lipid ch 47 pharm 2

cluster of metabolic problems that significantly raises long-term risk of atherosclerotic cardiovascular disease (ASCVD), stroke, and type 2 diabetes. Diagnosis requires meeting 3 or more of these parameters:

metabolic syndrome

paramteters fro metabolic syndrome

Insulin resistance

Abdominal obesity

Dyslipidemia

Hypertension

Proinflammatory state

Prothrombotic state

Insulin resistance diagnostic criteria fasting blood glucose

> 100 mg/dL

Abdominal obesity waist circumfernce in men and women

> 40 inches in males; > 35 inches in females

Dyslipidemia HDL male and female

HDL < 40 mg/dL in males; < 50 mg/dL in females

dyslepidemia triglycerides

> 150 mg/dL

HTN parameter

130/85 mm Hg (or higher)

proinflmamtarory state diagnositic crietria

Increased tissue macrophages; elevated interleukin-6 and tumor necrosis factor levels

prothrombin state disganositic criteria

Elevated circulating plasminogen activator inhibitor levels

atherosclerotic cardiovascular disease (ASCVD), modifiable risk

Cigarette smoking; physical inactivity; high-saturated-fat diet; obesity; stress; gout; hypertension; hyperlipidemia

waht to know about lipid metabolism

Fat and water do not mix, like oil in a water pipe. So the body wraps fats in protein "bubble-wrap" to ride in the blood. A fat + protein package is called a lipoprotein. Cholesterol itself is not evil: you need it for cell walls and for making steroid hormones. The problem is too much, or the wrong packaging

what does dietary fat injestion do for lipid metabolism

fats enter the small intestine, triggering the gallbladder to contract and release bile.

waht does Micelles and absorption do for lipid metabolism

bile emulsifies fats into micelles, which are absorbed across the intestinal wall and packaged into chylomicrons

waht does lymph anf liver do for lipid metabolism

chylomicrons travel through the lymphatic system into the bloodstream. The liver processes the remnants into functional lipoproteins

VLDL (very-low-density) formed in

liver; rich in triglycerides

VDL role

Carries triglycerides to adipose (fat) tissue for storage

is VDL good or bad

Becomes LDL as it loses triglycerides

LDL made from

Derived as VLDLs

lose triglycerides;

tightly packed cholesterol core

is triglyceride in LDL loose or tight

loose

is cholesterol in LDL tight or loose

Extracts excess cholesterol from tissues and artery walls and returns it to the liver for biliary excretion (reverse cholesterol transport)

LDL cholesterol

Carries cholesterol to peripheral tissues. Excess LDL penetrates injured vessel lining and oxidizes, driving atheroma (plaque) formation

is LDL good or bad

bad

HDL made from

Loose, protein-rich; produced in the liver

HDL role

Extracts excess cholesterol from tissues and artery walls and returns it to the liver for biliary excretion (reverse cholesterol transport)

is HDL good or bad

good

drug class that act on small intsetine brush border

Cholesterol absorption inhibitors (Ezetimibe)

what happens with Ezetimibe

blocks cholesterol absorption

drug class that work on intestinal lumen

Bile acid sequestrants (Cholestyramine)

(Cholestyramine) waht happpesn

Binds bile acids, forcing fecal excretion

drug class that work on Hepatic parenchyma (liver)

HMG-CoA reductase inhibitors / statins; PCSK9 inhibitors (Evolocumab

block cholesterol synthesis;

Statins

increase LDL receptor recycling

PCSK9 inhibitors

drug that work on Adipose tissue and plasma

Fibrates and niacin

waht happens Fibrates and niacin

Accelerate triglyceride lipolysis

waht to know about children

Rely on dietary restriction because cholesterol is vital for developing neural tissue.

Familial hypercholesterolemia may need drugs if diet fails.

Statins with approved pediatric use:

atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin (typically ages 10-17).

approved for pediatric familial hypercholesterolemia in adolescents 13 and older.

Evolocumab

strictly contraindicated (Pregnancy Category X): fetal developmental injury..

Statins

safest option if therapy is required for pregnancy

Bile acid sequestrants

are not absorbed systemically

waht to knowa bout older adults

Higher rates of renal impairment: lower initial statin doses and routine renal monitoring. Higher risk of myalgia and rhabdomyolysis; baseline and periodic monitoring of liver enzymes, lipid levels, and muscle pain is mandatory.

Bile is made from cholesterol. Cholestyramine is a sticky "sponge" in the gut that grabs bile and carries it out in the poop. The liver then has to burn more cholesterol from the blood to make replacement bile, so blood cholesterol drops.

waht to know about bile

A. Bile acid sequestrants (prototype:

CHOLESTYRAMINE)

CHOLESTYRAMINE) mechanism

Binds negatively charged bile acids in the intestinal lumen, forming an insoluble complex excreted in feces. The liver replaces lost bile acids by oxidizing circulating cholesterol, lowering serum LDL

CHOLESTYRAMINE) PK

Not absorbed systemically; excreted entirely in feces.

CHOLESTYRAMINE)indications

Primary hypercholesterolemia; relief of pruritus (itching) from partial biliary obstruction.

