Al-Quds University Faculty of Pharmacy Pharmacology 3 PDF

Al-Qdus University Faculty of Pharmacy Pharmacology 3 Dr. Dala Daraghmeh, PhD Course Credit Hours: 3 Textbook: Lippincott Illustrated Reviews: Pharmacology  Diabetes Meletus DM is a chronic metabolic disorder...

Al-Qdus University Faculty of Pharmacy Pharmacology 3 Dr. Dala Daraghmeh, PhD Course Credit Hours: 3 Textbook: Lippincott Illustrated Reviews: Pharmacology  Diabetes Meletus DM is a chronic metabolic disorder characterized by elevated glucose levels due to absolute or relative lack of insulin functionality Classification: üType1 DM üType2 DM üGestational& diabetes due to other causes Diabetes mellitus Type 1 diabetes : β- cell failure due to massive necrosis May be autoimmune, viral or chemical induced Classic symptoms of insulin deficiency Treatment: Insulin dependent Untreated: Life-threatening diabetic ketoacidosis Diabetes mellitus Type 2 diabetes - Gradual β- cell deterioration Influenced by genetic factors, aging, obesity & peripheral insulin resistance. Early stages: High levels of insulin, particularly in obese patients (insulin resistance) Late-stage: the β-cell mass gradually decline over time, thus require insulin therapy Insulin level Profile for Healthy and Diabetic Individuals  Glycosylated hemoglobin Hb-A1c Used to monitor the plasma glucose concentration over prolonged periods of time (4-6 weeks). Normal mean blood glucose is approximately 115 mg/dL or less (HbA1c < 5.7%)  Insulin During normal postabsorptive period, constant β-cell secretion maintains low basal levels of circulating insulin. This suppresses lipolysis, proteolysis, and glycogenolysis. A burst of insulin secretion occurs within 2 minutes after ingesting a meal, in response to transient increases in circulating glucose and amino acids. This lasts for up to 15 minutes, followed by the postprandial secretion of insulin  Regulation of Insulin Secretion Secretion is most often triggered by increased blood glucose. Glucose is taken up by the glucose transporter into the β cells of the pancreas. There, it is metabolized to generate adenosine triphosphate (ATP). The rise in ATP levels causes a blockade of K+ channels, leading to membrane depolarization and an influx of Ca2+. The increase in intracellular Ca2+ causes pulsatile insulin exocytosis  Insulin and insulin analogues Not active orally. Insulin is inactivated by insulinase (insulin transhydrogenase ) found mainly in liver and kidney. Insulin burst within 2 min, lasts for 15 min, then postprandial insulin secretion Dose reduced in renal insufficiency Insulin Delivery system  Side effects of insulin Hypoglycemia is the most serious and common adverse reaction to insulin.  Side effects of Insulin Hypoglycemia is the most serious and common adverse reaction to insulin (can result in Seizures and Coma) Other adverse reactions include: weight gain, local injection site reactions, and lipodystrophy. Lipodystrophy can be minimized by rotation of injection sites. Insulin-induced Lipodystrophy  Insulin and insulin analogues Human insulin is produced by recombinant DNA technology Modification of the amino acid sequence of human insulin produces insulins with different pharmacokinetic properties (onset and duration of action). Insulin preparations vary primarily in their onset and duration of action. Factors influencing the onset and duration of action: Dose, injection site, blood supply, temperature, and physical activity.  Insulin preparations Rapid acting insulin : Aspart, Lispro (Humalog®), Glulisine, Human insulin (Actrapid®) Short acting insulin: Regular (Humulin R®) Intermediate acting insulin: NPH (isophane) and Lente (insulin zinc) Long acting insulin: Glargine (Lantus®), Detimir, Protamine—zinc and Ultralente Mixtard ®: Regular and intermediate-acting (isophane) insulin  Rapid-acting and short-acting insulin preparations Rapid- or short-acting insulins are administered to mimic the prandial (mealtime) release of insulin and to control postprandial glucose. They may also be used in cases where swift correction of elevated glucose is needed. Rapid- and short-acting insulins are usually used in conjunction with a longer- acting basal insulin that provides control of fasting glucose.  