Quiz #4 (10/28-11/2)

Question 1

VLDL Conversions

Answer 1

VLDL is excreted from the liver and combines with HDL. At this point VLDL is primarily TG content, and B-100 apolipoprotein. As it moves along, it binds to LPL on endothelial cells, this binding releases HDL and lowers the proportion of TG:CE. Subsequent bindings on endothelial cells lowers the ratio of TG:CE until only CE is left which is now called LDL. If B-100 is oxidized it can no longer bind to LDL receptor and is taken up by the SR-B1 scavenger receptor or is added to a plaque.

Question 2

HDL Transport

Answer 2

Selective reuptake pathway. Through LCAT HDL takes up free cholesterol that is released from peripheral tissue. The HDL can either transfer the FC to plasma proteins through CTEP or it is taken up in the liver or steroidogenic tissues by the SR-B1 receptor.

Question 3

TC:HDL Ratio

Answer 3

TC:HDL ratio goal 40.

Not all forms of HDL are helpful, may want HDL3 as it has been shown with an inverse relationship between HDL and CHD incidence.

Question 4

Lipids Treatment: Nicotinic Acid (MOA, effects, use, receptor)

Answer 4

1. decreases lipolysis, increases HDL, cheap option but major side effect is flushing (treatable with aspirin)
2. MOA: Inhibition of AC leads to inhibition of lipolysis, decreased FFA levels. Less VLDL is synthesized and TAG and VLDL levels decrease. Unclear how it raises HDL levels but may be mediated through CETP
3. Effects: raises HDL, lowers LDL, VLDL and TG. Little to no affect on overall rate of cardiovascular deaths.
4. antiinsulinemic and hyperuricemic so not recommended in diabetics.
5. New orphan receptor identification may explain mechanism of action. GRP109A/HM74b coupling to Gi to inhibit adenylyl cyclase. Receptor is expressed in adipocytes

Question 5

CETP function

Answer 5

Forms a hydrophobic tunnel from large particles into HDL. Blockade of CETP causes net higher HDL lipid

Question 6

Lipid Treatments: CETP Inhibitors MOA

Answer 6

dalcetrapib forms a disulfide bond with CETP; torcetrapib stabilizes the association of CETP with its lipoprotein substrate creating a nonfunctional complex.

Question 7

Lipid Treatments: CETP inhibitors Effects

Answer 7

Thought to increase HDL levels 30-106% in normal subjects with low HDL-C levels, though recent trials suggest little or no benefit for dalcetrapib for decreasing CV death

Question 8

Lipid Treatments: CETP inhibitors withdrawn trials

Answer 8

1. Torcetrapib, stopped trial early due to an increase in deaths vs atorvastatin therapy alone. Thought that the deaths are due to increases in aldosterone, but not sure.
2. Dalcetrapib discontinued early due to lack of efficacy and small increase in deaths.
3. Evacetrapib discontinued due to lack of efficacy.
4. Anacetrapib is still in large scale trials. May be more beneficial than the others because data from the trials shows that it also lowers LDL cholesterol in addition to increasing HDL. And lowers Lpa as well.

Question 9

Cholesterol biosynthesis

Answer 9

acetyl-CoA through HMG-CoA reductase to form farnesyl pyrophosphate. Three actions:

1. trans-prenyl transferase: causes protein prenylation
2. formation of squalene which leads to cholesterol formation. Cholesterol causes negative feedback on HMG-CoA reductase
3. formation of Co-Q.

Question 10

Lipids Treatment: Statins Side Effects

Answer 10

Thought that the off-target effects of farnesyl pyrophosphate leads to many of the side effects of statins.

Question 11

Lipid Treatment: Statins MOA

Answer 11

high affinity competitive inhibitor of HMG-CoA reductase. Mimics the structure of an intermediate of the enzymatic pathway

Larger absolute effect than other agents on incidence of nonfatal MI or CHD death, though it takes several years for effects to show.

Question 12

Cholesterol signaling in liver

Answer 12

cholesterol brought into liver cell through B100:LDL and is taken into the lysosome and degraded. High levels of cholesterol produces bile salts and inhibits cholesterol synthesis and LDL receptor synthesis

Question 13

Lipid Treatments: Bile Resins MOA

Answer 13

physically remove cholesterol

MOA: bile salts are released from the liver to break down TG into micelles to be brought into body. Bile resins decrease the absorption of cholesterol into the blood stream and lowers serum cholesterol because they bind to bile salts and remove them from the blood, altering the cholesterol feedback loop to lower internal free cholesterol in the liver.

