Pharmacological Treatment of Lipid Disorders Flashcards
CV risk: HDL-C and LDL-C interaction relationship?
for any level of LDL-C, HDL-C is inversely related to CHD risk
what are the therapeutic goals of for treating lipid disorders
- Reduce formation and rate of progression in coronary and peripheral atherosclerosis from childhood to old age
- Prevention of coronary events and strokes in apparently healthy persons at risk, particularly middle-aged and elderly
- Prevention of heart attacks, strokes, need for revascularization in persons with established atherosclerosis
- Prevention and treatment of pancreatitis in hypertriglyceridemia
what is the basis for treating lipid disorders that cause ASCVD (Atherosclerotic cardiovascular disease=Heart attacks +strokes +peripheral arterial disease)?
• Lowering LDL with statins lowers risk
• Base treatment on risk
• Secondary prevention (already has ASCVD event) is treated aggressively with high intensity statin
• Primary prevention (no clinical disease) is assessed.
– If 10-year risk
• > 7.5%–>treat with statins
• 5% to 7.5%–> review other risk factors
• < 5%–>lifestyle
• Everyone else (kids)–>primordial risk–>lifestyle
3 HMG CoA Reductase Inhibitors (Statins)
- Atorvastatin (Lipitor) (synthetic compound)
- Lovastatin (Mevacor) (fungal metabolite)
- Simvastatin (Zocor) (synthetic compound)
mechanism of action of statins?
Competitive inhibitor for active site on HMG CoA reductase
• Structural analog of the HMG CoA intermediate
• statins inhibit HMGR by binding to the active site of the enzyme, thus sterically preventing substrate from binding
• by decreasing cholesterol synthesis, statins also cause an increase in LDL-R!!!
what role does HMG CoA reductase play in cholesterol biosynthesis?
Rate limiting step in cholesterol biosynthesis
pharmacokinetics of statins?
• Extensive first-pass metabolism by the liver
– LIMITS SYSTEMIC BIOAVAILABILITY
– TARGETS LIVER/SITE OF ACTION
(also makes it less likely to have adverse reactions from these drugs!)
how are statins metabolized?
- All the statins, except simvastatin and lovastatin, are administered in the -hydroxy acid form, which is the form that inhibits HMG-CoA reductase.
- Simvastatin and lovastatin are administered as inactive lactones, which must be transformed in the liver to their respective -hydroxy acids, simvastatin acid and lovastatin acid.
statins and cytochrome P450 metabolism?
- Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3A4.
- Under steady-state conditions, small amounts of the parent drug and its metabolites produced in the liver can be found in the systemic circulation.
Half-life of statins
• Half-life of statins is variable
– lovastatin(1-4hours)
– simvastatin(1-2hours)
– atorvastatin ( 20 hours )
review: pharmacokinetics of statins
• Extensive first-pass metabolism by the liver – LIMITSSYSTEMICBIOAVAILABILITY – TARGETSLIVER/SITEOFACTION • Lovastatin and Simvastatin administered as pro-drugs –Lactonehydrolyzedtoactiveform • High plasma protein binding • Half-life of statins is variable – lovastatin(1-4hours) – simvastatin(1-2hours) – atorvastatin ( 20 hours ) • Metabolism (in liver) Simvastatin,lovastatin,atorvastatin:CYP3A4
frequency of adverse effects (in general) experienced from statins
- significant number of patients (perhaps 10% or more) develop intolerant symptoms to statins
- another 1–2% develop serious side-effects such as myositis or liver enzyme elevations.
How will new guidelines effect incidence of adverse effects of statins?
more patients receiving statins and the recent recommendations for higher intensity therapy, creates a significant absolute number of people intolerant of statin therapy or who suffer side-effects
minor and major adverse effects of statins?
minor: GI side effects and increase in liver enzymes
major: myopathy and rhabdomyolysis
myopathy (from statins) risk factors
• Risk increases in direct relationship to statin dose and plasma concentration
genetics and statin intolerance
- A single nucleotide polymorphism in SLCO1B1, which encodes an organic anion transporter that regulates the hepatic uptake of statins, was strongly associated with statin induced myopathy.
