Download insulin

ANTIDIABETIC
AGENTS
Jiří Slíva
DIABETES MELLITUS
• Multifactorial disease with genetic component
• Main symptoms: hyperglycemia, metabolic disturbances
• Relative or total absence of insulin → increase of the glucose
blood level
• Borderline DM: concentration of glucose plasma level 7.0
mmol/L – fasting and 11.1 mmol/L 2 hours after the meal
TYPE l diabetes (IDDM, insulindependent diabetes mellitus)
• Formerly juvenile diabetes
• LADA (latent autoimmune diabetes in adults)
• Total absence of insulin
• Langerhans islets B-cells lesion (usually caused by
autoimmune disease) → infiltration of islets with Tlymphocytes
• Antibodies against islets tissue and insulin
TYPE ll diabetes (NIDDM, non-insulin
dependent diabetes mellitus)
• Formerly senile diabetes (onset in adulthood)
• Relative absence of insulin
• Levels of insulin could be normal or above or below
normal
• Insulin-sensitive tissues show a lack of insulin-sensitivity
or a reduction of insulin receptors is supposed
• NIDDM patients are often obese
ANTIDIABETIC AGENTS
DM l. type treatment
•
Insulin
DM ll. type treatment (PAD)
•
•
•
•
•
Sulphonylureas
Biguanides
α-glucosidase inhibitors
Glitazones (thiazolidinediones)
Glinides etc.
INSULIN
• Human insulin
– low molecular protein
– strong electronegative (binding to positively charged
proteins in circulation and to membrane insulin
receptors)
– two peptide chains A (21 AAs) a B (30 AAs), linked by
disulphide bridges
Structure of human insulin
INSULIN
• Proteohormone
- glucose utilization
- metabolism of lipids and proteins
(storage of these basal sources, „anabolic“ hormone)
Lack of insulin
(either absolute of relative)
►DIABETES MELLITUS
INSULIN SECRETION
Daily production: 20 – 40 IU
• Basal secretion (cca 50 %)
- independent on food intake
- blocks glucose production in liver
- responsible for fasting euglycaemia
• Stimulated secretion (cca 50%)
- stimulated by food intake
- regulates postprandial glycaemia
INSULIN TREAMENT INDICATIONS
• DM type 1
• Some DM type 2 patients or
patients with secondary diabetes
•
•
•
•
•
•
Insulin treatment in DM type 2 patients
PAD treatment failure
Allergy to PAD
Diabetes in pregnancy
Severe renal or liver insufficiency
Clinical situations with contemporary decompensated
diabetes (operation, infection, etc.)
INSULIN SYNTHESIS
• preproinsulin → proinsulin → insulin a C-peptide
(shows the endogenous insulin secretion)
• Insulin release from pancreatic B-cells each 15 30 min
HEALTHY
DIABETIC PATIENT
INSULIN RELEASE
FROM B-CELLS
 Controlled by glucose concentration
 a) influx of glucose to the B-cell by GLUT-2





transporter
b) metabolism of glucose by glukokinase
c) increase of ATP concentration in the cell
d) closure of ATP-sensitive potassium channels
e) depolarization and opening of voltage-sensitive
Ca2+ channels
f) degranulation of B-cells and insulin release to the
extra cellular space
INSULIN RECEPTORS
• glycoproteins (muscle, adipose tissue)
• two heterodimers linked by disulphide
bridges, each consists of α- and β- subunit
• α-subunit – extra cellular, binding place
for insulin
• β-subunit – transmembrane protein with
tyrosine kinase activity
Figure : Insulin-receptor complexes on the cell surface cause chemical responses to
occur within the cell. This figure was reproduced pending permission from the authors
of Life, 6th Ed (Purves et al, 2001).
INSULIN EFFECTS
• The main hormone of metabolic processes in
liver, muscle and adipose tissue
• stimulates anabolic and inhibits catabolic
processes
• Facilitates gathering of glucose, aminoacids and
lipids from food
• Acute effect of insulin ►hypoglycemia
ACUTE CONSEQUENCES
OF INSULIN SHORTAGE
• Lack of insulin in glucose metabolism →
hyperglycemia
• Osmotic diuresis → polyuria
• Renal loss of water, Na+ and K+ → dehydration,
thirst
• Dehydration → hypovolemia
• Release of fatty acids →hyperacidlipidemia
INSULIN THERAPY
• The daily dose as low as possible!