Rapid-acting and short-acting insulin preparations Regular insulin should be injected SC 30 minutes before a meal, whereas rapid- acting insulins are administered in the 15 minutes proceeding a meal or within 15 to 20 minutes after starting a meal. Rapid-acting insulins are commonly used in external insulin pumps, and they are suitable for IV administration. Regular insulin is most commonly used when the IV route is needed.  Intermediate-acting insulin Neutral protamine Hagedorn (NPH) (isophane) insulin is an intermediate- acting insulin formed by the addition of zinc and protamine to regular insulin. It has is less solubility, thus delayed absorption and a longer duration of action. It is used for basal (fasting) control in type 1 or 2 diabetes and is usually given along with rapid- or short-acting insulin for mealtime control. It should be given only subcutaneously (never IV) It should not be used when rapid glucose lowering is needed (for example, diabetic ketoacidosis).  Long-acting insulin preparations Insulin Glargine: has a slower onset than NPH insulin and a flat, prolonged hypoglycemic effect with no peak Insulin Detemir (association to albumin): Slow dissociation from albumin results in long-acting properties similar to those of insulin Glargine Both are used for basal control and should only be administered subcutaneously. Neither long-acting insulins should be mixed in the same syringe with other insulins  Ultra long-acting basal insulin analogue Insulin degludec (Tresiba) It is administered via subcutaneous injection. onset of action: 30–90 minutes. Duration of action: up to 40 hours It can be given daily or two to three-times a week has one single amino acid deleted in comparison to human insulin, and is conjugated to hexadecanedioic acid via gamma-L-glutamyl spacer at the amino acid lysine at position B29 This allows for the formation of multi-hexamers in subcutaneous tissues There is no peak in activity, due to the slow release into systemic circulation.  Insulin combinations Examples of premixed combinations: 70% NPH insulin plus 30% regular insulin, or 50% of each. The use of premixed combinations decreases the number of daily injections but makes it more difficult to adjust individual components of the insulin regimen. Examples of three regimens that provide both prandial and basal insulin replacement  Standard treatment versus intensive treatment Standard insulin therapy: involves twice-daily injections. Intensive insulin therapy: utilizes three or more injections daily with frequent monitoring of blood glucose levels. The recommended target mean blood glucose level of 154 mg/dL or less (HbA1c ≤ 7%) Intensive treatment is more likely to achieve this goal.  Standard treatment versus intensive treatment The frequency of hypoglycemic episodes, coma, and seizures is higher with intensive insulin regimens. Patients on intensive therapy show a significant reduction in microvascular complications of diabetes such as retinopathy, nephropathy, and neuropathy compared to patients receiving standard care.  Standard treatment versus intensive treatment Intensive therapy should not be recommended for patients with: Long-standing diabetes Significant microvascular complications Advanced age Those with hypoglycemic unawareness  Synthetic Amylin analog: Pramlintide Amylin is a peptide produced by beta cells and co-secreted with insulin. Pharmacological(physiological)Effects: Inhibits glucagon secretion Delay gastric emptying Suppress appetite Decreases postprandial glucagon secretion Improves satiety Indication: an adjunct to mealtime insulin therapy in patients with Type 1 or Type 2 diabetes. Synthetic Amylin analog: Pramlintide Administration of Pramlintide: subcutaneous injection immediately prior to meals. When pramlintide is initiated, the dose of rapid- or short-acting insulin should be decreased by 50% prior to meals to avoid a risk of severe hypoglycemia. Adverse effects: are mainly GI and consist of nausea, anorexia, and vomiting.  