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Pharmacology - Exam 3 > Lipid Lowering Drugs > Flashcards

Lipid Lowering Drugs Flashcards

1
Q

What is the mechanism of the body to replenish hepatic cholesterol/make more cholesterol in the liver?

A

inc HMG-CoA reductase (blocked by statins)

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2
Q

What is the mechanism to replenish the hepatic cholesterol “pool” (that isn’t making more cholesterol in the liver)?

A

inc LDL receptor expression leading to inc LDL clearance from blood

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3
Q

How is LDL receptor expression increased?

A

via transcriptional up-regulation

also occurs in response to statin therapy

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4
Q

What dietary change can be made to lower cholesterol?

A

increase fiber intake

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5
Q

Mechanism of fiber in lowering cholesterol?

A

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

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6
Q

How does omega-3 polyunsaturated fatty acids (PUFAs) dec cholesterol?

A

inc clearance of triglycerides

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7
Q

Provide an example of a PUFA drug

A

Lovaza

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8
Q

How does Lovaza work?

A

20-50% dec in fasting levels of triglycerides (no impact on pancreatitis)

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9
Q

Is fish oil supplementation helpful?

A

no dec in MIs, stroke deaths, cardiac related deaths, or sudden deaths

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10
Q

Is diet of fish helpful?

A

diet including fish (2x/week) decreases cholesterol and cardiac related deaths

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11
Q

What two forms do statins come in?

A

prodrug and active form

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12
Q

What are the two statins we need to know?

A

atorvastatin (Lipitor) and pravastatin (Pravachol)

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13
Q

What form are atorvastatin and pravastatin in?

A

active

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14
Q

How do statins work?

A

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

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15
Q

What does blocking/inhibiting HMG CoA Reductase do?

A

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)

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16
Q

What are statin’s effects on plasma lipids?

A

reduction of plasma LDL cholesterol!!!! (modest reduction in triglycerides and modest increase in HDL)

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17
Q

Metabolism of atrovastatin

A

metabolized by CYP3A4

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18
Q

Metabolism of pravastatin

A

metabolized by sulfation NOT P450-dependent

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19
Q

Physiologic disposition of atrovastatin

A

half-life 14 hours

administered at any time of day

dec absorption with food

lipophilic so can cross BBB easier

protein bound

20
Q

Physiologic disposition of pravastatin

A

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

21
Q

Adverse effects of statins

A

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

22
Q

1 adverse effect of statins

A

!!!Myopathy/Myalgia!!! (test question)

23
Q

Statin key points: atorvastatin

A

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

24
Q

Statin key points: pravastatin

A

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)

25
Q

Give an example of a cholesterol absorption blocker

A

Ezetimibe as monotherapy dec LDL 15-20% combination therapy with statin for example up to 60% dec in LDL

26
Q

mechanism of action of cholesterol absorption blocker

A

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

27
Q

physiological disposition of Ezetimimbe

A

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

28
Q

provide an example of bile acid sequestrants (resins)

A

cholestyramine

29
Q

mechanism of action of cholestyramine

A

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

30
Q

adverse effects of cholestyramine

A

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

31
Q

provide example of nicotinamide derivative

A

niacin

32
Q

what is Niacin good for

A

best agent to inc HDL

33
Q

mechanism of action of Niacin

A

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)

34
Q

physiologic disposition of Niacin

A

cleared by hepatic metabolism: big first pass effect (one reason why hepatic toxicity can be an issue)

35
Q

Adverse effects of Niacin

A

!!!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

36
Q

provide and example of a fibrate

A

Gemfibrozil

37
Q

how do fibrates work?

A

their impact on lipids varies but if patient is hypertriglycerides…dec TG by 50%, dec VLDL, inc HDL, and dec LDL

38
Q

mechanism of action of Gemfibrozil

A

agonist for PPAR-alpha receptor which dec triglycerides by increasing their clearance

39
Q

physiological disposition of Gemfibrozil

A

half-life is 1.1 hours

can cross placenta

40
Q

adverse effects of Gemfibrozil

A

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

41
Q

review slide of drug effects on TG, LDL, and HDL

A

see picture

42
Q

how does PCSK9 work?

A

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

43
Q

give and example of a PCSK9 inhibitor drug

A

Repatha (evolocumab)

44
Q

Repatha/Evolocumab + Statin results in

A

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)

45
Q

adverse effects of PCSK9 inhibitors

A

nasopharyngitis

Pharmacology - Exam 3 (12 decks)

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