Pharmacology

Pharmacology

Drugs
Drugs that
that Affect
Affect the
the Cardiovascular
Cardiovascular
System
System
Topics
Topics
•• Electrophysiology
Electrophysiology
•• Vaughn-Williams
Vaughn-Williams classification
classification
•• Antihypertensives
Antihypertensives
•• Hemostatic
Hemostatic agents
agents
Cardiac
Cardiac Function
Function
•• Dependent
Dependent upon
upon
–– Adequate
Adequate amounts
amounts ofof ATP
ATP
–– Adequate
Adequate amounts
amounts ofof Ca
Ca++++
–– Coordinated
Coordinated electrical
electrical stimulus
stimulus
Adequate
Adequate Amounts
Amounts of
of ATP
ATP
•• Needed
Needed to:
to:
–– Maintain
Maintain electrochemical
electrochemical gradients
gradients
–– Propagate
Propagate action
action potentials
potentials
–– Power
Power muscle
muscle contraction
contraction
Adequate
Adequate Amounts
Amounts of
of Calcium
Calcium
•• Calcium
Calcium isis ‘glue’
‘glue’ that
that links
links electrical
electrical and
and
mechanical
mechanical events.
events.
Coordinated
Coordinated Electrical
Electrical
Stimulation
Stimulation
•• Heart
Heart capable
capable of
of automaticity
automaticity
•• Two
Two types
types of
of myocardial
myocardial tissue
tissue
–– Contractile
Contractile
–– Conductive
Conductive
•• Impulses
Impulses travel
travel through
through ‘action
‘action potential
potential
superhighway’.
superhighway’.
A.P.
A.P. SuperHighway
SuperHighway
•• Sinoatrial
Sinoatrial node
node
•• Atrioventricular
Atrioventricular
node
node
•• Bundle
Bundle of
of His
His
•• Bundle
Bundle Branches
Branches
–– Fascicles
Fascicles
•• Purkinje
Purkinje Network
Network
Electrophysiology
Electrophysiology
•• Two
Two types
types of
of action
action potentials
potentials
–– Fast
Fast potentials
potentials
•• Found
Foundin
incontractile
contractiletissue
tissue
–– Slow
Slow potentials
potentials
•• Found
Foundin
inSA,
SA,AV
AVnode
nodetissues
tissues
Fast
Fast Potential
Potential
Phase 1
+20
Phase 2
0

-20
Phase 3
-40

-60
Phase 4
-80
controlled by Na+
RMP channels = “fast channels”
-80 to 90 mV
Fast
Fast Potential
Potential
•• Phase
Phase 0:
0: Na
Na++ influx
influx “fast
“fast sodium
sodium channels”
channels”
•• Phase
Phase 1:
1: KK ++ efflux
efflux
•• Phase
Phase 2:
2: (Plateau)
(Plateau) K K ++ efflux
efflux
–– AND
AND Ca
Ca ++++ influx
influx
•• Phase
Phase 3:
3: K
K++ efflux
efflux
•• Phase
Phase 4:
4: Resting
Resting Membrane
Membrane Potential
Potential
Cardiac
Cardiac Conduction
Conduction Cycle
Cycle
Slow
Slow Potential
Potential
dependent upon Ca++ channels = “slow channels”

-20
Phase 4 Phase 3
-40

-60

-80
Slow
Slow Potential
Potential
•• Self-depolarizing
Self-depolarizing
–– Responsible
Responsible for
for automaticity
automaticity
•• Phase
Phase 44 depolarization
depolarization
–– ‘slow
‘slow sodium-calcium
sodium-calcium channels’
channels’
–– ‘leaky’
‘leaky’ to
to sodium
sodium
•• Phase
Phase 33 repolarization
repolarization
–– K
K++ efflux
efflux
Cardiac
Cardiac Pacemaker
Pacemaker
Dominance
Dominance
•• Intrinsic
Intrinsic firing
firing rates:
rates:
–– SA
SA == 60
60 –– 100
100
–– AV
AV ==4545 –– 60
60
–– Purkinje
Purkinje ==1515 -- 45
45
Cardiac
Cardiac Pacemakers
Pacemakers
•• SA
SA isis primary
primary
–– Faster
Faster depolarization
depolarization rate
rate
•• Faster
FasterCa
Ca++++‘leak’
‘leak’
•• Others
Others are
are ‘backups’
‘backups’
–– Graduated
Graduated depolarization
depolarization rate
rate
•• Graduated
GraduatedCa
Ca++++leak
leakrate
rate
Potential
Potential Terms
Terms
RRP relative
refractor
y
period

