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The document discusses anti-diabetic agents and the mechanisms of diabetes mellitus, highlighting the differences between type 1 and type 2 diabetes, their pathophysiology, and the importance of insulin in glucose metabolism. It outlines the metabolic complications associated with diabetes, including diabetic ketoacidosis and hyperglycemic crises, and describes various pharmacological treatments, including insulin and oral hypoglycemic agents. Additionally, it emphasizes the significance of lifestyle management and careful monitoring of blood glucose levels for effective diabetes management.

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Anti-Diabetic Agents Dr. Harshika Patel KeMU PHRM 400 Pharmacology and therapeutics II
•Pancreatic hormones (insulin and glucagon) •Anti-diabetic drugs
Diabetes Mellitus •A chronic systemic disease characterized by metabolic and vascular abnormalities •Disorder of carbohydrate metabolism •Results from inadequate production or underutilization of insulin
Cont’d… •Characterized by glucosuria and hyperglycemia •Four forms—Type 1 and Type 2, others, and gestational diabetes mellitus •Type 1—patient secretes no insulin. Cause is felt to be autoimmune. •Type 2- patient secretes insufficient amounts of insulin and insulin receptors are resistant to existent circulating insulin https://www.diabetes.org.uk/diabetes-the-basics/types-of-diabetes
Cont’d…
•Reuqired Medical intervention is necessary otherwise, significant complications will ensue. •In both form need careful attention to diet, fasting and postprandial blood glucose concentrations, and serum concentrations of hemoglobin A1c, a glycosylated hemoglobin (marker of glycaemia) •Include: retinopathies, glaucoma, neuropathies, cardiovascular disease (PVD). •Increased incidence of toxemia of pregnancy. Cont’d…
IMPORTANCE OF EACH BIOCHEMICAL TEST •Fasting BS •Post-prandial BS •OGTT •HBA1C concentration •Learn this biochemistry
Brief Pathophysiology •Insulin secreted by beta cells •Insulin binds with and activates 80% of cells •Liver, muscle, and fat cells are primary tissues for insulin action •With insulin receptor binding, cell membranes permeable to glucose into the cells (see the next slide) •Increased cell permeability also allows for amino acids, fatty acids and electrolytes to enter cells •Changes cause anabolism and inhibit catabolism
Cont’d. •Various glucose transporters are available for this purpose: •Examples: •GLUT 1 •GLUT 2 •GLUT 3 •GLUT 4 •SGLT 1 (intestine  to blood stream (transfer through GLUT 2)) •SGLT2 (in kidney  glucose transfer through GLUT 2 /3  REABSORB) Basically insulin bind on insulin receptors and activates these transporters and allows glucose to enter into the cell
Endogenous Insulin •It is synthesized as a pro-hormones (proinsulin  86- amino-acid single-chain polypeptide) •Which cleaved and formed 2-chain 51-peptide insulin molecule + a 31-amino-acid residual C-peptide •Proinsulin and c-peptide have no physiological role •Glucose is the major stimulus of insulin secretion •Oral glucose is more effective than intravenous glucose because glucose in digestive tract increases the release of gastrin, secretin, cholecystokinin, and gastric inhibitory peptide •Also stimulates vagal activity
Cont’d… Other hormones that raise blood glucose levels include: •Cortisol •Glucagon •Growth hormone •Epinephrine •Estrogen •Progesterone Factors that inhibit insulin secretion include: • Hypoxia • Hypothermia • Stimulation of alpha-2 receptors
Classification of Two Types of Diabetes Type 1 diabetes results from an autoimmune disorder that destroys pancreatic beta cells Usually has sudden onset Associated with high incidence of complications Requires exogenous insulin 10% of those with diabetes are type I Associated with diabetic ketoacidosis
Diabetic Ketoacidosis (DKA) •Life-threatening complication occurs with insulin deficiency •Glucose cannot be used by body cells for energy so fat is mobilized for this purpose •Mobilized fat is then extracted by liver and broken down into glycerol and fatty acids •Fatty acids further broken down into ketones
Cont’d… •Accumulation of ketones results in academia: 1. Attempts to buffer acidic H+ occurs by ionic exchange, intracellular potassium exits cells. H+ ions enter cells. Result is excretion of potassium in urine electrolytes imbalance 2. Kidneys attempt to buffer by excreting ketones 3. Pulmonary attempt to buffer by Kussmaul breathing • Blood and urine is concentrated with ketones  need immediate treatment
Clinical symptoms of DKA •Kussmaul breathing •Nausea and vomiting •Thirst •Polydipsia, polyphagia and polyuria •Hypotension •Tachycardia •Shock
Type 2 Diabetes Mellitus •Characterized by hyperglycemia and insulin resistance •Results from increased production of glucose by liver and decreased uptake of glucose in liver, muscle and fat cells •Insulin resistance—higher than usual concentrations of insulin are required
Type 2 Diabetes Mellitus Occurs at any age Gradual onset Less severe symptoms initially Easier to control  higher incidence of MIs and strokes 90% of those with diabetes are Type 2 multifactorial
Hyperosmolar hyperglycemia non- ketotic coma (HHNC) •Occurs in Type 2 Diabetes •Because patient has some endogenous insulin, no ketosis develops •Blood sugars can be >800-1000 mg/dL •Can result in hypovolemic shock, renal problems, stroke, coma and even death
Metabolic Syndrome or Syndrome X Comprised of a set of risk factors which include: 1. Central abdominal adiposity (men waist size greater than 40 inches, women greater than 35 inches 2. Fasting triglycerides greater > or equal to 150 mg/dl (in adults), 3. HDL cholesterol (less than 40 in men, less than 50 mg/dl in women
Cont’d... 4. Blood pressure greater than or equal to 130/85 5. Fasting glucose greater than or equal to 110mg/dl Also possess prothrombotic and proinflammatory tendencies
Metabolic Syndrome cont. •All factors are interrelated •Obesity and lack of exercise tend to lead to insulin resistance •Insulin resistance has a negative effect on lipid production. Increase VLDL, LDL, TG and decreasing the HDL. •Insulin resistance leads to increased insulin and glucose levels in blood.
