Drug Interaction Of Antidiabetic Agents: Marianne, S.si., M.si., Apt

Drug Interaction of Antidiabetic Agents Marianne, S.Si., M.Si., Apt.

Depeptidyl Peptidase-4 Inhibitor Incretin Mimetic Agents AlphaGlucosidase Inhibitors

Sulfonylureas

Meglitinides

Biguanides

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 equivqlent doses (mg)

Doses/ day

Serum t1/2 (h)

Onset (h)

Duration (h)

Renal excreti on (%)

Active metabol ites

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

First generation

Sulfonylureas

Approximate equivqlent doses (mg)

Doses/ day

Serum t1/2 (h)

Onset (h)

Duration (h)

Renal excreti on (%)

Active metabol ites

10

1-2

2-4

1-3

10-24

80-85

No

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

Second generation Glipizide Glyburide

a

= weakly active b = moderate NA = Not aplicable

Precipitant Drug

Object Drug

Effect

Mechanism

Management

CHOLESTYRAMINE S: 4

Glipizide

↓ Serum glipizide levels may be decreased, producing a decrease in the hypoglycemic effects.

Administration of GLIPIZIDE with CHOLESTYRAMINE may impair the absorption of the hypoglycemic agent.

Consider having the patient ingest GLIPIZIDE 1 to 2 hours prior to CHOLESTYRAMINE. Monitor serum glucose levels and observe the patient for signs of hyperglycemia.

Magnesium Salts S: 4

SU

↑ Hypoglycemic effects of SULFONYLUREAS increased.

Increased or more rapid absorption of SULFONYLUREAS

If an interaction is suspected, measure blood glucose and adjust the SULFONYLUREA dose accordingly

Precipitant Drug

Object Drug

Effect

Mechanism

SALICYLATES S: 2

SU

↑ Increased hypoglycemic effect of SULFONYLUREAS

SALICYLATES reduce basal plasma glucose levels and enhance insulin secretion. Inhibition of prostaglandin synthesis may inhibit acute insulin responses to glucose. Displaced SULFONYLUREA protein binding has been suggested

Management Monitor the patient's blood glucose. If hypoglycemia develops, consider decreasing the SULFONYLUREA dose. Consider alternative therapy with acetaminophen (eg, Tylenol) or an NSAID (eg, sulindac [eg, Clinoril]).

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 Drug

Effect

Mechanism

Oral Anticoagulant (Dicumarol)

SU

↑ clinical hypoglycemia

Metabolic degradation (hepatic) of SULFONYLUREA is slowed by the oral ANTICOAGULANT (DICUMAROL) leading to SULFONYLUREA accumulation

Perform blood glucose monitoring and observe for signs of clinical hypoglycemia. Tailor dosages as needed

SU

↑ Hypoglycemia may occur

Proposed reduction in SULFONYLUREA hepatic clearance by CHLORAMPHENICOL, leading to SULFONYLUREA accumulation (Inhibitor CYP2C9)

Monitor blood glucose concentrations and observe patients for symptoms of hypoglycemia when initiating CHLORAMPHENICOL therapy in patients maintained on a SULFONYLUREA hypoglycemic agent.

Chloramphenicol S: 2 O: Delayed Se: Moderate D: Suspected

Management

Precipitant Drug

Object Drug

Effect

FLUCONAZOLE S: 2 O: D Se: M D: Suspected

SU

↑

FLUVOXAMINE S: 4 O: D Se: M D: Possible

SU

GEMFIBROZIL S: 4 O: D Se: M D: Possible

SU

The hypoglycemic effects of certain SULFONYLUREAS may be increased. ↑

The pharmacologic and adverse effects of certain SULFONYLUREAS may be increased ↑

The hypoglycemic effects of certain SULFONYLUREAS may be increased

Mechanism

Management

Inhibition of SULFONYLUREA metabolism (CYP2C9) by FLUCONAZOLE is suspected

Consider monitoring blood glucose levels during coadministration of certain SULFONYLUREAS and FLUCONAZOLE.

Inhibition of SULFONYLUREA metabolism (CYP2C9) by FLUVOXAMINE.

In patients receiving certain SULFONYUREAS, carefully monitor blood glucose levels when FLUVOXAMINE is started or stopped. Be prepared to adjust the SULFONYLUREA dose as needed

Inhibition of SULFONYLUREA metabolism (CYP2C9) by GEMFIBROZIL is suspected.

In patients receiving certain SULFONYLUREAS, closely monitor blood glucose levels when GEMFIBROZIL is added or discontinued. Adjust the dose of the SULFONYLUREA accordingly

Precipitant Drug

Object Drug

Effect

Mechanism

H2 ANTAGONIST S: 4 O: D Se: M D: Possible

SU

↑ Reduced clearance of SULFONYLUREAS that may result in hypoglycemia

H2 ANTAGONIST inhibition of SULFONYLUREA hepatic metabolism, resulting in an accumulation of SULFONYLUREA (Cimetidin: inhibitor CYP2C9)

Monitor blood glucose and observe for signs of clinical hypoglycemia after initiation of H2 ANTAGONIST therapy in patients maintained on a SULFONYLUREA. Adjust the SULFONYLUREA dosage as necessary

