Slide 1

ANTIDIABETIC DRUGS

DEFINITIONDiabetes mellitus is defined as an elevated blood glucose associated with absent or inadequate pancreatic insulin secretion with or without concurrent impairment of insulin action (Katzung B.G., 2009; WHO 2014)

ClassificationType 1 diabetesType 2 diabetesPancreas fails to produce the insulin which is essential for survival.

the body's inability to respond properly to the action of insulin produced by the pancreas.Genetic FactorsDecreased insulin seretionRelative insufficiency of insulin actionDevelopment of type 2 diabetesInteractionObesityInsulin resistanceHigh fat/lack of exerciseEnvironmental fc Lifestyle changes1Stress-related factors-overeating, especially excessive intake of simple sugars-smoking-Increase in alkohol intake-disorders of nervous and endocrine systems:increase in cortisol, abnormality in sex hormone secretion2Lowered energy consumption due to a lack of exercise 3Genetic factors4AgingFactors causing increase in visceral fat

PREDIABETESReflects failing pancreatic compensation to an underlying state of insulin resistance (caused by obesity)Current criteria: impaired glucose tolerance, impaired fasting glucose, or metabolic syndrome a 5-fold increase in future T2DM riskThe primary goal management : WEIGHT LOSSPREDIABETESAntihyperglycemic medications :Metformin and acarboseReduce the risk of future DM in prediabetic patients by 25 to 30%Well tolerated AND safe ThiazolidinedionesPrevented future DM in 60 to 70 % of subjects with prediabetes,but have a number of AEsCV benefits(Chiasson J.L., et al.1994; Gerstein H.C., et al.2006)

PHARMACOTHERAPYAchieving the glucose target and hemoglobin AIC goal AIC 6,5% for most patientsAIC > 6,5 % if the lower target cannot achieved without AEsIn large clinical trialintensive gluc-lowering th/ (target AIC < 6% in pt with baseline AIC >8,5% was associated with increased mortality in older and middle-aged patients with longstanding diabetes who were at high risk CVDIn other trial : higher AIC target for intensively treated pt no- between group diff in CVD endpoints, CV deaths, or overall death. (Duckworth W., et al. 2009 ; Gerstein H.C., et al. 2008)Pharmacotherapy 2Patients with recent-onset T2DM or mild hyperglycemia (AIC < 7,5%) TLC with monotherapy :

MetforminAlternatives: GLP-I agonists, ipeptidyl-peptidase-4 (DPP-4) inhibitors, and alpha-glucoside inhibitors (AGIs)TZD, Sulfonylureas (SFUs) and glinides may also be used but should be used with caution owing to the potential for weight gain,hypoglicemia, or other risk

Treatment The mainstay of non-pharmacological diabetes treatment is diet and physical activity.About 40% of diabetes sufferers require oral agents for satisfactory blood glucose control, and some 40% need insulin injections.People with Type 1 diabetes are usually totally dependent on insulin injections for survivalThe majority of people suffering from diabetes have the Type 2 form.

An algorithm for the treatment of type 2 diabetes mellitus

Subclass drugs used for DiabetesINSULINSULFONYLUREASMeglitinidesBIGUANIDESALPHA-GLUCOSIDASE INHIBITORSTHIAZOLIDINEDIONESTransition effect for split picture, slide 1(Basic)

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Farmakokinetika golongan sulfonilurea

GLYBURIDEMetabolized : Hepar into products with very low hypoglycemia activityUsual starting dosage: 2,5 mg/d or lessAverage maintenance :dosage : 5-10 mg/d, single morning doseMaintenance > 20 mg/d not recommendedA formulation micronized glyburide is available in a variety of tablet sizesGlyburide

Few Aes, potential for causing hypoglicemia

FDA recommends careful monitoring to retitrate dosage when switching from standart doses or from other sulfonylurea drugsContraindication : hepatic impairment and renal insufficiencyFlushing has rarely been reported after ethanol ingestion