- Genetic variants of SLCO1B1 lead to reduced hepatic uptake and increased levels of statins in the blood, providing the mechanism for increased risk of myopathy.
Pharmacokinetic mechanisms by which drugs increase myopathy risk
- Drugs are those metabolized primarily by CYP3A4
- (certain macrolide antibiotics (e.g., erythromycin )
- azole antifungals (e.g., itraconazole )
- cyclosporine
- HIV protease inhibitors.
- These pharmacokinetic interactions are associated with increased plasma concentrations of statins and their active metabolites.
contraindications to statin therapy
• Hypersensitivity • Active liver disease • Women who are pregnant, lactating, or likely to become pregnant should not be given statins
mechanism for statin-induced myopathy
- not well understood
- think it has to do with depletion of secondary metabolic intermediates
- Statins block the conversion of HMG-CoA to mevalonate by inhibiting HMG-CoA reductase, decreasing cholesterol production but also suppressing formation of isoprenoids required for the normal function of the muscle.
statin lipoprotein profile
TG:
> 250 mg/dl: decrease by 20-55%
< 250 mg/dl: decrease by 25%
• the higher the baseline TG level, the greater the TG-lowering effect.
LDL:
decrease by 20-55%
HDL:
increase by 5-10%
clinical uses for statins
First line therapy in hypercholesterolemia when at risk for myocardial infarction
mechanism of excretion of cholesterol
Conversion to bile salts is the only mechanism by which cholesterol is excreted (~0.8 g/day).
bile-acid binding agent
cholestyramine
mechanism of action of cholestyramine
- anion-exchange resins
- highly positively charged and binds negatively charged bile acids
- Because of their large size, the resins are not absorbed, and the bound bile acids are excreted in the stool.
- interruption of this process depletes the pool of bile acids, and hepatic bile-acid synthesis increases.
- As a result, hepatic cholesterol content declines, stimulating the production of LDL receptors, an effect similar to that of statins.
what is the dominant mechanism for controlling LDL plasma concentrations?
Regulation of Hepatic LDL Receptor Pathway is Dominant Mechanism for Controlling LDL Plasma Concentrations
how do bile acid binding resins lower intracellular cholesterol levels?
Like statins, bile acid binding resins lower intracellular cholesterol which activates the SREBP transcription factor and increases LDL receptor gene transcription
cholestyramine drug description and pharmacokinetics
- Quaternary amine, hygroscopic powder administered as chloride salt/insoluble in water
- Pharmacokinetics – not absorbed
adverse effects of cholestyramine
–most common=constipation/bloating sensation
– gritty consistency
– interferes with absorption of other drugs
– modest INCREASE in TG/with time returns to baseline values
cholestyramine lipoprotein profile
TG:
– Normal levels: only transient increase
– Levels > 250 mg/dl; further significant increase
LDL:
–decrease by 12-25%
» Dose-dependent
» Larger dose, more side effects
HDL:
– increase by 4-5%
clinical uses of cholestyramine
- hypercholesterolemia
- Not recommended for individuals with hypercholesterolemia and increased TG
- most often used as second agents if statin therapy does not lower LDL-C levels sufficiently
- recommended for patients 11-20 years of age.
nicotinic acid (a.k.a. niacin)
- Water-soluble B-complex vitamin
* MAIN EFFECT IS TO DECREASE TG!!! – But it does decrease cholesterol!
niacin mechanism of action
not well understood, but…
• In adipose tissue, inhibits FFA mobilization
– role for niacin receptor 1 (GPR109A) in adipose tissue
• In liver, decreases synthesis of VLDL-TG (Inhibits DGAT2 [diacylglycerol acyltransferase 2], enzyme that catalyzes the final reaction in TG synthesis)
• Inhibits synthesis and reesterification of fatty acids
• Inhibits uptake of HDL-apoA1
• Increases ApoB degradation
– apoB is major protein of VLDL/LDL
• selectively increases Apo-AI containing HDL particles through inhibition of their uptake and catabolism by hepatocytes=good thing!!
pharmacokinetics of niacin
• Oral administration
• 3 different formulations
- immediaterelease(2-3x/day)
- Longactingrelease
- extended release preparation (once day/bedtime)
– Remember that doses used for lowering cholesterol/TG much greater than those used as vitamin
• Prescription only
major adverse effects of niacin. does tolerance to this effect occur?
