CVS 5 - Lipids Flashcards

1
Q

Lipoproteins

A
  • Cardiovascular disease is a major killer in western world
  • Elevated LDL leading to atherosclerosis major contributor

Hydrophobic core: •cholesterol–fatty acid ester •triacylglycerol

Surface monolayer of phopholipid
•amphipathic nature allows transport in blood

•Apolipoprotein – amphipathic surface proteins -ligands for lipoprotein receptors

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

Pathophysiology

A

• Clear link between cardiovascular disease and elevated LDL & decreased HDL (HDL is protective)
• Lowering LDL/HDL ratio slows arthrosclerosis
• Hyperlipidemia’s:
– Hypercholesterolemia
– Hypertriglyceridemia
– Mixed hyperlipidemia
• Hyperlipidemia’s may be
– familial (genetic component) eg LDL-R mutations – diet

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

good and bad cholesterol

A

HDL = good cholesterol

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

Management of hyperlipidemias

A

• Multiple causes of atherosclerosis – should consider all of these
• Risk factors:
– Smoking 2x↑ coronary artery disease
– Diet & obesity ↑ risk MI & physical activity ↓ risk MI
– hypertension & diabetes→ risk ↑ MI treat these!
• Lifestyle changes before pharmacological intervention –can reduce LDL
• Pharmacological treatment
– Primary prevention versus secondary prevention
» Primary: treatment before clinical evidence of disease
– measure serum cholesterol in patients with family history of arterial disease, obesity, diabetes, hypertension
» Secondary: treatment after clinical evidence of vascular disease – significantly decreased risk of MI

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

Statins

A

– reduce mortality after myocardial infarction

– reduce mortality in absence of obvious cardiovascular disease

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

Statins indications and mechanism

A

• Indications
– occlusive arterial disorders (eg stroke) coronary heart disease (angina, MI)
– Patients at risk of arthrosclerosis even if asymptomatic eg
» diabetic patients>40 (increased risk of cv disease)
» familial hypercholesterolaemia • Mechanism
– Inhibit synthesis of cholesterol
– ↓liver cholesterol →active SREBP→↑ expression of LDL receptor →↑LDL uptake→ ↓plasma cholesterol
– Some reduction in triglyceride concentration – increased clearance VLDL, but fibrates often preferred

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

Statins drugs and effect

A
• Drugs
– Lovastatin - first statin approved, isolated from aspergillus fungus
– Simvastatin - prodrug activated by cyp3A4; short t1⁄2 ~2hr
– Pravastatin –short t1/2~2hr
– Fluvastatin –short t1/2~2hr
– Atorvastatin - long t1/2~14h
– Rosuvastatin- long t1/2~14h
– Pitavastatin – coming soon? t1/2~11 h

• Effect
– Up to 60% reduction LDL cholesterol (20-40% more typical)
– Combinations with other drugs if necessary

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

what determines what time of day to take statin

A

Short t1⁄2 - hepatic metabolism. Take at night – when cholesterol synthesis occurs

Longer t1⁄2 - can take during day

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

Statins PK, ADR, caution, contraindication and interaction

A

• PK
– most subject to high first pass metabolism (dominant site of therapy = liver)
– differences in metabolism affect drug-drug interactions » metabolised by Cyp3A4: simvastatin, atorvastatin » metabolized by Cyp2C9: fluvastatin
» not metabolised by Cyps: pravastatin, rosuvastatin (renal elimination)
• ADR
– generally well tolerated
– myopathy (esp at high dose). Mechanism unclear
» muscle pain, stiffness & can progress to rhabdomyolysis
» monitor by measuring serum creatine kinase level if necessary
» risk increased by renal insufficiency, co-treatment with fibrates or ciclosporin
• Cautions
– patients at risk of myopathy (eg muscular dystrophy)
• Contraindications
– liver disease
– pregnancy (avoid pregnancy 1 month after stopping drug)
– breastfeeding
• Interactions
– Significant! Drugs affecting Cyp P450
» eg warfarin –potential increase in level

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

define rhabdomyolysis

A

breakdown of muscle tissue

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

Drug -> metabolite ( by Cyp P450)

A

Co-administration of Cyp substrate with:
•Cyp inducer may lead to increased metabolism, potential treatment failure
•Cyp inhibitor may lead to reduced metabolism, potential ADR
•Cyp substrate may lead to reduced metabolism, potential ADR