ERP
effective refractory period

APD
action potential duration
Dysrhythmia
Dysrhythmia Generation
Generation
•• Abnormal
Abnormal genesis
genesis
–– Imbalance
Imbalance of
of ANS
ANS stimuli
stimuli
–– Pathologic
Pathologic phase
phase 44 depolarization
depolarization
•• Ectopic
Ectopicfoci
foci
Dysrhythmia
Dysrhythmia Generation
Generation
•• Abnormal
Abnormal
conduction
conduction
•• Analogies:
Analogies:
–– One
Oneway
wayvalve
valve
–– Buggies
Buggiesstuck
stuckin
in
muddy
muddyroads
roads
Reentrant
Reentrant Circuits
Circuits
Warning!
Warning!
•• All
All antidysrhythmics
antidysrhythmics have
have arrythmogenic
arrythmogenic
properties
properties
•• In
In other
other words,
words, they
they all
all can
can CAUSE
CAUSE
dysrhythmias
dysrhythmias too!
too!
AHA
AHA Recommendation
Recommendation
Classifications
Classifications
•• Describes
Describes weight
weight of
of •• View
View AHA
AHA definitions
definitions
supporting
supporting evidence
evidence
NOT
NOT mechanism
mechanism
•• Class
Class II
•• Class
Class IIa
IIa
•• Class
Class IIb
IIb
•• Indeterminant
Indeterminant
•• Class
Class III
III
Vaughn-Williams
Vaughn-Williams
Classification
Classification
•• Class
Class 11 •• Description
Description of
of
–– Ia
Ia mechanism
mechanism NOT
NOT
–– Ib
Ib evidence
evidence
–– Ic
Ic
•• Class
Class IIII
•• Class
Class III
III
•• Class
Class IV
IV
•• Misc
Misc
Class
Class I:I: Sodium
Sodium Channel
Channel
Blockers
Blockers
•• Decrease
Decrease Na Na++ movement
movement in in phases
phases 00 and
and 44
•• Decreases
Decreases rate
rate of
of propagation
propagation (conduction)
(conduction)
via
via tissue
tissue with
with fast
fast potential
potential (Purkinje)
(Purkinje)
–– Ignores
Ignores those
those with
with slow
slow potential
potential (SA/AV)
(SA/AV)
•• Indications:
Indications: ventricular
ventricular dysrhythmias
dysrhythmias
Class
Class Ia
Ia Agents
Agents
•• Slow
Slowconduction
conduction •• PDQ:
PDQ:
through
through ventricles
ventricles –– procainamide
procainamide
•• Decrease (Pronestyl
(Pronestyl®®))
Decrease
repolarization –– disopyramide
repolarization rate
rate disopyramide
(Norpace
(Norpace®®))
–– Widen
WidenQRS
QRSand
andQT
QT
intervals –– qunidine
qunidine
intervals
•• May
Maypromote
promoteTorsades
Torsades
–– (Quinidex
(Quinidex®®))
des
desPointes!
Pointes!
Class
Class Ib
Ib Agents
Agents
•• Slow
Slowconduction
conduction •• LTMD:
LTMD:
through
through ventricles
ventricles –– lidocaine
lidocaine(Xylocaine
(Xylocaine®®))
•• Increase
Increase rate
rate of
of –– tocainide
tocainide(Tonocard
(Tonocard®®))
repolarization
repolarization –– mexiletine
mexiletine(Mexitil
(Mexitil®®))
•• Reduce –– phenytoin
phenytoin(Dilantin
(Dilantin®®))
Reduce automaticity
automaticity
–– Effective
Effectivefor
forectopic
ectopic
foci
foci
•• May
May have
have other
other uses
uses
Class
Class Ic
Ic Agents
Agents
•• Slow
Slowconduction
conduction •• flecainide
flecainide
through
through ventricles,
ventricles, (Tambocor
(Tambocor®®))
atria
atria &
& conduction
conduction •• propafenone