Pharmacotherapy of Hypoglycemic Drugs- Insulin •Insulin lower glucose levels by increasing glucose uptake by cells •Indicated for Type 1 DM often, in Type 2 DM, in those with chronic pancreatitis, in those on TPN, to treat hyperkalemia (infusion with dextrose and insulin) •Available insulin's are from pork and human
Age-Related considerations Type 1 DM in children •Consistent diet, blood glucose monitoring, insulin injections and exercise •Blood sugar control essential to maintain normal growth and development •Infections and illnesses can cause wide fluctuations
Cont’d... •Children highly susceptible to dehydration •Rotation of sites is very important •Avoiding hypoglycemia is a major goal in infants and young children which affects the growth and development •s/s of hypoglycemia include: hunger, sweating, tachycardia, irritability and lethargy
Age related considerations in older adults •Close monitoring of blood glucose levels •Visual impairment may affect their ability to self administer medication •May have renal insufficiency so caution with certain anti-diabetic drugs •Caution with metformin if renal impairment •Glitazones can predispose to fluid retention and heart failure
Insulin • History: • Insulin was discovered in 1921 by Banting and Best (just done demonstration on extracted pancrease) • first obtained in pure crystalline form in 1926 • The chemical structure was fully worked out in 1956 by Sanger • Human insulin is chemically identical to endogenous insulin but it is not derived from the human pancreas • Cannot be given orally. • Insulins differ in onset and duration of action. Ultra- short, short, intermediate and long acting.
Regulation of insulin secretion •By three different mechanisms: •Chemical •Hormonal and •Neuronal
Action of insulin 1. Insulin facilitates glucose transport across cell membrane; skeletal muscle and fat are highly sensitive. • However, glucose entry in liver, brain, RBC, WBC and renal medullary cells is largely independent of insulin • Exercise has insulin sparing effect. 2. Intracellular utilization of glucose is its phosphorylation to form glucose-6-phosphate  which is enhanced by insulin through increased production of glucokinase. 3. Insulin facilitates glycogen synthesis from glucose in liver, muscle and fat by stimulating the enzyme glycogen synthase. 4. It also inhibits glycogen degrading enzyme phosphorylase → decreased glycogenolysis in liver
Cont’d… 5. Insulin inhibits gluconeogenesis (from protein, FFA and glycerol) in liver 6. Insulin inhibits lipolysis in adipose tissue and favors triglyceride synthesis  fat is broken down due to free action of lipolytic hormones (glucagon, Adr, thyroxine, etc.) → increased FFA and glycerol in blood. (check DKA) 7. Insulin enhances transcription of vascular endothelial lipoprotein lipase and thus increases clearance of VLDL and chylomicrons • Most of the above metabolic actions are exerted within seconds or minutes  called the rapid actions. • Others involving DNA mediated synthesis of glucose transporter and some enzymes of amino acid metabolism have a latency of few hours  called intermediate actions. • Exerts major long-term effects on multiplication and differentiation of many types of cells.
Mode of action - Insulin
Fate of Insulin •Oral administration – is not possible  as it is peptide and get degrade in GIT •Extracellular distribution – only possible •Metabolized  primarily in liver and to a smaller extent in kidney and muscles •During biotransformation the disulfide bonds are reduced—A and B chains are separated  Further broken down to the constituent amino acids. •The plasma t½ is 5–9 min.
Insulin preparations •Old ppn were obtained from beef and pork pancreases which had ~1% other proteins  and this proteins are antigenic in nature •Replace by newer highly purified pork/beef insulin/recombinant human insulin/insulin analogues
Ultra-short acting insulin •Insulin lispro (Humalog) or insulin aspart (Novolog) are very short acting insulins •More effective in decreasing post- prandial hyperglycemia •Less likely to cause hypoglycemia before the next meal •Onset is 15min, peaks in 1-3 hours, duration is 3-5 hours
Short acting Insulin 1. Regular Iletin II, Humulin R, Novolin R 2. May be given SC or IV 3. May be given as a continuous IV drip 4. The only insulin that may be given IV 5. Onset is ½-1 hour, peak is 2-3 hours and duration is 5-7 hours
Intermediate-acting Insulin •Isophane insulin suspension (NPH, NPH Iletin II, Humulin N, Novolin N) •Onset is 1-1.5 hours, peaks in 8-12 hours and duration is 18-24 Long-acting Insulin •Extended insulin zinc suspension •Onset is 4-8 hours, peaks in 10-30 hours and duration is 36+ hours
Insulin Mixtures •NPH 70/30 (Humulin or Novolin 70/30) •Durations of actions same as individual components Cont’d…
Highly purified insulin preparations • More stable and cause less insulin resistance or injection site lipodystrophy. • Immunogenicity of pork mono-component (MC) insulin is similar to that of recombinant human insulin. • Regular (soluble) insulin: injected ½-1 hour before a meal (thr’ SC route) • Lente insulin (Insulin-zinc suspension): two forms are available 1. large particles is crystalline and practically insoluble in water  long- acting 2. Smaller particles and is amorphous  has short acting. • Isophane (Neutral Protamine Hagedorn or NPH) insulin: • Injected s.c. twice daily before breakfast and before dinner • Mostly combined with regular insulin (70:30 or 50:50)
Insulin Analogs •Recombinant DNA products with improved pharmacokinetics parameter on SC route with same p. dynamics •Has Greater stability and consistency •Insulin Lispro: •SC  with quick pe and rapid peak and shorter duration of action. •Unlike regular insulin , this one can administered before or after the meal. •Lower incidence of hypoglycemia •Slightly greater reduction in HbA1c compared to regular insulin
