A PowerPoint presentation on "Oral hypoglycaemic drugs" suitable for undergraduate

1. Oral Hypoglycaemic
Drugs (OHA)
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong - 793018

2. Introduction
D
rugs which lower blood glucose level and are effective orally
U
sed in the treatment of Type 2 (NIDDM) diabetes mellitus not
controlled by diet and modification of lifestyle alone
T
ype 2 diabetes: Constitutional factors and genetic factors –
Decreased insulin secretion and Insulin Resistance (pre & post)
I
nsulin resistance is suboptimal response of body tissue – liver
skeletal muscle & fat to physiological amount of insulin
T
hey enhance the insulin secretion or overcome Insulin resistance

3. Classification
A.E
nhance Insulin secretion
 Sulfonylureas (KATP Channel Blockers): Tolbutamide, Glibenclamide, Glipizide,
Gliclazide, Glimepiride
 Meglitinide/phenyalanine analogues: Repaglinide, Nateglinide
 Glucagon-like peptide –1 receptor agonists: Exenatide, Liraglutide
 Dipeptidyl peptidase – 4 (DPP-4) inhibitors: Sitagliptin, Vidagliptin ,
Saxagliptin , Linagliptin
B
. Overcome Insulin resistance
 Biguanides (AMPK activator): Metformin
 Thiazolinediones (PPARȣ activator): Pioglitazone
C
. Miscellaneous antidiabetic drugs:
 α-Glucosidase inhibitors: Acarbose, Miglitol, Voglibose
 SGLT-2 inhibitor – Dapagliflozin; Amylin analogue – Pramlintide; and Bromocriptine

4. Sulfonylureas (SUs)
• All have similar pharmacological profile - lowers blood glucose in normal person
and Type 2 diabetics
• Only 2nd
generation drugs are used now – except Tolbutamide
• Mechanismof action: In the β cells - block the SU receptor (SUR 1) of pancreas (a
subunit of inwardly rectifying ATP-sensitive K+
channel (KATP )
– Insulin released at any glucose concentration (even at low conc.) – severe and
unpredictable hyperglycaemia risk
– Mainly the 2nd
phase of insulin release
– Presence of β cells is must for their action (no action on pancreatectomized subjects) -
action on Type 1 diabetics (?) – 1/3rd
β cells required for action
– Extrapancreatic action: Action wears off after a few months – down regulation of SUR1
receptors – but improvement in glucose tolerance maintained
– Sensitize target tissues (liver) to insulin action – due to increase in insulin receptors
– Also inhibits gluconeogenesis

5. Sulfonylureas - MOA
Source: Essentials of Medical pharmacology by KD Tripathi – 7th
Edition, JAYPEE, 2013

6. Sulfonylureas (SUs) – contd.
•Pharmacokinetics: Well absorbed orally, highly (90%) bound to plasma
proteins – low Vd
–Metabolized in liver to active / inactive – liver and kidney dysfunction
•Drug Interactions:
–Precipitate hypoglycemia:
–Displace from protein binding: Salicylates, sulfonamides
–Inhibits metabolism: acute alcohol intake, Ketoconzole, Warfarin, Sulfonamides,
Chloramphenicol
–Prolongs action (synergism): Salicylates, Propranolol
–Decrease SU action: Phenobarbitone, Rifampicin, alcoholism
•Adverse effects:
–Hypoglycaemia: Commonest (elderly, liver and kidney diseases)
–Nausea, vomiting, flatulence, diarrhoea – Weight gain
–Hypersensitivity: Rash, photosensitivity, purpura, flushing and disulfiram-like reaction

7. Meglitinide/phenyalanine analogues
•KATP Channel Blockers – Repaglinide and Nateglinide
•Repaglinide: Binds to SUR – closing of channel – depolarization – Insulin
release
–Rapidly metabolized, fast onset and short lasting action
–Administered just before meals - control of postprandial hyperglycaemia
–Lower risk of serious hypoglycaemia
–Uses: Type 2 DM with severe postprandial hyperglycaemia as supplementary to
metformin; Avoided in Liver diseases
•Nateglinide: D-phenylalanine derivative - ` stimulates 1st
phase of insulin
secretion – closure of β cell KATP Channel
–Shorter lasting and faster onset – less risk of hypoglycaemia than Repaglinide
–Less frequent hypoglycaemia – Used in Type 2 DM with others
–ADRs: Nausea, Flu like symptoms and joint pain … weight gain

8. Glucagon-like peptide –1 receptor agonists –
injection preparations
•GLP– 1 is an Incretin – induces insulin release and inhibits glucagon release
–slows gastric emptying, suppresses appetite via GLP – receptors (GPCR) – in α and β cells,
GIT mucosa, central neurons
–Incretins promote β cells health – its dysfunction in Type 2 DM
–GLP-1 not used clinically – rapid degradation by Dipeptidyl peptidase – (DPP-4) enzyme – in
luminal membrane of capillary endothelial cells, kidney, liver, gut mucosa ; Also glucose-
dependent Insulinotropic peptide (GIP) - insulin release
• Exenatide: Synthetic DDP-4 resistant analogue of GLP-1 – similar action with GLP-1
–Ineffective orally – given SC, half life 3 hours (6-10 hours duration) – used in Type 2 DM
along with others (Metformin); ADRs: Nausea and vomiting
–Benefits: Lowers body weight, postprandial and fasting glucose and HbA1c
•Liraglutide: Similar to Exenatide - ineffective orally – given SC
–longer duration of action ( >24 hours) – only once daily dosing; Benefit – weight loss

