Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Pharm block 4 hemostasis and cardiac > drugs to treat hyperlipidemia > Flashcards

drugs to treat hyperlipidemia Flashcards

1
Q

Protective roles of HDL in the prevention of atherosclerosis

A

1) HDLs (the “good cholesterol”) inhibit the oxidation of LDLs
- paraoxonase enzyme (PON1) present on HDL surface
- anti-oxidant activity

2) HDLs inhibit the expression of adhesion molecules on the endothelium
- prevents recruitment of monocytes to atherosclerotic plaque

3) HDLs inhibit the formation of FOAM cells

4) HDLs promote REVERSE CHOLESTEROL TRANSPORT
- the transport of cholesterol from the periphery back to the liver where it can be secreted as bile

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

PON1 enzyme

A

found on HDL’s surface and prevents the oxidation of LDL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

optimal LDL level

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

optimal HDL level

A

M: >40 mg/dL
W: >50 mg/dL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

optimal triglyceride level

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Very high LDL level

A

> 190mg/dL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

very high triglycerides

A

> 500 mg/dL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

initial drug of choice for someone with hypercholesterolemia

A

statin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what are the classes of drugs used to treat hyperlipidemia

A

statins
Bile acid-binding resins
Cholesterol absorption inhibitors
PCSK9 inhibitors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what are the bile acid binding resins

A

Cholestryamine (Questran®)
Colestipol (Colestid®)
Colesevelam (Welchol®)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what is the cholesterol absorption inhibitor

A

ezetimibe

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what are the PCSK9 inhitibitors

A

Evolocumab

Alirocumab

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

how do statins work

A

STATINS competitively inhibit HMG-CoA reductase
- inhibit endogenous cholesterol synthesis

induces the activation of the SREBP transcription factor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what is the primary clinical effect of statins

A

**Significant reduction in LDL-cholesterol (20-60%- dose/drug specific)
Modest reduction in triglycerides (10-20%)
Modest increase in HDL (5-10%)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what does SREBP transcription factor regulate

A

SREBP regulates expression of the LDL receptor gene

- leading to increased expression of the LDL-R at the PM
- increased LDL-R results in increased clearance of serum LDL
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

pathway by which statins work

A
  1. statins inhibit HMG-CoA reductase leading to decreased production of cellular cholesterol
  2. decreased cholesterol levels trigger the activation of SREBP transcription factor
  3. SREBP activation increases transcription of the LDL receptor gene
  4. increased expression of the LEL receptors increase the clearance of LDLs from the serum
  5. LDLs are internalized and their cholesterol can be excreted in the bile
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what 2 things are statins the drug of choice when treating

A

patients with increased LDL

primary and secondary prevention of CHD

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

primary prevention of CHD

A

even in patients with no clinical CHD and normal LDL, statin treatment lowered the number of coronary events, CHD death, stroke and total mortality

therefore statins are effective at lowing CHD risk regardless of initial baseline LDL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

effects of doubling the dose of a statin

A

very small further reduction in LDL level (5%)

significant increase in adverse effects

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what are the adverse effects of Statins

A

GI disturbances *most common
increased liver enzymes (rare)
type-2 diabetes (benefit outweighs risk)

  • effects on muscles (common 5-10%)
  • myalgia (pain)
  • myopathy (weakness)
  • dose dependent
  • Rhabdomyolysis (rare but serious)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

what is rhabdomyolysis

A

muscle inflammation & disintergration (very rare, but v. serious)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

what increases the chances of rhabdomyolysis in a patient taking statins

A

taking statin + an interacting drug (cyclosporin, macrolide, ketaconazole)
high doses

associated with a polymorphism in the Statin hepatic anion transporter

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

where are statins absorbed

A

the intestine 30-85%

Lovastatin, Simvastatin, Atorvastatin undergo metabolism by CYP3A4 in the intestine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

how does grapefruit juice affect statins

A

grapefruit juice inhibits CYP3A4 in the intestine therefore preventing metabolism and increasing the bioavailability of the drugs. Could lead to increased risk of adverse effects