Cont’d… •Insulin aspart: •mimics the physiological insulin release pattern after a meal, with the same advantages as Lispro. •Insulin glargine (Lantus) •long-acting biosynthetic insulin •Once daily dose at bedtime. Onset is 1.1 hours, peak is none, duration is 24 hours •Must not be diluted or mixed with any other insulin or solutions
Side effects •Hypoglycemia  treated b y oral glucose / IV in severe cases • And also , glucagon 0.5–1 mg IV or Adr 0.2 mg SC  when pt is not able to take glucose orally or IV ppn is not available. •Local reactions Swelling, erythema and stinging sometimes occur at the injected site, especially in the beginning. •Allergy (rare with highly purified insulin ppn) •Edema Some patients develop short-lived dependent edema (due to Na+ retention) when insulin therapy is started
Drug-drug interactions •With beta blockers  prolong hypoglycemia (symptoms, like palpitation, tremor and anxiety are masked), also rise BP through alpha receptor. •Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol, Nifedipine  inc’ blood sugar level  reduced effectiveness •With acute ingestion of alcohol cause hypoglycemia  by depleting glycogen in liver •Lithium, high dose aspirin and theophylline  inc’ hypoglycemia
Uses of insulin • All forms of diabetes mellitus • Must in type 1 DM • For post pancreatectomy diabetes • Gestational diabetes • In type 2, used in special conditions • Not controlled by diet and exercise • Primary or secondary failure of oral hypoglycemics or when these drugs are not tolerated. • Under weight patients. • Temporarily to tide over infections, trauma, surgery, pregnancy. • Any complication of diabetes, e.g. ketoacidosis, non-ketotic hyperosmolar coma, gangrene of extremities
DKA – treatment •IV fluids to rehydrate (Normal saline is infused i.v.,) •No use of hypotonic solutions at this time •Potassium supplementation (KCl)  resolve the lose of K+ during ketosis •IV insulin drip with gradual lowering of blood sugars • Insulin Regular insulin is used to rapidly correct the metabolic abnormalities (bolus dose of 0.1–0.2 U/kg i.v. is followed by 0.1 U/kg/hr infusion) •Judicious administration of sodium bicarbonate – correct the acidosis •Phosphate •Antibiotics and other supportive measures Supportive drugs
ORAL HYPOGLYCEMIC AGENTS
CLASSIFICATION A. Enhance Insulin secretion 1. Sulfonylureas (KATP Channel blockers) First generation: Tolbutamide Second generation: Glibenclamide (Glyburide), Glipizide, Gliclazide, Glimepiride 2. Meglitinide/phenylalanine analogues: Repaglinide, Nateglinide 3. Glucagon-like peptide-1 (GLP-1) receptor agonists (Injectable drugs): Exenatide, Liraglutide 4. Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Linagliptin
CONT’D… B. Overcome Insulin resistance 1. Biguanide (AMPK activator): Metformin 2. Thiazolidinediones (PPARγ activator): Pioglitazone C. Miscellaneous anti-diabetic drugs 1. α-Glucosidase inhibitors: Acarbose, Miglitol, Voglibose 2. Amylin analogue: Pramlintide 3. Dopamine-D2 receptor agonist: Bromocriptin 4. Sodium-glucose cotransport-2 (SGLT-2) inhibitor: Dapagliflozin
Sulfonylureas KATP Channel blockers •All have similar pharmacological profile •Reduce blood sugar level in normal subject, type 2 DM but apply in type 1 DM •The second generation SU are widely used in practice bcz of  more potency and clinically superior •Only tolbutamide is only in practice among all 1st generation SU, occasionally
Mode of Action of insulin enhancers
Cont’d… •SU and meglitinide analogues  block the SUR1  which constitutes a subunit of the inwardly rectifying ATP-sensitive K+ channel (KATP) in the membrane of pancreatic β cells. •Which inhibit the inward flow of K+ ions  and dropped the intracellular K+ conc.  and the membrane is partially depolarized augmenting Ca2+ channel opening with release of Ca2+ from intracellular stores. •The Ca2+ ions promote fusion of insulin containing intracellular granules with the plasma membrane  and insulin released by exocytosis
Cont’d… • Incretins such as glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP)  act on their own G-protein coupled receptors  on the β cell membrane  activate adenylyl cyclase  generate cAMP  inc’ Ca +2 conc  inc. release of insulin • Exenatide and liraglutide  eg. of GLP1 receptor agonists  have same intrinsic action. • The incretins GLP1 and GIP are rapidly inactivated by the capillary endothelial enzyme dipeptidyl peptidase-4 (DPP-4). • Their action is enhanced by  eg. sitagliptin and vildagliptin • The DPP-4 inhibitors thus markedly accentuate the insulin response to ingested glucose/meal and attenuate postprandial glycaemia.
Cont’d… Pancreatic action: •Provoke a brisk release of insulin •The rate of insulin secretion at any glucose concentration is inc’d,  even at low-glucose concentration  inc’ the chances of severe hypoglycemia (only in type 2 DM) •But why SU does not cause hypoglycemia in Type 1 and pancreactomised animal? •Extra-pancreatic action: •Eventually, cause SUR1 receptor down regulation on beta cell but improvement on glucose tolerance is maintained •It will improved overtime by improving sensitivity and it’s number (receptors on liver)
Side effects •Glyburide and glipizide  high tendency to cause hypoglycemia •Old agents may cause hypersensitivity reactions, rash and other allergic events •Weight gain
Meglitinide/phenylalanine analogues: Repaglinide, Nateglinide •Mode of action: see the slide number 53 and 54 •They induce rapid onset short lasting insulin release. •Administered before each major meal to control post prandial hyperglycemia.
