pharm: 9-29 Hyperlipidemia drugs Flashcards
Statins
Indications
High LDL
Statins
- Effect On [Serum Lipids]*
- -LDL*
- -TriAcylGlycerides*
- -HDL*
- DEC LDL by 20-60%
- DEC TriAcylGlycerides by 10-20%
- INC HDL by 5-10%
Statins
A: Adverse Effects (4)
A2: Which 2 Adverse Effects are Dose Dependent?
B: Contraindications (3)
A:
- Muscle myopathy —-> myalgia (Dose Dependent)
- RHABDOMYOLYSIS (Dose Dependent)
- Hepatitis
- small risk of [Type2DM] development
B: Contraindications
“Don’t give Statins to Pregnant Lady Girls “
(x) Pt with Severe Liver Dz
(x) Pt taking Gemfibrozil
(x) Pregnant Women
Statins
- Drug Interactions:*
- A: Name the compounds that inhibit* [CYP3A4] (7)
- B: How does this affect Statins?*
- C: Which Statins specifically does it affect? (3)*
A: “CYP3A4 is inhibited by a CHECK WIG”
1) Erythromycin / Cyclosporin / Ketaconazole / Itraconazole [HIV protease inhibitors] / Warfarin / [Ca+ channel blockers] / Grapefruit Juice
B: THESE INC RISK OF ADVERSE EFFECTS FROM STATINS
C: “S A L is easily affected by CYP3A4 inhibition”
( Simvastatin- Atorvastatin- Lovastatin )
Statins
Mechanism of Action
[HMG-CoA Reductase analogs] that Competitively Inhibit [HMG-CoA Reductase] once they bind—> and as a result DEC Endogenous Cholesterol–>triggers [S-REB-P tx factor] —–>
*INC [Hepatic LDL receptors]
*INC [LDL Clearance from Blood]
Statins
- Drug Interactions:*
- A: Name the compounds that inhibits* [CYP2C9] (2)
- B: Which Statins specifically do they affect? (2)*
A:
1) Ketaconazole and Metronidazole
B: INCREASES (Fluvastatin-Rosuvastatin)
Statins
- Drug Interactions:*
- A: Name the compounds that stimulate* [CYP3A4] (3)
- B: How does this affect Statins?*
- C: Which Statins specifically does it affect? (3)*
A:
1) Phenytoin / Rifambin / Phenobarbital - PRP
B: THESE DEC CLINICAL EFFICACY OF STATINS
C: DECREASES in (Lovastatin-Simvastatin-Atorvastatin)
Statins
Drug Interactions:
A: How does Gemfibrozil affect Statins? (2)
B: What serious condition can this lead to?
A: Gemfibrozil [Inhibits (Hepatic OATP2 Transporter)] –> [DEC Glucoronidation] AND [DEC (Hepatic UGTA1/3)] ———> INC ALL STATIN BIOAVAILABILITY
B: Rhabdomyolysis!!
[Bile Acid Binding Resins - BABR]
A: Name the 3 drugs in this class
B: Indications (5)
C: Mechanism of Action:
CATION tht Binds up _____ and prevents _____ ReAbsorption —> [INC _____]—-> [DEC Hepatic Cholesterol] —-> [INC _____] —> [DEC ______ by ___%]
A:
Cholestryramine / Colestipol / Colescelam
B: LA COP
[LDL elevated in Pregnant women and children]
[Adjunct tx with Statin]
- [Crohn’s Dz iLeal Resection Diarrhea - CDiRD]
- OD tx for Digoxin and Levothyroxine
- Pruritus 2º to Liver failure
C:
CATION tht Binds up [Anion Bile Acids] and prevents Intestinal ReAbsorption —> [INC Cholesterol 7alpha hydroxylase]—-> [DEC Hepatic Cholesterol] —-> [INC LDL Receptors] —> [DEC LDL in blood by 10-25%]
[Bile Acid Binding Resins]
- A: Adverse Effects (2)*
- B: Contraindications*
A:
(x) Can INC [TriAcylGlyceride] during hyperTriglyceridemia
(x) [Cholestyramine and Colestipol] at HIGH levels–> [DEC Vitamin DEKA absorption]
B: Contraindicated in [Type 3 Dysbetalipoproteinemia pts with TAG > 400 mg/dL]. BABR INC [HMG-CoA Reductase] which can cause VLDL levels to further INC
Niacin
Adverse Effects (5)
Dying Pigeons Should Help Hide Germs
- [DMType2 relative contraindication] (Niacin causes INC glucose)
- Skin Flushing that requires NSAID Tx (prostaglandin mediated)
- Gout Risk by Inhibiting [Uric Acid Secretion]
- Peptic Ulcer Exacerbation
- Hyperglycemia Risk
- Hepatitis
Fibrates
- A: Adverse Effects*
- B: Contraindications (3)*
- C: What are the Drugs in this class (2)*
A:
- INC gallstones
- Rhabdomyolysis (common with Gemfibrozil)
- Hepatitis
- Myopathy
B: Contraindicated in [Severe Liver OR Renal Dz Pts] / [Gallbladder Dz Pts]
C:
- Gemfibrozil
- Fenofibrate
A: Which [Bile Acid Binding Resins] have Drug Interaction problems?
