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DM Pharmacotherapy

Edy Junaidi

Diabetes Mellitus
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

DM

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, pp.684 - 707

Uncontrolled DM

Pharmacotherapy
Insulin OAD :

Sulfonylurea secretagogues
1st generation : acetohexamide, tolazamide, tolbutamide, chlorpropamide 2nd generation : glipizide, glimepiride, glyburide

Non-sulfonylurea secretagogous (nateglinide, repaglinide) Biguanide (Metformin) -glucosidase inhibitor (acarbose, miglitol) PPAR agonist Thiazolidinediones insulin sensitizer (pioglitazone, rosiglitazone) Dipeptydil peptidase-4 inhibitors (DPP-IV inhibitors: sitegliptin)

Regulation of blood glucose

Insulin
Key

tissue target of insulin in regulating of glucose : Liver, muscle and fat

Regulation of insulin secretion Involve interplay of : GI hormones, pancreatic hormones, & autonomic neurotransmitter

In general, any conditions that activate sympathetic nervous system (hypoxia, hypoglycemia, exercise, severe burns, surgery, etc) suppresses insulin release by stimulation of -adrenergic receptor. Oral glucose provoke insulin release better than if its administered intravenously; Oral route stimulate GI hormones & vagal activity, the most potent of which are Glucagon-dependent insulinotropic peptide (GIP) & glucagon-like peptide 1 (GLP-1)

ATP-dependent

Voltage-gated

Insulin signaling pathway

Increases the number of glucose transporters in the membrane; it may also increase the rate at each transporter. Alters the concentration of fructose 2,6-bisphosphate, which in turn dramatically alters the activity of phosphofructokinase and fructose 1,6-bisphosphatase. Increases the activity of pyruvate kinase but inhibits the activity and the synthesis of phosphoenolpyruvate carboxykinase. Iincreases the activity of pyruvate dehydrogenase, probably through the insulin mediator Promotes lipogenesis and forms fats for storage from glucose through acetyl CoA. Promotes the synthesis of glycogen by increasing the activity of glycogen synthase (independent form). Inhibits the breakdown of glycogen by inhibiting glycogen phosphorylase.

Physiological Effects of Insulin

Goodmann & Gillman, 2008

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, 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

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); metabolites status : active (less potent, equally 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

Glinides
Short-acting insulin secretagogues (repaglinide,

nateglinide) Mechanism of action :

Repaglinide closes ATP-dependent potassium channels in the -cell membrane by binding at characterizable sites potassium channel blockade depolarizes the -cell, which leads to an opening of calcium channels increased calcium influx induces insulin secretion. The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle

Kinetics:

Rapidly absorbed, short half-life (1 1.5 hours) Nateglinide predominantly metabolized by CYP450 2C9 (70%) and CYP3A4 (30%), renal elimination; repaglinide predominantly metabolized by CYP3A4, excreted in bile

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, 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

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 -cells Mechanisms:

AMP-activated protein kinase activity, tyrosine kinase activity enhancement, glucose transporter 4 are all contributes on the activity of metformin

Kinetics :

50 60 % oral bioavailability Low lipid solubility; 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 1.5 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 - 15%

Adverse effects:

GI side effects :

Abdominal discomfort, stomach upset, &/ diarrhea in approximately 30% of patients Anorexia & stomach fullness contribute on weight loss effect of metformin GI side effect tend to be transiet, 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, procainamide, digoxin, quinidine, trimethoprim, vancomicin

Peroxisome Proliferator Activator Receptor - agonists (PPAR )


Glitazones PPAR primarily located on fat cells & vascular cells Glitazones PPAR receptor interaction maturation of preadipocytes (small fat cells are more sensitive to insulin & more able to store FFA) influx FFA out of plasma, fat, & liver into subcutaneous fat less insulin-resistant storage- tissue Muscle intracellular fat products, which contribute to insulin-resistant, also decline

Kinetics:

Well absorbed & highly bound to protein plasma Half-life: pioglitazone:3 7 hours, 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 1.5%, lower glucose (FPG) level 60 70 mg/dl at maximal doses Glycemic lowering onset is slow, maximal effect may not observed until 3 4 months therapy The efficacy of both drugs is dependent on sufficient insulinemia

Adverse effects:

Troglitazone, the first thiazolidinedione, were removed from market in March 2000 because of idiosyncratic hepatotoxicity resulting in 28 deaths

No evidence of hepatotoxicity in more than 5.000 patients given pioglitazone & rosiglitazone It is recommended to check ALT periodically (every 2 months on the 1st year of therapy) Patients withALT level >2.5 times of upper limit of normal should not start either medication Patient on medication with ALT level > 3 times of upper limit of normal, medication should be STOP

Fluid retention edema, dose related Reduction of plasma Hb Weight gain

Drug interaction:

No significant drug interaction have been noted with either medication

-glucosidase Inhibitor
Competitively

inhibit enzymes (maltase, isomaltase, sucrase, & glucoamylase) in the small intestine, delaying breakdown of sucrose and complex carbohydrate

They do not cause any malabsorption of these nutrients

Kinetics:

Mechanism of -glucosidase inhibitor is limited to luminal site of intestine Some acarbose are absorbed sistemically & renally excreted, while majority of miglitol is absorbed & renally excreted unchanged

Efficacy:

Reduce postprandial glucose (40 50 mg/dl), fasting glucose level relatively unchanged Efficacy on glycemic control is modest (reduction in HbA1c 0.3 1%)

Adverse effects:

Flatulence, bloating, abdominal discomfort, and diarrhea are very common greatly limit the use of -glucosidase inhibitors

Distal intestinal degradation of undigested carbohydrate by microflora CO2 & methane production

Elevated ALT level in high doses of acarbose

Dipeptidyl peptidase-4 Inhibitor


The

newest therapeutic class of oral agents for Diabetes Sitagliptin is the only FDA approved (vildagliptin, saxagliptin are in clinical trial www.clinicaltrial.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

reduce HbA1c 0.7 0.8 % compared to placebo Renal function monitoring recommended prior to initiation and during treatment

Adverse effects:

Nasopharyngitis (5.2%) Upper respiratory infection (6.3%) Headache (5.1%)

No

current drug interaction data available