diabetes management... oral hypoglycemic agents

1. dr. Siham G. Altayib
MSc. Community Pharmacy
Queen’s University Belfast

2.  Achieve adequate glycaemic control.
 Avoid short term complications:-
hypoglcaemia
hyper glycaemia
DKA
 Prevent long term complications
 Improve quality of life

3.  The means of controlling blood glucose is
1 Life style modifications :-
 1- diet
 2- exercise
 3- weight loss
2 Drugs

4.  The medication available to treat type 2 diabetes
can be grouped according to their chemical class
and function :
 Medications that improve insulin action :
1- biguanides
2- thiazolidenedones
Medications that slow glucose absorption:
Alpha – glucosidase inhibitors

5.  Medication that increase insulin secretion :
1- sulphonylureas
2- meglitinide
3- D-phenaylalanine drevatives
Medication that restore or duplicate incretion action
on insulin secretion and glucagon suppression :
1- GLP-1 agonist
2- DPP-4 inhibitors

6.  Medication that provides additional insulin
exogenous pharmacological insulin
It is important to note that insulin is included in this
list not because oral medication faild to work or
when patient is not adherent BUT insulin is
typically used when
1- there is deceased endogenous insulin secretion
OR
2- to decrease glucose toxicity

7. There are many clinical markers that can reflect the
predominance of the various pathophysiologic
component that contributes to type2 diabetes SO
this can guide the selection of the treatment by the
doctor . These include :
1- body habits :
Apple-shaped body suggest insulin resistance
Overweight also suggest insulin resistance

8.  2- Age :
 Aging promotes insulin resistance ( therefore the
older the person the more likely he/she is to have
insulin resistabce
 3- weight change :
 Recent loss of weight , particularly concurrent
wirth poor diabetes control suggest insulin
deficiency
 BMI more than 27 suggest insulin resistance

9.  4 - duration of diabetes:
 The longer the patient has had diabetes , the more
like hood that there is insulin deficiency
 5- gender:
 Women with type 2 diabetes lose the protection
against macrovascular disease , so attention to
macrovascular risk factors is important

10.  6- co-existing disease:
 Presence of other component of the insulin
resistant syndrome suggest the presence of
insulin resistance (dyslipediemia , hypertension or
gout)
 7- side effect profile:
 Development of side effect from use of medication
might preclude its use e.g. metfornmin

11.  1-duration of diabetes
 2- age of the patient
 3- Patient's Life style consideration
 4- Degree of glycemic control( severity of
postprandial hyperglycemia)
 5- other illnesses
 6- Access to drug

12.  7- Economic status of the person with diabetes
 8- Mutual agreement between the patient &
doctor ( willingness and ability to use the drug or
inject insulin

13.  The ideal OHGA is that which ;
 1- conserve islets cell function . i.e . Delay the
subsequent use of insulin
 2- improve patient’s compliance ( single daily
dosing )
 3- reduce the incidence of oral hypoglycemic
events

14.  1- oral agents are never indicated for typ1
diabetes
 2- type 2 patients with acute illness
 3- surgery
 4- state of gastrointestinal disorders ( nausea ,
vomiting or diarrhea )

15.  Monotherapy should be the initial choice
 The step care approach is recommended because
of the progressive nature of diabetes

16.  1- combination of OHGAs with different mechanisms
can be indicated if MONOTHERAPY failed to control
BG.
NEVER use 2 drugs from the same class
 2- when oral therapy failed to achieve glycemic
control ISULIN should be added to the regimen OR
alternatively replace treatment with OHGAs.

