Pancreatic Hormones and Antidiabetic Drugs

Antidiabetic Drugs

Insulin

Sulfonylureas

Meglitinides

Biguanides

Thiazolidinediones

A-Glucosidase Inhibitors

GLP-1 Agonists

Dipeptidyl Peptidase 4 inhibitors

Amylin Analogs

SGLT-2 Inhibitors

Polypeptide hormone produced by the pancreatic beta cell

insulin

Insulin synthesis and release are modulated by the following proponents and pathways:

proponents:

Glucose

Amino acids, fatty acids, and ketone bodies

Islets of Langerhans

pathways:

a-adrenergic pathways

B-adrenergic stimulation

Elevated intracellular Ca2+ acts

– most important stimulus for insulin synthesis and release

Glucose

pathway that inhibit secretion of insulin – the predominant inhibitory mechanism

a-adrenergic pathways

pathway that increases insulin release

B-adrenergic stimulation

MOA:

• Binds to the extracellular domain of specific high-affinity receptors (with tyrosine kinase activity) on the surface of liver, muscle, and fat cells.

• specific tyrosine residues of the insulin receptor become phosphorylated which will lead to a signal transduction cascade.

Insulin

Actions of insulin for K+, liver, and muscles

• Insulin promoted systemic cellular K+ uptake

• Liver: inhibits glucose production

• Muscle: Increase glycogen deposition

how are insulin preparations classified

by the timing of its action in the body, including the onset of action and duration of action

Indications of insulin preparations:

used to treat all manifestations of hyperglycemia in both type 1 (insulin-dependent) and type 2 (non-insulin dependent) diabetes mellitus

Adverse effects of insulin preparations

• hypoglycemia: symptoms include tachycardia, tremor, sweating, confusion, agitation, and in more severe cases, loss of consciousness or coma

• Hypokalemia, hypertrophy of the SC fat at the injection site, weight gain

Rapid-acting onset, peak and duration, and directions for use?

10-30mins; 30-90mins; 3-5hrs

directions: Usually taken immediately before a meal to cover the blood glucose elevation from eating ; Often used with longer-acting insulin

examples of rapid-acting insulin preparations?

GluLisAsp

Insulin aspart, Insulin glulisine, Insulin lispro

Short-acting onset, peak and duration, and directions for use?

30-60mins; 2-4 hrs; 6-12hrs

Directions: Usually taken immediately before a meal to cover the blood glucose elevation from eating ; Often used with longer-acting insulin

example of short-acting insulin prep?

Regular Insulin

Intermediate-acting onset, peak and duration, and directions for use?

1-3hrs ; 4-8hrs; 12-16hrs

Directions for use: Often combined with rapid-or short acting insulin

example of intermediate-acting insulin prep?

Insulin NPH

Long-acting onset, peak and duration, and directions for use?

1-2hrs; Minimal; Up to 24 hrs;

Directions: Often combined with rapid-or short acting insulin

insulin preparations that lower blood glucose levels when rapid-acting insulin stops working

• Long-acting insulin preparations

  (Insulin determir ; Insulin glargine)

• Ultra-long acting insulin preparations

  (Insulin degludec)

examples of long-acting insulin preparations:

GlaDeter

Insulin determir Insulin glargine

Ultra-long acting onset, peak and duration, and directions for use?

Not available; Minimal; Up to 42 hrs

Directions: Often combined with rapid-or short acting insulin ; they lower blood glucose levels when rapid-acting insulin stops working

• These agents are modified with different amino acid residues to make them more soluble, allowing them to rapidly dissociate into monomers

• They are often injected minutes before a meal and provide better postprandial control of glucose levels than regular insulin

Rapid-acting insulin preparations

Regular crystalline insulin naturally self-associates into a hexameric molecule (6 insulin molecules) when injected SQ. before it is absorbed, it must dissociate to dimers and then to monomers

Short-acting insulin preparations

This insulin is modified with the addition of protamine, which prolongs the time required for absorption and increases the duration of action

Intermediate-acting insulin preparations

Insulin NPH, NPH stands for?

neutral protamine Hagedorn

These agents were modified to mimic basal insulin secretion and have a steady release with no peak effect

Long-acting

Dosing considerations of insulin preparations

(and why?)

