Beta-adrenergic blocking agents

Work by competing with endogenous catecholamines for beta-adrenergic

receptors. Reduce myocardial oxygen consumption via several effects, including decrease
in resting and exercise heart rates and reductions in myocardial contractility and
afterload. Classified as nonselective, beta-1 selective, and having intrinsic
sympathomimetic effects.

Drug Name Metoprolol (Lopressor, Toprol XL) -- Selective beta1-adrenergic receptor

blocker that decreases automaticity of contractions. Is lipophilic and
penetrates CNS.
Adult Dose 50-200 mg PO bid
Pediatric Dose Not established
Contraindications Documented hypersensitivity; uncompensated CHF; bradycardia; asthma;
cardiogenic shock; AV conduction abnormalities
Interactions Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts,
cholestyramine, and rifampin may decrease bioavailability and plasma
levels, possibly resulting in decreased pharmacologic effects; sparfloxacin,
phenothiazines, astemizole, calcium channel blockers, quinidine,
flecainide, and contraceptives may increase toxicity; may increase toxicity
of digoxin, flecainide, clonidine, epinephrine, nifedipine, prazosin,
verapamil, and lidocaine
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Beta-adrenergic blockade may mask signs and symptoms of acute
hypoglycemia and may decrease clinical signs of hyperthyroidism; abrupt
withdrawal may exacerbate symptoms of hyperthyroidism, including
thyroid storm; monitor patient closely and withdraw drug slowly; during
IV administration, carefully monitor BP, heart rate, and ECG; adverse
effects include hypotension, decreased libido, impotence, lethargy,
depression, and decreased HDL; may cause less bronchial tree and arterial
smooth muscle constriction

Drug Name Atenolol (Tenormin) -- Selectively blocks beta-1 receptors with little or no
effect on beta-2 receptors. Is hydrophilic and does not penetrate CNS.
Adult Dose 50-200 mg PO qd
Pediatric Dose Not established
Contraindications Documented hypersensitivity; CHF; pulmonary edema; cardiogenic shock;
 AV conduction abnormalities; heart block (without pacemaker)
Interactions Aluminum salts, barbiturates, calcium salts, cholestyramine, NSAIDs,
penicillins, and rifampin may decrease effects; haloperidol, hydralazine,
loop diuretics, and MAOIs may increase toxicity
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Beta-adrenergic blockade may hide symptoms of acute hypoglycemia and
mask signs of hyperthyroidism; abrupt withdrawal may exacerbate
symptoms of hyperthyroidism and cause thyroid storm; monitor patients
closely and withdraw drug slowly; adverse effects include bradycardia,
hypotension, decreased libido, impotence, and decreased HDL; beta1-
selective blockers may cause less bronchial tree and arterial smooth
muscle constriction; titrate dose carefully to level of patient tolerance and
effectiveness

Drug Name Propranolol (Inderal) -- Nonselective beta-blocker that is lipophilic

(penetrates CNS). Although generally short-acting agent, long-acting
preparations also available.
Adult Dose IR: 40-160 mg PO bid
SR: 60-320 mg PO qd
Pediatric Dose Not established
Contraindications Documented hypersensitivity; history of bronchospasm; uncompensated
CHF; bradycardia; cardiogenic shock; AV conduction abnormalities
Interactions Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts,
cholestyramine, and rifampin may decrease effects; calcium channel
blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity;
may increase toxicity of hydralazine, haloperidol, benzodiazepines, and
phenothiazines
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Beta-adrenergic blockade may mask signs of acute hypoglycemia and
hyperthyroidism; abrupt withdrawal may exacerbate symptoms of
hyperthyroidism, including thyroid storm; withdraw drug slowly and
monitor closely; adverse effects include bronchial constriction, Raynaud
phenomenon, hypotension, decreased libido, impotence, lethargy,
depression, and decreased HDL; caution in Wolff-Parkinson-White
syndrome and renal or hepatic dysfunction

Calcium channel blockers

 Reduce transmembrane flux of calcium via calcium channels. Cause smooth
muscle relaxation, resulting in peripheral arterial vasodilation and afterload reduction.
Indicated when symptoms persist despite treatment with beta-blockers or when beta-
blockers are contraindicated. Also indicated in patients with Prinzmetal angina with or
without nitrates.