– Intense cutaneous flush/pruritus
- Mediated by vasodilatory PGs - use of NSAIDs to block the effect
-luckily, tolerance to this effect occurs with continued use
other more severe but less frequent adverse effects of niacin
- GI: nausea/vomiting, abdominal pain, diarrhea = Avoid in patients with peptic ulcer
- elevated liver enzymes/usually no hepatic toxicity BUT MAJOR concern if combined with statins
- Hyperurecemia = contraindicated in patients with gout
- Increases fasting glucose levels/niacin-induced insulin resistance = Questionable use in patients with diabetes
summary of contradictions for niacin
- Peptic Ulcer
- Gout
- Hepatic Disease
- Diabetes
drug interactions of nicacin
Combined use with statin increases risk of myopathy
niacin lipoprotein profile
TG:
-decreased by 35-50% » Within 4-7 days
LDL:
-decreasedby25% » 3-6 weeks for maximal effect
HDL:
-increasedby15-30% » added benefit is increased HDL
Lp(a):
-reduced by 40% » May be risk factor
clinical uses of niacin
• Hypercholesterolemia & hypertriglyceridemia
– High LDL and low HDL
• Typically not first line therapy for hypercholesterolemia
– Severe cases that do not respond to resins
– Not first choice because of side effects
• Only lipid-lowering drug that reduces Lp(a)
cholesterol absorption inhibitor
ezetimibe
mechanism of action of ezetimibe
• Decreased rate of cholesteryl ester incorporation into chylomicrons via inhibition of NPC1L1 transporter
– Reduced cholesterol flux from intestine to liver
how does blockade of cholesterol absorption decrease plasma LDL cholesterol?
LDL receptor numbers increase resulting in increased uptake of LDL from circulation
pharmacokinetics of ezetimibe
• Oral administration
• Metabolized (glucuronidation) to active
metabolite
• Half-life 22 hours
adverse effects of ezetimibe
- Well tolerated
* Side effects increase if combined with other drugs, like statins
ezetimibe lipoprotein profile
TG:
-decrease by 5%
LDL:
-decrease by 15-20%
HDL:
-increase by 1-2%
clinical uses for ezetimibe
• Primary hypercholesterolemia
• Combined with statins
– Simvastatin + ezetimibe
– Further decrease in LDL-cholesterol
– Two differing pharmacological approaches
is there an advantage to combined therapy with ezetimibe/simvastatin?
safety and efficacy of ezetimibe/simvastatin (Vytorin) has been questioned after a trial suggested that the combination reduced LDL by 58% with no significant reduction in atherosclerotic-plaque progression
– And may increase side effects…
fibrin acids/fibrates/PPAR activators and their main goal
gemfibrozil
fenofibrate (2nd generation drug)
-primarily, triglyceride-lowering agents (lower the levels of TG-rich lipoproteins)
mechanism of action of fibrates
• Ligands for the nuclear transcription regulator
• peroxisome proliferator-activated receptor (PPAR-a)
– Expressed in liver, adipose tissue
• regulate gene transcription
(number of different genes)
• PPAR binds as heterodimers with retinoid X receptor
effect of fibrates
bind PPAR-a–> activate PPAR-a/RXR–> PPRE/target genes—>
lead to: •increased LDL particle size •increased HDL synthesis •increased reverse cholesterol transport •decreased inflammation •decreased triglycerides
pharmacokinetics of fibrates
- Oral administration
- Plasma protein binding
- Half-life varies (1 hr for gemfibrozil/20 hrs for fenofibrate) (increased with renal impairment)
metabolism of the vibrates
• Fenofibrate is metabolized to active metabolite – excreted predominantly as glucuronide conjugates;
60-90% of an oral dose is excreted in the urine