Patients with type 2 DM may require higher doses of insulin, due to insulin resistance - presence of honeymoon phase in T1DM patients

• may occur in patients recently diagnosed with Type 1 DM

• It occurs when beta cells in the pancreas can still secrete enough endogenous insulin to aid in blood glucose control, resulting in reduced exogenous insulin requirement

Honeymoon phase

• Oftentimes with acute illness, there is an increase in cortisol, which causes an elevation in blood glucose

• Patients with an acute illness may require higher insulin doses

Acute illness

1st generation of sulfonylureas

“-amide”

Tolbutamide, chlorpropamide, tolazamide

2nd generation sulfonylureas

“-ride/-zide”

Glyburide, glipizide, glimepiride

both gens are equally effective in lowering blood glucose

sulfonylureas

2nd generation agents are prescribed more often ; they are more potent and have fewer adverse effects and drug interactions

sulfonylureas

Indications of sulfonylureas

Approved for the management of adults with Type 2 DM since they require functional pancreatic beta cells to produce their effect on blood glucose;

NOT FOR TYPE 1 DM

MOA:

• These agents are oral insulin secretagogues ; they cause insulin release from pancreatic beta cells

• They bind to the SUR1 (sulfonylurea receptor), and block ATP- sensitive K+ channels resulting in depolarization. The voltage gated Ca2+ channels open, resulting in Ca2+ influx and triggering the insulin release

• Long term use also reduces serum glucagon, which may contribute to hypoglycemic effects

sulfonylureas MOA

AEs of sulfonylureas

hypoglycemia, weight gain

Precautions of sulfonylureas

caution must be used in patients with hepatic or renal dysfunction ; caution must also be used in patients with a sulfa allergy

Meglitinides

“-linide”

Repaglinide, Nateglinide

MOA: They are oral insulin secretagogues ; Have similar action to sulfonylureas, but they bind to distinct regions on the SUR1 molecule

Meglitinides (Repaglinide, Nateglinide)

indications of Meglitinides (Repaglinide, Nateglinide)

• Approved for Type 2 DM

• Since they have fast onset and short duration of action, they are recommended in patients with irregular meal schedules and in patients who develop late postprandial hypoglycemia when taking a sulfonylurea

• They are used instead of sulfonylureas in patients with a history of sulfa allergy

Adverse effects of Meglitinides (Repaglinide, Nateglinide)

hypoglycemia

what Meglitinides has an AE of weight gain?

Repaglinide

Metformin is what class of drug?

biguanides

Indication of Biguanides

Indication: Type 2 DM

MOA:

• It reduces the hepatic glucose production and intestinal absorption of glucose; it does not alter insulin secretion. These effects are believed to be due to an increase in the activity of AMP kinase, a key intracellular regulator of energy homeostasis.

• Also increases peripheral insulin sensitivity

• Its glucose lowering action does not depend on functional pancreatic beta cells

Biguanides MOA

Does metformin alter insulin secretion?

NO.

It reduces the hepatic glucose production and intestinal absorption of glucose: Biguanides

Advantages of biguanides: metformin

rarely causes hypoglycemia and weight gain

Adverse effects of Biguanides

GI distress, has potential to cause lactic acidosis (characterized by nonspecific symptoms: NV, abdominal pain, lethargy, hyperventilation, and hypotension)

Contraindications of Metformin/Biguanides

• Due to an increased risk of lactic acidosis, metformin should not be used in patients with CHF, renal impairment, or who are seriously ill

• Metformin should be temporarily discontinued before iodinated contrast, due to the potential for acute kidney injury and increased risk for lactic acidosis

(picture reference of what iodinated contrast means)

Thiazolidinediones

“-litazone”

Pioglitazone, Rosiglitazone

Indications: Type 2 DM

Pioglitazone, Rosiglitazone

MOA:

• These agents are insulin sensitizers; they act to decrease insulin resistance

• They bind to a specific intracellular receptor, PPAR-y (peroxisome proliferator-activated receptor-gamma), a member of the nuclear-receptor family

• They predominantly affect liver, skeletal muscle, and adipose tissue

  • In the liver, these agents decrease glucose output and insulin levels

  • In muscle, these agents increase glucose uptake

  • In adipose tissue, these drugs increase glucose uptake and decrease fatty acid release and may increase the release of hormones such as adiponectin and resistin

