ANTI DIABETIK A ANTI DIABETIK A ORALORAL

dr. Theodorus, MMedScdr. Theodorus, MMedScStaf Bagian FarmakologiStaf Bagian Farmakologi

FK UnsriFK Unsri

Stimulate insulin secretionStimulate insulin secretion

Cause hypoglycaemia Cause hypoglycaemia stimulate stimulate appetite and leads to weight gainappetite and leads to weight gain

Only effective if Only effective if ββ-cells are functional-cells are functional

Block ATP-sensitive K + channels in Block ATP-sensitive K + channels in ββ--cellscells

Glucose

Insulin

SecretionCa i

ATP

KATP

Channel

+ --

-

+ +Ca

Channel

Metabolism VoltageBinding

Sulfonylurea

Passive fluxCa trigger

Resting celllStimulated cell

Sulfonylurea

or

↑ ATP

Depolarization

VDCCKATP

K+

VDCC

Ca2+

KATP

Mechanism of Insulin Secretion

3 Pancreas : Insulin secretion Sulfonylureas ↑ Insulin secretion

SULFONILUREASULFONILUREA

1.1. Generasi I :Generasi I :

CarbutamideCarbutamide

TolbutamideTolbutamide

ChlorpropamideChlorpropamide

1.1. Generasi II :Generasi II :

GlyburideGlyburide

GlipizideGlipizide

1.1. Generasi III :Generasi III :

Glimepiride Glimepiride

Mechanism of action Mechanism of action ≈ Thiazolidinediones≈ Thiazolidinediones

SULFONILUREASULFONILUREA

SIDE EFFECTSSIDE EFFECTSHypoglicemic reactions including comaHypoglicemic reactions including coma

Particularly, elderly patients with impaired hepatic or renal functionParticularly, elderly patients with impaired hepatic or renal function

Glyburide=chlorpropamide > glipizide > tolbutamideGlyburide=chlorpropamide > glipizide > tolbutamide

Nausea and VomitingNausea and Vomiting

Aplastic and hemolytic anemiaAplastic and hemolytic anemia

Hypersensitivity and dermatological reactionsHypersensitivity and dermatological reactions

SULFONIL UREASULFONIL UREA

CONTRAINDICATIONSCONTRAINDICATIONSHypersensitivityHypersensitivity

Diabetic keto acidosisDiabetic keto acidosis

DRUG INTERACTIONDRUG INTERACTIONClofibrate, dicumarol, salysilates displace the sulfonyl Clofibrate, dicumarol, salysilates displace the sulfonyl ureas from binding siteureas from binding site

SECRETAGOGUE LAIN SECRETAGOGUE LAIN

MEGLITINIDES :MEGLITINIDES :

1.1. RepaglinideRepaglinide

2.2. MeglitinideMeglitinide

3.3. NateglinideNateglinide

BIGUANIDEBIGUANIDE (METFORMIN) (METFORMIN)

Increase glucose uptake in striated muscleIncrease glucose uptake in striated muscle

Inhibit hepatic glucose output & intestinal Inhibit hepatic glucose output & intestinal glucose absorbtionglucose absorbtion

Cause anorexia Cause anorexia assist in weight loss assist in weight loss

Are used with sulphonylurea when these have Are used with sulphonylurea when these have ceased to work adequatelyceased to work adequately

Reduction of total cholesterol, LDL cholesterol Reduction of total cholesterol, LDL cholesterol & trigliceride& trigliceride

Increase HDL cholesterol concentrationIncrease HDL cholesterol concentration

2. Muscle and adipose tissue : Glucose uptake Metformin ↑ glucose utilization

4. Liver : Hepatic Glucose Output Metformin ↓ HGO

METFORMINMETFORMIN

DRUG INTERACTIONDRUG INTERACTIONCimetidine and furosemide increased yhe metformin Cimetidine and furosemide increased yhe metformin plasmaplasma

Alcohol potentiate the effect of metforminAlcohol potentiate the effect of metformin

