Drugs for Diabetes Mellitus PDF

PHARMACOLOGY I ✓ Learning Objectives  General: Able to describ...

PHARMACOLOGY I ✓ Learning Objectives  General: Able to describe insulin & other common drugs used in diabetes mellitus.  Specific: Able to understand the different types of diabetes mellitus. Able to describe the different types of insulin administered Drugs for Diabetes Mellitus * intraperitoneally. % s a Able to discuss the different classes of oral 83 E antihyperglycaemic agents. Dr Wan Ezumi Mohd Fuad %{%% :S § e. % ? Able to understand the mechanism of action of certain antihyperglycaemic drugs. % ego for homme Pancreas { organ Outline of the lecture. The pancreas is a gland organ, contains 2 different types of parenchymal tissue. 1) Overview – Pancreas & Islet of Langerhans 1) endocrine gland - Glucose Metabolism - Islets of Langerhans producing several important hormones, eg. - Diabetes Mellitus insulin, glucagon and somatostatin 2) exocrine gland 2) Insulin & its analogues - secreting pancreatic juice containing digestive enzymes that pass to the small intestine. - These enzymes help in the further breakdown of the 3) Oral Antidiabetic drugs carbohydrates, protein and fat in the chyme.  Islets of Langerhans Blood glucose The Body Requires Blood Glucose  Brain requires a constant supply of blood glucose  Normally glucose is the only energy source for the brain The islets of Langerhans - regions of the pancreas that contain its endocrine (i.e., hormone-producing) cells. Hormones produced in the islets of Langerhans are secreted directly into the blood  Normal blood glucose: 70-110 mg/dl flow by different types of cells. - Alpha cells producing glucagon - Beta cells producing insulin - Delta cells producing somatostatin Glucose Metabolism Glucose Utilization in the Body  As we consume food, the digestive system  Requires Insulin predominately converts those foods into glucose.  Pancreas  Energy  Insulin binds with specific receptors on the cell membrane. rag  If glucose is not utilized for energy purposes at the time of digestion, it is stored.  Once bound, the receptors signal Glycogen in the liver and muscles protein messengers within the cell. Fatty acid in the adipose tissue  ↳ % * } µ, Glucose Utilization in the Body  Without insulin in the body  Excess glucose accumulates in the blood, which goes unused  Excreted in the urine – lead to diabetes mellitus Blood glucose Blood glucose Regulation of Blood glucose level Hypoglycemia Hyperglycemia - low blood glucose Reducing hormone: : * High blood glucose - It leads to:  Insulin It leads to Diabetes ☆ Hypoglycemic shock Mellitus (DM)  Elevating hormones: coma  Glucagon (mainly)   Epinephrine death  Steroids  Growth hormone etc.  Diabetes Mellitus (DM) Chronic complications Diabetes means high blood sugar (glucose) or a) Macrovascular  directly → hyperglycaemia - due to absolute or relative lack of insulin or less insulin sensitivity / insulin resistance. eg. Cardiovascular, Cerebrovascular,  Criteria: Peripheral vascular fasting plasma glucose level, > 126mg/dL (7mmol/L) system. or b) Microvascular plasma glucose levels, > 200mg/dL (11mmol/L) at two times points during an oral glucose tolerance test eg. Nephropathy, → renal ☆ ☆ Hanne (OGTT), which must be within 2 hrs of ingestion of Neuropathy & glucose. Retinopathy → eye damage Types of Diabetes Type 1 Diabetes 1) Type 1 diabetes - destruction of islet beta cells  Formally known as “insulin Dependent Diabetes Mellitus” 2) Type 2 diabetes (IDDM) or “Juvenile-onset diabetes” aids - insulin resistance / loss of response to insulin.  most common in children, 3) Gestational diabetes teenagers, and young adults - Pregnant women who have never had diabetes before but have high  result from an autoimmune blood sugar (glucose) levels during pregnancy destruction of the pancreatic -cells - Gestational diabetes affects about 7-10% of all pregnant women. - produce little or no insulin at all. - It may precede development of type 2.  