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

Statins have a risk of

A

myopathy (muscle disease)

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

Bile acid binding resins

A

• Positively charged resin that binds negatively charged bile acid & excreted:
– ↓decreased re-absorbtion bile (enterohepatic recirc.)→↑excretion
– ↑bile synthesis → ↓liver cholesterol →↑LDL receptor expression → ↓plasma cholesterol
• Drugs
– Cholestyramine
– Colestipol
• Indications
– patients in which statins are insufficient on own or contraindicated (eg pregnant women)
– Take before meal so present during bile acid secretion
– Decreases LDL cholesterol up to 30%
• PK
– insoluble in water – not absorbed
– inconvenient to take & gram doses
• ADR
– limited because not absorbed
– GI : constipation, bloating, flatulence
• Caution
– may also bind
» vitamin A, D,K - supplements may be necessary
» certain drugs (warfarin, digoxin, some statins, thiazides, aspirin ), reducing their bioavailability
– take other drug 1 hour before or 4 hr after resin

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

Inhibitors of cholesterol absorption

A

• Ezetimibe
– Inhibits transport of cholesterol across
intestinal brush border
– decreased cholesterol in chylomicrons, liver, VLDL and hence LDL
– upregulation of LDL receptor further reduces plasma cholesterol
• Indications
– hypercholesterolemia
– used with statin or on own if statin not appropriate
• PK
– is absorbed and undergoes repeated enterohepatic recirculation giving long t1/2~22h
– hence majority drug excreted in faeces • Caution
– hepatic impairment
• contraindication
– breast feeding
• ADR
– GI disturbances (diarrhoea, abdominal pain)
• Interactions
– plasma concentration increased with fibrates

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

Plant sterol

A
  • Similar structure to cholesterol
  • Displace cholesterol from micelles, so excreted not absorbed
  • Large quantities needed (g)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Fibrates

A

• Activate PPARa transcription factor
– decrease plasma triglyceride
– increase HDL (how ?)
– lower LDL
• Drugs
– Bezafibrate
– Ciprofibrate
– Gemfibrozil
• Indications
– hypercholesterolemia where statin unsuccessful/ inappropriate
– hypertriglyceridemia
• PK
– well absorbed, highly plasma protein bound
– excreted in urine as glucoronide conjugate
• Caution
– myotoxicity, esp in patients with renal disease
– displaces warfarin from plasma proteins
• Contraindication
– hepatic and renal impairment
– pregnancy & breast feeding
• ADR
– GI disturbances (nausea, abdominal discomfort), anorexia
– myopathy, more common if combined with statin

17
Q

PCSK9 inhibitors

A

• Alirocumab and evolucumab
– humanized monoclonal antibodies
– inhibit PCSK9 (proprotein convertase subtilisin–kexin type 9)

• PCSK9
– reduces the number of LDL-R in liver cells
– Inhibition of PCSK9 increases LDL-R, promoting LDL clearance

18
Q

Nicotinic acid

A

• Niacin (nicotinic acid)
– precursor of NADP, but mechanism probably not dependant on this
– Increases HDL
– ↓lipolysis in adipose tissue→ ↓ flux of FFA to liver →↓production of VLDL →↓LDL & ↓triglycerides
– new data: inhibition of triglyceride synthesis (diacylglycerol acyltransferase-2)
• Indication
– hyperlipidemia, with statin or if statin not tolerated – hyperglyceridemia
• ADR
– flushing and pruritus (itching).
» due to release of PG & vasodilation– can treat with aspirin (COX!) » limits use
» NB niacin increases risk of bleeding!
– diarrhoea, nausea, vomiting
– hyperuricemia – inhibits uric acid secretion (may cause gout)
– reduced insulin sensitivity (may cause diabetes)
• Caution
– unstable angina, MI, diabetes, gout
• Contraindications
– arterial bleeding, peptic ulcer disease, breast feeding

19
Q

Omega-3 fatty acids

A

• Reduced mortality from MI Eskimos & Danes → omega3 fatty acids protective?
• Fish oils
– eicosapentaenoic acid (EPA)
– docosahexaneoic acid (DHA)
• reduces triglyceride biosynthesis, but unclear if this decreases risk of cardiovascular disease.
• Fish Pharmacology:
– Sources - herring, mackerel, salmon, halibut, or omega-3 supplement
• ADR
– probably >20g/day !