Agents used in Dyslipidemia

Agents
1
2
3
4
5
6

HMG CoA Reductase Inhibitor / Statins

Niacin / Nicotinic acid
Fibrates
Bile acids binding resins
Ezetemibe
CEPT inhibitors

NCEP-ATP Guidelines: know this by heart

Total Cholesterol
LDL cholesterol
HDL cholesterol (men)
HDL cholesterol (women)
Triglycerides

<200 mg/dl
<130 mg/dl
>40 mg/dl
>50 mg/dl
<150 mg/dl

Dyslipidemia Primary Cause may be due to a genetic defect of enzymes involved in liver protein or protein metabolism

Familial Hypercholesterolemia causes markedly elevated LDL level. It can also be found in young patients.
Lipoprotein lipase(LPL)

Breakdowns lipoprotein into triglyceride, cholesterol and fatty acids. This is what you find in the capillaries.

Chylomicrons are the biggest attacked by LPL VLDL acted by LPLIDL attack by LPL LDL goes to liver which would be broken down by hepatic lipase triglycerides and fatty acids
Management:
Before any form of pharmacologic treatment lifestyle modification
Caloric requirement women-1000-1200, male 1000-15002000

Decrease fat intake

Dietary management

First line treatment

caloric restriction

Avoidance of alcohol fatty livers

Omega-3-fatty acids (fish oil) causes low triglyceride levels; tuna, salmon

activate P-Par-Alpha causes lowering of triglyceride it also has anti-inflammatory effects

HMG CoA Reductase inhibitor/STATINS
Statins: Its sTAtins!
1
Lovastatin
2
Atorvastatin
3
Fluvastatin
4
Pravastatin
5
Simvastatin
6
Rosuvastatin- not avail in
Philippine; most efficacious
7
Pitavastatiin- not avail in
Philippines
8
Pravastatin- catabolized in
other pathway; safest;
hydrophobic
Characteristics

Marked hepatic first pass

hepatic extraction. So you
need to monitor liver function
test.

Can be biliary excreted

T1/2: 1-3 hours

o
Long half life:
atorvastatin;
rosuvastatin;
pitavastatin. As long
as 19 hours
1.
Inhibit HMG-CoA Reductase. (rate
limiting enzyme in cholesterol
synthesize)
2.
Increase the numbers of high
affinity LDL receptors.
3.
Most effective drug in reducing

NIACIN/Nicotinic acid
NIACIN (NICOTINIC ACID)

Excreted in urine
1.
Most effective agent in increasing
HDL (good cholesterol)
If the patient only presents
an increase in HDL, give niacin
2.
Only agent that reduces
lipoprotein a (LPa)
3.
Inhibits VLDL secretion
4.
Increases VLDL clearance via LPL
(lipoprotein lipase) (found in
capillaries)
5.
Decreases HDL catabolism
6.
Inhibits adipose cell LPL
o
Adipose cell: breaks down
stored cholesterol TG,
fatty acids
Adverse effects

Flushing
o
Prostaglandin mediated
vasodilation
o
Give aspirin/ibuprofen 30
mins before taking niacin

Pruritus

Abdominal discomfort
o
Patients with peptic ulcer
disease, pain is aggravated

Avoid taking
niacin

Insulin resistance

Fibrates
FIBRATES

Gemfibrozil most notable

to inhibit cytochrome system
Fenofibrate, Bezafibrate

Usually given in patient that

has high Triglyceride levels

Renal excretion
1.
Activate PPAR-alpha
Reduces triglycerides
levels
2.
Increases hydrolysis of VLDL
& chylomicron TG
3.
Increases hepatic & skeletal
muscle fatty acid oxidation
4.
Increases synthesis of APO AI
& APO AII (found in HDL)
Increasing HDL
levels
5.
Inhibits cytochrome enzyme
system (increases the levels
of statins)
a.
So, reduce the dose
of statins to avoid
toxicity
6.
Potentiate action of
coumarin
o
Coumarin: oral
anticoagulant

Avoid in those with hepatic or

renal dysfunction

Bile acid binding resins

BILE ACID - BINDING RESINS
I.

1.
2.
3.

II.
1.

2.

3.

4.

