oral hypoglycemic agents
TRANSCRIPT
Oral Hypoglycemic Agents
dr. Siham G. AltayibMSc. Community Pharmacy
Queen’s University Belfast
Achieve adequate glycaemic control. Avoid short term complications:- hypoglcaemia hyper glycaemia DKA Prevent long term complications Improve quality of life
Goals of diabetes management
The means of controlling blood glucose is 1\ Life style modifications :- 1- diet 2- exercise 3- weight loss2\ Drugs
Con.
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
Options of the therapy
Medication that increase insulin secretion :1- sulphonylureas 2- meglitinide3- D-phenaylalanine drevatives
Medication that restore or duplicate incretion action on insulin secretion and glucagon suppression :
1- GLP-1 agonist2- DPP-4 inhibitors
con
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
con
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 resistanceOverweight also suggest insulin resistance
Medication selection for treatment of type2 diabetes
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
con
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
Con.
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
Con.
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
The choice of oral therapy should be based on :
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
The choice of oral therapy should be based on :
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
What is the ideal oral hypoglycemic agent?
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 )
Contraindications f OHGAs.
Monotherapy should be the initial choice
The step care approach is recommended because of the progressive nature of diabetes
Important points
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.
Important points con. :
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
1\ drugs that stimulates insulin relase from pancreas ( secretogogus):
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
Con. Mechanism of action SU.
2] Extra pancreatic effect: Potentiating of insulin action in target tissues :1- increase the number of insulin receptors2- increase post receptor insulin sensetivity 3- increase glycolysis4- increase glycogenesis ( glycogen storage in liver
and muscles )5- decrease the gluconeogensis ( glucose out put
from the liver
Con. Mechanism of action SU.
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 hours3- they circulate by binding to plasma protein and can be
potentially interact with other drugs such as sailcylates and sulphonamides which binds to albumin
Con. sulphonylureas
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
Con. sulphonylureas
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
Con. sulphonylureas
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
Sulphonylureas drug interactions
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
Sulphonylureas drug interactions
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)
Sulphonylureas \ adverse effects
2] stimulate appitaite & weight gain 3] gasteric upset ( nausea , flatulance , diarrhoea
or constipation )4] allergic skin reaction 5] headache 6] rarely bone marrow damage
Sulphonylureas \ adverse effects
1) Pregnancy2) Hepatic or renal insufficienty 3) Major surgary 4) Severe infection 5) Sesetivity to sulpha
Sulphonylureas \ contraindication
First generation :1- Chloropromide 2- tolbutamide
Second generation :1- Gliclazide 2- glibenclamide ( donil)3- glipizide
Third genteration :Glimepride
Con. sulphonylureas
1] Glibinclamide ( donil)
2] Glimipride ( amary)
3]Gliclazide ( dimicrone)
Sulphonylureas \ commonly used
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
1\ drugs that stimulates insulin relase from pancreas ( secretogogus):
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
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
Con .
Con. 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]
Side effects: 1- hypoglycemia { rare} 2- nausea and vomiting 3- arthralgia ( joint pain)
Con.
Very rapid onset of action Shorter duration of action 1-10 minutes before meal Lower incidence of hypoglycemia than repaglinide
Nateglinide
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
2\ insulin sensitizers :
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
Con.
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
Con.
Mechanism of action :
1- decrease the intestinal absorption of CHO2- decrease hepatic glucose production 3- increase insulin-mediated peripheral glucose
uptake4- increase glucose utilization (glycogen synthesis5- increase glycolysis through anaerobic pathway
( lactic acidosis)
Con. Metformin
6- dcrease fasting plasma glucose conc. By about 60-7-mg\dl
7- lower blood glucose but not cause hypoglycemia
NB: metformin is appropriate for obese patient with type2 diabetes
Con. Mechanism of action :
pharmakokinetics :1- well absorbed from small intestine2- stable 3- doesnot bind to plasma protein 4- excreted unchanged in urine 5- can be taken in 3 doses with meal6- maximum recommended daily dose is 3g\day ( currently we don’t give more than 2g\day in divided
doses with meal )
Con. Metformin
Secondery beneficial effects : on libids :1\ small reduction in total cholestrol level2- small reduction in triglycerides 3- reduction in LDL4- increase in HDL
Con. Metformin
Side effects :Occurs in 20-25% of patientsGastrointestinal 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
Con. Metformin
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
Con. Metformin
Contraindications:1- should be avoided in patients who predisposed to
lactic acidosis ( renal & hepatic disease , heart failure ..) impaired renal function serum cr. >1.4mg\dl for woman or 1.5 mg\l male
2- past history of lactic acidosis 3- chronic lung diseaseThese conditions predespose to increase lactate
production which cause hepatic lactic acidosis which is fetal.
4- all other situatios where OHGAs is contraindicated
Con. Metformin
Contraindications:5- type1 diabetes 6- surgary 7- myocardial infraction 8- elderly 9- pregnancy
Con. Metformin
Metformin in market
Metformin in market \combination
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)
2] Thiazlidenediones
Mechanism of action :Antihyperglycemic : 1- increase insulin sensetivity in liver and
muscle 2- do not increase insulin secretion3- reduce hepatic glucose output4-improve lipid profile 5- may induce weight gain
Con. Thiazlidenediones
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
Con. Thiazlidenediones
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
Con. Thiazlidenediones
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 )
Con. Thiazlidenediones
Contraindications 1- cardiac failure 2- impaired hepatic function 3- pregnancy and lactation
Drug interaction :Not recommended to be used with oral contraceptives )
Con. Thiazlidenediones
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
3] drugs that delay glucose absoption
There are 2 drugs :1- acarbose 2- miglitol Side effects :Gastric upset ( flatulanse , loose stool or diarrhae ,
abdominal paintolerability can be improved by slowly titrating the dose over
several days Drug interaction:Decrease metformin bioavailability when used concomitantly
Con. Alpha glucosidase inhibitors AGIs) :
Con. Alpha glucosidase inhibitors AGIs) :
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
4] incretins & DPP-4 inhibitors
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)
Con. Incretins & DPP-4 inhibitors
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)
Con. Incretins & DPP-4 inhibitors
DPP-4 inhibitors
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
DPP-4 inhibitors
SGLT-2 inhibitors
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
SGLT-2 inhibitors
Examples : Dapagliflozin Canagliflozin
SGLT-2 inhibitors
Life style :
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