INSULIN DAN OBAT

HIPOGLIKEMIA ORAL
 DEFINISI DIABETES MELLITUS
Penyakit dengan kelainan metabolik yang ditandai
dengan hiperglisemia (peningkatan kadar gula
darah).
Penyebab:
• ↓ sekresi insulin
• ↓ sensi+vitas insulin
Akibatnya:
Abnormalitas pada metabolisme kabohidrat, lemak,
dan protein menyebabkan komplikasi kronik
termasuk mikrovaskular, makrovaskular
Kriteria Diabetes
Regulasi Glukosa
 KLASIFIKASI DM
• DM tipe 1
• DM tipe 2
• DM gestasional
• DM tipe lain
DM Tipe 1 vs DM Tipe 2
• Type 2 diabetes mellitus (DM) is a disorder
characterised by insulin resistance and a
progressive decline in pancreatic beta-cell
function associated with increasing
hyperglycaemia.
• Defective betacell function occurs early and
can be detected in individuals with impaired
fasting and/or post-prandial glucose levels
(the so-called 'pre-diabetics')
• United Kingdom Prospective Diabetes (UKPD)1
study indicated that by the time type 2 DM is
diagnosed, individuals have already lost up to
50% of their betacell function.
• The decline in function proceeds at 6% per
year, which is 20 times greater than that
explained by normal ageing.
 Target terapi
• The targets for glycaemic control as set by the
American Diabetes Association (HbA1C <7%)2
and the American Association of Clinical
Endocrinologists (HbA1C <6.5%)
 OBAT DIABETES
• Insulin
• Insulin secretagogues
• Insulin sensitisers
• Glucosidase inhibitors (acarbose)
• New drug modalities: GLP-1, DPP4 inhibitor
 Terapi Farmakologi
1. Insulin
– Mekanisme kerja : menstimulasi pengambilan glukosa
perifer dan menghambat produksi glukosa hepatik
– Farmakokinetik :
• Waktu paruh pada orang normal sekitar 5-6 menit dan
memanjang pada pasien DM yang membentuk
antibodi terhadap insulin
• Dimetabolisme terutama di hati, ginjal, otot
• Difiltrasi juga di glomerulus ginjal
• Direabsorpsi di tubulus ginjal
 Insulin diperlukan pada keadaan:
• Penurunan berat badan yang cepat
• Hiperglikemia berat yang disertai ketosis
• Ketoasidosis diabetik
• Hiperglikemia hiperosmolar non ketotik
• Hiperglikemia dengan asidosis laktat
• Gagal dengan kombinasi OHO dosis optimal
• Stres berat (infeksi sistemik, operasi besar, IMA, stroke)
• Kehamilan dengan DM/diabetes melitus gestasionalyang
• tidak terkendali dengan perencanaan makan
• Gangguan fungsi ginjal atau hati yang berat
• Kontraindikasi dan atau alergi terhadap OHO
Berdasar lama kerja, insulin terbagi menjadi
empat jenis, yakni:
• Insulin kerja cepat (rapid acting insulin)
• Insulin kerja pendek (short acting insulin)
• Insulin kerja menengah (intermediate
actinginsulin)
• Insulin kerja panjang (long acting insulin)
• Insulin campuran tetap, kerja pendek dan
menengah
• (premixed insulin).
 Panduan penggunaan insulin
• Untuk memenuhi kebutuhan insulin basal
dapat digunakan insulin kerja menengah
(intermediate acting insulin) atau kerja
panjangn (long-acting insulin)
• untuk memenuhi kebutuhan insulin prandial
(setelah makan) digunakan insulin kerja
cepat (sering disebut insulin reguler/short-
acting insulin) atau insulin kerja sangat cepat
(rapid- atau ultra-rapid acting insulin).
 Efek samping utama terapi insulin
• hipoglikemia.
• Efek samping yang lain berupa reaksi
imunologi terhadap insulin yang dapat
menimbulkan alergi insulin atau resistensi
insulin.
