Drug Interaction of

Antidiabetic Agents

Marianne, S.Si., M.Si., Apt.

 Depeptidyl Sulfonylureas
Peptidase-4
Inhibitor

Incretin
Mimetic Meglitinides
Agents

Alpha-
Glucosidase Biguanides
Inhibitors
 Absorpsi

Distribusi

Farmakokinetika

Metabolisme

Interaksi Farmakodinamika

Ekskresi

Fisika-Kimia
 Pharmacology Sulfonylurea
• Hypoglycemic agents
• Sulfonamides derivatives but are devoid of
antibacterial activity
• First generation: acetohexamide,
chlorpropamide, tolazamide, tolbutamide
• Second generation: glipizide, glyburide
(glibenclamide), glimepiride
• Side effect: alergi dan hipoglikemi
 Pharmacokinetics Sulfonylurea
• Absorption
– Well absorbed after oral administration.
– All SU except glipizide can be taken with food
(absorption of glipizide is delayed by food).
– Tolbutamide, glyburide, glipizide are more
effective when taken approximately 30 minutes
before a meal
– Tolazamide is absorbed more slowly than the
other sulfonylureas
 Pharmacokinetics Sulfonylurea
• Distribution
– All sulfonylureas are strongly bound to plasma protein,
primarily albumin (90-99%).

• Excretion
– Excreted primarily in the urine.
– The renal elimination of chlorpropamide may be sensitive
to changes in urinary pH. Urinary alkalinization increases
its excretion in the urine. When the urine pH is less than 6,
urinary excretion decreases.

• Metabolism
– They are metabolized in the liver to active and inactive
metabolites
 Sulfonylureas Approximate Doses/ Serum Onset Duration Renal Active
equivqlent day t1/2 (h) (h) (h) excreti metabol
doses (mg) on (%) ites

First generation

Acetohexamide 500-750 1-2 ~6-8 1 12-24 100 Yes

Chlorpropamide 250-375 1 36 1 24-60 100 Yesb

Tolazamide 250-375 1-2 7 4-6 12-24 100 Yesa

Tolbutamide 1.000-1.500 2-3 4.5-6.5 1 6-12 100 No

 Sulfonylureas Approximate Doses/ Serum Onset Duration Renal Active
equivqlent day t1/2 (h) (h) (h) excreti metabol
doses (mg) on (%) ites

Second generation

Glipizide 10 1-2 2-4 1-3 10-24 80-85 No

Glyburide

Nonmicronized 5 1-2 10 2-4 16-24 50 Yesa

Micronized 3 1-2 ~4 1 12-24 50 Yesa

Glimepiride NA 1 ~9 2-3 24 60 Yesa

a = weakly active
b = moderate

NA = Not aplicable
Precipitant Drug Object Effect Mechanism Management
Drug
CHOLESTYRAMINE Glipizide ↓ Administration of Consider having the patient
S: 4 Serum glipizide GLIPIZIDE with ingest GLIPIZIDE 1 to 2 hours
levels may be CHOLESTYRAMINE may prior to CHOLESTYRAMINE.
decreased, impair the absorption of Monitor serum glucose levels
producing a the hypoglycemic agent. and observe the patient for
decrease in the signs of hyperglycemia.
hypoglycemic
effects.

Magnesium Salts SU ↑ Increased or more rapid If an interaction is suspected,

S: 4 Hypoglycemic absorption of measure blood glucose and
effects of SULFONYLUREAS adjust the SULFONYLUREA dose
SULFONYLUREAS accordingly
increased.
Precipitant Drug Object Effect Mechanism Management
Drug
SALICYLATES SU ↑ SALICYLATES reduce basal Monitor the patient's blood
S: 2 Increased plasma glucose levels and glucose. If hypoglycemia
hypoglycemic enhance insulin secretion. develops, consider decreasing
effect of Inhibition of prostaglandin the SULFONYLUREA dose.
SULFONYLUREAS synthesis may inhibit Consider alternative therapy
acute insulin responses to with acetaminophen (eg,
glucose. Displaced Tylenol) or an NSAID (eg,
SULFONYLUREA protein sulindac [eg, Clinoril]).
binding has been
suggested
INTERAKSI PADA FASE
METABOLISME
 Peluang Interaksi pada Fase Metabolisme
• Jika salah satu obat MENGINHIBISI enzim pemetabolisme
obat lainnya
– Terjadi penurunan sintesis enzim sitokrom P450 di retikulum
endoplasma
– Terjadi peningkatan penguraian enzim retikulum endoplasma

• Jika salah satu obat MENGINDUKSI enzim pemetabolisme

obat lainnya
– Terjadinya peningkatan aktivitas enzim sitokrom P450
– Terjadi peningkatan proliferasi retikulum endoplasma →
peningkatan jumlah enzim sitokrom P450