Drug Name Amlodipine (Norvasc) -- During depolarization, inhibits calcium ions from
entering slow channels and voltage-sensitive areas of vascular smooth
muscle and myocardium.
Adult Dose 5-10 mg PO qd
Pediatric Dose Not established
Contraindications Documented hypersensitivity; severe CHF; sick sinus syndrome; second-
or third-degree AV block; hypotension (<90 mm Hg systolic)
Interactions Fentanyl may increase hypotensive effects; may increase cyclosporine
levels; H2 blockers (eg, cimetidine) may increase toxic effects
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Severe aortic stenosis, CHF, hepatic dysfunction; adverse effects include
headache, edema, flushing, palpitation, drowsiness, and fatigue

Drug Name Diltiazem (Cardizem CD, Dilacor) -- During depolarization, inhibits

calcium ions from entering slow channels and voltage-sensitive areas of
vascular smooth muscle and myocardium.
Adult Dose IR: 120-360 mg PO divided tid/qid
SR: 120-480 mg PO qd
Pediatric Dose Not established
Contraindications Documented hypersensitivity; severe CHF; sick sinus syndrome; second-
or third-degree AV block; hypotension (<90 mm Hg systolic)
Interactions May increase carbamazepine, digoxin, cyclosporine, and theophylline
levels; when administered with amiodarone, may cause bradycardia and
decrease in cardiac output; when given with beta-blockers may increase
cardiac depression; cimetidine may increase levels
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in impaired renal or hepatic function; may increase LFT levels,
and hepatic injury may occur; adverse effects include constipation, AV
conduction block, worsening of heart failure, peripheral edema,
 bradycardia, and AV dissociation

Drug Name Verapamil (Calan, Covera) -- During depolarization, inhibits calcium ion
from entering slow channels or voltage-sensitive areas of vascular smooth
muscle and myocardium.
Adult Dose IR: 80-120 mg PO tid/qid
SR: 120-240 mg PO qd/bid
Pediatric Dose Not established
Contraindications Documented hypersensitivity; severe CHF; sick sinus syndrome; second-
or third-degree AV block; hypotension (<90 mm Hg systolic)
Interactions May increase carbamazepine, digoxin, theophylline, and cyclosporine
levels; amiodarone can cause bradycardia and decrease in cardiac output;
when administered concurrently with beta-blockers may increase cardiac
depression; cimetidine may increase levels
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Hepatocellular injury may occur; transient elevations of transaminases
with and without concomitant elevations in alkaline phosphatase and
bilirubin have occurred (elevations have been transient and may disappear
with continued treatment); monitor liver function periodically; adverse
effects include constipation, AV dissociation, worsening heart failure,
bradycardia, negative inotropism, and hypotension

Short-acting nitroglycerins
Suitable for immediate relief of exertional or rest angina. Can also be used for
prophylaxis several minutes before planned exercise to avoid angina. Reduce myocardial
oxygen demand by reduction of LV and arterial pressure, primarily by reducing preload.

Drug Name Nitroglycerin (Nitrostat, Nitro-bid, Nitrol) -- Causes relaxation of vascular

smooth muscle by stimulating intracellular cyclic GMP production. Result
is decrease in BP.
Adult Dose 0.3-0.6 mg SL prn
0.4 mg metered-dose spray PO prn
0.1-0.8 mg/h patch TD qd
Pediatric Dose Not established
Contraindications Documented hypersensitivity; severe anemia; shock; postural hypotension;
head trauma; closed-angle glaucoma; cerebral hemorrhage; hypertrophic
obstructive cardiomyopathy
Interactions Concurrent sildenafil (Viagra) may cause severe hypotension and death;
aspirin may increase serum concentrations; calcium channel blockers may
cause markedly symptomatic orthostatic hypotension (dose adjustment of
either agent may be necessary)
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in coronary artery disease and low systolic BP; adverse effects
include hypotension, flushing, headache, light-headedness, and tolerance
(8- to 12-h nitrate-free interval is most effective method to prevent
development of tolerance); high IV doses may cause methemoglobinemia,
heparin resistance, and ethanol intoxication; ischemia may worsen upon
withdrawal

Long-acting nitroglycerins
Reduce LV preload and afterload by venous and arterial dilation, which
subsequently reduces myocardial oxygen consumption and relieves angina. Also cause
dilation of epicardial coronary arteries, which is beneficial in patients with coronary
spasm. In addition, nitroglycerin has antithrombotic and antiplatelet effects in patients
with angina pectoris. No evidence suggests that nitrates improve survival or slow
progression of coronary artery disease.