(up to 40 IU / day)
• Shorter-acting insulin
→ more doses daily
→ better compensation of DM
→ using lower daily dose
INSULIN THERAPY
• „Conventional“ therapy
- insulin in one or two daily doses
(good compensation just in type 2 DM patients)
• „Intensified“ therapy
- covers basal and prandial need of insulin
(more doses, better compensation, lower daily dose)
ANIMAL INSULIN SOURCES
• bovine and porcine pancreas
→ complicated purification
• Bovine insulin is different from human
insulin in three amino acids, porcine in one
amino acid
• human insulin
ADVANTAGE: less allergic reactions
CLASSIFICATION OF
INSULIN PREPARATIONS
• According to sources and purity
• According to duration of action
CLASSIFICATION OF
INSULIN PREPARATIONS
• Sources and purity
– Animal
– Human
– Insulin analogues
• Duration of action
–
–
–
–
Short-acting
Intermediate-acting
Long-acting
Combined (mixtures)
ANIMAL INSULINS
• Bovine
• Porcine
• Mixtures
According to level of purity
• Chromatography purified (PUR)
• Highly purified – monocomponent (MC)
(significantly less contaminated)
HUMANE INSULINS
(HM)
• emp insulin – enzyme techniques to
modify porcine insulin
• crb insulin – chain recombinant DNA in
bacteria
INSULIN ANALOGUES
• short-acting (glulisine)
• intermediate-acting (lispro)
– chain recombinant DNA in bacteria technique
– the penultimate lysine and proline residues on the Cterminal end of the B-chain are reversed
• long-acting (glargine, detemir)
DURATION OF ACTION
•
Short-acting
- onset 30 minutes, peak 2-4 hours
Soluble simple insulin
Lispro
•
Intermediate- and long- acting
- duration of action between 16 and 35 hours
Semilente (suspension, amorphous insulin zinc)
Lente (suspension, mixture,amorphous insulin zinc, insulin zinc crystals)
Isophan insulin (NPH)(complex of protamine and insulin)
Ultralente (suspension, poorly soluble insulin zinc crystals)
•
Combined
- fixed mixtures (biphasic,..)
Time profiles
Pharmacokinetics of insulin
• The speed of absorption depends on pharmaceutical
properties, dosage, and tissue perfusion
• Practically no plasma protein binding
•
•
•
•
Degradation of insulin:
kidneys (35‒40 %), liver (60 %), the opposite in
exogenous insulin
biologic half-life: 7‒10 minutes
hydrolysis of S-S bridges between A and B chains by
insulinase
further degradation by proteolysis
Adverse reactions: acute
• hypoglycemic reaction – in insulin over dosage,
inadequate caloric intake (less food), higher
physical activity
→ sympathetic reaction (sweating, tremor,
tachycardia, weakness) and
→ parasympathetic reaction (hunger, nausea,
„clouded“ vision)
• Hypoglycemic coma
– i.v. glucose (20‒50 ml 40% Glu) or glucagon
(i.m., s.c.), than glucose or sweet drinks p.o.
Adverse reactions: long-term
• Long term therapy with repeated episodes
of hypoglycemia (namely in older patients)
=> CNS disturbances (fuzziness,
incoordinated speech, bizzare behavior)
Insulin application
Application forms
Insulin syrretes
• Special plastic syrretes, volume 1 ml with sealed needle
• 1 scale segment = 1 IU of insulin
• Single use
• Most common application form (adults)
• Cheap
Note: One international unit of insulin (1 IU) is defined as the "biological equivalent" of 34.7 μg of pure crystalline
insulin. This corresponds to the old USP insulin unit, where one unit (U) of insulin was set equal to the amount required
to reduce the concentration of blood glucose in a fasting rabbit to 45 mg/dl (2.5 mmol/L).
Application forms
Insulin pens
• Injectors like pen
• Extensible needle
• Perfect for intensified
insulin therapy
Structure of insulin pen
Application forms
Insulin pumps
• subcutaneous continual infusion
• highly reliable, digital, miniature
• advantage: exchange each 48
hours, comfortable for the patient
• disadvantage: expensive,
repeated measurement of glycemia
during the day, higher risk of
cutaneous infection (permanent
needle)
Inhalable insulin
• currently not available
• previously approved in U.S (Exubera)
• effective, but no better than injected short-acting insulin
• it is unlikely to be cost-effective
• in 2011 announced that when applied deep into the
nostrils may delay the onset of Alzheimer's disease
Note: under development ‒ buccal spray, insulin pills, insulin patch, …
ORAL
ANTIDIABETIC
DRUGS
Oral Antidiabetic Drugs
Classification of oral antidiabetics:
•
Sulphonylureas
•
Biguanides
•
Intestinal glucosidase inhibitors
•
Glitazones (thiazolidinediones)
•
Glinides
•
Gliptins (syn. dipeptidyl-peptidase 4 (DPP-4)
•
SGLT inhibitors
Other antidiabetics:
Incretinoenhancers
Oral Antidiabetic Drugs
• insulin „sensitizers“
– biguanides
– glitazones (thiazolidinediones)
• insulin „secretagogues“
– sulphonylureas
– fast (short) insulin secretagogues (Glinides)
– incretins and DPP-4 Inhibitors
• Intestinal glucosidase inhibitors
• SGLT inhibitors
Biguanides
• Mechanism of action:
– peripheral insulin uptake enhancement (skeletal
muscle,...)
