Medical Pathophysiology and Pharmacology: Dyslipidemia Drugs

What are the 3 major risk factors for cardiovascular risk?

• high levels of LDL-C (bad cholesterol)

• high levels of TGs

• low levels of HDL-C (good cholesterol)

What is the optimal level of LDL-C in the blood?

• < 100 mg/dL

What is the optimal level of TGs in the blood?

• < 150 mg/dL

What is the optimal level of HDL-C in the blood?

• > 40mg/dL

How is LDL-C taken up into cells?

• via receptor mediated endocytosis

• LDL-C binds LDL receptors at surface → internalized

Which organ is the most important for regulating overall circulating LDL-C levels?

• the liver

• it does uptake

What are the 2 things that can happen to an LDL receptor once it is endocytosed into the cell?

• recycled to the surface of the liver cell to bring in more LDL-C

• destroyed inside

What are the 2 ways in which intracellular cholesterol is regulated?

• by LDL receptor expression and HMG CoA Reductase

  • if intracellular cholesterol is high → decreased LDL receptor expression (to reduce how much LDL is uptaken) and decreased HMG CoA reductase (to reduce cholesterol synthesis)

  • and vice versa

What is the precursor to LDL in circulation?

• VLDL → composed of TGs + LDL-C

  • TGs composed of FAs

What is liver synthesis of VLDL affected by?

• cholesterol and TG synthesis

• circulating FAs

Describe the schematic of cholesterol synthesis in the hepatocyte. Include endocytosis, receptor pathway, and VLDL

1. LDL-C + cholesterol binds LDL-R on liver cell

2. receptor mediated endocytosis

3. receptor+LDL are engulfed into an endosome

4. receptor is either destroyed or recycled to the surface and LDL remains in lysosome

5. cholesterol then inhibits HMG CoA reductase and LDL receptor expression when levels are high and stimulates them when levels are low

   1. cholesterol also precursor for bile acid levels in GI tract

6. cholesterol is used for TG synthesis

7. TG made into VLDL

8. LPL cleaves VLDL, freeing up LDL-C and TG in the circulation

What is the name and the suffix for the statin drug?

• Atorvastatin

• -statin = suffix for statin drug

Where do statins act?

• they are taken up by liver and act inside the liver

Describe the MOA of Statins

• enters liver cell and inhibits HMG CoA reductase from synthesizing cholesterol → intracellular cholesterol decreases → LDL receptor expression increases → liver cell takes up more LDL-C from circulation → we get decreased LDL-C in the blood and decreased TG and VLDL synthesis (good! 🙂 )

What are the other 2 CV-associated beneficial effects of statins?

• decrease CV risk by:

  • plaque stabilization so they dont rupture

  • reversal of endothelial dysfunction (associated w artherosclerosis)

What are the lipid effects of statins and how effective are they?

• VERY efficacious

  • large reduction in LDL-C

  • reduction in TG

  • increase in HDL-C

When are statins typically used?

• used as FIRST line drug to treat dyslipidemia AND for decreasing CV risk

Describe what happens to the liver cell when someone takes a statin

1. Statin is brought into the liver cell and directly blocks HMG CoA reductase inside

2. leads to decreased intracellular cholesterol

3. decreased TG synthesis → decreased VLDL → decreased LPL cleavage → decreased LDL-C in circulation

4. LARGE increase in LDL-C Receptors on surface to uptake MORE LDL-C

What are the 2 major AEs of statins?

• hepatotoxicity

• skeletal muscle toxicity

What are the 4 muscle conditions that could occur that tell you someone may be suffering from statin induced skm toxicity?

1. myalgia → muscle discomfort

2. myopathy → muscle weakness

3. myositis → muscle inflammation

4. rhabdomyolysis → renal myoglubinuria → renal toxicity

Describe what rhabdomyolysis is

• when the SKM cells lyse/rupture open and spill out myoglobin (which is what binds to oxygen in muscle cells)

• myoglobin can enter kidney and damage it (AKI)

Which 3 baseline tests need to be ordered for a patient that is starting a statin drug and why?