Question 14

Lipids Treatment: Fibric Acid

Answer 14

Effect: lowers TG and VLDL, modest increase in HDL

MOA: agonist of the PPAR-alpha receptor (RXR heterodimer) which is a transcription factor that alters levels of enzymes. Stimulation of fatty acid oxidation, increased LPL and decreases apo C3.

Usually used in patients with high TG even with other therapy or those who are statin intolerant

Combination of gemfibrozil with either niacin or a statin can cause severe myositis (muscle inflammation)

Question 15

Lipid Treatment: Sterols

Answer 15

Ezetimbe (Zetia): blocks absorption of cholesterol in the gut by blocking transport.

Probably most effective when given with a statin (Vytorin is a combination with simvastatin).

Questions regarding efficacy, data has shown that Vytorin may be no better than statins alone.

Question 16

Lipid Treatment: PCSK9 Inhibitors (MOA, examples, use)

Answer 16

MOA: inhibits PCSK9 which is an endogenous ligand that causes internalization and degradation of LDL Receptors.

Drugs: All are monoclonal antibodies and subQ injections. Repatha (evolocumab), Praulent (alirocumab). About $14,000 annually. Long term efficacy endpoints are not known

Use: patients with familial or primary hypercholesterolaemia in addition to maximum dose statin therapy. Used in patients who are intolerant to statin therapy

Question 17

Lipid Treatment: VLDL packaging inhibitors (MOA, use, examples)

Answer 17

MOA: target VLDL particle synthesis and release

Use: homozygous familial hypercholesterolemia

Lomitapide (Juxtapid): inhibitor of microsomal triglyceride transfer protein (MTP) which is necessary for synthesis of chylomicrons and VLDL

Mipomersen (Kynamro): antisense oligonucleotide inhibitor of apoB synthesis thereby decreasing chylomicron and VLDL.

Question 18

Lipid Treatment: probucol

Answer 18

Probucol: antioxidant. May prevent oxidized forms of LDL from being taken up into foam cells.

Question 19

Calcium Levels

Answer 19

About 200 mg/day regulated, goal is about 1.2 mM free serum Calcium

Question 20

Parathyroid hormone

Answer 20

Parathyroid glands are small and located on the thyroid. Common cause of parathyroid disease is iatrogenic, or physician induced, when removing the thyroid hormone in hyperthyroidism because it is so difficult to remove the thyroid without harming the parathyroid glands.

Question 21

PTH actions in the gut

Answer 21

Actions in the gut: Increases calcium absorption in the gut, indirectly

Question 22

PTH actions in the kidney

Answer 22

1. decrease calcium loss from the kidney
2. increase PO4 loss from the kidney
3. stimulate 1-hydroxylase in kidney to form the active form of vitamin D3.

Question 23

PTH action in kidney: decrease calcium loss MOA

Answer 23

1. PTH increases cAMP/PKA which increases the number of transporters on the luminal side of the nephron.
2. PKA also stimulates Na/Ca co-transporters on the serosal side as well to cause a net reabsorption of calcium from the lumen.
3. Calbindin binds to free calcium in the cell to keep free Ca levels constant and not toxic to the cell.
4. PKA mediated mechanism.

Question 24

PTH action in kidney: increase PO4 loss MOA

Answer 24

1. Occurs in renal proximal tubule cells.
2. PKC mediated mechanism
3. PTH binds the PTH1R to activate PKC. PKC then activates NHERF-1 which is an adapter protein that tethers PTH1R to Npt2a
4. Npt2a is a Na/Pi transporter. There is increased endocytosis of the Npt2a transporter and therefore decreased reabsorption of PO4 and it is excreted into the urine.

Question 25

PTH action in bones

Answer 25

Effect: increases bone resorption by increasing the osteoclast to osteoblast ration.

1. Binding of PTH to a GPCR, PTH1R on osteoblasts or stromal cels
2. Activation of Gs causes increased PKA, through cAMP, and transcription factor activation and gene expression.
3. Activation of Gq causes increased PKC and MAPK activity, leading to proliferation of osteoclasts
4. Both the PKA and PKC pathways leads to increases in RANKL and CSF to form more osteoclasts. OPG, osteoprotegerin is decreased and is a decoy receptor.

Question 26

Vitamin D metabolites

Answer 26

Provitamin D is converted to vitamin D3 by irradiation in the skin. Vitamin D3 is converted to 25-DCC by 25-hydroxylase. In the kidney 25-DCC is converted to 1,25 - D(OH)2 the active form by 1-hydroxylase this reaction is controlled by PTH regulation.

