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Pharmacology > Atherosclerosis→ > Flashcards

Atherosclerosis→ Flashcards

1
Q

Reasons of treating dyslipidemia?

A

Elevation of plasma lipoproteins containing apolipoproteins B-48 and B-100 [including low-density lipoprotein (LDL) very low-density lipoprotein (VLDL) and chylomicrons]

→buildup of lipids in the artery wall

→activation of macrophages →→ inflammatory responses
→→→plaque formation →→→→narrowing of arteries
→Atherosclerosis

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2
Q

Lipoproteins

A

Macromolecular Complexes of Lipids and Proteins
-lipid components core regions containing cholesteryl esters, triglycerides (TG) surrounded by unesterified cholesterol and phospholipids]
→protein components
→→apolipoproteins (apo) [to provide structural stability for lipoprotein receptor
interactions as co-factors in enzymatic processes]

Different Compositions
→different in size and density
→→chylomicrons [contains high MW apo B 48 and apo E]
→→very low density lipoprotein ( VLDL)[contains apo E]
→→low density lipoprotein (LDL)
→→lipoprotein (a) Lp (a) LDL with apo (a)
- high density lipoprotein (HDL)[contains apo A I]

→different roles in the transport of lipid in circulation
[apo (a) structurally related to plasminogen → inhibits thrombolysis]

VLDL, LDL, Lp(a) [contains high MW apo B 100]

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3
Q

Lipoproteins

Chylomicrons

A

Transport Triglycerides (TG) and Cholesterol (C) from Gastrointestinal Tract to Circulation

→lipoprotein lipase in tissues converts triglycerides to free fatty acids, which is taken
up into tissues

→chylomicron remnants [=chylomicrons with decreased triglycerides]
→→taken up into the liver by receptor-mediated endocytosis

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4
Q

Lipoproteins

VLDL (very low density lipoprotein)

A 
Transport Triglycerides (TG and Cholesterol (C) from Liver to Circulation
→lipoprotein lipase in tissues converts triglycerides to free fatty acids, which is taken
up into tissues
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5
Q

Lipoproteins

LDL (low density lipoprotein)

A

Contain High Content of Cholesterol VLDL without triglycerides]
→taken up into liver 70 and tissues 30 by receptor-mediated endocytosis

Cholesterol
→synthesis of cell membrane or steroids in tissues
→synthesis of bile acids in liver for elimination
→elimination in liver by secretion

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6
Q

Lipoproteins

HDL (high density lipoprotein)

A

→Take Up Cholesterol from Peripheral Tissues and Transfer it to VLDL or
LDL in the Circulation

→Possess Anti inflammatory, Antioxidative, Platelet Antiaggregatory,
Anticoagulant and Profibrinolytic Activities

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7
Q

Name and Effect of 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG CoA) Reductase Inhibitors
(Statins)

A

e.g. lovastatin, simvastatin, atorvastatin

Decreased Plasma Level of LDL
-by inhibiting 3 hydroxy 3 methylglutaryl coenzyme A (HMG CoA) reductase in
the liver
→decreased synthesis of cholesterol in the liver
→→decreased cholesterol level in the liver

→→promote the synthesis of LDL receptors in the liver
→→→decreased clearance of plasma LDL

Modest decreased Plasma Triglycerides

Small increased Plasma Level of HDL
- due to decreased plasma level of LDL

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8
Q

Clinical Uses, Duration of actions and adverse effects of Statins

A

Clinical Uses

  • prevention of atherosclerosis in patients with elevated LDL
  • NOT for pregnant/nursing women

Duration of Action
- short half life 1 4 hours) e g lovastatin, pravastatin, fluvastatin
→ taken at bedtime
-long half life 14 20 hours) e g atrovastatin rosuvastatin
→taken at any time of day

Adverse Effects
- mainly mild unwanted effects (eg gastrointestinal disturbance) → relatively safe

  • risk of hepatotoxicity (rare and unpredictable)
    measurement of serum alanine aminotransferase (ALT) level

-risk of myopathy [risk increased with higher plasma concentration of statins]
→muscle pain, weakness and fatigue in severe cases → rhabdomyolysis, renal failure and death
→→monitored by measuring plasma creatine kinase ( level

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9
Q

Factors Leading to increased Plasma Levels of Statins

A
  • advanced age [especially 80 years of age]
  • hepatic or renal dysfunction
  • small body size
  • concurrent drug intake
    → decreased hepatic uptake of statins by the organic anion transporter OATP1B1
    eg gemfibrozil [not with fenofibrate]
    → decreased metabolism of statins by cytochrome P 450 enzymes and glucuronidases
    e g gemfibrozil [not with fenofibrate], warfarin, erythromycin (antibiotics) itraconazole (antifungals)
    ( HIV protease inhibitors
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10
Q

Name and Effectof Niacin (Nicotinic Acid)

A

[Vitamin B3]

