Drugs for Diabetes Mellitus
Content
Drugs for Diabetes Mellitus Pancreas Endocrine Gland Islet of Langerhans Produce Insulin (β cell) Glucagon (α cell) Somatostatin (δ cell) Glucose Exocrine Gland Pancreatic Juice Contain Digestive Enzymes Further Breakdown Carbohydrates, Protein, Fat in chime Blood Gl ucose Levels
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Fasting Random Venous Plasma Glucose ≥ 7.0 mmol/L ≥ 11.1 mmol/L Fasting Test – Most Appropriate to determine blood glucose levels (Diabetes) Managing Diabetes Diet Exercise Medication – Insulin, Oral Anti-Diabetic Agents
Hypoglycaemia ↓ Blood Glucose Hypoglycaemic Shock
↓
Hyperglycaemia ↑ Blood Glucose Diabetes Mellitus (DM)
Coma
↓
Death Diabetes Mellitus ↑ Blood Sugar (Glucose)/ Hyperglycaemia Due to Absolute, Relative lack of Insulin (Insulin Resistance) Chronic Complications Macrovascular Cardiovascular Cerebrovascular Peripheral Vascular System Microvascular Nephropathy Neuropathy Retinopathy Types Type 1 Destruction of Islet β cells Insulin Dependent DM (IDDM) Juvenile-onset Diabetes Children, Teenagers, Young Adults Autoimmune destruction of pancreatic β cells (produce little, no insulin) Requires exogenous In sulin (Insulin Injections ) Type 2 Insulin Resistance Loss of response to Insulin Non-Ins ulin Dependent Diabetes (NIDDM) Older Individuals Insulin Deficiency, Resistance
Gestational Pregnant women who never had diabetes before ↑ Blood Sugar during Pregnancy Affects 4% of Pregnant Women May Precede Development Type 2 Congenital Diabetes Genetic Defects of Insulin Secretion Cystic Fibrosis-related Diabetes Steroid Diabetes Induced by ↑ Dose Glucocor coids
Risk Factors • Age • Lack of Exercise • Obesity • Hypertension • Dyslipidemia • Genetic Signs, Symptoms • Dry Mouth • Extreme Thirst • Frequent Urination • Drowsiness • Frequent Bed Wetting • Stomach Pain
Insulin Exogenous Insuli n Required in Gestational Diabetes Diabetes Type 1 Diabetes Type 2 (sometimes) Orally Subcutaneous Insulin is degraded in Injections GIT (polypeptide) by Insulin Pump Proteolytic enzymes Drug Onset Length of Time before insulin reaches bloodstream, begin to ↓ Blood Sugar Types of Insulin Examples Onset Peak Duration Injections / Day Two Morning Late Afternoon (Mix of Short, Intermediate) Onset, Duration of Action Rapid-Acting Insulin Lispro (Hu malog®) Insulin Aspart (NovoLog®) 25 mins 30 mins – 1 hour 2 – 4 hours Peak Time Period when Insulin is most Effective in ↓ Blood Sugar
Insulin Types, Actions
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IV Acute Care settings
Duration Duration Insulin continues to ↓ Blood Sugar
Short-Acting Regular (Humulin ®) 30 mins – 1 hour 2 -5 hours 5 – 10 hours
Intermediate-Acting Isophane Insulin (N PH®) Insulin Zinc (Lente®) 1-3 hours 6-14 hours 18 – 24+ hours Insulin Inje ction Devices Syringe/ Needle
Long-Acting Insulin Zinc, Extended (Ultralente®) Insulin Glargine (Lantus®) 4 – 6 hours 16 – 24 hours 24 – 28+ hours
Three → Four Mainly used for More Control of DIabetes
Insulin Pump/ Refillable Catheter at the end of the Insulin Pump is inserted through a needle Into the Abdominal Fat Dosage Instructions – Inserted into pump’s comp uter (Appropriate amount of Insulin Injected into body, Controlled Manner)
