6.6.2 - Drugs For Dyslipidaemia

Front 1

Name the agents used for lowering cholesterol/triglycerides by class/drug

Back 1

1. Statins
2. Ezetimibe
3. Fibrates (gemfibrozil, fenofibrate)
4. Bile acid binding resins (cholestyramine, colestipol)
5. Nicotinic acid
6. Fish oils

Front 2

What is the MOA of the statins?
What is the clinical result and what sort of dyslipidaemia are they useful?

Back 2

Competitive inhibitors of HMG-CoA reductase(hydroxymethylglutaryl coenzyme A)
This enzyme is the rate limiting enzyme in cholesterol synthesis.
Results in increased uptake of cholesterol into the liver from the blood, reducing concentrations of TC, LDL, TAGs (modest); and produces a small increase in HDL

Reduce LDL 30-50%

Hypercholesterolaemia (HC); Adjunct for Hypertriglyceridaemia (HT)
HIgh risk of CAD with or without HLc

Front 3

What is the MOA of the bile acid binding resins?
Clinical result?
Which dyslipidaemia are they useful for?

Back 3

Bind bile acid in the intestinal lumen, preventing reabsorption, and increasing excretion into the feces. This increases the demand for cholesterol for bile acid synthesis and results in an increase in LDL uptake and removal from the plasma.

Reduce LDL by 15-25% - May worsen TAGs if TAGs >3mmmol/L; Reduces risk of MI and death due to MI if TC >6.8mmol/l

Isolated hypercholesterolaemia; Adjunct to other treatment of hypercholesterolaemia

Front 4

MOA of fibrates?
Clinical Result?
Indications?

Back 4

1. Activate PPAR (peroxisome proliferator activated receptor) to modulate lipoprotein synthesis to increase HDL (moderately), with a variable effect on LDL
2. Decrease LDL 5-15% (gemfibrozil) and <25% (fenofibrate); Reduce TAGs by 40-80%; Increase HDL 10-30%; Reduce MI in low HDL and elevated TAGs where there is no CVD

3. 1st choice for HT (better tolerated than nicotinic acid); last choice for HC!

Front 5

1. MOA of ezetemibe?
2. Clinical effect
3. Place in therapy

Back 5

Reduces dietary and biliary absorption of cholesterol by inhibiting its transport across intestinal wall. Increases hepatic uptake of LDL --> reduced plasma LDL

2. Reduce LDL 18%; well tolerated; little clinical experience

3. HC, not HL

Front 6

1. MOA of nicotinic acid?
2. Clinical effect?
3. Place in therapy?

Back 6

1. Unclear. Probably suppresses release of FAs from lipocytes. Reduces LDL, TAGs, increases HDL, and uniquely lowers potentially atherogenic lipoprotein(a)

2. Approximately 25% reduction in LDL (similar to BABR), reduction in TAGs, increase in HDL

3. Poorly tolerated. Fibrates preferred for HTr. BABRs and statins, ezetemibe preferred for HC.

Front 7

Fish oil?!
(c) effect?
(a) required dosage
(b) safety

Back 7

(c) reduce TAGs
(a) 2-5g of omega-3 FAs (may require high pill burden; check formulation)
(b) appears safe

Front 8

Fibrates
(1) Indications

Back 8

1. Severe HT with risk of pancreatitis
2. Mixed HL / DL associated with diabetes
3. HC, 2nd line

Front 9

Fibrates
(2) CI (3+1+1)
(4) Preg/ BF
(5) LF / RF

Back 9

1.
(a)Severe biliary tract disease: Gallstones, gallbladder disease, primary billiary cirrhosis;
(b)Severe RI; Liver impairment
(c)PHOTOTOXIC REACTION to fenofibrate or ketoprofen (fenofibrate only),
Treatment with repaglinide (gemfibrozil only)
4. Cat B3: Avoid (see next slide); BF: No data
5. LF - CI; RF: lower dose of fenofibrate in mild disease

Front 10

Hyperlipidaemia in Pregnancy?- I.E. Management of
1. HC?
2. HL?

