Methabolic Hemostasisi.pptx

Pharmacology of Metabolic
Hemostasis
Sagni Hanbisa (B-Pharm, MSc in
Pharmacology)
Department of Pharmacy
Institute of Health Sciences
Wallaga University
1

Outline
• Pharmacology of drugs used for treatment of
gout
• Pharmacology of drugs used for treatment of
hyperlipidemia
2

Drug therapy of Gout
Gout
• A metabolic inflammatory disease characterized by:
– Hyperuricemia (>6 mg/dl)
– Deposition of uric acid crystals in joint/synovial spaces
– Inflammatory rxn with intense pain, erythema & joint
swelling
• Most common inflammatory arthritis in men (4x)
• Affects about 3% of adults
• Incidence increases with age
 Hyperuricemia can occur by 2 mzms:
1. Excessive production (>800 mg/day)
2. Impaired renal excretion (80%, <600 mg/day)
3

Pathophysiology
• Abnormality in uric acid[UA] metabolism:
– Formed from degradation of purine bases
– Excreted by kidneys
• Forms monosodium urate (MSU) crystals
[high conc,]:
– Their collections, microtophi in joint spaces
– Occurs in distal extremities
– Larger tophi (> 10 yrs)
4

• Free urate crystals activate several
proinflammatory mediators:
– TNF-α, IL-1 & IL-8
– Attract neutrophils into joint spaces
– Ingest MSU, lysed & release lysosomal enzymes
– Clinical manifestations acute attack
• Uric acid nephrolithiasis [25%]:
– Uric acid stones [nephropathy & renal failure]
– Higher risk if SUA > 11 mg/dl & UA overexcretors
• Tumor lysis syndrome (TLS):
– Extreme hyperuricemia
– From cancer chemotherapy
5

• Complications:
– Cartilage & joint destruction
– Tophi
– Nephrolithiasis
– Nephropathy
6
Chronic tophaceous gout
tophus = localized deposit of monosodium
urate crystals

• Risk factors:
– Animal purines [kidneys, liver]
– Fructose [corn syrup, sweetbreads]
– Alcohol (beer)
– Male gender
– Obesity, HTN, & dyslipidemia
– Metabolic syndrome
– T2DM, CKD, & CAD
7

 Goal of Drug Therapy
• Short term
– To relieve acute symptoms of gouty
attack
 Due to crystallization of Na urate in
synovial space
» NSAIDs, glucocorticoids &
colchicines
• Long term
– To lower blood levels of UA
 For chronic gout, tophaceous gout, or
frequent gouty attacks
8

Drugs for hyperuricemia:
1. Agents that decrease UA
production
» Allopurinol & febuxostat
2. Agents that increase UA excretion
» Uricosuric drugs-Probenecid &
sulfinpyrazone
 The earlier the treatment, the better the
outcome
9

Drug treatment for acute gouty arthritis
1. NSAIDs-indomethacin, naproxen, & diclofenac
 Most effective when given within 24 hrs of
pain onset
 Better tolerated and have more predictable
effect
 ↓ Mov’t of granulocytes into affected area
 ↓ Pain & inflammation
 Inhibit crystal phagocytosis
• Continued at full doses until 24 hrs after symptoms
subside
– Aspirin is contraindicated
 Competes with UA for organic acid secretion
12

• Caution with/in:
– Peptic ulcers [with PPIs]
– Anticoagulants
– Renal insufficiency
– HTN & HF
13

NSAIDs- COX Inhibitors
 Prostanoids:
• Classes of eicosanoids:
– Membrane lipid derivatives (arachidonic acid)
– A 20-carbon fatty acid with 4 double bonds
– Released from membrane phospholipids by
phospholipase A2
• Wide spectrum of biologic activity
• Most important mediators of inflammation
14

Cyclooxygenases [COX; PG endoperoxide
synthases]:
16

Cyclooxygenase inhibitors (COXIs):
• Consists of aspirin & related drugs
• Useful effects:
– Suppress inflammation [anti-inflammatory]
– Relieve pain [analgesic]
– Reduce fever [antipyretic]
– Prevention of MI & stroke [aspirin]
• Their principal adverse effects:
– GI ulceration, bleeding and renal impairment
17

