Endocrine pharmacology

Question 1

GH is associated with:

Answer 1

Height growth, calcium retention, strengthening of bone, increase in muscle mass, promotion of lipolysis, increased protein synthesis, and growth (anabolic processes).

Question 2

Pituitary dwarfism

Answer 2

• Pituitary gland may not secrete sufficient growth hormone either due to lesion or no known cause.
• In pygmies, pituitary dwarfism may occur with normal GH levels; receptors on the bone may fail to function normally.
• Disorders on cartilage, general or specific bones, vertebrae, etc. have been cited, with GH being a key player.

Question 3

Early Pituitary Gland Tumours: Gigantism

Answer 3

Benign pituitary tumors in adults can lead to
overgrowth of the extremities, swelling of soft-tissue, abnormalities in jaw structure and cardiac disease (95% of cases).

Question 4

Late Pituitary gland tumors: Acromegaly

Answer 4

Acromegaly is often the result of pituitary tumours, and thus treatments include surgical removal of pituitary tumors, radiation treatment, and growth hormone antagonists, such as octreotide, an analog of naturally occurring GH receptor antagonist, somatostatin.
Surgery has a good success rate, however, damage to adjacent tissue may require lifetime pituitary hormone replacement.

Question 5

Insulin preparations

Answer 5

• As insulin is a protein, it is degraded by the digestive enzymes. This requires the injection of insulin for effective delivery.
• Short, rapid acting – soluble insulin; insulin lispro/aspart; does not form hexamers.
• Intermediate acting – isophane insulin
• Long acting – insulin glargine

Question 6

Hexamers

Answer 6

• Human insulin, in the presence of Zn2+ ions, self-associates into hexamers.
• This is physiologically useful, as a hexamer is much smaller than 6 monomers, so
packing in the secretory granules of the beta cells is better.
• However, hexamers are too large for diffusion across the cell membrane for absorption into circulation.
• Short-acting insulin formulations have a reduced tendency to form hexamers; they are more likely to be mono- or dimers.
• By removing the dissociation step, absorption is much more rapidly achieved

Question 7

Insulin structure

Answer 7

Insulin lispro and aspart are fast-acting as they have reduced self-association after injection. has reversed two amino acids relative to control, creating charge repulsion and steric hindrance between beta-pleated sheets in the beta chains, favouring monomers.
has two extra arg residues on the B chain, with a glycine on the A chain to stabilise.
promotes reversible binding of insulin to albumin, delaying its absorption from blood.

Question 8

Day to day control of T1 DM

Answer 8

• Patients adjust the timing and proportions of short/intermediate or long-acting insulin.
• A typical regimen is twice daily injections of soluble insulin (peak effect 2-4 hours, duration of action 6-8 hours) combined with an intermediate or long-acting preparation.
• For tighter control, use soluble or short-acting insulin lispro shortly before meals.

Question 9

Treatment for T2DM

Answer 9

Diet and physical activity are major factors in the control of blood glucose levels.
For overweight patients, weight control can have a significant effect on insulin resistance. Thus, weight loss can increase insulin sensitivity and improve glucose homeostasis.
For some patients, the combination of low sugar in diet and exercise can maintain their health without the need of medications.
Monitoring fasting glucose levels is crucial, and should maintenance not be achieved, medication may be used to assist.
Diet and exercise, however, should ALWAYS be encouraged in diabetic patients.

Question 10

Blood glucose lowering medicines: MOA

Answer 10

Liver: Biguanides and thiazolidinediones reduce glucose productions

Pancreas: GLP-1 (incretins) improve response to glucose level.
Insulin secretagogues: sulphonylureas and meglitinides increase insulin production.

Small intestine: Alpha-glucosidase inhibitors slow absorption of sucrose and starch

Skeletal muscle/adipose tissue: Thiazolidinediones and biguanides reduce insulin resistance

Question 11

Oral Hypoglycaemic Drug Classes for Diabetes Type 2

Answer 11

Sulphonylureas: Stimulate release of insulin from pancreas; enhance cellular glucose uptake.

Biguanides: Inhibit pancreatic gluconeogenesis; slow glucose absorption from the gut; enhance cellular glucose use

Alpha-glucosidase inhibitors: Slow glucose absorption from gut

Thiazolidinediones: Insulin sensitizers; enhance cellular glucose use

Question 12

Sulphonylureas: Insulin secretagogues

Answer 12

Effective in about 30% of patients, sulphonylureas work as antagonists on the ATP-sensitive potassium ion channels on the beta cells of the pancreas.

By blocking these channels, the beta cells depolarise, allowing for the inward flow of calcium ions and the release of insulin. By stimulating insulin release, maximal uptake of glucose is hoped.