• baseline ALTs, ASTs, and CK

• we need to know the levels of these BEFORE starting drug to be able to monitor changes in these down the line to asses the level of liver and SKM damage

What are the 2 factors that increase the risk of SKM toxicity?

• increased statin dose

• drug-drug interactions

• they both increase the plasma concentration of statin

Why does increased statin dose increase the risk of SKM toxicity?

• because there is a higher circulating level of the drug, it can get uptaken somewhere else instead of the liver (like SKM) and can have damaging effects there

How do drug-drug interactions increase the risk of SKM toxicity?

• they decrease hepatic uptake and decrease metabolism/clearance of the drug → increases the concentration of stain in circulation

Describe the role of CYP 3A4 in statin-induced SKM toxicity

• CYP 3A4 metabolizes statin drugs

• when it is inhibited, metabolism is decreased, and plasma level of statin increases

What are the clinical signs of hepatotoxicity?

• jaundice (yellowing of the skin and eyes)

• dark urine

What is the name of the cholesterol absorption inhibitor?

• Ezetimibe

When do we usually give a cholesterol absorption inhibitor?

• if someone is on a statin drug and needs a second one or if statin is not working well, it is the second choice!!

Where do cholesterol absorption inhibitors act?

• they act on intestinal cells (on transporters)

What is the MAO of Ezetimibe?

• they inhibit NPCL1 cholesterol transporters in the intestinal cells to decrease the absorption of cholesterol by the GI tract → decreases addition of cholesterol into chylomicrons → decreases delivery of cholesterol to the liver to decrease intracellular cholesterol → increases LDL-R expression to increase hepatic uptake of LDL-C and decrease LDL-C in the plasma

What is one downside that can happen with these drugs from decreasing intracellular cholesterol?

• when we use these drugs to lower intracellular cholesterol, we can attenuation of the LDL-C lowering action because we get an increase in HMG CoA reductase activity

• this happens because we arent inhibiting the synthesis of cholesterol

How effective are these drugs?

• not as effective as statins but are a second choice usually

Describe the lipid effects of these drugs

• decreases LDL-C a bit

• decreases TG minimally

• increases HDL-C minimally

Why are cholesterol absorption inhibitors not as effective as statins? But why are they good to combine with a statin?

• bc they lower LDL-C by decreasing absorption of cholesterol so HMG CoA reductase is still available to produce cholesterol → we also get less receptors on the cell surface

• good to add w statin because it decreases the risk of skm toxicity by lowering the required dose of statin

What are the adverse effects of Ezetimibe?

• minimal AEs

What is the name of the Bile Acid Sequestrant? What is the prefix?

• Colesevelam

• prefix is cole- / chole-

Where do BA sequestrants act?

• in the GI tract where they bind BA in the intestine

What is the MAO of Colesevelam?

• it directly binds BA in the intestine and forces them to be excreted in feces so they do not get recycled → causes decrease in intracellular BAs and an increase in BA synthesis → this decreases the intracellular cholesterol → increases LDL R expression → increases LDL-C uptake by the liver → decreases LDL-C in the plasma

What downside do we get from BA sequestrants as a result of decreasing intracellular cholesterol?

• we get an increase in HMG CoA reductase activity and increased intracellular cholesterol synthesis → so its LDL lowering action is attenutated (like with the cholesterol absorption inhibitors)

How effective are BA sequestrants?

• not very effective

• even less effective than cholesterol absorption inhibitors

Describe the lipid affects of BA sequestrants

• decrease LDL-C

• actually have an increase in TGs

• small increase in HDL-C

What are the adverse effects of BA sequestrants and what are they restricted to?

• they are restricted to the GI tract bc that is where they act and are not absorbed into circulation

• bloating, constipation, nausea, flatulence

• can also impact absorption of other drugs and fat-soluble vitamins

What is the name of the PCSK9 inhibitor?

