【Pharmacology】Drug for diabetes

Drug for diabetes

1. Diabetes mellitus
2. Diabetes mellitus type
3. Insulin
4. Drug for diabetes
    a. Insulin & analogs
    b. Synthetic amylin
    c. Incretin mimetics
    d. DPP-4 inhibitors
    e. Sulfonylureas
    f. Glinides
    g. Biguanides
    h. Thiazolidinediones
    i. Sodium-glucose cotransporter-2 inhibitors
    j. Alpha-glucosidase inhibitors
5. Reference

1. Diabetes mellitus

Diabetes mellitus is a chronic disorder characterized by high levels of blood glucose.

This results from inadequate insulin production or resistance of the body's cells to the action of insulin.

Symptoms:

• Increased thirst
• Frequent urination
• Extreme hunger
• Unexplained weight loss
• Presence of ketones in the urine (ketones are a byproduct of the breakdown of muscle and fat that happens when there's not enough available insulin)
• Fatigue
• Irritability
• Blurred vision
• Slow-healing sores
• Frequent infections, such as gums or skin infections and vaginal infections

2. Diabetes mellitus type

Type 1: Insulin producing cells are destroyed thus eliminating insulin production 

Risk: 

• Family history
• Environmental factors. 
• Circumstances such as exposure to a viral illness likely play some role in type 1 diabetes.
• The presence of damaging immune system cells (autoantibodies). 
• People with the presence of diabetes autoantibodies have an increased risk of developing type 1 diabetes. 
• But not everyone who has these autoantibodies develops diabetes.
• Geography. 
• Certain countries, such as Finland and Sweden, have higher rates of type 1 diabetes.

Type 2: Insulin resistance and gradual insulin deficiency

• Weight
• The more fatty tissue, the more resistant cells become to insulin.
• Inactivity
• Physical activity helps control weight, uses up glucose as energy and makes cells more sensitive to insulin.
• Family history
• Race or ethnicity. 
• Black, Hispanic, American Indian and Asian American people — are at higher risk.
• Age
• Risk increases as you get older. 
• may due to old people tend to exercise less, lose muscle mass and gain weight
• But type 2 diabetes is also increasing among children, adolescents and younger adults.
• Gestational diabetes
• Women who developed gestational diabetes when pregnant, may increase risk of developing prediabetes and type 2 diabetes increases. 
• Women who gave birth to a baby weighing more than 4 kg, you're also at risk of type 2 diabetes.
• Polycystic ovary syndrome
• A common condition characterized by irregular menstrual periods, excess hair growth and obesity 
• High blood pressure. 
• Having blood pressure over 140/90 millimeters of mercury (mm Hg) 
• Abnormal cholesterol and triglyceride levels. 
• Low levels of high-density lipoprotein (HDL)
• High levels of triglycerides 

3. Insulin

Overview

Insulin is a hormone that comes from a gland situated behind and below the stomach (pancreas).

• The pancreas secretes insulin into the bloodstream.
• The insulin circulates, enabling sugar to enter cells.
• Insulin lowers the amount of sugar in your bloodstream.
• When blood sugar level drops, the secretion of insulin from pancreas also decrease.

Storyline

• Digestive system digest food into glucose
• Blood glucose levels rise
• Beta cells of the pancreas islets start secreting insulin
• Insulin binds to the insulin receptor and stimulates glucose uptake by cells
• Liver and skeletal muscle store absorbed glucose in form of glycogen
• Many other cells quickly break down absorbed glucose to make ATP a molecule which provides immediately available energy 

When blood glucose levels fall too low

• Alpha cells of the pancreatic islets release glucagon
• Glucagon acts on the liver it causes breakdown of stored glycogen into glucose 
• Glucose released into the bloodstream
• Blood glucose levels rise

4. Drug for diabetes

💉💉Inject

a. Insulin & analogs

💪Insulin can be reproduced by

• recombinant DNA technology using bacteria or yeast 
• altered the amino acid sequence of human insulin 

