Insulin and Hypoglycemic Agents-1

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INSULIN AND ORAL

HYPOGLYCEMIC
AGENTS

Syed Tajamul
BHCNMT
INTRODUCTION
• The endocrine pancreas consists of aaproximately about one million
islets of Langerhans which secrete at least five hormones:
• 1. Insulin: storage and anabolic hormone of the body
• 2. Amylin: modulates appetite,gastric emptying, glucagon and and
Insulin secretion
• Glucagon: Hyperglycemic factor that mobilizes glycogen stores
• 4. Somatostatin: universal inhibitory of secretory cells
• 5. Gherlin: a peptide to increase pituitary growth hormone release
DIABETES MELLITUS
• Diabetes mellitus is
defined as an elevated
blood glucose associated
with absent or inadequate
pancreatic insulin
secretion, with or without
concurrent impairment of
insulin action. The disease
states underlying the
diagnosis of diabetes
mellitus are now classified
into four categories: type
1, type 2, other, and
gestational diabetes
mellitus.
INSULIN
• Insulin is a small protein with molecular weight of 5808, contains 51
amino acids arranged in two chains A&B linked to disulphide bridges.
• Proinsulin a long chain protein molecule is hydrolysed into insulin in
Golgi apparatus of beta cels.
• Insulin is released from pancreatic beta cells at a low basal rate and at
a much higher stimulated rate in response to a variety of stimuli,
especially glucose.
• After insulin has entered the circulation, it diffuses into tissues,
where it is bound by specialized receptors that are found on the
membranes of most tissues.
Mechanism of action of Insulin
• The insulin receptors is composed of two alpha and two Beta subunits linked by
disulfide bonds to constitute Beta-alpha Alpha beta heterotetramer.
• When insulin binds to receptors this results in cascade of phosphorylation and
dephosphorylation reactions of Alpha and Beta subunits called Insulin Receptor
Substrate (IRS).
• This result in activation of specific phospholipase-C, believed to mediate the rapid
action of insulin on different metabolising enzymes
• Also stimulates the glucose transport across cell membrane by ATP-dependent
translocation of glucose transporter-4(GLUT-4) to plasma membrane present on
skeletal and and adipose tissue.
• IRS also result in transcription of DNA synthesis and proliferation and
differentiation of several cell types— long term effects of insulin
• Finally, the insulin receptor complex is internalised by endocytosis followed by
degradation of insulin and recycling of the receptor to the cell surface.
Pharmacokinetics
• Insulin is rapidly inactivated after oral administration; I/M insulin
injections have rapid absorption; I/V insulin injections can be give in
emergencies. Hence insulin is usually given Subcutaneously.
• Metabolized in liver and kidneys. 60% is destroyed in liver by Hepatic
Insulinase. Plasma half life is 10 mins.
Insulin Preparations
1. Ultrashort acting( Rapid/ Fast acting ) Insulin
• Insulin Lispro S/C
• Insulin Aspart S/C; IV
• Insulin Glulisine S/C
• Absorption: Rapidly absorbed as monomers from subcutaneous
tissue, action starts within 10-30 mins and lasts for 3-4 hrs.
• Useful in hyperglycemia that occurs after meals, used in combination
with long acting insulins to maintain baseline levels of insulin
between meals.
2. Short Acting Insulin( Regualr Insulin)
• Regular insulin –Homulin-R, Novolin-R) U100-U500
• Regular insulin inhaled
• Soluble human crystalline insulin made by recombinant DNA tech.
Added with zinc ions for stability
• Exists as hexamer absorbed as monomer; Onset of action 30-60mins
lasts upto 6-8hrs.
• Indications: post meal hyperglycemia and management of Diabetic
Ketoacidosis(I/V)
3. Intermediate acting Insulin
• Isophane Insulin ( Neutral protamine Hagedorn- NPH) U100 S/C and
no other route
• NPH is a cloudy complex of insulin and a protein –protamine Derived
from fish sperm, contains 6 molecules of insulin per molecule of
protamine.
• Onset of action 2hrs lasts about 16-20hrs
• Indications: diabetic control except DKA
Long acting Insulin
• Insulin Glargine U100
• Insulin DetemirU100-U300
• Insulin Degludec U100, U200
• These human insulins are embedded with extra amino acids and fatty
acid chains. Soluble at PH 4 but less soluble at pH in cutaneous tissue
as a result steady and sustained release of insulin of insulin from site
of injection
• Onset of action more than 4 hrs lasts more than 24 hrs.
Premixed Insulins
• 70 NPH/30 regular U100
• 75/25 NPL, Lispro U100
• 50/50 npl, Lispro u100
• 70/30Degludec u100
• INHALED INSULINS : due accumulation of insulin deposits in pharynx
causing pharyngitis and pulmonary fibrosis, and formation of
antibodies two inhaled recombinant human regualar insulins have.
Been developed:
• 1. EXUBERA 2. AFREZZA
• NPH=Neutral protamine Hagedorn
Clinical Uses of Insulin
• Type 1 DM—NPH and short acting before meals
• Type 2 DM
• Gestational Diabetes
• Emergency treatment of DKA( diabetic Coma) — complication of type1 DM
• Bolus dose of 0.1U/kg IV of short acting regular insulin f/b 0.1U/kg/hr IV till glucose falls to
300mg/dL f/b 2-3 U/hr(not per kg) untill patient gains consciousness
• Normal salin to correct dehydration and 5% glucose if patient is hypoglycaemic
• Inj KCL 20mEq/hr to correct hypokalemia
• Inj sodium bicarbonate 50mEq iv drip to prevent respiratory acidosis due to
hyperventilation
• Non ketones hyperglycemia( hyperosmolar coma)—Type2 Complication
• For emergency treatment of hyperkalemia
Adverse effects
• Hypoglycemia
• Lipodystrophy— due to sc injections
• Allergic reactions— urticaria. And angioedema
• Insulin resistance
1. ORAL HYPOGLYCAEMIC AGENTS