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

how are statins taken up by the liver

A

via the OATP2 transporter

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

where are statins metabolized and excreted

A

STATINS are metabolized in the liver and excreted in the bile and feces (primarily hepatic excretion)

all STATINS are glucoronidated by glucurornyl transferase enzymes (UGT1A1/1A3)

- facilitates both further metabolism and excretion - STATINs are variably metabolized by the CYP450 system
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

which statin is not metabolized by CYP450 enzymes

A

Pravastatin (hepatic and renal excretion)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

what is responible for low serum concentrations of statins

A

OATP2 transporter

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

STATINS: Drug interactions

A

Drugs that inhibit cytochrome P450 enzymes will increase the concentration of specific STATINs leading to increased risk of adverse effects especially myopathy and Rhabdomyolysis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

which statins are affected by CYP3A4 inhibitors

A

Lovastatin, Simvastatin & Atorvastatin (LSA) (increases their levels)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

which statins are metabolized by CYP2C9 and are therefore affected by CYP2C9 inhibitors

A

Fluvastatin & Rosuvastatin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

how do inducers of CYP3A4 affect statins

A

reduce plasma concentrations of Lovastatin, Simvastatin & Atorvastatin, thereby reducing clinical efficacy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

what is the statin of choice when there is a concern about a drug interaction

A

Pravastatin (especially for transplant pts on a cyclosporin)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

interaction between Gemfibrozil and statins

A

is strongly associated with an increased risk of STATIN-induced myopathy and Rhabodmyolysis.

A) inhibits OATP2 transporter-mediated uptake of STATINS into the liver (by competition)
- can increase STATIN systemic bioavailability >2X

B) inhibits the glucoronidation of STATINs, which is involved in the metabolism and ultimate excretion of ALL STATIN drugs (including Pravastatin)
- can cause an increase in the systemic levels of ALL STATIN drugs.

35
Q

UGT1A1 and UGT1A3

A

glucoronyl transferases responsible for the glucoronidation of statins

  • inhibited by gemfibrozil
36
Q

STATINS: Contraindications

A
  1. Pregnancy, Nursing mothers and women who may become pregnant
  2. Patients with liver disease
    - due to predominant HEPATIC ELIMINATION
    - can result in increased serum drug concentrations leading to increased risk of Rhabdomyolysis
    - PRAVASTATIN safer choice due to dual HEPATIC/RENAL elimination
37
Q

Bile Acid-binding resins primary clinical effect

A
  • Modest reduction in LDL-C (10-25%)

* However-can potentially cause a small increase in serum triglycerides

38
Q

bile acid binding resins MOA

A
  1. Resins are cationic polymers that bind to negatively charged bile acids and prevent their reabsorption in the small intestine.
    • Resin/bile acid complexes are excreted in the feces (~10X increase)
  2. Decreased bile acid resorption causes increased bile acid production in the liver resulting in a decrease in the hepatic cholesterol concentration
    • this triggers upregulation of LDL-R and increased LDL clearance (by the same SREBP mechanism
39
Q

Process of MOA of bile acid-binding resins (steps)

A
  1. drugs bind to bile acids and inhibit their reabsorption
  2. decreased bile acid resorption upregulates cholesterol 1a-hydroxylase the rate limiting enxyme in bile acid synthesis resulting in increased conversion of cholesterol to bile acids
  3. decreased cholesterol induces increased LDL-R
  4. increased LDL clearance
40
Q

why may there be an increase in triglycerides with bile acid-binding resins

A

Bile Acids normally serve to suppress endogenous triglyceride synthesis - therefore bile acid resins can actually increase triglyceride levels especially in patients with
Hypertriglyceridemia/type III dysbetalipoproteinemia

41
Q

bile acid-binding Resins: Therapeutic Uses

A
  1. Demonstrated by clinical trials to reduce the risk of CHD events (usually 2nd line due to efficacy of statins)
  2. Can be used in combination with a STATIN
    • to aggressively reduce LDL-C - additive effect
    • and/or to allow use of a lower STATIN dose in order to avoid STATIN-dependent adverse effects at high doses of STATIN i.e. Rhabdomyolysis
  3. Can be used in patients for whom STATINs are either not effective or contraindicated
42
Q

for what patient population is bile acid-binding resin the drug of choice to treat hypercholesterolemia?

