Module 8: Drugs for Diabetes Flashcards
Insulin Physiology
-pivotal hormone in the regulation of blood glucose levels
Synthesis of Insulin
Biosynthesis of Insulin
Insulin is synthesized in the β-cells of the Islets of Langerhans in the pancreas. The process begins with the transcription of the INS gene to produce preproinsulin mRNA, which is then translated into preproinsulin, a precursor molecule. Preproinsulin undergoes sequential enzymatic modifications: first, the removal of its signal peptide to form proinsulin, and subsequently, the cleavage of C-peptide to produce mature insulin. This mature insulin, composed of an A and a B chain linked by disulfide bonds, is stored in secretory granules within the β-cells until secretion is triggered.
Secretion of Insulin
Insulin secretion is primarily regulated by blood glucose levels through a glucose-sensing mechanism in β-cells. When blood glucose levels rise (e.g., after a meal), glucose is taken up by β-cells through the GLUT2 transporter. Glucose metabolism within these cells leads to an increase in ATP production, which in turn closes ATP-sensitive potassium channels, causing cell depolarization. This depolarization opens voltage-gated calcium channels, leading to calcium influx and triggering the exocytosis of insulin-containing granules into the bloodstream.
Metabolic Actions of Insulin
Insulin facilitates the uptake and utilization of glucose by cells, especially in muscle and adipose tissues, through the activation of GLUT4 glucose transporters. It promotes the synthesis of glycogen in liver and muscle cells (glycogenesis) and inhibits glycogen breakdown (glycogenolysis). Insulin also enhances lipid synthesis (lipogenesis) and inhibits lipolysis, reducing free fatty acid levels in the blood. Additionally, it stimulates protein synthesis and inhibits protein degradation, supporting growth and repair processes.
Metabolic Consequences of Insulin Deficiency
Metabolic Consequences of Insulin Deficiency
Insulin deficiency, as seen in type 1 diabetes or advanced type 2 diabetes, shifts the body into a catabolic mode, characterized by:
Increased Glycogenolysis: The breakdown of glycogen into glucose in the liver is enhanced, contributing to hyperglycemia.
Increased Gluconeogenesis: The liver increases the production of glucose from non-carbohydrate sources, further elevating blood glucose levels.
Reduced Glucose Utilization: Without sufficient insulin, glucose cannot be efficiently taken up by muscle and fat cells, exacerbating hyperglycemia.
Ketogenesis: Lipid breakdown increases due to the reduced inhibitory effect of insulin on lipolysis, leading to an excess of free fatty acids in the liver. These are converted into ketone bodies, which can accumulate and cause ketoacidosis, a life-threatening condition.
Types of Insulin
Short duration: Rapid acting
Insulin lispro [Humalog]
Insulin aspart [NovoLog]
Insulin glulisine [Apidra]
Short duration: Slower acting
Regular insulin [Humulin R, Novolin R]
Intermediate duration
Neutral protamine Hagedorn (NPH) insulin
Long duration
Insulin glargine
Insulin determir [Levemir]
Short-Duration,
Rapid-Acting Insulin
Insulin lispro [Humalog]
Analog of human insulin
Rapid onset (10 to 20 minutes)
Short duration (3 to 5 hours)
Administered immediately before eating or even after eating
Insulin aspart [NovoLog]
Insulin lispro [Humalog]
Rapid-acting analog of regular insulin
Onset: 15 to 30 minutes after subcutaneous (subQ)
injection
Duration: 3 to 6 hours
Usual route is subQ via injection or use of an insulin pump
Acts faster than regular insulin but has a shorter duration of action
Should be injected 5 to 10 minutes before meal
Insulin glulisine [Apidra]
Synthetic analog of natural human insulin
Rapid onset (10 to 15 minutes)
Short duration (3 to 5 hours)
Should be administered close to the time of eatin
Short-Duration,
Slower-Acting Insulin
Regular insulin [Humulin R, Novolin R]
Unmodified human insulin
Four approved routes: SubQ injection, subQ infusion,
intramuscular (IM) injection (used rarely), and oral
inhalation (approved but not currently used)
Effects begin in 30 to 60 minutes
Peak in 1 to 5 hours
Duration up to 10 hours
Clear solution
U-100 (100 units/mL)
U-500 (500 units/mL)
Intermediate-Duration Insulin
NPH insulin [Humulin N, Novolin N]
Drug is injected twice or 3 times daily to provide
glycemic control between meals and during the night
NPH insulin is the only one suitable for mixing with
short-acting insulins
Allergic reactions are possible
NPH insulins are cloudy suspensions that must be
agitated before administration
NPH insulins are administered by subQ injection only
Long-Duration Insulin
Insulin glargine [Lantus]
Modified human insulin
Prolonged duration of action (up to 24 hours)
Once-daily subQ dosing to treat adults and children
with type 1 diabetes and adults with type 2 diabetes
Clear solution
Insulin detemir [Levemir]
Human insulin analog
Slow onset and dose-dependent duration of action
Used to provide basal glycemic control
Clear, colorless solution
Dosing: Once or twice daily by subQ injection
Do not mix with other insulins
Must not be given IV
Insulin Appearance