• Jika kedua obat BERSAING menjadi substrat pada enzim

pemetabolisme yang sama
Inhibitor Inducer Substrate
 Precipitant Drug Object Effect Mechanism Management
Drug
Oral Anticoagulant SU ↑ Metabolic degradation Perform blood glucose
(Dicumarol) clinical (hepatic) of monitoring and observe for
hypoglycemia SULFONYLUREA is slowed signs of clinical hypoglycemia.
by the oral Tailor dosages as needed
ANTICOAGULANT
(DICUMAROL) leading to
SULFONYLUREA
accumulation

Chloramphenicol SU ↑ Proposed reduction in Monitor blood glucose

S: 2 Hypoglycemia SULFONYLUREA hepatic concentrations and observe
O: Delayed may occur clearance by patients for symptoms of
Se: Moderate CHLORAMPHENICOL, hypoglycemia when initiating
D: Suspected leading to SULFONYLUREA CHLORAMPHENICOL therapy in
accumulation patients maintained on a
(Inhibitor CYP2C9) SULFONYLUREA hypoglycemic
agent.
Precipitant Drug Object Effect Mechanism Management
Drug
FLUCONAZOLE SU ↑ Inhibition of Consider monitoring blood
S: 2 The SULFONYLUREA glucose levels during
O: D hypoglycemic metabolism (CYP2C9) by coadministration of certain
Se: M effects of certain FLUCONAZOLE is SULFONYLUREAS and
D: Suspected SULFONYLUREAS suspected FLUCONAZOLE.
may be
increased.

FLUVOXAMINE SU ↑ Inhibition of In patients receiving certain

S: 4 The SULFONYLUREA SULFONYUREAS, carefully
O: D pharmacologic metabolism (CYP2C9) by monitor blood glucose levels
Se: M and adverse FLUVOXAMINE. when FLUVOXAMINE is started
D: Possible effects of certain or stopped. Be prepared to
SULFONYLUREAS adjust the SULFONYLUREA dose
may be increased as needed
GEMFIBROZIL SU ↑ Inhibition of In patients receiving certain
S: 4 The SULFONYLUREA SULFONYLUREAS, closely
O: D hypoglycemic metabolism (CYP2C9) by monitor blood glucose levels
Se: M effects of certain GEMFIBROZIL is when GEMFIBROZIL is added or
D: Possible SULFONYLUREAS suspected. discontinued. Adjust the dose
may be increased of the SULFONYLUREA
accordingly
 Precipitant Object Effect Mechanism Management
Drug Drug
H2 SU ↑ H2 ANTAGONIST Monitor blood glucose and observe for
ANTAGONIST Reduced clearance inhibition of signs of clinical hypoglycemia after
S: 4 of SULFONYLUREAS SULFONYLUREA hepatic initiation of H2 ANTAGONIST therapy in
O: D that may result in metabolism, resulting in patients maintained on a
Se: M hypoglycemia an accumulation of SULFONYLUREA. Adjust the
D: Possible SULFONYLUREA SULFONYLUREA dosage as necessary
(Cimetidin: inhibitor
CYP2C9)
KETOCONAZO SU ↑ Possibly inhibition of In patients receiving TOLBUTAMIDE,
LE TOLBUT Serum TOLBUTAMIDE consider monitoring blood glucose
S: 2 AMIDE SULFONYLUREA metabolism concentrations and observing the patient
O: D concentrations for symptoms of hypoglycemia when
Se: M may be elevated, KETOCONAZOLE is added to or
D: Suspected increasing the discontinued from the treatment
hypoglycemic regimen. Adjust the dose of
effect TOLBUTAMIDE accordingly
Methyldopa SU ↑ METHYLDOPA may Monitor the blood sugar of patients
S: 5 The biologic t½ of impair the metabolic receiving this combination. Reduce the
O: D TOLBUTAMIDE may breakdown of dose of TOLBUTAMIDE if necessary
Se: Mi be prolonged. The TOLBUTAMIDE
D: Possible hypoglycemic
effect may be
enhanced if the
drug accumulates
 Precipitant Object Effect Mechanism Management
Drug Drug
Omeprazole SU ↑ Possible inhibition of Based on available information, no
S: 4 Serum sulfonylurea sulfonylurea metabolism special precautions are needed. If an
O: D concentrations interaction is suspected, adjust the dose
Se: M may be elevated, of the SULFONYLUREA as indicated
D: Possible increasing the
hypoglycemic
effects
RIFAMYCINS SU RIFAMYCINS may The hepatic metabolism Closely monitor blood glucose. The dose
S: 2 decrease the t½ of certain of the SULFONYLUREA may need to be
O: D and serum levels SULFONYLUREAS may be increased
Se: M while increasing increased by
D: Probable the clearance of RIFAMYCINS
some
SULFONYLUREAS,
possibly resulting
in hyperglycemia
 Precipitant Object Effect Mechanism Management
Drug Drug
SULFINPYRAZ SU SULFINPYRAZONE SULFINPYRAZONE Monitor patient's blood glucose during
ONE may decrease the impairs the hepatic concurrent TOLBUTAMIDE and
S: 2 clearance and metabolic conversion of SULFINPYRAZONE therapy. The dose of
O: D increase the half- TOLBUTAMIDE TOLBUTAMIDE may need to be decreased
Se: M life of
D: Suspected TOLBUTAMIDE;
hypoglycemia may
result
SULFONAMID SU May increase the SULFONAMIDES may Monitor blood glucose. The
ES half-life of the impair hepatic SULFONYLUREA dose may need to be
S: 4 SULFONYLUREA; metabolism of decreased. Glyburide may be a
O: D hypoglycemia may SULFONYLUREAS or alter noninteracting alternative
Se: M occur plasma protein binding
D: Possible
INTERAKSI PADA FASE EKSKRESI
 Aliran
darah ginjal