Back 10

Lowering cholesterol with drugs or diet is usually inappropriate
Lowering triglycerides may be appropriate if there is a risk of pancreatitis - seek specialist advice
HW, physiological HL of preg occurs - doesn't need treating

Front 11

Fibrates - Drug interactions (5)

Back 11

1. cyclosporin - may decrease cyclosporin; increased nephrotox; monitor
2. warfarin - may increase INR; monitor
3. statins - increased risk of rhabdomyolysis. test CK after 1/12 then q6/12. Do not exceed 10mg simvar; do not exceed 10mg crestor with gemfibrozil
4. gemfibrozil + repaglinide - CI: increases and prolongs repaglinide conc--> hypo-s
5. gemfibrozil + TZDs - increases conc of TZD & risk of AEs and hypo-s; avoid combo in HF; may need to reduce dose of TZD by 50-70%
6. ezetimibe+fenofibrate - increases risk of gall bladder disease

Front 12

Fibrates - A/Es
1. common
2. rare

Back 12

1. GI upset (dyspepsia, abdominal pain)
gemfibrozil: myalgia, dry mouth, headache
fenofibrate: increased transaminase concentrations
2. cholestatic jaundice, gallstones, anaemia, myopathy, rhabdomyolysis, anaphylaxis, leucopenia

Front 13

Fenofibrate
(1) brand
(2) dose forms
(3) dose

Back 13

1. Lipidil
2. 145mg.30, 48mg.60 tabs
3. 145mg d; 48mg d if CrCl 10-20ml/min; 96mg d if CrCl 20-60ml.min

Front 14

Gemfibrozil
(a) brand
(b) dose forms
(c) dose

Back 14

1. Lopid, Jezil, Lipazil, Ausgem
2. 600mg.60 tab
3. 600mg bd

Front 15

Gemfibrozil
with or without food?

Back 15

This medicine is best absorbed half an hour before food. If it upsets your stomach take it with meals.

Front 16

Monitoring of fibrates

Back 16

Monitor FBE and LFTs and CK and RF
- Fenofibrate: monitor transaminase conc q3/12 for 12/12
- With a statin: monitor CK at 1/12 then q6/12

Front 17

Counselling on fibrates

Back 17

1. Report signs of rhabdomyolysis but not LF (brown dark urine, muscle pain, tenderness)
2. gemfibrozil - better on an empty tummy if doesn't cause stomach upset
3. fenofibrate - L8

Front 18

Why might fenofibrate be good in gout and why might Jezil be not so good in heart disease?

Back 18

1. uricosuric - lowers uric acid by ~25%
2. infrequently causes AF

Front 19

Nicotinic Acid
- Indications (4)

Back 19

1. Mixed HL
2. HC
3. Severe HTG
4. Pellagra = malnourished state causing (a) GI upset, (b) redness of exposed areas followed by desquamation, and (c) nervous and mental disturbances

Front 20

Nicotinic Acid
- Contraindications (3)
- Cautions
- Preg/BF

Back 20

(a) symptomatic hypotension, pregnancy, manufacturer CI use after MI because of arrythmia risk
(b)
1. May exacerbate diabetes, gout (increase uric acid), PUD, and antihypertensive hypotensive effects.
2. May produce arrhythmias, so avoid in CAD; and CI by manufacturer after an MI
(d) Preg Cat B2 - Contraindicated; BF - contact pregnancy drug info centre

Front 21

Nicotinic Acid
- Drug Interactions (1 specific & 2 general)

Back 21

1. Statins - increased risk of rhabdomyolysis; monitor; limit simvastatin to 10mg d.
2. Increases BGLs
3. Causes flushing and hypotension

Front 22

Nicotinic Acid
- Common adverse Effects (3)

Back 22

common:
1. vasodilation, face and neck flushing, hypotension
2. dyspepsia, diarrhoea, n/v
3. hyperpigmentation

Front 23

Nicotinic Acid
- Management of common a/es

Back 23

1. Flushing and stomach upset usually stop after 2-6 weeks. This tolerance to flushing may be lost if 3 of more doses are missed.
2. Flushing can be prevented by giving aspirin 150mg 30 min before hand (as flushing is caused by prostaglandins)
3. To reduce stomach upset, take dose with food or antacids. Also increase the doses and use divided doses.