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Glipizide90% of glipizide : metabolized in the liver to inactive products10% is excreted unchanged in the urineContraindication: hepatic or renal impairmentGLIMEPIRIDEOnce daily use as monotherapy or combination with insulinA single daily dose of 1 mg has been shown to be effectiveThe recommended maximal daily dose :8 mgHas a long duration of effect with a half-life of 5 hoursIt is completely metabolized by the liver to inactive productMeglitinidesRepaglinidea new non-sulfonylurea insulin secretagogue agent, the first available from the meglitinide class.Nateglinidethe newest member of the class, has recently become availableRepaglinideIt is hepatically cleared by CYP3A4Plasma half-life: 1 hourOnset : rapid controlling glucose excursionShould be taken before each meal in doses of 0,25 mg 4 mg (maximum 16 mg/d)If the meal contains inadequate CH hypoglycemiaCaution : renal and hepar impairmentIs approved as monotherapy or its combination with biguanidesThere is no sulfur in structure can be used by T2DM with sulfur or sulfonylurea allergy

NateglinideStimulates very rapid and transient release of insulin from beta-cells through closure of the ATP sensitive K+ channel.Ingestion : just before mealAbsorption : 20 minutesMetabolism : hepar, by CYP2C9 and CYP3A4A half-life of 1,5 hoursThe overall duration of action : < 4 hoursBIGUANIDESBIGUANIDE-METFORMINAccumulation of metformin in the liver has been shown to be higher than in other tissues, reaching hundreds of M in the periportal area (Wilcock C, et al. 1994)Deletion of the OCT1 gene in mouse dramatically reduces metformin uptake in hepatocytes and human individuals carrying polymorphisms of the gene (SLC22A1) display an impaired effect of metformin in lowering blood glucose levels (Shu Y, et al.2007)

BIGUANIDE-METFORMINThe activation of AMP-activated protein kinase (AMPK) was intimately associated with the pleiotropic actions of metformin ( Zhou g., et al.2001)AMPK is a heterotrimeric protein consisting of a catalytic -subunit and two regulatory subunits and and each subunit has at least two isoforms.AMPK is activated by increase in the intracellular AMP-on-ATP ratio resulting from imbalance between ATP production and consumption. BIGUANIDE-METFORMINMetformin most likely does not directly activate either LKB1 or AMPK as the drug does not influence the phosphorylation of AMPK by LKB1 in cell-free assay (Hardie D.G. 2006)There is evidence that AMPK activation by metformin is secondary to its effect on the mitochondria, the primary target of the drug.

After hepatic uptake through OCT1, the mitochondria is the primary target of metformin which exerts specific and AMPK-independent inhibition of respiratory-chain complex 1. The resultant mild decrease in energy status leads to acute and transient inhibition of energy-consuming gluconeogenic pathway. In addition, through AMPK-dependent and -independent regulatory points, metformin can lead to the inhibition of glucose production by disrupting gluconeogenesis gene expression. In parallel, the LKB1-dependent activation of AMPK triggered by ATP depletion could reduce hepatic lipogenesis and exert an indirect effect on hepatic insulin sensitivity to control hepatic glucose output.32BIGUANIDS-METFORMINFirst line therapy for T2DM Does not increase weight or provoke hypoglicemiaDecreases the risk of macrovascular and microvascular diseaseAlso indicated for use in combination with insulin secretagogues or thiazolidinediones in T2DM in whom oral monoth/ is inadequateEficacy: prevent the new onset T2DM in middle-aged, obese person with impaired glucose tolerance and fasting hyperglicemiadid not prevent diabetes in older, leaner prediabetics (the landmark Diabetes Prevention Program)the dosage : 500 mg 2,55 g/dailyCan be initiated as a once-daily dose a bedtime or before a meal.common schedule : fasting hyperglycemia begin with a single 500 mg tablet If tolerated wo/ GI dicomfort and hyperglicemia persist, a second 500 mg tablet added to be taken with breakfast or the midday meal or the larger (850 mg) tablet 2 daily

BIGUANIDS-METFORMINBIGUANIDES-METFORMINMost common toxic effects : GI (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea) occurs in up to 20% ptDose relatedOccur at the onset of therapyPersistent diarrhea stop (3-5% pt)CI renal disease, alcoholism, hepatic disease, conditions predisposing to tissue anoxia coz of an increased risk of lactid acidosis induced by biguanide drugsTHIAZOLIDINEDIONESRosiglitazonePioglitazone Combination preparations are also availableTHIAZOLIDINEDIONESTHIAZOLIDINEDIONESThe principal mechanism

Stimulation of PPAR- enhance insulin sensitivity

PPAR- is expressed at highest levells in adipose tissue, and less so in muscle and liverTHIAZOLIDINEDIONESACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action.ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output.