KETOCONAZO LE S: 2 O: D Se: M D: Suspected

SU TOLBUT AMIDE

↑

Possibly inhibition of TOLBUTAMIDE metabolism

In patients receiving TOLBUTAMIDE, consider monitoring blood glucose concentrations and observing the patient for symptoms of hypoglycemia when KETOCONAZOLE is added to or discontinued from the treatment regimen. Adjust the dose of TOLBUTAMIDE accordingly

Methyldopa S: 5 O: D Se: Mi D: Possible

SU

METHYLDOPA may impair the metabolic breakdown of TOLBUTAMIDE

Monitor the blood sugar of patients receiving this combination. Reduce the dose of TOLBUTAMIDE if necessary

Serum SULFONYLUREA concentrations may be elevated, increasing the hypoglycemic effect ↑ The biologic t½ of TOLBUTAMIDE may be prolonged. The hypoglycemic effect may be enhanced if the drug accumulates

Management

Precipitant Drug

Object Drug

Effect

Mechanism

Management

Omeprazole S: 4 O: D Se: M D: Possible

SU

↑ Serum sulfonylurea concentrations may be elevated, increasing the hypoglycemic effects

Possible inhibition of sulfonylurea metabolism

Based on available information, no special precautions are needed. If an interaction is suspected, adjust the dose of the SULFONYLUREA as indicated

RIFAMYCINS S: 2 O: D Se: M D: Probable

SU

RIFAMYCINS may decrease the t½ and serum levels while increasing the clearance of some SULFONYLUREAS, possibly resulting in hyperglycemia

The hepatic metabolism of certain SULFONYLUREAS may be increased by RIFAMYCINS

Closely monitor blood glucose. The dose of the SULFONYLUREA may need to be increased

Precipitant Drug

Object Drug

Effect

Mechanism

Management

SULFINPYRAZ ONE S: 2 O: D Se: M D: Suspected

SU

SULFINPYRAZONE may decrease the clearance and increase the halflife of TOLBUTAMIDE; hypoglycemia may result

SULFINPYRAZONE impairs the hepatic metabolic conversion of TOLBUTAMIDE

Monitor patient's blood glucose during concurrent TOLBUTAMIDE and SULFINPYRAZONE therapy. The dose of TOLBUTAMIDE may need to be decreased

SULFONAMID ES S: 4 O: D Se: M D: Possible

SU

May increase the half-life of the SULFONYLUREA; hypoglycemia may occur

SULFONAMIDES may impair hepatic metabolism of SULFONYLUREAS or alter plasma protein binding

Monitor blood glucose. The SULFONYLUREA dose may need to be decreased. Glyburide may be a noninteracting alternative

INTERAKSI PADA FASE EKSKRESI

Aliran darah ginjal pH cairan tubulus ginjal Sistem transport aktif

Obat mempengaruhi

Peluang interaksi obat

Precipitant Drug

Object Drug

Effect

Mechanism

Management

CLOFIBRATE S: 2 O: Delayed Se: Moderate D: Suspected

SU

SULFONYLUREA hypoglycemic actions may be amplified. The antidiuretic action of CLOFIBRATE in patients with diabetes insipidus can be antagonized by glyburide.1

Unknown Clofibrate can reduce the clearance of chlorpropamide, leading to its accumulation.10 However, clofibrate may have additive hypoglycemic effects.6

Monitor blood glucose concentrations and observe patients for signs of hypoglycemia. Adjust the SULFONYLUREA dose accordingly.

Urinary Acidifiers S: 3 O: Delayed Se: Minor D: Suspected

SU

Acidification of the urine by agents such as AMMONIUM CHLORIDE may increase the bioavailability of CHLORPROPAMIDE; hypoglycemic actions may be enhanced

Urinary pH appears to determine the relative contribution of metabolic and renal clearance of CHLORPROPAMIDE; with an acidic urine, metabolic clearance dominates elimination and renal clearance is decreased

Monitor patient's blood glucose during coadministration of CHLORPROPAMIDE and a URINARY ACIDIFIER; a lower CHLORPROPAMIDE dose may be necessary

Precipitant Drug Urinary Alkalinizers

Object Drug

Effect

Mechanism

Management

SU

Alkalinization of the urine by an agent such as SODIUM BICARBONATE may increase the elimination of CHLORPROPAMIDE. This may be useful in the treatment of CHLORPROPAMIDE intoxication; however, patients taking SODIUM BICARBONATE for other reasons may have a decreased therapeutic response to CHLORPROPAMIDE

The renal clearance of CHLORPROPAMIDE increases as urinary pH increases. It appears that urinary pH affects the ratio of renal and metabolic clearance

Alkalinization of the urine may be useful in the treatment of CHLORPROPAMIDE toxicity. However, the dose of CHLORPROPAMIDE may need to be increased in a patient routinely taking SODIUM BICARBONATE. Monitor the patient's blood glucose during coadministration

Precipitant Drug Probenecid S: 4 O: D Se: M D: Possible

Object Drug

Effect

SU

↑ The actions of CHLORPROPAMIDE may be enhanced

Mechanism It has been postulated that PROBENECID may compete with CHLORPROPAMIDE for renal tubular excretion, resulting in CHLORPROPAMIDE accumulation

Management Monitor blood glucose levels and decrease the dose of CHLORPROPAMIDE if indicated

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