Drug Name Isosorbide (Isordil, ISMO) -- Relaxes vascular smooth muscle by

stimulating intracellular cyclic GMP. Decreases LV pressure (ie, preload)
and arterial resistance (ie, afterload). Reduces cardiac oxygen demand by
decreasing LV pressure and dilating arteries.
Adult Dose Isosorbide dinitrate:
2.5-10 mg SL prn IR
10-30 mg PO bid/tid SR
80-120 mg PO qd IR
Isosorbide mononitrate:
10-20 mg PO bid SR
30-120 mg PO qd
Pediatric Dose Not established
Contraindications Documented hypersensitivity; severe anemia; closed-angle glaucoma;
 postural hypotension; head trauma; cerebral hemorrhage
Interactions Alcohol may cause severe hypotension and cardiovascular collapse;
aspirin may increase serum concentrations and actions; calcium channel
blockers may increase symptomatic orthostatic hypotension (adjust dose of
either agent); may decrease effects of heparin
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Tolerance to vascular and antianginal effects of nitrates may develop;
minimize tolerance by using smallest effective dose or pulse therapy
(intermittent dosing) or by alternating with other coronary vasodilators
(take last daily dose of short-acting agent no later than 7 pm); caution
when administering to patients with glaucoma

Angiotensin-converting enzyme inhibitors

Recently shown to reduce rates of death, MI, stroke, and need for
revascularization procedures in patients with coronary artery disease or diabetes mellitus
and at least one other cardiovascular risk factor, irrespective of the presence of
hypertension or heart failure.
Drug Name Ramipril (Altace) -- Prevents conversion of angiotensin I to angiotensin II,
a potent vasoconstrictor, resulting in lower aldosterone secretion.
Adult Dose 2.5-5 mg PO qd; not to exceed 20 mg/d
Pediatric Dose Not established
Contraindications Documented hypersensitivity; history of angioedema
Interactions May increase digoxin, lithium, and allopurinol levels; probenecid may
increase levels; coadministration with diuretics increases hypotensive
effects; NSAIDs may reduce hypotensive effects
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Category D in second and third trimesters of pregnancy; adverse effects
include persistent cough, angioedema, hypotension, and prerenal azotemia;
caution in renal impairment, valvular stenosis, or severe CHF

Anti-ischemic agents, miscellaneous

Ranolazine elicits action unlike beta-blockers, calcium antagonists, or nitrates. It
does not affect hemodynamics or contractile and conduction parameters.
Drug Name Ranolazine (Ranexa) -- Cardioselective anti-ischemic agent (piperazine
derivative) that partially inhibits fatty acid oxidation. Also inhibits late
 sodium current into myocardial cells and prolongs QTc interval. Indicated
for chronic angina unresponsive to other antianginal treatments. Used in
combination with amlodipine, beta-blockers, or nitrates. Unlike beta-
blockers, calcium channel blockers, and nitrates, does not reduce blood
pressure or heart rate. Effect on angina rate or exercise tolerance appears
to be smaller in women than in men. Absorption is highly variable but
unaffected by food.
Adult Dose 500 mg PO bid initially; if necessary, may increase to 1000 mg PO bid
Pediatric Dose Not established
Contraindications Documented hypersensitivity; preexisting QT prolongation; hepatic
impairment (Child-Pugh class A [mild], B [moderate], or C [severe]); QT-
prolonging drugs (see Interactions); potent or moderate CYP4503A
inhibitors (eg, ketoconazole, diltiazem)
Interactions CYP4503A and P-gp substrate; potent CYP3A inhibitors (eg,
ketoconazole at 200 mg bid) increase levels approximately 3.2-fold,
moderate CYP3A inhibitors (eg, diltiazem at 180-360 mg/d) increase
levels approximately 1.8- to 2.3-fold, and verapamil (a CYP3A and P-gp
inhibitor) increases levels approximately 2-fold; caution with other P-gp
inhibitors (eg, ritonavir, cyclosporine); toxicity may occur when
coadministered with other drugs that increase QTc interval (eg, class I and
III antiarrhythmic agents, certain macrolide and quinolone antibiotics,
phenothiazines, TCAs)
Inhibits CYP4503A, CYP 4502D6, and P-gp; may increase plasma levels
of digoxin, simvastatin, dextromethorphan, TCAs, and antipsychotics
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Causes dose-related QTc-interval prolongation (obtain baseline and
follow-up ECGs to monitor for torsades de pointes and potential for
sudden death; mild and moderate hepatic impairment increases QTc
interval compared with normal hepatic function at same plasma level;
increases blood pressure by approximately 15 mm Hg in persons with
severe renal impairment; common adverse effects include dizziness,
headache, constipation, and nausea

Antiplatelet agents
Prevent thrombus formation by inhibiting platelet aggregation. Aspirin is proven
beneficial in primary and secondary prevention of coronary artery disease. In patients
with aspirin intolerance, use clopidogrel. Clopidogrel is also used in combination with
aspirin after coronary stent placement. Recently, clopidogrel use in addition to aspirin has
been shown to be significantly superior to aspirin alone in patients with acute coronary
syndrome without ST-segment elevation MI.
Drug Name Aspirin (Bayer, Empirin, Anacin) -- Prevents platelet aggregation by
irreversible cyclooxygenase inhibition with subsequent suppression of
thromboxane A2. Antiplatelet effect can last as long as 7 d.
Adult Dose 81-325 mg PO qd