Requires exogenous insulin to 4) Other forms sustain life - almost all persons with Eg. congenital diabetes due to genetic defects of insulin secretion, type 1 diabetes must take insulin cystic fibrosis-related diabetes, steroid diabetes induced by high doses injections. of glucocorticoids  Type 2 Diabetes Why Type 2 Diabetes  Age  Formally known as “Non-Insulin Dependent  Lack of exercise Diabetes (NIDDM)”  Obesity  Can occur at any age, including adolescence -  Hypertension usually affects older individuals  Dyslipidemia – abnormal amount of lipids in the  Due to insulin deficiency or resistance blood  A strong genetic disposition plays a contributing role in developing type 2 diabetes, although there are still much to investigate on the specific genetic link Signs & Symptoms Managing Diabetes  Diet Exercise  Medication § ÷  Insulin  Oral anti-diabetic agents § By %  His * % Insulin Administration % %  Exogenous insulin is required in: Gestational diabetes 1%3 Type 1 Insulin & Its Analogue Sometimes Type 2  Because insulin is polypeptide, it is degraded in GIT (proteolytic enzymes) if taken orally.  Subcutaneous injection - either by injections or by an insulin pump  IV injection - in acute care settings # memorise Insulin Types Insulin Types…..con’t They are classified by how fast they start to work and onset how long their effects last. - the length of time before insulin reaches the bloodstream The types of insulin include: and begins to lower blood sugar  Rapid-acting peak Humalog - the time period when the insulin is the most effective in  Short-acting lowering blood sugar Regular – slightly longer onset of action compared to rapid-acting  Intermediate-acting duration Lente - how long insulin continues to lower blood sugar  Long-acting Ultralente These three factors may vary, depending on our body's  Insulin Combination response.  # memoirs Rapid-Acting Insulin mat Short-Acting Insulin mama : →  Humalog - rapid  Regular shut  FDA (1996) – first available rapid-acting insulin  Longer onset of action compared to rapid-acting  Injected 15 minutes before meal Onset = ½ – 1 hr.  Onset = < 30 min  Peak = 2 – 5 hrs.  Peak = 30 min to 1 hour (longer depending on type)  Duration = 5 – 10 hrs.  Duration = 2 to 4 hours (+/-) Intermediate-Acting Insulin Long-Acting Insulin  Lente  Ultralente  Onset = 1 – 3 hrs.  Onset = 4 – 6 hrs.  Peak = 6 – 14 hrs.  Peak = 16 – 24 hrs.  Duration = 18 – 24 hrs. (+/-)  Duration = 24 – 28 hrs (+/–)  Insulin Types and Actions Injections/Day  Two (standard treatment)  One in the morning  One in the late afternoon Mix of short and intermediate  Three to Four (intensive treatment)  Mainly used for more control of the diabetes Adverse Effects of Injections Onset and Duration of Action  Insulin shock – Hypoglycemia → low blood text  Excess levels of insulin in the body  Weak, drowsy, confused, hungry, or dizzy  Loss of consciousness and possibly coma  Insulin Injection Devices Insulin Injection Devices  Insulin pump/refillable  Syringe/needle The catheter at the end of the insulin pump is inserted through a needle into the abdominal fat of a person with diabetes. Dosage instructions are entered into the pump's small computer and the appropriate amount of insulin is then injected into the body in a calculated, controlled manner. Insulin Injection Devices MoD  Prefilled insulin pens Oral Antidiabetic Agents  Oral Antidiabetic Agents Oral Antidiabetic Agents Treatments of DM include:  Anti-diabetic drugs treat DM by lowering glucose levels in the blood. 1) agents which increase the amount of insulin secreted by the pancreas - Secretagogues  Administered orally - also called oral antidiabetic agents or oral antihyperglycemic agents. 2) agents which increase the sensitivity of target organs to insulin - Sensitizers  Several classes of antidiabetic drugs - their selection depends on the nature of the diabetes, 3) agents which decrease the rate of glucose absorption age and situation of the person etc. from the gastrointestinal tract - Alpha-glucosidase inhibitors ☒ Insulin Secretagogues Sulfonylureas  First-generation agents - agents that promote insulin release 1) tolbutamide - useful in the treatment of patients who have Type 2 diabetes but who cannot be managed by diet alone.  