oral hypoglycemic agents (1)

8/3/2019 Oral Hypoglycemic Agents (1)

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Oral hypoglycemic agents

Biguanides

Sulfonylureas- glucosidase inhibitors

Thiazolidinediones

Prandial glucose regulator


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Biguanides

Biguanides are derivatives of the

antimalarial agent Chloroguanide.

Which is found to have hypoglycemic

action.

The most commonly used member ofbiguanides is Metformin.


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Biguanides

Indication:

Type 2 diabetes failed on diet

Metformin can be given alone or in

combination with sulfonylureas or

Insulin


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Biguanides

Mode of actionBiguanides [Metformin] is an

Antihyperglycemic and not

Hypoglycemic agent.It does not stimulate pancreas to secrete

insulin and does not cause hypoglycemia

(as a side effect) even in large doses.

Also it has no effect on secretion of

Glucagon or Somatostatin.


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Biguanides

Mode of action:Decreases the intestinal

absorption of CHOIncreases glucose uptake (GLUT 4(

Increases glucose utilization

(glycogensynthase(Increases glycolysis via anaerobic

pathway (lactic acidosis(


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Biguanides

Pharmacokinetics:Metformin is well absorbed

from small intestine, stable,does not bind to plasmaproteins, excreted unchanged

in urine.Half life of Metformin is 1.5 -

4.5 hours, taken in three doseswith meals


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Biguanides

Side effects:

occur in 20-25 % of patients.

include.. Diarrhea, abdominal

discomfort, nausea, metallic

taste and decreased absorption

of vitamin B12.


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Biguanides

ContraindicationsPatients with renal or hepatic

impairment.

Past history of lactic acidosis.Heart failure, Chronic lung disease.

..These conditions predispose to

increased lactate production whichcauses lactic acidosis which is fatal.


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SUs., have been discovered during

the 2nd

. World war (sulfonamide(.SUs are drugs that used orally to

control blood glucose levels of type2 diabetes.

SULFONYLUREAS


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SULFONYLUREASTypes:

First generation,Chlorpropamide

TolbutamideSecond generation,

GliclazideGlibenclamide

GlipizideThird generation,

Glimepiride


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SULFONYLUREAS

Mechanism of action:

Pancreatic effect

Extra-pancreatic effect


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Pancreatic effect:

Increase insulin release frompancreas

Suppress secretions of Glucagon

SULFONYLUREAS


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SULFONYLUREASPharmacokinetics:

They are effectively absorbedfrom gastrointestinal tract.

Food can reduce the absorption ofsulfonylurea.Sulfonylureas are more effective

when given 30 minutes before

eating.Plasma protein binding is high 90

99 % .. mainly bind to albumen.


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1st generation members haveshort half lives.

2nd generation is administered

once, twice or several times

daily.

3rd generation is administered

once daily.


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All sulfonylurea are metabolized by

liver and their metabolites are

excreted in urine with about 20 %

excreted unchanged.

Sulfonylurea should be administered

with caution to patients with either

renal or hepatic insufficiency.


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SULFONYLUREAS

Adverse Reactions:

Very few adverse reactions [4 %] inthe first generation and rare in the 2nd

and 3rd generation.

SUs may induce hypoglycemia especiallyin elderly patients with impaired

hepatic or renal functions-These casesof hypoglycemia are treated by I/V

glucose infusion.


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SULFONYLUREAS

Adverse Reactions:First generation may induce other

side effects as nausea andvomiting & dermatologicalreactions

These side effects are fewer inthe 2ndgeneration and rare in the

3rdgeneration.


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SULFONYLUREAS

Drug interactions:Some drugs may enhance or

suppress the actions of

sulfonylureas Either byaffecting:

Their metabolism and excretion

The concentration of freesulfonylureas in plasma throughcompeting them on plasma

proteins.


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Drug Drug interaction

NSAIDs

Salicylates

Sulfonamide

-blockers

Chloramphenicol

Diazepam

MAOI

Barbiturates

Thiazide and loop

diureticsSympathomimetics

Corticosteroids

Oestrogen /Progesterone

combinations


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SULFONYLUREAS

Contraindications:

Type 1 DMPregnancy and Lactation.

