DM DAN PENATALAKSANAANNYA

Farmakologi FK UNRAM
 Diabetes Mellitus
• Dasar penyakit adalah resistensi reseptor
insulin dan defisiensi insulin

• Gejala klinis penyakit :

– Hiperglikemia
– Glikosuria
– Dapat diikuti gangguan sekunder metabolisme
protein dan lemak
– Dapat berakhir dengan kematian
– Polifagi, poliuri, polidipsi

• Penyakit ini diturunkan secara autosomal resesif

dan bersifat poligenetik
 DEFISIENSI
DEFISIENSI INSULIN
INSULIN

HIPERGLIKEMIA
POLIURIA

POLIDIPSIA
GLIKOSURIA

POLIPHAGIA
 Cara kerja insulin
Ada 2 teori cara kerja insulin
• Teori 1 = Teori Levine :
– Insulin mentransfer glukosa melalui membran sel
otot serat lintang, tetapi tidak menggangu
perpindahan glukosa melalui sel membran hati
• Teori 2
– Insulin diperlukan untuk fosforilasi glukosa dalam sel
→ glukosa 6 posfatase
– Untuk pengikatan ini dibutuhkan enzim hexokinase
yang dihasilkan oleh sel hati
– Kelenjar hipofisis menghasilkan zat inhibitor
hexokinase
– Insulin merupakan zat antagonis terhadap
hexokinase
 Acanthus Insensitivitas
nigricans Jaringan Endokrinopati
Intoleransi Ggn Pankreas
KH Eksokrin
Diabetogenic
Lifestyle Pregnancy

Faktor RESISTENSI
Genetik Medikasi
INSULIN
 Diabetes Mellitus
• Symptoms

– Polyuria
– Polydipsia
– Polyphagia
– Glycosuria
– Unexplained weight loss
– Fatigue
– Hyperglycemia
• Reduksi hiperglikemia  kadar
gula (glukose) darah normal

• Menurunkan atau menghilangkan

komplikasi kronik

• Memperbaiki kualitas dan

kuantitas hidup
TERAPI FARMAKOLOGI
 Oral
• Insulin secretagogues:
– Sulfonylureas (oldest)
– Meglitinides
• Insuline sensitizers:
– Biguanide
– Thiazolidinediones
• Alpha-glucosidase inhibitors
– Acrabose
– Miglitol
 Oral Hypoglycemics
• GLP-1R agonists or GLP-1 analogue
• DPP-4 inhibitors
• Sodium-glucose transport proteins
 Indications for Oral
Hypoglycemics
• They are used to lower blood sugar levels
in patients that diet and exercise have
failed.
• The patient must have some pancreatic
function left.
• They can be used as a monotherapy or in
conjunction with other oral hypoglycemics.
 Contraindications
• Know drug allergy
• Active hypoglycemia
• Usually not used during pregnancy
• Liver disease
• Kidney disease
– Depending on the metabolic pathways of the
medication
 Sulfonylureas (Oral Hypoglycemic drugs)

First generation Second generation

Short Intermediate Long Short Long

acting acting acting acting acting

Glyburide
Tolbutamide Acetohexamide Chlorpropamide Glipizide
(Glibenclamide)
Tolazamide
Glimepiride
 Sulfonylureas
• Stimulate insulin secretion from the beta cells of
the pancreas, thus increasing insulin levels

• Beta cell function must be present

• Result: lower blood glucose levels

• First-generation drugs not used as frequently

now
 FIRST GENERATION SULPHONYLUREA COMPOUNDS
Tolbutamid Acetohexamide Tolazamide Chlorpropamide
short- intermediate- intermediat long- acting
acting acting e-acting

Absorption Well Well Slow Well

Metabolis Yes Yes Yes Yes
m
Metabolite Inactive* Active +++ ** Active ++ Inactive **
s **
Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrs
Duration of Short Intermediate Intermediat Long
action (6 – 8 hrs) (12 – 20 hrs) e ( 20 – 60 hrs)
(12 – 18
hrs)
Excretion Urine Urine Urine Urine