Drugs
Colestipol
Cholestyramine
Colesevelam
Indications or Uses
For isolated increase in LD
because these resins
upregulate LDL receptors ->
more LDL receptors -> LDL in
blood goes into the cell ->
LDL levels in blood goes
down
Prevent intestinal bile acid reabsorption
cholesterol in blood diverted
to more bile acid formation ->
cholesterol level in blood will
go down
Increase incretin secretion
incretin = "INtestinal
seCRETion of INtestine"
hormones released by
intestines after eating a high
carbohydrate meal
decreases appetite -> lowers
blood sugar
Relieves pruritus secondary to
cholestasis and bile acid accumulation
one of the symptoms of
obstructive jaundice is

Ezetimibe
Ezetimibe
o
the only agent
that inhibits
intestinal
absorption of
cholesterol
o
reduce LDL
levels
o
fecal excretion
o
levels increase
with fibrates (so
decrease the
dose)
o
levels reduced
by
cholestyramine
(so increase the
dose)
o
synergistic with
statins (problem:
very expensive)
o
may cause
hepatic
dysfunction

CEPT inhibitors
CETP Inhibitors
(Cholesteryl Ester
Transfer Protein)
1.
Torcetrapib
(withdrawn)
2.
Anacetrapib
3.
Dalcetrapib
o

normally: CETP
transfers
cholesteryl esters
from HDL to LDL
and to other
lipoproteins in
exchange to
triglycerides -> we
don't want this
MOA: Cholesteryl
esters will stay in
HDL. HDL is a
reverse
cholesterol
transporter, it
transports
cholesterol from
the periphery to
the liver and the
liver converts it to
other substances.
under
investigation

4.

LDL
Pleiotropic effects
a.
Stabilization of
atherosclerotic plaque
b.
Reduce vascular
inflammation
Used for MI and acute
coronary syndrome without
any regards on their lipid levels
Night time is the best time to
give. Because cholesterol
deposits at night.

Most efficacious: ROSUVASTATIN

10mg Rosuvastatin on patient =
40mg Simvastatin
ATORVASTATIN 2nd most
efficacious
PROVASTATIN only statin that is lipid
soluble
Toxicity

elevation of serum
aminotransferases

myopathy

myoglobinuria

drug interaction
Elevation of serum aminotransferase

Should have periodic evaluation

of liver function test

Reduce dose or stop the drug in

extreme cases
Myopathy

Usually affects calf muscles

Stop statins may lead to

rhabdomyolysis
May cause Myoglobinuria which is fatal

Should immediately discontinue

Check for CK
Drug interaction
-catabolize by cytochrome system
CYP3A4
dependent
catabolism
Lovastatin
Simvastatin
Atorvastatin
-

CYP2C9
dependent
catabolism
Fluvastatin
Rosuvastatin
Pitavastatin

Inhibitors: grape juice,

macrolides, fibrates,
metronidazole, amiodarone
Inducers: anticonvulsant

Remember:
Enzyme inhibitor- increase drug level in the
body because it cannot be metabolized
Enzyme Inducer- decrease amount of drug
in the body because it increases
metabolism

Increased glucose
Dont give to patients who
are hyperglycemia
o
Acathosis nigricans:
hyperpigmentation on the
nape (sign of insulin
resistance)
Hyperuricemia
Macular edema
o
Blurring of vision
Potentiates action of
antihypertensive
o
Due to prostaglandin
mediated vasodilation
o
o

Increased risk of cholesterol

gallstones
Beta-shift phenomenon
o
Shift in the
formation of beta
lipoprotein when
the triglyceride
levels are lower
o
B-100: LDL
o
Triglycerides go
down, LDL goes up

5.
III.

a)

b)

c)

d)

intense pruritus
Bind digitalis glycosides
Adverse Effects
Constipation and bloating
o
improve bowel movement by:

Ingesting more
fibers

Taking laxatives
esp. fiber-rich ones

(e.g.
Psyllium
fiber)
Vitamin K malabsorption
o
if taking warfarin or other
anticoagulant, adjust the
dose
o
PTT with INR to see if right
dose
Impairs absorption of drug
o
should be given 1 hr before
the drug or 2 hours after
giving the resin (not
simultaneously)
Avoid in patients with diverticulitis
o
since it causes constipation
and bloating, it can aggravate
diverticulitis

markedly increase
HDL and reduces
LDL *Niacin
increases HDL too

IV.

Drug Combinations
a.
If failure of monotherapy
b.
Mixed hyperlipoproteinemia
c.
Markedly increased in VLDL during treatment of hypercholesterolemia with a resin
d.
Use the lowest effective dose
e.
Monitor for toxicity

Seatwork: Case
Cholesterol
Triglycerides
HDL
LDL
Normal SGOT / SGPT

205 mg/dl
1,067 mg/dl
35 mg/dl
100 mg/dl

Increased
markedly increased
decreased
slightly increased

NSAIDS
Low-dose ASA

DOC: Fibrates
1.
It is the best drug for lowering triglycerides
2.
Promotes HDL synthesis
3.
Prevents the risk of having acute pancreatitis