Glucagon-like peptide-1 (GLP-1) receptor agonists •A member of the incretin family of peptide hormones, release from endocrine cell of bowel in response to food •GLP-1 is an important incretion released from the gut in response to ingested glucose. •It induces insulin release from pancreatic β cells, inhibits glucagon release from α cells, slows gastric emptying and suppresses appetite. •A long-acting injectable peptide analog •Uses: with metformin or a sulfonylurea for type 2 diabetes •Drugs available: Exenatide, Liraglutide(Victoza)
Dipeptidyl peptidase-4 (DPP-4) inhibitors •DPP-4 in rapid degradation of endogenous GLP-1 •Orally active inhibitors of DPP-4 have been developed as indirectly acting insulin secretagogues. •ADR: Headache, nasopharyngitis, and upper respiratory tract infection. •Examples: Sitagliptin, Vildagliptin, Saxagliptin
Drugs which overcome insulin resistance •Biguanide •Phenformin higher risk of lactic acidosis banned in many countries since 2003. •Metformin (Glucophage) increases insulin-mediated glucose uptake by muscle and fat cells, decreases hepatic glucose production, and decreases intestinal absorption of glucose
Cont’d… •Does not cause hypoglycemia •May be used alone or in combination •Adverse effects: Lactic acidosis, g.i. intolerance •Contraindicated in liver or renal impairment. Can result in lactic acidosis. •Must check renal function before beginning this medication •Caution with parenteral radiographic contrast media containing iodine. May cause renal failure and has been associated with lactic acidosis.
Thiazolidinedione (PPAR-gamma agonist) • Example: Pioglitazone • MOA: Glitazones tend to reverse insulin resistance by enhancing GLUT4 expression and translocation. • This nuclear receptor regulates the transcription of genes encoding proteins involved in carbohydrate and lipid metabolism. • Increase the uptake of glucose into muscle and adipose tissues • Inhibit hepatic gluconeogenesis • Reduce both fasting and postprandial hyperglycemia • Rosiglitazone banned in many countries  bcz increase in risk of myocardial infarction, CHF, stroke and death.)
Adverse effects: •fluid retention  presents as mild anemia and edema  may increase the risk of heart failure •Routine LFT is required (C/I  in patients with liver disease or who have ALT levels > 2.5 of normal) •In female: increased risk of bone fractures •Induce cytochromeP450 , CYP3A4  reducethe serum concentrations of some drugs like, oral contraceptives, cyclosporine) •May be used as monotherapy or in combination with insulin, metformin (Glucophage) or a sulfonylurea •Caution in patients with heart failure
α Glucosidase inhibitors • Example: Acarbose • MOA: Inhibits α-glucosidases, the final enzymes for the digestion of carbohydrates in the brush border of small intestine mucosa. • Taken just before a meal • Prevent type 2 diabetes in prediabetic persons • Adverse effects: Flatulence, abdominal discomfort and loose stool are produced in about 50% patients due to fermentation of unabsorbed carbohydrates • Hypoglycemia should be treated with oral glucose (dextrose) and not sucrose (absorption might be delayed) • Contraindicated in cirrhosis, malabsorption, severe renal impairment
Pramlintide • An injectable (S.C.) synthetic analog of amylin, 37- aminoacid hormone produce from pancreatic beta cells • Control the glycemia by activating high-affinity receptors involved in both glycemic control and osteogenesis • Other actions: • Suppresses glucagon release • Slows gastric emptying • Works in the CNS to reduce appetite • SC route  has short duration of action • Used with insulin to suppress the post prandial glycemia • ADR: hypoglycemia, GIT discomfort
Sodium-glucose transporter 2 (SGLT2) inhibitors •Examples: canagliflozin and dapagliflozin •MOA: 90% of renal glucose reabsorption  occurs by SGLT 2  inhibition causes glycosuria and lowers glucose levels in patients with type 2 diabetes •ADR: incidence of genital infections and urinary tract infections. •The osmotic diuresis can also cause intravascular volume contraction and hypotension
Hyperosmolar (nonketotic hypergly- caemic) coma • Occurs in type 2 DM. • Uncontrolled glycosuria of DM produces diuresis resulting in dehydration and haemo-concentration over several days → urine output is finally reduced and glucose accumulates in blood rapidly to > 800 mg/dl, plasma osmolality is > 350 mOsm/ L → and can cause coma, and death • Management • Same as for ketoacidotic coma, (except that faster fluid replacement is to be instituted ,Alkali is usually not required). • These patients are prone to thrombosis (due to hyper viscosity and sluggish circulation)  prophylactic heparin therapy is recommended.
Herbals and Dietary Supplements that affect blood glucose levels •Bee pollen, gingko biloba and glucosamine are thought to increase blood sugars or may potentially affect beta-cell function and insulin secretions •Basil and bay leaf, okra, black plums and bitter guards may cause hypoglycemia •Chromium may increase production of insulin receptors and increase insulin effectiveness
Management approaches in DM
Hyperglycemic agents 1. Glucagon: a single chain polypeptide hormones release from α cells of the islets of Langerhans • Synthetically obtained from recombinant DNA tech. • MOS: thr’ Gs-PCR mechanism  inc. AC  release cAMP  Ca+2 cons inc’ in liver, fat cells, heart and other tissues • PK: inactivate thr’ oral route • Endogenous glucagon is broken down in liver, kidney, plasma and other tissues • Its t½ is 3–6 min • Uses: hypoglycemia, 0.5–1.0 mg i.v. or i.m., followed by oral glucose/sugar • Cardiogenic shock to stimulate the heart in β adrenergic blocker treated patients (intoxication of blockers) • In radiographic examination of upper/lower g.i. tract by relaxing stomach and intestines
Cont’d… 2. Diazoxide: related to thiazides • It inhibits insulin release from β cells and causes hyperglycaemia lasting 4–8 hours • Act on ATP sensitive K+ channels of β cells is opposite to that of Sus • Also decreased peripheral utilization of glucose and release of catecholamines 3. Somatostatin • By inhibiting insulin release 4. Streptozocin • Causes selective damage to insulin secreting β cells.

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antidiabetic_drugs.pptx

  • 1.
    Anti-Diabetic Agents Dr. Harshika Patel KeMU PHRM400 Pharmacology and therapeutics II
  • 2.
    •Pancreatic hormones (insulin andglucagon) •Anti-diabetic drugs
  • 3.
