Download Type 2 DM

ANTIDIABETIC
DRUGS
(Abstract)
© Assoc. Prof. Iv. Lambev, PhD
E-mail: [email protected]
Glucose occupies a central position
in metabolism as the predominant
substrate for energy production.
NORMOGLYCEMIA
2.8-6.1 mmol/l
Suspected diabetes mellitus
75 g glucose p.o.: 2 h later
random blood glucose
less than 8 mmol/l
8 to 11 mmol/l
greater than 11 mmol/l
Normal
Impaired glucose tolerance
Diabetes
1/3 become normal
1/3 remain IGT
1/3 become diabetic
Worldwide prevalence of diabetes mellitus
Diabetes mellitus (DM)
Type 1 DM (beta-cell destruction) – about 10% of all patients.
a) Autoimmune DM (so called insulin-dependent DM – IDDM
or juvenile-onset diabetes). It results from autoimmune mediated
destruction of the beta cells of the pancreas. The rate of destruction
is quite variable (and may reach 80% of beta- cells of Langerhans
islets), being rapid in some individuals and slow in others. The
rapidly progressive form is commonly observed in children, but also may
occur in adults. The slowly progressive form generally occurs in adults
and is sometimes referred to as latent autoimmune DM in adults (LADA).
b) Idiopathic type 1 DM, which have no known etiology (have no
evidence of autoimmunity). This form is more common among
individuals of African and Asian origin. Patients periodically
develops ketoacidosis.
Type 2 DM (predominantly insulin resistance with relative insulin
deficiency or predominantly an insulin secretory defect with/without
insulin resistance). DM of this type previously encompassed noninsulin-dependent diabetes (NIDDM), or adult-onset diabetes. It is
a term used for individuals who have relative (rather than absolute)
insulin deficiency. People with this type of diabetes (> 80% of
patients with DM) frequently are resistant to the action of insulin.
Other specific types of DM
•Genetic defects of beta-cell function (mutations on chromosome 12 in a hepatic nuclear transcription factor referred to as
HNF13. A second form is associated with mutations in
the glucokinase gene on chromosome 7p.
•Genetic defects in insulin action (e.g. Leprechaunism and
Rabson–Mendenhall syndrome are pediatric syndromes that
have mutations in the insulin receptor gene with subsequent
alterations in insulin receptor function and extreme insulin
resistance).
•Diseases of the exocrine pancreas (pancreatitis, trauma, cancer)
•Endocrinopathies (acromegaly, Cushing’s syndrome, glucagonoma and pheochromocytoma).
•Drug- or chemical-induced (pentamidine, glucocorticoids etc.).
•Viral infections may cause beta-cell destruction (e.g. mumps,
adenovirus, cytomegalovirus, Coxsackie B, congenital rubella).
•Other genetic syndromes sometimes associated with
DM (Down’s, Klinefelter’s and Turner’s syndromes etc.
Gestational diabetes (Includes the former categories
of gestational impaired glucose tolerance and gestational DM).
>400 000 patients
with DM
DM – complications:
large blood vessel atherosclerosis
•coronary heart disease (CHD)
•limb ischaemia (diabetic foot!)
•stroke
small blood vessel atherosclerosis
•retinopathy
•neuropathy
•nephropathy
•skin ulceration
infection (mycoses etc.)
Diabetic retinopathy results in scattered haemorrhages,
yellow exudates, and neovascularization
Management goals
•Normoglycemia
- avoiding hypoglycemia or ketosis
- HBA1C < 6.5%
•Reduce
- nephropathy
- neuropathy
- retinopathy
- infections
•Control blood pressure
•Avoid smoking
•Diet
– weight control BMI
18.5–24.9
– low fat intake
– normal protein intake
– carbohydrates ~ 50% of total energy
•Motor activity
t1/2 5–6 min
Insulin is a protein, secreted
from the b-cells of the islets of
Langerhans in the pancreas
in response to a rise in blood
glucose, and inhibited by a fall.
glucagon
cortisol
adrenaline
somatropin (GH)
hyperglycemia
insulin hypoglycemia
Mechanism of action
•Insulin acts via receptors that
are transmembrane
glycoproteins.
•Each receptors has two insulin
binding sites. Receptor occupancy results in:
1. Activation of insulin-dependent
glucose transport processes in
adipose tissue and muscle.
2. Inhibition of adenylyl cyclasedependent processes (lipolysis,
proteolysis, glycogenolysis).
4. Intracellular accumulation of
potassium and phosphate
(which are linked to glucose
transport in some tissue).
5. Increased cellular amino acid
uptake, DNA and RNA synthesis.
6. Increased oxidative
phosphorylation.
Insulin
(-)
AC cAMP PD
ATP
3’,5’-AMP
(+)
Lipolysis in adipose tissue
(hypercholesterolemia)
Insulin is extracted either
from cattle or pig pancreas.
Bovine (B) insulin differs
from human insulin in three
amino acid residues, and
porcine (S) insulin in one,
but their action is very similar
to human.
More recently, recombinant
DNA technology has allowed
in vitro manufacture of insulin
with the same structure as
human (H) insulin.
All current insulin preparations
have a low content of impurities.
Insulin is initially purified by
protein extraction to form a
crystalline product. It may then
undergo either gel filtration to
produce a single peak (SP)
insulin or gel filtration and ion
exchange chromatography
which generates:
•monocomponent (MC),
•single component (SC) and
•rarely immunogenic (RI) insulin.
Other abbreviations
which use for insulins are:
•Hum- and -man (for human ...),
•PP (purified preparation)
MAIN TYPES
INSULIN PREPARATIONS
•Short-acting
•Intermediate-acting
(they contain protamin or Zn)
•Long-acting
(they contain protamin & Zn)
Injectors (with cartridge):
OptiPen, OptiSet, Penfill etc ...
Comparisons among insulins
Type
Onset of Peak
Duration
action
activity
Shortacting
10–20 min
Intermediate-act. 1–2 h
Long-act. 2–4 h
1–2 h
5–7 h
5–7 h
8–14 h
13–18 h
18–36 h
Insulins use mainly in type 1 DM.
Patients with type 2 DM use
insulins in the follow cases too:
•acute infections
•pregnancy
•surgical operations
•burn
•myocardial infarction
•ketoacidosis
Therapy of DM
with insulin is
a replacement
therapy.
1. Short-acting insulins
and analogues
a) Insulins: Actrapid, Humulin R
b) Analogues: Insulin aspart, Insulin lispro
s.c. 15 min before meal 4 times daily
chronobiologically (4:3:2:1)
c) Per inhalation: Exubera
Ketoacidosis
Short-acting
insulin (i.v.
or i.v. infusion)
with physiological saline
and potassium chloride
2. Intermediate-acting
insulins and analogues