• Gemfibrozil metabolized into inactive metabolites
adverse Effects/drug interactions/contraindications of the fibrates
• generallywell-tolerated
– GI symptoms-most common
– Increased risk of gall stones
– Less common are hematological/hepatic function abnormalities
– increased creatine kinase if also being treated with a statin….lead to renal failure
fibrate contraindications and interactions
– Use is contraindicated in patients with renal impairment
– Gemfibrozil can increase systemic statin concentrations by blocking transporter in liver
gemfibrozil-related drug interaction
• Fibric acid used to lower TGs
• Gemfibrozil inhibits uptake of active hydroxy acid forms of
statins by transporter
– first-pass hepatic uptake of these statins by transporter OATP1B1 after their oral administration
– If not taken up into liver, increased plasma concentration
fibrates lipoprotein profile
dependent on starting lipoprotein profile
TG:
-decrease 30-50%
LDL:
-decrease 15-20%
• HIGHLY VARIABLE
• 2nd generation drugs (fenofibrate) more likely to decrease LDL 15-20% in patients with TG < 400 mg/dL
HDL:
-increase 5-15%
clinical uses for fibrates
- patients with high TGs and low HDL associated with metabolic syndrome or type 2 diabetes
- not used as primary therapy in patients with elevated hypercholesterolemia without hypertriglyceridemia
DRUGS OF CHOICE FOR
HYPERCHOLESTEROLEMIA: HMG CoA reductase inbibitors
-first choice agents
– Which one? =we will learn this through clinical practice
– Safety? =start to worry when we have increased patients and increasing dosages
– Lifetime treatment
DRUGS OF CHOICE FOR
HYPERCHOLESTEROLEMIA: bile acid resins
– Long-term safety
– Younger patient age range – Add on to statins
DRUGS OF CHOICE FOR
HYPERCHOLESTEROLEMIA: ezetimibe
– Safety as monotherapy vs MAYBE…add-on to statins
DRUGS OF CHOICE FOR
HYPERCHOLESTEROLEMIA: niacin
– Patient compliance side effects
– Both elevated TG and cholesterol
– Low HDL
– Care when combined with statins
Drugs of choice for hypertriglyceridemia
- Gemfibrozil/Fenofibrate-should be first choice
- Niacin
- Omega-3FattyAcids
Omega-3-Acid Ethyl Ester
• lipid-lowering effects of fish (marine) oils
– despite a diet high in saturated fat and cholesterol, serum lipids— particularly TG —were significantly lower in the Greenland Eskimos.
- Eicosapentaenoic acid – (EPA 20:5 n−3)
- Docosahexaenoic acid – (DHA 22:6 n−3)
- omega-3 FAs appeared to have unique TG-lowering properties not shared by the omega-6 FAs
- Fish oil and fatty fish such as salmon, mackerel, herring, and tuna are the primary dietary sources of EPA and DHA
mechanism of action of omega-3-acid-ethyl esters
-tends to look a lot like niacin
• inhibit (−) lipogenesis
– inhibit diacylglycerol acyl transferase (DGAT), phosphatidic acid phosphohydrolase (PA), and hormone- sensitive lipase
• stimulate (+) β-oxidation, phospholipid synthesis, and apolipoprotein (apo) B degradation.
• The end result is a reduced rate of secretion of very-low-density lipoprotein (VLDL) TG
Other effects of omega-3 FAs
- reductions in risk for fatal arrhythmias
- enhanced plaque stability
- reductions in heart rate
- improved endothelial function
pharmacokinetics of omega-3 FAs
• only one FDA-approved omega-3 FA
– Oral: 4 g/day as a single daily dose or in 2 divided
doses.
• Onset of action is slow; typically stop drug if no benefit seen after 2 months of therapy
adverse effects of omega-3 FAs
- Fish allergy
- May increase LDL levels
- May increase liver enzymes.
