niper notes by pharmacrystal

7/31/2019 Niper Notes By Pharmacrystal

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number of patients with type 2 diabetes fail toachieve persistent good metabolic control. In theU.K. Prospective Diabetes Study (UKPDS) 28% and53% of drug treated type 2 diabetes patients hada fasting plasma glucose concentration more than140 mg % after 3 and 6 years4 and irrespective of

mode of therapy, a steady increase in HbA1C wasseen over 9 years follow-up5.The limitations of currently availablepharmacological agents for control of bloodglucose has stimulated research on novelantidiabetic agents with different mechanism ofaction. The magic word CURE is no longer elusiveand prevention is very much on the cards. Indeedfor those who already have diabetes and aresuffering with complications, much can be offeredin the new millennium. The newer drugs, alreadydeveloped or in the process of development for

management of type 2 diabetes can be classifiedinto (1) Insulin secretagogues, (2) Insulinsensitisers, (3) Drugs delaying GI glucoseabsorption, (4) Inhibitors of intermediarymetabolism, (5) Insulinomimetic drugs. (Table I).Table I : Newer Antidiabetic Agents in TheNew Millenium1. Insulin secretagoguesNewer sulphonylureas glimeperideNon-sulphonylureas repaglinideGLP-1GLP-1 receptor agonists (extendin 9-39)/DPPIV

Amylin antagonistsOthers246 Journal, Indian Academy of Clinical Medicine_Vol. 1, No. 3 _October-December 2000

2. Insulin sensitisersBiguanides

PPAR() antagonist fibratesRexinoids

PPAR() antagonists thiazolidinedionesProtein tyrosine kinase inhibitors CLX 0300/0301/0900/0901Antiobesity drugsB-3 receptor antagonists

3. Inhibitors of intermediary metabolismAntilipolytic and antihyperlipidaemic drugsFatty acid oxidation inhibitors (Lisophyllin)4. Inhibitors of GI glucose absorptionGlucosidase inhibitorsAmylin analogues (Pramlinitide)5. Insulinomimetic drugsVanadium salts

Insulin secretagogues


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New SU insulin secretagogue:GlimeperideThis is a third generation SU which binds to a 65kd protein of the putative SU receptor differentfrom the 140 kd protein targeted by other SU6. Ithas a three fold faster rate of association and ninefold faster rate of dissociation than glibenclamide6and thus has rapid onset and prolonged durationof action, permitting once daily administration7.Though its initial action is stimulation of insulinsecretion, it has also an insulin-mimetic effect inperipheral tissues possibly mediated by GLUT-4recruitment8. The extrapancreatic effects mayexplain lesser degree of stimulatedhyperinsulinaemia. Unlike glibenclamide, this drugprevents post-exercise insulin release, therebydecreasing the risk of hypoglycaemia7. It isabsorbed completely in either fasting or fed state.It does not accumulate in the body with reducingrenal function (upto GFR 10 ml/min) and itshydroxy metabolite has negligible effects on bloodglucose and are excreted equally by the liver andkidney. Hence it is safe in renal failure and in theelderly7. It does not exhibit any drug interactionand because of its poor binding to extrapancreatic,myocardial, and vascular system ATP dependentK+ channels, the risk of coronary vasoconstrictionand adverse cardiovascular events are reducedin comparison to other SUs9. On a weight forweight basis glimeperide is the most potent SUwith suggested doses between 1-6 mg once daily,but doses upto 8 mg may give additional glucoselowering effect9.

Non-sulfonylurea insulinsecretagogues(i) RepaglinideRepaglinide is a new chemical entity, acarbamoymethyl benzoic acid derivativewhich differs structurally from thesulphonylureas and belongs to themeglinitide group of drugs10. Its molecular

formula is C27 H36 N2 O4 and it has amolecular weight of 452.6. Theinsulinotropic action of repaglinide ismediated via the inhibition of ATP dependentpotassium ion channels in the pancreaticbeta cell membrane which results in thedepolarisation of the cell membrane and aninflux of calcium ions through voltage-gatedcalcium channels. Intracellular calcium


