Lipid Lowering Drugs

Question 1

Name the HMG-CoA Reductase Inhibitors

Answer 1

(Statins)
Lovastatin
Atorvastatin
Fluvastatin
Pravastatin
Simvastatin
Rosuvastatin

Question 2

Name the PCSK9 inhibitors

Answer 2

Alirocumab

Evolocumab

Question 3

Name the Cholesterol Absorption Inhibitors

Answer 3

Ezetimibe

Question 4

Name the Resins

Answer 4

Colestipol
Cholestyramine
Colesevelam

Question 5

Name the Niacins

Answer 5

(nicotinic acid, vitamin B3)

Question 6

Name the Fibric acid derivatives

Answer 6

Gemfibrozil

Fenofibrate

Question 7

HMG-CoA reductase inhibitors MoA

Answer 7

• Competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, converts HMG-CoA to melavonate, an early and rate limiting step in cholesterol biosynthesis-> inhibits cholesterolgenesis-> increases expression of LDL receptor-> increases removal of LDL from blood-> decreases hepatic VLDL production

Question 8

HMG-CoA reductase inhibitors Pharmacokinetics

Answer 8

-Absorption: enhanced by food;varies except for fluvastatin (almost complete
-1st pass extraction by liver
-Excreted in bile
1/2 life: 1-3 except atorvastatin (14 hours) , rosuvastatin (19 hours)
-Take in evening

Question 9

HMG-CoA Reductase inhibitors Therapeutic Use

Answer 9

• Use alone or in combo w/ resins, PCSK9 inhibitors, ezetimibe
• Don’t give to women who are prenant, lactating or becoming pregnant (tetraogenic)
• familial hypercholesterolemia

Question 10

Most efficacious statins are?

Answer 10

-Atorvastatin & rosuvastatin -> severe hypercholesterolemia

Question 11

What are statin’s toxic/adverse effects?

Answer 11

• Elevations in serum alanine aminotransferase activity (3x normal) -> meds should be stopped if >3x is persistent or signs of hepatotoxicity present (precipitous decrease in LDL, anorexia, malaise)
• Myopathy- w/ or w/out inc. in creatine kinase -> intense myalgia, fatigue
• Rhabdomyolysis -> myoglobinuria -> renal failure (CK levels 10x over normal)

Question 12

What are statin’s drug interactions?

Answer 12

• Metabolized by CYP3A4
• Do not drink grapefruit juice
• Inhibitors of organic anion transporter (OAT), cyclosporin, gemfibrozil
• Genetic influences-> increased incidence of myopathy ass. w/ polymorphisms in gene encoding liver-specific OAT -> increase accumulation of simvastatin acid in plasma and increased risk of myopathy

Question 13

What are PCSK9 inhibitors MOA? How are they given? and What is their 1/2 lives?

Answer 13

• Monoclonal antibodies against PCSK9 proteins-> prevents the degradation of LDLRs
• Normal: PCSK9 diverts LDLR from recycling pathway towards lysosome for degradation
• SubQ admin.
• Evolocumab: 11-17 days
• Alirocumab: 12 days

Question 14

What are the Cholesterol Absorption Inhibitors? MOA?

Answer 14

Ezetimibe- active glucuronide metabolite circulate enterohepatically
MOA: Selectively inhibits intestinal cholesterol absorption-> targets NPCL1 transport protein in enterocytes
-decreases intestinal delivery of cholesterol to the liver
-increases the expression of hepatic LDL receptors
-decreases cholesterol content of atherogenic particles

Question 15

Bile acid Sequestrants (resins) MOA?

Answer 15

-Highly positively charged -> binds negatively charged bile acids-> prevents reabsorption -> excreted in stool -> hepatic bile-acid synthesis increases -> hepatic cholesterol content declines-> LDLR increased in hepatocytes-> increased clearance of LDL from plasma

Question 16

Why should you give resins with a statin?

Answer 16

-Lower LDL-C, but HMG-CoA reductase is upregulated-> incr. cholesterol synthesis part. offsets reduction in LDL-C s

Question 17

What type of patient should you use resins with extreme cauton?

Answer 17

Pts w/ severe hypertriglyceridemia-> resin induced increase in bile acid production-> leads to increase in hepatic TG synthesis

Question 18

Bile acid sequestrants: Therapeutic Uses

Answer 18

• Take w/ meals or no effect
• Het. FH
• Pts w/ bile salt accumulation and cholestasis
• removal of digitalis from GI tract
• Combined hyperlipoproteinemia in combo w/ other drugs

Question 19

Adverse effects of Resins

Answer 19

• Constipation & bloating-> relieved by increasing fiber or mixing psyllium seed w/ resin
• heartburn & diarrhea
• Malabsorption of vit. K (rare) & folic acid (rare)
• *Increased hepatic TG synthesis (concern in pts w/ TGs >250 mg/dl)

Question 20

What is Niacin (Nicotinic acid)’s MOA?

Answer 20

• Adipose tissue: Inhibits lipolysis of TG by hormone-sens. lipase-> reduces transport of free FA to liver-> decreases hepatic TG synthesis
• Liver: Reduces TG synthesis-> inhibiting synthesis and esterification of FA -> reduces hepatic VLDL production -> enhances LPL activity-promotes clearance of chylomicrons, VLDL, TGS

Question 21

Niacin’s adverse effects:

Answer 21

• Cutaneous vasodilation, warmth-red flushed face
• Pruritus, rashes, dry skin
• nausea and vomiting
• Hyperuricemia, precip. gout
• Hyperglycemia

Question 22

Fibrates MOA

Answer 22

• Activates the peroxisome proliferator-activated receptor-alpha (PPARalpha)-> regulating genes that control lipid metabolism -> induces HDL synthesis
• Upregulates LPL-> increases TG clearance

Question 23

Fibrates Side Effects

Answer 23

• GI symptoms
• Myopathy risk increased in patients on statins (Gemfibrozil)
• Increased cholesterol content of bile-> increased risk of gallstones
• Do not give to preggo and kids
• No no for pts w/ renal failure or hepatic dysfunction