Sulfonylureas Meglitinide Analogues


• 1st generation • Repaglinide 0.25-4mg before meals
• Tolbutamide 250-2g/day & chlorpropamide 100-250mg/day • Nateglinide 60-120mg before meals
• 2nd Generation • Well absorbed, Rapid. Action less than 1 hr ; Duration of action 5-8hrs
• Glimepiride 1-6mg/day, Glipizide 2.5-5mg/day , Gliclazide • Metabolised by liver and excreted 90% through bile
320mg/day & Glyburide 1.5-20mg/day
• MOA: same as Sulfonylureas
• Absorption: well absorbed highest for Glimpiride-98% plasma protein
binding; • Adverse effects: Hypoglycaemia and respiratory infections
• Metabolised in liver and kidneys; excreted through urine • Contra indications: type 1 DM
• Onset 1-3hrs; Duration of action upto 24hrs
• MOA: bind Sulfunylurea receptor in Beta cells—reduce K+ efflux—
causing depolarisation f/b Ca+ entry and insulin secretion in healthy
beta cells. Also Supress glucagon secretion and increase peripheral
tissue sensitivity to insulin
• Antifungal and anticoagulants inhibit their metaboilism
&Corticosteroids and estrogen inhibit their action
• Adverse effects: Hunger, Weight gain,GIT disturbances & dark colour
urine, sweating, dizziness and confusion & Hypoglycaemia
2. ANTI HYPERGLYCAEMIC AGENTS