Prefilled Insulin Pens Adverse Effects of Injections Insulin Shock – Hypoglycaemia Excess Levels of Insulin in Body Weak Drowsy Confuse d Hungry Dizzy Loss of Consciousness, Coma
Inhalable Ins ulin Exubera (Withdrawn from market due to lack of acceptance) Powdered form of Re combinant Human Insulin Inhaler → Lungs → Absorbed
Transdermal Insulin Insulin is too large to get through the skin Patches using Electrical Currents, Ultrasound waves, Chemicals to help transport insulin through skin
jslum.com | Medicine
Oral Antidiabetic Agents (Oral Antidiabetic Agents, Oral Antihyperglycemic Agents) Secretagogues Sensitizers (Type II) (Type II) ↑ Amount of Insulin Secreted by Pancreas ↑ Sensitivity to Target Organs to Insulin (Without ↑ Insulin) Thiazolidinedi ones (TZD) Sulfonylureas Meglitinides Biguanides (Glitazones)
1 Generation Repaglinides Nateglinides Tolbutamide (Orinase) Short-acting Secretagogues Acetohexamide (Dymelor) ↑ Rapidly Absorbed, Eliminated Tolazamide (Tolinase) Taken before meals (10 mins) Chlorpropamide (Diabinese) If Meal Skipped, Medication Skipped nd 2 Generation ↓ Risk – Hypoglycaemia Glipizide (Glucotrol) Can Combine with Glyburide/ Glibenclamide (Daonil) Metformin Glimepiride (Amaryl) TZD Gliclazide (Diamicron) α-Glucosidase Inhibitors nd 2 Generation Drugs ↑ Commonly Used ↑ Effectiv e ↓ Side Effects Safe for Long-Term Treatment Can Combine with OAD, Insulin MOA Stimulate Insulin Release from β cells Blocking ATP-Sensitive K+ channels Depolarization, Ca2+ Influx ↑ Insulin Pharmacokinetics Pharmacokinetics Orally Orally (10 mins before main meals) Binds to Serum Proteins Half-Life – Shorter (30 mins) Metabolized by Liver Metabolized to Inactive Products by Excreted – Liver, Kidney CYP3A4 in Liver Excreted through Bile (4-6 hours) Side Effects Weight Gain Repaglinides Nateglinides Hyperinsulinemia Side Effects Side Effects Hypoglycaemia Hypoglycaemia Nausea Caution URTI Diarrhoea (Renal, Hepatic Insufficiency) Rhinitis Dizziness Delayed Exc retion of Drugs Bronchitis Light Headedness ↓ Headache Hypoglycaemia Results in Accumulation Weight ↑
↓ st
α-Glucosi dase Inhi bitors ↓ Rate of Glucose Absorption from GIT Acarbose Miglitol
Similar Action as Acarbose Almost Completely Absorbed in GIT ↑ Bioavailability Taken with Main Meals ↓ Postprandial Glucose without causing Hypoglycaemia Synergistic Effects (Combination) OAD Agents Insulin If Hypoglycaemia when used in Combination Take Monosaccharides (eg. Glucose)
Dipeptidyl Peptidase-IV Inhibitors (DPP-IV) (Gliptin) ↑ Insulin, ↓ Glucagon Sitagliptin Vildagliptin
Metformin (Glucophage/ Glucamet) Phenformin (Withdrawn) Buformin (Withdrawn) No Weight ↑ Caution – Impaired Liver, Kidney Best choice with Heart Failure Combination Other OAD agents
Rosiglitazone (Avandia) Pioglitazone (Actos) Troglitazone (Rezulin) (Withdrawn) Combination Other OAD agents Use with Insulin is not recommended MOA Bind to PPARγ
↓
Uses There is a tablet Monotherapy that contain both Combination Vildagliptin and • Sulfonylurea Metformin • Metformin • TZD May be combined with other OAD Agents
Involved in Transcription of Genes (Glucose, Fat Metabolism)
↓
Sitagliptin
MOA Competitively Inhibits Dipeptidyl Peptidase 4 (DPP-4)
↓
PPARs act on PPRE (Proliferator Responsive Elements)
↓
