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⇨ A group
of chronic metabolic disorders characterized by hyperglycemia that may result in long-term microvascular, macrovascular, and neuropathic complications ⇨ DM is the leading cause of
⇨ ⇨ ⇨
New cases of blindness among adults End-stage renal disease Non-traumatic lower limb amputations
Contribution on increasing cardiovascular risk
Type 1 (previously known as IDDM, juvenile-onset DM)
⇨ ⇨ ⇨
Usually diagnosed in children and adults younger than 30 years of age although the disease can present at any age Characterized by absolute insulin deficiency LADA (latent autoimmune diabetes in adult) – slow onset type 1 or Type 1.5 DM → occur at older age than the usual age of onset; Often mistakenly diagnosed as Type 2
Type 2 (previously known as NIDDM, adult-onset DM)
90 – 95% of all diagnosed cases Usually preceded by pre-diabetes ⇨ Insulin resistance or relative insulin deficiency ⇨ Other specific types (WHO/NCD/NCS/99.2)
The easiest way of differentiating Type 1 and Type 2 is by measuring Cpeptide level : < 1 ng/ml (type 1); Type 2 > 1 ng/ml
Disorder of glycaemia: Etiological type & clinical stages
Clinical presentation of DM .
Criteria for Diagnosis of DM Cook et al. 2008..707 . pp.684 .
Uncontrolled DM .
repaglinide) Biguanide (Metformin) α-glucosidase inhibitor (acarbose. tolbutamide. miglitol) PPARγ agonist → Thiazolidinediones – insulin sensitizer (pioglitazone. glyburide ⇨ ⇨ ⇨ ⇨ ⇨ Non-sulfonylurea secretagogous (nateglinide. tolazamide.Pharmacotherapy ⇨ Insulin ⇨ OAD : ⇨ ⇨ ⇨ Sulfonylurea secretagogues 1st generation : acetohexamide. glimepiride. chlorpropamide 2nd generation : glipizide. rosiglitazone) Dipeptydil peptidase-4 inhibitors (DPP-IV inhibitors: sitegliptin) .
Regulation of blood glucose .
hypoglycemia.Insulin ⇨ Key tissue target of insulin in regulating of glucose : Liver. exercise. etc) suppresses insulin release by stimulation of α-adrenergic receptor. muscle and fat Regulation of insulin secretion ⇨ Involve interplay of : GI hormones. pancreatic hormones. severe burns. & autonomic neurotransmitter – In general. any conditions that activate sympathetic nervous system (hypoxia. surgery. Oral route stimulate GI hormones & vagal activity. –Oral glucose provoke insulin release better than if its administered intravenously. the most potent of which are Glucagon-dependent insulinotropic peptide (GIP) & glucagon-like peptide 1 (GLP-1) .
ATP-dependent Voltage-gated .
Insulin signaling pathway .
• Promotes the synthesis of glycogen by increasing the activity of glycogen synthase (independent form).6-bisphosphatase. it may also increase the rate at each transporter. Physiological Effects of Insulin .• Increases the number of glucose transporters in the membrane. probably through the insulin mediator • Promotes lipogenesis and forms fats for storage from glucose through acetyl CoA. • Increases the activity of pyruvate kinase but inhibits the activity and the synthesis of phosphoenolpyruvate carboxykinase.6-bisphosphate. • Iincreases the activity of pyruvate dehydrogenase. • Inhibits the breakdown of glycogen by inhibiting glycogen phosphorylase. • Alters the concentration of fructose 2. which in turn dramatically alters the activity of phosphofructokinase and fructose 1.
2008 .Goodmann & Gillman.
intermediate acting insulin given at bedtime may normalize fasting blood glucose • Intermediate acting insulin • Long acting insulin – Provide low basal concentration of insulin throughout the day .Classification of Insulin • Short.and Rapid-acting Insulin – Short acting insulin before or after meal – All rapid acting insulin may be administered postprandially to provide smoother glycemic control and to prevent hypoglycemia – Usually given once a day before breakfast or twice a day – In T2DM patients.