17. 1 ] sulphonylureas:
Mechanism of action :
Stimulates basal as well as glucose - mediated
insulin secretion. Thus resulting in continuous
stimulation of the beta cells to release insulin
With progressive betacell failure sulphonyluras fails
to control BG So additional OHGA is added or
insulin may be required for glycemic contol

18. 1] pancreatic effect :
a) Increase insulin release from the pancreas by :
stimulating the release of insulin from functioning
beta cell by blocking ATP –sensitive K chanells
resulting in depolarization and calcium influx
which causes microtubular contraction and
release of insulin
b) Suppress the secretion of glucagon from alpha
cells

20.  2] Extra pancreatic effect:
 Potentiating of insulin action in target tissues :
1- increase the number of insulin receptors
2- increase post receptor insulin sensetivity
3- increase glycolysis
4- increase glycogenesis ( glycogen storage in liver
and muscles )
5- decrease the gluconeogensis ( glucose out put
from the liver

21. Measurement of C-peptide level gives indication of
residual ß-cell function
Early use of combination has been shown to reduce
glucose toxicity & preserve ß-cell mass
Pharmakokinetics :
1- SU. Are well absorbed orally .
2- peak plasma concentration within 2-4 hours
3- they circulate by binding to plasma protein and can be
potentially interact with other drugs such as sailcylates
and sulphonamides which binds to albumin

22. 4- elimination is through kidneys .so the half life can
be significantly prolonged in the elderly and those
with renal diseases
5- SU. Cross placenta & can stimulate foetal beta
cell to secret insulin
Clinical use of SU:
SU . Is indicated for type2 D. when diet alone is
insufficient to achieve glycemic control.
Treatment should be commenced at low doses and
titrated every 4-7 days as needed

23. SU. Can be used alone or in combination with other
OHGA or insulin .
Early use of combination has been shown to reduce
glucose toxicity & preserve ß-cell mass
A higher effect is observed with high fasting BG. And
with high A1c levels
There are 2 generations of SU.
The second generation agents are more potent ,
have more rapid onset of action & longer duration
of action

24. Drugs that incrase sulphonyl urease action :
1] by displacing from the protein binding :
Phenylbutazone , sulphonamides ( trimethoprime)
2} inhibit metabolism excretion :
Cimetidin (H2 blockers) , warfarin , chlorampheincol
3] synergize or prolong plasma
pharmacodynemic action :
Salicylate ( aspirin) , probranolol , theophelline

25. Drugs which reduce sulphonylureas action :
1] drugs which induce SU metabolism :
Phenobarbitones , chronic alcohiolism
2] drugs that oppose suppress action ( insulin
release ):
Corticosteroids, thiazide diuretics , furosemide . Oral
contraceptives

26. 1] hypoglycemia :
The most serious complication ( often result from
law coloric intake )
Risk of HG increase in :-
elderly &Those with hepatic or renal impairemnt so
long acting SU. Should be avoided in this group of
patients
- The highest incidence occures with chlorobromide
& glibencalmide ( donil)

27. 2] stimulate appitaite & weight gain
3] gasteric upset ( nausea , flatulance , diarrhoea
or constipation )
4] allergic skin reaction
5] headache
6] rarely bone marrow damage

28. 1) Pregnancy
2) Hepatic or renal insufficienty
3) Major surgary
4) Severe infection
5) Sesetivity to sulpha

29. First generation :
1- Chloropromide
2- tolbutamide
Second generation :
1- Gliclazide
2- glibenclamide ( donil)
3- glipizide
Third genteration :
Glimepride

30. 1] Glibinclamide ( donil)
2] Glimipride ( amary)
3]Gliclazide ( dimicrone)

34.  2] Non-sulphonylureas insulin secretogogues:
[Meglinitides ]
Meglinitides stimulating the release of insulin from
bancreas by binding to the SUR at a site different from
the sulphonylurea –binding site .
They inhibit ATP dependant potassium channels in the
beta cell membrane which depolarize the cell leading
to opening of calcium channels and insulin secretion .
In contrast to SU this release of insulin is glucose
dependant , it diminishes at low glucose concentration

