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arebef > Dawes: Lipid Lowering Therapy > Flashcards

Dawes: Lipid Lowering Therapy Flashcards

1
Q

What are the different plasma lipids?

A
  • Cholesterol
  • Triglycerides
  • Fatty Acids
  • Phospholipids
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2
Q

What are the cholesterol subfractions?

A
  • Total Cholesterol (mmol/L)
  • LDL cholesterol
    • Adverse effects
  • HDL Cholesterol
    • Beneficial effects
  • Triglycerides (mmol/L)
    • Adverse Vascular Effects
    • Pancreatitis
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3
Q

What is the pathway of lipid transport?

A
  1. Dietary cholesterol absorbed in the gut is transported to the liver in chylomicrons which are rich in triglycerides.
  2. Cholesterol is also synthesised de novo in the liver, gut and CNS.
  3. Cholesterol in the liver is packaged with triglycerides and converted to VLDL.
  4. VLDL is converted to LDL in the circulation.
  5. LDL delivers cholesterol to most tissues and its uptake is facilitated by LDL receptors.
  6. Excess cholesterol is removed by HDL and then reconverted to LDL and VLDL where it is reuptaken by the liver.
  7. Some of the cholesterol is then excreted in the bile as either free cholesterol or bile acids.
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4
Q

What does total plasma cholesterol mainly reflect?

A

LDL cholesterol.

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5
Q

In a fasting state, what does plasma triglyceride levels reflect?

A

VLDL Concentration

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6
Q

Why do you want to lower cholesterol?

A
  • Primary Prevention
    • Reduction in vascular events with a small effect on mortality.
  • Secondary Prevention
    • Large beneficial effects with reduced CVS mortality and morbidity.
    • 1mmol/L reduction in total cholesterol reduces the risk of a vascular event by 25%.
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7
Q

What are the effects of increasing TC levels on the risk for coronary heart disease in the presence of other risk factors?

A
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8
Q

What is the clinical assessment for hyperlipidaemia?

A
  • A history of end organ damage
    • Primary Prevention
    • Secondary Prevention
  • Examination
    • Increased Blood Pressure
    • Xanthoma - Fatty Growths underneath the skin.
    • Xanthelasma - Fatty Deposits underneath the skin.
  • Investigations
    • U + Es
    • Fasting Cholesterol/ LDL/ HDL/ Trigylcerides
    • Glucose
    • ECG
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9
Q

What patients should be treated for a high lipid count?

A
  • Primary Prevention
    • Those with CVS risk >30% over next 10 years (NZ)
    • Those with CVS risk >7.5% over next team years (US)
  • Secondary Prevention
    • Angina/MI
    • Cerebrovascular Attack
    • Peripheral Vascular Disease
  • Diabetics
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10
Q

What should be peoples target LDL concentrations?

A

,<1.8 mmol/L

This should be achieved through both lifestyle changes and drugs.

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11
Q

Which drugs should be used to treat high lipid concentrations?

A
  • Statins - Act to reduce TC, LDL, Triglyceride and increase HDL.
    • Simvastatin 10 - 40mg
    • Atorvastatin
  • Fibrates - Massive reduction in triglyceride count and increase in HDL.
    • Bezafibrate 200-400mg od
  • Ezetimibe - Decrease TC and LDL
  • Nicotinic Acid - Reduce Triglycerides
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12
Q

When are statins presecribed?

A
  • Primary Prevention
    • Diabetics
    • High CVS risk patients
    • Familial Hypercholesterolaemia
  • Secondary Prevention
    • Previous MI
    • Angina
    • CVS
    • TIA
    • PVD
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13
Q

What is the mechanism of action for statins?

A

Competitively inhibit 3-Hydroxy-3-Methylglutaryl CoA reductase resulting in a reduction in cholesterol synthesis with a secondary upregulation of LDL receptor expression on hepatocytes. As a result, should be given at night.

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14
Q

What are the pharmacokinetics of simvastatin?

A
  • Tmax = 1.3 - 2.4 hours
  • Cmax = 10 - 34 ng/mL
  • Low bioavaliability (5%)
  • High protein binding (94 - 98%)
  • Metabolised by CYP3A4 in the liver.
  • Half-life of 2-3 hours.
  • Urinary and Faecal excretion.
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15
Q

What are the side effects of statins?

A
  • Myalgia
  • Myositis
    • Stop if CK x 10
  • Rhabdomyolysis
  • Deranged LFTs
    • Stop if ALT x 3
  • Teratogenic
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16
Q

What does simvastatin interact with?

A

Drugs that are also metabolised by CYP3A4 such as amiodarone, verapamil, diltiazem and erythromycin.

17
Q

What is the risk of myopathy in patients taking statins?

