Lipid Lowering Drugs Flashcards
What is the mechanism of the body to replenish hepatic cholesterol/make more cholesterol in the liver?
inc HMG-CoA reductase (blocked by statins)
What is the mechanism to replenish the hepatic cholesterol “pool” (that isn’t making more cholesterol in the liver)?
inc LDL receptor expression leading to inc LDL clearance from blood
How is LDL receptor expression increased?
via transcriptional up-regulation
also occurs in response to statin therapy
What dietary change can be made to lower cholesterol?
increase fiber intake
Mechanism of fiber in lowering cholesterol?
fiber absorbs cholesterol and bile acids which contain cholesterol so slows absorption of cholesterol and facilitates excretion AND causes GI motility changes that leads to increase speed of passage so slows absorption of cholesterol, glucose, and macronutrients
How does omega-3 polyunsaturated fatty acids (PUFAs) dec cholesterol?
inc clearance of triglycerides
Provide an example of a PUFA drug
Lovaza
How does Lovaza work?
20-50% dec in fasting levels of triglycerides (no impact on pancreatitis)
Is fish oil supplementation helpful?
no dec in MIs, stroke deaths, cardiac related deaths, or sudden deaths
Is diet of fish helpful?
diet including fish (2x/week) decreases cholesterol and cardiac related deaths
What two forms do statins come in?
prodrug and active form
What are the two statins we need to know?
atorvastatin (Lipitor) and pravastatin (Pravachol)
What form are atorvastatin and pravastatin in?
active
How do statins work?
structural analog of 3-hydroxy-3-methylglutaryl (HMG) Co A thus BLOCK HMG CoA REDUCTASE –> dec in cholestrol synthesis…
Also statins lower serum LDL levels indirectly by inc hepatic LDL receptor expression
What does blocking/inhibiting HMG CoA Reductase do?
decrease cholesterol synthesis which increases synthesis of hepatic LDL receptors which increases clearance of LDL and VLDL remnants from blood (so statins lower serum LDL levels indirectly by inc hepatic LDL receptor expression)
What are statin’s effects on plasma lipids?
reduction of plasma LDL cholesterol!!!! (modest reduction in triglycerides and modest increase in HDL)
Metabolism of atrovastatin
metabolized by CYP3A4
Metabolism of pravastatin
metabolized by sulfation NOT P450-dependent
Physiologic disposition of atrovastatin
half-life 14 hours
administered at any time of day
dec absorption with food
lipophilic so can cross BBB easier
protein bound
Physiologic disposition of pravastatin
half-life 2 hours
administered at night (when most cholesterol biosynthesis takes place)
dec absorption with food
hydrophilic so less smooth muscle cell effects AND more hepatoselective b/c better substrates for hepatic transporters
excreted unchanged in urine (only one)
NOT protein bound
Adverse effects of statins
1) Myopathy/Myalgia
2) Hepatic toxicity so elevation of serum aminotransferase activity so be careful with patients with liver disease and hx of alcohol abuse
3) Increased myopathy and rhabdomyolysis when used with other drugs like Gemfibrozil cuz inhibits uptake transporter and metabolism by CYPs
4) Drugs that compete/inhibit CYP3A4 or 2C9 can impact statin exposure (exception pravastatin cuz not metabolized by P450s)
5) small risk of inc DM
6) possible cognitive effects but inconsistent findings
1 adverse effect of statins
!!!Myopathy/Myalgia!!! (test question)
Statin key points: atorvastatin
lipophilic so penetrate muscle and cross BBB
source is made synthetically
undergo P450 metabolism so drug interactions
renal impairment not an issue
protein bound
dec absorption when taken with food
can take any time of day
half-life 14 hours
Statin key points: pravastatin
hydrophilic so hepatoselective and less smooth muscle cell effects
source is from fungi
no P450 metabolism (so no drug interactions with those that are)
renal impairment an issue
NOT protein bound
dec absorption when taken with food