Question 27

Reasons why vitamin D is a hormone

Answer 27

: synthetic cells, specific receptors, activation/inactivation, feedback regulation, disease syndrome, circulates bound to a carrier protein. However, vitamin D acts on multiple cell types which is uncharacteristic for a hormone.

Question 28

Vitamin D MOA

Answer 28

Vitamin D binds VDR on the RXR heterodimer of transcription factors. There are many gene targets, including TRPV6, PMCA1 and CaBP (calbindin) all in the gut.

Question 29

Rickets

Answer 29

Type 1: genetic loss of hydroxylase, so you must supplement with an active form of vitamin D.

Type 2: VDR doesn’t bind vitamin D as tightly as it should. Supplement with huge doses of vitamin D3

Question 30

Vitamin D resistant rickets

Answer 30

genetic problem with vitamin D receptor

Question 31

Osteoporosis Treatments

Answer 31

Treatments: calcitonin, bisphosphonates, fluoride (still being evaluated in US), intermittent PTH, cytokines/bone regulatory proteins

Question 32

Osteoporosis treatments: Bisphosphonates

Answer 32

analogs of pyrophosphate and inhibit osteoclastic activity. Fosamax (Alendronate) has side effects of jaw and heart problems. Efficacy on decreasing hip fractures is not strong, best when given before too much bone loss has occurred.

Question 33

Osteoporosis treatments: nitrogen containing bisphosphonates

Answer 33

Examples: Pamidronate, alendronate, risedronate, ibandronate and zoledronae.

MOA: All inhibit FPP synthase in the mevalonate pathway and prevent prenylation of regulatory proteins, end result is loss of osteoclast function and inhibition of bone resorption.

Not advised to use for longer than 5 years in a row though due to increasing adverse events of ONJ and atypical femur fractures.

Question 34

Zoledronic Acid

Answer 34

Zometa, Reclast. Used to prevent skeletal fractures in patients with cancers as well as to treat osteoporosis. Once annual dosing for osteoporosis because the drug gets incorporated into the bone where it is slowly released as a result of osteoclast activity.

Question 35

Osteoporosis treatments: denosumab

Answer 35

mAb against RANKL in osteoclasts. osteoblasts and bone marrow produce osteoprotergerin to inhibit RANK stimulation. denosumab is “neutralizing” and prevents RANKL from binding to receptor RANK. RANKL acts as regulator of osteoclast activity.

Question 36

Osteoporosis treatments: romosozumab

Answer 36

mAb against sclerotsin, which is a bone protein that is produced by osteocytes and has anti-anabolic effects on bone formation. (osteoblast)

Question 37

Osteoporosis treatments: Odanacatib

Answer 37

inhibitor of cathepsin K (osteoclast)

Question 38

Osteoporosis treatments: Saracatanib

Answer 38

inhibitor of Src kinase (osteoclast). repurposed cancer drug

Question 39

Vitamin D analogs for treatment

Answer 39

Vitamin D2: ergocalciferol, source is plants
Vitamin D3: cholecalciferol

Activated forms: 25-hydroxy vitamin D3 (calcifediol), 1,25 dihydroxy vitamin D3 (calcitriol), paricalcitol (partial agonist for calcium with relatively greater effect on suppression of PTH release)

Question 40

Cinacalcet (Senisipar): MOA, use

Answer 40

MOA: targets an allosteric site on the extracellular CR to act as a calcium sensitizer so that the same levels of serum calcium cause a greater inhibition of PTH release.

Use: secondary hyperparathyroidism due to end stage renal disease. Also indicated for treatment of hypercalcemia in patients with parathyroid carcinoma. Often used in dialysis patients in conjunction with paracalcitol or calcitriol.

End-stage renal disease: renal failure causes high serum PO4 and low serum calcium. This leads to high PTH and uncontrolled regulation of vitamin D and calcium absorption leading to hyperparathyroidism

Question 41

Calcium Regulation in parathyroid gland

Answer 41

Calcium binds to CR stimulating Ga which activates PLC. PLC cleaves PIP2 into DAG and IP3. IP3 promotes release of Ca from the ER. This calcium activates PLA2 to form arachodonic acids. AA’s inhibit secretion of PTH and increase VDR expression in the nucleus

Question 42

Type 1 diabetes treatment options

Answer 42

immunosuppresive therapy (because autoimmune but not used because of side effects), and insulin therapy

goals of insulin therapy: control acidosis (leads to death), control blood sugar (prevent long term side effects of glycosylation of B-100 which would result in atherosclerotic plaques) and extend healthy life span.