A

Children and women who are lactating or pregnant

43
Q

adverse effects of bile acid-binding resins

A

a) Resins not absorbed or metabolized- therefore very safe/few side effects
b) GI disturbances (e.g. constipation, bloating flatulence) are most common
c) At high concentrations Cholestyramine and Colestipol, but not Colesevelam, impair the absorption of the fat soluble vitamins A, D E & K

44
Q

Resins: Drug Interactions

A

Cholestyramine and Colestipol, but not Colesevelam, interfere with the absorption of many drugs

e.g. tetracyline, penicillin, vancomycin, phenobarbital, digoxin, warfarin, propanalol, parvastatin, fluvastatin, aspirin, and thiazide diurectics

These drugs should be taken either 1-2 hrs before or 4-6 hrs after Resins

45
Q

contraindications of bile acid-binding resins

A

Type III Dysbetalipoproteinemia and raised triglycerides (>400 mg/dL) due to risk of further increasing VLDL levels

46
Q

Inhibitors of Cholesterol Absorption (Ezetimibe (Zeita®)) primary affect

A

Reduces LDL-C (~18%)

Minimal effect on HDL and triglycerides

47
Q

advantage of Ezetimibe over bile acid-binding resins

A

Ezetimibe does not raise triglyceride levels

48
Q

MOA of Ezetimibe

A

a) Inhibits the action of the Niemann-Pick C1-like 1 protein (NPC1L1) involved in the absorption of dietary and biliary cholesterol in the small intestine
b) Reduced cholesterol absorption results in the decreased delivery of cholesterol to the liver, thereby reducing VLDL and LDL production and increasing LDL-R

49
Q

Ezetimibe: Therapeutic Uses

A
  1. Reduces LDL-C in patients with primary hypercholesterolemia
    • i.e. not completely dependent upon intact LDLR
  2. Can induce a significant further LDL-C lowering effect when combined with a STATIN
    • further 25% reduction in LDL-C than with STATIN alone
    • allows the use of a lower STATIN dose to avoid adverse effects
50
Q

Ezetimibe: Adverse Effects

A

Generally well tolerated

- Flatulence and Diarrhea the most common effects

51
Q

PCSK9

A

a secreted enzyme produced by the liver & other cell types

Binds to the LDLR at the cell surface and is internalized with the receptor and LDLs

Prevents LDLR recycling back to the plasma membrane and instead targets the receptor to degradation in the lysosome
- thought to be responsible for tonically controlling the levels of LDLR expressed on liver cells

52
Q

gain of function mutations of PCSK9 causes

A
  • Autosomal dominant FH
  • serum LDL >350 mg/dL
  • increased Risk of CVD (death
53
Q

Loss of function mutations in PCSK9 causes

A
  • 40% decrease in LDL levels
  • 88% reduction in CVD risk
  • increased expression of hepatic LDL-R
54
Q

how does Alirocumab and Evolocumab affect PCSK9

A

are human antibodies specific for PCSK9
bind to PCSK9 and prevent its binding to the LDLR
- thereby prevent the targeting of LDL-R to the lysosome
- result in increased expression of LDL-R at the cell surface

55
Q

who can benefit from taking Alirocumab or Evolocumab

A

approved for treatment of heterozygous FH & patients that have not achieved goals with maximally tolerated STATINs

shown to decrease serum LDL even in the presence of a maximally tolerated statin

56
Q

how is Alirocumab or Evolocumab administered

A

Injected subQ every 2 weeks

57
Q

Mipomersen

A
  • Antisense oligonucleotide specific for apoB100

* Reduces expression of apoB100 resulting in reduced production of VLDLs and hence lower levels of LDLs

58
Q

elevated triglycerides (>500) put a pt at high risk for?