• Two major categories of COXIs:
1) Anti-inflammatory COXIs [NSAIDs]:
– 1st-generation/conventional/traditional
– 2nd-generation/selective COX-2Is/coxibs
2) COXIs without anti-inflammatory ppties:
– Acetaminophen
First-Generation NSAIDs
• Inhibit both COX-1 & COX-2
• A large & widely used family of drugs
• Used to treat:
– Inflammatory disorders
– Mild to moderate pain
– Fever
– Dysmenorrhea
18

Aspirin
• A derivative of salicylic acid (ASA)
• An irreversible inhibitor of COX
• Extensively bound to albumin [80-90%]
• A highly valuable & effective drug [COX2I]:
– Mild to moderate pain [joint, muscle, headache,
postoperative]
– Fever [in adults]
– Arthritis [rheumatoid, osteo-], & rheumatic fever
– Thrombotic disorders [COX1I; MI & stroke]
– Dysmenorrhea [but ibuprofen & naproxen as
DOC]
19

• Adverse effects:
– GI irritations & bleeding
– Bleeding
– Renal impairment [edema]
– Salicylism [tinnitus, sweating, headache,
dizziness, alkalosis]
– Reye's syndrome [children with
influenza/chickenpox]
– Hypersensitivity rxns (25%; asthma, rhinitis,
urticaria)
• PRC-D (anemia, postpartum bleeding
& prolong labor)
20

Nonaspirin NSAIDs[>20]
• Ibuprofen, Indomethacin, Diclofenac….
• Similar actions as aspirin:
– Inhibit both COX-1 & COX-2 [reversibly]
• Equal or better analgesia vs. aspirin
• Preferred agents for mild to moderate pains:
– Rheumatoid arthritis
– Osteoarthritis
– Menstrual cramps
– Postsurgical pain
– Bone metastasis
21

Second-Generation NSAIDs
• Selective COX-2 inhibitors (coxibs)
• As effective as traditional ones:
– Anti-inflammatory & analgesic effects
• Lower risk of GI harm
• Impair renal function: HTN & edema
• Increase the risk of MI & stroke:
– Not suppress platelet aggregation
– Inhibit prostacyclin[PGI2; VC]
• Available drugs: Celecoxib
22

Acetaminophen
• Analgesic & antipyretic effects
• Does not:
– Have anti-inflammatory & anti-rheumatic
actions
– Suppress platelet aggregation
– Cause gastric ulceration
– Cause renal impairment
• Inhibits central COX only: dec fever & pain
• Readily absorbed orally
• Overdose can cause severe liver injury
23

• Relief of pain & fever[<4 gm/d]:
– Headache, myalgia, & postpartum pains
– Pains of low back & osteoarthritis [DOC]
– Children with viral infections
– Pts with Hx of PUD, hemophilia, & asthma
– As an alternative for NSAID-
hypersensitivity
• Adverse effects (rare):
– Liver injury (overdose)
• Drug interactions:
– Alcohol and Warfarin
24

2. Colchicine [IV or PO]
– anti-inflammatory agent used in gout only
– No analgesic property
– Inhibition of leukocyte migration /infiltration
• Via disruption of microtubules, Hence:
» No phagocytosis of uric acid
» No release of lysosomal enzymes
• Clinical uses [NSAID intolerance or
refractory]:
– Acute gouty attack (large doses)
– Prophylaxis of gouty attacks (low doses,
0.6 mg/day)
– Prophylaxis during initiation of urate-
lowering agents 25

• Currently its clinical use is limited:
– Low therapeutic index
– Increased cost
 Adverse effect [common with IV]:
– GI toxicity-NVD, & abdominal pain (80%)
– Bone marrow suppression [neutropenia]
– Renal failure
– Hepatic necrosis
– Seizures
– Death
26

3. Corticosteroids(CSs)
• Administered via intra-articular, systemic, or SC
• Systemic CSs are a useful options in pts with:
– Hypersensitive to NSAIDs
– C/I to NSAIDs/colchicine [renal impairment]
– Unresponsive to NSAIDs
– Severe gout or polyarticular attacks [in elders]
• Prednisone, prednisolone, & methylprednisolone
[PO]
27

– Fluid retention
– Hyperglycemia
– CNS stimulation
– Wt gain
– GI upset
– Increased risk of infection
 Combination therapy
• For severe polyarticular attacks:
– Colchicine + NSAID/CS
– Intra-articular CS + NSAID/colchicine
28