Daily glucose spikes in diabetics leads to blindness, kidney disease and atherosclerosis.

Question 43

T2DM goals of therapy

Answer 43

maintain fasting blood sugar at 120 mg and HBA1c

Question 44

T2DM therapy: sulfonylureas (examples, MOA)

Answer 44

Examples: Tolbutamide, Glipizides, Glyburides.

MOA: Increase insulin release from beta cells by mimicing ATP, ATP is responsible for inhibition of potassium channels causing depolarization of the cell and increased calcium secretion which leads to insulin secretion. Probably have additional control pathways as well: KO sulfonylurea receptor mice have insulin secretion control.

Question 45

T2DM therapy: Meglitinides (examples, MOA)

Answer 45

Examples: Repaglinide (Prandin), Nateglinide (Starlix)
MOA: Inhibit K channels at a different site than the sulfonylureas.

Question 46

T2DM therapy: Biguanides (examples, MOA)

Answer 46

Metformin

MOA: Mechanism is not well known, but we do know that metformin inhibits mitochondrial complex I and increases the AMP/ATP ration. Increases in AMP cause inhibition on AC and decreased cAMP/PKA ultimately resulting in less glucose.

Question 47

T2DM therapy: Thiazolidinediones (examples, MOA, combo products)

Answer 47

Examples:
Rosiglitazone (Avandia): Special program to get this because of issues with heart failure and stroke

Pioglitazone (Actos): Possible increases in bladder cancer

Troglitazone (Rezulin): Withdrawn from market due to liver toxicity

MOA:Bind to the RXR heterodimer transcription factor at PPAR-gamma. PPAR-gamma causes increased insulin sensitivity and increased beta cell function.

Saroglitizar/Lipaglyn: dual PPAR alpha/gamma agonist used for hypertriglycidemia particularly in type 2 diabetic patients.

Question 48

T2DM therapy: alpha-glucosidase (use, MOA, advantages, side effects)

Answer 48

Acarbose

MOA: delays carbohydrate absorption by decreasing conversion of complex carbohydrates to glucose.

Use: Can be taken alone or with diabetes drugs. Take with meals

Advantages: lowers postprandial blood glucose levels without stressing the pancreas by stimulating excess insulin production.

Side effects: diarrhea, abdominal pain, gas

Question 49

Glucagon and GLP-1

Answer 49

Glucagon: increases blood sugar by stimulating gluconeogenesis and glycogenolysis.

GLP-1 endogenous: decreases blood sugar by stimulating insulin secretion and protecting beta-cells. Activates AC/cAMP/PKA.

Both GLP-1 and glucagon are derived from the same proglucagon by alternate processing.

Question 50

T2DM therapy: GLP-1 agonists (examples)

Answer 50

Exendin: Derived from the venom of the Gila monster because it has similar sequence to GLP-1 but has a longer half-life.

Exenatide: synthetic version of Exendin that is DPP-4 resistant. Possibility to have antibody reaction because it is a peptide

Question 51

T2DM therapy: DPP-4 inhibitors (examples, MOA)

Answer 51

DPP-4 Inhibitors

Examples: Saxagliptin, Sitagliptin (Januvia)

Orally active

MOA: inhibitor DPP-4 which naturally degrades GLP-1. May decrease the loss of beta cells.

Question 52

T2DM therapy: Gliflozins (example)

Answer 52

Dapagliflozin

Question 53

T2DM Therapy: Na/glucose cotransport inhibitors (examples, MOA)

Answer 53

Examples: dapagliflozin (Forxiga), Canagliflozin (Invokana)

MOA: Inhibit the SGLT2 Na/glucose cotransporter on the lumen side of the proximal tubule, preventing reuptake of glucose back into the blood stream.

Question 54

Insulin formations

Answer 54

Formations. Note that recombinant formulations are designed to alter PK

Fast acting: lispro, aspart, gulisine

Long acting: glargine, detemir

Inhaled: Exubera

Question 55

Insulin MOA

Answer 55

insulin binds to the insulin receptor and has pleiotropic effects in the liver, muscle and fat. In fat and muscle it increases glucose transport. In muscle and liver it increases glycogen synthesis and inhibits gluconeogenesis. It also increases lipid metabolism, protein synthesis and gene expression.

Question 56

Insulin cascades

Answer 56

1. PI3K pathway: most important. Involves activation of pY and IRS-1 (muscle and fat) and IRS-2 (liver/brain).
2. Glucose transport pathway: large macromolecule activated that effects transport. May be altered in type 2 diabetes.
3. Cell Proliferation pathway: Is a MAP kinase pathway to produce cell proliferation.