 Insulin secretagogues
• Sulfonilurea: glibenklamid, glimepirid,
gliklasid, glipisid)
• Rapid-acting prandial insulin releasers
(repaglinide, nateglinide)
Sulfonilurea
– Mekanisme kerja : merangsang sekresi insulin pada pankreas
• Sulfonilurea terikat pada reseptor selektif sulfonilurea pada sel β
pankreas
• Ikatan tersebut menutup adenosine triphosphate-dependent
potassium ion (K+) channel, menyebabkan penurunan potassium
efflux sehingga terjadi depolarisasi membran
• Voltage-dependent calcium ion (Ca2+) channels membuka sehingga
Ca2+ masuk melalui membran
• Peningkatan Ca2+ intraselular menyebabkan translokasi granul
yang mensekresi insulin ke permukaan sel dan terjadi eksositosis
yang diakibatkan oleh granul insulin
• Peningkatan sekresi insulin dari pankreas didistribusi melalui vena
portal dan menekan produksi glukosa hepatik
Sulfonilurea
– Farmakokinetik:
• Dimetabolisme di hati, menjadi bentuk aktif maupun
metabolik inaktif
• Sebagian besar sulfonilurea dimetabolisme di hati dengan
keterlibatan sitokrom P450 (CYP) 2C9
• Disekresi melalui ginjal
– Efek merugikan :
• Hipoglikemia
• Hiponatremia
• Peningkatan berat badan
• Jarang : ruam kulit, anemia hemolitik, gangguan
gastrointestinal, kolestasis
 Rapid-acting prandial insulin
releasers (repaglinide, nateglinide)
• Taken orally shortly before a meal, they can
stimulate rapid, short-lived insulin release.
• The mechanism of action of prandial insulin
releasers indicate that they bind to the SUR-1
receptor in much the same way as the
sulphonylureas.
• The short half-life of these drugs potentiates
the effect of the first phase of insulin secretion
 Insulin sensitisers
• Biguanides (metformin)
• Thiazolidinediones (pioglitazone,
rosiglitazone)
Biguanida
• Berasal dari : Galega officinalis
• Biguanides are generally considered the drugs of
choice in obese type 2 diabetics.
• Metformin can be used in combination with any other
class of oral antidiabetic drug or with insulin.
• Metformin is also used in the treatment of polycystic
ovarian syndrome (PCOS) to improve insulin sensitivity
and to lower circulating androgen levels.
• It also improves ovulation and menstrual cyclicity
• metformin for gestational diabetes seems to be safe
• Contraindications include the presence of underlying
impairment of renal function
• the decrease in fasting glucose levels with a drop
in HbA1C levels of 1 - 2%.
• The UKPDS study also showed that overweight
patients started on biguanides had a lower
myocardial infarction risk (of 39%) than patients
on conventional therapy (cardioprotektif)
• Side-effects can include lactic acidosis
• Abdominal discomfort and diarrhoea are the
most frequent side-effects
Biguanida
– Mekanisme kerja : meningkatkan sensitivitas
insulin di hati maupun jaringan periferal sehingga
terjadi peningkatan uptake glukosa ke jaringan
yang sensitif terhadap insulin tersebut
• adenosine 5-monophosphate–activated protein,
aktivitas kinase, peningkatan aktivitas tirosin kinase,
dan glukosa transporter-4 berperan dalam sensitisasi
insulin
• Kerjanya tidak memiliki pengaruh langsung pada sel β
pankreas
 Tiazolidindion
• Peroxisome proliferator activated receptor
(PPAR)-γ agonists
PPAR gamma reseptor
Tiazolidindion
• The net effect of these drugs results from
stimulation of a nuclear PPAR-γ that regulates
the transcription of genes culminating in an
increase in insulin sensitivity.
• Troglitazone: fatal hepatotoxicity,
• Rosiglitazone: increased risk of myocardial
infarction and cardiovascular-related deaths
Tiazolidindion
• This class of drug can be used as monotherapy
in obese as well as non-obese patients who
have failed other conservative measures.
• TZDs can be used in combination with
metformin and sulphonylureas.
• The use in combination with insulin is
prohibited
Tiazolidindion
• in Europe because of the increased risk of
weight gain in the form of adipogenesis and
fluid retention.
