Hyperlipidemia Drugs Flashcards
1
Q
Hypertriglyceridemia
A
- increased CHD (coronary heart disease) risk associated with TG > 150 mg/dl
- elevated triglycerides can lead to pancreatitis (>500 mg/dl)
2
Q
Hypercholesterolemia and Atherosclerosis Risk Indicators
A
- LDL-C
- Apo B100
- Non HDL-C
3
Q
Total Cholesterol Levels
A
-Desirable (240 mg/dl)
4
Q
HDL-C Levels
A
-Low (60 mg/dl)
5
Q
LDL-C
A
-Optimal for very high risk (190)
6
Q
Triglycerides
A
-Normal (500 … can lead to pancreatitis)
7
Q
Recommendations for Statin Therapy
A
- individuals with clinical ASCVD (arteriosclerotic cardiovascular disease)
- individuals with primary elevations of LDL-C (>190 mg/dl)
- individuals 40 to 75 years of age with diabetes with LDL-C 70-189 mg/dl
- individuals without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL-C 70-189 mg/dl and an estimated 10 year ASCVD risk of 7.5% or higher
8
Q
Familial Hypercholesterolemia
A
- LDL receptors genetically defective in liver
- increased LDL levels in blood
- treated with bile acid binding resin and an inhibitor of HMG-CoA reductase
9
Q
Rationale for the use of bile acid binding resin and HMG-CoA inhibitor for FH heterozygotes
A
- reduces production of cholesterol
- increased cholesterol uptake from LDL binding to liver
- increased cholesterol secretion into intestines via bile acids
10
Q
Statins: Mechanism of Action
A
- competitive inhibitors of HMG-CoA reductase
- inhibit cholesterolgenesis
- increase expression of LDL receptor
- increase removal of LDL (VLDL, IDL) from blood
- decrease hepatic VLDL production
- TG levels >250 mg/dl reduced by statins
- HDL-C levels: some studies show slight increase
- LDL-C Levels: lower by 20%-55% (dose dependent)
11
Q
Statins: Pharmacokinetics
A
- Lovastatin and Simvastatin are inactive lactone prodrugs, hydrolyzed to active form in liver
- absorption varies from 40% to 75% except for fluvastatin (almost complete)
- absorption is enhanced by food
- high first pass extraction by liver
- most absorbed dose excreted in bile as metabolites
- 5% to 30% excreted in urine (statin-dependent)
- half-lives: 1-3 hrs except for atorvastatin (14 hrs) and rosuvastatin (19 hrs)
- hepatic cholesterol biosynthesis maximal midnight - 2 am, take in evening (except ones with long half-lives)
12
Q
Statins: Therapeutic Use
A
- alone or in combination with resins, niacin, or ezetimibe
- contraindicated in pregnancy, lactating, or likely to become pregnant
- some approved for children with FH hypercholesterolemia
13
Q
Lovastatin
A
-HMG-CoA Reductase Inhibitor (statin)
14
Q
Atorvastatin
A
- HMG-CoA Reductase Inhibitor (statin)
- longer half-life (14 hours), so doesn’t have to be dosed in the evenings
- most efficacious agent for severe hypercholesterolemia (along with rosuvastatin)
- more TG lowering activity compared to other statins
15
Q
Fluvastatin
A
-HMG-CoA Reductase Inhibitor (statin)
16
Q
Pravastatin
A
-HMG-CoA Reductase Inhibitor (statin)
17
Q
Simvastatin
A
-HMG-CoA Reductase Inhibitor (statin)
18
Q
Rosuvastatin
A
- HMG-CoA Reductase Inhibitor (statin)
- longer half-life (19 hours), so doesn’t have to be dosed in the evenings
- most efficacious agent for severe hypercholesterolemia (along with atorvastatin)
- more TG lowering activity compared to other statins
19
Q
Statins: Toxic/Adverse Effects
A
