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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
LDL-C + cholesterol binds LDL-R on liver cell
receptor mediated endocytosis
receptor+LDL are engulfed into an endosome
receptor is either destroyed or recycled to the surface and LDL remains in lysosome
cholesterol then inhibits HMG CoA reductase and LDL receptor expression when levels are high and stimulates them when levels are low
cholesterol also precursor for bile acid levels in GI tract
cholesterol is used for TG synthesis
TG made into VLDL
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
Statin is brought into the liver cell and directly blocks HMG CoA reductase inside
leads to decreased intracellular cholesterol
decreased TG synthesis → decreased VLDL → decreased LPL cleavage → decreased LDL-C in circulation
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?
myalgia → muscle discomfort
myopathy → muscle weakness
myositis → muscle inflammation
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