Incretin mimetics Oral glucose results in a higher secretion of insulin than occurs when an equal load of glucose is given IV. This effect is referred to as the “incretin effect” and is markedly reduced in type 2 diabetes. The incretin effect occurs because the gut releases incretin hormones, notably glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in response to a meal. GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4)  Incretin mimetics Incretin hormones are responsible for 60% to 70% of postprandial insulin secretion. Exenatide and Liraglutide are injectable incretin mimetics used for the treatment of type 2 diabetes. Must be administered subcutaneously. Indication: Adjunct to therapy in patients with Type 2 diabetes who have failed to achieve adequate glycemic control on oral hypoglycemic agents. Exenatide has a shorter duration of action  Mechanism of action and pharmacological effects of Incretin mimetics Analogs of GLP-1 that exert their activity by acting as GLP-1 receptor agonists. Pharmacological effects: Improve glucose-dependent insulin secretion Slow gastric emptying time Reduce food intake by enhancing satiety (a feeling of fullness) Decrease postprandial glucagon secretion by α-cells Promote β-cell proliferation Consequently, weight gain and postprandial hyperglycemia are reduced, and HbA1c levels decline Adverse effects of Incretin mimetics Nausea and vomiting Diarrhea, and constipation Associated with pancreatitis  Oral hypoglycemic agents Sulfonylureas Insulin secretagoues Meglitinides (Glinides) agents Biguanides Thiazolidinediones Insulin sensitizer α-Glucosidase inhibitors Dipeptidyl peptidase-4 inhibitors Sodium–glucose cotransporter 2 (SGLT2) inhibitors  Sulfonylureas https://youtu.be/2wk44c1Qa7I  Sulfonylureas Insulin secretagoues Mechanism of action: stimulating insulin secretion from beta cells in the pancreas. It may also increase insulin sensitivity and lower hepatic glucose production.  Sulfonylureas Three generations: First generation : Acetohexamide, Chlorpropamide, Tolbutamide, Tolazamide (no longer used) Second generation : Glipizide, Glyburide (Glibenclamide) Third generation : Glimiperide (more potent, more efficacious , fewer adverse effects).  Adverse effects of Sulfonylureas Hyperinsulinemia and Hypoglycemia Cholestatic jaundice Weight gain Cross placenta – fetal hypoglycemia Notes: Glyburide has minimal transfer across the placenta and may be an alternative to insulin for diabetes in pregnancy. Use with caution in hepatic or renal insufficiency to avoid accumulation Sulfonylureas Dose (mg) Duration (h) First Generation Tolbutamide 1000-1500 6-8 Chlorpropamide 250-375 24-60 Tolazamide 250-375 12-24 Second generation Glipizide 10 10-24 Glyburide (Glibenclamide) 5 16-24 Third generation Glimepiride 1-2 24 Meglitinides (glinides) Repaglinide, Nateglinide Insulin enhancers with shorter duration than sulfonylurea (mealtime anti-diabetic drugs) These are insulin secretagogues that act by blocking ATP-dependent K+ channels. This leads to increased insulin secretion by pancreatic β-cells. Hypoglycemia is the common adverse effect. Less weight gain The drug has minimal renal excretion thus useful in patients with DM and impaired renal function. Meglitinides (glinides) Repaglinide, Nateglinide : By inhibiting hepatic metabolism, the lipid-lowering drug Gemfibrozil may significantly increase the effects of repaglinide, and concurrent use is contraindicated. These agents should be used with caution in patients with hepatic impairment  Biguanides (Metformin) Pharmacological actions: Insulin sensitizer: It increase the sensitivity of liver and muscle to insulin (increase uptake of glucose) Inhibits glucose output (gluconeogenesis) Slows intestinal absorption of sugars Does not promote insulin secretion It causes modest weight loss: loss of appetite It does not cause hypoglycemia. It produces a significant ↓TG and LDL, and ↑HDL.  