Front 24

Nicotinic Acid
- Rare A/Es (3)

Back 24

liver failure
myopathy, increase CK
gout

Front 25

Nicotinic Acid
- Brand name
- Dose form
- Dose
- Scheduling

Back 25

- no brand name
- 250mg.100 TAB

HL: 1 tds initially, increse to 2-4 tds

Pellagra: 1 bd
Prophylaxis: 15-50mg d (OTC products)
- S3 if more than 100mg/tablet

Front 26

Nicotinic Acid
- Counselling points

Back 26

1. Avoid flushing
2. Avoid stomach upset
3. Report any signs of myopathy: muscle pain, tenderness or weakness (NB not rhabdomyolysis!)

Front 27

Nicotinic Acid
- Monitoring

Back 27

LFTs and BGLs periodically (not myopathy - no rhabdomyolysis occurs)

Front 28

Ezetimibe
- Brands inc combos
- Dose forms
- Dose

Back 28

- Ezetrol, Vytorin
- 10mg.30 TAB, 10/20mg.30, 10/40, 10/8- (simvastatin)
- 10md d

Front 29

Ezetimibe
- Indications (3)

Back 29

1. HC
2. Homozygous sitosterolaemia
3. HC when a statin alone isn't enough, or when high statin doses aren't tolerated (Combo)

Front 30

Ezetimibe
- CI
- Cautions
- RF / LF
- Preg / BF

Back 30

- ZERO
-
1. Fenofibrate - further increased risk of gall bladder disease
2. Elderly - reports of depression, esp in the first week of use
3. Children - if >10, have used adult dose; see specialist
- RF: no issues; LF: Avoid in mod-severe (Child-Pugh >6)
- Preg Cat.B3: avoid, no data (& no need)
- BF: no data

Front 31

Ezetimibe
- Drug interactions

Back 31

1. fenofibrate - increased risk of gall bladder disease
2. bile acid binding resins - reduce absorption of ezetemibe if taken at the same time & may reduce its effect on LDL; avoid preferably or take ezet. 2hr b4 or 4hr after resin
3. Rifampicin: decreas ezetimibe - monitor LDL over long courses; change treatment prn

Front 32

Ezetimibe
- Adverse effects

Back 32

- common: headache, diarrhoea
- rare: allergy, pancreatitis, myopathy, cholelithiasis

Front 33

Ezetimibe
- Counselling
- What limits use?

Back 33

- Report signs of myopathy (muscle pain, tenderness, weakness)
- No evidence for long term effectiveness or reduction in clinical events

Front 34

Bile acid binding resins -
1. drugs in class (& brands)
2. MOA
3. Indications

Back 34

1. cholestyramine (Questran), Colestipol (Colestid)
2. Prevent bile acid reabsorption in intestinal lumen
3. HC, Mixed hyperlipidaemia,
*Itch associated with partial biliary tract obstruction
* Diarrhoea following ileal resection or disease (Short bowel syndrome, IBD, etc)

Front 35

Bile acid binding resins -
1. CIs
2. Cautions
3. RF / LF
4. Preg / BF

Back 35

1 - no CIs
(like ezetimibe)
2. TAGs >3mmol/L - may exacerbate HTr
* Complete biliary obstruction - ineffective
*Constipation - may worsen; encourage high fluid and fibre intake; take laxative prn
* Diverticular disease, severe haemorrhoids - may worsen
3. LF - OK, RF - OK (like ezetemibe)
4. Cat B2 - contact pregnancy drug info centre prn; BF: avoid use

Front 36

Bile acid binding resins -
DIs

Back 36

An Anionic Exchange Resin, reduces the absorption of many drugs, particularly acidic drugs. If so seperate by taking other drugs at least 1hr before or 4-6hr after resin
e.g. tetracyclines (colestipol), digoxin, warfarin, hydrocortisone, amiodarone, vancomycin, raloxifene, MMF, thyroxine, HCTZ
2. Interferes with absorption and enterohepatic circulation (avoid concomitant use) of: meloxicam, piroxicam, sulindac, ezetimibe (N.B. also decreases Ezetrol's efficacy)
3. MTX enterohepatic recycling (has been used to treat toxicity)
4. Acarbose - may enhance each other; causes rebound postprandial insulin release if both ceased suddenly.
N.B. many DIs apply only to Questran

