Lipid lowering drugs, Drugs to treat Diabetes Flashcards
What are the steps in plaque formation and growth?
1) Cholesterol particles infiltrate the wall of the artery at the site of the damaged inner lining of the artery
2) Plaque develops in the artery
3) As more cholesterol and materials are incorporated into the plaque, the plaque grows
4) The plaque may continue to grow blocking blood flow through the artery or
5) The plaque may rupture and blood clots may form, completely blocking blood flow through the artery
What are “bad cholesterols”?
LDL - stores cholesterol in the blood stream
What are “good cholesterols”?
HDL - regulates LDL storage and promotes excretion
What contributes to plaque buildup?
LDLs
Triglycerides
Inflammatory component
What are some mechanical procedures to treat plaque buildup in the circulatory system?
Balloon angioplasty to treat blocked coronary artery
Stent placement in carotid artery
High pressure jetting
Dyslipidemia
High cholesterol
An imbalance of lipids circulating in the blood stream
What are drugs used to treat dyslipidemia?
Derivatives of fibric acid Nicotinic acid Bile Acid sequestrants Inhibitors oh HMG CoA Reductase Cholesterol absorption inhibitors
What do fibric acids do?
Increase peripheral lipolysis
Decrease hepatic triglyceride production
What are side effects of fibric acid derivatives?
Abdominal discomfort Diarrhea Nausea Blurred vision Increased risk of gallstones Prolonged prothrombin time Liver studies may show increased function
What are the two mechanisms of action for Nicotinic acid?
1) Agonist for GPR 109A and 109B receptors
2) Inhibitor of diacylglycerol acyltransferase
What is the result of using Nicotinic acid?
Increase HDL-particles
Decrease Triglyceride
What are the side effects of nicotinic acid?
Flushing (due to histamine release)
Pruritis (itching)
GI distress
What happens to cholesterol in the liver?
It is converted to bile acid, which is excreted to the intestine through the action of C7H
By preventing bile acid resorption, the sequestrants increase cholesterol metabolism to bile acid
What are the major actions of bile acid sequestrants?
Reduce LDL-C 15-30%
Increase HDL-C 3-5%
May increase TG
What are the major side effects of Bile acid sequestrants?
GI distress/constipation
Decreased absorption of other drugs
Inhibitors of HMG CoA Reuctase
HMG-CoA reductase is an enzyme along the pathway of cholesterol synthesis
By inhibiting it, it prevents the synthesis of cholesterol
Statins (HMG-CoA Reductase inhibitor) lowers cholesterol, but do they help people live longer?
The current prevailing opinion is that they are helpful for people at risk of having a heart attack
NPC1L1
A transport protein moving cholesterol from the lumen into the enterocyte and ultimately back into the blood
Blocked by Ezetimbie (Cholesterol Absorption inhibitor)
What do Cholesterol Absorption inhibitors do?
Inhibit absorption of both dietary and biliary cholesterol
Lower LDL formation - increases expression of hepatic LDL receptors
What is the mechanism of Cholesterol Absorption inhibitors?
Inhibit LDL formation by increasing hepatic LDL receptors and taking it up to be secreted
What are adverse effects of Cholesterol Absorption inhibitors?
Mild abdominal pain and diarrhea
What is a major complication of diabetes that WE care about (hint, hint)
Dental disease
Glycogenesis
Process of glycogen synthesis, in which glucose molecules are added to chains of glycogen for storage
(glucose –> glycogen)
Glycogenolysis
The reverse process to glycogenesis
The breakdown of glycogen to Glucose-6-Phosphate and glycogen
(glycogen –> glucose)
Gluconeogenesis
Metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as pyruvate
One of the two main mechanisms used to maintain blood-glucose levels
(Carbon substrates –> glucose)
What are the principal hormones regulating blood sugar levels?
Glucagon
Insulin
What cells secrete glucagon?
alpha cells
What cells secrete insulin?
beta cells
A1C test
Measures glycation of hemoglobin
It provides a window into the average blood sugar of an individual over a period of months
What are the ranges of A1c test scores
Excellent = 4-6
Good = 7-8
Action suggested = 9-14
What are the actions of insulin?
Glucose uptake Glycolysis Glycogen syntesis Protein synthesis Uptake of Ions Stop gluconeogenesis Stop glucogenolysis Stop liposysis Stop ketogenesis Stop proteolysis
Type 1 diabetes
Not enough insulin, so cells can’t absorb glucose
Type 2 diabetes
Cells do not respond to insulin, so cells can’t absorb glucose
What drugs can be used to treat diabetes?
Insulin Sulfonylureas Meglitinides Drugs working on GLP-1 receptors Biguanides Thiazolidinediones a-glucosidase inhibitors
Secretagogues
A K+ channel that regulates insulin release from pancreatic B cells by sensing ATP/ADP
What happens to secretagogues when ATP/ADP is low (fasting)
The channel opens, the cell hyperpolarizes, L-type Ca channels close, and insulin is not secreted
What happens to secretagogues when ATP/ADP is high (after a meal)
Channel is closed, cell depolarizes, L-type Ca channels open, and insulin is secreted
What drugs affect the secretagogues process?
Sulfonylureas
Meglitinides
Drugs working on GLP-1 receptors
Sulfonylureas
Have a duration of 12-24 hours
Used to generally beat down glucose levels
Sulfonylureas mechanism
Sulfonylureas binds to an ATP/ADP regulated K channel complex, reducing the efflux of K ions, leading to the channel to close, depolarizing the membrane, leading to an influx of Ca and secretion of insulin
Meglitinides
More rapid onset of action and shorter duration than sulfonylureas
Used before meals
Hypoglycemia is a concern if drug is taken and person doesn’t eat
Meglitinides mechanism
Very similar to Sulfonylureas
Binds to a ATP/ADP regulated K channel complex, reducing the efflux of K ions, leading to the channel to close, depolarizing the membrane, leading to an influx of Ca and secretion of insulin
GLP-1 receptor
Glucagon-like peptide 1 (GLP-1) and Glucose dependent insulinotropic polypeptide (GIP) act at the GLP-1 receptor on B cells and stimulate insulin release
Metformin (Biguinide)
A first-line medication used for treatment of type 2 diabetes in conjunction with diet, exercise, and weight loss
Does no stimulate insulin secretion, but is insulin ‘sparing’
Usually not accompanied by hypoglycemia
What is the mechanism of action of metformin?
Decrease hepatic glucose produciton through a mild inhibition of the mitochondrial respiratory-chain complex
Decreases intestinal absorption of glucose
Thiazolidinediones
Decrease insulin resistance
Agonists of the peroxisome proliferator-activated receptor y (PPAR-y)
Insulin resistance
Pathological condition in which cells fail to respond to the normal actions of insulin
What happens when the body produces insulin under the condition insulin resistance?
The cells in the body are unable to use it efficiently, leading to high blood sugar
PPAR-y
Regulates fatty acid storage and glucose metabolism
The genes activated by PPAR-y stimulate lipid uptake and adipogenesis by fat cells
What do PPAR-y agonist do?
Diminish insulin resistance
a-glucosidase inhibitors
Act by inhibiting the digestion of glucose
Delay digestion and absorption of carbs in the GI tract
a-glucosidase
Breaks down starch and disaccharides to glucose
