Download Antidiabetic drugs

ANTI-DIABETIC DRUGS
Assoc. Prof. Iv. Lambev
E-mail: [email protected]
www.medpharm-sofia.eu
Glucose occupies a central position
in metabolism as the predominant
substrate for energy production.
NORMOGLYCEMIA (WHO)
Fasting glucose:
3.8-6.1 mmol/l
HbA1C: 4.7–6.0%
Suspected diabetes mellitus
75 g glucose p.o.: 2 h later
Random
blood glucose
<7.8 mmol/l
7.8–11.1 mmol/l
≥11.1 mmol/l
Normal
Impaired Glucose
Tolerance (IGT)
Diabetes mellitus
IGT
(7.8–11.1 mmol/l)
1/3 become
normal
1/3 remain
IGT
1/3 become
DM
HbA1C is a lab test that shows
the average amount of sugar
in blood over 2–3 months. It shows
how well you are controlling DM.
An HbA1C of 6% or less is normal.
The following are the results
when the HbA1C is being used
to diagnose diabetes:
•Normal: Less than 5.7%
•Pre-diabetes: 5.7% to 6.4%
•DM: 6.5% or higher
Values of HbA1C ≥ 7% are a signal
for emergency change in treatment.
Worldwide prevalence of diabetes mellitus
Diabetes mellitus (DM)
Type 1 DM (beta-cell destruction) – about 10% of all patients.
a) Autoimmune DM (the 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 the beta- cells of the 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 has no known etiology (has no
evidence of autoimmunity). This form is more common among
individuals of African and Asian origin. Patients periodically
develop 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 (It is connected with
some pediatric syndromes that have mutations in the insulin
receptor gene with subsequent alterations in the 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.
> 520 000 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
Diabetic nephropathy
Management goals
•Normoglycemia
- avoiding hypoglycemia
or ketosis
- HbA1C < 6.5%
(glycosylated hemoglobin)
•Reduce
- nephropathy
- neuropathy
- retinopathy
- infections (mycoses, etc)
Glucometers
•Control blood
pressure (120/80 mm)
•Diet
– weight control BMI
!
– low fat intake 18.5–24.9
– normal protein intake
– carbohydrates ~ 50% of total energy
•Motor activity and compliance!
I. Insulin
t1/2: 5–6 min
molecule mass: 5734 Da
Insulin is a protein, secreted
from the β-cells of the islets of
Langerhans in the pancreas
in response to a rise in blood
glucose, and inhibited by a fall.
Glucagon
hyperCortisol
glyceAdrenaline
mia
Somatotrophin (GH)
Insulin
hypoglycemia
Amylin
Amylin (Islet Amyloid Polypeptide – IAPP)
reperesents a 37-residue peptide hormone.
It is cosecreted with insulin from the pancreatic
β-cells in the ratio of approximately 100:1.
Amylin plays a role in glycemic regulation by
slowing gastric emptying and promoting satiety,
thereby preventing post-prandial spikes
in blood glucose levels.
Mechanism of action
•Insulin acts via receptors that
are transmembrane
glycoproteins.
•Each receptors has two 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).
Insulin
(-)
AC cAMP PD
ATP
3’,5’-AMP
(+)
Lipolysis in adipose tissue
(hypercholesterolemia)
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 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
Nobel prize
similar to human.
(1923)
More recently, recombinant
DNA technology has allowed
in vitro manufacturing 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 are used for insulins are:
•Hum- and -man (for human ),
•PP (purified preparation)
MAIN TYPES OF
INSULIN PREPARATIONS
•Short-acting
•Intermediate-acting
(they contain protamin or Zn)
•Long-acting
(they contain both 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 are used mainly in type 1 DM.
Patients with type 2 DM use
insulins in the following cases too:
•acute infections
•pregnancy
•surgical operations
•burn
•myocardial infarction
•ketoacidosis
Therapy of DM
with insulin is
a replacement
therapy.
High compliance!
s.c.:
6 sec
s.c.
Insulin pumps:
They infuse
subcutaneously
fast-acting
insulin through
small catheter
(very handy
and very
expensive).
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)
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
II. Oral hypoglycemic and
other drugs, used
in DM type 2
1. Biguanides:
Metformin
•usually first line drug for type 2 DM
•reduces intestinal glucose absorption
•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 MR )
•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. Meglitinides: stimulate the release of insulin
from pancreas by closing ATP-dependent
potassium channels.
- Nateglinide
- Repaglinide
4. Glucosidase inhibitors
- Acarbose (Gluco Bay): p.o.
•Inhibits intestinal alpha-glucosidase
•Decreases intestinal absorption
of the mono- and polysaccharides.
•Produces flatulence and diarrhoea.
5. Thiazolidinediones (TZDs)
They increase tissue insulin sensitivity
but have serious ADRs and the EMA
recommended in Sept (2010) that they
be suspended from the EU market:
- Rosiglitazone (Avandia)
has high cardiovascular risks.
- Pioglitazone causes bladder tumors.
- Troglitazone causes hepatitis.
6. Glucagon-like peptide-1 (GLP-1)
agonists (in type 2 DM): increase
pancreatic secretion of insulin:
Exenatide
Bydureon (s.c./7 days):
$323/4 doses, resp.
$4200 per year
Liraglutid
Liraglutid
is a GLP-1
agonist,
which reduces,
BM, HbA1C,
and systolic
blood pressure,
and improves
beta cell function
of the pancreas
(s.c. once a day)
7. Inhibitors of Dipeptidil
peptidase-4 (DPP-4): prevent
degradation of incretin GLP-1
Sitagliptin (p.o.)
Vildagliptin (p.o.)
8. Inhibitors of reabsorption
of glucose (SGLT2 inhibitors): p.o.
•Canagliflozin blocks in renal proximal
tubule sodium / glucose co-transporter
protein 2 (SGLT2), which re-absorbed
90% of the filtrated glucose.
The result is increased glucosuria and
plasma glucose levels are lowered.
ADRs: Hypoglycaemia, vulvovaginal candidiasis
urinary tract infections, polyuria, frequent urination.