• Main drugs:
– metformin
• Adverse effects:
– lactate acidosis
Glitazones
(Thiazolidinediones)
• Mechanism of action:
– peripheral insulin receptors sensitization
– targeting peroxisome proliferator-activated receptor (PPARgamma)
– improving insulin resistance
• Main drugs:
– Pioglitazone (Actos)
– [Rosiglitazone (Avandia) – withdrawn in 2010, because of
problems with cardiovascular safety)]
• Adverse effects:
– hepatotoxicity
– congestive heart failure…
Sulphonylureas
• Mechanism of action : insulin secretion
stimulation
• Main drugs: Tolbutamide, Glibenclamide,
Glipizide, Gliclazide
• Adverse effects : hypoglycemia
Fast (short) insulin secretagogues: glinides
• Mechanism of action:
– insulin secretion stimulation (glycaemia
dependent)
• Main drugs:
– repaglinide, nateglinide
• Adverse effects:
– hypoglycemia, GIT disturbances
x
Sulphonylureas vs. glinides
Sulphonylureas
Glinides
1) moderate to long-lasting eff.
2) 1x or 2x daily
3) decreased FBG
4) low eff. on the early secretion of insulin
5) low influence of postprandial
glycaemic oscilation
6) clinically significant risk of
hypoglycaemia (mostly at night)
7) weight gain 2–4 kg
8) average decrease of HbA1c: 1.5 %
9) lower price
1)
2)
3)
4)
5)
6)
7)
8)
9)
short action
administration with each meal
postprandial decrease of glycaemia
improved postprandial secretion of
insulin
signif. influence of PP glycaemic
oscilation
low risk of hypoglycaemia
lower weight gain
average decrease of HbA1c is
comparable in repaglinide;
nateglinide: 0.8 %
higher price
Intestinal (Alpha) Glucosidase Inhibitors
• Mechanism of action:
– decrease of intestinal carbohydrate absorption
• Main drugs:
– acarbose
– miglitol
• Adverse effects:
– diarrhoe
Physiology of incretins
Note: GLP-1 …Glucagon-like peptide 1; GIP …glucose-dependent insulinotropic polypeptide
Baggio LL, 2007
Physiology
of GLP-1
Drucker D, 2006
Note: Glucagon-like peptide 1 (GLP-1)
Physiology
of GIP
Note: GIP …glucose-dependent insulinotropic polypeptide
Baggio LL, 2007
Structure of GLP-1 and incretinomimetics
Drucker D, 2006
Gliptins: mechanism of action
• sitagliptin, vildagliptin, saxagliptin
- inhibitors of dipeptidyl
peptidase-4 (DPP-4)
= incretin enhancers =>
increased level of GLP-1
& GIP
GIP …glucose-dependent insulinotropic polypeptide
Lauster CD, 2007
Gliptins + metformin
HbA: Hemaglobin A; ITT: Intent to treat; LAF: Vildagliptin; MET: Metformin; PBO: Placebo
Fonseca V, 2007
Characteristics and effects of GLP-1
receptor agonists and DPP-4 inhibitors
Ahrén B, 2011
Glycosuric agents
Marsenic O, 2009
Glycosuric agents
• dapagliflozin
– SGLT-2 inhibitor
Marsenic O, 2009
Petr Potměšil
• Extension of presentation about
antidiabetics
Possible risk of pancreatic damage after use of drugs
influencing incretins
Increased incidence of pancreatitis (?)
actually re-assessment of safety in course by EMA,
no change in recommendations for therapy available at the
moment (published in Mar-2013, details: www.ema.europa.eu)
• DPP-4 inhibitors
(inhibitors of
dipeptidylpeptidase IV)
Sitagliptin
Vildagliptin
Saxagliptin
• Analogues of GLP-1
(glucagone like peptide)
• Liraglutid
• Agonists of receptor for
GLP-1
• Exenatid
Diabetes – comparison of metabolic effects of
insulin and glucagone
A/ Insulin
B/ Glucagone
• 1) ↑ oxidation of
glucose and ↓
gluconeogenesis
• 1) ↑ glycogenolysis
• 2) ↑ synthesis of
glycogen and lipids
• 3) anabolic effect
• 2) hyperglycaemia
Comparison of pharmacokinetic parameters of
sulphonylureas and biguanides
A/ Sulphonylureas
B/ Biguanides
• ↑ binding to plasm.
• do not bind to plasm.
proteins
proteins
• ↑ biotransformation,
• no extensive
biotransformation,
thus contraindicated in
elimination mainly by
patients with severe
renal excretion, thus
impairment of hepatic/renal
contraindicated in
function
patients with severe
impairment of renal
functions
Some treatment options for
diabetic neuropathic pain
• Tricyclic antidepressants: low tolerability (antimuscarinic eff.)
• SSRI - limited efficacy: sometimes not recommended for pain
• SNRI antidepressants (AE: disturbed sleep at start)
1/ venlafaxine (Effectin): ↑ dose - possible hypertension
2/ duloxetine (Cymbalta): also approved for urinary
stress incontinence and GAD (general. anxiety disorder)
• Antiepileptic drugs (AE: sedation, weight gain)
1/ gabapentin (Neurontin)
2/ pregabalin (Lyrica), also for GAD, improves sleep
3/ carbamazepin – many interactions with other drugs