• The use of TZDs is contraindicated in acute
liver disease owing to the increased risk of
hepatotoxicity.
• Since they decrease hepatic glucose output,
the concern exists that they could possibly
aggravate hypoglycaemia.
Tiazolidindion
– Mekanisme kerja : meningkatkan sensitivitas insulin pada otot dan
jaringan adiposa serta menghambat glukoneogenesis hepatik
• Glitazon membentuk ikatan dengan peroxisome proliferator-activated
receptor-γ (PPAR-γ) yang terletak di sel lemak dan sel pembuluh
• Glitazon meningkatkan sensitivitas otot, hati, dan jaringan lemak secara
tidak langsung
• Glitazon menyebabkan preadiposit berdiferensiasi menjadi mature fat
cells di penyimpanan lemak di subkutan
• Sel lemak kecil tersebut lebih sensitif terhadap insulin dan lebih mampu
menyimpan asam lemak bebas
• Hasilnya, terjadi flux asam lemak bebas keluar plasma, lemak viseral, dan
hati ke lemak subkutan; sebuah jaringan penyimpanan yang lebih tidak
resisten terhadap insulin
• Glitazon juga mempengaruhi adipokin yang meningkatkan sensitivitas
insulin
Tiazolidindion
– Farmakokinetik :
• Mudah diabsorpsi dengan atau tanpa makanan
• Bersifat highly (>99%) protein bound terhadap albumin
• Pioglitazon terutama dimetabolisme oleh CYP2C8 dan sebagian
kecil (17%) oleh CYP3A4, yang utamanya dieliminasi melalui feses
• Rosiglitazon dimetabolisme oleh CYP2C8 dan sebagian kecil oleh
CYP2C9, lalu terkonjugasi dengan dua pertiganya ditemukan di
urin dan sepertiganya di feses
• Waktu paruh pioglitazon 3 – 7 jam
• Waktu paruh rosiglitazon 3 – 4 jam
• Glitazon memiliki durasi aksi antihiperglikemik hingga lebih dari
24 jam
 Glucosidase inhibitors
(acarbose)
― Mekanisme kerja : menginhibisi enzim di usus halus (maltase, isomaltase,
sukrase, glukoamilase) secara kompetitif sehingga mencegah penguraian
sukrosa dan karbohidrat kompleks dalam usus halus. Dengan demikian,
terjadi penghambatan dan perlambatan dalam penyerapan karbohidrat
post prandial
― Farmakokinetik :
– Konsentrasi plasma puncak bertahan selama 14 – 24 jam setelah
konsumsi obat
– Konsentrasi plasma puncak dari zat aktif sendiri bertahan sekitar 1 jam
– Akarbosa dimetabolisme di saluran cerna oleh bakteri intestinal dan
enzim pencernaan
– Fraksi metabolit ini diabsorpsi (34% dari dosis) dan diekskresikan
melalui urin
• The drug should be taken with the first bite of food during a
meal and not more than 15 minutes after the start of the
meal
Glucosidase inhibitors
• contraindicated in pregnancy and breastfeeding.
• Efficacy measures show that postprandial glucose
levels can be lowered by 1 - 4 mmol/l.
• An average decrease in HbA1C of 0.5 - 1.0% can
be expected.
• Side-effects include flatulence, abdominal
discomfort and diarrhoea, but tolerance of the
side-effects quickly develops.
• Hypoglycaemia can occur only if used in
conjunction with a sulphonylurea or insulin
 New drug
• Incretins (exendin-4, liraglutide, vildagliptin,
sitagliptin)
• DPP4 inhibitor
• The small intestine secretes glucagon-like peptide-1
(GLP-1) as well as glucose-dependent insulinotropic
polypeptide (GIP, previously called gastric inhibitory
peptide) in response to food intake.
• These hormones stimulate insulin secretion, insulin
gene expression and pancreatic beta-cell growth.
Furthermore, they me diate the incretin effect which
augments insulin secretion following oral
administration of glucose.
• The GLP-1 molecule is subject to rapid degradation by
the DPP-IV (dipeptidyl peptidase) enzyme.