Except for NPH insulins, all insulins made in the
United States are formulated as clear, colorless
solutions
NPH insulin is a cloudy suspension
Patients should inspect their insulin before using
it and should discard the vial if the insulin looks
abnormal
Insulin Administration
Concentration
100 units/mL (U-100)
500 units/mL (U-500)
Mixing insulins
NPH with short-acting insulins
Short-acting insulin drawn first
Subcutaneous injection
Syringe and needle
Pen injectors
Jet injectors
Subcutaneous infusion
Portable insulin pumps
Implantable insulin pumps
Intravenous infusion
Inhalation
Insulin Therapy of Diabetes
Dosage
Dosing schedules
Three dosing schedules
* Twice daily premixed insulin regimen
* Intensive basal/bolus strategy
* Continuous subcutaneous insulin
Complications of Insulin Treatment
Hypoglycemia: Blood glucose below 70 mg/dL
Drug interactions
Blood glucose below 70 mg/dL
* Rapid treatment mandatory
* Conscious patients: Fast-acting oral sugar (eg, glucose
tablets, orange juice, sugar cubes, nondiet soda)
* If swallowing reflex or gag reflex is suppressed:
Nothing should be given by mouth
IV glucose or parenteral glucagon is the preferred treatment
Lipohypertrophy (Lipohypertrophy is a medical condition characterized by an abnormal accumulation of fat in specific areas of the body, creating lumps or fatty masses beneath the skin’s surface. This condition often arises as a complication of insulin therapy for diabetes, where repeated injections of insulin in the same area lead to localized increases in subcutaneous fat tissue.)
Allergic reactions
Hypokalemia
Drug interactions
Hypoglycemic agents
Hyperglycemic agents
Beta-adrenergic blocking agent
Oral Hypoglycemics
Biguanides
Metformin [Glucophage]
Sulfonylureas
Thiazolidinediones (also known as glitazones)
Rosiglitazone [Avandia]
Pioglitazone [Actos]
Meglitinides (also known as glinides)
Repaglinide [Prandin]
Nateglinide [Starlix]
Biguanides
Biguanides
Metformin [Glucophage]
* Drug of choice for initial therapy in most patients with type 2 diabetes
* Most common side effects: Gastrointestinal (GI) disturbances
* Lactic acidosis, a potentially fatal complication, is rare
* Prevention of type 2 diabetes
* Gestational diabetes
* Polycystic ovary syndrome (PCOS)
* Drug interactions
Sulfonylureas
Sulfonylureas
First oral antidiabetics available
Promote insulin release
Can be used only for type 2 diabetes
Major side effects: Hypoglycemia, weight gain
First generation
Second generation
Cardiotoxicity
Drug interactions
Meglitinides (glinides)
Meglitinides (glinides)
Repaglinide [Prandin]
* Generally well tolerated
* Adverse effect: Hypoglycemia
* Drug interactions: Gemfibrozil [Lopid]
Nateglinide [Starlix]
* Pharmacology nearly identical to that of repaglinide
Thiazolidinediones (glitazones)
Thiazolidinediones (glitazones)
Reduce glucose levels primarily by decreasing insulin
resistance
Only indication is type 2 diabetes, mainly as an add-
on to metformin
Rosiglitazone [Avandia]: Restricted use
Pioglitazone [Actos
Pioglitazone [Actos]
Pioglitazone [Actos]
Reduces insulin resistance and may also decrease
glucose production
Indication: Adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes
Adverse effects: Generally well tolerated; most
common reactions are upper respiratory tract
infection, headache, sinusitis, and myalgia
Drug interactions
Alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors
Act in the intestine to delay absorption of
carbohydrates
Indication: Type 2 diabetes
Acarbose [Precose]
* Adverse effects: Frequently causes flatulence, cramps,
abdominal distention, borborygmus, and diarrhea, liver dysfunction
Miglitol [Glyset]
Miglitol [Glyset]
* Especially effective among Latinos and African Americans
* Adverse effects: Flatulence, abdominal discomfort, and other GI effects
* Has not been associated with liver dysfunction
DPP-4 inhibitors (also called gliptins)
DPP-4 inhibitors (also called gliptins)
Promote glycemic control by enhancing the actions of incretin hormones
Stimulate glucose-dependent release of insulin
Suppress postprandial release of glucagon
Sitagliptin [Januvia]
Saxagliptin [Onglyza]
Saxagliptin [Onglyza]
* Most common adverse effects: Upper respiratory infection, urinary tract infection, and headache
Linagliptin [Tradjenta]
Alogliptin [Nesina]
Sodium-glucose co-transporter 2 (SGLT-2)
inhibitors
Sodium-glucose co-transporter 2 (SGLT-2)
inhibitors
Block reabsorption of filtered glucose in the kidney,
leading to glucosuria
Indication: Type 2 diabetes mellitus
Canagliflozin [Invokana]
* Side effects: Genital fungal infections in female patients, urinary tract infections, increased urination
Dapagliflozin [Farxiga]
Dapagliflozin, marketed under the brand name Farxiga, is a medication used to treat type 2 diabetes and, in some cases, heart failure. It belongs to a class of drugs known as sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 is a protein in the kidneys that facilitates glucose reabsorption into the bloodstream. By inhibiting this protein, dapagliflozin promotes the excretion of glucose through urine, thereby lowering blood glucose levels in individuals with type 2 diabetes.