* Good for pts with renal impairment

** Patiens with renal impairment can expect long t 1/2
 SECOND GENERATION SULPHONYLUREA
COMPOUNDS

Glipizide Glibenclamide Glimepiride

Short- (Glyburide) Long-acting
acting Long-acting
Absorption Well Well Well
Metabolism Yes Yes Yes
Metabolites Inactive Inactive Inactive
Half-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrs
Duration of 10 – 16 hrs 12 – 24 hrs 12 – 24 hrs
action
Excretion Urine Urine Urine
 Adverse Effects
• Sulfonylureas
 Hypoglycemia
 hematologic effects
 nausea
 epigastric fullness
 heartburn
 many others
 Interactions
• Hypoglycemic effect increases when taken
with alcohol, anabolic steroids

• Adrenergics (beta blockers) may mask many of

the symptoms of hypoglycemia

• Hyperglycemia: corticosteroids,
phenothiazines, diuretics, oral contraceptives,
thyroid replacement hormones, phenytoin,
diazoxide and lithium.
 Interactions
• Allergic cross-sensitivity may occur with
loop diuretics and sulfonamide antibiotics

• May interact with alcohol / OTC medication

containing alcohol)
– causing a disulfiram (Antabuse) -type
reaction (facial flushing, pounding
headache, feeling of breathlessness, and
nausea)
 Meglitinides
• Meglitinides
– repaglinide
– nateglinide

• Meglitinides
– Action similar to sulfonylureas
– Increase insulin secretion from the pancreas
 Adverse Effects
• Meglitinides
– Headache
– hypoglycemic effects
– Dizziness
– weight gain
– joint pain
– upper respiratory infection or flu-like
symptoms
 Biguanides
• Biguanides
– metformin

• Mechanism action
– Increase peripheral glucose utilization
– Inhibits gluconeogenesis
– Impaired absorption of glucose from the gut
– Decrease blool glucagon
– Does not increase insulin secretion from the
pancreas (does not cause hypoglycemia)
 Adverse Effects
• Primarily affects GI tract: abdominal
bloating, nausea, cramping, diarrhea,
feeling of fullness
• May also cause metallic taste, reduced
vitamin B12 levels
• Lactic acidosis is rare but lethal if it occurs
• Does not cause hypoglycemia
 Thiazolidinediones
• Thiazolidinediones
– pioglitazone
– rosiglitazone
– Also known as “glitazones”
• Mechanism action:
– Decrease insulin resistance
– “Insulin sensitizing drugs”
– Increase glucose uptake and use in skeletal
muscle
– Inhibit glucose and triglyceride production in
the liver
 Adverse Effects
– Moderate weight gain
– Edema
– Mild anemia
– Hepatic toxicity—monitor liver function tests
 Alpha-glucosidase Inhibitors
• Alpha-glucosidase inhibitors
– acarbose
– miglitol

• Mechanism action:
– Reversibly inhibit the enzyme alpha-
glucosidase in the small intestine
– Result: delayed absorption of glucose
– Must be taken with meals to prevent
excessive postprandial blood glucose
elevations (with the “first bite” of a meal)
 Adverse Effects
• Flatulence
• Diarrhea
• abdominal pain

• Do not cause hypoglycemia,

hyperinsulinemia, or weight gain
 GLP-1R agonists or GLP-1
analogues
• GLP-1 receptor agonists
– Exendin-4
– Exenatide
• GLP-1 analogues
– Liraglutide  a long-acting
glucagon-like peptide-1 (GLP-1
 DPP-4 inhibitors

• Their mechanism of action is thought to

result from increased Incretin levels (GLP-
1 and GIP), which inhibit glucagon
release, increases insulin secretion and
decreases gastric emptying.
 Sodium-glucose transport
proteins
Gene Location Co-transport ratio and % of glucose
reabsorption
SGLT1 Located in the S3 Has a 2Na+:1Glucose co-transport ratio
segment of the and is responsible for 2% of glucose
proximal tubule reabsorption

SGLT2 Is predominately SGLT2 Is predominately located in the S1

located in the S1 and S2 segments of the proximal
and S2 segments tubule.Has a 1Na+:1Glucose co-transport
of the proximal ratio and is responsible for 98% of glucose
tubule. reabsorption.
Insulin
 Insulins
• Mechanism of Action
– Substitute for & same effects as endogenous
insulin
• Restores the diabetic patient’s ability to:
– Metabolize carbohydrates, fats, and proteins
– Store glucose in the liver
– Convert glycogen to fat stores
• Most now human-derived, using recombinant DNA
technologies
• Goal: tight glucose control , to reduce the
incidence of long-term complications
 Indications
• To treat both types of diabetes