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concentration is therefore increased andalong with it, the insulin secretion.Repaglinide binds with high affinity to areceptor which is distinct from sulphonylureareceptor. In addition, repaglinide binds withlow affinity to the classic sulphonylurea

receptor. This differential binding results inmore potent stimulation of insulin release.It is rapidly absorbed from the GI tract andhas a half life of less than 1 hour. It ismetabolised primarily in the liver and isexcreted predominantly in the bile, thus it issafer in renal failure and the elderly11. It isan effective post prandial glucose regulatorand can be administered 3 times a daybefore meals for an effective glycaemiccontrol12. Doses may vary from 1-4 mg twiceor thrice a day. Adverse effects include GI

intolerance and hypoglycaemia, though theJournal, Indian Academy of Clinical Medicine_Vol. 1, No. 3 _October-December 2000 247

latter is not prolonged as withglibenclamide11,12.(ii) GLP-IGlucagon like peptide (7-36) amide (GLP-1)is a potent gut hormone playing the role ofincretin, i.e., stimulating meal related insulinrelease from the B cells13. It potentiates theinsulin releasing effect of glucose bystimulating adenylate cylase and increasingcAMP in the B cells13. It also suppresses

glucagon release. It exerts insulinomimeticeffects on gluconeogenesis in liver and musclesand lipogenesis in the adipose tissues. Sincethe insulin release is glucose dependent, it doesnot lower blood glucose further from normalblood glucose concentrations, hencedecreasing the risk of hypoglycaemia14. It alsoreduces post prandial glycaemia by delayinggastric emptying11. Because of its shortduration of action and need for parenteraladministration, it is not a viable option forroutine management of type 2 diabetes. To

overcome these drawbacks GLP-1 receptoragonists such as Extendin 9-39 for oraladministration are being developed11. Extendinis a 39 amino acid peptide derived fromHeloderma suspectumvenom. Anotherpromising approach is prevention ofdeactivation of GLP-1. The enzyme responsiblefor deactivation is DPP IV and oral inhibitorsof this enzyme are currently under development


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NVP-DPP 728 is one such inhibitor undergoinganimal studies15.(iii)Other agentsThe knowledge that islet amyloidpolypeptide (IAPP, Amylin) suppressesinsulin secretion and action and further it

has been linked with the development ofinsulin resistance at very highconcentrations, has led to thedevelopment of amylin antagonist (IAPP-8-37) which stimulates insulin secretion16.It has been found to be effective in animalstudies; human trials are ongoing16.A-4166 (N-Trans-4-isopropylcyclohexylcarboxylphenylalanine)a phenylalanine analogue,stimulates meal related insulin release anddecreases post prandial hyperglycaemia by64%17. It is short acting and needs to be

administered prior to meals in a dosage of120 mg17.Guanidino related compounds (BTS 67582)act on a site different from SU receptors onthe B-cells and offer an alternative mechanismto stimulate insulin release16. They may havea promising role to play15.Attempts to treat defects of glucose sensingproinsulin biosynthesis and proinsulinprocessing by the B-cells, by pharmacologicalmeans are under development, but are still ata preliminary stage.

Insulin sensitisersInsulin resistance is a universal feature in patientswith type 2 diabetes mellitus. The key role played byperipheral and hepatic insulin resistance suggest thatenhancement of insulin action might be an effectivepharmacological approach for treatment of type 2diabetes as well as an ideal way to manage themetabolic syndrome of associated obesity,hypertension, and dyslipidaemia. These agents donot stimulate release of insulin from pancreatic Bcellsbut only increase the sensitivity of peripheraltissues to insulin. Moreover, sole peripheral action

means, that these agents are unlikely to producehypoglycaemia on their own.

BiguanidesThey were introduced in 1958. Following UGDPstudy, they were out of favour because of fear oflactic acidosis, but have bounced back as theyare known to significantly counteract insulinresistance. Metformin is preferred to phenformin


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as it does not inhibit mitochondrial oxidation oflactate and lactic acidosis with this drug is a rarity.Significant improvement in glycaemic control, lipidprofile, and with no notable increase in plasma248 Journal, Indian Academy of Clinical Medicine_Vol. 1, No. 3 _October-December 2000

lactate, serum insulin, weight gain, and frequency

of hypoglycaemia have been observed with thisgroup of drugs18. Its major modes of action include(a) inhibition of gluconeogensis, (2) reduction ofhepatic glucose output, (3) reduction of weight19;the improvement in insulin sensitivity is a byproductof these alterations.

ThiazolidinedionesThe discovery of perioxisome proliferator activatedreceptor (PPAR) and their subtypes has led to thediscovery of a new generation of drugs. The two

major PPAR receptors are & and both areexpressed by obligate heterodimerisation with

retinoic acid x receptor (Rx R and Rx R). ThePPAR () is primarily responsible for lipolysis byactivation of enzymes such as acylCOA oxidase,lipoprotein lipase, malic enzyme, bifunctionalenzyme, and medium chain acylCOA

dehydrogenase. On the other hand, PPAR() isprimarily responsible for the adipocytedifferentiation and at the metabolic level, in FFAand lipid anabolism and storage. The pronounced

hypoglycaemic effect seen by PPAR() agonists isattributed primarily to adiposite differentiationand/or activation20.