propafenone
system
system (Rythmol
(Rythmol®®))
•• Decrease
Decrease
repolarization
repolarization rate
rate
•• Decrease
Decrease contractility
contractility
•• Rare
Rare last
last chance
chance drug
drug
Class
Class II:
II: Beta
Beta Blockers
Blockers
•• Beta
Beta11 receptors
receptors in
in heart
heart attached
attached to
to Ca
Ca++++
channels
channels
–– Gradual
Gradual Ca
Ca++++ influx
influx responsible
responsible for
for
automaticity
automaticity
•• Beta
Beta11 blockade
blockade decreases
decreases Ca
Ca++++ influx
influx
–– Effects
Effects similar
similar to
to Class
Class IV
IV (Ca
(Ca++++ channel
channel
blockers)
blockers)
•• Limited
Limited ## approved
approved for
for tachycardias
tachycardias
Class
Class II:
II: Beta
Beta Blockers
Blockers
•• propranolol
propranolol (Inderal
(Inderal®®))
•• acebutolol
acebutolol (Sectral
(Sectral®®))
•• esmolol
esmolol (Brevibloc
(Brevibloc®®))
Class
Class III:
III: Potassium
Potassium Channel
Channel
Blockers
Blockers
•• Decreases
Decreases KK++ efflux
efflux during
during repolarization
repolarization
•• Prolongs
Prolongs repolarization
repolarization
•• Extends
Extends effective
effective refractory
refractory period
period
•• Prototype:
Prototype: bretyllium
bretyllium tosylate
tosylate (Bretylol
(Bretylol®®))
–– Initial
Initial norepi
norepi discharge
discharge may
may cause
cause temporary
temporary
hypertension/tachycardia
hypertension/tachycardia
–– Subsequent
Subsequent norepi
norepi depletion
depletion may
may cause
cause
hypotension
hypotension
Class
Class IV:
IV: Calcium
Calcium Channel
Channel
Blockers
Blockers
•• Similar
Similareffect
effectas
asßß •• verapamil
verapamil (Calan
(Calan®®))
blockers
blockers •• diltiazem
diltiazem (Cardizem
(Cardizem®®))
•• Decrease
DecreaseSA/AV
SA/AV
automaticity
automaticity
•• Decrease
DecreaseAV AVconductivity
conductivity •• Note:
Note: nifedipine
nifedipine
•• Useful
Usefulininbreaking
breaking doesn’t
doesn’t work
work on
on heart
heart
reentrant
reentrantcircuit
circuit
•• Prime
Primeside
sideeffect:
effect:
hypotension
hypotension& &
bradycardia
bradycardia
Misc.
Misc. Agents
Agents
•• adenosine
adenosine (Adenocard
(Adenocard®®))
–– Decreases
Decreases CaCa++++ influx
influx &
& increases
increases K
K++ efflux
efflux via
via
22ndnd messenger
messenger pathway
pathway
•• Hyperpolarization
Hyperpolarizationofofmembrane
membrane
•• Decreased
Decreasedconduction
conductionvelocity
velocityvia
viaslow
slowpotentials
potentials
•• No
Noeffect
effecton
onfast
fastpotentials
potentials
•• Profound
Profound side
side effects
effects possible
possible (but
(but short-
short-
lived)
lived)
Misc.
Misc. Agents
Agents
•• Cardiac
Cardiac Glycocides
Glycocides
•• digoxin
digoxin (Lanoxin
(Lanoxin®®))
–– Inhibits
Inhibits NaKATP
NaKATP pumppump
–– Increases
Increases intracellular
intracellular Ca
Ca++++
•• via
viaNa
Na++-Ca
-Ca++++exchange
exchangepump
pump
–– Increases
Increases contractility
contractility
–– Decreases
Decreases AV
AV conduction
conduction velocity
velocity
Pharmacology
Pharmacology