• Alirocumab

Where does this drug act and how is it administered?

• acts on protein PCSK9

• administered as an injection

What is PCSK9?

• a protease protein released by the liver that binds LDL-R and LDL-C and gets uptaken into the liver cell → prevents the recycling of LDL-R by forcing it into degradation by lysosomes

Describe the MOA of Alirocumab

• a monoclonal antibody that acts to bind PCSK9 → prevents degradation of LDL-R → increases LDL-R expression → increases hepatic uptake of LDL-C → decreases LDL-C in plasma

How effective is the PCSK9 inhibitor?

• super effective!!

• usually chosen after statin and azetamide are tried first

What are the lipid effects of Alirocumab?

• decreases LDL-C A LOT

What are the 2 adverse effects of PCSK9 inhibitors?

• injection site reaction

• allergic reaction

What is the name of the nicotinic acid drug?

• Niacin (B-vitamin)

Where does Niacin act?

• fat cells on GPCR

Explain the mechanism of action of Niacin

• Niacin binds and activates niacin GPCR (Gi-coupled) on fat cells to decrease HSL activity → decreased lipolysis → decreased FA release

• also taken up by the liver to decreased TG synthesis enzymes by liver → decreased VLDL production and decreased LDL-C (since we dont have VLDL)

What are the lipid effects of Niacin?

• decrease LDL-C

• decrease TGs very well!!

• increase HDL-C very well

What is the primary reason for Niacin use?

• to decrease TGs and increase HDL-C

• not really used as a LDL-C lowering med

How exactly does Niacin exert its job? Explain the Gi mechanism

• there are glucagon receptors on fat cells that are Gs and increase cAMP → PKA → and activate HSL-p to act on TGs → causes release of FA and lipolysis in the plasma

• niacin binds its Gi receptor on the cell, acts inside the fat cell and inhibits cAMP from increasing PKA and activating HSL

• also uptaken into the liver cell to suppress TG enzymes and TG synthesis

What are the adverse effects of Niacin?

• flushing, itching, dyspepsia, headache

• hepatotoxicity

• hyperglycemia

• hyperuricemia

• Drug-Drug interaction w/ Statin: increased risk of SKM toxicity

Why do we get the flushing/itching/dyspepsia/headache AEs?

• due to increased prostaglandin and histamine release

What is the name of the fibrate drug and what is the suffix?

• fenofibrate

• suffix = -fib

Where does fenofibrate act?

• acts on nuclear receptor PPARalpha

What does PPARalpha do?

• has effects on lipid metabolism

Describe the MOA of fenofibrate

• activates PPARalpha nuclear receptor → causes increase in LPL → increases the clearance of TG-rich VLDL and chylomicrons (which essentially decreases TG synthesis) → decreases VLDL → can possibly increase LDL-C (since it gets rid of TG rich VLDL we have LDL rich left over)

What is the effect of fenofibrate on apoproteins and fatty acid oxidation?

• increases fatty acid oxidation and acts on lipid carrying proteins (apoproteins) to decrease VLDL secretion from the liver

What are the lipid effects of Fenofibrate?

• targets TGs first!! to decrease a lot

• increases HDL-C

• has variable affect on LDL-C but can slightly increase

What are the adverse effects of Fenofibrate?

• GI: abdominal pain, diarrhea, constipation

• Drug-Drug interaction w Statin: increased risk of SKM toxicity

What do Niacins and Fenofibrates mainly target?

• lowering TGs

Which 2 drugs have the highest LDL-C lowering capacity?

• Statins

• PCSK9 inhibitors

Which 3 drugs have the highest TG lowering capacity?

• Fibrates

• Niacin

• Statins

Which drug has the highest HDL-C raising capacity?

• niacin

What are the 3 major dopaminergic pathways?

• Nigrostriated

• Mesolimbic/Mesocortical

• Tuberinfundibular

What is the Nigrostriated pathway’s general function?

• motor feedback that helps with movement

What is the Mesolimbic/Mesocortical pathway’s general function?

