PHARMACOTHERAPY

of
DIABETES MELLITUS

dr. Ave Olivia Rahman, MSc.

Bagian Farmakologi FKIK UNJA
 DIABETES MELLITUS (DM)

TYPE 1 TYPE 2

 Insulin-dependent  Non-insulin-dependent
Diabetes Mellitus diabetes
 Destruction of insulin-  Relative insulin deficiency,
producing B cells in the Insulin resistance.
pancreas.
 GOAL OF THERAPY

BLOOD SUGAR CONTROL AT NORMAL OR

NEAR-NORMAL VALUE  DIET, EXERCISE,
DRUG

TREAT ASSOCIAETED CONDITIONS &

COMPLICATION RISK CONTROL
PHARMACOTHERAPY OF
DM TYPE 1

INSULIN
REPLACEMENT
 INSULIN ACTION
In healthy subjects, the amount of insulin is “automatically”
matched to blood glucose concentration.
 Continue...Insulin Action
• STIMULATES glucose storage in the liver as glycogen and
in adipose tissue as triglycerides and amino acid storage
in muscle as protein
• INHIBITS gluconeogenesis.
• inhibits lipolysis, stimulates fatty acid synthesis,
decreases the hepatic concentration of carnitine.
• Enhances the transcription of lipoprotein lipase in the
capillary endothelium. This enzyme hydrolyzes
triglycerides present in VLDL and chylomicrons
Insulin Replacement

 Subcutaneous
administration
 Absorption is usually
most rapid from the
abdominal wall,
followed by the arm,
buttock, and thigh
 Different type of insulin
according to their
duration of action
 History of Insulin Development

• 1930s : the first long-acting preparation,

protamine zinc insulin.
• 1950s : neutral protamine Hagedorn (NPH)
and insulin zinc (Lente) were introduce.
• 1980s, : the development of purified pork
insulin and then recombinant human insulin.
• 1990s : insulin analogues introduce.
Continue...
 Type of Insulin...based on it’s acting

Type Onset Peak Duration

Ultra rapid- acting 15-30 minutes 30 minute-2
hours
Short- 30 minutes-1 2-4 hours 6-8 hours
acting/Regular hours
Intermediate- 2-4 hours 1-8 hours 14-15 hours
acting
Long-acting 1-3 hours Witout peak 24 hours
 Continue...
Ultra rapid- • lispro (humalog), Aspart
acting (novorapid), Glulisine (apidra)

Short-acting • Regular, Humulin R, actrapid

Intermediate- • NPH, Humulin N

acting • Insulatard, lente

• Glargine (lantus), detemir,

Long-acting ultralente, protamine zinc
Type of Insulin..based on composition

Single
composition
Human
70,30 humulin/mixtard
(70% NPH, 30% reguler)
- 50,50 humulin

Premixed
Analogue insulin
-75/25 humalog
-50,50 humalog
- 70,30 novomix
- 50,50 novomix
 Factors Affecting Insulin Absorption

• Site of injection
• Type of insulin
• Subcutaneous blood flow
• Smoking
• Regional muscular activity at the side of
injection
• Volume& concentration of injected insulin
• Depth of injection.
 Indication of Insulin Therapy
• DM type 1
• DM type 2 uncontrolled with diet, excersice, oral
antidiabetic drugs
• Gestational DM
• DM with severe kidney and liver disease
• DM with infection, major operation, malnutrition,
tumor, corticosteroid therapy, grave’s disease
• DM Ketoacidosis
 Insulin Dosing
• Insulin replacement therapy includes long
acting insulin (basal) and short acting insulin
to provide postprandial needs.
• Average dose of insulin : 0,2-1 U/kgBB/day
Pathophysiological Alterations Leading to Hyperglycemia in
Type 2 Diabetes and Specific Types of Treatment.
 ORAL HYPOGLICEMIC AGENTS
• BIGUANIDE
• INSULIN SECRETAGOGUES:
– SULFONYLUREAS
– NON SULFONYLUREAS (MEGLITINIDE): REPAGLINIDE,
NATEGLINIDE
• THIAZOLIDINEDIONES
• GLP-1 AGONIST : EXENATIDE
• DIPEPTIDYL PEPTIDASE 4 INHIBITORS : SAXAGLIPTIN,
SITAGLIPTIN, VIDAGLIPTIN
• ALPHA GLUCOSIDASE INHIBITORS
• PRAMLINTIDE
 BIGUANIDES
• Metformin. 1st line therapy in DM type 2.
• Metformin is antihyperglycemic  by decreasing
hepatic glucose production (gluconeogenesis)
and by increasing insulin action in muscle and fat.
• Does not bind to plasma proteins. Half life : about
2 hours.
• Only Metformin has been demonstrated to
reduce macrovascular events in type 2 DM (U.K.
Prospective Diabetes Study Group, 1998b).
 Continue...Metformin
• CONTRAINDICATION : renal impairement,
hepatic disease, history of lactic acidosis,
cardiac failure, cronic hypoxic lung disease.
• SIDE EFFECTS: lactic acidosis, diarrhea,
abdominal discomfort, nausea, metallic taste,
anorexia.
• Metformin can be administered in
combination with sulfonylureas,
thiazolizinediones, and/or insulin.
• Available Fixed-dose combinations.
 Dosing of Metformin
 Available generic Tablet 500 mg, forte 850
mg.
 Dose : 2-3 x 500 mg daily with meals, max 2,5
g/daily.
 SULFONYLUREAS

• TOLBUTAMIDE,
GROUP ACETOHEXAMIDE,
TOLAZAMIDE,
1 CHLORPROPAMIDE

• GLIBURYDE
GROUP (GLIBENCLAMID),
GLIPIZIDE, GLICLAZIDE,
2 GLIMEPIRIDE
SULFONYLUREAS : Stimulating insulin release from
pancreatic β cells
SULFONYLUREAS
 PHARMACOKINETICS
• Effectively absorbed from the gastrointestinal
tract.
• Variaty half-lives among agents
• More effective when given 30 minutes before
eating.
• 90% - 99% bound to protein (especially
albumin)
• Metabolism in hepar, excreted in urine.
INCREASED INSULIN SECRETION
 SIDE EFFECT : mild- severa hipoglycemia, (glibenclamide
cause up to 20-30%), nausea, vomiting, cholestatic
jaundice, agranulocytosis, aplastic and hemolytic
anemias, hypersensitivity reactions, hyponatremia.