• The actions of these drugs require the presence of insulin

• Can reduce plasma glucose and TG

Thiazolidinediones MOA

Thiazolidinediones indication

Type 2 DM

Adverse Effects of Thiazolidinediones

edema, weight gain

Precautions of Thiazolidinediones

cause an increased risk for fractures and bladder cancer, can cause or exacerbate CHF

Contraindications of Thiazolidinediones

heart failure, liver disease

A-glucosidase inhibitors

Acarbose, Miglitol

MOA:

• Act as competitive, reversible inhibitors of pancreatic a- amylase and intestinal a-glucosidase enzymes; they act in the lumen of the intestine

• Inhibition of a-glucosidase prolongs the digestion of carbohydrates and reduces peak plasma glucose levels

A-glucosidase inhibitors (Acarbose, Miglitol) MOA

Indications of A-glucosidase inhibitors (Acarbose, Miglitol)

Type 2 DM ; helpful in reducing postprandial glucose

Adverse effects of A-glucosidase inhibitors (Acarbose, Miglitol)

GI distress and flatulence

CI of A-glucosidase inhibitors (Acarbose, Miglitol)

intestinal diseases such as intestinal obstruction & inflammatory bowel disease (IBD)

Glucagon-like Peptide-1 agonists

“-natide, -glutide”

Exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide

Indication of GLP-1 agonists

Type 2 DM ; also cause weight loss

GLP-1 agonist that is tx for T2DM and causes weight loss

Liraglutide

Adverse effect of GLP-1 agonists

GI distress

Precautions of GLP-1 agonists

increased risk for acute pancreatitis and thyroid tumors

• Analogs of the hormone incretin (GLP-1)

• Increase glucose-dependent insulin secretion; decrease inappropriate glucagon secretion, slow gastric emptying, decrease food intake, and promote B-cell proliferation

GLP-1 agonists MOA

“-liptin”

Sitagliptin, saxagliptin, linagliptin

DPP-4 inhibitors: Dipeptidyl peptidase 4 inhibitors

Indications:

• Type 2 DM

DPP-4 inhibitors

AEs of DPP-4 inhibitors

rhinitis and URTI ; may cause pancreatitis

MOA:

• DPP-4 is responsible for the proteolysis of incretins, including GLP-1 and glucose-dependent insulinotropic peptide

• These agents inhibit DPP-4 to increase active incretins. This leads to an increase in insulin synthesis and release and suppresses glucagon production in a glucose-dependent manner.

DPP-4 inhibitors MOA

amylin analogs

Pramlintide

Amylin analogs: Pramlintide indication

used in combination with insulin for Type2 DM

Amylin analogs: Pramlintide AEs

nausea, hypoglycemia, gastroparesis

MOA:

• Amylin is a polypetide stored and secreted by beta cells of the pancreas ; it is cosecreted with insulin to reduce blood sugar. Concentrations are abnormally low in patients with DM.

• Pramlintide can reduce postprandial glucose through prolongation of gastric emptying, reduction of prostprandial glucagon secretion, and reduction of caloric intake through centrally mediated appetite suppression.

• Causes weight loss and reduces postprandial glucose levels

Amylin analogs: Pramlintide MOA

SGLT-2 inhibitors

Canagliflozin, empagliflozin, dapagliflozin

SGLT-2 inhibitors

Indications: Type 2 DM

advantages of SGLT-2: Canagliflozin, empagliflozin, dapagliflozin

weight loss and a modest decrease in BP

Adverse effects of SGLT-2 inhibitors

include genitourinary infections and increased serum potassium

CI of SGLT-2 inhibitors

severe renal impairment

MOA:

• SGLT2 is the main site of filtered glucose reabsorption

• These agents inhibit SGLT2 in the proximal renal tubules; this results in reduced reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RTG)

• Reduction of filtered glucose reabsorption and lowering of RTG results in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.

SGLT2 inhibitors MOA

hyperglycemic agents

glucagon

diazoxide

MOA:

• Stimulates adenylate cyclase to produce increased cAMP

• It increases blood glucose by stimulating glycogenolysis and gluconeogenesis in the liver

• In general, its actions oppose the actions of insulin

• Large doses produce marked relaxation of the smooth muscle in the stomach, intestines and colon.

glucagon

MOA: this agent opens ATP-dependent potassium channels on pancreatic beta cells, resulting in inhibition of insulin release.

diazoxide

indication of diazoxide

hyperinsulinemic hypoglycemia

diazoxide AEs

sodium retention, GI distress, and changes in circulating white blood cells