Effects on
PGI
(antithrombo
tic)

Effects on
TXA
(prothrombot
ic)

Conventional
(Nonselective)
NSAIDS

COX-2
inhibitors

No effect

Thrombotic
Risk

(may be
due to renal
effects and
not due to
of PGI )
( because
of PGI-2)

Goals of treatment:
1. Relief of pain and maintenance of function
2. Slowing/ arrest of tissue-damaging process
NSAIDS
-

all are weak organic acids

metabolized in the liver by CYP450 enzymes
renally excreted
dont alter the course of arthritis
strictly for pain relief
MOA :
1. Nonselective NSAIDS: block both COX-1 and COX-2 pathways
- causes GI discomfort
2. COX-2 Inhibitors: no effect on COX-1 pathway
-less GI effects
Renovascular Effects of NSAIDS: may lead to renal toxicity
Side effects should be discussed to the patient
should be taken only PRN and for a short period of time
may aggreviate MI
use opioid analgesiscs instead for patients with unstable angina, acute coronary syndromes and MI
conventional NSAIDS are safer than COX-2 NSAIDS regarding thrombotic risks

I. Non-acetylated
Salicylates
- nonselective cox inhibitors
- anti-inflammatory >
analgesic
- safer but weaker against pain
- desirable in px with asthma,
bleeding tendencies, and renal
dysfunction

II. COX-2 Selective NSAIDS

similar efficacy with
nonselective NSAID
only advantage: less
gastric side effects
no cardioprotective effect,
only cardiodetrimental
drugs available:
Celecoxib, Meloxicam,
Etoricoxib, Parecoxib

III. Traditional/ Non-selective NSAIDS

1. Diclofenac
most notorious in elevating
aminotransferases in the serum
- CI: liver problems
- Diclofenac + PPI (esomeprazole) =
lesser GI irritation
2. Diflunisal
- as strong as than morphine
- for pain with bone meds
3. Ibuprofen
- closes PDA
- antagonize ASA- induced antiplatelet
aggregation
4. Indomethacin
- inhibit COX and Phospholipase A and
Phospholipase C just like steroids
- closes PDA
- T prolonged by probenecid
5. Ketoprofen

DMARDS
given to RA patients with no relief from NSAIDS
- slow down/ reverse joint damage
- slow-acting: benefit seen after 6 wks- 6 months
-usually toxic
- MOA; suppress T-cells, B-cells, cytokines and TNF
- immunomodulating agents

Arachido
nic Acid
COX-1
(Constitutiv
e) Pathway

COX-2
(Inducibl
e)
Pathway

I.Thromboxa
Biologic DMARDS
PGI
-MC side ne
effect: infection
PGE-1
(prostacyclin)
- may also cause malignancies
& PGE-2
-screen px for TB
-Hemostasis
may reactivate TB
Cytoprote
1.
Abatacept: T cell modulator
pain, fever
renal
2.
Rituximab : B-cell cytotoxicctive
and
protecti
3.
Toclizumab: anti_IL6 receptor antibody
inflammati
4.
TNF-blocking agents:
on
on
adalimumab, certolizuman, Etarecept, Golinumab, Infliximab

- inhibit COX and LOX

- safe for asthmatic patients
-T prolonged by probenecid
6. Ketorolac
- decreases opioid requirement as much
as 50% if given together
7. Oxaprozin
-longest T (58-60 hrs in the blood)
- mildly uricosuric
8. Nabumetone and Piroxicam
- also has long t but < Oxaprozin
9. Piroxicam
- inhibit COX and PMN migration
- O2 radical formation
- inhibit lymphocyte function=
immunosuppressive
10. Sulindac
- Preventive for colon CA
- suppresses Familial Intestinal
Polyposis
11. Tolmetin
- shortest T1/2 (1 hr)
12. Acetaminophen (Paracetamol)
- weak COX inhibitor
- only affect COX in peripheral tissues
-no effect on COX in the CNS= weak
analgesic
-no anti-inflammatory effect
-short T = relatively safe for patients
with renal dysfunction
-for children with viral infection
- hepatotoxic: 4gm/ day
- lethal: 15gms/day
-nephrotoxic- may be prevented by
oral fluid intake and by taking in acetylcysteine
(antidote)

GOUT

Agents are used for the relief of acute gouty attacks and prevent recurrent gout and ureate lithiasis
Asymptomatic gout = with or without treatment
Symptomatic = give treatment

Arachidonic
Acid
blocked by
Nonselective
and COX-2
NSAIDS
sodium
retention
(Most common)

Peripheral
edema

Acute Renal
Failure

Hyperkalemia

Prerenal
azotemia and
decreased
bloodflow

Type 4 Tubular
Necrosis

Hyponatremia
HPN

CHF

Acute Tubular
Necrosis (ATN)

