Communication and the Manager by lonyoo


Dyslipidemia pharmacology

Hypertriglyceridemia – high VLDL, hypercholesterolemia – high LDL, mixed dyslipidemia – IDL/VLDL/LDL

-    HMGCoA reductase inhibitors
-    Structurally similar to HMGCoA reductase (competitive inhibition, reduce intrahepatic cholesterol synthesis)
-    Reduce VLDL synthesis and therefore LDL synthesis
-    Upregulate LDL receptor activity
-    Liver creates more HMGCoA reductase and upregulates LDL receptors thus taking in more LDL from the blood
-    Statins reduce LDL by 25-60%, increase HDL by 5% and decrease TG by 10-15%
-    % reduction is proportional to initial level (the higher the baseline reduction, the bigger reduction)
-    correlated with LDL lowering potency (Atorvastatin and Simvastatin strongest)
-    useful in treatment of mixed dyslipidemias (if TG < 500 mg/dL)
-    ineffective in reducing chylomicrons (if TG > 500 mg/dL)
-    6% rule – doubling the statin dose reduces LDL by an additional 6%, maximal reductions = 47% for simvastatin and
     60% for atorvastatin
-    contraindications – pregnant women, liver disease, children or muscle disease
additional benefits
-    increased endothelial NO production (improves endothelial function)
-    suppression of tissue-factor release
-    inhibit platelet aggregation – decrease thrombosis?
-    Decrease serum fibrinogen levels
-    Immunosuppression after organ transplantation (less rejection of transplanted organs)
-    Should be given in evening/night as most cholesterol synthesis is in early morning (similar to corticosteroids)
-    Well absorbed orally, lovastatin with food, pravastatin with an empty stomach
-    Excretion mainly hepatic, renal 10-33%, atorvastatin and fluvastatin better in renal disease
-    Penetration of blood brain barrier: lovastatin, simvastatin (lipophilic = yes), pravastatin, atorvastatin (hydrophilic = no)
Hepatic metabolism
-    Majority metabolized by P450 enzymes (Lovastatin, simvastatin, atorvastatin, fluvastatin)
-    Pravastatin metabolized by sulfation
-    Fibrates, erythromycin, cyclosporins, anti-fungals and HIV protease inhibitors all increase statin concentration
-    Barbiturates and carbamezapine decrease statin concentration
-    Potentially dangerous interaction with warfarin, use pravastatin if this is the case
Adverse effects
-    Rare, dose-dependent, GI, Rash, Peripheral neuropathy, Insomnia/bad dreams, Hepatitis, Myopathy
-    Rare, dose-dependent, <1%
-    Influenza like symptoms – fatigue, anorexia, low-grade fever
-    Elevated transaminases (SGOT, SGPT), less than x2  continue Rx, close followup, x3  decrease dose d/c drug
-    Subsides within weeks of discontinuation
-    Variable presentation
-    Asymptomatic CPK elevation: x4  observe, x5 or more  d/c drug
-    Muscle aches with normal CPK  d/c drug
-    Rhabdomyolysis – elevated CPK, muscle pain, dark urine, fever, renal failure
-    Combination therapy: drugs that inhibit cytochrome P450, niacin?
-    Renal failure
-    Underlying muscle disease
-    Small, elderly patients
-    Hypercholesterolemia – familial and polygenic
-    Combined dyslipidemia, type III dyslipidemia
-    NOT in pure triglyceridemia
Bile acid binding resins
-    Bile acids allow for excretion of cholesterol
-    Most bile acids are reabsorbed
-    Acts by binding bile acids, so that they do not go back to the liver and more cholesterol is excreted
-    Decrease LDL by 15-20%, increase HDL by 1-2%, increase VLDL/TG
-    You need a large mass as they are usually powders
-    Insoluble in water, suspend in juice/yogurt, taste like sand  low patient compliance (30-50%)
Adverse effects
-    GI – dehydration, abdominal fullness, gas, constipation, occasional diarrhea
-    Reduced fat-soluble vitamins
-    Reduced absorption of polar drugs: warfarin, digoxin, thyroxin, statins, thiazides, folic acid
-    No systemic adverse effects: therefore good for pregnant women
-    Indications - Adjunct to other lipid lowering drugs, pregnant women and children
-    Contraindications - Hypertriglyceridemia, intestinal disease

-   Blocks dietary and biliary cholesterol
-   No known side effects
-   Good for people who eat more cholesterol and have low levels of HMGCoA reductase

-   Reduce triglycerides
-   “lopid” – gemfibrozil, prevents CHD, primary and secondary prevention
-   fenofibrate
-   bezafibrate (evidence in secondary prevention)
-   ciprofibrate
-   PPAR are intracellular receptors involved in glucose and triglyceride metabolism
-    agonist of PPAR, increases mRNA synthesis
-   increases ABC receptor, increases SR-B1, increases HDL
-   thus increases metabolism of TG’s
-   increase LDL depending on LDL metabolism
-   increase HDL by 5-15%
-   decreased VLDL and TG by 30-50%
-   increase LDL size (less atherogenic)
-   decrease fibrinogen levels (decrease thrombogenicity?)
adverse effects
-   GI
-   Gallstones (increases concentration of cholesterol in bile)
-   Hepatitis (rare)
-   Increased activity of warfarin (displaced from albumin)
-   Myopathy – combination Rx (with statins), renal failure
-   Contraindications – renal failure…serum concentrations increase in renal failure, beware when creatinine > 2.0 mg/dL
-   Indications – severe hypertriglyceridema (TG > 500mg/dL), chylomicronemia, mixed dyslipidemia (elevated LDL and
    VLDL, elevated IDL), low HDL
-   May need combination therapy to lower LDL levels

-   Also reduce TG
-   Aka nicotinic acid
-   Vitamin B class – daily intake from food is 30-50mg, available over the counter and least expensive
-   In pharmacological doses is a very efficient lipid modifying agent, used since the 50s and has good secondary
-   Do not use with nicotiniamide
-   Since fatty acids combine with TG to make VLDL, niacin leads to decreased FFA release from adipose tissue
-   Decreases LDL by 10-15% (needs high doses)
-   increases HDL by 10-30%
-   decreases VLDL/TG by 30-50%
-   Increases LDL size and buoyancy (less atherogenic)
-   Reduces Lp(a) levels (only drug that does that)
Adverse effects
-  Flushing (almost universal), found to be intolerable – increases vasodilation through prostaglandins
-  Tachyphylaxis usually develops within several weeks (long term tolerance)
-  Can be reduced by gradual increase in dose, taking drugs with food, avoiding hot drinks/alcohol, sustained-release
-  GI
-  Hepatitis – more with sustained release, can lead to fulminant failure and is dose dependent
-  Elevations in glucose/uric acid
-  Conjunctivitis, nasal stuffiness
-  Atrial arrhythmias? Duodenal ulcer? Acanthosis nigricans
-  Sustained release preparations – reduce flushing, less potent, more GI side effects and more hepatotoxicity
-  Contraindications – liver disease, diabetes, active duodenal ulcer, gout
-  Indications – hypertriglyceridemia, mixed dyslipidemia, low HDLc, hypercholesterolemia (when statins are

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