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!!