Question 13

Biguanides: Insulin sensitizers

Answer 13

Metformin activates AMPK, the cellular energy sensor
Activation of AMP-K reduces hepatic glucose production, and increases the peripheral sensitivity insulin sensitivity and utilisation and uptake of glucose in skeletal muscle.

In the obese insulin-resistant state, hepatic lipid accumulation leads to activation of PKC-ε and its suppression of insulin receptor signaling. Metformin increases intracellular AMP, which activates AMPK to phosphorylate and inhibit ACC1 and ACC2, thereby preventing hepatic synthesis of fatty acids.
Lowered lipid stores result in loss of PKC-ε–mediated suppression of insulin receptor signaling, and a more effective blockade of gluconeogenesis.
Thus, by reducing hepatic lipid accumulation, ACC inhibition results in lowering of glucose levels in the blood.

Question 14

By targeting AMPK, a number of effects are generally positive in glucose:

Answer 14

Liver: reduced fatty acid and cholesterol synthesis. Increased lipid oxidation. Reduced gluconeogenesis

Skeletal muscle: increased lipolysis and lipogenesis

Heart: Increased fatty acid uptake and oxidation. Increased glucose uptake and glycolysis

This leads to weight loss, increased insulin sensitivity, improved vascular function

Question 15

Alpha-glucosidase inhibitors

e.g. acarbose

Answer 15

a-Glucosidase inhibitors are competitive, reversible inhibitors of pancreatic a-amylase and membrane- bound intestinal a-glucosidase hydrolase enzymes.

This thus blocks enzymatic degradation of complex carbohydrates in the small intestine, delaying and reducing the overall absorption.

In general, these drugs lower glucose levels without risk for weight gain or hypoglycemia.

Unfortunately, these drugs have gastrointestinal side effects that often limit their acceptance.

Question 16

Thiazolidinediones (TZDs): ligands for the transcription factor PPARγ receptors

Answer 16

TZDs as “insulin sensitizers”: PPARγ (peroxisome proliferator-activated receptors, subtype gamma) is expressed in multiple tissue types (e.g. skeletal muscle, fat & liver). PPARγ stimulation upregulates the expression of genes involved in lipid & glucose metabolism, insulin signal transduction, and adipocyte differentiation.

One such mechanism contributing to the hypoglycemic effect of TZDs is an increased expression of the glucose transporter GLUT4. The increased expression of GLUT4 (in addition to mediators of insulin signal transduction) increases the ability of cells (e.g. adipocytes) to take up glucose when stimulated by insulin.

Question 17

7 steps in inflammation: injury response

Answer 17

1. Bacteria and other pathogens enter the wound
2. Platelets from blood release blood-clotting proteins at wound site
3. Mast cells secrete factors that mediate vasodilation and vasoconstriction. Delivery of blood, plasma and cells to injured area increases
4. Neutrophils secrete factors that kill and degrade pathogens
5. Neutrophils and macrophages remove pathogen by phagocytosis
6. Macrophages secrete hormones called cytokines that attract immune system cells to the site and activate cells involved in tissue repair.
7. Inflammatory response continues until the foreign material is eliminated and the wound is repaired.

Question 18

Inflammation: What is underlying mechanism of interest?: SAIDS

Answer 18

Steroidal Anti-Inflammatory Drugs (SAIDS).

• Corticosteroids indirectly inhibit PLA2- via a protein call annexin-1.
• This reduces PLA2 activity and prevents the production of all subsequent steps; leading to reduced inflammation.

Question 19

How do corticosteroids work?

Answer 19

• they are hydrophobic so they easily pass through cell membrane
• once inside cell, they bind to glucocorticoid receptors, and this complex moves into nucleus
• Induction of mRNA expression for annexin
• Inhibition of prostaglandin and leukotriene synthesis
• Corticosteroids have many and major adverse side effects so long-term use is not encouraged.

Question 20

Long-term adverse effects of glucocorticoids

Answer 20

• cataracts in rheumatoid arthritic patients receiving 20mg of prednisone/day for 4 years, >50% will develop cataracts;
• Inhibits tissue growth, especially in children;
• Patients may become immunosuppressed with chronic use.

Brain - mental disturbances
Cushing's syndrome and hypertension 
Stomach - dyspepsia
Suppression of HPA axis
Vertebrae: osteoporosis

Question 21

NSAIDS

Answer 21

NSAIDS inhibit cyclo-oxygenase (COX) enzymes,

• thus inhibiting prostaglandin syntheses, and thereby reducing inflammation.

Question 22

Osteoclast differentiation: regulated by osteoblasts

Answer 22

Osteoclast precursor cells express RANK receptor, while osteoblasts express RANKL, a cytokine (RANK Ligand).