    Diabetes Mellitus •A chronicsystemic disease characterized by metabolic and vascular abnormalities •Disorder of carbohydrate metabolism •Results from inadequate production or underutilization of insulin
  • 4.
    Cont’d… •Characterized by glucosuriaand hyperglycemia •Four forms—Type 1 and Type 2, others, and gestational diabetes mellitus •Type 1—patient secretes no insulin. Cause is felt to be autoimmune. •Type 2- patient secretes insufficient amounts of insulin and insulin receptors are resistant to existent circulating insulin https://www.diabetes.org.uk/diabetes-the-basics/types-of-diabetes
  • 5.
  • 7.
    •Reuqired Medical interventionis necessary otherwise, significant complications will ensue. •In both form need careful attention to diet, fasting and postprandial blood glucose concentrations, and serum concentrations of hemoglobin A1c, a glycosylated hemoglobin (marker of glycaemia) •Include: retinopathies, glaucoma, neuropathies, cardiovascular disease (PVD). •Increased incidence of toxemia of pregnancy. Cont’d…
  • 8.
    IMPORTANCE OF EACHBIOCHEMICAL TEST •Fasting BS •Post-prandial BS •OGTT •HBA1C concentration •Learn this biochemistry
  • 10.
    Brief Pathophysiology •Insulin secretedby beta cells •Insulin binds with and activates 80% of cells •Liver, muscle, and fat cells are primary tissues for insulin action •With insulin receptor binding, cell membranes permeable to glucose into the cells (see the next slide) •Increased cell permeability also allows for amino acids, fatty acids and electrolytes to enter cells •Changes cause anabolism and inhibit catabolism
  • 11.
    Cont’d. •Various glucose transportersare available for this purpose: •Examples: •GLUT 1 •GLUT 2 •GLUT 3 •GLUT 4 •SGLT 1 (intestine  to blood stream (transfer through GLUT 2)) •SGLT2 (in kidney  glucose transfer through GLUT 2 /3  REABSORB) Basically insulin bind on insulin receptors and activates these transporters and allows glucose to enter into the cell
  • 12.
    Endogenous Insulin •It issynthesized as a pro-hormones (proinsulin  86- amino-acid single-chain polypeptide) •Which cleaved and formed 2-chain 51-peptide insulin molecule + a 31-amino-acid residual C-peptide •Proinsulin and c-peptide have no physiological role •Glucose is the major stimulus of insulin secretion •Oral glucose is more effective than intravenous glucose because glucose in digestive tract increases the release of gastrin, secretin, cholecystokinin, and gastric inhibitory peptide •Also stimulates vagal activity
  • 13.
    Cont’d… Other hormones that raiseblood glucose levels include: •Cortisol •Glucagon •Growth hormone •Epinephrine •Estrogen •Progesterone Factors that inhibit insulin secretion include: • Hypoxia • Hypothermia • Stimulation of alpha-2 receptors
  • 14.
    Classification of TwoTypes of Diabetes Type 1 diabetes results from an autoimmune disorder that destroys pancreatic beta cells Usually has sudden onset Associated with high incidence of complications Requires exogenous insulin 10% of those with diabetes are type I Associated with diabetic ketoacidosis
  • 15.
    Diabetic Ketoacidosis (DKA) •Life-threateningcomplication occurs with insulin deficiency •Glucose cannot be used by body cells for energy so fat is mobilized for this purpose •Mobilized fat is then extracted by liver and broken down into glycerol and fatty acids •Fatty acids further broken down into ketones
  • 16.
    Cont’d… •Accumulation of ketonesresults in academia: 1. Attempts to buffer acidic H+ occurs by ionic exchange, intracellular potassium exits cells. H+ ions enter cells. Result is excretion of potassium in urine electrolytes imbalance 2. Kidneys attempt to buffer by excreting ketones 3. Pulmonary attempt to buffer by Kussmaul breathing • Blood and urine is concentrated with ketones  need immediate treatment
  • 17.
    Clinical symptoms ofDKA •Kussmaul breathing •Nausea and vomiting •Thirst •Polydipsia, polyphagia and polyuria •Hypotension •Tachycardia •Shock
  • 18.
    Type 2 DiabetesMellitus •Characterized by hyperglycemia and insulin resistance •Results from increased production of glucose by liver and decreased uptake of glucose in liver, muscle and fat cells •Insulin resistance—higher than usual concentrations of insulin are required
  • 19.
    Type 2 DiabetesMellitus Occurs at any age Gradual onset Less severe symptoms initially Easier to control  higher incidence of MIs and strokes 90% of those with diabetes are Type 2 multifactorial
  • 20.
    Hyperosmolar hyperglycemia non- ketoticcoma (HHNC) •Occurs in Type 2 Diabetes •Because patient has some endogenous insulin, no ketosis develops •Blood sugars can be >800-1000 mg/dL •Can result in hypovolemic shock, renal problems, stroke, coma and even death
  • 21.
    Metabolic Syndrome orSyndrome X Comprised of a set of risk factors which include: 1. Central abdominal adiposity (men waist size greater than 40 inches, women greater than 35 inches 2. Fasting triglycerides greater > or equal to 150 mg/dl (in adults), 3. HDL cholesterol (less than 40 in men, less than 50 mg/dl in women
  • 22.
    Cont’d... 4. Blood pressuregreater than or equal to 130/85 5. Fasting glucose greater than or equal to 110mg/dl Also possess prothrombotic and proinflammatory tendencies
  • 23.
    Metabolic Syndrome cont. •Allfactors are interrelated •Obesity and lack of exercise tend to lead to insulin resistance •Insulin resistance has a negative effect on lipid production. Increase VLDL, LDL, TG and decreasing the HDL. •Insulin resistance leads to increased insulin and glucose levels in blood.
  • 24.
    Pharmacotherapy of Hypoglycemic Drugs-Insulin •Insulin lower glucose levels by increasing glucose uptake by cells •Indicated for Type 1 DM often, in Type 2 DM, in those with chronic pancreatitis, in those on TPN, to treat hyperkalemia (infusion with dextrose and insulin) •Available insulin's are from pork and human
  • 25.