B: What are the drug interactions (4)
“BABRs, Tyra and Pol didn’t get along with Dudes Who Play Tennis”
A:
- Cholestyramine
- Colestipol
B: DEC Absorption of
Digoxin / Warfarin / Phenobarbital / Tetracycline
Fibrates
- A: Drug Interactions (2)*
- B: Indications (2)*
- Fibrates are Strong Protein Binders—> [INC Warfarin and Sulfonylurea] –> bleeding and hypOglycemia
- Fibrates Inhibit [OATP2/glucoronidation] —> INC ALL STATINS —> Rhabdomyolysis
B: Fibrates are used for:
- HIGH VLDL
- Low HDL
Ezetimibe
- A: Indication (2)*
- B: Mechanism of Action*
A:
- [High LDL in pt with Primary Hypercholesterolemia] since it doesn’t fully rely on [Hepatic LDL Receptor INC]
- Adjunct with Statin
B: Prevents [Cholesterol Intestinal absorption] by inhibiting NPCL1. —> DEC Hepatic Cholesterol —> [INC LDL Receptors] —> [DEC Serum LDL by 18%]
- niACin*
- A: Indications (3)*
- B: Mechanism of Action (7)*
A: [Low HDL] OR [HIGH VLDL OR HIGH LDL] in pt with Familial Combined Hyperlipidemias and [Familial Dysbetalipoproteinemia]
B: “ niACin Dec MALT”
- [INC ApoA-1 half life]—> NIACIN IS MOST EFFECTIVE HDL INCREASER (by [10-30%] )
- [ApoC-3] hepatic expression blocker –> [INC LPL] –> [INC VLDL CLEARANCE!]
- Inhibits DGAT2 –> [DEC VLDL hepatic synthesis]
- DEC Macrophage recruitment to atherosclerosis
- DEC Adipocyte Lipolysis as an agonist for [Gi-GPR109A] –> [DEC VLDL from FFA]
- DEC LPA —> DEC Thrombosis–> DEC Atherosclerosis
- DEC TAG by 30-80% —> DEC VLDL
Fibrates
A: Mechanism of Action (4)
B: Effect On Serum Lipids (4)
A: Ligands for [PPARalpha TF]:
- DEC Apo-C3
- INC LPL Expression
- INC Fatty Acid Oxidation
- INC [Apo-A1 Expression]
**** and this all
(x) [DEC VLDL synthesis]
(x) [DEC TriAcylGlycerides]
(x) [INC VLDL Clearance]
(x) [INC HDL production]
PCSK9 Inhibitors
A: What are the 2 Drugs
B: Effect On Serum Lipids
A:
- Alirocumab
- Evolocumab
B: DEC LDL by more than 50%
PCSK9 Inhibitors
Indications (2)
- HETEROzygous Familial Hypercholesteremia
- [HIGH LDL that is STATIN RESISTANT]
PCSK9 Inhibitors
Mechanism of Action
Inhibits PCSK9 –> prevents [LDL Receptor] from being sent to lysosome –> INC LDL clearance
loMiTaPide
- A: Indications*
- B: Adverse Effects*
- C: Contraindications*
- D: Drug Interactions*
A: Homozygous Familial Hypercholesteremia
B:
(x) Hepatotoxic
(x) CONTRAINDICATED IN PREGNANCY
D: loMiTaPide inhibits [CYP3A4 and P-gp]
loMiTaPide
Mechanism of Action
Inhibits MTP in [Enterocytes AND Liver] —> DEC production of
- Chylomicrons
- VLDL
- LDL
Mipomersen
- A: Indications*
- B: Adverse Effects*
- C: Contraindications*
A: homozygous Familial Hypercholesteremia
B: Hepatotoxic
C: CONTRAINDICATED IN MILD/MODERATE HEPATIC IMPAIRMENT
Mipomersen
- A: Mechanism of Action*
- A: Effect On Serum Lipids (2)*
A: [Antisense Oligonucleotide] that’s specific for DECREASING ApoB100 Expression —>
B: DEC VLDL and LDL
A: List the 5 Steps of how [Endothelial Injury] + LDL cause Atherosclerotic Plaques
B: ____ Cells contribute to this in what 3 ways?