Biguinides Alpha- Glucosidase Inhibitors


• Metformin 500 mg-2500mg/day • Acarbose 50-100mg PO tid before meals
• Phenformin 200-400mg/day • Miglitol 25-50 mg IV, PO, and Intra duodenal
• Metformin only drug being currently used • Voglibose 0.2mg PO tid before meals
• Absorption: 1-6hrs with rapid distribution; not metabolised & • Absorption: poor
have oral bio availability of 40-60% with T1/2 4-8hrs,
duration of action is 6-10hrs and is excreted unchanged • Metabolism: local in GIT by intestinal microbial flora with oral
through urine. bioavailability of upto 2% only except for Migliitol upto 70%,
excreted through stools except for megilitol
• MOA: does not promote insulin release instead increase
uptake of glucose by skeletal muscles; inhibit • MOA: inhibit action of alpha glucosidase- prevents digestion
gluconeogenesis, slow down absorption of glucose from GIT. of starch, oligosaccharides and disaccharides into
And promotion of insulin binding to its receptors. monosaccharides(prevent their absorption) – lower
postprandial hyperglycaemia.
• Does not lower glucose in normal person, also lowers LDL,
VLDL and elevates HDL levels • Adverse. Effects: flatulence, diarrhoea, abdominal pain
• Averse effects : Nausea, metallic taste, anorexia, diarrhoea • Used as mono therapy in early type 2 DM
and flatulence
2. ANTI HYPERGLYCAEMIC AGENTS

Glitazones-PPAR-g Agonists Incretin mimetic agents


• Rosilitazone 45mg PO OD • Incretin is a group of hormones that include Gluvagon Like
Peptide(GLP-1) and Glucose-Dependent Insulinotropic
• Pioglitazone 4-8mg PO OD Plypeptides(GIP) released after meals form upper and Lower
• MOA: agonists of Peroxisome-proliferator-Activated GIT and augment insulin secretion after nutrients are
absorbed .
Receptor –gamma(PPAR-g) - a Nuclear receptor
• Exenatide 5-10mcg sc BD before meals
• Activation of PPAR-g promotes transcription of insulin
responsive genes which control glucose and lipid • MOA: Increase insulin secretion from Beta cells, decrease
metabolism. release of Glucagon, delay gastric emptying, decrease
appetite
• Increase GLUT-4 transporter in liver, seltzer and adipose
tissue—increase sensitivity to insulin • Amylin mimetic agents
• Also decrease HBA1-C levels
• Pramlnitide 15-60 mcg S.C before meals in type-2DM & 60-
• Also increase HDL-C and lower Triglyceride levels 120mcg in Type-1 DM
• Adverse effects: weight gain, fluid overload and oedema, • MOA: Inhibit glucagon secretion, delay gastric emptying and
hepatotoxicity, effects pregnancy and children, risk of heart suppress appetite
failure and MI.
2. ANTI HYPERGLYCAEMIC AGENTS
Sodium-Glucose Cotranspoter -2(SGLT-2) Inhibitors

• Dapaglifozin 2.5-10mg/ day PO


• Cangliflozin 10-25mg/day
• SGLT-2 reabsorbs glucose from proximal tubules in kidneys.
• MOA: inhibition of SGLT-2 transporter in kidneys- prevents
reabsorption of Glucose
• Also cause Weight loss , no hypoglycaemia as they promote
excretion of excess glucose, impoverish insulin resistance
• Adverse effects: polyurea, plydipsia, hyponatraemia,
NEWER ORAL AGENTS FOR DIABETES
MELLITUS
Dopamine Receptor Agonists Bile Acid Sequestrant resin
• Bromocriptine 1.5-2.5 mg PO/day 2hrs after • Colesevelam 625mg/day
waking up
• MOA: Binds bile acid in intestines. And prevent
• MOA: introduced in 2017; reduces HbA1-C levels their reabsorption
• Poorly understood, MOA believed to suppression • Poorly understood in management of DM-2
of hepatic glucose production by a Dopamine believed to increase GLP-1 secretion—increase
induced hepatic- hypothalamic circuitary. secretion of insulin an d prevents glycogenolysis.
• Dual PPAR-alpha and PPAR-gama • Lower HbA1-C by 0.5%
recptor agonists
• Saraglitazor2-4mg/day; Alegliazor 150-600g/day
• MOA: similar and more potent than Glitazones-
(PPAR-g)
SUMMARY

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