Drug Treatment for chronic gout
 Hyperuricemia-caused by:
» A genetic defect
» Renal deficiency
» Blood dyscrasias
» Cancer chemotherapy
 Treatment strategies- long term t/t
» ˂ 7/6 mg/dl of UA level in blood
• Urate-Lowering Agents
– Increasing UA excretion[Uricosuric drugs]:
– Probenecid & sulfinpyrazone
– Inhibition of UA formation
– Allopurinol & febuxostat
– Selective inhibitor of terminal steps
29

• Candidate pts for prophylactic therapy:
– Recurrent attacks (>2/yr)
– Evidence of tophi
– CKD stage 2 or worse
– Past urolithiasis
• Goal of treatment: [Uric acid] < 6.8 mg/dl
– Long-term treatment
– Exacerbates/induce acute gouty attack[initially]
30

Allopurinol
• Current DOC for tophaceous gout:
– Effective in both overproducers & underexcretors
– Well tolerated
• By reducing blood UA levels
– Prevents tophus formation
– Causes regression of tophi
– Improve joint function
– ↓s risk of nephropathy
32

• Also used for secondary hyperuricemia:
– Cancer chemotherapy
– Blood dyscrasias
 Adverse effects
– Hypersensitivity syndrome
– GI rxns
– Neurologic effects
– Cataracts [chronic use]
– Stevens-Johnson syndrome,in doses of more
than 100 mg/day.
Febuxostat
- Like allopurinol Lowers urate by inhibiting XO
– Expensive
– Reserved for intolerant or refractory pts for allopurinol 33
Target skin lesions mucous
membrane erosions epidermal
necrosis with skin detachment

Probenecid
• Uricosuric agent
• Inhibits renal tubular reabsorption of UA
– Reduces hyperuricemia
– Prevents formation of new tophi
– Facilitates regression of existing tophi
• Alternative first-line drug: Intolerance or C/I to
XOI agents
• Adverse effects
– Mild GI effects
– Hypersensitivity rxn
– Renal injury
– Hepatic toxicity 34

Sulfinpyrazone -Like probenecid
• Adverse effects
– GI effects
– Exacerbate GI ulcer
– Renal injury
 Pegloticase [IV]
• Newest urate-lowering agent [2010]
• derived from a genetically modified strain of
E. coli.
• A recombinant mammalian uricase [urate
oxidase]:
– Oxidizes uric acid to more water soluble, allantoin,
which is then renally excreted.
• Reserved for refractory cases with tophi or
nephropathy 35

– Infusion rxns
– Anaphylaxis
– Nephrolithiasis
– Arthralgia & muscle spasm
– Headache
– Hemolytic anemia [G6PD deficiency]
36

Drugs for treatment of Gout from STG of
Ethiopia
 Acute Gout
– First line
» Indomethacin
– Alternatives
» Colchicine, OR
» Prednisolone
 Chronic Gout
– First line
» Allopurinol
– Alternative
» Probenecid
37

Introduction
• lower the levels of lipids and
lipoproteins in blood
• prevent cardiovascular disease
– Used to prevent or slow progression of
atherosclerosis to reduce the risk of
coronary artery disease and prolong life
39

• Cholesterol
– Advantages
• Serves as a component of cell membranes and
intracellular organelle membranes
• Is involved in the synthesis of certain hormones
including estrogen, progesterone, testosterone,
adrenal corticosteroids
• Needed for the synthesis of bile salts which are
needed for digestion and absorption of fats.
• Is deposited in the stratum corneum of the skin
to help ↓ evaporation of water and create
impermeability to water soluble compounds
(helps keep moisture in skin)
40

– Origin
• Is synthesized in the liver. Acetyl CoA is converted to
mevalonic acid and ultimately to cholesterol by
hydroxymethyl glutaryl coenzyme A (HMG-CoA)
reductase.
• Endogenous synthesis of cholesterol increases at night
• An increase in dietary cholesterol produces only a
small ↑ in blood levels of cholesterol because
ingestion inhibits endogenous synthesis
• Dietary saturated fats ↑ blood cholesterol levels
because they are converted to cholesterol in the body.
41

• Lipoproteins
– Serve as carriers for transporting lipids
(cholesterol and triglycerides) in the blood.
– Apolipoproteins
• Embedded in the lipoprotein shell
• Three functions
– 1. Serve as recognition sites for cell-surface
receptors; allowing cells to bind and ingest the
lipoprotein.
– 2. Activate enzymes that will metabolize the
lipoprotein
– 3. ↑ structural stability of the lipoprotein 42

