Flashcards in L40 – Lipid-Lowering Drugs Deck (88):
Conditions caused by atherosclerosis in coronary artery and cerebral artery?
Coronary artery > angina, MI
Cerebral artery > Stroke
What are some general risk factors of atherosclerosis?
Lifestyle- smoking, diet
Age & arterial age
What are some biochemical disorders that are risk factors of atherosclerosis?
Increase vascular inflammation
Increase coagulation factors
What lipoprotein disorders are risk factors for atherosclerosis?
Lipid components of liproprotein? Protein components?
Lipid components = cholesteryl esters, triglycerides (TG)
Protein components = apolipoproteins
List 3 roles of protein components of lipoproteins?
Provide structural stability
For lipoprotein-receptor interactions
As co-factors in enzymatic processes
Which liporproteins are high in Molecular weight?
LDL VLDL Chylomicrons
HDL relay cholesterol esters to what?
Mostly to VLDL and LDL
What enzyme is used for HDL to transfer cholesterol to VLDL?
cholesteryl ester transfer protein (CETP)
What levels of LDL is desirable and what is high?
Normal = <3.4 (130) mmol/L (mg/dL)
High = >4.1 (160) mmol/L (mg/dL)
What levels of Total cholesterol is desirable and what is high?
Normal = <5.2 (200) mmol/L (mg/dL)
High = >6.2 (240) mmol/L (mg/dL)
What risk is assessed to determine need for drug therapy for lipid lowering?
10- year Coronary Heart Disease risk
The higher the CHD risk, the higher or lower the drug therapy threshold and LDL target?
Higher CHD risk, lower LDL target and lower drug therapy threshold
What 10 years CHD risk is low risk, moderate risk and High risk?
Low risk = CHD risk lower than 10%
Moderate risk = CHD risk 10-20%
High risk = CHD risk > 20%
How to reduce intake of cholesterol in managing lipoprotein disorder?
Cholesterol absorption inhibitors (drugs)
What drugs can lower plasma level of LDL?
Statins (HMG-CoA reductase inhibitor)
Niacin (nicotinic acid)
Resins (bile acid sequestrants)
What drugs can lower plasma VLDL?
Fibrates (fibric acid derivatives)
omega- 3 fatty acid
What drug raises plasma HDL?
Name 3 most common Statins
Explain the action of statin on cholesterol, LDL and triglycerides.
1) Decrease synthesis of cholesterol in liver by inhibiting HMG-CoA reductase
2) + Increase clearance of plasma LDL by increase synthesis of LDL receptor in liver
>> Decrease plasma triglycerides
How do statins change plasma HDL levels?
Statins lower plasma LDL levels
Lower LDL = Less HDL able relay choelsterol to LDL
Increase in plasma HDL
Under what circumstances is statins used and when is it not?
Used: Prevention of atherosclerosis in patients with elevated LDL
Not used: pregnant women or children
Why is statins not used in pregnant women and children?
Pregnant women: Lower cholesterol synthesis > insufficient for fetus
Children> statins cause some genetic defect with high risk of CHD
What is different between types of statins?
Duration of action
Different efficacy and potency
How is the response in patients with homozygous familial hypercholesterolemia to statins?
Difference in half-life between different statins? Difference in time of taking drugs?
Short = 1-4 hours, take at night
Intermediate = 12 hours, take at night
Long = 20 hours, take anytime
Give examples of different half-life statins?
Short= LOVAstatin, (PARAVAstatin, FLUVAstatin)
Intermediate = SIMVAstatin
Long = ATROVAstatin, (ROSUVAstatin)
Why are short and intermediate half life statins taken at night before sleep?
Hepatic cholesterol synthesis is at maximal between midnight and 2:00am
What are the 3 main adverse effects of statins?
Mild GI disturbances
Risk of Hepatotoxicity
Risk of Myopathy
How do Statins increase risk of hepatotoxicity? Symptoms?
Increase plasma level of liver enzymes
How is hepatotoxicity measured?
Measure serum alanine aminotransferase level (ALT)
What symptoms and complications arise from high statin level induced myopathy?
Muscle pain (myalgia), weakness & fatigue
complications : renal failure, death
How is myopathy measured?
plasma creatine kinase (CK) level
Factors that affect plasma levels of statins?
Hepatic or renal dysfunction
Small body size (female)
Other drug intake
All increase plasma level of statins
What drugs can lead to increased plasma levels of statins?
drugs that decrease uptake of statins or decrease metabolism of statins
What enzymes metabolize statins and are subject to drug action that leads to increased plasma statin levels?
Cytochrome P450 metabolize statins
Subject to Glucuronidases (e.g. warfarin, macrolides, azole antifungal)
What is niacin?
Nicotinic acid /Vitamin B3
How does Niacin change plasma lipoprotein levels?
Decrease LDL, VLDL
Reduce TAG level
How does Niacin decrease VLDL, LDL?
1) Inhibit hormone-sensitive lipase in adipose tissue
> decrease flux of free fatty acids to liver
> Less hepatic TAG synthesis > less TAG end up in VLDL, LDL
2) Enhance Lipoproteinlipase activity > clearance of VLDL into LDL (LPL turn VLDL to LDL)
How does niacin raise HDL level?
Niacin decreases clearance of HDL apo A-1 in liver
What are 2 distinct advantages of niacin?
Most effective in raising HDL level
Can normalise LDL in patients with LDLR genetic defects
What are some adverse effects on skin by niacin?