A

Pacreatitis

59
Q

what do you use to treat hypertriglyceridemia

A

Niacin

OR

Fibrates:
Gemfibrozil
Fenofibrate

60
Q

high triglycerides should be treated before or after high LDL

A

if triglycerides are greater than 500 then they should be addressed first

61
Q

Niacin primary clinical effect

A

30-80% reduction in triglycerides
10-20% reduction in LDLs
10-30% increase in HDLs - most effective drug at raising HDLs

62
Q

therapeutic uses of niacin

A
  1. Lowers both plasma cholesterol and triglycerides
  2. Most effective agent at increasing HDL levels
  3. In patients with a history of previous MI NIACIN has been shown in clinical trials to reduce the incidence of:
    - re-infarctions
    - cerebrovascular events
    - overall mortality
  4. Often combined with another lipid lowering drug such as a STATIN or RESIN (especially when high LDL and low HDL is present)
63
Q

Niacin MOA

A
  1. Agonist for Gi-coupled GPCR (GPR109A) expressed in adipose tissue
    • inhibits cAMP-induced lipolysis (stimulated via the Gs-coupled β-AR)
    • reduces the release of FFA from adipose tissue
    • less FFA available for hepatic triglyceride synthesis and production of VLDL resulting in decreased serum triglycerides
  2. Inhibits DGAT2 (diacylglycerol acyltransferase)
    • rate limiting enzyme in hepatic triglyceride synthesis
    • reduces hepatic VLDL synthesis
  3. Reduces hepatic expression of apoCIII (secreted inhibitor of LPL)
    • leads to increased LPL activity (i.e. greater VLDL breakdown)
    • resulting in increased VLDL clearance
  4. Increases the half life of apoAI
    • the major lipoprotein present in HDLs
    • increases concentration of serum HDLs
    • promotes reverse cholesterol transport
  5. Inhibits macrophage recruitment to atherosclerotic lesions (via activation of GPR109A)
  • *6. Niacin reduces the level of Lp(a) lipoprotein
    • a modified form of LDL that is covalently linked to the Lp(a) protein
    • Lp(a) is homologous to plasminogen (involved in thrombolysis pathway)
      - Lp(a) blocks the formation of plasmin and prevents thrombolysis, thereby increasing the risk of a CLOT forming* (therefore Niacin decreases the risk)
64
Q

the niacin receptor is

A

GPR109A (GPCR)

65
Q

affects of Niacin

A

increased thrombolysis
decreased risk of clots
decreased risk of MI/Stroke

66
Q

what is the effect of niacin on Lp(a) lipoprotein

A

niacin reduces the levels

67
Q

what does Lp(a) lipoprotein do

A

a modified form of LDL that is covalently linked to the Lp(a) protein

- Lp(a) is homologous to plasminogen (involved in thrombolysis pathway)
	- Lp(a) blocks the formation of plasmin and prevents thrombolysis, thereby increasing the risk of a CLOT forming
68
Q

what is the adverse effect of niacin that most commonly causes discontinuation

A

Skin flushing and itching (pruritis) (causes ~26% discontinuation)

prostaglandin-mediated effect and can be diminished by prior treatment with an NSAID e.g. Aspirin or Ibuprofen

69
Q

what are the adverse effects of Niacin

A
  1. GI distress, nausea and abdominal pain are common
  2. Skin flushing and itching (pruritis) (causes ~26% discontinuation)*
  3. Inhibits tubular secretion of URIC ACID- predisposes to GOUT (20%)*
  4. Can exacerbate PEPTIC ULCER DISEASE
  5. Can cause modest hyperglycemia in some Type-2 diabetes patients
  6. Rare cases of Hepatic toxicity have been reported
70
Q

Niacin: Contraindications

A

a) Peptic Ulcer disease
b) Patients with a history of gout
c) Used with caution in diabetics
d) Used with caution in patients with impaired liver function

71
Q

what are the 2 Fibrates

A

Fenofibrate (Tricor®/Lofibra®)

Gemfibrozil (Lopid®)

72
Q

what is the clinical effect of fibrates

A

40-60% reduction in triglycerides
Mild (10-20%) reduction in LDL
10-20% increase in HDL