9. Dipeptidyl peptidase – 4 (DPP-4) inhibitors
•S
itagliptin, Vidagliptin, Saxagliptin
•M
OA: Prevents rapid degradation of GLP-1 by DPP-4 – orally effective adjunctive drugs
– indirectly acting insulin secretagogue
•S
iptagliptin: Competitive and selective DPP-4 inhibitor
•A
ctions: Potentiates action of GLP-1 and increases insulin secretion and inhibits
glucagon, improves β cell health, body weight neutral, well tolerated
– No effects of gastric emptying and appetite and no hypoglycaemia
– Lowers HbA1c (equivalent to metformin)
– Uses: as adjunctive drug with others. Monotherapy only if not controlled by
Metformin/SU/Pioglitazone
– Kinetics: Orally absorbed, metabolized little, excreted unchanged in urine (renal impairment!) –
half life – 12 hours
– ADRs: Nausea, loose stool, headache rash – cough & nasopharyngitis (Substance P)

10. DPP-4 inhibitors – Vidagliptin
•B
inds to DPP-4 covalently – complex dissociates slowly
•K
inetics: Short plasma half-life 2 – 3 hours, but duration of action
12 – 24 hours; Metabolized in liver – only 20 – 25% unchanged
form
•D
ose reduction in liver and kidney diseases
•D
rawback: Less selective DPP-4 than Sitagliptin and
hepatotoxicity

11. Biguanides (AMPK activator): Metformin and
Phenformin
•M
etformin: Different action (counters insulin resistance) - no hypoglycaemia in normal,
even in diabetics less episodes– no β cell stimulation
•M
OA: AMP dependent protein kinase (AMPK) activation …. (1) Suppresses hepatic
neoglucogenesis and glucose output from liver (2) Overcome insulin resistance in
Type 2: enhance insulin-mediated glucose uptake and disposal in Muscles and Fats –
more glycogen storage enhanced fatty acid oxidation (3) Promotes peripheral glucose
utilization through anaerobic glycolysis – mitochondrial action (4) Retards absorption
of glucose and others
•K
inetics: half-life 1 – 3 hours and 6- 8 hours duration of action
•A
DRs: Frequent but less severe – Abdominal pain, anorexia, nausea, metallic taste,
tiredness – but no hypoglycaemia; Lactic acidosis and Vit B12 deficiency
•U
ses: First choice drug in all Type 2, if tolerated

12. Thiazolinediones (PPARȣ activator):
Pioglitazone (?Rosiglitazone)
•M
OA: Selective agonist of nuclear pe ro xiso m e pro life rato r-activate d re ce pto r γ (PPAR γ) –
mainly in fat cells and also muscles – enhances transcription of insulin responsive genes
•A
ctions: (1) Enhances GLUT4 expression and translocation (2) Suppression of hepatic
neoglucogenesis (3) Activation of genes regulating fatty acid metabolism and lipogenesis
in adipose tissue – insulin sensitizing action (4) Reduction of lipolysis and plasma fatty acid
level (5) accelerated adipocyte turn over and differentiation
– Lesser spectrum than SU in blood glucose lowering
– Additionally – lowers triglyceride level and raises HDL
•K
inetics: Metabolized in Liver – half-life 3-5 hours but duration of action 24 hours; failure of
OCPs (Rifampicin and Ketoconazole ?)
•A
DRs: Plasma volume expansion, oedema, weight gain, headache, myalgia, and anaemia –
no hypoglycaemia; hepatic dysfunction and fracture
•U

13. α Glucosidase inhibitors - Acarbose, Miglitol,
Voglibose
•M
OA: (1) inhibits α-glucosidase enzyme – brush border of small
intestine - decreases absorption of poolysaccharides (starch
etc.) and sucrose (2) Release GLP-1
•R
educes postprandial glycaemia – no significant increase in insulin
level
•R
educes HbA1c level - but no effect on weight and lipid levels
•A
DRs: Flatulence, abdominal discomfort, loose stool – unabsorbed
carbohydrate, poor patient compliance
•U

14. Summary of OHA
Source: Essentials of Medical pharmacology by KD Tripathi – 7th
Edition, JAYPEE, 2013

15. Current status of OHA
•C
ontroversy – Insulin/SU/Biguanides/Diet & Exercise
•I
nsulin and SU Vs Metformin
•I
ndications of OHA (along with diet and exercise) in Type 2 DM
– (1) Age > 40 years at onset of disease (2) Obesity (3) Duration of disease < 5 years (4) FBS <
200 mg/dl (6) Insulin requirement < 40 U/day (6) No ketoacidosis or history
•S
tart with Metformin, diet and exercise – delay progression by restoring β cells, Obese –
weight reduction, reduce risk of MI and Stroke
•I
f monotherapy not adequate - add SU as 2nd
drug – good patient compliance, high
efficacy; but – prolong use β cell apoptosis and failure, weight gain, hypoglycaema,
receptor desensitization
•P
atient with post-prandial hyperglycaemia and post meal hypoglycaemia –
Meglitinide/phenylalanine analogue
•P
ioglitazone – 3rd
choice – added to Metformin or with Metformin + SU combination

16. To remember
D
IET CONTROL
S
ULFONYLUREAS
M
ETFORMIN
P
IOGLITAZONE

17. Thank you