- Prolongation of bleeding time has been observed in some clinical studies
clinical use of omega-3- FAs
• Adjunct to diet therapy in the treatment of hypertriglyceridemia (≥500 mg/dL)
future therapies…
- PCSK (Proprotein convertase subtilisin/kexin type 9) inhibitors
- MTP (Microsomal triglyceride transfer protein) inhibitors
- ApoB-100 (Apolipoprotein B-100) inhibition
Proprotein convertase subtilisin/kexin type 9 (PCSK9)
• Decreases the steady-state level of expression of the LDL receptor on
the hepatocyte cell membrane
- LDLr/PCSK9 complex gets internalized and targeted to the lysosomal compartment for degradation–>
- Inhibition of the recycling of the LDLr back to the cell surface results in increased plasma LDL levels (antibodies, siRNA)
- No change in plasma cholesterol levels in PCSK9/LDLr KO’s, suggesting that effect of PCSK9 is mediated solely via LDLr
• Levels of hepatic LDLRs are controlled by
– sterol regulatory element-binding protein 2 (at the transcriptional level)
– PCSK9 (at the post-transcriptional level).
• PCSK9 binds to LDLRs and, upon internalization, directs the receptor to the lysosome for destruction, thus decreasing the level of LDLRs at the cell surface
• PCSK9 is synthesized as a proprotein that undergoes autocatalytic cleavage in the ER, becoming a self-inhibited enzyme with the prodomain non-covalently attached to the catalytic site.
PCSK9 Inhibitors -Mechanism of Action
• REGN727
• AMG145
• PCSK9 antibody prevents binding of PCSK9 to the LDLR-LDL complex, increasing the availability of cell- surface LDLRs.
-not FDA approved, yet!
Microsomal triglyceride transfer protein (MTP)
• major cellular protein that transfers neutral lipids between membrane vesicles.
• essential chaperone for the biosynthesis of apolipoprotein B (apoB)-containing triglyceride-rich lipoproteins
– abetalipoproteinemia patients carry mutations in the MTTP gene resulting in the loss of its lipid transfer activity.
• Role in the regulation of cholesterol ester biosynthesis.
MTP Inhibitors -Mechanism of Action
- Lomitapide
- directly binds to and inhibits MTP
- MTP inhibition prevents the assembly of apo-B containing lipoproteins in enterocytes and hepatocytes resulting in reduced production of chylomicrons and VLDL and subsequently reduces plasma LDL-C concentrations.
MTP Inhibitors -Pharmacokinetics
- Oral administration
* Primarily hepatic (extensive) through CYP3A4 to M1 and M3 (major [inactive in vitro] metabolites)
MTP Inhibitors –Adverse Effects
- Significant gastrointestinal events (eg, diarrhea, nausea, dyspepsia, vomiting) occur commonly
- Hepatotoxicity
MTP Inhibitors –Clinical Use
• Adjunct to dietary therapy and other lipid- lowering treatments to reduce LDL-C, total cholesterol, apolipoprotein B, and non-HDL- C in patients with homozygous familial hypercholesterolemia
Apolipoprotein B-100 (apoB-100)
- structural apolipoprotein that is an essential component of LDL-C and VLDL.
- ApoB-100 is the ligand that binds LDL to its receptor and is important for the transport and removal of atherogenic lipids.
- Elevated levels of apoB, LDL-C and VLDL are associated with increased risk of atherosclerosis and cardiovascular diseases.
ApoB-100 Inhibition-Mechanism of Action
- Mipomersen
- 20-base sequence second-generation antisense oligonucleotide developed to inhibit synthesis of apoB-100 in the liver.
- hybridizes within the coding region of apoB-100 mRNA and activates RNase H. RNase H degrades the mRNA strand but leaves the antisense oligonucleotide intact
ApoB-100 Inhibition-Pharmacokinetics
- Once/week via subcutaneous injection
* lipid-lowering effect persisted for up to 3 months after the last dose
ApoB-100 Inhibition –Adverse Effects
• injection site reactions
– erythema, pain, hematoma, pruritus, swelling and discoloration
• flu-like symptoms
– Increase in anti-mipomersen antibodies
• Headache
• elevation of liver enzymes (risk of hepatotoxicity)
ApoB-100 Inhibition–Clinical Use
• FDA approved in January 2013 as an orphan
drug
• first-in-class drug for treatment of homozygous familial hypercholesterolemia
• Adjunct to dietary therapy and other lipid- lowering treatments to reduce LDL-C, total cholesterol, apolipoprotein B, and non-HDL-C in patients with homozygous familial hypercholesterolemia
