© Assoc. Prof. Iv. Lambev, PhD

E-mail: itlambev@mail.bg

ANTIDIABETICDRUGS(Abstract)

ANTIDIABETICDRUGS(Abstract)

NORMOGLYCEMIA2.86.1 mmol/l

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

N orm a l

less th an 8 m m ol/l

1 /3 b ecom e n orm a l 1 /3 rem a in IG T 1 /3 b ecom e d iab e tic

Im p a ired g lu cose to le ran ce

8 to 1 1 m m ol/ l

D iab e tes

g rea te r th an 1 1 m m ol/l

ran d om b lood g lu cose

Suspected diabetes mellitus

75 g glucose p.o.: 2 h later

Worldwide prevalence of diabetes mellitus

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 mediateddestruction of the beta cells of the pancreas. The rate of destructionis quite variable (and may reach 80% of beta- cells of 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 have no known etiology (have noevidence of autoimmunity). This form is more common amongindividuals of African and Asian origin. Patients periodicallydevelops 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 (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, glucago- noma 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 categoriesof gestational impaired glucose tolerance and gestational DM).

>400 000 patientswith DM

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.)

DM – complications:

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

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

•Control blood pressure•Avoid smoking

BMI18.5–24.9

•Motor activity

t1/2 5–6 min

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

glucagoncortisol adrenalinesomatropin (GH)

glucagoncortisol adrenalinesomatropin (GH)

hyper- glyce- mia

insulin insulin hypoglycemia

Mechanism of action•Insulin acts via receptors that are transmembrane glycoproteins. •Each receptors has two insulin binding sites. Receptor occu- pancy 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).

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.

ATP cAMP 3’,5’-AMP

Lipolysis in adipose tissue (hypercholesterolemia)

AC PD

(+)

()Insulin

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 similarto human.

More recently, recombinantDNA technology has allowed in vitro manufacture 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 use for insulins are:•Hum- and -man (for human ...), •PP (purified preparation)

MAIN TYPESINSULIN 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

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 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 DMwith insulin isa replacementtherapy.

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)

c) Per inhalation: Exubera

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

Ketoacidosis

•Humulin M

•Humulin N

•Insulatard

•Mixtard

2. Intermediate-actinginsulins and analogues

(s.c. 20 min before meal 2 times dailychronobiologically)

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 subcutane- ous 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

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

Metformin

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

II generation:•Glibenclamide (Maninil: tab. 5 mg) •Gliclazide (Diaprel: tabl. 80 mg)•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 polysacharides.•Produces flatulence and diarrhoea.

Acarbose (Gluco Bay): p.o.Zuccarin: p.o.

4. Thiazolidinediones (TZDs) – increase tissue insulin sensitivity

Rosiglitazone (Avandia): p.o.

3. Glucosidase inhibitors

3.5. Incretinomimetics Exenatide (analogue of GLP-1)

3.6. Inhibitors of Dipeptidil peptidase-4 (DPP-4) Sitagliptin Vildagliptin