PHR 938 - Pharmacology of Orals & Noninsulin Injectables - Loftin (dis good stuff)

What is the difference between a same dose of glucose given orally vs IV?

Oral dose results in greater insulin blood levels

*less difference in insulin blood levels after oral or IV glucose

What is an incretin?

a hormone produced by the intestine which increases insulin synthesis and release from the pancreas

What are examples of incretins?

glucose-dependent insulintropic polypeptide (GIP)

glucagon-like peptide-1 (GLP-1)

What do incretins require to stimulate insulin secretion?

A basal level of glucose (> 70 mg/dL)

What are the effects of the incretin GLP-1?

maintains insulin secreting activity during hyperglycemia - increased transcription of proinsulin gene, insuling biosynthesis, and direct stimulation of secretion

inhibition of gastric motility - reduces early postprandial glucose spike

promotes sensation of satiety - reduces food intake

stimulates beta cell proliferation

inhibition of glucagon secretion

What happens to GLP-1 blood concentrations in T2DM?

they are decreased (when given by IV normalizes fasting and postprandial insulin)

The insulinotropic effect of GLP-1 is dependent on what?

Glucose dependent

What enzyme rapidly inactivates GLP-1?

DPP-4

What is DPP-4?

main enzyme that degrades GLP-1 and G1P on the surface of endothelial cells and in the circulation

What do DPP-4 inhibitors do?

increase plasma cocnentratios of GIP and GLP-1

- increased insulin secretion

- reduced glucagon levels

- improvements in both fsting and postprandial hyperglycemia

What is a rare potential side effect of DDP-4 inhibitors?

arthralgia

What is the administration of a DPP-4 inhibitor like?

Once oral daily w/o regard for meals

What are the four DPP-4 inhibitors?

Sitagliptin

Alogliptin

Saxagliptin

Linagliptin

What are the labeled indications of DPP-4 inhibitors?

add-on therapy with other oral agents and as monotherapy

What is SGLT2 the main site of?

Filtered glucose reabsorption

What do SGLT2 inhibitors block?

They block reabsorption of filtered glucose by the kidney

- increased urinary excretion

- lowers blood glucose concentrations

What are the five SGLT2 inhibitors?

Canagliflozin

Dapagliflozin

Empagliflozin

Ertugliflozin

Bexagliflozin

T or F: Efficacy of SGLT2 inhibitors is reduced in patients with severe renal impairment

True

T of F: SGLT2 inhibitors can be used to treat T1DM

False; they cannot

What adverse effects are seen with SGLT2is?

UTIs

The GLP-1 based therapy Exenatide (Byetta) has a peptide discovered from teh salivary gland of what?

Gila monster

What does exenatide (Byetta) do?

delayed gastric emptying

reduced glugagon lvls

reduced food intake

How is Exenatide (Byetta, Bydureon-ER) excreted?

entirely renally and not recommended with severe renal impairment

What is the structural difference in liraglutide compared to GLP-1?

amino acid substitiutions with fatty acid group

binding to albumin extended half-life

How is liraglutide taken?

SQ once daily at any time of the day independent of meals

What are the structural properties of dulaglutide?

recombinant fusion protein composed of two identical disulfide-linked chains of GLP-1 analog

covalently fused to human immunoglobulin

amino acid substituitions in human GLP-1

What is unique to orally administered semaglutide Rybelsus?

first oral GLP-1 RA

peptide analogue of GLP-1 formulated in a tablet

tablet has buffering agent to protect semaglutide from low pH gastric degradation

administer >30 mins before first food, beverage, orother oral meds of the day with <4 oz of plain water only

What are the effects of using a dual GLP-1 and GIP based therapy? What is the drug?

Tirzepatide (Mounjaro)

more potent increased glucose-dependent insulin secretion

slows gastric emptying

decreases inappropriate glucagon secretion

adverse effects comparable to GLP-1 RAs

What is the US boxed warning for most GLP-1 analogues?

thyroid cancer

Although most GLP-1 RAs require injection, why are they widely accepted?

improved glucose control and weight loss

What is pramlintide?

synthetic analog of amylin

What is amylin?

An amino acid peptide, secreted by beta cells of the pancreas along with insulin in response to food intake.

What does pramlintide do?

binds amylin receptors in the brain

- reduces postprandial glucagona secretion

- delays gastric emptying

- produces satiety

What is pramlintide used for?

adjunct treatment for T1DM or T2DM with mealtime insulin when glucose control fails with optimal insulin therapy

What is insulin and how is it prepared?

a small protein

no oral preparations / injections required (except inhaled insulin)

What is the structure of insulin like?

51 amino acids

two chains (A and B) linked by disulfide bridges

What is proinsulin processed into?

insulin and C-peptide

What is the goal of insulin therapy for T1DM?

reproduce physiological secretion

What are the two ways insulin is secreted?

Basal release

- between meals

- restrains glucose production by the liver

- ~50 pM

bolus release

- prandial rlease (meal-time)

- allows for tissue absorption of glucose

- ~500 pM

What is glucose homeostasis like in the fasting state (non-diabetic)?

glucose maintained at 70-11 mg/dL

supplied primarily from the liver

plasma insulin is low but still functional - maintains correct level of liver glucose production and w/o basal level, FBG goes too high

plasma glucagon is high

What is glucose homeostasis like in the post-prandial state (non-diabetic)?

increased plasma glucose (130 mg/dL)

promotes insulin secretion

glucose uptake by liver, skeletal muscle and adipose tissue

How is insulin cleared from the blood?

by enzymes in liver and kidney

What is the half-life of circulating insulin?

5 minutes

Where is the primary site of endogenous insulin clearance?

Liver

Where is the primary site of exogenous insulin clearance?

Kidneys

Insulin receptor structure

two covalently linked heterodimers

alpha subunit - entirely extracellular and recognition site

beta subunit - spans the membrane, contains tyrosine kinase

How does insulin binding to the outside surface of a receptor work?

insulin binds activating the receptor

conformational change

tyrosine kinase activity acts on cytoplasmic proteins

translocation of glucose transporters - GLUT 4 (skeletal muscle, adipose tissue)

Where are the following located:

GLUT 1:

GLUT 2:

GLUT 3:

GLUT 4:

GLUT 1: brain

GLUT 2: beta cells of pancreas, liver

GLUT 3: brain

GLUT 4: skeletal muscle, adipose tissue

What are the functions of the following:

GLUT 1:

GLUT 2:

GLUT 3:

GLUT 4:

GLUT 1: transport across the BBB

GLUT 2: regulation of insulin release and other aspects of glucose homeostasis

GLUT 3: uptake into neurons

GLUT 4: insulin-mediated glucose uptake

What are the effects of insulin on the liver?

insulin promotes glucose uptake in live

not by affecting a transport but stimulates phosphorylation and trapping of glucose in the cell (glucose-6-phosphate)

- promotes glucose storage as glycogen

- promotes glucose metabolism for ATP

- inhibits glycogenolysis and gluconeogenesis

What are the effects of insulin on skeletal muscle?

required for glucose transport into the cell

allows for glucose utilization for ATP

increased glycogen synthesis

increases protein synthesis

inhibits breakdown of proteins

What are the effects of insulin on adipose tissue?

required for glucose transport into the cell

glucose used to make glycerol for esterification of fatty acids

inhibits breakdown of fat

allows for glucose utilization for ATP