- Endothelial Injury allows LDL Entry
- LDL is oxidized and [OxLDL] activates endothelium to express [Monocyte adhesion]
- Monocytes adhese to damaged endothelium and extravasate into [Tunica Intima]–> macrophages
- Macrophages uptake [OxLDL] and become FOAM CELLS
- FOAM CELLS secrete [proteases and growth factors] that
- INC smooth muscle migration and proliferation
- promote Extracell matrix synthesis
- Foam cells eventually become necrotic–>release cholesterol —> Contributes to Fatty Streak production
Composition of Lipoprotein particles (3)
- Lipid Membrane - Phospholipids/Cholesterol
- Hydrophobic core - Triglycerides and Cholesterol Esters
- Apolipoproteins - structural proteins & ligands for particle uptake
LDL Lipid Composition (2)
60% of serum Cholesterol
25% of serum Triglyceride
iDL Lipid Composition (2)
35% of serum Cholesterol
25% of serum Triglyceride
VLDL Lipid Composition (2)
20% of serum Cholesterol
55% of serum Triglyceride
Chylomicron Composition (2)
85% of serum Triglyceride
~3% Dietary Cholesterol
HDL Lipid Composition (3)
20% Cholesterol
5% Triglyceride
35% Phospholipid
A: Which vasculature do Chylomicrons utilize to travel to Peripheral tissues?
B: 4 Uses for Cholesterol
A: Lymphatics / [Thoracic Duct]
B: [Steroid Hormones] / lipoproteins / Membranes / [bile acids]
A: Which Receptor does HDL use to enter the Liver (transporting Cholesterol Esters) ?
B: Which Transporter does HDL use to uptake cholesterol from Foam Cells?
A: [SR-B1 scavenger receptor] to enter Liver
B: [ABCA1 Transporter] to take up Cholesterol from Foam Cells
Protective roles of HDL from atherosclerosis (4)
1) inhibit oxidation of LDLs via paraoxonase enzyme (PON1) present on HDL surface (also has anti-oxidant activity)
2) Inhibits expresion of endothelial adhesion molecules—>prevents recruitment of monocytes to atherosclerotic plaque
3) inhibit the formation of FOAM cells
4) Transports Cholesterol from periphery to the Liver where it’s excreted as Bile
3 Main Causes of HyperLipidemia / Hyperlipoprotienemia
B: Also list examples of each
C: When is Drug therapy indicated in Hypercholesterolemia specifically? (2)
- Genetics ([Monogenic LDL Receptor disorder] vs. [Polygenic Familial combined Hyperlipoproteinemia] )
- [Lifestyle(smoking and EtOH) / Diseases(DM and Anorexia) / Drugs(BCP and Corticosteroids)]
- Combination of Genetics and Lifestyle (mutant ApoE2 allele–> Type 3 Dysbetlipoprotinemia)
C: [Severe Hypercholesterolemia] and/or [High Cardiovascular Risk]
7 Risk Factors for Developing [Coronary Artery Disease]
CHD Risk Factors: “ CHAD has Family Medical Hx of CAD “
- DM - Type2
- Hypertension (Greater than 140/90)
- HDL lower than 40
- [Metabolic Syndrome X]
- Family history of CAD (<55yrs M; <65 yrs W),
- Cigarettes
- Age: M > 45yrs; W > 55yrs
A: Tx Criteria for [Primary Prevention with STATINS] (3)
B: Tx Criteria for [Secondary HIGH RISK] prevention with STATINS]
C: What is the difference between these two Preventions?
A: Stain Primary Prevention Criteria
- LDL Greater than 190
- [LDL Greater 70 + DM]
- 10 Year [Cardiovascular Disease Risk] > 7.5%
B: Stain Secondary Prevention Criteria:
-Current clinical evidence of CVD
C:
Primary = LDL is within normal range
Secondary= HIGH RISK or hx of CAD + LDL elevation
Why does Doubling a STATIN Dose not necessarily better for therapy?