    Age-Related considerations Type 1DM in children •Consistent diet, blood glucose monitoring, insulin injections and exercise •Blood sugar control essential to maintain normal growth and development •Infections and illnesses can cause wide fluctuations
  • 26.
    Cont’d... •Children highly susceptibleto dehydration •Rotation of sites is very important •Avoiding hypoglycemia is a major goal in infants and young children which affects the growth and development •s/s of hypoglycemia include: hunger, sweating, tachycardia, irritability and lethargy
  • 27.
    Age related considerationsin older adults •Close monitoring of blood glucose levels •Visual impairment may affect their ability to self administer medication •May have renal insufficiency so caution with certain anti-diabetic drugs •Caution with metformin if renal impairment •Glitazones can predispose to fluid retention and heart failure
  • 28.
    Insulin • History: • Insulinwas discovered in 1921 by Banting and Best (just done demonstration on extracted pancrease) • first obtained in pure crystalline form in 1926 • The chemical structure was fully worked out in 1956 by Sanger • Human insulin is chemically identical to endogenous insulin but it is not derived from the human pancreas • Cannot be given orally. • Insulins differ in onset and duration of action. Ultra- short, short, intermediate and long acting.
  • 29.
    Regulation of insulinsecretion •By three different mechanisms: •Chemical •Hormonal and •Neuronal
  • 30.
    Action of insulin 1.Insulin facilitates glucose transport across cell membrane; skeletal muscle and fat are highly sensitive. • However, glucose entry in liver, brain, RBC, WBC and renal medullary cells is largely independent of insulin • Exercise has insulin sparing effect. 2. Intracellular utilization of glucose is its phosphorylation to form glucose-6-phosphate  which is enhanced by insulin through increased production of glucokinase. 3. Insulin facilitates glycogen synthesis from glucose in liver, muscle and fat by stimulating the enzyme glycogen synthase. 4. It also inhibits glycogen degrading enzyme phosphorylase → decreased glycogenolysis in liver
  • 31.
    Cont’d… 5. Insulin inhibitsgluconeogenesis (from protein, FFA and glycerol) in liver 6. Insulin inhibits lipolysis in adipose tissue and favors triglyceride synthesis  fat is broken down due to free action of lipolytic hormones (glucagon, Adr, thyroxine, etc.) → increased FFA and glycerol in blood. (check DKA) 7. Insulin enhances transcription of vascular endothelial lipoprotein lipase and thus increases clearance of VLDL and chylomicrons • Most of the above metabolic actions are exerted within seconds or minutes  called the rapid actions. • Others involving DNA mediated synthesis of glucose transporter and some enzymes of amino acid metabolism have a latency of few hours  called intermediate actions. • Exerts major long-term effects on multiplication and differentiation of many types of cells.
  • 32.
    Mode of action- Insulin
  • 33.
    Fate of Insulin •Oraladministration – is not possible  as it is peptide and get degrade in GIT •Extracellular distribution – only possible •Metabolized  primarily in liver and to a smaller extent in kidney and muscles •During biotransformation the disulfide bonds are reduced—A and B chains are separated  Further broken down to the constituent amino acids. •The plasma t½ is 5–9 min.
  • 34.
    Insulin preparations •Old ppnwere obtained from beef and pork pancreases which had ~1% other proteins  and this proteins are antigenic in nature •Replace by newer highly purified pork/beef insulin/recombinant human insulin/insulin analogues
  • 36.
    Ultra-short acting insulin •Insulinlispro (Humalog) or insulin aspart (Novolog) are very short acting insulins •More effective in decreasing post- prandial hyperglycemia •Less likely to cause hypoglycemia before the next meal •Onset is 15min, peaks in 1-3 hours, duration is 3-5 hours
  • 37.
    Short acting Insulin 1.Regular Iletin II, Humulin R, Novolin R 2. May be given SC or IV 3. May be given as a continuous IV drip 4. The only insulin that may be given IV 5. Onset is ½-1 hour, peak is 2-3 hours and duration is 5-7 hours
  • 38.
    Intermediate-acting Insulin •Isophane insulinsuspension (NPH, NPH Iletin II, Humulin N, Novolin N) •Onset is 1-1.5 hours, peaks in 8-12 hours and duration is 18-24 Long-acting Insulin •Extended insulin zinc suspension •Onset is 4-8 hours, peaks in 10-30 hours and duration is 36+ hours
  • 39.
    Insulin Mixtures •NPH 70/30(Humulin or Novolin 70/30) •Durations of actions same as individual components Cont’d…
  • 40.
    Highly purified insulinpreparations • More stable and cause less insulin resistance or injection site lipodystrophy. • Immunogenicity of pork mono-component (MC) insulin is similar to that of recombinant human insulin. • Regular (soluble) insulin: injected ½-1 hour before a meal (thr’ SC route) • Lente insulin (Insulin-zinc suspension): two forms are available 1. large particles is crystalline and practically insoluble in water  long- acting 2. Smaller particles and is amorphous  has short acting. • Isophane (Neutral Protamine Hagedorn or NPH) insulin: • Injected s.c. twice daily before breakfast and before dinner • Mostly combined with regular insulin (70:30 or 50:50)
  • 41.
    Insulin Analogs •Recombinant DNAproducts with improved pharmacokinetics parameter on SC route with same p. dynamics •Has Greater stability and consistency •Insulin Lispro: •SC  with quick pe and rapid peak and shorter duration of action. •Unlike regular insulin , this one can administered before or after the meal. •Lower incidence of hypoglycemia •Slightly greater reduction in HbA1c compared to regular insulin
  • 42.
    Cont’d… •Insulin aspart: •mimics thephysiological insulin release pattern after a meal, with the same advantages as Lispro. •Insulin glargine (Lantus) •long-acting biosynthetic insulin •Once daily dose at bedtime. Onset is 1.1 hours, peak is none, duration is 24 hours •Must not be diluted or mixed with any other insulin or solutions
  • 43.
