304

SEC TION III

Cardiovascular
C ardiovascularpharmacology

``
CARDIOVASCULARPHARMACOLOGY
Antihypertensive therapy
Primary (essential)
hypertension

Thiazide diuretics, ACE inhibitors, angiotensin

II receptor blockers (ARBs), dihydropyridine
Ca2+ channel blockers.

See the Renal chapter for more details about

diuretics and ACE inhibitors/ARBs.

Hypertension with
heart failure

Diuretics, ACE inhibitors/ARBs, -blockers

(compensated HF), aldosterone antagonists.

-blockers must be used cautiously in

decompensated HF and are contraindicated in
cardiogenic shock.

Hypertension with
diabetes mellitus

ACE inhibitors/ARBs, Ca2+ channel blockers,

thiazide diuretics, -blockers.

ACE inhibitors/ARBs are protective against

diabetic nephropathy.

Hypertension in
pregnancy

Hydralazine, labetalol, methyldopa, nifedipine.

Calcium channel
blockers

Amlodipine, clevidipine, nicardipine, nifedipine, nimodipine (dihydropyridines, act on vascular

smooth muscle); diltiazem, verapamil (non-dihydropyridines, act on heart).

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

Dihydropyridines (except nimodipine): hypertension, angina (including Prinzmetal), Raynaud

phenomenon.
Nimodipine: subarachnoid hemorrhage (prevents cerebral vasospasm).
Clevidipine: hypertensive urgency or emergency.
Non-dihydropyridines: hypertension, angina, atrial fibrillation/flutter.

TOXICITY

Cardiac depression, AV block (non-dihydropyridines), peripheral edema, flushing, dizziness,

hyperprolactinemia (verapamil), constipation, gingival hyperplasia.

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

Compensatory tachycardia (contraindicated in angina/CAD), fluid retention, headache, angina.

Lupus-like syndrome.

Hypertensive
emergency

Drugs include clevidipine, fenoldopam, labetalol, nicardipine, nitroprusside.

Nitroprusside

Short acting; cGMP via direct release of NO. Can cause cyanide toxicity (releases cyanide).

Fenoldopam

Dopamine D1 receptor agonistcoronary, peripheral, renal, and splanchnic vasodilation. BP,

natriuresis.

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C ardiovascularpharmacology

Nitrates

SEC TION III

Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate.

MECHANISM

Vasodilate by NO in vascular smooth muscle in cGMP and smooth muscle relaxation.

Dilate veins >> arteries. preload.

CLINICAL USE

Angina, acute coronary syndrome, pulmonary edema.

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

305

Goal is reduction of myocardial O2 consumption (MVO2) by 1 or more of the determinants of

MVO2: end-diastolic volume, BP, HR, contractility.

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

Verapamil is similar to -blockers in effect.

Pindolol and acebutololpartial -agonists contraindicated in angina.

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SEC TION III

Cardiovascular
C ardiovascularpharmacology

Lipid-lowering agents
DRUG

LDL

HDL

TRIGLYCERIDES

MECHANISMS OF ACTION

HMG-CoA reductase
inhibitors (lovastatin,
pravastatin,
simvastatin,
atorvastatin,
rosuvastatin)

Inhibit conversion of HMG- Hepatotoxicity ( LFTs),

CoA to mevalonate, a
myopathy (esp. when used
cholesterol precursor;
with fibrates or niacin)
mortality in CAD patients

Bile acid resins

(cholestyramine,
colestipol,
colesevelam)

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

Myopathy ( risk with statins),

cholesterol gallstones

Niacin (vitamin B3)

Inhibits lipolysis (hormonesensitive lipase) in adipose

tissue; reduces hepatic
VLDL synthesis

Red, flushed face, which is

by NSAIDs or long-term
use
Hyperglycemia
Hyperuricemia

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

Bile acid resins

Lipid
oxidation

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Cardiac glycosides

307

SEC TION III

Digoxin.

MECHANISM

Direct inhibition of Na+/K+ ATPase indirect inhibition of Na+/Ca2+ exchanger.

[Ca2+]i positive inotropy. Stimulates vagus nerve HR.

CLINICAL USE

HF ( contractility); atrial fibrillation ( conduction at AV node and depression of SA node).

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

Slowly normalize K+, cardiac pacer, anti-digoxin Fab fragments, Mg2+.

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SEC TION III

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

Quinidine, Procainamide, Disopyramide.

The Queen Proclaims Disos pyramid.

MECHANISM

AP duration, effective refractory period

(ERP) in ventricular action potential, QT
interval.

CLINICAL USE

Both atrial and ventricular arrhythmias,

especially re-entrant and ectopic SVT and VT.

TOXICITY

Cinchonism (headache, tinnitus with

quinidine), reversible SLE-like syndrome
(procainamide), heart failure (disopyramide),
thrombocytopenia, torsades de pointes due to
QT interval.

Class IB

Lidocaine, MexileTine. Id Buy Liddys

Mexican Tacos.

MECHANISM

AP duration. Preferentially affect ischemic or

depolarized Purkinje and ventricular tissue.
Phenytoin can also fall into the IB category.

CLINICAL USE

Acute ventricular arrhythmias (especially postMI), digitalis-induced arrhythmias. IB is Best

post-MI.

TOXICITY

CNS stimulation/depression, cardiovascular

depression.

Class IC

Flecainide, Propafenone. Can I have Fries,

Please.

MECHANISM

Significantly prolongs ERP in AV node and

accessory bypass tracts. No effect on ERP in
Purkinje and ventricular tissue.
Minimal effect on AP duration.

CLINICAL USE

SVTs, including atrial fibrillation. Only as a last

resort in refractory VT.

TOXICITY

Proarrhythmic, especially post-MI

(contraindicated). IC is Contraindicated in
structural and ischemic heart disease.

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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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Antiarrhythmics
-blockers (class II)

SEC TION III

309

Metoprolol, propranolol, esmolol, atenolol, timolol, carvedilol.

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.

Membrane potential (mv)

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

300 400 500 600

Time (ms)
Pacemaker cell action potential

Amiodarone, Ibutilide, Dofetilide, Sotalol.

700

AIDS.

MECHANISM

AP duration, ERP, QT interval.

CLINICAL USE

Atrial fibrillation, atrial flutter; ventricular

tachycardia (amiodarone, sotalol).

TOXICITY

Sotaloltorsades de pointes, excessive

blockade.
Ibutilidetorsades de pointes.
Amiodaronepulmonary fibrosis,
hepatotoxicity, hypothyroidism/
hyperthyroidism (amiodarone is 40% iodine by
weight), acts as hapten (corneal deposits, blue/
gray skin deposits resulting in photodermatitis),
neurologic effects, constipation, cardiovascular
effects (bradycardia, heart block, HF).

Remember to check PFTs, LFTs, and TFTs when

using amiodarone.
Amiodarone is lipophilic and has class I, II, III,
and IV effects.

Class III
0 mV
Markedly prolonged
repolarization (IK)

85 mV
Cell action potential

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SEC TION III

Antiarrhythmics
calcium channel
blockers (class IV)

Cardiovascular
C ardiovascularpharmacology

Verapamil, diltiazem.

MECHANISM

conduction velocity, ERP, PR interval.

CLINICAL USE

Prevention of nodal arrhythmias (e.g., SVT), rate control in atrial fibrillation.

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+

Effective in torsades de pointes and digoxin toxicity.

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