THIAZOLIDINEDIONES

Action of Pioglitazone in a Diabetic PatientTHIAZOLIDINEDIONES

Rosiglitazone and pioglitazone rapidly and nearly completely absorbed (1-2 hours to peak concentration)Absorption is slightly delayed when taken with foodBoth agents are extensively metabolised by the liverRosiglitazone is metabolised mainly to very weakly active metabolites with lesser activity that are excreted in urineTHIAZOLIDINEDIONES

The metabolites of pioglitazone are more active excreted mainly in the bile Pioglitazone is metabolised by CYP3A4No clinically significant reductions in plasma concentration of other drugs ( e.g oral contraceptives)THIAZOLIDINEDIONES

As a monotherapy in non-obese and obese patients with type 2 diabetes in whom diabetes is not adequately controlled by nonpharmacologycal measuresCan be used in combination with other AD drugs and in combination with insulinCan cause fluid retention with increased plasma volume, a reduced haemotocrit, and a decreased in Hb concentrationTHIAZOLIDINEDIONES

In Europe, CI CHFAHA and ADA : patient treated with a combination of insulin plus thiazolidinediones higher risk of oedema careful clinical monitoring (check : Hb before starting a thiazolidinediones)Liver function should be assessed by measuring serum ALT before starting therapy an subsequently at 2-monthly intervals during the 1st year of treatmentTHIAZOLIDINEDIONES

Rosiglitazone : 4 mg/d in combination with sulphonylurea, increasing to 8 mg/d in combination with metforminPioglitazone : a once-daily dosage of 15 mg/d, increasing to 30 mg if necessaryIf no effect is observed after 3 months treatment stop the treatmentCan be used in the elderly, mild-to-moderate renal impairment

ALPHA-GLUCOSIDASE INHIBITORS

ALPHA-GLUCOSIDASE INHIBITORSAcarbose and MiglitolCompetitive inhibitors of the intestinal -glucosides and reduce post-meal glucose excursions by delaying the digestion and absorption of starch and disaccharidesALPHA-GLUCOSIDASE INHIBITORSAcarbosethe first alpha-glucoside inhibitors introduce in the early 1990sDo not cause weight gainCan reduce postprandial hyperglycemiaHave lowered plasma triglyceride concentrations in some studies (Lebovitz H.E., et al. 1998)ALPHA-GLUCOSIDASE INHIBITORS

Pharmcokinetics:Is absorbed only < 2%Is degraded by amilase in the small intestine and by intestinal bacteriaSome of these degradation products are systemically absorbed to be eliminated in the urine Can be used as monotherapy for pt T2DM that is inadequately controlled by nonpharmacological measures

ALPHA-GLUCOSIDASE INHIBITORSCan be a useful first-line treatment in pt who have a combination of only slightly raised basal glucose concentrations and more marked postprandial hyperglycemiaSTOP-NIDDM : confirmed the utility of acarbose in preventing the transition from impaired glucose tolerance to diabetes (Chiasson J.L., et al. 2002)ALPHA-GLUCOSIDASE INHIBITORSWhen starting th/ ensure that pt is taking diet rich in complex CHShould be taken with mealsStarting with a low dose, for example 50 mg/daySlowly titrating up over several weeksHigh dosages can occasionally increase liver enzyme concentrations transaminase concentration are measured at intervals in pt receiving the max dosage.ALPHA-GLUCOSIDASE INHIBITORSIf liver enzymes are raised the dosage should be reduced to a level at which normal enzyme concentrations are re-etablishedAes: gastrointestinal in th STOP-NIDDM trial: 31% of acarbose treated pt compared with 19% on placebo discontinued treatment earlyIf dosage is too high undigested oligosaccarides pass into the large bowel fermented by flora flatulance, abdominal discomfort, and sometimes diarrhoea. can be minimised by slow titrationALPHA-GLUCOSIDASE INHIBITORSHypoglycemia in combination with a sulphonylurea or insulin (Krentz A.J., et al. 1994)