CHOLESTYRAMINE)adverse effects

Severe constipation, fecal impaction, flatulence, abdominal cramps, aggravated hemorrhoids, deficiencies of fat-soluble vitamins (A, D, E, K), increased bleeding tendency (hypoprothrombinemia from vitamin K malabsorption).

CHOLESTYRAMINE)interactions

Binds and impairs absorption of fat-soluble vitamins, thiazide diuretics, digoxin, warfarin, thyroid hormones, corticosteroids.

timing to give other oral drugs with cholestyramine

Give other oral meds 1 hour BEFORE or 4-6 hours AFTER the sequestrant.

HMG-CoA reductase is the "factory machine" in the liver that makes cholesterol. Statins shut the machine down. The liver, now short on cholesterol, builds more LDL "catching hands" (receptors) on its surface and pulls LDL out of the blood. Statin names end in -statin.

what to know about HMG-CoA reductase inhibitors ("statins"

HMG-CoA reductase inhibitors ("statins") (prototype:

ATORVASTATIN)

ATORVASTATIN) mechanism

Competitively inhibits HMG-CoA reductase, the rate-limiting enzyme in hepatic cholesterol synthesis. Lower intracellular cholesterol makes hepatocytes increase surface LDL receptors, clearing more circulating LDL.

ATORVASTATIN) PK

oral

Metabolized in liver and cells; excreted mainly in bile

ATORVASTATIN) onset peak duration half life

Onset slow. Peak 1-2 hours. Duration 20-30 hours. Half-life 14 hours.

atorvastatin indication

Primary hypercholesterolemia, dyslipidemia; primary and secondary prevention of MI, stroke, revascularization in ASCVD or diabetes.

Approved for pediatric familial hypercholesterolemia (ages 10-17)

ATORVASTATIN) adverse effect

Hepatotoxicity (elevated transaminases), rhabdomyolysis (skeletal muscle breakdown with possible acute renal failure), myalgias, headache, abdominal cramps, constipation

ATORVASTATIN) monitoring

Baseline liver function tests and periodic ophthalmic exams for cataracts.

food to avoid statins

patients on statins metabolized by CYP3A4 must avoid grapefruit juice.

It inhibits intestinal CYP3A4 metabolism, markedly raising serum statin levels and the risk of severe muscle toxicity, myopathy, and rhabdomyolysis.

Cholesterol absorption inhibitors (prototype:

EZETIMIBE)

EZETIMIBE) mechanism

Acts at the brush border of the small intestine to inhibit absorption of dietary and biliary cholesterol, reducing cholesterol delivery to the liver.

EZETIMIBE) PK

oral

Metabolized in liver and small intestine; excreted in feces and urine.

EZETIMIBE) onset peak half life

Onset moderate. Peak 4-12 hours. Half-life 22 hours

EZETIMIBE)indications

Adjunct to diet, alone or with statins, for primary hypercholesterolemia, homozygous familial hypercholesterolemia, or homozygous sitosterolemia.

EZETIMIBE) adverse effect

Mild abdominal pain, diarrhea, headache, dizziness, fatigue, URI symptoms, back pain, myalgias, rare hepatitis.

PCSK9 is a "demolition worker" that destroys the liver's LDL catching-hands (receptors). Evolocumab is an antibody that grabs PCSK9 so it cannot demolish them. More receptors survive, so more LDL is cleared from the blood. Names end in -mab (monoclonal antibody); it is injected.

waht to know about PCSK9

D. PCSK9 inhibitors (prototype:

EVOLOCUMAB)

EVOLOCUMAB) mechanism

Human monoclonal antibody that binds free PCSK9. Prevents PCSK9 from degrading LDL receptors, increasing liver LDL-receptor density and speeding hepatic clearance of LDL.

EVOLOCUMAB) PK

subq

Eliminated by binding PCSK9 and general protein catabolism

EVOLOCUMAB) onset supression half life

Onset fast. Maximum PCSK9 suppression in 4 hours. Half-life 11-17 days

EVOLOCUMAB) indication

Reduce MI, stroke, and revascularization risk in adults with established ASCVD; adjunct to diet and statin for primary hyperlipidemia or homozygous familial hypercholesterolemia.

EVOLOCUMAB) adverse effect

Nasopharyngitis, URIs, influenza, injection-site reactions, hypersensitivity (rash, urticaria)

Fibrates ex drug

(fenofibrate, gemfibrozil)

Fibrates (fenofibrate, gemfibrozil) how it work

Stimulate PPAR-alpha to increase lipolysis and clearance of triglyceride-rich particles

Fibrate + statin =

higher risk of rhabdomyolysis

Niacin ex

(vitamin B3)

Niacin (vitamin B3) how it work

Inhibits free fatty acid release from adipose tissue; reduces hepatic VLDL synthesis

Niacin (vitamin B3) key point

Frequently causes cutaneous flushing and warmth; blunted by pre-administering aspirin

Omega-3 fatty acids ex

(Lovaza, Vascepa)

Omega-3 fatty acids (Lovaza, Vascepa) how it work

Inhibit hepatic enzyme systems, decreasing liver triglyceride synthesis

Omega-3 fatty acids (Lovaza, Vascepa) key point

Triglyceride lowering