Significant hepatic or renalfailure.


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Glucosidase Inhibititor

Acarbose

Indicated for type 2 diabetesIn addition with diet

In addition with other anti-

diabetic therapies


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Acarbose (Glucobay(

Mode of action:Poorly absorbed 1% (act locally in

G.I.T.(

Inhibits glucosidase, so inhibitsCHO degradation

Dose:50mg to 100mg 3 times daily

before meals


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Acarbose (Glucobay(

Side effects:

Flatulence (77%(

Diarrhea

Abdominal pain (21%(

Decreased iron absorption


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Thiazolidenedione

Rosiglitazone

Pioglitazone


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Thiazolidenedione

Mode of action:Insulin sensitizer (increase insulin

sensitivity in muscle, adiposetissue & liver(

They are not insulin secretagogues

(Not insulin releasers(


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ThiazolidenedioneDrawbacks:

They are not effective alone in case ofsevere insulin deficiency and should be

combined with sulfonylurea ormetformin or both

Side effects:Hepatotoxicityweight gainDyslipidaemia (increases LDL(


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Prandial glucose regulators

(Meglitinide(Example:

Repaglinide

Rational:Fast acting, short duration non-

sulfonylurea

Designed to minimize mealtimeblood glucose peaks


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Repaglinide

Mechanism of action:Stimulation of pancreatic insulin

release by closing -cells KATP

channelsVery rapid onset of action and

short duration (TMAX = 1 hour,

metabolized by liver T1/2 = 70minutes(

No hypoglycemic metabolites


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Repaglinide

Clinical efficacy:Improves postprandial glycemiaLess effective in decreasing fasting

blood glucose levels and HbA1Cdrawbacks:

Fails to provides a stable 24 hoursblood glucose control

Complicated dosage style (3-8tablets/daily(

How to adapt the dosage to the mealvolume?


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Sitagliptin:Adverse Reactions

Overall:Adverse reactions and discontinuation rates were similar

to placebo (both as monotherapy and as combinationtherapy(

Incidence of hypoglycemia with sitagliptin was similarto placebo (1.2% vs 0.9%(

The adverse reactions, reported regardless ofinvestigator assessment of causality in 5% of patientstreated with sitagliptin 100 mg daily as monotherapy orin combination with pioglitazone and more commonly thanin patients treated with placebo, were upper respiratory

tract infection, nasopharyngitis, and headache.Incidence of selected GI adverse reactions in patients

treated with sitagliptin vs placebo was as follows:Abdominal pain (2.3%, 2.1%(Nausea (1.4%, 0.6%(Diarrhea (3.0%, 2.3%(


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ContraindicationsNone

Warnings and Precautions

Use in patients with renal insufficiency:A dosage adjustment is recommended in patients with moderate or

severe renal insufficiency and in patients with ESRD requiring

hemodialysis or peritoneal dialysis.

Use with medications known to cause hypoglycemia:

As monotherapy and as part of combination therapy with metformin orpioglitazone, rates of hypoglycemia were similar to rates in patients

taking placebo.

The use of sitagliptin in combination with medications known to cause

hypoglycemia, such as sulfonylureas or insulin, has not been adequately

studied.

Sitagliptin:Contraindications/Warnings andPrecautions


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Summary of Sitagliptin

Sitagliptin is an oral, selective inhibitor of the DPP-4 enzymeIndication:

Indicated as monotherapy and in combination with metforminor TZDs

Usual recommended dose is 100 mg once dailyIn clinical studies:

Sitagliptin significantly improved A1C, FPG, and PPGMean A1C response with sitagliptin appears to be related to

baseline A1C level

Overall: Incidence of adverse reactions was similar to that with placeboOverall incidence of hypoglycemia similar to that with placeboA neutral effect on weight relative to that with placebo

oral hypoglycemic agents (1)

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