ALPHA-GLUCOSIDASE INHIBITORSALPHA-GLUCOSIDASE INHIBITORSINSULININSULINA small protein with a molecular weight in humans of 5808It contains 51 amino acids arranged in 2 chains (A nd B) linked by disulfide bridgesThe entire human pancreas contains up to 8 mg of insulin

Model of glucose-induced insulin release

The Key Elements in Insulin Secretion

Glucose transport 2 (GLUT2)Glucokinase (GK)MitochondriaATP-sensitive K+ channels (K+ATPchannels)Voltage-dependent Ca2+-channels (VDCC)Exocytosis

INSULIN DEGRADATIONThe liver and kidney 2 main organs that remove insulin from the circulationThe liver normally clears blood of approximately 60% of the insulin released from pancreas, removing by kidney : 35-40%That atio is reversed in insulin-treated diabetis receiving sc insulin injectionsThe half-life of circulating insulin : 3-5 minutes

Circulating InsulinBasal insulin values : 5-15 U/mLPeak rise to 60-90 U/mL during meals

Diagrammatic structure of stimulation of the insulin receptor

Insulin-activated intracellular signal transduction pathwaysINSULIN PREPARATIONSPrincipal types and duration of action of insulin preparations4 principal types of injected insulins are available:Rapid-acting , with very fast onset and short durationShort-acting, with rapid onset of actionIntermediate-actingLong-acting, with slow onset of action

Rapid-acting insulinThree injected rapid-acting insulin analogs : Insulin Lispro, Insulin aspart and Insulin glulisinerapid onset and early peak action more closely mimic normal endogenous prandial insulin secretion than does regular insulinDuration of action : rarely more than 4-5 hours decreases the risk of late postmeal hypoglicemia Rapid-acting insulinHave the lowest variability of absorption (app. 5 %) of all available commercial insulins .Lispro -> the first monomeric insulin analog to be marketed, is produced by recombinant technology : proline at position B28 has been moved to B29 and lysin at position B29 has been moved to B28Lispro when injected SC quickly dissociates into monomers and is rapidly absorbed with onset of action 5-15 minutes and peak activity 1 hour.Short-acting insulin= regular insulin : a short acting acting crystalline zinc insulin made by recombinant DNA techniquesIts effect appears within 30 inutesPeaks between 2 and 3 hours after SC injection and generally last 5-8 hoursShoul be injected 30-45 or more minutes before the meal Is the only type that should be administrated IV diabetic ketoacidosisIntermediate-acting and long-acting insulinsNPH (Neutral protamine Hagedon, or isophane) absorption and onset of action are delayed by combining insulin and protamine onset : 2-5 hours Duration : 4-12 hours it is usually mixed with regular, lispro,aspart, or glulisine insuline and given 2-4 times daily for insulin replacementVariabiliy of absorption :> 50%

Insulin glargine :Has a slow onset : 1-1,5 hoursachieves a max effect after 4-6 hoursMax activity maintained for 11-24 hours or longeronce dailyShould not be mixed with other insulinsHas 6-7 fold greater binding than native insulin to the IGF-1 receptorIntermediate-acting and long-acting insulinsMixtures of insulin:Because intermediate-acting NPH insulin require several hours to reach adequate therapeutic levels requires supplements of rapid- or short-acting insulin before mealsMixed together in the same syringe before injectionInsulin lispro, aspart and glulisine can be acutely mixed just before injection with NPH insulin without affecting their absorptionIntermediate-acting and long-acting insulinsCatatan!Rapid Insulin (Novorapid), insulin rapid action untuk mengatasi lonjakan post prandial glucose. Long Acting Insulin (Levemir) untuk mengatasi kebutuhan insulin basal (GDP) efeknya 24 jam menyerupai insulin endogen dan tidak mempunyai puncak (peak) sehingga mengatasi nocturnal Hypoglicemia. Mixed Insulin (Novomix) gabungan antara basal dan prandial insulin digunakan untuk meningkatkan compliance px sebagai alternatif insulin basal plus dan basal bolusCatatan 2!Insulin long acting (Levemir) berfungsi 24 jam dan tidak ada puncak (no peak) sehingga dapt menghindari hipoglikemia Nocturnal. Intermediate hanya 12-20 jam sehingga saat tidur bisa hipoglikemia