    Side effects •Hypoglycemia treated b y oral glucose / IV in severe cases • And also , glucagon 0.5–1 mg IV or Adr 0.2 mg SC  when pt is not able to take glucose orally or IV ppn is not available. •Local reactions Swelling, erythema and stinging sometimes occur at the injected site, especially in the beginning. •Allergy (rare with highly purified insulin ppn) •Edema Some patients develop short-lived dependent edema (due to Na+ retention) when insulin therapy is started
  • 44.
    Drug-drug interactions •With betablockers  prolong hypoglycemia (symptoms, like palpitation, tremor and anxiety are masked), also rise BP through alpha receptor. •Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol, Nifedipine  inc’ blood sugar level  reduced effectiveness •With acute ingestion of alcohol cause hypoglycemia  by depleting glycogen in liver •Lithium, high dose aspirin and theophylline  inc’ hypoglycemia
  • 45.
    Uses of insulin •All forms of diabetes mellitus • Must in type 1 DM • For post pancreatectomy diabetes • Gestational diabetes • In type 2, used in special conditions • Not controlled by diet and exercise • Primary or secondary failure of oral hypoglycemics or when these drugs are not tolerated. • Under weight patients. • Temporarily to tide over infections, trauma, surgery, pregnancy. • Any complication of diabetes, e.g. ketoacidosis, non-ketotic hyperosmolar coma, gangrene of extremities
  • 47.
    DKA – treatment •IVfluids to rehydrate (Normal saline is infused i.v.,) •No use of hypotonic solutions at this time •Potassium supplementation (KCl)  resolve the lose of K+ during ketosis •IV insulin drip with gradual lowering of blood sugars • Insulin Regular insulin is used to rapidly correct the metabolic abnormalities (bolus dose of 0.1–0.2 U/kg i.v. is followed by 0.1 U/kg/hr infusion) •Judicious administration of sodium bicarbonate – correct the acidosis •Phosphate •Antibiotics and other supportive measures Supportive drugs
  • 48.
  • 49.
    CLASSIFICATION A. Enhance Insulinsecretion 1. Sulfonylureas (KATP Channel blockers) First generation: Tolbutamide Second generation: Glibenclamide (Glyburide), Glipizide, Gliclazide, Glimepiride 2. Meglitinide/phenylalanine analogues: Repaglinide, Nateglinide 3. Glucagon-like peptide-1 (GLP-1) receptor agonists (Injectable drugs): Exenatide, Liraglutide 4. Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Linagliptin
  • 50.
    CONT’D… B. Overcome Insulinresistance 1. Biguanide (AMPK activator): Metformin 2. Thiazolidinediones (PPARγ activator): Pioglitazone C. Miscellaneous anti-diabetic drugs 1. α-Glucosidase inhibitors: Acarbose, Miglitol, Voglibose 2. Amylin analogue: Pramlintide 3. Dopamine-D2 receptor agonist: Bromocriptin 4. Sodium-glucose cotransport-2 (SGLT-2) inhibitor: Dapagliflozin
  • 51.
    Sulfonylureas KATP Channel blockers •Allhave similar pharmacological profile •Reduce blood sugar level in normal subject, type 2 DM but apply in type 1 DM •The second generation SU are widely used in practice bcz of  more potency and clinically superior •Only tolbutamide is only in practice among all 1st generation SU, occasionally
  • 52.
    Mode of Actionof insulin enhancers
  • 53.
    Cont’d… •SU and meglitinideanalogues  block the SUR1  which constitutes a subunit of the inwardly rectifying ATP-sensitive K+ channel (KATP) in the membrane of pancreatic β cells. •Which inhibit the inward flow of K+ ions  and dropped the intracellular K+ conc.  and the membrane is partially depolarized augmenting Ca2+ channel opening with release of Ca2+ from intracellular stores. •The Ca2+ ions promote fusion of insulin containing intracellular granules with the plasma membrane  and insulin released by exocytosis
  • 54.
    Cont’d… • Incretins suchas glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP)  act on their own G-protein coupled receptors  on the β cell membrane  activate adenylyl cyclase  generate cAMP  inc’ Ca +2 conc  inc. release of insulin • Exenatide and liraglutide  eg. of GLP1 receptor agonists  have same intrinsic action. • The incretins GLP1 and GIP are rapidly inactivated by the capillary endothelial enzyme dipeptidyl peptidase-4 (DPP-4). • Their action is enhanced by  eg. sitagliptin and vildagliptin • The DPP-4 inhibitors thus markedly accentuate the insulin response to ingested glucose/meal and attenuate postprandial glycaemia.
  • 55.
    Cont’d… Pancreatic action: •Provoke abrisk release of insulin •The rate of insulin secretion at any glucose concentration is inc’d,  even at low-glucose concentration  inc’ the chances of severe hypoglycemia (only in type 2 DM) •But why SU does not cause hypoglycemia in Type 1 and pancreactomised animal? •Extra-pancreatic action: •Eventually, cause SUR1 receptor down regulation on beta cell but improvement on glucose tolerance is maintained •It will improved overtime by improving sensitivity and it’s number (receptors on liver)
  • 56.
    Side effects •Glyburide andglipizide  high tendency to cause hypoglycemia •Old agents may cause hypersensitivity reactions, rash and other allergic events •Weight gain
  • 57.
    Meglitinide/phenylalanine analogues: Repaglinide, Nateglinide •Modeof action: see the slide number 53 and 54 •They induce rapid onset short lasting insulin release. •Administered before each major meal to control post prandial hyperglycemia.
  • 58.
    Glucagon-like peptide-1 (GLP-1) receptoragonists •A member of the incretin family of peptide hormones, release from endocrine cell of bowel in response to food •GLP-1 is an important incretion released from the gut in response to ingested glucose. •It induces insulin release from pancreatic β cells, inhibits glucagon release from α cells, slows gastric emptying and suppresses appetite. •A long-acting injectable peptide analog •Uses: with metformin or a sulfonylurea for type 2 diabetes •Drugs available: Exenatide, Liraglutide(Victoza)
  • 59.
