ANTI-DIABETIC DRUGSANTI-DIABETIC DRUGS

Assoc. Prof. Iv. LambevE-mail: itlambev@mail.bgwww.medpharm-sofia.eu

NORMOGLYCEMIA (WHO)NORMOGLYCEMIA (WHO)Fasting glucose:Fasting glucose:

3.83.86.1 mmol/l6.1 mmol/lHbAHbA1C1C: 4.7–: 4.7–66.0%.0%

GlucoseGlucose occupies a central positionin metabolism as the predominantsubstrate for energy productionenergy production.

Random Random blood glucoseblood glucose

<7.8 mmol/l<7.8 mmol/l 7.8–11.1 mmol/l7.8–11.1 mmol/l ≥≥11.1 mmol/l11.1 mmol/l

NormalNormalImpaired GlucoseImpaired GlucoseTolerance (IGT)Tolerance (IGT) Diabetes mellitusDiabetes mellitus

Suspected diabetes mellitusSuspected diabetes mellitus75 g glucose p.o.: 75 g glucose p.o.: 2 h later2 h later

IGTIGT(7.8–11.1 mmol/l)(7.8–11.1 mmol/l)

1/3 become1/3 becomenormalnormal

1/3 remain1/3 remainIGTIGT

1/3 become1/3 becomeDMDM

HbAHbA11CC is a lab test that shows is a lab test that shows the average amount of sugar the average amount of sugar in blood over in blood over 2–2–3 months. It shows3 months. It showshow well you are controlling how well you are controlling DMDM. . AAn HbAn HbA11CC of 6% or less is normal. of 6% or less is normal.The following are the resultsThe following are the resultswhen the HbAwhen the HbA11CC is being used is being usedto diagnose diabetes:to diagnose diabetes:

•NormalNormal: Less than 5.7%: Less than 5.7%•Pre-diabetesPre-diabetes: 5.7% to 6.4%: 5.7% to 6.4%•DDMM: 6.5% or higher: 6.5% or higher

Values of HbA1C1C ≥ 7% are a signal for emergency change in treatment.

Worldwide prevalence of diabetes mellitus

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 mediateddestruction of the beta cells of the pancreas. The rate of destructionis quite variable (and may reach 80% of the beta- cells of the Langerhansislets), being rapid in some individuals and slow in others. Therapidly progressive form is commonly observed in children, but also mayoccur in adults. The slowly progressive form generally occurs in adultsand is sometimes referred to as latent autoimmune DM in adults (LADA).b) Idiopathic type 1 DM, which has no known etiology (has noevidence of autoimmunity). This form is more common amongindividuals of African and Asian origin. Patients periodicallydevelop ketoacidosis.

Diabetes mellitus (DM)

Type 2 DM (predominantly insulin resistance with relative insulindeficiency or predominantly an insulin secretory defect with/withoutinsulin resistance). DM of this type previously encompassed non-insulin-dependent diabetes (NIDDM), or adult-onset diabetes. It isa term used for individuals who have relative (rather than absolute)insulin deficiency. People with this type of diabetes (> 80% ofpatients with DM) frequently are resistant to the action of insulin.

Other specific types of DM•Genetic defects of beta-cell function (mutations on chromo- some 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.

> > 52520 000 patients0 000 patientswith DMwith DM

large blood vessel atherosclerosis•coronary heart disease (CHD)•limb ischaemia (diabetic foot!diabetic foot!)•stroke

small blood vessel atherosclerosis•retinopathy•neuropathy•nephropathy•skin ulceration

infection (mycoses, etc.)

DM – complications:

Diabetic retinopathyresults in scattered haemorrhages, yellow exudates, and neovascularization

Diabetic nephropathy

•Normoglycemia- avoiding hypoglycemia or ketosis- HbAHbA1C1C < 6.5% < 6.5% ((glycosylated hemoglobinglycosylated hemoglobin)

•Reduce - nephropathy - neuropathy - retinopathy - infections (mycoses, etc)

Management goals

GlucometersGlucometers

•Diet – weight control – low fat intake – normal protein intake – carbohydrates ~ 50% of total energy

•Control blood pressure (120/80 mm)

BMI18.5–24.9

•Motor activity and compliance!

!

Insulin is a protein, secretedfrom the β-cells of the islets ofLangerhans in the pancreasin response to a rise in bloodglucose, and inhibited by a fall.

t1/2: 5–6 minmolecule mass: 5734 Da

t1/2: 5–6 minmolecule mass: 5734 Da I. InsulinI. Insulin

GlucagonCortisol AdrenalineSomatotrophin (GH)

GlucagonCortisol AdrenalineSomatotrophin (GH)

hyper- glyce- mia

Insulin Amylin Insulin Amylin hypoglycemia

Amylin (Islet Amyloid Polypeptide – IAPP)reperesents a 37-residue peptide hormone.It is cosecreted with insulin from the pancreaticβ-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 cyclase- dependent processes (lipolysis, proteolysis, glycogenolysis).