35.  These agents stimulate first phase insulin release
in glucose dependent manner {reducing the risk of
hypoglycemia}
 Drugs in this group are :
 1- repaglinide
 2- Nateglinide
 Pharmakokinetics :
 Fast acting
 Short duration of action (2-6 hours) doses 2-4
dose per day

36.  Designed to minimize meal time blood glucose
peaks .( taken before the main meal) , as they
help control prandial glucose) so these agents is
suitable options for those who need flexible meal
timing and in the elderly
 Patients are advised to skip dose if meal is missed
 Metabolize in liver ( to inactive product ) and
excreted in bile

37.  Repaglinide :
 Form available in sudan is NovoNorm
 Strength 0.5-4.0 mg tablets staring dose 0.5-2
mg
 Given just before each major meal 15 kin.
 Rapid & short duration of action
 Improve postprandial glycemia
 Less likely to develop repeated hunger , frequent
eating and weight gain [unlike sulphonylureas]

38.  Side effects:
 1- hypoglycemia { rare}
 2- nausea and vomiting
 3- arthralgia ( joint pain)

40.  Very rapid onset of action
 Shorter duration of action
 1-10 minutes before meal
 Lower incidence of hypoglycemia than repaglinide

41.  These are drugs that improve the sensitivity to insulin
in muscle , liver & fat tissues
 Medication in this group share the following
characteristics :
 1- they require the presence of endogenous or
exogenous insulin to have their effects
 2- the patient must have insulin resistance
 3- hence they reduce insulin resistance rather than
insulin quantity so they have good effects in higher
glucose levels ..and not likely to cause significant
hypoglycemia as treatments that increase insulin levels

42.  1- biguanides
 2- thiazolidenediones
 1] Biguanides :
 These are class of antidiabetic drugs originate
from the french lilac (flower)
 The only one used now and is effective is
metformin

43.  Metformin :
Use alone or in combination with other drugs
Recommended as first-line drug in patient with
type2 diabetes ( guidelines)
Approved for prevention of type 2 diabetes in high
risk individuals
Used for polycystic ovary syndrome : insulin
resistance with ovarian hyperandrogenism

44. Mechanism of action :
1- decrease the intestinal absorption of CHO
2- decrease hepatic glucose production
3- increase insulin-mediated peripheral glucose
uptake
4- increase glucose utilization (glycogen synthesis
5- increase glycolysis through anaerobic pathway (
lactic acidosis)

45. 6- dcrease fasting plasma glucose conc. By about
60-7-mgdl
7- lower blood glucose but not cause hypoglycemia
NB: metformin is appropriate for obese patient with
type2 diabetes

46. pharmakokinetics :
1- well absorbed from small intestine
2- stable
3- doesnot bind to plasma protein
4- excreted unchanged in urine
5- can be taken in 3 doses with meal
6- maximum recommended daily dose is 3gday
( currently we don’t give more than 2gday in divided
doses with meal )

47. Secondery beneficial effects :
on libids :
1 small reduction in total cholestrol level
2- small reduction in triglycerides
3- reduction in LDL
4- increase in HDL

48. Side effects :
Occurs in 20-25% of patients
Gastrointestinal side effects:
1- abdominal discomfort , bloating , nausea ,
metallic taste
2- weight loss and diarrhea observed in 10-15% of
patient , depending on dose
3- decrease absorption of vit,B 12

49. adverse effects :
1- hypoglycemia : occurs only when combined with
other drugs
2- rarely : severe lactic acidosis particularly in
patients with CHF
Drug interaction:
Cimetidine , nifedipine , frusemide

50. Contraindications:
1- should be avoided in patients who predisposed to
lactic acidosis ( renal & hepatic disease , heart failure
..) impaired renal function serum cr. >1.4mgdl for
woman or 1.5 mgl male
2- past history of lactic acidosis
3- chronic lung disease
These conditions predespose to increase lactate
production which cause hepatic lactic acidosis which
is fetal.
4- all other situatios where OHGAs is contraindicated