Doubling the STATIN dose usually results in only a 5-6% further decrease in LDL, while significantly
increasing potential for ADVERSE EFFECTS!!!
6 “OTHER” anti-atherogenic Effects of STATINS
Inhibits…
- Endothelial Adhesion molecule–> Inhibits Monocyte adhesion
- Monocyte Proliferation / Migration
- Oxidation process of LDL
- Smooth Muscle Cell proliferation
- Inflammatory Responses
- Stimulates Endothelial Stabilization –> DEC Plaque Rupture Risk
A: Symptoms of Rhabdomyolysis (5)
B: Which STATIN has less likely chance of developing these sx
C: Which 3 Demographics are at INC risk
A:
A:
-fever / malaise / [diffuse myalgia and/or tenderness] /
[marked elevation of serum (CK)], [myoglobin present in the urine-dark]
B: Pravastatin
C: Incidence INC in pt with [Renal and Liver Failure] or [STAIN Hepatic Anion Transporter- HAT polymorphism]
A: Relationship between Grapefruit Juice and Statins?
B: How do Statins enter the Liver?
C: How are Statins metabolized and excreted?
A: Grapefruit Juice INC bioavailability of [SAL - Simvastatin / Atorvastatin / Lovastatin] (most STATINS are absorbed in intestine. Normal bioavailability is 5-30% )
B: STATINS are directly taken into Liver by OATP2 = STATINS have strong effect in the liver
C: Once in liver, STATINS are [CYP450 metabolized] and glucoronidated by [UGATA1 and 1A3] –> Excreted
Which Statins are metabolized by these CYP450 enzymes?
A: CYP3A4 (3)
B: CYP2C9
C: CYP2C19
D: Which Statin is NOT metabolized by CYP450 system? How is this statin different in excretion?
A: CYP3A4 = SAL = Simvastatin/Atorvastatin/Lovastatin
B: CYP2C9 = Fluvastatin
C: CYP2C19 = Rosuvastatin
D: Pravastatin is NOT metabolized by CYP450 and is partially renal excreted (vs. all others are strictly hepatic):-)
A: 3 Common Disorders associated with [Elevated TriAcylGlycerdies]
B: [Elevated TriAcylGlycerdies] is usually associated with what condition?
C: What 2 medications are tx for this
A: [Pancreatitis / Atherosclerosis / CV Dz]
B: [HIGH TAG] usually comes from [low HDL]
C: Niacin and Fibrates both DEC TAG and INC HDL
A: Therapy of Choice for Familial Dysbetalipoproteinemia (2)
B: Long term Fibrates do what clinically?
Fibrates or niACin
B: DEC Coronary Events / Stroke / TIA
[Fish Oils: O3pUFA (Omega 3 Polyunsaturated Fatty Acids)]
A: Clinical Effect (2)
B: MOA (2)
C: Clinical USES
D: Drug Interactions
[Fish Oils: O3pUFA (Omega 3 Polyunsaturated Fatty Acids)
A: [DEC TAG by 30-50%] / [INC HDL]
B: Inhibits [Hepatic TAG synthesis] Gene Expression and uses [Macrophage GPCR] to carry out antiinflammation
C:
1) Adjunct to Diet in Tx of Hypertriglyceridema in pt with TAG >500
D: ARE SAFE AND DO NOT INC RHABDOMYOLYSIS RISK WITH STATINS
A: 4 Circumstances in which Combination Drug Therapy is indicated
B: Which tx do you use for each circumstances
- LDL levels are not reduced in high-risk individuals even with HIGHEST STAIN DOSE–> Use Vytorin
- BOTH LDL and VLDL are HIGH such as in [combined hyperlipoproteinemia] –> Use Fenofibrate
- HDL deficiency co-exist with other hyperlipidemias –> [Use Niacin OR Fibrate]
- VLDL levels are INC during [Bile Acid Binding Resin] Tx —> Use Niacin
4 Steps to how Gut Microbiota can INC risk for Atherosclerosis
1st: Pt eats [L-Carnitine from Red Meat]
2nd: [Gut flora-Peptostrep Clostridiaceae] metabolizes [L-Carnitine from Red Meat] —> TMA
3rd: TMA is processed in Liver —> [Active TMAO]
4th: [Active TMAO] INC risk for Atherosclerosis development