Antihypertensives
Antihypertensives
Antihypertensive
Antihypertensive Classes
Classes
•• diuretics
diuretics
•• beta
beta blockers
blockers
•• angiotensin-converting
angiotensin-converting enzyme
enzyme (ACE)
(ACE)
inhibitors
inhibitors
•• calcium
calcium channel
channel blockers
blockers
•• vasodilators
vasodilators
Blood
Blood Pressure
Pressure == CO
CO X
X PVR
PVR
•• Cardiac
Cardiac Output
Output == SV
SV xx HR
HR
•• PVR
PVR == Afterload
Afterload
 BP = CO x PVR

cardiac factors circulating volume

heart rate 1. Beta Blockers salt ACEi’s
2. CCB’s
contractility 3. C.A. Adrenergics aldosterone Diuretics

Key:

CCB = calcium channel blockers

CA Adrenergics = central-acting adrenergics
ACEi’s = angiotensin-converting enzyme inhibitors
 BP = CO x PVR

Hormones Peripheral Sympathetic

1. vasodilators Receptors
2. ACEI’s alpha beta
3. CCB’s 1. alpha blockers 2. beta blockers

Central Nervous System Local Acting

1. CA Adrenergics 1. Peripheral-Acting Adrenergics
Alpha
Alpha11 Blockers
Blockers
Stimulate
Stimulate alpha
alpha11 receptors
receptors ->
-> hypertension
hypertension
Block
Block alpha
alpha11 receptors
receptors ->
-> hypotension
hypotension

•• doxazosin
doxazosin (Cardura
(Cardura®®))
•• prazosin
prazosin (Minipress
(Minipress®®))
•• terazosin
terazosin (Hytrin ))
(Hytrin ®®
Central
Central Acting
Acting Adrenergics
Adrenergics
•• Stimulate
Stimulatealpha
alpha22 receptors
receptors
–– inhibit
inhibitalpha
alpha11stimulation
stimulation
•• hypotension
hypotension

•• clonidine
clonidine (Catapress
(Catapress®®))
•• methyldopa
methyldopa (Aldomet
(Aldomet®®))
Peripheral
Peripheral Acting
Acting Adrenergics
Adrenergics
•• reserpine
reserpine (Serpalan
(Serpalan®®))
•• inhibits
inhibits the
the release
release of
of NE
NE
•• diminishes
diminishes NE NE stores
stores
•• leads
leads to
to hypotension
hypotension
•• Prominent
Prominent side
side effect
effect of
of depression
depression
–– also
also diminishes
diminishes seratonin
seratonin
Adrenergic
Adrenergic Side
Side Effects
Effects
•• Common
Common
–– dry
dry mouth,
mouth, drowsiness,
drowsiness, sedation
sedation &
& constipation
constipation
–– orthostatic
orthostatic hypotension
hypotension
•• Less
Less common
common
–– headache,
headache, sleep
sleep disturbances,
disturbances, nausea,
nausea, rash
rash &
&
palpitations
palpitations
 RAAS
ACE
ACE Inhibitors
Inhibitors Angiotensin I
.

ACE

Angiotensin II

1. potent vasoconstrictor
- increases BP
2. stimulates Aldosterone
- Na+ & H2O
reabsorbtion
Renin-Angiotensin
Renin-Angiotensin
Aldosterone
Aldosterone System
System
•• Angiotensin
Angiotensin IIII == vasoconstrictor
vasoconstrictor
•• Constricts
Constricts blood
blood vessels
vessels && increases
increases BP
BP
•• Increases
Increases SVR
SVR oror afterload
afterload
•• ACE-I
ACE-I blocks
blocks these
these effects
effects decreasing
decreasing SVR
SVR&&
afterload
afterload
ACE
ACE Inhibitors
Inhibitors
•• Aldosterone
Aldosterone secreted
secreted from
from adrenal
adrenal glands
glands
cause
cause sodium
sodium && water
water reabsorption
reabsorption
•• Increase
Increase blood
blood volume
volume
•• Increase
Increase preload
preload
•• ACE-I
ACE-I blocks
blocks this
this and
and decreases
decreases preload
preload
Angiotensin
Angiotensin Converting
Converting
Enzyme
Enzyme Inhibitors
Inhibitors
•• captopril
captopril (Capoten
(Capoten®®))
•• enalapril
enalapril (Vasotec
(Vasotec®®))
•• lisinopril
lisinopril (Prinivil
(Prinivil®® &
& Zestril
Zestril®®))
•• quinapril
quinapril (Accupril
(Accupril®®))
•• ramipril
ramipril (Altace
(Altace®®))
•• benazepril
benazepril (Lotensin
(Lotensin®®))
•• fosinopril
fosinopril (Monopril
(Monopril®®))
Calcium
Calcium Channel
Channel Blockers
Blockers
•• Used
Used for:
for:
•• Angina
Angina
•• Tachycardias
Tachycardias
•• Hypertension
Hypertension
CCB
CCB Site
Site of
of Action
Action
diltiazem & verapamil