• All lipoproteins that deliver lipids to peripheral tissues
(nonhepatic tissues) contain apolipoprotein B-100 (Ex:
VLDL, LDL)
• All lipoproteins that transport lipids from peripheral tissues
back to the liver contain apolipoprotein A-I (Ex: HDL)
• Lipoproteins of importance
• VLDL (very low density lipoprotein)
– Contain triglycerides (TGs) and some cholesterol
– Account for nearly all TGs in the blood
– Contain B-100
– Deliver triglycerides from the liver to adipose
tissues and muscles.
– Remnants of hydrolysis are IDL (intermediate
density lipoproteins), which can be transported to
liver or converted to LDL
43

Doi H et al. Circulation 2000;102:670-676
Colome C et al. Atherosclerosis 2000;149:295-
302
Cockerill GW et al. Arterioscler Thromb Vasc
Biol
1995;15:1987-1994
HDL
LDL
Chylomicrons,
VLDL, and
their catabolic
remnants
> 30 nm 20–22 nm
Potentially
pro-inflammatory
9–15 nm
Potentially
anti-
inflammatory
Lipoprotein Classes
44

• LDL (low density lipoprotein)
– “Bad cholesterol”
– Contain cholesterol
– Account for 60-70% of cholesterol in the blood
– Contains B-100
– Delivers cholesterol to peripheral tissues
– Formed from IDL, the remnants of VLDL
– Makes the greatest contribution to coronary
atherosclerosis
• Oxidized LDL contributes to atherosclerotic
plaque
– Removed from plasma via endocytosis by liver
converting it to bile acids excreted in GI 45

The Role of Lipoproteins in Atherogenesis
HDL
Liver
Oxidative
modification
of LDL
LDL
+
VLDL
Cholesterol
excreted
High plasma
LDL
LDL
infiltration
into intima
+
Macrophage
s
Foam cells
Fatty streak
Advanced
fibrocalcific
lesion
Endothelial
injury
Adherence
of platelets
Release
of PDGF
Other
growth
factors
LCAT
APO-A1
APO-A1=Apolipoprotein A1, HDL=High
density lipoprotein, LCAT=Lecithin
cholesterol acyltransferase, LDL=Low density
lipoprotein, PDGF=Platelet-derived growth
factor, VLDL=Very low density lipoprotein
46

• HDL (high density lipoprotein)
– “Good cholesterol”
– Contain cholesterol
– Account for 20-30% of cholesterol in the blood
– Some contain Apo A-I and Apo A-II
– Apo A-I is cardio protective
– Transports cholesterol from the peripheral tissues
back to the liver – promotes cholesterol removal
– Antiatherogenic
47

LIPOPROTE
IN CLASS
DENSITY
OF
FLOTATIO
N, g/ml
SIGNIFICAN
T
APOPROTEI
NS
SITE OF
SYNTHESI
S
MECHANISM(S) OF
CATABOLISM
Chylomicrons
and remnants
<<1.006 B-48, E, A-I,
A-IV, C-I, C-
II, C-III
Intestine Triglyceride hydrolysis
by LPL
ApoE-mediated
remnant uptake by
liver
VLDL <1.006 B-100, E, C-I,
C-II, C-III
Liver Triglyceride hydrolysis
by LPL
IDL 1.006-1.019 B-100, E, C-II,
C-III
Product of
VLDL
catabolism
50% converted to LDL
mediated by HL, 50%
apoE-mediated uptake
by liver
50% apoE-mediated
uptake by liver
LDL 1.019-1.063 B-100 Product of
VLDL
catabolism
ApoB-100-mediated
uptake by LDL
receptor (~75% in
liver)
HDL 1.063-1.21 A-I, A-II, E,
C-I, C-II, C-
III
Intestine,
liver,
plasma
Complex:
Transfer of cholesteryl
Characteristics of Plasma Lipoproteins
48

The major pathways involved in the metabolism of
chylomicrons synthesized by the intestine and VLDL
synthesized by the liver
49

Classification of Plasma Lipid
Levels
Total cholesterol
<200 mg/dl Desirable
200-239 mg/dl Borderline high
≥240 mg/dl High
HDL-C
<40 mg/dl Low (consider <50 mg/dl as low for women)
>60 mg/dl High
LDL-C
<70 mg/dl Optimal for very high risk (minimal goal for CHD
equivalent patients)
<100 mg/dl Optimal
100-129 mg/dl Near optimal
160-189 mg/dl High
≥190 mg/dl Very high
Triglycerides
<150 mg/dl Normal
200-499 mg/dl High
≥500 mg/dl Very high
50

