antidiavitikafarmakastonsakharodidiavititypoyiijuly2015diamantisklimentidis

, MSc

| http://clinicalpharmacist.gr

1 ........................................................................................................................... 5

1.1 ......................................................................................................................... 5

1.2 ................................................................ 6

1.3 ............................................................................. 8

2 ............................................ 10

2.1 ............................................................................................................. 10

2.1.1 ....................................................................................... 10

2.1.2 , , .............................. 11

2.1.3 ....................................................................................................... 12

2.2 .................................................................................................... 12

2.2.1 ....................................................................................... 12

2.2.2 , , ,

12

2.2.3 ....................................................................................................... 14

2.3 ....................................................................................... 14

2.3.1 ....................................................................................... 14

2.3.2 , , ,

15

2.3.3 ....................................................................................................... 16

2.4 () ............................................................................. 16

2.4.1 ....................................................................................... 16


2.4.2 , , ,

17

2.4.3 ....................................................................................................... 18

2.5 - ...................................................................... 18

2.5.1 ....................................................................................... 18

2.5.2 , , ,

18

2.5.3 ....................................................................................................... 19

2.6 : DPP4 ...................................................................... 19

2.6.1 ....................................................................................... 20

2.6.2 , , ,

20

2.6.3 ....................................................................................................... 22

2.7 SGLT-2 .................................................................................................. 23

2.7.1 ....................................................................................... 23

2.7.2 , , ,

23

2.7.3 ....................................................................................................... 25

3 .................................................................................................... 26

3.1 ................................................................................................................. 26

3.1.1 .......................................................... 27

3.1.2 .................................. 27

3.2 : GLP-1............................................................. 28


3.2.1 ....................................................................................... 28

3.2.2 , , ,

29

3.2.3 ....................................................................................................... 30

3.3 .................. 31

4 ............................................................................................... 32

5 .................................................................................................................. 35


1

1.1

2

,

.

2,

-,

. ,

. 9 10

(Authors/Task Force

Members et al. 2013).

(International Diabetes Federation,

IDF), 387 ,

. , 2014 585.390 199.060

, 7,04%

2.354 (International

Diabetes Federation 2014).

:

126 mg/dl (7 mmol/l), 8


200 mg/dl (11,1 mmol/l)

(.. , , )

200 mg/dl (11,1 mmol/l), 2 75 gr

,

HbA1c 6,5%,

,

. , HbA1c

6,5%

(World Health Organization

2011).

1.2

,

.

,

. ,

(Morrish et al. 2001),

.

,

(Morrissey, Patel 2008), :


ADVICE ():

, , ,

, .

LOOD PRESSURE ( ) : 130-140/80 mmHg,

,

,

.

CHOLESTEROL (): < 200 mg/dl

< 100 mg/dl LDL-C.

DIABETES ( ). HbA1c

< 7%, 6,5%.

YE CARE ( ): .

FOOT CARE ( ): .

GUARDIAN DRUGS ( ):

: , ,

..

, ,

. ,

,

(Authors/Task Force Members et al. 2013).


,

. ,

,

(Lee et al. 2014).

,

.

1.3

, , Kumamoto

(1995) UKPDS (1998),

2, 10-

UKPDS (Holman

et al. 2008). ,

, . ADVANCE (2008), VADT (2009)

ACCORD (2010) HbA1c :

, , ,

,

, ,

. , ,

.

, ,


, (Inzucchi et al. 2012, Authors/Task

Force Members et al. 2013, American Diabetes Association 2015a):

HbA1c 7%

.

,

.

,

(.. 6,5%),

.

/ ,

.

, ,

,

, ,

(

2

2.1

.

.

,

, ,

,

. ,

.

2.1.1

, .

.

,

.

AMPK ,

-CoA 1 2,

(Fullerton et al. 2013). ,

, ,

(Miller et al. 2013).


2.1.2 , ,

(, , , ),

10-25% .

B12 20-30%.

.

,

,

. ,

.

(eGFR < 30ml/min/1,73m2), ,

, . ,

,

.

(

, ),

, (Brunton, Chabner & Knollman 2011). ,

,

(Amin, Suksomboon 2014).


2.1.3

2,5gr,

(0,85-1gr ).

,

.

2.2

, -

. .

( ),

:

, .

2.2.1

-

KATP. ,

, .

-, -

.

2.2.2 , , ,

2,

.

. , ,

. ,


,

.

( 1).

(%)

(%)

97 95 CYP2C9 CYP2C19

90 99 CYP2C9 & CYP3A4

50% 50%

100 >99 CYP2C9 60% 35%

1: (Harrower 2000).

, .

/

, ,

(Gangji et al. 2007).

, (Schernthaner et al. 2004,

Landman et al. 2014).

, , ,

, , ,

.

,

(Brunton, Chabner & Knollman 2011).


,

CYP2C9,

(, , , ), ,

, (DPP-4 ,

GLP-1). , CYP2C9, ,

.

(, ) - -


, .

.

2.2.3

, 30-120mg , , .

, 1-6 mg , .

, 2,5-15mg , .

, 2

.

2.3

, .

2.3.1

,

KATP -

, :

D-.


2.3.2 , , ,

,

( ).

, ,


,

, .

,

, ,

. 2

.

CYP3A4 ~10% CYP3A4 (, , , ..)

(- -, , , )

CYP3A4 (, , , , )

CYP2C9 : 30% CYP3A4 : 70%

. 16%

: , , )

: , , -, .

2: (Brunton, Chabner & Knollman 2011)


,

.

.

.

2.3.3

30 ,

16mg. 1-10

, 120mg 360mg (Brunton, Chabner &

Knollman 2011).

2.4 ()

, .

, 2010 (European Medicines

Agency EMA) , ,

,

(European Medicines Agency 2010).