Catatan 3!Kapan diberikan IV? Yaitu pada saat krisis HiperglikemiaKAD (klinis : ketonuri, Kussmaul, Asidosis metabolic)HONK (pake rumus 3 yes 1 No, hiperglikemi, keton (-), Kussmaul (-) osmolaritas >325Infark MyocardCVASepsisSteroid dosis tinggi

THYROID AGENTSThyroid PhysiologyThe normal thyroid gland secretes amounts of the thyroid hormonesTriiodothyronine (T3)Tetraiodothyronine (T4,thyroxine)These hormon contain 59% and 65% (respectively) of iodineT4 and T3 are critically important for normal growth and development and for controlling energy metabolism.Calcitonin, the second type of thyroid hormoneis involved in the control Calsium plasma and is used to treat osteoporosis and other metabolic bone diseasesThe thyroid secretes about 80 micrograms of T4, but only 5 micrograms of T3 per day.However, T3 has a much greater biological activity (about 10X) than T4.An additional 25 micrograms/day of T3 is produced by peripheral monodeiodination of T4The main steps in the synthesis, storage and secretion of thyroid hormon:Uptake of plasma iodide by the follicle cellsOxidation of iodide and iodination of tyrosine residues of thyroglobulinSecretion of thyroid hormone

Thyroid PhysiologyIodine Metabolism Dietary iodine is absorbed in the GI tract, then taken up by the thyroid gland (or removed from the body by the kidneys). The transport of iodide into follicular cells is dependent upon a sodium/iodine co-transport system. Iodide taken up by the thyroid gland is oxidized by peroxide in the lumen of the follicle:peroxidaseI- I+ Oxidized iodine can then be used in production of thyroid hormones.Byosynthesis of Thyroid HormonesThe thyroid hormones thyroxine (T4) and T3 are formed within the thyroid glandOnce taken up by the thyroid gland, iodine undergoes a series of enzymatic reactions before it converts into active thyroid hormones

Thyroid Hormone SynthesisThyroid Hormone SynthesisThyroid Hormone SynthesisThe T3 and T4 released from the thyroid by proteolysis reach the bloodstream where they are bound to thyroid hormone binding proteins. The major thyroid hormone binding protein is thyroxin binding globulin (TBG) which accounts for about 75% of the bound hormone.Thyroid Hormone SynthesisThyroid Hormone Synthesis

Transport Of Thyroid Hormones

DRUGS USED IN DISEASES OF THE THYROIDHYPERTHYROIDISMRADIOIODINEEmits both and radiation.The rays pass through the tissue without causing damageThe rays have very short range and exert a powerful cytotoxic action resulting in significant destruction of the tissueT1/2: 8 days, so by 2 months its radioactivity has dissaperedSingle dose

RADIOIODINEGraves diseases is treated by Radioiodine, and after treatment hypothyroidismcan be managed by replacement therapy with T4Avoided in children and pregnant patientsCan be used diagnostically as a test of thyroid funcionTHIOUREYLENESTHIOUREYLENESGiven orallyCarbimazole is rapidly converted to its active metabolite methimazoleAn average dose of carbimazole produces more than 90% inhibition of thyroid incorporation of iodine within 12 h Comparisons of PTU and methimazolePTUMethimazoleSerum protein binding75%NilSerum half-life75 minutes4-6 hoursGI absorptionAlmost completeAlmost completePeak serum concentration1 hour after ingestion1 h after ingestionDuration of action12-24 hPossibly >24 hMetabolitesGlucuronideNot-well characterizedTransplancetal passageLowerHigherLevels in breast milklowerhigherEffects of Antithyroid Drugs: peripheral

Effects of Antityhroid Drugs : intrathyroidal

The Uses of Antithyroid Drugs

2 contexts of antithyroid drug use . Short Term Therapy (weeks-months) To cool down the patient prior to radioiodine.Long-Term Therapy (1-2 years) remission, that may or may not occur, usually followed by radioiodine therapy HYPOTHYROIDISMHYPOTHYROIDISMLiothyroxine has a faster onset but a shorter duration of action, and is generally reserved for acute emergencies such as the rare condition of myxoedemeOverdoseunwanted effects: hyperthyroidism and angina pectoris, cardiac dysrhythmias or cardiac failure

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