nifedipine
(and other
dihydropyridines)
CCB
CCB Action
Action
•• diltiazem
diltiazem &
& verapamil
verapamil
•• decrease
decreaseautomaticity
automaticity&&conduction
conductionin
inSA
SA&&AV
AVnodes
nodes
•• decrease
decreasemyocardial
myocardialcontractility
contractility
•• decreased
decreasedsmooth
smoothmuscle
muscletone
tone
•• decreased
decreasedPVR
PVR
•• nifedipine
nifedipine
•• decreased
decreasedsmooth
smoothmuscle
muscletone
tone
•• decreased
decreasedPVR
PVR
Side
Side Effects
Effects of
of CCBs
CCBs
•• Cardiovascular
Cardiovascular
•• hypotension,
hypotension, palpitations
palpitations &
& tachycardia
tachycardia
•• Gastrointestinal
Gastrointestinal
•• constipation
constipation &
& nausea
nausea
•• Other
Other
•• rash,
rash, flushing
flushing &
&peripheral
peripheral edema
edema
Calcium
Calcium Channel
Channel Blockers
Blockers
•• diltiazem
diltiazem (Cardizem
(Cardizem®®))
•• verapamil
verapamil (Calan
(Calan®®,, Isoptin
Isoptin®®))
•• nifedipine
nifedipine (Procardia
(Procardia®®,, Adalat
Adalat®®))
Diuretic
Diuretic Site
Site of
of Action
Action

Distal
tubule
proximal
tubule
Collecting
duct

loop of Henle
Mechanism
Mechanism
•• Water
Water follows
follows Na
Na++
•• 20-25%
20-25% of all Na
of all Na++ isisreabsorbed
reabsorbed into
into the
the blood
blood
stream
streamin
in the
the loop
loop of
of Henle
Henle
•• 5-10%
5-10% in in distal
distal tubule
tubule &
& 3%3% in in collecting
collecting ducts
ducts
•• IfIf itit can
can not
not be
be absorbed
absorbed itit isis excreted
excretedwith
with the
the
urine
urine
  Blood volume ==  preload
Blood volume preload !!
Side
Side Effects
Effects of
of Diuretics
Diuretics
•• electrolyte losses [[Na
electrolyte losses &K
Na++ & K++ ]]
•• fluid
fluid losses
losses [dehydration]
[dehydration]
•• myalgia
myalgia
•• N/V/D
N/V/D
•• dizziness
dizziness
•• hyperglycemia
hyperglycemia
Diuretics
Diuretics
•• Thiazides:
Thiazides:
•• chlorothiazide
chlorothiazide(Diuril
(Diuril®®))&
&hydrochlorothiazide
hydrochlorothiazide
(HCTZ
(HCTZ®®,,HydroDIURIL
HydroDIURIL®®))
•• Loop
Loop Diuretics
Diuretics
•• furosemide
furosemide(Lasix
(Lasix®®),),bumetanide
bumetanide(Bumex
(Bumex®®))
•• Potassium
PotassiumSparing
Sparing Diuretics
Diuretics
•• spironolactone
spironolactone(Aldactone
(Aldactone®®))
Mechanism
Mechanism of
of Vasodilators
Vasodilators
•• Directly
Directly relaxes
relaxes arteriole
arteriole smooth
smooth muscle
muscle
•• Decrease
Decrease SVR
SVR == decrease
decrease afterload
afterload
Side
Side Effects
Effects of
of Vasodilators
Vasodilators
•• hydralazine
hydralazine (Apresoline
(Apresoline®®))
–– Reflex
Reflex tachycardia
tachycardia
•• sodium
sodium nitroprusside
nitroprusside (Nipride
(Nipride®®))
–– Cyanide
Cyanide toxicity
toxicity in
in renal
renal failure
failure
–– CNS
CNS toxicity
toxicity == agitation,
agitation, hallucinations,
hallucinations, etc.
etc.
Vasodilators
Vasodilators
•• diazoxide
diazoxide [Hyperstat
[Hyperstat®®]]
•• hydralazine
hydralazine [Apresoline
[Apresoline®®]]
•• minoxidil
minoxidil [Loniten
[Loniten®®]]
•• sodium
sodium Nitroprusside
Nitroprusside [Nipride
[Nipride®®]]
Pharmacology
Pharmacology