Skin rashes and acanthosis nigricans (dark skin folds)
What adverse effects do niacin and statins share?
Risk of hepatotoxicity
Not suitable for pregnant women - risk of birth defect
Niacin is not used in which patients?
Severe peptic disease (GI ulcers caused by H. pylori and long term use of aspirin, NSAIDS)
What drug is used to counter niacin for flushing?
Is niacin short or long acting?
Tachyphylaxis (sudden unresponsiveness) occurs within days
What are 2 rare adverse effects of niacin?
Maculopathy (damage to eye)
What are fibrates?
Fibric acid derivatives
PPAR alpha activators
Name 3 most common fibrates. CFG
How does fibrate change plasma lipoprotein levels?
Increase OR lower LDL (not very effective against LDL)
How does fibrate lower VLDL?
1) Increase LPL synthesis > lower TG and increase VLDL break down
2) Increase FA oxidation in liver > decrease VLDL secretion
How does fibrate increase HDL level?
Increase HDL, apo A-I and apo A-II production
How come fibrate is ineffective against LDL regulation?
Fibrate can lower level of VLDL and so lower LDL
But also increases conversion of TAG to FA by increasing LPL activity
Fibrate is used for which patients and not for which?
Not used: Combined hyperlipidemia (high LDL), pregnant women, children, patients with hepatic or renal dysfunction, biliary tract disease
What are some uncommon adverse effects of fibrates?
GI disturbances, rashes
What adverse effect do statins and fibrates share?
Risk of myopathy
Which statin can be safely used with fibrate? Why?
limits statin uptake and metabolism, no need to take extreme caution with statin dosage
Lowest RISK in all statin- fibrate combos
Why is niacin administered with great care for diabetics and gout patients?
Diabetics: Niacin decreases glucose tolerance
Gout patient: Niacin increase uric acid levels
How does fibrate affect plasma level of liver enzymes, action of warfarin?
Increase plasma level of liver enzymes
Increase action of warfarin
How come fibrates are not used in patients with biliary tract disease?
Increases risk of cholesterol gallstones
What are Resins?
Bile acid sequestrants
Name 3 most common resins
How does Resin alter cholesterol levels?
Bind to bile acids > Increase secretion of bile acids in jejunum and ileum
Increase conversion of cholesterol to bile acid in liver > to be excreted
How does Resin change plasma LDL levels?
Promote LDLR synthesis in liver > increase LDL uptake
How come the body naturally offsets the effect Resins have on LDL?
Increased LDLR synthesis, more uptake of LDL from plasma > LDL converted to bile acid and excreted > overall lower LDL conc. in liver
Natural compensation for low LDL conc. in liver by promoting LDLR production & enhance cholesterol synthesis > offset resin action
Resin is used and not used in which patients?
Used: High LDL patients (e.g. mixed hyperlipidemia)
Not used: Hyperglyceridemia patients (may cause increase hepatic TAG synthesis), patients with diverticulitis (intestinal inflammation/ infection)
What alternative effects/ advantages does Resin have apart from lipid lowering?
Counteract Digoxin toxicity
Relieve Pruritus due to cholestasis and bile acid accumulation
No systemic toxicity
Are resins absorbed in GI?
What common adverse effects on the GI does resin cause?
Bloating, Dyspepsia, constipation
Decrease absorption in GI of fat-soluble vitamins and other drugs
How can GI disturbances caused by Resin be reduced?
suspend drug in liquid before ingestion
increase dietary fiber intake
What is Ezetimibe?
Cholesterol Absorption inhibitor
How does ezetimibe change cholesterol levels?
Decrease cholesterol absorption in intestines:
1) binding to NPC1L1
2) inhibiting ACAT
Both lowering LDL level in plasma and liver
How does ezitimibe change plasma LDL level?
promote synthesis of LDLR in liver
Ezetimibe conc. in plasma is changed by which other lipid lowering drugs?
Increased by fibrates
Reduced by Resins
What are some adverse effects of Ezetimibe?
mild (e.g. headache, diarrhea)
What are PCSK9 inhibitors?
Human monoclonal antibodies against PCSK9
Name 2 common PCSK9 inhibitors?
Alirocumab and Evolocumab
How does PCSK9 inhibitor change plasma LDL level?
Bind to PCSK9 > inhibit PCSK9 from binding to LDLR and cause LDLR degradation
> decrease LDLR degradation = more LDL absorption into liver, less plasma LDL
PCSK9 inhibitors are used in what patients?
Used as second line treatment in:
patients with heterozygous or homozygous familial hypercholesterolemia,
Adults with cardiovascular diseases and hypercholesterolemia (prevent MI, stroke... etc)
What are some adverse effects of PCSK9 inhibitors?
Mild muscle ache, injection site reaction, nasopharyngitis
Are Resins effective against TG?
What 2 precautions are taken when giving combo therapy?
Use lowest effective dose
Closely monitor for potential toxicity
Which combos are synergistic with statins?
Statin + Ezetimibe or Resins or PCSK9 inhibitors
Which combos are synergistic with PCSK9 inhibitor?
PCSK9 inhibitor + Statins or Ezetimibe
Which 2 combos are used for combined hypercholesterolemia?
Statin + niacin
Niacin + resin
What are the 2 combs that may cause myopathy?
Statin + Fenofibrate
Statin + Niacin
Statin + Fenofibrate, although lowest risk of all statin- fibrate combos, may still cause which two disorders?
myopathy and hepatotoxicity