51. Contraindications:
5- type1 diabetes
6- surgary
7- myocardial infraction
8- elderly
9- pregnancy

54.  Also known as :
1- PPRAs ( peroxisome prolifelator activated
receptors )
2- glitazones ( TZDs.)
Untilrecently there were 3 TZDs :
1- pioglitazone ( Actos)
2- posiglitazone ( Avandia)
3- troglitazone ( rezulin)

55. Mechanism of action :
Antihyperglycemic :
1- increase insulin sensetivity in liver and
muscle
2- do not increase insulin secretion
3- reduce hepatic glucose output
4-improve lipid profile
5- may induce weight gain

56. Rosiglitazone :
Bioavailability of oral dose 99%Extenseivelly 98.5% bound to
plasma protein
Metabolites have no significant activity
Plasma half life is 3-4 hours
Excreted in urine and stool
Use as single or divided to two doses per day

57. Pioglitazone:
Execreted primarily in the stool
Half life 3-7 h
Extensively 99% bound to plasma proteins
Can be given in single dose
No evidence of drug induced hepato toxicity

58. Side effects :
1- weight gain because of insulin like effects
2- fluid retention ( lower limb oedema )
3- liver enzyme elivation ( the firstTZDs troglitazone was
withdrawn from market because of hepatotoxicity )
4- most common sside effects :
Headache , CHF , fatigue , slight decrease in
heamoglobin , hepatic cellular injury ( rare )

59. Contraindications
1- cardiac failure
2- impaired hepatic function
3- pregnancy and lactation
Drug interaction :
Not recommended to be used with oral contraceptives )

61. Alpha glucosidase inhibitors AGIs) :
Acts in the proximal small intestine
They reduce the rate of digestion of polysaccarides
. They reduce intestinal absorption of starch ,
dextrin , and disaccharides by inhibiting action of
alpha glucosidase enzyme , thereby primarily
lowering postprandial glucose levels .
AGIs , donot prevent absorption of complex
carbohydrates but delay it

62. There are 2 drugs :
1- acarbose
2- miglitol
Side effects :
Gastric upset ( flatulanse , loose stool or diarrhae ,
abdominal pain
tolerability can be improved by slowly titrating the dose
over several days
Drug interaction:
Decrease metformin bioavailability when used
concomitantly

66.  Are naturally occurring hormones secreted by the
intestine in response to meal when BG is elevated
 Increased incretin levels signals :
 1- incrase insulin secretion
 2- stop hepatic glucose production
 The levels of incretins increases significantly when
food is ingested

67.  Endogenous hormones are :
 1- GLP-1 ( glucagon like peptide 1)
 2-,GIP ( glucose dependant insulinotropic peptide
)
 1 GIP :
 42 amino acid peptide
 Secreted from dudenum & proximal jejenum )
 2] GLP_1:
 30 amino acid peptide
 Secreted from the distal GI tract ( ielum & colon)

68.  Action :
 Increase insulin production from beta cells
 Decreas glucagon secretion )
 The physiological activity of incretin is limited by
the enzyme dipeptidyle peptidase-4 (DPP-4)
.which rapidly degrades active incretin after its
release
 Consequently both GLP-1 & GIP are rapidly
inactivated by the enzyme dipeptidyle peptidase-4
(DPP-4)

70.  Mechanism of Action :
 Slow the inactivation of incretin hormones ( GLP-1
& GIP)
 Increased glucose stimulated insulin secretion
 Cause glucose stimulated glucagon suppression
 Primarily reduce postprandial glucose levels but
also has been shown to reduce fasting BG levels

77.  Inhibit the reabsorption of glucose by kidneys
so glucose levels in urine will be increased {
this is an insulin independent mechanism to
lower blood glucose levels
 Advantages :
 Improve glycemic control
 Weight lloss
 Carry low risk of hypoglycemia

78.  Examples :
 Dapagliflozin
 Canagliflozin

81. Thank
you