💪Typically administered by subcutaneous injection

• as insulin is a polypeptide it is susceptible to degradation in the gastrointestinal tract

💪Three major categories:

• Rapid and short acting insulins preparations
• Rapid: Peak effect---30 minutes; Duration---up to 5 hours
• insulin Lispro
• insulin Aspart 
• insulin Glulisine
• Short: Peak effect---2 hours; Duration---less than 8 hours
• Regular insulin
• Intermediate acting insulin preparation
• Peak effect---6 hour; Duration---18 hours
• Longer lasting effects are accomplished by addition of zinc and protamine to regular insulin, results in a complex that is less soluble
• NPH (Isophane insulin)
• Long-acting insulins with slow onset of action preparations
• Long lasting effect result from modifications to the insulin molecule
• insulin Detemir
• Peak effect---between 6 and 8 hours; Duration---up to 24 hours
• fatty acid side chain was added to the insulin molecule that allows it to bind to albumin 
• slow down its release into the bloodstream
• insulin Glargine
• Peak effect---N/A (steady); Duration---up to 24 hours
• modified to have low solubility at neutral pH
• form precipitate in the subcutaneous tissue that slowly releases insulin into the bloodstream
• insulin Degludec
• Peak effect---N/A (steady); Duration---up to 24 hours
• form long chains of hexamers in subcutaneous tissue
• serve as a depot from which insulin is continuously and slowly released 

insulin Detemir, insulin Glargine, insulin Degludec

What gives rapid and short acting insulins preparations the ability to act quickly?

• Naturally, six insulin molecules bound together forming hexamers 
• These hexamers too large to cross from the subcutaneous tissue into the bloodstream 
• must first separate into single insulin molecules before absorption
• Altered amino acid sequence of insulin molecules to make them less likely to aggregate
• faster absorption and more rapid action 

Side effect of using insulin

• hypoglycemia
• lipodystrophy: can develop at the site of repeated insulin injections

b. Synthetic amylin

Amylin:

• secrete by pancreatic beta cells
• Function:
• delay gastric emptying to suppress postprandial glucagon secretion
• promote satiety

Drug: Pramlintide

Benefit: allows insulin doses to be reduced

Side effect of using Pramlintide

• hypoglycemia
• nausea 
• modest weight loss

c. Incretin mimetics

Incretins

• a group of metabolic hormones that are secreted from the gut
• stimulate pancreas to produce more insulin (in response to food ingestion)

Two primary incretin hormones:

• glucagon-like peptide-1 (GLP-1)
• glucose-dependent insulinotropic polypeptide (GIP)
• actions are actually quite limited
• due to rapid inactivation by the enzyme dipeptidyl peptidase-4 (DPP-4)

GLP-1 mimetics: resistant to degradation by DPP-4 enzyme

• stimulating insulin secretion by slow gastric emptying and promote satiety
• eg, Exenatide & Liraglutide

Side effect of using Incretin mimetics

• increased risk of pancreatitis
• thought to be due to their proliferative effects on pancreas

*Less common side effect

d. DPP-4 inhibitors

Function: enhance the effects of incretin by inhibit DPP-4 enzyme

Result: increase insulin secretion, decrease gastric emptying and reduce glucagon release

Drug: Alogliptin, Linagliptin, Saxagliptin and Sitagliptin

Side effects of DPP-4 inhibitors

• nasopharyngitis
• headache 

👄👄Oral

e. Sulfonylureas

Mechanism of glucose

• Dependent insulin secretion from pancreatic beta cells, so available glucose enters beta cell through glucose transporter 2 (GLUT2)
• Once inside the cell, glucose gets metabolized to create a bunch of ATP
• Rising levels of ATP 
• → inhibition of ATP-sensitive potassium channels 
• →blocking the inflow of potassium 
• → depolarization of the cell's membrane 
• → triggers activation of voltage-gated calcium channels 
• → influx of calcium 
• → mediate fusion of insulin containing vesicles with the membrane
• → insulin release