Drugs
Drugs Affecting
Affecting Hemostasis
Hemostasis
Hemostasis
Hemostasis
•• Reproduce
Reproduce figure
figure 11-9,
11-9, page
page 359
359 Sherwood
Sherwood
Platelet
Platelet Adhesion
Adhesion
Coagulation
Coagulation Cascade
Cascade
•• Reproduce
Reproduce following
following components
components of
of
cascade:
cascade:
–– Prothrombin
Prothrombin ->
-> thrombin
thrombin
•• Fibrinogen
Fibrinogen->
->fibrin
fibrin
–– Plasminogen
Plasminogen ->
-> plasmin
plasmin
Platelet
Platelet Inhibitors
Inhibitors
•• Inhibit
Inhibit the
the aggregation
aggregation of of platelets
platelets
•• Indicated
Indicated inin progressing
progressing MI,
MI, TIA/CVA
TIA/CVA
•• Side
Side Effects:
Effects: uncontrolled
uncontrolled bleeding
bleeding
•• No
No effect
effect on
on existing
existing thrombi
thrombi
Aspirin
Aspirin
–– Inhibits
Inhibits COX
COX
•• Arachidonic
Arachidonicacid
acid(COX)
(COX)->
->TXA2
TXA2(
(aggregation)
aggregation)
GP
GP IIB/IIIA
IIB/IIIA Inhibitors
Inhibitors