Indication • Management of type 1 DM • Management of type 2 DM which is not controlled by diet &/ OAD alone. • Post pancreatectomy diabetes • Gestational diabetes • Diabetic ketoacidosis • Non ketotic coma • Perioperative management of patient with type 1 & type 2 DM .
Adverse Effects • Hypoglycemia • Insulin allergy & resistance • Lipoatrophy & lipohypertrophy – Atrophy probably is immune response to insulin – Hypertrophy is considered as lipogenic action of high local insulin at the site of injection • Both problems are rare with more purified preprarations • Insulin edema .
Sulfonylurea ⇨ Insulin secretion enhancer SUR = specific sulfonylurea receptor .
⇨ Classification of sulfonylurea based on : ⇨ Difference in relative potency ⇨ Relative potential side effects ⇨ Different protein binding properties ⇨ All sulfonylurea are equally effective at equipotent doses ⇨ All sulfonylurea are metabolized in liver (CYP450 2C9). equally potent). metabolites status : active (less potent. inactive ⇨ Half-life directly relate to the risk of hypoglycemia → cautious use in patient with hepatic or renal impairment .
⇨ Adverse effects : ⇨ Hypoglycemia ⇨ Hyponatremia ⇨ Weight gain ⇨ Skin rash ⇨ Hemolytic anemia ⇨ GI upset ⇨ Cholestasis ⇨ Drug ⇨ interactions : Close monitoring concomitant use of CYP450 2C9 inducer /inhibitor with sulfonylurea .
which leads to an opening of calcium channels → increased calcium influx induces insulin secretion. excreted in bile .5 hours) Nateglinide predominantly metabolized by CYP450 2C9 (70%) and CYP3A4 (30%).Glinides ⇨ Short-acting insulin secretagogues (repaglinide. nateglinide) Mechanism of action : ⇨ ⇨ Repaglinide closes ATP-dependent potassium channels in the β-cell membrane by binding at characterizable sites → potassium channel blockade depolarizes the β-cell. The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle Kinetics: ⇨ ⇨ Rapidly absorbed. short half-life (1 – 1. repaglinide predominantly metabolized by CYP3A4. renal elimination.
15% repaglinide vs glyburide (15%) & glipizide (19%) ⇨ Weight gain : 2 – 3 kg with repaglinide. < 1 kg with nateglinide Drug interaction ⇨ No significant drug interaction have been reported .Efficacy ⇨ ⇨ Both (monotherapy) significantly reduce postprandial glucose and HbA1c level Lower efficacy of glinides vs sulfonylureas should be considered when patients are >1% above their HbA1c goal Adverse effects ⇨ Hypoglycemia (less than sulfonylurea) ⇨ Rates of hypoglycemia : 3% with nateglinide.
tyrosine kinase activity enhancement.Biguanide ⇨ Metformin : the only biguanide available in use ⇨ (Phenformin & Buformin withdrawn from market due to toxic effects) ⇨ Enhance insulin sensitivity in liver and peripheral (muscle) tissues ⇨ No direct effect on β-cells ⇨ Mechanisms: ⇨ AMP-activated protein kinase activity. glucose transporter 4 are all contributes on the activity of metformin .
Kinetics : ⇨ ⇨ ⇨ ⇨ ⇨ 50 – 60 % oral bioavailability Low lipid solubility.5 – 2 % Reduce fasting plasma glucose 60 – 80 mg/dl Retain its glucose-reducing ability at extremely high glucose level (>300 mg/dl) Reduce plasma triglycerides & LDL-C by 8 . Vd approximate body water Metformin is not metabolized & does not bind to plasma protein Eliminated by renal tubular secretion & glomerular filtration Average half-life 6 hours Efficacy ⇨ ⇨ ⇨ ⇨ Consistently reduce HbA1c level by 1.15% .
