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Cardiovascular
C ardiovascularpharmacology
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CARDIOVASCULARPHARMACOLOGY
Antihypertensive therapy
Primary (essential)
hypertension
Hypertension with
heart failure
Hypertension with
diabetes mellitus
Hypertension in
pregnancy
Calcium channel
blockers
MECHANISM
Block voltage-dependent L-type calcium channels of cardiac and smooth muscle muscle
contractility.
Vascular smooth muscleamlodipine = nifedipine > diltiazem > verapamil.
Heartverapamil > diltiazem > amlodipine = nifedipine (verapamil = ventricle).
CLINICAL USE
TOXICITY
Hydralazine
MECHANISM
cGMP smooth muscle relaxation. Vasodilates arterioles > veins; afterload reduction.
CLINICAL USE
Severe hypertension (particularly acute), HF (with organic nitrate). Safe to use during pregnancy.
Frequently coadministered with a -blocker to prevent reflex tachycardia.
TOXICITY
Hypertensive
emergency
Nitroprusside
Short acting; cGMP via direct release of NO. Can cause cyanide toxicity (releases cyanide).
Fenoldopam
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C ardiovascular
C ardiovascularpharmacology
Nitrates
MECHANISM
CLINICAL USE
TOXICITY
Reflex tachycardia (treat with -blockers), hypotension, flushing, headache, Monday disease in
industrial exposure: development of tolerance for the vasodilating action during the work week
and loss of tolerance over the weekend tachycardia, dizziness, headache upon reexposure.
Antianginal therapy
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COMPONENT
NITRATES
-BLOCKERS
NITRATES + -BLOCKERS
End-diastolic volume
No effect or
No effect or
Blood pressure
Contractility
No effect
Little/no effect
Heart rate
(reflex response)
No effect or
Ejection time
Little/no effect
MVO2
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Cardiovascular
C ardiovascularpharmacology
Lipid-lowering agents
DRUG
LDL
HDL
TRIGLYCERIDES
MECHANISMS OF ACTION
HMG-CoA reductase
inhibitors (lovastatin,
pravastatin,
simvastatin,
atorvastatin,
rosuvastatin)
Slightly
Slightly
Prevent intestinal
reabsorption of bile acids;
liver must use cholesterol to
make more
Ezetimibe
Prevent cholesterol
Rare LFTs, diarrhea
absorption at small intestine
brush border
Fibrates (gemfibrozil,
clofibrate,
bezafibrate,
fenofibrate)
Upregulate LPL TG
clearance
Activates PPAR- to induce
HDL synthesis
SIDE EFFECTS/PROBLEMS
Endothelial
cells
Blood
Gut
GI upset, absorption of
other drugs and fat-soluble
vitamins
Hepatocytes
Ezetimibe
LDL
Ac-CoA
HMG-CoA
reductase
inhibitors
HMG-CoA
LDL
Cholesterol
Bile acids
Fibrates
R
LDL
IDL
Lipoprotein
lipase
Niacin
VLDL
VLDL
Lipid
oxidation
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C ardiovascular
C ardiovascularpharmacology
Cardiac glycosides
307
Digoxin.
MECHANISM
CLINICAL USE
TOXICITY
Cholinergicnausea, vomiting, diarrhea, blurry yellow vision (think van Gogh), arrhythmias, AV
block.
Can lead to hyperkalemia, which indicates poor prognosis.
Factors predisposing to toxicity: renal failure ( excretion), hypokalemia (permissive for digoxin
binding at K+-binding site on Na+/K+ ATPase), verapamil, amiodarone, quinidine ( digoxin
clearance; displaces digoxin from tissue-binding sites).
ANTIDOTE
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Antiarrhythmics
sodium channel
blockers (class I)
Cardiovascular
C ardiovascularpharmacology
Slow or block () conduction (especially in depolarized cells). slope of phase 0 depolarization. Are
state dependent (selectively depress tissue that is frequently depolarized [e.g., tachycardia]).
Class IA
Class IA
MECHANISM
CLINICAL USE
TOXICITY
Class IB
MECHANISM
CLINICAL USE
TOXICITY
Class IC
MECHANISM
CLINICAL USE
TOXICITY
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0 mV Class IA
Class IA
0 mV
Slope of
0 mV
phase 0
Slope
INa of
phase
0
Slope
of
INa 0
phase
INa
Class IB
Class IB
0 mV
Class IB
Slope of
0 mV
phase 0
Slope
0 mV
INa of
phase
0
Slope
of
INa 0
phase
INa
Class IC
Class IC
0 mV Class IC
0 mV
Slope of
0 mV
phaseof
0
Slope
I
Na
phaseof
0
Slope
INa 0
phase
INa
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C ardiovascular
C ardiovascularpharmacology
Antiarrhythmics
-blockers (class II)
309
MECHANISM
Decrease SA and AV nodal activity by cAMP, Ca2+ currents. Suppress abnormal pacemakers by
slope of phase 4.
AV node particularly sensitive PR interval. Esmolol very short acting.
CLINICAL USE
SVT, ventricular rate control for atrial fibrillation and atrial flutter.
TOXICITY
Impotence, exacerbation of COPD and asthma, cardiovascular effects (bradycardia, AV block, HF),
CNS effects (sedation, sleep alterations). May mask the signs of hypoglycemia.
Metoprolol can cause dyslipidemia. Propranolol can exacerbate vasospasm in Prinzmetal angina.
-blockers cause unopposed 1-agonism if given alone for pheochromocytoma or cocaine toxicity.
Treat -blocker overdose with saline, atropine, glucagon.
Class II
60 Decrease slope
of phase 4
30 depolarization
0
30
Threshold
potential
60
90
Antiarrhythmics
potassium channel
blockers (class III)
Prolonged
repolarization
(at AV node)
100
200
700
AIDS.
MECHANISM
CLINICAL USE
TOXICITY
Class III
0 mV
Markedly prolonged
repolarization (IK)
85 mV
Cell action potential
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Antiarrhythmics
calcium channel
blockers (class IV)
Cardiovascular
C ardiovascularpharmacology
Verapamil, diltiazem.
MECHANISM
CLINICAL USE
TOXICITY
Constipation, flushing, edema, cardiovascular effects (HF, AV block, sinus node depression).
Membrane potential (mv)
Class IV
60
Slow rise of
action potential
30
0
Prolonged
repolarization
(at AV node)
30
Threshold
potential
60
90
100
200
300 400
Time (ms)
500
600
700
Other antiarrhythmics
Adenosine
K+ out of cells hyperpolarizing the cell and ICa. Drug of choice in diagnosing/abolishing
supraventricular tachycardia. Very short acting (~ 15 sec). Effects blunted by theophylline and
caffeine (both are adenosine receptor antagonists). Adverse effects include flushing, hypotension,
chest pain, sense of impending doom, bronchospasm.
Mg2+
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