Secondary Causes of
Dyslipidemia
DISORDER MAJOR LIPID EFFECT
Diabetes mellitus Triglycerides > cholesterol; low
HDL-C
Nephrotic
syndrome
Triglycerides usually > cholesterol
Alcohol use Triglycerides > cholesterol
Contraceptive use Triglycerides > cholesterol
Estrogen use Triglycerides > cholesterol
Glucocorticoid
excess
Triglycerides > cholesterol
Hypothyroidism Cholesterol > triglycerides
Obstructive liver Cholesterol > triglycerides 51

Treatment of
hyperlipidemia
1.Non pharmacological
2.Pharmacological
52

– Non-Pharmacological Therapy – 1st line
tx
1. Diet modification
– Decrease intake of total fat and especially
saturated fat
– Increase fiber intake
– Increase Omega-3-fatty acids (found in fish)
– ↑ fruits and vegetables (antioxidants)
– ↓ simple sugars (sucrose)
2. Exercise (will ↑ HDL levels)
3. Reduce risk factors if possible
53

Therapy Dose
(g/day)
Effect
Dietary soluble
fiber
2-8  LDL-C 5-
10%
Soy protein 20-30  LDL-C 5-7%
Stanol esters 1.5-4  LDL-C 10-
15%
Dietary Adjuncts: Efficacy at Reducing LDL-
C
54

–Drug Therapy
Sites of action of drugs used for treatment of
dislypidemia
MOA:
• inhibit synthesis of
LDL-C
• inhibit reabsorption
of LDL-C/Bile salt
• inhibit release of
FFA and VLDL
from adipose tissue
and hepatocytes
respectively
• activate synthesis of
lipoprotein lipase
55

• Niacin (vitamin B3)
– Decreases VLDL and LDL and significantly ↑ HDL
– MOA
1. Inhibits VLDL secretion into the blood thereby
preventing production of LDL
2. Increases clearance of VLDL via lipoprotein lipase
pathway
3. Inhibits FFA release from adipose tissues by inhibiting
the intracellular lipase system
4. Reduces circulating fibrinogen (contributes to clot
formation) and ↑ tissue plasminogen activator (clot
dissolver)
5. HDL catabolic rate is decreased
6. Reduces the plasma level of Lp(a) lipoprotein, which
56

–Indications
• Drug of choice for ↓ levels of TG (VLDL) in
pts at risk for pancreatitis
• Mixed elevation of LDL and VLDL (alone or
in combination with reductase inh.)
• Elevation of TG (VLDL) and low levels of
HDL (Niaspan® - approved for elevating
HDL levels)
• Start with low dose and gradually increase
• Given 1-3g/day in divided doses or once
daily with extended release. Give at night 58

• Adverse effects
– Flushing
• Harmless cutaneous vasodilation
• Uncomfortable sensation of warmth
• Occurs after drug is started or ↑ dose
• Lasts for the first several weeks
• Can give 325mg aspirin 30 minutes before
each dose (prevents prostaglandin synthesis).
Can also take ibuprofen QD in place of ASA
59

– Pruritis, rashes, dry skin
– acanthosis nigricans (eruption of velvet
warty benign growths and
hyperpigmentation)
• Associated with insulin resistance
• Will have to d/c drug if occurs
– Nausea and abdominal discomfort
• Reduce dosage and may need to use
inhibitors of gastric acid secretion or
antacids (not containing aluminum)
60

– Hepatotoxicity
• Severe is rare, and reversible
• Occurs mostly with older sustained release
forms
• Monitor liver fx regularly
• Liver injury is less likely with Niaspan®
(given once daily) the new extended release
formulation
– Carbohydrate tolerance may be
moderately impaired (hyperglycemia)
• Reversible 61

– Hyperuricemia
• Occurs in about 1/5 of pts
• Occasionally precipitates gout
– Hypotension
• Especially seen in pts on antihypertensive
meds
– Can ↑ homocysteine levels which ↑ risk
of CAD (give folic acid to ↓
homocysteine levels)
62