• Each patient requires careful

customization of the dosing regimen for
optimal glycemic control
 Adverse Effects

• Are all signs and symptoms of

hypoglycemia including shock and death.
 Human-Based Insulins
• Rapid-Acting
• Most rapid onset of action
• Shorter duration

Insulin Onset Peak (hrs) Duration (hrs)

(mins)
aspart (Novolog) 2-33 1-3 3-5
lispro (Humalog) 2-33 30mins – 2.5 3-6.5
glulisine (Apidra) 2-33 30mins – 1.5 1.-25

May be given SC or via continuous SC infusion

pump (but not IV)
 Human-Based Insulins
• Short-Acting
– regular insulin (Humulin R, Novolin R)

Insulin Onset (mins) Peak (hrs) Duration

(hrs)

Humulin R 30 mins to 4 hrs 2.5-5 5-10

Novolin R 30 2.5-5 8

– Onset 30 – 60 minutes
• The only insulin product that can be given by
 Sliding-Scale Insulin Dosing
• SC rapid or short-acting doses adjusted according to
blood glucose test results

• Typically used in hospitalized diabetic patients

– Or in patients on TPN / enteral tube feedings or receiving
steroids

• Subcutaneous insulin is ordered in an amount that

increases as the blood glucose increases
 Human-Based Insulins
• Intermediate-Acting
– isophane insulin suspension (also called NPH)
(Humulin N, Novolin N)
– isophane insulin suspension & insulin injection
(Humulin 50/50 , Humulin 70/30, Novolin 70-30)
– Lispro protamine suspension (Humalog 75/25, Novolog
Mix 70/30)
– insulin zinc suspension (Lente, Novolin L)
» Cloudy appearance
» Slower in onset and more prolonged duration
than endogenous insulin
 Human-Based Insulins
Intermediate-Acting

Insulin Onset (hrs) Peak (hrs) Duration (hrs)

Isophane (NPH):
Humulin N 1-4 4-12 16-28
Novolin N 1-5 4-12 24
Isophane & Insulin:
Humulin 50/50 0.5 4-8 24
Humulin 70/30 0.5 4-12 24
Novolin70/30 0.5 2-12 24
 Human-Based Insulins
Intermediate-Acting

Insulin Onset Peak (hrs) Duration (hrs)

(hrs)
lispro protamine & lispro:
Humalog Mix 75/25 0.25-0.5 0.5-1.5 12-24
Novolog Mix 70/30 0.2-0.33 2.4 24
Insulin Zinc Suspension:
Lente Iletin II 1-1.5 8-12 24
Novolin L 1-4 7-15 20-28
 Human-Based Insulins
• Combination Insulin Products

– NPH 70% and regular insulin 30% (Humulin

70/30, Novolin 70/30)

– NPH 50% and regular insulin 50% (Humulin

50/50)

– insulin lispro protamine suspension 75% and

insulin lispro 25% (Humalog Mix 75/25)
 Human-Based Insulins
Long-Acting

Insulin Onset Peak Duration

glargine (Lantus 1 No peak activity 24 (when
administered at hs)
detemir (Levemir) 1 6-8 6-28
Injection Sites
 Insulin Pumps
External Internal
ADOLESCENT PEDIATRI

NON - OBESE
Sulfonilurea Glinid

add Metformin Glitazon

add Insulin
 INSULIN

AFINITAS

IgG

Mutasi
Reseptor Insulin

Acanthosis nigricans :

Aging
Androgenic women
RESISTENSI INSULIN EKSTRIM

AFINITAS

IgG

Mutasi
Reseptor Insulin

Acanthosis nigricans :

Aging
Androgenic women
 Inhibitor
Sulfonilurea Glinid
-Glukosidase

Substi
tusi
Insulin

Acanthosis nigricans :

Aging
Androgenic women
 JUMLAH
SEL-B

Sekresi
Insulin
Pankreas
 Pankreas Output Glukose
Hepatik 

Ekses :
Rilis
Insulin  • Katekholamin
• GH
• Glukokortikoid
• Glukagon
• Somatostatin
 PADA
TRIMESTER II DAN III
SINDROM CUSHING :
EKSES KORTISOL INSULIN