Enhance Production of mRNAs of Insulin Dependent Enyzmes MOA ↓ Hepatic Glucose Production ↑ Skeletal Muscle Glucose Uptake, Metabolism ↓ Free Fatty Acids (FFA) (Thiazolidinedione) Pharmacokinetics Orally Not Bound to Serum Proteins Not Metabolised Excretion via Urine Side Effects Generally Well Tolerated Nausea Vomiting Diarrhoea Stomach Pain Anorexia ↓ Side Effects Extended Release Formulation Pharmacokinetics Orally Extensively Bound to Serum Albumin Undergo Extensive Metabolism by different CYP Isozymes Rosiglitazone Pioglitazone Metabolites Some excreted in metabolites Urine have activity Excreted in Bile Eliminated in Feces Side Effects Fluid Retention Tissue Swelling (Edema) Weight ↑ MOA Inhibits Enzymes that Breakdown Polysaccharides, Sucrose (in Small Intestine) ↓ Glucose Absorption from Gut Pharmacokinetics Metabolised by Intestinal Bacteria Some Metabolites are Absorbed, Excreted in Urine Side Effects GIT Disturbances (majority) Flatulence Diarrhoea Bloating Abdominal Discomfort Contraindications Inflammatory Bowel Disease Cirrhosis ↑ Plasma Creatinine Pharmacokinetics Well Absorbed Excreted Unchanged by Kidney
Inactivation of GLP-1
↓
Secretion of Insulins Supress Glucagon Release
↓
Drive Blood Glucose Level Towards Normal Pharmacokinetics Well Absorbed Orally Food does not affect absorption extent Excreted unchanged in Urine Dose adjustment in Renal Dysfunction Side Effects Nasopharyngitis Headache DPP-4 Function Breakdown Incretins Hormones (Eg. GLP-1)(Glucagon-Like Peptide-1) GLP-1 Usually released in response to a meal
Hypoglycaemia Drug- Drug Interac tions (↑ Hypoglycaemic action) Displace from plasma proteins • Phenybutazones • Salicylates • Sulfonamides ↓ Hepatic Metabolism • Dicumarol • Chloramphenicol • Monoamines oxidase inhibitor • Phenylbutazone ↓ Urinary Exc retion • Allopurinol • Probenecid • Phenylbutazone • Salicylates • Sulfonamides
jslum.com | Medicine
Fasting Random Venous Plasma Glucose ≥ 7.0 mmol/L ≥ 11.1 mmol/L Fasting Test – Most Appropriate to determine blood glucose levels (Diabetes) Managing Diabetes Diet Exercise Medication – Insulin, Oral Anti-Diabetic Agents
Hypoglycaemia ↓ Blood Glucose Hypoglycaemic Shock
↓
Hyperglycaemia ↑ Blood Glucose Diabetes Mellitus (DM)
Coma
↓
Death Diabetes Mellitus ↑ Blood Sugar (Glucose)/ Hyperglycaemia Due to Absolute, Relative lack of Insulin (Insulin Resistance) Chronic Complications Macrovascular Cardiovascular Cerebrovascular Peripheral Vascular System Microvascular Nephropathy Neuropathy Retinopathy Types Type 1 Destruction of Islet β cells Insulin Dependent DM (IDDM) Juvenile-onset Diabetes Children, Teenagers, Young Adults Autoimmune destruction of pancreatic β cells (produce little, no insulin) Requires exogenous In sulin (Insulin Injections ) Type 2 Insulin Resistance Loss of response to Insulin Non-Ins ulin Dependent Diabetes (NIDDM) Older Individuals Insulin Deficiency, Resistance
Gestational Pregnant women who never had diabetes before ↑ Blood Sugar during Pregnancy Affects 4% of Pregnant Women May Precede Development Type 2 Congenital Diabetes Genetic Defects of Insulin Secretion Cystic Fibrosis-related Diabetes Steroid Diabetes Induced by ↑ Dose Glucocor coids
Risk Factors • Age • Lack of Exercise • Obesity • Hypertension • Dyslipidemia • Genetic Signs, Symptoms • Dry Mouth • Extreme Thirst • Frequent Urination • Drowsiness • Frequent Bed Wetting • Stomach Pain