M
•Humulin
•Humulin N

•Insulatard

•Mixtard
(s.c. 20 min before meal 2 times daily
chronobiologically)
3. Long-acting insulins
•Insulin detemir (Levemir)
•Insulin glargine (Lantus)
(s.c. 20 min before meal once daily)
Adverse effects of insulins
•hypoglycemia/coma
•allergic reactions
•insulin resistance
•lipodystrophia of subcutaneous fat at or near injection
•local fibrosis
Oral hypoglycemic drugs
•Used in type 2 DM
1. Biguanides metformin:
•usually first line drug for type 2 DM
•reduces intestinal glucose absorbtion
•stimulates anaerobic glycolysis
•stimulates glucose uptake
•enhances insulin receptor binding
Metformin
•excreted exclusively
by the kidney
•does not increase weight
and preferable in the obese
•GI side effects
•rarely lactic acidosis
2. Sulfonylureas
I generation:
•Chlorpropamide and Tolbutamide (Out...)
II generation:
•Glibenclamide (Maninil: tab. 5 mg)

•Gliclazide (Diaprel : tabl. 80 mg)
•Glipizide
•Gliquidone
Mechanism of action
•promote enhanced insulin release
from the pancreas
•leads to a reduction in hepatic
glucose production
Unwanted effects
•hypoglycemia weight gain
•facial flushing following
alcohol ingestion
Sulfonylureas –
important drug interactions:
•displacement from protein binding sites
– salicylates and sulphonamides
•interference with hepatic metabolism
– inducers: rifampicin, phenytoin
– inhibitors: cimetidine
•reduction of renal elimination
– allopurinol, salicylates
3. Glucosidase inhibitors
Acarbose (Gluco Bay): p.o.
Zuccarin: p.o.
•Inhibits intestinal alpha-glucosidase
•Decreases intestinal absorption
of the mono- and polysacharides.
•Produces flatulence and diarrhoea.
4. Thiazolidinediones (TZDs) –
increase tissue insulin sensitivity
Rosiglitazone (Avandia): p.o.
3.5. Incretinomimetics
Exenatide (analogue of GLP-1)
3.6. Inhibitors of Dipeptidil
peptidase-4 (DPP-4)
Sitagliptin
Vildagliptin