Gout could be the Swelling of the first metatarsal joint, tophi etc.
Purine diet
o
Not a factor for gouty arthritis
o
The sudden change in the uric acid level is the factor for gouty arthritis

ACUTE GOUT
Colchicine

Magic drug

Both diagnostic and therapeutic

o
More specific for gout than other
agents

Reduces the migration of leukocytes and

phagocytosis

Reduces production of LTB4

Excreted in the intestinal tract and urine

Side Effect: Diarrhea

o
This side effect is used to determine
the dose of colchicine that will be
given to the patient
o
Start with a low dose; if no diarrhea
occurs add another, until a slight
diarrhea develops. This will now
serve as the basis of the dose.
o
However if the diarrhea becomes
worse or has not subsided, reduce
the dose of colchicine
Indication:

Acute attack of gout

Prophylaxis of recurrent gout

Hepatic cirrhosis
Route of administration:

Can be given IV
o
But withdrawn from the
because it causes death

Can be given per orem as tablet

NSAIDS

Inhibit uric acid crystal phagocytosis

Avoid low dose aspirin ( 2.6 g/d)

o
Can cause renal retention of
uric acid

will exacerbate the

gouty attack
o
However high dose of aspirin
is uricosuric (more than
3.6g/day). It can enhance the
excretion of uric acid.

Also avoid Salicylates and Tolmetin

Oxaprozin

Uricosuric agent

BUT: not for patients with

uric
acid
stones

promotes further stone

formation (true for
uricosuric agents)

Glucocorticoids

Causes
GI
bleeding,
hyperglycemia,
immune
suppression

Slows down appearance on new

bone erosions

Oral: Prednisone
</=7.5mg/day not to be
given in a long period of time,
gradual redcution

For acute attacks

Intra-articular
injection
of
Triamcinolone acetonide

Interleukin-1
Inhibitor
investigational

Canakinumab

Anakinra

Rilonacept

For
those
refractory
NSAIDS and colchicine

to

market

Chronic Tophaceous Gout

Uricosurics

Probenecid, Sulfinpyrazone, ASA (Aspirin)

more than 3.6g/day, Benzbromarone

Reduces uric acid reabsorption at the

proximal convoluted tubule

Can be used for chronic tophaceous gout

and uric acid under excretors intolerant to
allopurinol or febuxostat

Augments uric acid stone formation

o
Not used for patients with uric
acid stones

Use 2-3 weeks after acute attack of gout

o
Give colchicine first for the
acute attack/inflammation
o
Once
inflammation
has
subsided, you can now give
uricosuric agents

***Remember adequate hydration and

alkalinize urine to prevent stone formation

Side effect: GI irritation

Allopurinol

Hypoxanthine isomer; inhibits xanthine oxidase

o
Hypoxanthine is more water soluble; easier
excretion in the urine

Can be used for patients with intercritical gout

(asymptomatic gout) in between attacks

Used as adjunct in cancer chemotherapy

o
In chemotherapy, there is the production of
purines which can become uric acid
o
To prevent this phenomenon, we give
allopurinol prior to chemotherapy

It is also an anti-protozoal drug

Initial use warrants combination with colchicine/NSAIDs

o
to prevent acute attack

Drug Interactions:

can cause an increase in the concentration of:

o
Chemotherapeutic purines
o
Cyclophosphamide
o
Probenecid
o
Anticoagulants

Toxicity:

Precipitates acute attack of gout

o
Concomitant
administration
with

Febuxostat

Non-purine inhibitor of xanthine oxidase

Hepatic metabolism

Renal excretion

Use with colchicine or NSAIDs at the start

of treatment (to prevent acute gout
attack)

Adverse effect:
o
liver function abnormality
o
CARDIOTOXIC at high doses

Available doses are 40, 80, 120 mg

o
Higher dose can lead to cardiac
problems

Pegloticase

Recombinant of mammalian uricase (converts uric

acid to allantoin)
o
Remember uricase is not found on man
we cant really convert uric acid to
allantoin thus it accumulates and causes
stone formation

Long half-life: 1-2wks

Given IV

Causes rapid reduction of uric acid levels

Infusion reaction and gout flare common

Avoid in patients with G6PD deficiency

o
It produces hydrogen peroxide

causes lysis of rbc

thus can aggravate the disease

Colchicine needed on initiation to prevent acute gout

attack

colchicine to prevent this

GI upset, peripheral neuritis, vasculitis
Hepatotoxic, interstitial nephritis
Exfoliative dermatitis
o
Steven Johnson Syndrome