Front 37

Bile acid binding resins -
Adverse effects

Back 37

Common
Constipation>diarrhoea, n/v, dyspepsia, abdominal pain, flatulence

Rare
Fecal impaction, aggravatin of haemarrhoids, decreased ADEC absorption

Front 38

Questran
(a) generic
(b) dose form
(c) dosage

Back 38

(a) Cholestyramine
(b) 4g.50 sachets (Questran Lite), 8g.50 sachets
(c)
In combo with another agent for HL: 4-8g d (use dd prn)
On own: 12-36g d (start on 8g d) & use d.d.

Front 39

Colestipol
(a) brand
(b) dose form
(c) dosage

Back 39

(a) Colestid
(b) 5g.120
(c)
In combo: 5-10g d (or as dd)
start: 10-30g d (2-4 d.d) (start on 5-10g d)

Front 40

Bile acid binding resins -
Counselling (4)

Back 40

1. Mix with water, juice, or highly fluid foods like soup - about 100ml for Lite and 200ml for normal
**plenty of fluid to prevent constipation
2. For Questran, the gritty texture can be reduced by mising and standing in the refrigerator for at least 4hr
3. Seperate from other medicines by at least 1hr before to 4-6hr after this medicine
4. Consider and ADEK supplement if on high doses for a long time

Front 41

Statins
- Drugs in class (& brand names & dose forms)
Don't include combo products

Back 41

*Atorvastatin (Lipitor): 10,20,40,80x30
*Fluvastatin (Lescol, Vastin, 80mg=Lescol XL which is CR): 20,40,80mg.28
*Pravastatin (Pravachol, Lipostat, Cholstat, Liprachol): 10/20/40/80mg.30
*Rosuvastatin (Crestor): 5/10/20/40mg.30
*Simvastatin (Simvar, Zimstat, Zocor, Lipex, Ransim): 5/10/20/40/80

Front 42

Statins
- Indications

Back 42

HC, mixed HL, High risk of CAD even without HC

Front 43

Statins
- CI (1)
- Cautions (1)
- RI/LF
- Preg/BF

Back 43

- no CIs except preg
- Increased risk of myopathy and rhabdomyolysis with severe intercurrent illness, other lipid lowering agent causing myopathy, elderly >80 or frail, surgery
- RI: start lower, monitor regularly
- LF: start lower, monitor
- Cat D: CI in pregnancy as use in first trimester --> malformations; Women should use appropriate contraception
BF: Avoid use

Front 44

Statins
- DIs

Back 44

Fluvastatin - CYP2C9 >>3A4
Sim & Ator - CYP3A4
Prav & Rosuv - NA

1. Increased risk of rhabdo: nicotinic acid & fibrate & cyclosporin; limit simvar 10mg and rosuvastatin 5-10mg doses
2. Decreases absorption: resins; give 1hr before or 4hr after
3. Increase metabolism: rifampicin: Flu, Ator, Simvar
4. Inhibit metabolism of sim/ator: clarithromycin or erythromycin (w/hold statin); verapamil and diltiazem (avoid); itracon/ketoconazole (avoid)

Front 45

Statins:
Starting doses?
Intervals for increasing doses?
High doses vs combos?

Back 45

1. Start low to reduce risk of A/Es - If high risk of CAD then can start on high doses
2. 4 weeks
3. More than 80% of the AEs achieved with 50% max dose - a combo may be much more effective LDL

Front 46

Given risk with serious illness, what should we do if there is a MI>

Back 46

Continue - stopping is associated with an increased risk of CV events, especially in the first week

Front 47

Statins - What if CK monitoring shows high results?

Back 47

- Stop if transaminase conc are persistently >3x normal
- Stop if CK conc >10x normal
- Stop if there is persistent unexplained muscle pain
- If myopathy was mild and CK returns to normal after 4/52 can restart but stop immediately if it recurs. Consider using an alrenative statin or a lower dose

Front 48

Combination statins

Back 48

Vytorin - simastatin/ezetimibe 10/20, 10/40, 10/80

Pravigard: Pravastatin 40mg and aspirin 81mg x30