- elevations in serum alanine aminotransferace activity (up to 3x normal) … intermittent… not usually associated with other evidence of hepatic toxicity… therapy may be continued in absence of other symptoms and if ALT measured frequently… elevated ALT in patients with nonalcoholic fatty liver disease and hepatitis C is not a risk factor for statin-induced liver toxicity
- elevations in ALT exceeding 3x normal (~2% of patients, some with underlying liver disease or history of alcohol abuse)… medication should be discontinued if >3x is persistent or signs of hepatotoxicity present (precipitous decrease in LDL, anorexia, or malaise)
20
Q
Statins: Toxic/Adverse Effect - Myopathy
A
- with or without elevations in CK
- intense myalgia, first in arms and thighs, then entire body
- fatigue
- reversible when drug stopped
- rhabdomyolysis –> myoglobinuria –> renal failure has been reported in pts with CK levels 10x over normal
- very rare
- effect is pharmacokinetic: seen when some statins given with other drugs and substances (e.g. grapefruit juice) metabolized by CYP3A4
- gemfibrazole: competes with statins for glucuronidation enzymes, increased risk of rhabdomyolysis
- amiodarone: relative risk of nearly 10 with high dose simvastatin
21
Q
Polymorphisms in SLCO1B1
A
- the gene that encodes the organic anion-transporting polypeptide 1B1 (OATP1B1)
- genetically impaired OATP1B1 reduces hepatic uptake of active simvastatin acid, causing accumulation of simvastatin acid in plasma and an increased risk of myopathy
22
Q
Bile Acid Sequestrants (Resins): Mechanism
A
- highly positively charged –> bind negatively charged bile acids
- large size is not absorbed
- bound bile acids excreted in stool (normally, 95% of bile acids reabsorbed)
- hepatic bile-acid synthesis (from cholesterol) increases
- hepatic cholesterol content declines
- LDL receptors increased in hepatocytes
- increased clearance of LDL from plasma
- lower LDL-C (maximal in 1-2 weeks)
- HMG-CoA reductase upregulated and increased cholesterol synthesis partially offsets reduction in LDL-C (therefore, coadministration of a statin substantially increases effectiveness of resin)
- resin-induced increase in bile acid production leads to increase in hepatic TG synthesis (use with extreme caution or avoid in pts with severe hyptriglyceridemia)
- HDL-C levels increase 4%-5%
23
Q
Colestipol
A
- bile acid binding resin
- old, safe (not absorbed from GI)
- can reduce LDL-C by 25%
- second line if statin insufficient
- pregnancy Class C
- anion-exchange resin
- hygroscopic powders
- insoluble in water
24
Q
Cholestyramine
A
-bile acid binding resin
25
Colesevelam
- bile acid binding resin
- newer
- safety in kids not studied
- reduction in LDL-C by 18%
- recently approved as adjunct in treatment of DM type 2
- Pregnancy Class B
- cross-linked polymer
- hydrophilic gel
- insoluble in water
26
Resins: Therapeutic Use
- take with meals or no effect
- for heterozygous FH
- for combined hyperlipoproteinemia in combination with other drugs
- also for pts with bile salt accumulation and cholestasis
- also for removal of digitalis from GI tract
27
Resins: Toxicity/Adverse Effects
- constipation
- bloating
- heartburn
- diarrhea (occasionally)
- malabsorption of Vitamin K (rarely) --> hypoprothrombinemia (impaired blood clotting)
- malabsorption of folic acid (rarely)
- increased hepatic triglyceride synthesis (concern in pts with triglycerides >250 mg/dl)
28
Resins: Contraindicated with other Drugs
- cholestyramine and colestipol BIND OTHER DRUGS! including thiazides, warfarin, thyroxine, tetracycline, DIGOXIN, metoprolol, quinidine, valproic acid, some statins, etc.