Sulfonylureas

• Action: bind to and inhibit the activity of ATP-sensitive potassium channels
• increased sensitivity of beta cells to glucose
• reduced hepatic glucose production
• eg, Glimepiride, Glyburide, Glipizide

Side effects of using Sulfonylureas

• hypoglycemia 
• weight gain

**As sulfonylureas are highly protein bound and most are extensively metabolized in the liver by cytochrome p450 enzymes, they tend to interact with wide variety of other drugs

f. Glinides

Glinides (act like sulfonylureas)

• stimulate insulin secretion from pancreatic beta cells 
• accomplish that by binding to ATP-sensitive potassium channels at a different site and with different kinetics than sulfonylureas, so it has more rapid onset and shorter duration of action
• good choice for patients with primarily postprandial hyperglycemia
• eg. Nateglinide and Repaglinide

Side effects of using Glinides (Risk lower than Sulfonylureas)

• hypoglycemia 
• weight gain

g. Biguanides

Exact cellular mechanism of action of biguanides is not entirely understood that being said the main blood glucose lowering activity appears to be primarily through

• reduction of hepatic glucose production
• slow intestinal absorption of glucose
• increase insulin sensitivity 
• enhances peripheral glucose uptake

Drug: Metformin

Side effects of Metformin

• Limited to GI tract
• nausea 
• vomiting 
• diarrhea
• loss of appetite which may lead to weight loss
• Increase risk of lactic acidosis
• particularly in patients with organ dysfunction, such as congestive heart failure or renal impairment 
• This is because Metformin decreases hepatic uptake of lactate

h. Thiazolidinediones

Thiazolidinediones 

• work primarily by selectively activating nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR-γ)
• activated this receptor binds to DNA
• triggering expression and repression of specific genes encoding proteins that regulate glucose and lipid metabolism as well as insulin signal transduction 
• Lead to
• increased insulin sensitivity in adipose tissue skeletal muscle and liver 
• inhibition of hepatic glucose production
• promote fatty acids uptake and utilization in adipocytes
• decrease in fatty acid concentrations & increased uptake and utilization of glucose

Drug: Pioglitazone and Rosiglitazone

Side effects of Thiazolidinediones 

• lowering blood glucose levels 
• increase HDL levels (especially in Pioglitazone)
• increase LDL levels (limited only to larger less atherogenic LDL particles)
• weight gain and fluid retention → peripheral edema
• hepatotoxicity (Few)

i. Sodium-glucose cotransporter-2 inhibitors

• inhibit glucose transporter located in the proximal convoluted tubules of the kidneys that is responsible for about 90% of glucose reabsorption
• Lead to 
• increased urinary glucose excretion 
• reduced levels of blood glucose 
• increase in glucose and sodium in urine, generate mild osmotic diuresis which may contribute to small reduction in blood pressure and weight loss

Drug: Canagliflozin and Dapagliflozin 

Side effects of Sodium-glucose cotransporter-2 inhibitors 

• thirst 
• increased urination 
• increased risk of urinary tract and genital infections

j. Alpha-glucosidase inhibitors

Alpha-glucosidase

an enzyme located in the intestinal brush border

responsible for breaking down carbohydrates into simple sugars such as glucose 

Alpha-glucosidase inhibitors

Blocks Alpha-glucosidase → the absorption of glucose is delayed → lower postprandial glucose levels 

Drug: Acarbose and Miglitol

Side effects of alpha-glucosidase inhibitors 

• Significant gastrointestinal side effects
• abdominal cramps 
• bloating 
• flatulence
• diarrhea

5. Reference

https://youtu.be/LWDQyaKVols

https://www.mayoclinic.org/diseases-conditions/diabetes/symptoms-causes/syc-20371444

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