Insulin Exogenous Insuli n Required in Gestational Diabetes Diabetes Type 1 Diabetes Type 2 (sometimes) Orally Subcutaneous Insulin is degraded in Injections GIT (polypeptide) by Insulin Pump Proteolytic enzymes Drug Onset Length of Time before insulin reaches bloodstream, begin to ↓ Blood Sugar Types of Insulin Examples Onset Peak Duration Injections / Day Two Morning Late Afternoon (Mix of Short, Intermediate) Onset, Duration of Action Rapid-Acting Insulin Lispro (Hu malog®) Insulin Aspart (NovoLog®) 25 mins 30 mins – 1 hour 2 – 4 hours Peak Time Period when Insulin is most Effective in ↓ Blood Sugar
Insulin Types, Actions
jslum.com | Medicine
IV Acute Care settings
Duration Duration Insulin continues to ↓ Blood Sugar
Short-Acting Regular (Humulin ®) 30 mins – 1 hour 2 -5 hours 5 – 10 hours
Intermediate-Acting Isophane Insulin (N PH®) Insulin Zinc (Lente®) 1-3 hours 6-14 hours 18 – 24+ hours Insulin Inje ction Devices Syringe/ Needle
Long-Acting Insulin Zinc, Extended (Ultralente®) Insulin Glargine (Lantus®) 4 – 6 hours 16 – 24 hours 24 – 28+ hours
Three → Four Mainly used for More Control of DIabetes
Insulin Pump/ Refillable Catheter at the end of the Insulin Pump is inserted through a needle Into the Abdominal Fat Dosage Instructions – Inserted into pump’s comp uter (Appropriate amount of Insulin Injected into body, Controlled Manner)
Prefilled Insulin Pens Adverse Effects of Injections Insulin Shock – Hypoglycaemia Excess Levels of Insulin in Body Weak Drowsy Confuse d Hungry Dizzy Loss of Consciousness, Coma
Inhalable Ins ulin Exubera (Withdrawn from market due to lack of acceptance) Powdered form of Re combinant Human Insulin Inhaler → Lungs → Absorbed
Transdermal Insulin Insulin is too large to get through the skin Patches using Electrical Currents, Ultrasound waves, Chemicals to help transport insulin through skin
jslum.com | Medicine
Oral Antidiabetic Agents (Oral Antidiabetic Agents, Oral Antihyperglycemic Agents) Secretagogues Sensitizers (Type II) (Type II) ↑ Amount of Insulin Secreted by Pancreas ↑ Sensitivity to Target Organs to Insulin (Without ↑ Insulin) Thiazolidinedi ones (TZD) Sulfonylureas Meglitinides Biguanides (Glitazones)
1 Generation Repaglinides Nateglinides Tolbutamide (Orinase) Short-acting Secretagogues Acetohexamide (Dymelor) ↑ Rapidly Absorbed, Eliminated Tolazamide (Tolinase) Taken before meals (10 mins) Chlorpropamide (Diabinese) If Meal Skipped, Medication Skipped nd 2 Generation ↓ Risk – Hypoglycaemia Glipizide (Glucotrol) Can Combine with Glyburide/ Glibenclamide (Daonil) Metformin Glimepiride (Amaryl) TZD Gliclazide (Diamicron) α-Glucosidase Inhibitors nd 2 Generation Drugs ↑ Commonly Used ↑ Effectiv e ↓ Side Effects Safe for Long-Term Treatment Can Combine with OAD, Insulin MOA Stimulate Insulin Release from β cells Blocking ATP-Sensitive K+ channels Depolarization, Ca2+ Influx ↑ Insulin Pharmacokinetics Pharmacokinetics Orally Orally (10 mins before main meals) Binds to Serum Proteins Half-Life – Shorter (30 mins) Metabolized by Liver Metabolized to Inactive Products by Excreted – Liver, Kidney CYP3A4 in Liver Excreted through Bile (4-6 hours) Side Effects Weight Gain Repaglinides Nateglinides Hyperinsulinemia Side Effects Side Effects Hypoglycaemia Hypoglycaemia Nausea Caution URTI Diarrhoea (Renal, Hepatic Insufficiency) Rhinitis Dizziness Delayed Exc retion of Drugs Bronchitis Light Headedness ↓ Headache Hypoglycaemia Results in Accumulation Weight ↑