Decreased Plasma Levels of VLDL
-mainly by inhibiting hormone sensitive lipase in adipose tissue
→→ decreased flux of free fatty acids to liver
→→→ decreased hepatic triglyceride synthesis
- modestly increased clearance of chylomicrons and VLDL
by enhancing lipoprotein lipase activity

Decreased Plasma Level of LDL
→due to decreased level of VLDL

Increased Plasma Level of HDL
→due to decreased clearance of HDL apolipoprotein A I in the liver

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11
Q

Clinical Uses and Adverse effects of Niacin

A

Clinical Uses

  • normalize LDL in patients with or without genetic defects of LDL receptors
  • most effective in increased HDL level and cause marked reduction of triglyceride level

Adverse effects
- flushing [reversed by aspirin tachyphylaxis occurs within a few days]
- skin rashes and acanthosis nigricans
- gastrointestinal disturbances
→avoided in patients with severe peptic disease
- risk of hepatotoxicity →monitoring of ALT level
- decreased glucose tolerance →caution with diabetic patients
- increased uric acid levels→ caution in patients with history of gout
- risk of birth defects → NOT for pregnant women
- rare atrial arrhythmias, maculopathy

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12
Q

Name and effect Fibric Acid Derivatives (Fibrates)

A

e.g. clofibrate , gemfibrozil , fenofibrate

Decreased Plasma Level of VLDL
- mainly by increasing synthesis of lipoprotein lipase
→ increased conversion of triglycerides to fatty acid in tissues  LDL formation]
- by increasing fatty acid oxidation in the liver
→Decreased VLDL secretion from liver

Increased/Decreased Plasma Level of LDL
- decreaseddue to decreased plasma level of VLDL
- increased due to increasead triglyceride breakdown
Modest increased Plasma Level of HDL
- due to increased production of HDL apolipoproteins A-I and A-II

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13
Q

Clinical Uses and Adverse effects of Fibrates

A

Clinical Uses
-treatment for hypertriglyceridemia [caution in patients with combined hyperlipidemia]

NOT for pregnant women or children

Adverse Effects
- mainly mild unwanted effects (eg gastrointestinal disturbance, rashes)  relatively safe
- risk of myopathy
→caution with combination with statins [risk reduced by reducing dose of statins less likely with fenofibrate combining with statin]
- increased plasma level of liver enzymes → avoided in patients with hepatic or renal dysfunction
-increased risk of cholesterol gallstones → caution in patients with biliary tract disease
- increased anticoagulant action of warfarin

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14
Q

Name and effect of Bile Acid Sequestrants

A

e.g. cholestyramine , colestipol , colesevelam

Decreased Plasma Level of LDL
- by binding to bile acids in the intestines
→ decreased reabsorption of bile acids back to the liver
→→ excretion of bile acids
→→→ increased conversion of cholesterol to bile acids in the liver
→→→→ decreased cholesterol level in the liver
→→→→ promote the synthesis of LDL receptors in the liver
[this effect is partially offset by enhanced cholesterol synthesis
caused by up-regulation of HMG CoA reductase]
→→→→→ increased clearance of plasma LDL

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15
Q

Clinical Uses and Adverse effects of Bile Acid Sequestrants

A

Clinical Uses

-in conditions with increased LDL only
[may
cause increased hepatic triglyceride synthesis → contraindicated in patients with hypertriglyceridemia]

  • recommended for patients 11 to 20 years old
  • not effective in patients with dysfunction LDL receptors

Adverse Effects
- no systemic toxicity [because resins are not absorbed from gastrointestinal tract]

  • gastrointestinal disturbances eg bloating, dyspepsia and constipation
    →avoided in patients with diverticulitis
    [risk reduced by completely suspending the drug in liquid several hours before ingestion]
    →→ relieved by increasing dietary fiber intake
  • decreased absorption from gastrointestinal tract
    →of fat soluble vitamins e g vitamin K
    →→measure prothrombin time [especially with anticoagulant therapy]
  • of drugs e g warfarin, thiazides, aspirin, fluvastatin
    →other medication taken 1 hour before, or 2 hour after resin
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16
Q

Name, mechanism, drug interaction and adverse effects of Cholesterol Absorption Inhibitors

A

Ezetimibe
– a cholesterol absorption inhibitor

Decreased Plasma Level of LDL
- by binding to Niemann Pick C 1-like 1 protein
(NPC1L1)
→ decreased incorporation of cholesterol into chylomicrons
→→ decreased delivery of cholesterol by chylomicron remnants to the liver
→→→ decreased absorption of cholesterol level in the liver
→→→ promote the synthesis of LDL receptors in the liver
[this effect is partially offset by enhanced cholesterol
synthesis caused by HMG CoA reductase up regulation]
→ increased clearance of plasma LDL

Drug Interaction
- plasma level of ezetimibe increased by fibrates and reduced by bile acid sequestrants