should be taken at night (when most cholesterol biosynthesis takes place)
half-life 2 hours
excreted unchanged in urine (only one)
Give an example of a cholesterol absorption blocker
Ezetimibe as monotherapy dec LDL 15-20% combination therapy with statin for example up to 60% dec in LDL
mechanism of action of cholesterol absorption blocker
acts to block the absorption of cholesterol from the intestinal track…inhibits Riemann-Pick C1-Like 1 (NPC1L1) which dec delivery of intestinal cholesterol to the liver which dec cholesterol in chylomicrons/remnants (atherogenic)…reduction of cholesterol absorption leads to inc LDL receptors and inc clearance of LDL from plasma (so similar effect as statins)…lower blood LDL levels
physiological disposition of Ezetimimbe
not metabolized by P450s (so no significant effects with P450 dependent drugs like statins)
both parent drug and metabolite inhibit cholesterol absorption
repeated enterohepatic circulation results in long duration of action…22 hr half life
provide an example of bile acid sequestrants (resins)
cholestyramine
mechanism of action of cholestyramine
binds bile acids/metabolites of cholesterol…prevents reabsorption…excretion is promoted…depletes pool of bile acids…inc conversion of cholesterol to bile aids…up regulation of LDL receptors and inc LDL clearance from plasma…can also lead to up regulation of HMG-CoA reductase so why include statin in combo therapy
adverse effects of cholestyramine
absorption of some drugs may be impaired (resins bind digoxin, thiazides, warfarin, tetracycline, some statins so give medications one hour before or two hours after resin) AND GI effects such as constipation, bloating, heartburn, diarrhea, relieved by inc dietary fiber intake, should be avoided in patients with diverticulitis
provide example of nicotinamide derivative
niacin
what is Niacin good for
best agent to inc HDL
mechanism of action of Niacin
inhibits lipolysis (lipase) in adipose tissue and decreases free fatty acid transport to liver which means dec VLDL synthesis in liver
also dec triglyceride synthesis in liver
overall dec triglycerides and LDL while raising HDL (additive with statins)
physiologic disposition of Niacin
cleared by hepatic metabolism: big first pass effect (one reason why hepatic toxicity can be an issue)
Adverse effects of Niacin
!!!cutaneous flushing!!! defining adverse effect/test question (symptoms decline over time of 1-2 weeks) others contraindicated in pregnancy hepatotoxicity GI discomfort: dyspepsia (inc gastric acid secretion), nausea, diarrhea, etc
provide and example of a fibrate
Gemfibrozil
how do fibrates work?
their impact on lipids varies but if patient is hypertriglycerides…dec TG by 50%, dec VLDL, inc HDL, and dec LDL
mechanism of action of Gemfibrozil
agonist for PPAR-alpha receptor which dec triglycerides by increasing their clearance
physiological disposition of Gemfibrozil
half-life is 1.1 hours
can cross placenta
adverse effects of Gemfibrozil
renal and hepatic dysfunction are contraindications for this drug
should not use in kids or pregnant women
GI discomfort
myopathy (increased risk of this when given with statin)
some drug interactions like potentiates effects of warfarin and oral contraceptives
review slide of drug effects on TG, LDL, and HDL
see picture
how does PCSK9 work?
PCSK9 is a protein that degrades LDL receptors so if PCSK9 is blocked/inhibited the LDL receptors are not degraded so with more LDL receptors on cell membrane there is more clearance of LDL from the blood…result is dec LDL
give and example of a PCSK9 inhibitor drug
Repatha (evolocumab)
Repatha/Evolocumab + Statin results in
dec in major CV events (CV death, MIs, stroke, hospitalizations for unstable angina, revascularization)
dec in composite CV death, MI, and stroke
(so drug works but numbers are not as astounding as we would have hoped for)
adverse effects of PCSK9 inhibitors
nasopharyngitis