GP IIb/IIIa
Receptor

Fibrinogen

GP IIb/IIIa
Inhibitors
GP
GP IIB/IIIA
IIB/IIIA Inhibitors
Inhibitors
•• abciximab
abciximab (ReoPro
(ReoPro®®))
•• eptifibitide
eptifibitide (Integrilin
(Integrilin®®))
•• tirofiban
tirofiban (Aggrastat
(Aggrastat®®))
Anticoagulants
Anticoagulants
•• Interrupt
Interrupt clotting
clotting cascade
cascade at
at various
various points
points
–– No
No effect
effect on
on platelets
platelets
•• Heparin
Heparin && LMW
LMW Heparin
Heparin (Lovenox
(Lovenox®®))
•• warfarin
warfarin (Coumadin
(Coumadin®®))
Heparin
Heparin
•• Endogenous
Endogenous
–– Released
Releasedfrom
frommast
mastcells/basophils
cells/basophils
•• Binds
Binds with
with antithrombin
antithrombin IIIIII
•• Antithrombin
Antithrombin IIIIII binds
binds with
with and
and inactivates
inactivates excess
excess
thrombin
thrombin to
to regionalize
regionalize clotting
clotting activity.
activity.
–– Most
Mostthrombin
thrombin(80-95%)
(80-95%)captured
capturedin
infibrin
fibrinmesh.
mesh.
•• Antithrombin-heparin
Antithrombin-heparin complex
complex 1000X
1000X as
as effective
effective
as
as antithrombin
antithrombin III
III alone
alone
Heparin
Heparin
•• Measured
Measured in
in Units,
Units, not
not milligrams
milligrams
•• Indications:
Indications:
–– MI,
MI, PE,
PE, DVT,
DVT, ischemic
ischemic CVA
CVA
•• Antidote
Antidote for
for heparin
heparin OD:
OD: protamine.
protamine.
–– MOA:
MOA: heparin
heparin isis strongly
strongly negatively
negatively charged.
charged.
Protamine
Protamine isis strongly
strongly positively
positively charged.
charged.
warfarin (Coumadin ®)
®
warfarin (Coumadin )
•• Factors
Factors II,
II, VII,
VII, IXIX and
and XX all
all vitamin
vitamin K K
dependent
dependent enzymes
enzymes
•• Warfarin
Warfarin competes
competes withwith vitamin
vitamin K K in
in the
the
synthesis
synthesis ofof these
these enzymes.
enzymes.
•• Depletes
Depletes the
the reserves
reserves of
of clotting
clotting factors.
factors.
•• Delayed
Delayed onset
onset (~12
(~12 hours)
hours) due
due toto existing
existing
factors
factors
Thrombolytics
Thrombolytics
•• Directly
Directly break
break up
up •• streptokinase
streptokinase
clots
clots (Streptase
(Streptase®®))
–– Promote
Promotenatural •• alteplase
natural alteplase (tPA
(tPA®®,,
thrombolysis
thrombolysis Activase
Activase®®))
•• Enhance
Enhance activation
activation •• anistreplase
anistreplase(Eminase
(Eminase®®))
of
of plasminogen
plasminogen •• reteplase
reteplase (Retevase
(Retevase®®))
•• ‘Time
‘Time isis Muscle’
Muscle’ •• tenecteplase
tenecteplase (TNKase
(TNKase®®))
Occlusion
Occlusion Mechanism
Mechanism
tPA
tPA Mechanism
Mechanism
Cholesterol
Cholesterol Metabolism
Metabolism
•• Cholesterol
Cholesterol important
important component
component in
in
membranes
membranes andand as as hormone
hormone precursor
precursor
•• Synthesized
Synthesized inin liver
liver
–– Hydroxymethylglutaryl
Hydroxymethylglutaryl coenzyme
coenzyme A
A reductase
reductase
–– (HMG
(HMG CoA
CoA reductase)
reductase) dependant
dependant
•• Stored
Stored in
in tissues
tissues for
for latter
latter use
use
•• Insoluble
Insoluble inin plasma
plasma (a (a type
type of
of lipid)
lipid)
–– Must
Must have
have transport
transport mechanism
mechanism
Lipoproteins
Lipoproteins
•• Lipids
Lipids are
are surrounded
surrounded byby protein
protein coat
coat to
to ‘hide’
‘hide’
hydrophobic
hydrophobic fatty
fatty core.
core.
•• Lipoproteins
Lipoproteins described
described by
by density
density
–– VLDL,
VLDL,LDL,
LDL,IDL,
IDL,HDL,
HDL,VHDL
VHDL
•• LDL
LDL contain
contain most
most cholesterol
cholesterol in
in body
body
–– Transport
Transportcholesterol
cholesterolfrom
fromliver
liverto
totissues
tissuesfor
foruse
use
(“Bad”)
(“Bad”)
•• HDL
HDL move
move cholesterol
cholesterol back
back to
to liver
liver
–– “Good”
“Good”b/c
b/cremove
removecholesterol
cholesterolfrom
fromcirculation
circulation
Why
Why We
We Fear
Fear Cholesterol
Cholesterol
•• Risk
Risk of
of CAD
CAD linked
linked to
to LDL
LDL levels
levels
•• LDLs
LDLs are
are deposited
deposited under
under endothelial
endothelial surface
surface and
and
oxidized
oxidized where
where they:
they:
–– Attracts
Attractsmonocytes
monocytes->
->macrophages
macrophages
–– Macrophages
Macrophagesengulf
engulfoxidized
oxidizedLDL
LDL
•• Vacuolation
Vacuolationinto
into‘foam
‘foamcells’
cells’
–– Foam
Foamcells
cellsprotrude
protrudeagainst
againstintimal
intimallining
lining
•• Eventually
Eventuallyaatough
toughcap
capisisformed
formed
–– Vascular
Vasculardiameter
diameter&
&blood
bloodflow
flowdecreased
decreased
Why
Why We
We Fear
Fear Cholesterol
Cholesterol
•• Plaque
Plaque cap
cap can
can rupture
rupture
•• Collagen
Collagen exposed
exposed
•• Clotting
Clotting cascade
cascade activated
activated
•• Platelet
Platelet adhesion
adhesion
•• Thrombus
Thrombus formation
formation
•• Embolus
Embolus formation
formation possible
possible
•• Occlusion
Occlusion causes
causes ischemia
ischemia
Lipid
Lipid Deposition
Deposition
Thrombus
Thrombus Formation
Formation
Platelet
Platelet Adhesion
Adhesion
Embolus
Embolus Formation
Formation
Occlusion
Occlusion Causes
Causes Infarction
Infarction
Antihyperlipidemic
Antihyperlipidemic Agents
Agents
•• Goal:
Goal: Decrease
Decrease LDL
LDL •• lovastatin
lovastatin (Mevacor
(Mevacor®®))
–– Inhibition
Inhibitionof
ofLDL •• pravastatin
LDL pravastatin (Pravachol
(Pravachol®®))
synthesis
synthesis •• simvastatin
simvastatin (Zocor
(Zocor®®))
–– Increase
IncreaseLDL
LDL
receptors •• atorvastatin
atorvastatin (Lipitor
(Lipitor®®))
receptorsin
inliver
liver
•• Target:
Target: << 200
200 mg/dl
mg/dl
•• Statins
Statins are
are HMG
HMG
CoA
CoA reductase
reductase
inhibitors
inhibitors