Adverse Effects
-mainly mild eg headache, diarrhea → relatively safe

17
Q 
Name, mechanism, usage and adverse effects of Proprotein
Convertase Subtilisin Kexin
Type 9 (PCSK9) Inhibitors
A

Alirocumab and Evolocumab
–human monoclonal antibodies against proprotein convertase subtilisin/ kexin type 9 (PCSK9)

Decreased Plasma Level of LDL
- by binding to PCSK 9 thus preventing PCSK 9 from
binding to LDL receptor
→ decreased degradation of LDL receptors in the liver
→ increased clearance of plasma LDL

Use as Second Line Treatment
- for patients refractory to diet modification and maximally tolerated statin therapy
→prevent cardiovascular events e g heart attacks, strokes and coronary revascularization

Adverse Effects
- mainly mild e g muscle complaints, injection site reactions, and nasopharyngitis  relatively safe

18
Q

Name, mechanism, usage and adverse effects of Microsomal Triglyceride Transfer
Protein (MTP) Inhibitor

A

Lomitapide
– a small molecule that binds to the enzyme microsomal triglyceride transfer protein (MTP) in the liver and intestine

Decreased Plasma Level of VLDL and LDL
- by binding to MTP thus inhibiting the transfer of newly synthesized triglycerides in the endoplasmic reticulum onto the newly synthesized apolipoprotein B
→→ decreased assembly of chylomicrons in the intestine
→→ decreased assembly of VLDL in the liver
→→→ proteasomal degradation of apolipoprotein B
→→→ decreased secretion of chylomicrons and VLDL to the plasma

Use as Second Line Treatment
- available only through a restricted Risk Evaluation and Mitigation Strategy
( program

-adjunct to a low fat diet and other lipid lowering treatments

  • contraindicated in patients with concomitant intake of CYP3A4 inhibitors
  • NOT for pregnant women

Adverse Effects

  • diarrhea, vomiting and abdominal pain improved tolerability by strict low fat diet]
  • risk of hepatotoxicity and liver steatosis → elevated serum ALT and AST levels]
19
Q

Name, mechanism, usage and adverse effects of Apolipoprotein

B Synthesis Inhibitor

A

Mipomersen
–an antisense oligonucleotide targeting the mRNA of apolipoprotein B-100 in the liver [for subcutaneous administration

Decreased Plasma Level of VLDL and LDL
- by binding to apolipoprotein B 100 mRNA thus leading to the degradation or
disruption of the apolipoprotein B 100 mRNA
→ decreased expression of apolipoprotein B 100 protein
→→decreased assembly of VLDL in the liver
→→→ Decreased secretion of VLDL to the plasma

Use as Second Line Treatment

  • available only through a restricted REMS program
  • adjunct to a low fat diet and other lipid lowering treatments
  • contraindicated in patients with mipomersen hypersensitivity or liver diseases

Adverse Effects
- injection site reactions [pain, itching and hematoma]

  • flu-like symptoms, fatigue and headache
  • risk of hepatotoxicity and liver steatosis → elevated serum ALT and AST levels]
20
Q

Name, mechanism, usage and adverse effects of Adenosine
Triphosphate Citrate Lyase
Inhibitor

A

Bempedoic acid
– a prodrug [activated by long chain acyl coenzyme A synthetase 1 (ACSVL1) in liver to the active
metabolite ETC 1002 CoA which is the adenosine triphosphate (ATP) citrate lyase inhibitor]

Decreased Plasma Level of LDL
- by inhibiting adenosine triphosphate ( citrate lyase in the liver
→ decreased synthesis of cholesterol in the liver
→ → decreased cholesterol level in the liver
→ →promote the synthesis of LDL receptors in the liver
→ → → decreased clearance of plasma LDL

Use as Second Line Treatment
- as an adjunct to diet modification and maximally tolerated statin therapy in patients
→ prevent cardiovascular events
- contraindicated in patients with concomitant intake of simvastatin 20 mg) or
pravastatin 40 mg)mg)[to avoid  risk of myopathy]

Adverse Effects
- mild to moderate [ urinary tract infection, arthralgia]

  • long term safety to be determined
  • risk of hyperuricemia [due to inhibition of renal organic anion transporter 2
  • risk of tendon rupture [rare]
  • risk of hepatotoxicity and liver steatosis → elevated serum ALT and AST levels]
21
Q

Combination Therapy

A

Lowest Effective Doses Used

More Closely Monitoring for Potential Toxicity

Common Regimens
- Statins and Ezetimibe [highly synergistic]

  • Statins and Resins [highly synergistic]
  • Statins and PCSK 9 inhibitors [highly synergistic]
  • Ezetimibe and PCSK 9 inhibitors [highly synergistic]
  • Statins and Fenofibrate [risk of myopathy and hepatotoxicity]
  • Statins and Niacin [combined hyperlipidemia risk of myopathy (rare)
  • Niacin and Resins [combined hyperlipidemia]
  • Statins, Resins and Niacin

Pharmacology (30 decks)

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