• emotion

• cognition

• reward

What is the Tuberofundibular pathway’s general function?

• endocrine function to inhibit prolactin

List the major dopaminergic receptor

• D2 (Gi)

What is the disease state involving DA?

• Schizophrenia psychiatric disorder characterized by positive and negative symptoms

Give examples of the positive and negative symptoms of Schizophrenia

• positive = extra things that should not be there

  • hallucinations

  • delusions

• negative = lacking something that should be there

  • decreased expression/affect

  • decreased energy

  • decreased social interaction

What is the name of the first generation psychotic?

• Haloperidol

What is the MOA of Haloperidol?

• D2 receptor antagonist (blocks D2)

How effective is Haloperidol at treating + and - symptoms?

• effective at treating + symptoms but not effective with - ones

Which dopaminergic pathway is adversely affected by Haloperidol? What are these effects called?

• Nigrostriated → causes movement side effects bc the pathway is inhibited

• it’s called EPS (extra-pyramidal side effects)

What are the 3 Acute EPS AEs that can occur with Haloperidol?

• dystonia

• akanthasia

• parkinsonism

What is Dystonia?

• sustained involuntary SKM contraction

• ex. when your neck gets stuck in a certain position

What is Akanthisia?

• most common acute EPS with Haloperidol

• subjective feeling of inner restlessness

  • '“ants in your pants”

What is Parkinsonism and which 3 symptoms characterize this?

• bradykinism (slow movement)

• increased muscle tone (rigidity)

• resting tremor

• looks like parkinson’s disease but it isnt

What are the 3 ways in which we could treat Acute EPS?

• give a lower dose of drug

• give an antimuscarinic drug

• change to a second gen drug

Why does giving an antimuscarinic drug help treat Acute EPS?

• this is because ACh signaling balances DA signaling in the Nigrostriated pathway

• when you block DA, you get an imbalance of ACh signaling

• by blocking muscarinic receptors, you bring the balance BACK

What are the 2 Late EPS that can occur with chronically taking Haloperidol?

• Tardive Dyskinesia

• Tuberinfundibular Hyperprolactemia

Describe what Tardive Dyskinesia is and how this can happen

• involunary, purposeless, repetitive movement

• caused by blocking D2 receptors → this causes upregulation/sensitization of D2-R → can cause too much DA stimulation and too much movement

What is Hyperprolactemia and what 3 adverse effects can occur because of this?

• excessive PRL (bc DA normally inhibits PRL but it cant when levels are low)

• could have galactorrhea (increased milk production)

• decreased reproductive and sexual function (due to PRL inhibiting gonadotropins)

What are the 3 receptors that can be affected by first and second generation drugs?

• alpha1

• muscarinic

• H1

What are the effects of blocking these receptors with these drugs?

• alpha1 block: orthostatic hypotension + reflex tachycardia

• muscarinic block: antimuscarinic effects

• H1 block: sedation + weight gain

What is the name of the second generation drug?

• Olanzipine

What is the MOA of Olanzipine? How effective is the second drug at treating ± symptoms?

• block D2 and 5HT receptors

• treats both symptoms!!

What are the differences between the 1st gen and 2nd gen drugs?

• second gen drugs:

  • have less EPS

  • are more effective at treating both - and + symptoms

  • have another set of AEs

How do we get less EPS with 2nd gen drugs?

• when you block the 5HT-R, it causes an increase in DA in the Nigrostriated pathway that could overcome the EPS symptoms

What are the other AEs of 2nd gen drugs?

• same as 1st gen (alpha1/muscarinic/H1)

• increase in CV risk

What 5 AEs contribute to the very serious increase in CV risk caused by 2nd gen drugs?

• metabolic syndrome (extreme weight gain)

• weight gain

• hyperglycemia (DM)

• hyperlipidemia (due to increased LDL-C/TGs

• increased BP

Based on AEs of Olanzipine, which 4 tests should be done to someone taking this?

• lipids test

• glucose

• BP

• weight