2.4.1

.

(PPAR),


,

.


2.4.2 , , ,

,

/ ,

, .

,

. ,

, ,

, ,

. ,

50 (Aubert et al. 2010). ,

EMA (2011),

.

CYP2C8,

()

(, , , ) ,

.

, .

:

, , , (Amin, Suksomboon 2014).


2.4.3

, 15-30mg,

45mg.

2.5 -

, ,

.

2.5.1

, -

.

. ,

,

-. , GLP-1

, - (Brunton,

Chabner & Knollman 2011).

2.5.2 , , ,

HbA1c

2,

30%-50%,

. ,

.

,

.

.


,

, .

: , , .

,

.

2.5.3

,

: 25mg 4-8

25mg 4-8 , 75mg


200mg, (British Medical Association and the Royal Pharmaceutical

Society of Great Britain 2014).

2.6 : DPP4

. GLP-

1 GIP. , GIP

2

, GLP-1 .

GLP-1 .

GLP-1 (

),



GLP-1 4 (DPP-4)

1-2 .

GLP-1: GLP-1 DPP-4

,

DPP-4, .

2.6.1

DPP-4

GLP-1 GIP

2 - .

. DPP-4

AUC GLP-1 GIP (Brunton, Chabner

& Knollman 2011).

2.6.2 , , ,

DPP-4 ,

, , .

,

. 3

.


(%)

(%)

87 38 . CYP3A4 & CYP2C8

: 78% : 13%

85 9 . P450

: 85% : 4,5%

67 CYP3A4/5 : 75% : 22%

30 >80 . CYP3A4.

: 5% : 80%

100 20 . CYP3A4 CYP2D6.

: 76% : 13%

3: DPP-4 (Scheen 2010)

, DPP-4

, HbA1c 0,8% .

GLP-1 ,

DPP-4 . , ,

. ,

CYP3A4 CYP3A5 (Amin, Suksomboon 2014).

, /


. ,

,

(Clifton 2014, Standl, Erbach

& Schnell 2014). ,

,

(Wang et al. 2015).

, DPP-4

.

,

,

.

2.6.3

: , 100mg . ,

50mg .

: 50mg ,

, & , ( ). 50mg

.

: 5mg (2 x 2,5mg ).

: 5mg (2 x 2,5mg ).

: 25mg (2 x 12,5mg ).


2.7 SGLT-2

.

, .

2.7.1

- 2 (sodium-glucose co-

transporter 2, SGLT2) S1

. 90%

.

50-100gr ,

HbA1c 0,5-1%,

. , ,

.

2.7.2 , , ,

. SGLT2

,

,

. 4

5

(Scheen 2015):


(%)

(%)

~65 98

. )

5% ( > )

( > )

5: /

.

(HbA1c > 8%), ,

.

, ,

. ,

.


, , SGLT2

,

, . ,

(2015b),

,

. ,

2

. ,

.

2.7.3

: , 100mg , .

300mg

. ,

300mg UDP-

(, , ..).

eGFR < 45 ml/min/1,73m2. eGFR

45 60 ml/min/1,73m2, 100mg .

: 5mg , . 10mg

, .

eGFR < 60 ml/min/1,73m2.

: 10mg , . 25mg

, .

45 ml/min/1,73m2.


3

3.1

2 -

, .

2 :

, ,

.

.

.

2

:

, ,

/ .

(pre-mixed)

, /

.

(basal)

(bolus) , .

,

. ,

.


, ,

.

3.1.1

3.1.1.1

,

. 30

2 . 3 6 .

3.1.1.2

insulin lispro, insulin glulisine insulin aspart.

(15 )

(2-4 ).

3.1.2

3.1.2.1 (NPH)

. ,

6-10

12 ,

18 .

3.1.2.2 - (basal)

, 24 .

, (basal)


, .

:

Insulin glargine: , .

Insulin detemir: .

Insulin degludec: ,

2-3 .

3.2 : GLP-1

2.6. GLP-1

,

GLP-1,

DPP-4.

,

.

3.2.1

,

: GLP-1.

GLP-1 - , ,

cAMP-PKA .



3.2.2 , , ,

GLP-1 ,

, , ,

, . ,

(Carris, Taylor & Gums

2014). /

,

(BMI 35 kg/m2).

,

, ,

.

.

, 40-50%

(Brunton, Chabner &

Knollman 2011), (Schmidt et al.

2014). (British

Medical Association and the Royal Pharmaceutical Society of Great Britain 2014).

,


, ,

. eGFR <

30ml/min/1.73m2 60 ml/min/1.73m2.


3.2.3

: 5mcg , 2 ,

2 , 6 . ,

10mcg 2 , .

2mg

.

: 0,6mg , 1,2 mg

, 1,8 mg.

: 10mcg ,

14 . ,

20mcg .


1: (American Diabetes Association 2015b)

3.3


4

,

2.

. ,

SGLT2

.


2:


3: (American Diabetes Association 2015b)


5

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1 1.1 1.2 1.3

2 2.1 2.1.1 2.1.2 , , 2.1.3

2.2 2.2.1 2.2.2 , , , 2.2.3

2.3 2.3.1 2.3.2 , , , 2.3.3

2.4 ()2.4.1 2.4.2 , , , 2.4.3

2.5 -2.5.1 2.5.2 , , , 2.5.3

2.6 : DPP42.6.1 2.6.2 , , , 2.6.3

2.7 SGLT-22.7.1 2.7.2 , , , 2.7.3

3 3.1 3.1.1 3.1.1.1 3.1.1.2

3.1.2 3.1.2.1 (NPH)3.1.2.2 - (basal)

3.2 : GLP-13.2.1 3.2.2 , , , 3.2.3

3.3

4 5

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