A

There is 1 case per 10000 patients per year. This is related to the statin concentration and there is increased incidence with SLC01B1 (chromosome 12) with encodes for an organic anion-transporting polypeptide OATP1B1. This anion-transporting polypeptide acts to mediate hepatic uptake of drugs.

18
Q

What is the effects of statins on CV endpoints?

A
  • Total Mortality decreased by 12%
  • Major Vascular Event risk decreased by 21%
19
Q

What is the pleiotropic effect of statins?

A

Statins also appear to have anti-thrombotic, anti-inflammatory and immune modulatory effects before lowering cholesterol.

20
Q

When should you use a fibrate such as bezafibrate?

A
  • Isolated Hypertriglyceridaemia - Also treated with diet, exercise, weight loss and reduced alcohol consumption.
  • Combine therapy with statins
21
Q

What is the mechanism behind fibrates?

A

PPAR-alpha (Peroxisome Proliferator-Activated Receptor Alpha) agonist.

  • Liver and Skeletal Muscle Lipid Metabolism
    • Reduced Hepatic VLDL production
    • Increased Hepatic VLDL clearance
    • Increased Skeletal Muscle FA storage.
  • Activate Lipoprotein Lipase
    • Breaks down TG
22
Q

What are the side effects of fibrates?

A
  • GI upset
  • Deranged LFTs
  • Myositis - Increased risk with concurrent statins.
23
Q

What is the mechanism for ezetimibe?

A
  • Reduce Cholesterol Absorption
  • Reduce Intestinal Delivery of Cholesterol to Liver
  • Increase Expression of Hepatic LDL receptors

Low efficacy as monotherapy so used with statins.

24
Q

What are the side effects of ezetimibe?

A
  • Abdominal Pain
  • Diarrhoea
25
Q

Why does the combination therapy of a statin plus ezetimibe have a high efficacy?

A
  • Cholesterol Production inhibited by a statin.
    • Reduce Synthesis
    • Increase clearance of LDL from blood with upregulation of LDL receptors on hepatocytes.
  • Inhibit intestinal cholesterol absorption with ezetimibe.
26
Q

What are the side effects of nicotinic acid?

A
  • GI intolerance
  • Flushing - Due to increased prostaglandin synthesis
  • Dry Skin

Use in combination with statin or fibrate.

27
Q

What is the mechanism of action for nicotinic acid?

A
  • Reduced FA mobilization from the periphery
  • Reduced hepatic triglyceride/VLDL production.
  • Reduced HDL degradation.
28
Q

What are bile acid binding resins?

A
  • Cholestyramine
    • Bind bile acids
    • Increase hepatic LDLR expression
    • Stop enterohepatic circulation
      • Reduce absorption of exogenous cholesterol
      • Increase conversion of endogenous cholesterol to bile acids.
  • These are given orally and not absorbed systemically.
29
Q

What are the side effects of bile acid binding resins?

A
  • GI side effects
    • Nausea, bloating, constipation and/or diarrhoea.
  • Impair A,D,E,K absorption
  • Interfere with drug absorption
    • Digoxin, warfarin, Thiazides and T4
30
Q

What is the mechanism of action for bile acid resins?

A
  1. Prevent reabsorption of bile acids.
  2. Increase LDL Receptors and therefore increase VLDL and LDL removal.
  3. Increase cholesterol 7-alpha hydroxylase activity and therefore increases conversion of cholesterol to BA.
  4. Increased BA secretion into the intestine.
  5. No reabsorption.

Net Effect: Reduced LDL-C

31
Q

What are CETP inhibitors?

A

These act to increase HDL by inhibiting cholesteryl ester transfer protein.

32
Q

is the reaction of cholesterol to statins effective?

A
  • 50% of CVD patients had no cholesterol measured.
  • 50% of CVD patients had a cholesterol measured.
    • 50% were controlled.
    • 50% were uncontrolled.

Need to increase the monitoring of cholesterol in CVD patients and change dosing effectively.

33
Q

How long do you need to take lipid-lowering medications for?

A

Lifelong!

34
Q

What are the recent controversies for lipid-lowering drugs?

A
  • Secondary Prevention
    • Statins definitely to be given.
  • Primary Prevention
    • Lifestyle changes definitely to be made.
    • Statins benefit is less than it is for secondary prevention.
    • Questions as to patients 10-year risk.
    • Questions as to whether it should be down to patients preference.
35
Q

What are PCSK 9 inhibitors?

A

A protease formed from a heaptocyte binds to LDL-Receptors → receptors endocytosed and broken down. This increases LDL as they’re less likely to be taken up. By blocking this you can decrease LDL levels

Comes as either a monoclonal antibody (evolocumad) or RNA inhibitor (inclisiran) both of which drastically reduce risk of CVS mortality/morbidity.

arebef (29 decks)

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