pH cairan
tubulus
ginjal
Sistem
transport
aktif

Obat
mempengaruhi Peluang
interaksi
obat
Precipitant Object Effect Mechanism Management
Drug Drug
CLOFIBRATE SU SULFONYLUREA Unknown Monitor blood glucose
S: 2 hypoglycemic actions may Clofibrate can reduce the concentrations and observe
O: Delayed be amplified. The clearance of patients for signs of
Se: antidiuretic action of chlorpropamide, leading hypoglycemia. Adjust the
Moderate CLOFIBRATE in patients to its accumulation.10 SULFONYLUREA dose
D: Suspected with diabetes insipidus can However, clofibrate may accordingly.
be antagonized by have additive
glyburide.1 hypoglycemic effects.6

Urinary SU Acidification of the urine by Urinary pH appears to Monitor patient's blood glucose
Acidifiers agents such as determine the relative during coadministration of
S: 3 AMMONIUM CHLORIDE contribution of metabolic CHLORPROPAMIDE and a
O: Delayed may increase the and renal clearance of URINARY ACIDIFIER; a lower
Se: Minor bioavailability of CHLORPROPAMIDE; with CHLORPROPAMIDE dose may be
D: Suspected CHLORPROPAMIDE; an acidic urine, metabolic necessary
hypoglycemic actions may clearance dominates
be enhanced elimination and renal
clearance is decreased
 Precipitant Object Effect Mechanism Management
Drug Drug
Urinary SU Alkalinization of the urine The renal clearance of Alkalinization of the urine may
Alkalinizers by an agent such as CHLORPROPAMIDE be useful in the treatment of
SODIUM BICARBONATE increases as urinary pH CHLORPROPAMIDE toxicity.
may increase the increases. It appears that However, the dose of
elimination of urinary pH affects the ratio CHLORPROPAMIDE may need to
CHLORPROPAMIDE. This of renal and metabolic be increased in a patient
may be useful in the clearance routinely taking SODIUM
treatment of BICARBONATE. Monitor the
CHLORPROPAMIDE patient's blood glucose during
intoxication; however, coadministration
patients taking SODIUM
BICARBONATE for other
reasons may have a
decreased therapeutic
response to
CHLORPROPAMIDE
 Precipitant Object Effect Mechanism Management
Drug Drug
Probenecid SU ↑ It has been postulated Monitor blood glucose levels and
S: 4 The actions of that PROBENECID may decrease the dose of CHLORPROPAMIDE
O: D CHLORPROPAMIDE compete with if indicated
Se: M may be enhanced CHLORPROPAMIDE for
D: Possible renal tubular excretion,
resulting in
CHLORPROPAMIDE
accumulation
 Conclusion
• Interaksi obat sulfonilurea terjadi pada fase
A,D,M,E
• The majority of these drug interactions have been
found to truly be due to hepatic metabolism.
Drugs that are inducers or inhibitors of CYP450
2C9 should be monitored carefully when used
with a sulfonylurea.
• Jika berinteraksi dengan obat lain, sulfonilurea
menjadi object drug
• Jika interaksi terjadi pada fase absorpsi:
– bedakan waktu pemberian obat
– Pengaturan dosis
• Jika interaksi terjadi pada fase metabolisme:
– Atur dosis obat object
– Ganti obat objek
– Ganti obat presipitan

• Jika interaksi terjadi pada fase ekskresi:

– Atur jarak penggunaan

• Jika interaksi terjadi pada fase distribusi:

– Ganti obat presipitan atau object