetics
Amylin
A hormone co-secreted with insulin from β- cells
Inhibit glucagon secretion
Delay gastric emptying
Suppress appetite

Pramlintide
Stimulates amylin receptor (a G-protein coupled receptor)
SC before meals
No hypoglycemia

Adverse Effect
Nausea, diarrhea, headache
Kidney as a site of target

SGLT - 2
 SGLT-2 Inhibitors
SGLT-2 Inhibitors
Newer antidiabetic drugs
Kidney continuously filters glucose through glomerulous which is reabsorbed back from PT
by Na2+ glucose co-transporter -2 (SGLT-2)
Inhibition of SGLT – 2 decreases glucose re-absorption
Dapaglifozin, Serglifozin, Remoglifozin
Advantages
Weight loss
No hypoglycemia
Disadvantages
Because of polyuria there will be more polydipsia
Increased risk of urinary infection in presence of glycosuria
Risk of Na2+loss
ADA, 2016
Thankyo
u