The PPAR() agonists, ciglitazone, pioglitazone,englitazone, troglitazone, and rosiglitazone aresome of the members of this class. They decreasehepatic glucose output and increase peripheralglucose utilisation by improving insulin sensitivity athepatic and muscle sites21. They restore the sensitivityof phosphophenol pyruvate carboxy kinase (PEPCK)to insulin thereby decreasing glycogenolysis. Theyalso increase peripheral triglyceride clearance anddecrease hepatic triglyceride synthesis, independentof insulin21. At the cellular level, they increase thebinding and tyrosine kinase activity of insulinreceptors, activate post receptor signaling proteinsand enhance insulin induced translocation of GLUT-4 on to the plasma membranes16,21. All these effectsare dependent on insulin. These agents do not

stimulate insulin secretion from -cells and aretherefore not effective in insulinopenic subjects22.Troglitazone was marketed in USA, but wassubsequently withdrawn due to hepatotoxicity.


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Rosiglitazone and pioglitazone are devoid ofhepatotoxicity.

PPAR() agonists such as fibrates are not effectivehypoglycaemic agents, but lowers LDL cholesteroland triglycerides and raise HDL, thus offeringprotection against increased coronary morbidity

and mortality which is seen in type 2 diabetes21.Retinoids, which activate RxR receptors are beingdeveloped to control diabetes, one such productLG 100268 has shown significant promise, in that,in addition to being an insulin sensitiser it causes

weight reduction in contrast to PPAR() agonists22.A new class of drugs which are plant extracts andact through inhibition of protein tyrosine kinase arebeing investigated. In additon to hypoglycaemiceffect it blocks the formation of proinflammatory

cytokines such as TNF . Compounds in this classincludes CLX 0301, CLX 0302, CLX 0900, and CLX

0901. This group of drugs also lowers cholesteroland triglycerides. Again these are sensitisers andare not effective in type 1 diabetes23,24.

3adrenergic receptor agonists3 adrenergic receptor present in brown and whiteadipose tissues, mediate catecholamine stimulatedthermogenesis and lipolysis. A polymorphism in

3 adrenergic receptor due to missense mutationin the gene coding for it, has been identified inFinns and Pima Indians. This has been linked tolower basal metabolic rate, greater visceral

adiposity, and early onset of type 2 diabetes inthese ethnic groups. This observation has

stimulated the use of selective 3 adrenoceptoragonists such as CL 316, 2443, which do not cross

react with other - adrenoceptor, for treatingobesity and improving insulin senstivity25. In obese

diabetic animal models, 3 adrenergic receptoragonists reduce body weight by increasing energyexpenditure and reduce fat depots withoutinducing a decrease in food intake. Reduction inblood glucose along with triglyceride concentrationare observed within a week of their usage24.

Preliminary results in type 2 diabetes patients withJournal, Indian Academy of Clinical Medicine_Vol. 1, No. 3 _October-December 2000 249these drugs have confirmed these beneficialeffects25.

Inhibitors of intermediary metabolismType 2 diabetes is invariably associated with adisordered lipid metabolism. In the muscle, aglucose, fatty acid cycle has been recognised formany years. The oxidation of fatty acids decreases


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glucose uptake and utilisation through substratecompetition, causing a post receptor insulinresistance. As the rate of fatty acids oxidationdetermines the rate of gluconeogenesis, a goodcorrelation exists between raised fasting NEFAlevels, impaired lipid oxidation, and reesterfication

and hepatic glucose output (HGO)in patients with type 2 diabetes. Since increase inHGO is responsible for fasting hyperglycaemia intype 2 diabetes, drugs decreasing fatty acid levelsor inhibiting fatty acid oxidation are attractiveoptions for controlling fasting hyperglycaemia26.

Drugs decreasing fatty acidsThese are anti-hypertriglyceridaemic drugs, e.g.,acipimox and bezafibrate16. Acipimox is a longacting nicotinic acid analogue, which significantlyreduces plasma NEFA and HGO26. Its effects onHGO are more sustained than nicotinic acid which

has a variable effect on glycaemic controlfrequently worsening due to discrepant effects onglycogen breakdown and gluconeogenesis. In astudy of 8 obese type 2 diabetic patients overnightsuppression of plasma NEFA with acipimoxsignificantly reduced lipid oxidation, HGO, andincreased the glucose disposal rate27.

Bezafibrate, a PPAR() agonist is effective inreducing the dyslipidaemia of diabetes. However,it is important to note that these agents can besupplementary but cannot be used alone fortherapy of diabetes21.