RANKL works via a range of second
messenger pathways to promote osteoclast maturation.

Osteoprotegerin (OPG) is also secreted by osteoblasts as a decoy receptor for RANKL, thus inhibiting RANK/RANKL interaction.

The ratio of RANKL:OPG expressed by osteoblasts dictates osteoclast differentiation and activity; ratio is determined by systemic hormones (oestrogen and PTH), glucocorticoids, IL-1 and PE2.

In postmenopausal women, with oestrogen decline, expression of RANKL ligand increases. This leads to increased osteoclast formation and function, with osteoblasts being insufficient to replace lost matrix. This results in increased bone loss, weakening architecture, and bone fracture.

Question 23

How to pharmacologically treat osteoporosis?

Answer 23

• First choice for post-menopausal women: bisphosphonates.

General MOA: decrease of osteoclast-mediated bone resorption by interfering with recruitment, differentiation and inhibition of the effects of enzymes on the cell’s ruffled border. As bisphosphonates are absorbed by osteoclasts, apoptosis results.
In clinical trials, this drug class has achieved greater BMD increases than any other.

Question 24

Bisphosphonates

Answer 24

• These drugs reduce risk of fracture by increasing bone density and reducing the turnover of bone.
• On average, these drugs lead to an increase in bone density by approximately 4-8% at the spine and 1-3% at the hip over the first 3-4 years of treatment, and reduce the incidence of vertebral fractures by as much as 30- 65% and in the hip by as much as 25-50%.
• Treatment duration is uncertain, but half-life in bone may be 10+ years.

Adverse effects:
Alendronate – irritation of oesophagus, gastric mucosa, dyspepsia, heartburn, nausea or vomiting.
No drug interactions reported. Contraindicated for patients with oesophageal pathology.

Question 25

zoledronic acid (5 mg) (IV bisphosphonates)

Answer 25

Ensure sufficient intake of
vitamin D, calcium
• Ensure effective renal clearance
• Vertebral fractures reduced by 70%, hip fractures by 40%, non vertebral fractures by 25% over 3 years; 100% enters bones.
• Effective in all ages of women trialled (65-89 years)
• No oesophageal issues imposed, and patients with gastic reflux, malabsorption, and IBD can use.

Question 26

Concerns for IV bisphosphonate use

Answer 26

• Osteonecrosis of the jaw
• Risks are 1:100 while on bisphosphonate for osteoporosis.
• Try to have preventative dental work done prior to starting IV bisphosphonate.
• Flu-like cluster of symptoms in up to 20% of patients; low-grade fever, nausea, increased bone pain, arthralgia or myalgia. (occurs after first and second infusions within 24 hours, usually abates by third infusion.)

Question 27

Oestrogen Replacement Therapy

Answer 27

Oestrogen deficiency results in high bone turnover and accelerated bone loss leading to increased risk of fragility fracture.

Oestrogen replacement therapy reverses these skeletal effects, but its detrimental actions on other tissues preclude its use in osteoporosis prevention and treatment.

These other effects include increased risk of coronary heart disease, breast cancer, and thromboembolic disease.

Question 28

Selective estrogen receptor modulators (SERMs)

Answer 28

Selective ER modulators (SERMs) exhibit varying degrees of ER agonist activity, leading to tissue selectivity.

The second-generation SERM raloxifene is used as a second-line treatment for osteoporosis and reduces vertebral fracture risk with protective effects against breast cancer. However, it has a similar risk of thromboembolic disease to estrogen.

Question 29

Raloxifene

Answer 29

MOA: agonist on oestrogen receptors on bone and antagonistic effects on other oestrogen-receptive tissues such as breast and endometrium.

Increases BMD in postmenopausal women, but less so than oestrogen.

In women with osteoporosis, it decreases risk of vertebral fractures, but not risk of non-vertebral fractures.

Is a viable option for women who are at risk of breast cancer, and so do not wish to use supplemental oestrogen.

Use for more than 5 years indicates that there is decreased breast cancer with raloxifene without increasing risk for endometrial cancer.

Increases risk of thromboembolic disease similar to that found with hormone replacement therapy (HRT).
Precautions: History of VTE contraindicated

Question 30

Denosumab

Answer 30

Immunotherapy treatment: denosumab, which is a human monoclonal IgG1 antibody which binds tightly to RANKL, preventing RANK from being activated.

Question 31

Teriparatide

Answer 31

Intermittent use stimulates osteoblasts more than osteoclasts. By mimicking this effect of parathyroid hormone, teriparatide aims to stimulate bone formation in patients with osteoporosis.

Teriparatide increases vertebral BMD and decreases risk of vertebral fractures in postmenopausal women with established osteoporosis;