↓ st
α-Glucosi dase Inhi bitors ↓ Rate of Glucose Absorption from GIT Acarbose Miglitol
Similar Action as Acarbose Almost Completely Absorbed in GIT ↑ Bioavailability Taken with Main Meals ↓ Postprandial Glucose without causing Hypoglycaemia Synergistic Effects (Combination) OAD Agents Insulin If Hypoglycaemia when used in Combination Take Monosaccharides (eg. Glucose)
Dipeptidyl Peptidase-IV Inhibitors (DPP-IV) (Gliptin) ↑ Insulin, ↓ Glucagon Sitagliptin Vildagliptin
Metformin (Glucophage/ Glucamet) Phenformin (Withdrawn) Buformin (Withdrawn) No Weight ↑ Caution – Impaired Liver, Kidney Best choice with Heart Failure Combination Other OAD agents
Rosiglitazone (Avandia) Pioglitazone (Actos) Troglitazone (Rezulin) (Withdrawn) Combination Other OAD agents Use with Insulin is not recommended MOA Bind to PPARγ
↓
Uses There is a tablet Monotherapy that contain both Combination Vildagliptin and • Sulfonylurea Metformin • Metformin • TZD May be combined with other OAD Agents
Involved in Transcription of Genes (Glucose, Fat Metabolism)
↓
Sitagliptin
MOA Competitively Inhibits Dipeptidyl Peptidase 4 (DPP-4)
↓
PPARs act on PPRE (Proliferator Responsive Elements)
↓
Enhance Production of mRNAs of Insulin Dependent Enyzmes MOA ↓ Hepatic Glucose Production ↑ Skeletal Muscle Glucose Uptake, Metabolism ↓ Free Fatty Acids (FFA) (Thiazolidinedione) Pharmacokinetics Orally Not Bound to Serum Proteins Not Metabolised Excretion via Urine Side Effects Generally Well Tolerated Nausea Vomiting Diarrhoea Stomach Pain Anorexia ↓ Side Effects Extended Release Formulation Pharmacokinetics Orally Extensively Bound to Serum Albumin Undergo Extensive Metabolism by different CYP Isozymes Rosiglitazone Pioglitazone Metabolites Some excreted in metabolites Urine have activity Excreted in Bile Eliminated in Feces Side Effects Fluid Retention Tissue Swelling (Edema) Weight ↑ MOA Inhibits Enzymes that Breakdown Polysaccharides, Sucrose (in Small Intestine) ↓ Glucose Absorption from Gut Pharmacokinetics Metabolised by Intestinal Bacteria Some Metabolites are Absorbed, Excreted in Urine Side Effects GIT Disturbances (majority) Flatulence Diarrhoea Bloating Abdominal Discomfort Contraindications Inflammatory Bowel Disease Cirrhosis ↑ Plasma Creatinine Pharmacokinetics Well Absorbed Excreted Unchanged by Kidney
Inactivation of GLP-1
↓
Secretion of Insulins Supress Glucagon Release
↓
Drive Blood Glucose Level Towards Normal Pharmacokinetics Well Absorbed Orally Food does not affect absorption extent Excreted unchanged in Urine Dose adjustment in Renal Dysfunction Side Effects Nasopharyngitis Headache DPP-4 Function Breakdown Incretins Hormones (Eg. GLP-1)(Glucagon-Like Peptide-1) GLP-1 Usually released in response to a meal
Hypoglycaemia Drug- Drug Interac tions (↑ Hypoglycaemic action) Displace from plasma proteins • Phenybutazones • Salicylates • Sulfonamides ↓ Hepatic Metabolism • Dicumarol • Chloramphenicol • Monoamines oxidase inhibitor • Phenylbutazone ↓ Urinary Exc retion • Allopurinol • Probenecid • Phenylbutazone • Salicylates • Sulfonamides