Fatty acid oxidation inhibitorsSuppression of fatty acid oxidation decreaseshepatic gluconeogenesis and increases peripheralglucose utilisation. The drugs of this class inhibitcarnitine palmitoyl transferase-1 (CPT-1) which isa rate limiting enzyme for the transfer of long chainfatty acids into mitochondria28. Etoximer is theprototype and this has been shown to be effectivein reducing HGO, increase peripheral glucoseutilisation, and pyruvate dehydrogenase activity.However, the drawbacks with this drug include fearof myocardial damage and refractoryhypoglycaemia28. Studies however, are in progressto develop short acting inhibitors of long chainfatty acid oxidation which may help reduceketogenesis in type 1 diabetes29. Lisofylline is onesuch drug which has shown promise in animalstudies.

Inhibitors of gastro-intestinal glucoseabsorption


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Alpha glucosidase inhibitorsThese drugs competitively inhibit the glucosidasesat the small intestinal brush border, responsiblefor breakdown of complex polysaccharides(Starches) and sucrose into glucose30. This resultsin decrease of postprandial glycaemia. The drugs

approved in this class for clinical use are acarbose& miglitol.

AcarboseOriginally developed in Germany, is being widelyused for post prandial glucose regulation. It isusually used in type 2 diabetes either as amonotherapy or in conjunction with SUs orbiguanides30. The average decrease in postprandial blood glucose during acarbose treatmentin diet treated type 2 diabetic patients was 3 mmol/1 and maximal decrease in HbA1C was 1%.Acarbose is recommended thrice daily in doses

of 50-200 mg with the first bite of each majormeal30. Titration of dose is important to optimisebenefits and minimise its side effects, which includeflatulence, cramping, and diarrhoea30.

MiglitolThis is a newer-glucosidase inhibitor, derived from1-deoxy nojirimycin and is structurally similar to250 Journal, Indian Academy of Clinical Medicine_Vol. 1, No. 3 _October-December 2000

glucose11. It is almost completely absorbed fromGI tract, is short acting and hence is expected tohave less GI side effects than acarbose. The usualdose is 50-100 mg. daily31.

Insulinomimetic drugsVanadium saltsVanadium is an ultra trace element. Its compoundssuch as vanadyle orthovandate, metavandate andperoxovandate have been shown to haveinsulinomimetic effects on adipocytes, hepatocytes,and the skeletal muscles as well as inhyperinsulinaemic and hypoinsulinaemic animalmodels of the diabetes. They act by a mechanismindependent of insulin and near euglycaemia isachieved in animal models within 1-2 weeks. Inanimal models, vanadium salts induce decreasein body weight, attributed to its central anorecticeffects32. These salts act by increasing thephosphorylation of insulin receptor either byactivation of the intrinsic tyrosine kinase activityor by inhibition of the phosphotyrosyl phosphatasethat dephosphorylates the receptor32 and may alsoact on post receptor sites (mitogen activatedprotein kinase and cytosolic insulin independent


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tyrosine kinase)32. Importantly these compunds areeffective even in situations where the insulin signaltransduction pathway is defective16. Usual dosageis 100 mg/day and the effects lasts for upto 2weeks after discontinuation. Major side effects aregastrointestinal; however, there are fears of its

mitogenic potential, as it stimulates tyrosine kinase.A synthetic organic complex of vanadyl (bismaltatato) oxovanadium with high lipophilicity andperoxovanadium compounds appear promising32.IGF-1 receptor agonists are also being developedfor selective hypoglycaemic action, prolongedduration of effects, and perhaps for use by theoral route.Additionally, new drugs are being developed tocounter complications in diabetes. These includeaminoguanidine, tenisetam, OPB-9195 which areAGE receptor antagonists; protein kinase C

inhibitors (LYS 333531, WAY 151003, andCremophor EL), nerve growth factors, octreotide,hismanal, topical clonidine, picotamide, and a lotof research is focused on antioxidants such as

vitamin E and lipoic acid33.In conclusion, the management and approach fordiabetes mellitus is on the threshold of a revolution.Increasing realisation of the need for optimalglycaemic control and the pitfalls of availabletherapeutic options in type 2 diabetes has led toactive search for newer modalities of therapy.Despite simultaneous research on oral antidiabetic

agent having different mechanisms of action, inorder to overcome the deficiencies of currentlyavailable antidiabetic medication onlyglimeperide, repaglinide, thiazolidenediones, andacarbose have been introduced for routine use. Itis hoped that some of the other such agents wouldbe soon introduced in India at an affordable price;the remainder and perhaps many newerformulations may be available a few years laterdown the road.

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