ATP cAMP 3’,5’-AMP

Lipolysis in adipose tissue (hypercholesterolemia)

AC PD

(+)

(-)(-)InsulinInsulin

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 eitherfrom cattle or pig pancreas.Bovine (B) insulin differsfrom human insulin in three amino acid residues, and porcine (S) insulin in one,but their action is very similar to human. Nobel prize

(1923)

More recently, recombinantDNA technology has allowed in vitro manufacturing of insulin with the same structure as

human (H) insulin. All current insulin preparationshave a low content of impurities.

Insulin is initially purified by protein extraction to form acrystalline product. It may thenundergo either gel filtration toproduce a single peak (SP)insulin or gel filtration and ionexchange chromatography which generates:

•monocomponent (MC),•single component (SC) and•rarely immunogenic (RI) insulin.

Other abbreviationswhich are used for insulins are:•Hum- and -man (for human ), •PP (purified preparation)

MAIN TYPES OFINSULIN 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

Short- acting 10–20 min 1–2 h 5–7 hInterme-diate-act. 1–2 h 5–7 h 13–18 hLong-act. 2–4 h 8–14 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 DMTherapy of DMwith insulin iswith insulin isa replacementa replacementtherapy.therapy.

s.c.:6 secs.c.:6 sec

High compliance!

s.c.s.c.

Insulin pumps:Insulin pumps:They infuseThey infusesubcutaneouslysubcutaneouslyfast-actingfast-actinginsulin throughinsulin throughsmall cathetersmall catheter(very handy(very handyand veryand veryexpensive).expensive).

a) Insulins: Actrapid, Humulin R

b) Analogues: Insulin aspart, Insulin lispro

1. Short-acting insulinsand analogues

s.c. 15 min before meal 4 times dailychronobiologically (4:3:2:1)

Ketoacidosis

Short-actinginsulin (i.v. or i.v. infusion) with physiological salineand potassium chloride

•Humulin M

•Humulin N

•Insulatard

•Mixtard

2. Intermediate-actinginsulins and analogues

s.c. 20 min before meal 2 times dailyChronobiologically

3. Long-acting insulins

s.c. 20 min before meal once daily

•Insulin detemir (Levemir)•Insulin glargine (Lantus)

Adverse effects of insulins•hypoglycemia/coma•allergic reactions•insulin resistance•lipodystrophia of subcutane- ous fat at or near injection•local fibrosis

II. Oral hypoglycemic andII. Oral hypoglycemic andother drugs, used other drugs, used

in DM type 2in 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

•excreted exclusively by the kidney•does not increase weight and preferable in the obesepreferable in the obese•GI side effectsGI side effects•rarely lactic acidosislactic acidosis

MetforminMetformin

2. SulfonylureasI generation: •Chlorpropamide and Tolbutamide (Out)

II generation:•Glibenclamide (Maninil: tab. 5 mg) •Gliclazide (Diaprel MR) •Glipizide•Gliquidone

Unwanted effects•Hypoglycemia, weight gain•facial flushing following alcohol ingestion

Mechanism of action•promote enhanced insulin release from the pancreas•leads to a reduction in hepatic glucose production

•displacement from protein binding sites– salicylates and sulphonamides

•interference with hepatic metabolism– inducers: rifampicin, phenytoin – inhibitors: cimetidine

•reduction of renal elimination– allopurinol, salicylates

Sulfonylureas – important drug interactions:

•Inhibits intestinal alpha-glucosidase•Decreases intestinal absorption of the mono- and polysaccharides.•Produces flatulence and diarrhoeaflatulence and diarrhoea.

- Acarbose (Gluco Bay): p.o.4. Glucosidase inhibitors

3. Meglitinides: stimulate the release of insulin from pancreas by closing ATP-dependent potassium channels.

- Nateglinide - Repaglinide

5. Thiazolidinediones (TZDs) They increase tissue insulin sensitivitybut have serious ADRs and the EMAbut have serious ADRs and the EMArecommended in Sept (2010) that theyrecommended in Sept (2010) that theybe be suspended from the EU marketsuspended from the EU market: - Rosiglitazone (Avandia) has highhigh cardiovascular risks cardiovascular risks.- Pioglitazone causes bladder tumorsbladder tumors.- Troglitazone causes hepatitishepatitis.

66. . Glucagon-like peptideGlucagon-like peptide-1-1 (GLP (GLP-1-1))agonists (in type 2 DM):agonists (in type 2 DM): increasepancreatic secretion of insulin: Exenatide Bydureon (sBydureon (s..c./c./7 7 daysdays)):: $323/4 doses, resp.$323/4 doses, resp. $4200 per year$4200 per year

LiraglutidLiraglutid

LiraglutidLiraglutid

is a GLP-1agonist,which reduces, BM, HbA1C, and systolicblood pressure, and improvesbeta cell functionof the pancreas(s.c. once a day)(s.c. once a day)

77. Inhibitors of Dipeptidil. Inhibitors of Dipeptidilpeptidasepeptidase-4 (-4 (DPPDPP-4)-4):: preventdegradation 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.