- take other drugs either 1 hour before or 3-4 hours after resin
29
Niacin (nicotinic acid)
- water-soluble vitamin (B3)
- converted to niacinamide (nicotineamide), incorporated into NAD
- excreted in urine unmodified and as metabolites (including nicotinamide)
- nicotinamide does not effect lipid levels
- favorable effects on all lipid profiles
- best agent for increasing HDL (30-40%)
- lowers triglycerides (35-45%)
- reduces LDL-C by 20-30%
- reduces Lp(a) levels by ~40%
30
Niacin (mechanism of action)
- multiple effects on lipoprotein metabolism
- primary effect probably involves inhibition of VLDL secretion, thereby decreasing production of LDL
- inhibits lipolysis of TG by hormone-sensitive lipase
- reduces transport of free fatty acids to liver
- decreases hepatic TG synthesis
- reduces TG synthesis by inhibiting synthesis and esterification of fatty acids (increase apoB degradation)
- reduces hepatic VLDL production (accounts for reduced LDL levels)
- enhances LPL activity (promotes clearance of chylomicrons, VLDL, TGs)
* ** DECREASES LDL & TGA, INCREASES HDL ***
31
Niacin: Pharmacokinetics
- almost completely absorbed
- peak plasma concentrations in 30 to 60 min
- half-life of ~60 min
- at low doses, mostly taken up by liver, only major metabolite found in urine
- at higher doses, greater proportion excreted in urine unchanged
32
Niacin: Therapeutic Uses
- hypertriglyceredemia and elevated LDL-C
- especially useful in hypertriglyceridemia and low HDL-C
- available OTC in prompt and sustained release forms, Rx extended release forms
- start with low dose, increase stepwise every 7 days
33
Niacin: Toxicity/Adverse Effects
- may cause severe hepatotoxicity (sustained release preparations), monitor liver functions
- concurrent use with statin can cause myopathy
- harmless cutaneous vasodilation, warmth (reduced by aspirin or ibuprofen)
- pruritus, rashes, dry skin reported
- nausea and vomiting in some pts
- may cause hyperuricemia, precipitate gout
- in diabetics, may necessitate adjustment of medications used for glycemic control
- Pregnancy Class C
34
Fibrates: Mechanism of Action
- activates the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a transcription factor regulating genes that control lipid metabolism
- expressed primarily in liver and brown adipose tissue
- reduces TG by stimulating fatty acid oxidation
- increases LPL synthesis (enhancing clearance of TG-rich lipoproteins)
- reduces expression of ApoC-III (inhibitor of lipolytic processing and receptor-mediated clearance) --> enhances clearance of VLDL
- stimulation of apoA-I and apoA-II expression (increases HDL levels)
- PRIMARY EFFECT IS TO REDUCE PLASMA TG
- ONLY MODEST DECREASES IN LDL IN MOST PATIENTS
- INCREASED LDL IN SOME PATIENTS AS TG LEVELS ARE REDUCED
35
Fibrates (Fibric Acid Derivatives): Pharmacokinetics
- absorbed rapidly and efficiently with meals; less efficiency on empty stomach
- fenofibrate isopropyl ester hydrolyzed in intestine
- tightly bound to plasma proteins
- peak plasma concentrations in 1 to 4 hrs
- half-lives vary
- widely distributed, concentrations in liver, kidney, and intestine exceed plasma level
- gemfibrozil crosses placenta
- excretion impaired in renal failure (no shit)
36
Gemfibrozil
- fibric acid derivative
- half-life of 1.5 hrs
- crosses the placenta
- used in hypertriglyceridemias in which VLDL predominate
- used in dysbetalipoproteinemia (type III hyperlipoproteinemia)(Apo E2/E2, poor liver uptake of chylomicron particles, VLDL, and IDL)
- causes increased risk of myopathy in patients on statins
37
Fenofibrate
- fibric acid derivative
- half-life of 20 hrs
- used in hypertriglyceridemias in which VLDL predominate
- used in dysbetalipoproteinemia (type III hyperlipoproteinemia)(Apo E2/E2, poor liver uptake of chylomicron particles, VLDL, and IDL)
38
Fibrates: Toxicity/AEs
- GI sxs (5%)
- may potentiate action of oral anticoagulants (displacement of warfarin from plasma proteins)
- gemfibrozil causes increased myopathy risk for pts on statins
- increased cholesterol content of bile, modest increased risk of gallstones
- relative contraindication, pts with renal failure or hepatic dysfunction
- should not be used by children or pregnant women!
39
Ezetimibe
- selectively inhibits intestinal cholesterol absorption, also plant sterols
- targets NPCL1 transport protein in enterocytes
- decreased intestinal delivery of cholesterol to the liver
- increased expression of hepatic LDL receptors
- decreased cholesterol content of atherogenic particles
- ezetimibe and its active glucuronide metabolite circulate enterohepatically and deliver agent back to the site of action and limit systemic exposure
- average reduction in LDL-C with drug alone is ~18%
- synergistic with statins (additional 25% decrease compared to statin alone)
- initially approved based on decrease in LDL cholesterol
- subsequent trials in FH heterozygotes led to questions regarding effect on CHD