• Patients with type 2 diabetes have greatly
impaired or absent incretin-mediated insulin
secretion due to a decrease in the level of
GLP-1 which leads to a decrease in glucose-
dependent secretion of insulin by the
pancreatic beta-cells
 Exendin-4 (exenatide)
• isolated from the venom of the Gila monster
(Heloderma lizard species) and has a synthetic
version (exenatide)
• has a longer half-life than native GLP- 1.
• This ‘incretin mimic’ improves glycaemic control
mainly by stimulating glucose-dependent insulin
secretion and suppressing postprandial glucagon
secretion.
• It also delays gastric emptying, reduces food
intake and facilitates weight loss.
• It is given as a twice-daily subcutaneous
injection and can decrease HbA1C levels by a
further 1% if given in combination with other
drugs
Vildagliptin
• This drug is taken in oral form as a once-daily
dosage.
• Inhibition of dipeptidyl peptidase-IV (DDP-IV)
stimulates the secretion of insulin in a glucose-
dependent fashion, so minimising possible
hypoglycaemic side-effects.
• Inhibition of DDP-IV is dose-dependent.
• Recent data suggest restorative effects on
pancreatic islet cells, thereby fuelling the hope
that the DDP-IV inhibitors could potentially slow
or reverse the course of beta-cell failure.
Sitagliptin
• This drug is also a DDP-IV inhibitor and can be
used as monotherapy in type 2 diabetes or in
combination with metformin, the SUs or the
TZDs if the existing regimen no longer
provides adequate glycaemic control.
• It has not yet been studied in combination
with insulin.
• Sitagliptin is taken orally and has been shown
to reduce HbA1C levels by 0.6 - 1%.
 Amylin analogues (Pramlintide)
• Human amylin is a 37-amino acid glucoregulatory peptide
that is co-secreted with insulin by the pancreatic beta-cells.
• Pramlintide, a synthetic analogue, exerts its effect by
slowing down gastric emptying and increasing satiety.
• Post-prandially, it decreases glucose levels and reduces the
reintroduction of glucose in the circulation
• Pramlintide is administered as a subcutaneous injection
immediately before a meal.
• The peptide undergoes renal clearance and has a t½ of 50
minutes.
• It is well tolerated and is not associated with the risk of
hypoglycaemia
 Inhibitor Dipeptidil Peptidase-IV
(Gliptin)
– Contoh obat : sitagliptin, vildagliptin
– Mekanisme kerja : Inhibitor DPP-IV memperpanjang
waktu paruh glucagon-like peptide-1 (GLP-1)
endogen
• Pada penderita DM tipe 2, terjadi defisiensi GLP-1
• Inhibitor DPP-IV mereduksi peningkatan glukagon
setelah makan dan menstimulasi sekresi insulin glucose-
dependent
• Karena gliptin memblokade enzim DPP-IV hingga hampir
100% selama 12 jam, mendekati normal, level GLP-1
nondiabetik dapat dicapai
Peran GLP-1
DPP -4
– Interaksi obat :
• Sitagliptin dan vildagliptin tidak memiliki interaksi
obat yang signifikan
• 20% sitagliptin dimetabolisme oleh CYP3A4 dengan
beberapa keterlibatan oleh CYP2C8
• Sitagliptin memiliki efek terhadap digoksin tetapi
sangat kecil dan diabaikan
• Sitagliptin meningkatkan AUC siklosporin A sebesar
30%
• Vildagliptin tidak memiliki interaksi dengan obat-obat
lain secara signifikan
 Terapi Farmakologi
Efek samping :
• Sitagliptin dan vildagliptin ditoleransi dengan
baik dan tidak menyebabkan gangguan GI
• Efek samping paling signifikan adalah
hipoglikemia
Dosis :
• Vildagliptin = 50 – 100 mg sehari
• Sitagliptin = 100 mg sehari kecuali jika ada
gangguan ginjal
 Materi
• Pengantar farmol
• Farmol dasar
• Obat otonom
• Autakoid
• obat sal cerna
• Obat hipertensi
• Obat hipoglikemi oral dan isulin