-
AKROMEGALI :
EKSES GH GLUKOSE
DARAH
 • Adrenokortikoid
• Jar. Tiroid
• Tiroglobulin
• Parietal Gastrik

OTOIMUN

• Penyakit Addison
• Sindrom Schmidt
• Gagal Poliglanduler
 o Kortikosteroid
o Diazoksid
o Fenitoin
nsulin o Thiazid
o Niasin
o Bloker-β
DM tipe - 2 o Interferon-α
o Pentamidin
o Kontrasepsi oral
KETOASIDOSIS DIABETIK

HIPERGLIKEMIA HIPEROSMOLAR

HIPOGLIKEMIA
GLUKOSE
JARINGAN

LEMAK KATALISIS ASETIL Co-A

CEPAT

SENYAWA ASETOASETAT
DAN –HIDROKSIBUTIRAT

PROTEIN KATALISIS KETON

Fruity breath odor
GLUKOSE
JARINGAN

Memperbaiki
LEMAK KATALISIS ASETIL Co-A
status metabolik pasien :
CEPAT

- larutan hipotonikSENYAWA
: glukose darah 
ASETOASETAT
- suplemen potassium
DAN –HIDROKSIBUTIRAT
- Infus insulin konstan
PROTEIN KATALISIS KETON
Fruity breath odor
HIPERGLIKEMIK HIPEROSMOLAR

• Usia lanjut DM tipe-2

• Muda, prolong hyperglemic,
dehidrasi, ggn fs ginjal
• Glukose darah > 1000 mg/dl
• Mortality

• Cairan hipotonik
• Infus Insulin dosis rendah
Mikrovaskuler
 Lemah
Mudah merasa lelah

 Hilangnya kalium dalam tubuh

 Katabolisme protein otot

KONDISI PARAH LEBIH LANJUT

Mikrovaskuler Lemak Subkutan Akan Hilang Dan Otot Sulit

Digerakkan
(Muscle Wasting).
 PAIN OR BURNING

Neuropati Diabetik
( Pain Or Burning )

Akibat Akumulasi Metabolit Glukose Aktif yang Dapat

Mikrovaskuler Mempengaruhi Tekanan Osmose

Berkaitan Dengan Enzim Aldose Reduktase

 PAIN OR BURNING

Neuropati Diabetik
• Tx DM (Kontrol glikemia)
( Pain Or Burning )
• Antidepresan trisiklik
•Akibat Akumulasi
Antikonvulsan Metabolit
: Fenitoin,
Glukose Aktif yang
gabapentin, Dapat
Karmabazepin
Mempengaruhi Tekanan Osmose
• Topical Capsaicin
•Berkaitan Dengan NSAIDs
Pain medication Enzim Aldose
Reduktase
 PARESTHESIA NUMBNESS

KAKI >> TANGAN

• Tx DM (Kontrol glikemia)
• Antikonvulsan : Fenitoin,
gabapentin, Karmabazepin

Mikrovaskuler
Mikrovaskuler
 Hambatan Vasodilatasi
Arteria Cavernosa

• Tx DM
• SILDENAFIL
• Mimba, Brototowali, Sambiloto, Daun
Sendok
 GASTROPARESIS

• Tx DM (Kontrol Glikemia)
• Obat -2 slow gastric motility
dihentikan
• Metoklopramid
• Eritrosin

Mikrovaskuler
 • Kontrol Glukose darah
• Kontrol Tekanan Darah :
Inhibitor ACE, Diuretik

Mikrovaskuler
 NONHEALING FOOT ULCER

Stop Smoking

Revaskularisasi Terapi
Hiperbarik
Makrovaskuler

Perawatan kaki Antiplatelet Kontrol Lipid

 KOMPLIKASI KRONIS
DM-LIPID

• STATIN : Simvastatin, Pravastatin

• NIACIN
• FIBRAT : Klofibrat, Benzafibrat

Makrovaskuler
 KOMPLIKASI KRONIS
DM-HIPERTENSI

• Tx awal : Inhibitor ACE

• Tx 2nd : Diuretik Thiazid

• Antagonis Kalsium :

Nifedipin,Verapamil, Diltiazem

Makrovaskuler
CORONARY HEAT DISEASE

• Kontrol lipid
• Kontrol hipertensi
• Antiplatelet
• Berhenti merokok
• β – Blocker
• ACEI : vasculer protective effect