Biguanides (Metformin) Contraindicated for patients with renal dysfunction due to the risk of lactic acidosis. It should be discontinued in disorders that can cause acute renal failure: e.g. acute MI, exacerbation of heart failure and sepsis. Metformin should be used with caution in patients older than 80 years and in those with heart failure. Should be temporarily discontinued in patients undergoing procedures requiring IV radiographic contrast  Other uses of Metformin Metformin is effective in the treatment of polycystic ovary syndrome It lowers insulin resistance seen in this disorder and can result in ovulation and, therefore, possibly pregnancy  Thiazolidinediones (TZDs) (glitazones) Insulin sensitizers The TZDs lower insulin resistance by acting as agonists for the peroxisome proliferator–activated receptor-γ (PPARγ), a nuclear hormone receptor. Activation of PPARγ regulates the transcription of several insulin responsive genes, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle. Enhance sensitivity to insulin in muscle and fat by increasing the GLUT 4 glucose transporters. Enhance glucose and lipid metabolism through action on Peroxisome Proliferator Activated Receptor (PPAR–γ) Beneficial effects on serum lipid; ↓TG and ↑HDL.  Thiazolidinediones (TZDs) (glitazones) TZDs do not promote insulin release from the β cells, so hyperinsulinemia is not a risk. Troglitazone, was withdrawn in 1990s from the market due to an increased incidence of drug-induced hepatitis. The main side effect of all thiazolidinediones is water retention, leading to edema.  Alpha-Glucosidase Inhibitors Acarbose and Miglitol Taken at the beginning of the meal They inhibit α-glucosidase which converts dietary starch and complex carbohydrates into simple sugars It reduces absorption of glucose after meals. The main side effects includes flatulence and diarrhea. Not recommended in patients with inflammatory bowel disease (IBDs), colonic ulceration or intestinal obstruction  Dipeptidyl peptidase-4 inhibitors Alogliptin, Linagliptin, Saxagliptin, and Sitagliptin Orally active dipeptidyl peptidase-4 (DPP-4) inhibitors Used for the treatment of type 2 diabetes  Mechanism of action of Dipeptidyl peptidase-4 inhibitors They inhibit the enzyme DPP-4, which is responsible for the inactivation of incretin hormones such as GLP-1. Prolonging the activity of incretin hormones increases insulin release in response to meals and reduces inappropriate secretion of glucagon. DPP-4 inhibitors may be used as monotherapy or in combination with other drugs. Unlike incretin mimetics, these drugs do not cause satiety, or fullness, and are weight neutral  Sodium–glucose cotransporter 2 (SGLT2) inhibitors (Canagliflozin and Dapagliflozin) Mechanism of action: (SGLT2) is responsible for reabsorbing filtered glucose in the tubular lumen of the kidney. By inhibiting SGLT2, these agents decrease reabsorption of glucose, increase urinary glucose excretion, and lower blood glucose. Inhibition of SGLT2 also decreases reabsorption of sodium and causes osmotic diuresis. Therefore, SGLT2 inhibitors may reduce systolic blood pressure. They are not indicated for the treatment of hypertension. Used for type 2 diabetes  Sodium–glucose cotransporter 2 (SGLT2) inhibitors (Canagliflozin and Dapagliflozin) Pharmacokinetics These agents are given once daily in the morning before the first meal. About one-third of a dose is renally eliminated. These agents should be avoided in patients with renal dysfunction  Sodium–glucose cotransporter 2 (SGLT2) inhibitors (Canagliflozin and Dapagliflozin) Side effects: Female genital mycotic infections (for example, vulvovaginal candidiasis) Urinary tract infections Urinary frequency Hypotension, particularly in the elderly or patients on diuretics.  Agents that increase blood glucose (hyperglycemics) Glucagon : Uses First aid in cases of severe hypoglycemia when the victim is unconscious or for other reasons cannot take glucose orally. Treatment of overdose with beta blockers It has positive inotropic action and chronotropic action on the heart. It acts by stimulation of glucagon receptors and not through beta 1 receptors.  Agents that increase blood glucose (hyperglycemics) Diazoxide Diazoxide is a nondiuretic thiazide that promptly increases blood glucose levels by direct inhibition of insulin secretion. Diazoxide is useful in cases of insulinoma or leucine-sensitive hypoglycemia Diazoxide may cause sodium retention, gastrointestinal irritation, and changes in circulating white blood cells.