    Dipeptidyl peptidase-4 (DPP-4)inhibitors •DPP-4 in rapid degradation of endogenous GLP-1 •Orally active inhibitors of DPP-4 have been developed as indirectly acting insulin secretagogues. •ADR: Headache, nasopharyngitis, and upper respiratory tract infection. •Examples: Sitagliptin, Vildagliptin, Saxagliptin
  • 60.
    Drugs which overcomeinsulin resistance •Biguanide •Phenformin higher risk of lactic acidosis banned in many countries since 2003. •Metformin (Glucophage) increases insulin-mediated glucose uptake by muscle and fat cells, decreases hepatic glucose production, and decreases intestinal absorption of glucose
  • 61.
    Cont’d… •Does not causehypoglycemia •May be used alone or in combination •Adverse effects: Lactic acidosis, g.i. intolerance •Contraindicated in liver or renal impairment. Can result in lactic acidosis. •Must check renal function before beginning this medication •Caution with parenteral radiographic contrast media containing iodine. May cause renal failure and has been associated with lactic acidosis.
  • 62.
    Thiazolidinedione (PPAR-gamma agonist) • Example:Pioglitazone • MOA: Glitazones tend to reverse insulin resistance by enhancing GLUT4 expression and translocation. • This nuclear receptor regulates the transcription of genes encoding proteins involved in carbohydrate and lipid metabolism. • Increase the uptake of glucose into muscle and adipose tissues • Inhibit hepatic gluconeogenesis • Reduce both fasting and postprandial hyperglycemia • Rosiglitazone banned in many countries  bcz increase in risk of myocardial infarction, CHF, stroke and death.)
  • 63.
    Adverse effects: •fluid retention presents as mild anemia and edema  may increase the risk of heart failure •Routine LFT is required (C/I  in patients with liver disease or who have ALT levels > 2.5 of normal) •In female: increased risk of bone fractures •Induce cytochromeP450 , CYP3A4  reducethe serum concentrations of some drugs like, oral contraceptives, cyclosporine) •May be used as monotherapy or in combination with insulin, metformin (Glucophage) or a sulfonylurea •Caution in patients with heart failure
  • 64.
    α Glucosidase inhibitors •Example: Acarbose • MOA: Inhibits α-glucosidases, the final enzymes for the digestion of carbohydrates in the brush border of small intestine mucosa. • Taken just before a meal • Prevent type 2 diabetes in prediabetic persons • Adverse effects: Flatulence, abdominal discomfort and loose stool are produced in about 50% patients due to fermentation of unabsorbed carbohydrates • Hypoglycemia should be treated with oral glucose (dextrose) and not sucrose (absorption might be delayed) • Contraindicated in cirrhosis, malabsorption, severe renal impairment
  • 65.
    Pramlintide • An injectable(S.C.) synthetic analog of amylin, 37- aminoacid hormone produce from pancreatic beta cells • Control the glycemia by activating high-affinity receptors involved in both glycemic control and osteogenesis • Other actions: • Suppresses glucagon release • Slows gastric emptying • Works in the CNS to reduce appetite • SC route  has short duration of action • Used with insulin to suppress the post prandial glycemia • ADR: hypoglycemia, GIT discomfort
  • 66.
    Sodium-glucose transporter 2(SGLT2) inhibitors •Examples: canagliflozin and dapagliflozin •MOA: 90% of renal glucose reabsorption  occurs by SGLT 2  inhibition causes glycosuria and lowers glucose levels in patients with type 2 diabetes •ADR: incidence of genital infections and urinary tract infections. •The osmotic diuresis can also cause intravascular volume contraction and hypotension
  • 67.
    Hyperosmolar (nonketotic hypergly- caemic)coma • Occurs in type 2 DM. • Uncontrolled glycosuria of DM produces diuresis resulting in dehydration and haemo-concentration over several days → urine output is finally reduced and glucose accumulates in blood rapidly to > 800 mg/dl, plasma osmolality is > 350 mOsm/ L → and can cause coma, and death • Management • Same as for ketoacidotic coma, (except that faster fluid replacement is to be instituted ,Alkali is usually not required). • These patients are prone to thrombosis (due to hyper viscosity and sluggish circulation)  prophylactic heparin therapy is recommended.
  • 68.
    Herbals and DietarySupplements that affect blood glucose levels •Bee pollen, gingko biloba and glucosamine are thought to increase blood sugars or may potentially affect beta-cell function and insulin secretions •Basil and bay leaf, okra, black plums and bitter guards may cause hypoglycemia •Chromium may increase production of insulin receptors and increase insulin effectiveness
  • 69.
  • 70.
    Hyperglycemic agents 1. Glucagon:a single chain polypeptide hormones release from α cells of the islets of Langerhans • Synthetically obtained from recombinant DNA tech. • MOS: thr’ Gs-PCR mechanism  inc. AC  release cAMP  Ca+2 cons inc’ in liver, fat cells, heart and other tissues • PK: inactivate thr’ oral route • Endogenous glucagon is broken down in liver, kidney, plasma and other tissues • Its t½ is 3–6 min • Uses: hypoglycemia, 0.5–1.0 mg i.v. or i.m., followed by oral glucose/sugar • Cardiogenic shock to stimulate the heart in β adrenergic blocker treated patients (intoxication of blockers) • In radiographic examination of upper/lower g.i. tract by relaxing stomach and intestines
  • 71.
    Cont’d… 2. Diazoxide: relatedto thiazides • It inhibits insulin release from β cells and causes hyperglycaemia lasting 4–8 hours • Act on ATP sensitive K+ channels of β cells is opposite to that of Sus • Also decreased peripheral utilization of glucose and release of catecholamines 3. Somatostatin • By inhibiting insulin release 4. Streptozocin • Causes selective damage to insulin secreting β cells.