DRUG INTERACTION : other sulfonamides, clofibrate, and

salicylates, ethanol.

CONTRAINDICATIONS : type 1 DM, pregnancy,

lactation, significant hepatic or renal insufficiency for the
older preparations
 Dosing of Sulfonylureas
Glibenclamide :
 Available in generic tablet 5 mg.
 Initial Dose ; 1x ½-1 tablet ,can be increased < 2,5 mg during 1 week
until reached controled DM or max dose 20 mg has been given.

Glimepiride:
 Available in generic tablet 1,2,3 mg
 Initial Dose : 1x 1 mg , can be increased during 1 week based on
glucose monitoring, max dose 8 mg/day

Gliquidone:
 Available in generic tablet 30 mg
 Initial Dose : 1x 1 5mg , can be increased until 45-50 mg/daily
divided dose 2-3 times. Max dose 120 mg/day.
 Repaglinide

• Stimulates insulin release by closing ATP-

dependent potassium channels in pancreatic β
cells.
• Absorbed rapidly from the gastrointestinal
tract, peak blood levels : within 1 hour, half-
life : about 1 hour, metabolism in hepar and
renal.
• Side effects : hypoglicemicemia.
 Dosing of Repaglinide

 NOVONORM : Repaglinide 0,5 mg, 1, 2 mg

 Initial dose 0,5 mg every timt before meals. Max dose
16 mg/day
 Nateglinide
• Stimulates insulin secretion by blocking ATP-
sensitive potassium channels in pancreatic β
cells.
• Dose of 120 mg, 1 to 10 minutes before a
meal.
• Metabolism in hepar, excreation in urine.
• Side effects : hypoglicemia (more rare)
 Dosing of Nataglinide

 STARLIX : Nataglinide 125 mg

 Dose 3x1 tab/day
 Thiazolidinediones
• Troglitazone (withdrawn because causing severe
hepatic toxicity), Rosiglitazone, and Pioglitazone.
• Can be combined with insulin or other classes.
• Rosiglitazone and pioglitazone are taken once a
day, absorbed within about 2 hours, maximum
clinical effect observed within 6 to 12 weeks,
Metabolized in hepar.
• Side effects : hepatotoxicity, anemia, weight gain,
edema, and plasma volume expansion
 Mechanism of action
• Thiazolidinediones are selective agonists for
nuclear peroxisome proliferator–activated
receptor-γ (PPARγ)  activates insulin-
responsive genes that regulate carbohydrate
and lipid metabolism.
• Increasing insulin sensitivity in peripheral
tissue, lowering glucose production by the
liver, increasing glucose transport into muscle
and adipose tissue
 Dosing of Pioglitazone

 PIONIX : pioglitazone 15 mg, 30 mg; GLIABETES,

DECULIN, etc
 Dose : 1x 15-30 mg/day.
 GLP-1 AGONIST
• EXENATIDE, LIRAGLUTIDE
• GLP-1 is incretin (hormon that released after
meals and stimulate insulin secretions). Also
inhibit glucagon release, delay gastric
emptying, reduce food intake, normalizes
fasting and postprandial insulin secretaion.
 DPP 4 Inhibitors
• Increase AUC GLP-1 and GIP (Incretins) when
their secretion.
 α-Glucosidase Inhibitors
• Acarbose, Miglitol.
• Inhibition of α-glucosidase enzyme in the
intestinal brush border  slows the
absorption of carbohydrates.
• Used in combination with other oral
antidiabetic agents and/or insulin.
• SIDE EFFECTS : malabsorption, flatulence,
diarrhea, and abdominal bloating.
Mechanism of Actions
Acarbose
 Dosing of Acarbose

 GLUCOBAY : acarbose 50, 100 mg.

 Initial dose 3x 50 mg, can be increase after 4-8
weeks 3x 100-200 mg
 PRAMLINTIDE
• Bind to amylin receptor  reduction in
glucagon release, delayed gastric emptying.
 Posttest
1. First line obat antidiabetik oral adalah....;
mekanisme kerjanya .....
2. Acarbose termasuk golongan .......;
mekanisme kerja.....
3. Glibenklamid termasuk golongan.......;
mekanisme kerja .....
4. Tipe insulin berdasarkan onset kerja .....
5. Efek samping dari insulin dan obat
antidiabetik oral yang paling sering adalah ....
 kasus
• Tn M, 50 tahun datang berobat untuk kontrol
gula darah, sebelumnya kadar gula darahnya
tinggi dan didiagnosa DM tipe 2. Sebagai
langkah pertama, telah dilakukan konseling
perubahan pola diet dan exercise. Ternyata
setelah 3 bulan kontrol, tekanan gula darah
masih tinggi. Dokter memutuskan untuk
memberikan antidiabetik oral. Tuliskan resep
antidiabetik oral yang akan diberikan untuk tn
M.