vancomicin . digoxin. procainamide. stomach upset. quinidine. lessening within several weeks ⇨ ⇨ Lactic acidosis (rare) Metformin is contraindicated in renal insufficiency (renal elimination) Drug interaction: ⇨ Cationic drugs may compete on renal tubular secretion :cimetidine. trimethoprim. &/ diarrhea in approximately 30% of patients Anorexia & stomach fullness → contribute on weight loss effect of metformin GI side effect tend to be transiet.Adverse effects: ⇨ GI side effects : ⇨ ⇨ ⇨ Abdominal discomfort.
also decline . & liver into subcutaneous fat less insulin-resistant storage.tissue ⇨ Muscle intracellular fat products.γ agonists (PPARγ ) Glitazones ⇨ PPARγ primarily located on fat cells & vascular cells ⇨ Glitazones – PPARγ receptor interaction → maturation of preadipocytes (small fat cells are more sensitive to insulin & more able to store FFA) → influx FFA out of plasma. which contribute to insulin-resistant. fat.Peroxisome Proliferator Activator Receptor .
rosiglitazone 3 – 4 hours Active metabolites with longer half-life deliver the majority of activity at steady state Both have 24 hours duration of antihyperglycemic activity Efficacy ⇨ ⇨ ⇨ Reduce HbA1c 1. maximal effect may not observed until 3 – 4 months therapy The efficacy of both drugs is dependent on sufficient insulinemia .5%.Kinetics: ⇨ ⇨ ⇨ ⇨ Well absorbed & highly bound to protein plasma Half-life: pioglitazone:3 – 7 hours. lower glucose (FPG) level 60 – 70 mg/dl at maximal doses Glycemic lowering onset is slow.
Adverse effects: ⇨ Troglitazone. the first thiazolidinedione. medication should be STOP ⇨ ⇨ ⇨ Fluid retention – edema. were removed from market in March 2000 because of idiosyncratic hepatotoxicity resulting in 28 deaths ⇨ ⇨ ⇨ ⇨ No evidence of hepatotoxicity in more than 5. dose related Reduction of plasma Hb Weight gain Drug interaction: ⇨ No significant drug interaction have been noted with either medication .5 times of upper limit of normal should not start either medication Patient on medication with ALT level > 3 times of upper limit of normal.000 patients given pioglitazone & rosiglitazone It is recommended to check ALT periodically (every 2 months on the 1st year of therapy) Patients withALT level >2.
α -glucosidase Inhibitor ⇨ Competitively inhibit enzymes (maltase. delaying breakdown of sucrose and complex carbohydrate ⇨ They do not cause any malabsorption of these nutrients Kinetics: ⇨ ⇨ Mechanism of α-glucosidase inhibitor is limited to luminal site of intestine Some acarbose are absorbed sistemically & renally excreted. sucrase. while majority of miglitol is absorbed & renally excreted unchanged . & glucoamylase) in the small intestine. isomaltase.
Efficacy: ⇨ ⇨ Reduce postprandial glucose (40 – 50 mg/dl). fasting glucose level relatively unchanged Efficacy on glycemic control is modest (reduction in HbA1c 0. bloating. and diarrhea are very common → greatly limit the use of α-glucosidase inhibitors ⇨ Distal intestinal degradation of undigested carbohydrate by microflora → CO2 & methane production ⇨ Elevated ALT level in high doses of acarbose . abdominal discomfort.3 – 1%) Adverse effects: ⇨ Flatulence.
Dipeptidyl peptidase-4 Inhibitor ⇨ The newest therapeutic class of oral agents for Diabetes ⇨ Sitagliptin is the only FDA approved (vildagliptin.gov) ⇨ DPP-IV inhibitors slow inactivation of incretin hormones within the gut ⇨ Incretin hormones are release throughout the day and increase level with meal ⇨ Drug activity – glucose dependent . saxagliptin are in clinical trial www.clinicaltrial.
7 – 0.⇨ ⇨ reduce HbA1c 0.3%) Headache (5.8 % compared to placebo Renal function monitoring recommended prior to initiation and during treatment Adverse effects: ⇨ ⇨ ⇨ Nasopharyngitis (5.1%) ⇨ No current drug interaction data available .2%) Upper respiratory infection (6.
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