Second-generation agents 1) glipizide 2) glyburide (glibenclamide) need 3) glimepiride 1) Sulfonylureas memos Ey CQ) k. { 2) Meglitinides The "second-generation" drugs are now more commonly used. They are more effective than first- generation drugs and have fewer side effects. Sulfonylureas - Mechanism of action These include Ashton   Sulfonylureas – Side effects Weight gain Hyperinsulinemia 1) stimulation of insulin release  Hypoglycemia from the  cells of the pancreas by blocking the  These drugs should be used with caution in patients with hepatic & ATP-sensitive K+ channels, renal insufficiency resulting in depolarization & delayed excretion of the drug Ca2+ influx 2) reduction in hepatic glucose production resulting in its accumulation 3) increase in peripheral insulin sensitivity may cause hypoglycemia Meglitinides Meglitinides – side effects - This class of agents include Repaglinides Nateglinides 1) repaglinide 1) nausea 1) hypoglycemia 2) nateglinide 2) upper respiratory tract 2) diarrhea - often called "short-acting secretagogues" infection 3) dizziness - have a mechanism of action similar to that of the 3) rhinitis 4) light headedness. sulphonylureas, but are more rapidly absorbed and 4) bronchitis - The incidence of mild hypoglycemia is lower eliminated 5) headache with nateglinide than for - pose a smaller risk of hypoglycaemia when 6) weight gain repaglinide compared to sulphonylureas  Insulin Sensitizers → improve Biguanides target cell - these agents lower blood glucose by improving response to insulin target cell response to insulin without increasing The only currently available biguanide pancreatic insulin secretion 1) metformin ⊕ ① 1) Biguanides ② 2) Thiazolidinediones / Glitazone Metformin - Mechanism of action Metformin – Side effects 1) Reduce hepatic glucose production – inhibit  Metformin can cause nausea, vomiting, diarrhoea, hepatic gluconeogenesis. weight loss and stomach pain. 2) Increase skeletal muscle glucose uptake & metabolism. 3) Slow intestinal absorption of sugars. 4) Reduce free fatty acids (FFA).  Thiazolidinediones (TZDs) TZD - Mechanism of action ④ TZD bind to Peroxisome Proliferator Activated - also known as glitazones By Receptor γ (PPARγ), that function as ligand- activated transcription factors This class of agents include These PPAR involved in transcription of genes 1) rosiglitazone regulating glucose and fat metabolism. 2) pioglitazone These PPARs act on Peroxysome Proliferator Responsive Elements (PPRE). The PPREs influence insulin sensitive genes, - Pioglitazone is approved for use in combination with which enhance production of mRNAs of insulin insulin, metformin or a sulfonylurea dependent enzymes. The final result is better use of glucose by the cells. TZD – Side effects -Glucosidase Inhibitors ⑥ - agents which decrease the rate at which  water retention glucose is absorbed from the gastrointestinal  tissue swelling (edema) tract  weight gain g 1) Acarbose 2) Miglitol  -Glucosidase Inhibitors -Glucosidase Inhibitors - Mechanism of action  The first of the -glucosidase inhibitor in clinical use - The -glucosidase was acarbose. inhibitor inhibits enzymes that break down  Miglitol is a newer -glucosidase inhibitor. polysaccharides and - it has a similar action as acarbose sucrose in the small intestine - but it is almost completely absorbed ⑤ ② from the GIT - leading to a slow down of - so it has higher bioavailability. glucose absorption from the gut -Glucosidase Inhibitors – Side effects  The major side effects are related to gastrointestinal disturbances.  These include flatulence, diarrhea, bloating, and abdominal discomfort.  Acarbose is contraindicated in patients with inflammatory bowel disease, cirrhosis, or elevated plasma creatinine