• Fibrates
• Gemfibrozil,
• Fenofibrate,
• Clofibrate,
• Bezafibrate
– Little or no effect on LDL
– ↓ VLDL (TG)
– moderate ↑ of HDL
– MOA
• Ligand for the nuclear transcription
regulator, peroxisome proliferator-activated 63

– MOA…
• ↑ activity of lipoprotein lipase for lipolysis
of triglyceride (↑ clearance)
• ↓ lipolysis in adipose tissue, ↓ FFA release
• ↓ secretion of VLDL by liver
• ↓ uptake of FFA by liver
• ↑ HDL levels moderately
64

Hepatic and peripheral effects of
fibrates
66

Fibrate: Mechanism of Action
Liver
TG
IDL
VLDL
LPL
CE
CE FC
F
C
Macrophage
Mature HDL
Nascent
HDL
LDL-R
Intestin
e
CE=Cholesterol ester, FC=Free cholesterol,
HDL=High density lipoprotein,
IDL=Intermediate density lipoprotein, LDL-
R=Low density lipoprotein receptor,
LPL=Lipoprotein lipase, TG=Triglyceride,
Fibra
te
+
+
67

–Indication: Hypertriglyceridemia
• Gemfibrozil – 600mg QD-BID (half
life 1.5hrs)
• Fenofibrate – 1-3 67mg tablets QD
(half life 20hrs)
• Taken with food - ↑ absorption
• Max reduction of VLDL is achieved
within 3-4 weeks of treatment
–Adverse Effects
68

– Gallstones (upper abdominal discomfort,
intolerance of fried food, bloating)
• Gemfibrozil ↑ biliary cholesterol saturation
• Use with caution in pts with biliary tract ds,
women, obese pts, and Native Americans
– Myopathy (muscle injury)
• Tenderness, weakness, or unusual muscle
pain
• Will increase risk of statin-induced
myopathy when used together
(rhabdomyolysis has occurred rarely) 69

– Hepatoxicity
– Arrythmias
– Hypokalemia
– Displaces warfarin from plasma albumin
since drug is highly protein bound. Need
to ↓ warfarin dose
70

• Bile Acid-Binding Resins
• Colestipol and
• Cholestyramine
– Will ↓ LDL, may ↑ VLDL (would require
niacin combo if ↑ TG prior to tx)
– MOA
• Bile acids, the metabolites of cholesterol, are
normally reabsorbed in the jejunum and
ileum. When resins are given, they bind to
bile acids in the intestinal lumen, prevent 71

Gall Bladder
 LDL Receptors
 VLDL and LDL
removal
 Cholesterol 7-
hydroxylase
 Conversion of cholesterol
to BA
 BA Secretion
Liver
 BA Excretion
Terminal Ileum
Bile Acid
Enterohepatic
Circulation
Reabsorption of
bile acids
Bile Acid Sequestrant: Mechanism of Action
 LDL-C
BA=Bile acid, LDL-C=Low density lipoprotein
cholesterol, VLDL=Very low density lipoprotein
cholesterol
72

Bile Acid-Binding Resins :chemistry
73

– MOA…
• ↑ excretion creates a demand for ↑ synthesis
of bile acid. Liver cells must have an ↑
cholesterol supply (provided by LDL) to
synthesize bile acid. Liver cells will ↑ their
LDL receptors, ↑ing uptake of LDL from
plasma.
– Indication
• Used alone to ↓ LDL (by 15-20%)
• Normally used as adjuncts to the statins to ↓
LDL (by 50%)
74

– Adverse Effects
• Max reductions of LDL occur in one
month
• Must be taken with meals
• Constipation
• Bloating, indigestion, nausea
• Large doses may impair absorption of
fats or fat soluble vitamins (A, D, E,
and K)
75

– Drug Interactions
– Resins bind
– Digoxin
– Warfarin
– Thiazide diuretics,
– Tetracycline,
– Thyroxine,
– Iron salts,
– Pravastatin,
– Fluvastatin,
– Folic acid,
– Phenylbutazone,
– Aspirin,
– Ascorbic acid
• These agents should be given 1 hour before
the resin or 4 hours after 76

• HMG COA Reductase Inhibitors
(“statins”)
• Lovastatin
• Fluvastatin
• Pravastatin
• Simvastatin
• Atorvastatin
• Cerivastatin
– Most Effective for ↓ LDL 77