1. Intestine : glucose absorption

Acarbose ↓ glucose absorbtion secondary

to ↓ digestion of carbohydrate

2. Muscle and adipose

Tissue : glucose uptake

ACARBOSEACARBOSE

SIDE EFFECTS: usually during the first SIDE EFFECTS: usually during the first week of therapy; most commonly mild-to-week of therapy; most commonly mild-to-moderate GI tracts such as flatulantce, moderate GI tracts such as flatulantce, diarrhea, and abdominal discomportdiarrhea, and abdominal discomport

CONTRAINDICATION:CONTRAINDICATION:

- Hypersensitifity- Hypersensitifity

- Diabetic ketoacidosis- Diabetic ketoacidosis

- Cirrhosis- Cirrhosis

THIAZOLIDINEDIONESTHIAZOLIDINEDIONES

Antidiabetic agents that increase insuline Antidiabetic agents that increase insuline sensitivity through the modulation of several sensitivity through the modulation of several processesprocessesThese agents affect:These agents affect:

- insulin receptor kinase activity- insulin receptor kinase activity - insulin receptor phosphorylation- insulin receptor phosphorylation - insulin receptor numbers- insulin receptor numbers - hepatic glucose metabolism- hepatic glucose metabolism

May activate PPAR-May activate PPAR-γγ (Peroxisome Proliferator – (Peroxisome Proliferator – Activated Receptor) in adipose tissue, skeletal Activated Receptor) in adipose tissue, skeletal muscle and livermuscle and liver

Liver : Hepatic Glucose OutputThiazolidinediones ↓ HGO

Improve β –

cell function

Promoter Coding Region

Nucleus

Gene transcription

PPAR PPAR ΥΥ RXR

Response elements

mRNA

Thiazolidinedione

Proteins involve in glucose lipid metabolism

Thiazolidinediones activate nuclear receptors, resulting in expression of proteins involved inglucose and lipid metabolism

TZDTZD

CONTRAINDICATIONCONTRAINDICATION - Hypersensitivity- Hypersensitivity - Liver disease- Liver disease - Pregnancy category C- Pregnancy category C - Nursing woman- Nursing woman

DRUG INTERACTIONDRUG INTERACTION - May induce drug metabolism by CYP3A4: - May induce drug metabolism by CYP3A4:

Consider this when prescribing with others Consider this when prescribing with others CYP3A4 substrate such as CCB, cisapride, CYP3A4 substrate such as CCB, cisapride, steroid and HMG-CoA reductase inhibitorssteroid and HMG-CoA reductase inhibitors

GLIPTINEGLIPTINE

DPP-4 inhibitors (Dipeptidyl peptidase-4)DPP-4 inhibitors (Dipeptidyl peptidase-4)

Linagliptin, sitagliptin, and saxagliptin Linagliptin, sitagliptin, and saxagliptin

Mechanism of action: enhance and prolong Mechanism of action: enhance and prolong the action of incretin hormones by the action of incretin hormones by competitively antagonizing the enzyme competitively antagonizing the enzyme DPP-4 DPP-4

gliptingliptin

PharmakokineticsPharmakokineticsRapidly absorbed after oral administration, Rapidly absorbed after oral administration, with peak plasma concentration occuring with peak plasma concentration occuring in 1- 4 hoursin 1- 4 hoursBioavaibility is more than 87%Bioavaibility is more than 87%79% is excreted unchanged in the urine, 79% is excreted unchanged in the urine, primarily via renal excretionprimarily via renal excretionOnly slightly is metabolized by using Only slightly is metabolized by using CYP3A4 and CYP2C6 in liverCYP3A4 and CYP2C6 in liver

gliptingliptin

CONTRINDICATIONCONTRINDICATION DM type 1DM type 1 HipersensitivityHipersensitivity PregnancyPregnancy

SIDE EFFECTSSIDE EFFECTSUpper respiratory tract infectionUpper respiratory tract infectionHeadache, nauseaHeadache, nauseaHypersensitivity reactionHypersensitivity reaction

gliptingliptin

DRUG INTERACTION:DRUG INTERACTION:

Alpha adrenergic agonist, isoniazid, Alpha adrenergic agonist, isoniazid, antipsychotic first generation reduced it’s antipsychotic first generation reduced it’s effecteffect

Etanol and quinolone enhanced it’s effect Etanol and quinolone enhanced it’s effect