Other Drugs
Colesevelam [Welchol]
Bromocriptine
Colesevelam (Welchol)
Colesevelam is a medication classified as a bile acid sequestrant. It’s primarily used to treat high cholesterol and to improve glycemic control in adults with type 2 diabetes mellitus, often in combination with other medications.
Bromocriptine
For Diabetes: Bromocriptine is a dopamine D2 receptor agonist. Its use in diabetes is based on the concept of resetting the biological clock, which may be related to circadian rhythms of neurotransmitter action in the brain. It’s thought to reduce insulin resistance and glucose production in the liver. Its precise mechanism for improving glycemic control is not fully understood but involves modulation of dopaminergic and possibly serotonergic pathways.
Non-Insulin Injectable Drugs
Pramlintide - Amylin mimetic
Pramlintide
Pramlintide is a synthetic analogue of amylin, a hormone that is naturally secreted by the pancreatic β-cells along with insulin in response to food intake. Because pramlintide acts as an amylin mimetic, it is used in the treatment of diabetes to complement insulin therapy. Amylin plays several roles in glucose regulation, including the modulation of gastric emptying, suppression of postprandial glucagon secretion, and enhancement of satiety, which helps to reduce food intake. By mimicking these actions, pramlintide aids in the management of blood glucose levels.
Mechanism of Action:
Slows Gastric Emptying: Pramlintide delays the rate at which food empties from the stomach into the small intestine, resulting in a slower and more gradual absorption of glucose into the bloodstream.
Suppresses Glucagon Secretion: After meals, pramlintide inhibits the secretion of glucagon, a hormone that raises blood glucose levels by promoting the release of glucose stored in the liver. By suppressing glucagon, pramlintide helps to prevent the postprandial rise in blood glucose.
Enhances Satiety: Pramlintide promotes a feeling of fullness, leading to a reduction in food intake and potentially aiding in weight management, which is beneficial for individuals with type 2 diabetes.
Non Insulin Injectable Drugs
GLP1 meds
GLP-1 receptor agonists (also called incretin
mimetics)
Slow gastric emptying, stimulate glucose-dependent
release of insulin, inhibit postprandial release of
glucagon, and suppress appetite
Exenatide [Byetta]
* Adverse effects: Hypoglycemia and gastrointestinal effects, including pancreatitis
* Drug interactions
Liraglutide [Victoza]
* May cause medullary thyroid carcinoma (MTC)
Acute Complications of
Poor Glycemic Control
Diabetic ketoacidosis (DKA)
Hyperosmolar hyperglycemic state (HHS)
Cardinal features of both conditions: Hyperglycemic
crisis and associated loss of fluid and electrolytes
Both conditions can be life-threatening
Differences
Hyperglycemia more severe in HHS
Ketoacidosis characteristic of DKA, absent in HHS
Treatment of the two disorders is similar
Diabetic Ketoacidosis
Severe manifestation of insulin deficiency
Symptoms evolve quickly within hours or days
Most common complication in pediatric patients and
leading cause of death
Characteristics
Hyperglycemia
Ketoacids
Hemoconcentration
Acidosis
Coma
Hyperosmolar Hyperglycemic
State (HHS)
Also called hyperglycemic hyperosmolar
nonketotic syndrome (HHNS)
Large amount of glucose excreted in urine
Results in dehydration and loss of blood volume
Increases blood concentrations of electrolytes
and nonelectrolytes (particularly glucose); also
increases hematocrit
Blood “thickens” and becomes sluggish
Little or no change in ketoacid levels
Little or no change in blood pH
No sweet or acetone-like smell to urine or breath
Occurs most frequently with type 2 diabetes with
acute infection, acute illness, or some other
stress
Can evolve slowly
Metabolic changes begin a month or two before signs and symptoms become apparent
If left untreated, can lead to coma, seizures, and
death
Management
Correct hyperglycemia and dehydration with IV
insulin, fluids, and electrolytes