Inhibition of HMG-
CoA reductase
79

– MOA
• Inhibits hepatic HMG CoA reductase
• Inhibition of cholesterol synthesis
causes hepatocytes to synthesize more
LDL receptors
• Hepatocytes are able to remove more
LDLs from the blood
• Decrease production of apolipoprotein
B-100, thereby ↓ production of VLDL
• ↓ plaque cholesterol content
80

• Improve abnormal endothelial
function
• Enhance the ability of blood vessels to
dilate
• ↓ risk of thrombosis (inhibits platelet
aggregation and blocks thrombin
synthesis)
• Statins have high first pass extraction
by liver (only a small fraction of each
81

HMG-CoA Reductase Inhibitor: Mechanism
of Action
Acet
yl
CoA
HM
G-
CoA
Mevalon
ate
Farnesyl
pyrophosph
ate
Squalen
e
Choleste
rol
Squalene
synthase
Dolichol
Farnesyl-
transferas
e
Farnesyla
ted
proteins
E,E,E-
Geranylgerany
l
pyrophosphat
e
Geranylgeranyl
ated
proteins
Ubiquino
nes
HMG-CoA
Reductase
Inhibition of the Cholesterol Biosynthetic Pathway
82

LDL-R–mediated
hepatic uptake of
LDL and VLDL
remnants
Serum VLDL remnants
Serum LDL-
C
Cholesterol
synthesis
LDL
receptor
(B–E
receptor)
synthesis
Intracellular
Cholesterol
Apo B
Apo E
Apo B
Systemic Circulation
Hepatocyte
The reduction in hepatic cholesterol synthesis lowers intracellular
cholesterol, which stimulates upregulation of the LDL receptor and
increases uptake of non-HDL particles from the systemic circulation
LDL
Serum IDL
VLDLR
VLDL
HMG-CoA Reductase Inhibitor: Mechanism
of Action
83

• Indications
– Used alone to ↓ LDL
– Used with bile acid – binding resins to
↓ LDL
– Used with niacin to ↓ LDL, ↓ VLDL,
and ↑ HDL
– Enhanced if taken with food (except for
pravastatin – taken without food)
– Give in the evening
– Half life is 1-3 hours (except
84

– High potency (>40-50% LDL lowering)
– atorvastatin, simvastatin, cerivastatin
– Low potency (20-40% LDL lowering) –
lovastatin, fluvastatin, pravastatin
– ↓ LDL within 2 weeks; max reduction in
4-6 weeks
– New Drug: Altocor®
• Extended release lovastatin
• Slightly more effective than regular
lovastatin
85

• Adverse Effects
– Since LDL cholesterol levels will return to
pretreatment values if drugs are withdrawn,
treatment must continue lifelong
– Statins are pregnancy category X
– rash, GI disturbances (dyspepsia, cramps,
flatulence, constipation, abdominal pain)
– Hepatotoxicity
– Myopathy (0.5% of pts)
• Risk highest with lovastatin and
especially in combination with Fibrates 86

• Ezetimibe
– ezetimibe reduced cholesterol absorption
by 54%
– Cholesterol lowering agent
– Approved for monotherapy or in combo
with statins
– reduction of 60% with simvastatin for
LDL-C
87

Dietary
cholesterol
Production in
liver
Absorption from
intestine
Bloodstream
LDL-C VLDL
Cholesterol
synthesis
Biliary cholesterol
Chylomicrons
Fecal sterols and neutral
sterols
Ezetimibe: Mechanism of Action
88

• Inhibitors of Cholesteryl Ester
Transfer Protein
– a plasma glycoprotein synthesized by the
liver
– mediates the transfer of cholesteryl esters
– In animal models
• inhibition of CETP result in:
– higher HDL levels
– decreased LDL levels
– resistance to developing atherosclerosis
– JTT-705 and torcetrapib 89

HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol,
TC=Total cholesterol, TG=Triglycerides
*Daily dose of 40mg of each drug, excluding rosuvastatin
Good
 9%
1%
18%
 13%
Ezetimibe
Good
 14-29%
4-12%
 25-50%
 19-
37%
Statins*
Good
30%
11-13%
4-21%
19%
Fibrates
Reasona
ble to
Poor
 30-70%
14-35%
 10-20%
 10-
20%
Nicotinic
acid
Poor
Neutral
or
3%
10-18%
7-10%
Bile acid
sequestra
nts
Patient
tolerabilit
y
TG
HDL-C
LDL-C
TC
Therapy
Cholesterol Management
Pharmacotherapy—summary
90

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