73
Q

Fibrates MOA

A

Mechanism of Action
a) Fibrates act as ligands for the nuclear hormone transcription factor PPARα

b) Fibrates activate PPARα to promote the expression of genes involved in Lipoprotein structure, function and metabolism

74
Q

PPARa activation cause what effects

A

increased apoAI (increase plasma HDL)

decreased apoCIII synthesis in hepatocytes, leads to increased LPL and increased peripheral VLDL clearence (decreased plasma triglycerides)

Increased hepatic expression of genes involved in fatty acid transport/metabolism, decreased hepatic Triglyceride synthesis and decreased VLDL secretion (decreased plasma triglycerides)

75
Q

Fibrates therapeutic uses

A
  1. Treatment of hypertriglyceridemia associated with low HDL
    ↓serum triglyceride levels and ↑HDL levelsTherapy of choice for patients with
    Familial dysbetalipoproteniemia/Type III Hyperlipoproteinemia:
    ↑plasma triglycerides and IDL/VLDL remnants
  2. Treatment of patients with high levels of trigylcerides (>500 mg/dL)
    - at risk of developing pancreatitis (potentially fatal)
  3. Long-term fibrate usage has been clinically proven to reduce the incidence of:
    - Coronary events (22%)
    • Stroke (25%)
    • Transient ischemia events (59%).
76
Q

Fibrates are the drug of choice for

A

Familial dysbetalipoproteniemia/Type III Hyperlipoproteinemia:

↑plasma triglycerides and IDL/VLDL remnants

77
Q

Fibrates: Adverse Effects

A
  1. Generally well tolerated: Most common side effects are mild GI disturbances - Only 10% of patients discontinue therapy
  2. Increased predisposition to gallstones
  3. Myopathy and Rhabdomyolysis leading to acute renal failure (V. RARE)- more common with Gemfibrozil (15x vs fenofibrate)
    - increased risk when given with a high dose of STATIN (esp Gemfibrozil)
  4. Hepatitis- increased liver transaminases (~5% of patients)
78
Q

how do fibrates increase predispostion to gallstones

A
  • Fibrates inhibit expression of cholesterol 7α-hydroxylase
    (rate-limiting enzyme in bile acid synthesis) thereby decreasing Bile acid production.
  • decreased production of bile acids results in the increased secretion of free Cholesterol which can lead to the increased formation of gallstones
79
Q

Fibrates drug interactions

A

Both Gemfibrozil and fenofibrate are strong protein binders and can displace other protein-bound drugs from albumin resulting in increased concentrations

  1. Gemfibrozil can increase the serum concentration of STATINS leading to an increased risk of myopathy and Rhabdomyolysis
80
Q

Fibrates: Contraindications

A
  1. Pregnant/lactating women or women who may become pregnant
  2. Patients with severe hepatic dysfunction
    • due to the increased risk of hepatic damage with these drugs
  3. **Patients with severe renal dysfunction
    • both gemfibrozil and fenofibrate are renally excreted
    • drug concentration can be significantly elevated
    • associated with increased risk of Rhabdomyolysis
  4. **Patients with pre-existing gallbladder disease
    • due to the effects of drugs on cholesterol excretion
      i. e. inhibition of cholesterol 7α-hydroxylase gene expression
81
Q

Fish Oils: Omega-3 long chain polyunsaturated fatty acids

Ethyl esters of eicosapentaenoic acid & Docosahexaenoic acid (Lovaza®) primary clinical effects

A

Lowers serum TG levels by ~30-50%
Minor increase in HDL
Can increase LDL in some individuals

82
Q

Fish Oils: Omega-3 long chain polyunsaturated fatty acids therapeutic uses

A

Currently approved only as an adjunct to diet in the treatment of hypertriglyceridema in individuals with trigylceride levels >500 mg/dl

83
Q

fish oils MOA

A

Mechanism of action is unclear, but appears to involve inhibiting the expression of genes involved in hepatic triglyceride synthesis

also posses anti-inflammatory activity- acts via GPCR expressed on macrophages
May explain reported benefits of omega-3 fatty acids in treatment of chronic inflammatory diseases

Pharm block 4 hemostasis and cardiac (12 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions