PHA 6115 LEC - ENDOCRINE DRUGS

Endocrine System

- composed of several hormone-releasing organs

Hormones

- endocrine system which maintains body functions and homeostasis by releasing ____________________ which are used for several body functions like growth, reproduction and defense

Endocrine Drugs

- usually work like hormones as a natural, semi synthetic or synthetic compound.

replacement therapy, treatment for disorders, and diagnostic purposes

- primary use of endocrine drugs

Based on Structure:
- peptide (majority and steroidal (adrenal ckrtex/sex hormones)

Based on Function
- releasing hormones
- stimulating hormones
- Thyroid and pancreatic hormones, and adrenal hormones (mineralocorticoids, glucocorticoids, and sex hormones)

classification of endocrine drugs and its sub-classification

Anti-Diabetic Agents

Insulin and Other Anti-hyperglycemic Agents

Diabetes

is a complex disease characterized by uncontrolled glucose homeostasis associated with several minor and major complications.

3 Cardinal signs of Diabetes

Polyuria (excessive urine)
Polyphagia (excessive eating)
Polydipsia (thirstiness)

Diabetes Mellitus Type 1
Diabetes Mellitus Type 2
Gestational Diabetes
Secondary Diabetes Mellitus

Types of Diabetes

Diabetes Mellitus Type 1

Insulin-dependent; has a juvenile onset, patients require insulin therapy for their lifetime.

Diabetes Mellitus Type 2

Insulin-independent; has a adult onset (commonly), patients may or may nor require insulin therapy.

Gestational Diabetes

glucose intolerance during pregnancy

Secondary Diabetes Mellitus

Results for non-usual causes or from other diseases present in the patient

True

T or F: Therapy is directed at maintaining euglycemic states (normal blood sugar)

Insulin

is a 51-amino acid protein with two chains linked by a disulfide bond.

Beta cell of the pancreas

insulin is produced by which?

MOA of Insulin

transports glucose into adipose and muscle cells by releasing glucose transporter (GLUT 4)

SAR of Insulin

- N- and C- terminals of the amino acid Chain A and B are essential for insulin receptor binding.

- produced via proteolytic modifications of proinsulin

Classification and Pharmacokinetics of Insulin Preparation (Types)

Rapid-acting
Short-acting
Intermediate-acting
Long-acting

Rapid-Acting (Examples)

Lispro, Aspart, Glulisine

Short-Acting (examples)

Human Insulin (Regular)

Intermediate-Acting(examples)

Lente, NPH* insulin (isophane)

Long-acting

Ultralente, Glargine, Detemir

Insulin secretagogues

are agents that stimulate the release of insulin from the beta cells of the pancreas.

Insulin secretagogues (Agents)

Sulfonylureas (pharmacophore) and Meglitinides

Sulfonylureas MOA

binds to sulfonylurea receptor type 1 (SUR1) at ATP-sensitive K-channel and opens the voltage-gated Ca-channel leading to increased intracellular Ca and exocytotic release of insulin

Sulfonylureas SAR (1st generation)

small lipophilic at R1, alkyl/cyclic substituent at R2;
high dose
long plasma T1/2
short DOA
high chance for ADR (hypoglycemia)

Sulfonylureas SAR (2nd generation)

has large p-(β-arylcarboxyamideoethyl) group at R1
high potency
rapid onset
short plasma T1/2
Long DOA

First Generation (Sulfonylurea)

Tolbutamide
Chlorpropramide
Acetohexamide

Second Generation (Sulfonylurea) (Gli-)

Glyburide/Glibenclamide
Glipizide
Glimepiride

Meglitinides MOA

similar to sulfonylureas
Repaglinide binds also to SUR1, SUR2A and SUR2B leading to extrapancreatic effects

Meglitinides SAR

Meglitinide is a prototype structure - it is a benzoic acid derivative of the non-sulfonylurea moiety of glibenclamide/glyburide

Meglitinides Metabolism (Repaglinide)

CYP 2C8 and 3A4 hydroxylation of piperidine ring and glucuronidation

Meglitinide Metabolism (Nateglinide)

CYP 2C9 (70%) and 3A4 hydroxylation of isopropyl moiety

Meglitinide Drugs

Repaglinide
Nateglinide

Repaglinide

rapid onset
short DOA
does not cause prolonged hyperinsulinemia

Nateglinide

rapid onset
longer DOA

Biguanides

1st line treatment with lifestyle change. It is highly distributed and excreted unchanged in the urine.

Biguanides MOA

decreases glucconeogenesis
increases glycogenolysis and glycoslysis
increases insulin sensitivity

Biguanides SAR

structure is made of 2 linked guanidine moiety

Metformin

only biguanide approved for use
may cause GI discomfort, lactic acidosis, metallic taste

Insulin Sensitizers/PPAR-Agonists (MOA)

PPAR controls gene expression
PPARɣ (gamma) agonist increase glucose transporter expression leading to increasing insulin sensitivity of the body
slows down gluconeogenesis and lower systematic fatty acids

Insulin Sensitizers/PPAR-Agonists (SAR)

it has a thiazolidinedione pharmacophore

For agonist activity: R must be a para- substituted phenyl ring attached to the pharmacophore with a methylene bridge.

Insulin Sensitizers/PPAR-Agonists (Metabolism)

CYP2C9 (most metabolites are still possess agonist activity)

Insulin Sensitizers/PPAR-Agonists (Drugs) (-glitazone)

Pioglitazone
Troglitazone
Rosiglitazone

Pioglitazone

only available "glitazone" in the market
useful for patients that cannot tolerate sulfonylurea or metformin

Troglitazone

not used due to severe hepatoxicity

Rosiglitazone

limited availability dur to increase cardiovascular effects

Alpha-Glucosidase Inhibitors (α-glucosidase)

is an enzyme made of maltase, sucrase, isomaltase, and glucoamylase found in the small intestine

Alpha-Glucosidase Inhibitors (MOA)

inhibits α-glucosidase to inhibit carbohydrates breakdown which prevents absorption of mono/disaccharides leading to inhibition of post-prandial hyperglycemia

Alpha-Glucosidase Inhibitors (SAR)

inhibitors mimic the natural substrates of a α-glucosidase by having similar structures

Alpha-Glucosidase Inhibitors (Drugs)

Acarbose
Voglibose
Miglitol

Acarbose

extremely low oral bioavailability

Voglibose

poorly absorbed

Miglitol

absorbed orally, not metabolized
excreted unchanged

Glucagon-like Peptide-1 (GLP-1)

is a 30-31 amino acid peptide produced by prohormone convertase enzymes from proglucagon. It is indicated for additional therapy with sulfonylurea or metformin to reach HbA1c

GLP-1 MOA

GLP-1 is released from L-cells of GIT in response to food.
GLP-1 promotes insulin secretion from pancreas

GLP-1 SAR

GLP-1 agonist analogs have penultimate amino acid modification to resist metabolism by Dipeptidyl peptidase IV (DPP-IV)

GLP-1 Agents (-glutide)

Exenatide
Liraglutide
Albiglutide
Dulaglutide

Exenatide modification

Penultimate Ala - Gly

Liraglutide modification

Lys28 has a α-glutamoyl-(N-α-hexadaconyl)

Lys84 is replaced by Arg84

Albiglutide modification

fusion of 2 modified GLP-1 to albumin

Dulaglutide modification

fusion of 2 N-terminal GLP-1 analog to IgG4 Fc domain

Exenatide (remarks)

first isolated, self-regulating, longer T1/2 than GLP-1

Liraglutide (remarks)

T1/2 is 11 hours = ↑ albumin binding, may cause medullary thyroid cancer or multiple endocrine neoplasia syndrome.

Albiglutide and Dulaglutide (remarks)

T1/2 is 5 days = albumin moiety, may cause meduallary thyroid cancer or multiple endocrine neoplasia syndrome

Dipeptidyl Peptidase IV Inhibitors (DPP IV Inhibitors ) MOA

binds to the active serine site in DPP-IV, alternatives to GLP-1 agonist analogs

α-aminoacylpyrrolidine, xanthine, and pyrimidine-2,4-dione

3 pharmacophore structure of DPP IV Inhibitors (SAR)

True

T or F: The cyano group binds to the active serine site in DPP-IV (SAR)

True

T or F: DPP IN Inhibitors can be taken alone or with metformin or thiazolidinedione and rarely causes hypoglycemia.

DPP IV Inhibitors (Drugs) (-gliptin)

Sitagliptin
Alogliptin
Saxagliptin
Vildagliptin
Linagliptin

Sitagliptin

has piperazine fused pyrazole with α-aminoacyl moiety

Alogliptin

pyrimidine-2,4-dione pharmacophore

Saxagliptin and Vildagliptin

α-aminoacylpyrrolidine pharmacophore

Linagliptin

xanthine pharmacophore

Amylin

is a 37-amino acid hormone released with insulin

Amylin Agonist MOA

suppress glucagon secretion, delaying gastric emptying time, to modulate appetite centers which aids in maintaining glucose plasma level.

Pramlintide

amylin agonist analog (SAR)
Proline replacement for Ala25, Ser28, Ser29

Sodium Glucose Cotransporter (SGLT2) Inhibitor

aids in reabsorption of glucose from renal proximal tubules

Not recommended for Type 1 diabetes and patients with renal impairment

SGLT2 MOA

inhibit SGLT2 leading to decreased renal threshold for glucose which results to increased urinary glucose excretion.

SGLT2 SAR

It has a phlorizin pharmacophore and a glucose moiety that binds to Thr156 and Lys157 moiety of the transporter.

SGLT2 Drugs

Phlorizin (pharmacophore w/ glucose)
Empagliflozin
Dapagliflozin
Canagliflozin

Recommended pharmacotherapeutic management of diabetes at diagnosis

study slide 28

Thyroid Hormones and Thyroid Drugs

Thyroid Hormones
Thyroid Agents
Anti-thyroid Agents

Thyroid gland

the only mammalian organ that can incorporate iodine into organic molecule and is the source thyroxine (T4) and triiodothyronine (T3)

Thyroxine (T4) and Triiodothyronine (T3)

these hormones are needed for fetal development and adult metabolism.

overactivity (hyper-) or under activity (hypo-)

TSH, T3, and T4

disorders associated to thyroid function are usually due to what activity and diagnose through what levels

hormone replacement therapy and/or antithyroid drugs

medications for thyroid glands

Thyroxine Metabolism (inactivation)

Deamination
Decarboxylation conjugation (glucuronide or sulfate)

Thyroxine Deiodination

Activation : 3,5,3'-Triidothyronine (T3)

Inactivation: 3,3'5'-Triiodothyronine (reverse T3)

Integumentary (Hypothyroidism)

Pale, cool skin (reduced secretions), brittle hair and nails

Integumentary (Hyperthyroidism)

Warm, moist skin (more secretions), Plummer's nails, pretibial dermopathy

CV (Hypothyroidism)

Bradycardia, reduced cardiac output

CV (Hyperthyroidism)

Tachycardia (most prominent), increased cardiac output

Respiratory (Hypothyroidism)

Pleural effusions, hypoventilation

Respiratory (Hyperthyroidism)

Dyspnea

CNS (Hypothyroidism)

Lethargy, slowing of mental processes

CNS (Hyperthyroidism)

Nervousness, tremor

GIT (Hypothyroidism)

Reduced appetite

GIT (Hyperthyroidism)

increased appetite