Pediatric Dose Not established

Contraindications Documented hypersensitivity; liver damage; hypoprothrombinemia;
vitamin K deficiency; bleeding disorders; asthma
Because of association with Reye syndrome, do not use in children (<16
y) with flu
Interactions Antacids and urinary alkalinizers may decrease effects; corticosteroids
decrease salicylate serum levels; anticoagulants may cause additive
hypoprothrombinemic effects and increased bleeding time; may
antagonize uricosuric effects of probenecid and increase toxicity of
phenytoin and valproic acid; doses >2 g/d may potentiate glucose-
lowering effect of sulfonylurea drugs
Pregnancy D - Unsafe in pregnancy
Precautions May cause transient decrease in renal function and aggravate chronic
kidney disease; avoid use in patients with severe anemia, history of
blood coagulation defects, or taking anticoagulants; adverse effects
include prolonged bleeding time, rhinitis, asthma, urticaria, and
exacerbation of gout; monitor BP, BUN, and uric acid level; consider
discontinuing 7 d before surgery

Drug Name Clopidogrel (Plavix) -- Selectively inhibits ADP binding to platelet

receptor and subsequent ADP-mediated activation of GPIIb/IIIa complex,
thereby inhibiting platelet aggregation. Consider in patients with
contraindication to aspirin.
Adult Dose 75 mg PO qd
Pediatric Dose Not established
Contraindications Documented hypersensitivity; active pathological bleeding
Interactions Naproxen associated with increased occult GI blood loss; prolongs
bleeding time; safety of coadministration with warfarin not established
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in patients at increased risk of bleeding from trauma, surgery, or
other pathological conditions; caution in patients with lesions with
 propensity to bleed (eg, ulcers); adverse effects include rash, diarrhea,
purpura, GI ulcers, neutropenia, and rare cases of agranulocytosis;
consider discontinuing 7 d before surgery

Antiplatelet Drugs
Mechanism of action:
Antiplatelet therapy is an important means in the prevention and
treatment of thromboembolic artery occlusions in cardiovascular diseases.
Platelets are discoid cell fragments, derived from megakaryocytes in the
bone marrow, that circulate freely in the blood. Under normal conditions
they neither adhere to each other nor to other cellular surfaces. However,
when blood vessels are damaged at their luminal side, platelets adhere to the
exposed subendothelium. This adhesion is mediated by collagen and von
Willebrand factor (vWf) both of which are exposed at or have been
deposited at the subendothelial surface. Adherent platelets release various
factors (see below) which activate other nearby platelets resulting in the
recruitment of more platelets at the site of vascular injury.
Most platelet activators function directly or indirectly through G-
protein-coupled receptors and induce several intracellular signalling
pathways which eventually lead to secretion of granule contents, change of
shape and inside-out activation of GP-IIb/IIIa (integrin α IIbβ 3). Activation
of GP-IIb/IIIa allows fibrinogen (Fb) or vWf to cross bridge adjacent
platelets. The main pathway that leads to platelet activation involves the
Gq/phospholipase C-β (PLC-β )-mediated formation of inositol 1,4,5
trisphosphate (IP3) and diacyl glycerol (DAG). This in turn results in the
release of Ca2+ fro intracellular stores and the activation of protein kinase C
(PKC) isoforms. Aspirin blocks the conversion of arachidonic acid (AA) to
prostaglandin G2 and H2 (PGG/H2) by irreversibly inhibiting
cyclooxygenase-1. Active metabolites of thienopyridines block ADP(P2Y12)-
receptors on platelets and GPIIb/IIIa-blockers interfere with fibrinogen- and
vWf-mediated platelet aggregation. TXA2 stands for thromboxane A2.

TXA2 is produced by activated platelets by the sequential conversion of

arachidonic acid by phospholipase A2, cyclooxygenase-1 (COX-1) and thromboxane
synthase. Similar to ADP, TXA2 acts as a positive feedback mediator. In vascular
endothelial cells, COX-1 is involved in the generation of prostacyclin which inhibits
platelet activation and leads to vasodilation. Low doses of acetylsalicylic acid (aspirin)
have an antiplatelet effect by inhibiting the TXA2 production by irreversibly acetylating
COX-1 at serine-530 close to the active site of the enzyme. This results in impaired
platelet function for the rest of its lifespan (7-10 days). Anucleated platelets, in contrast to
nucleated cells, are unable to de novo synthesize COX-1. The aspirin doses required for
this antiplatelet effect are therefore considerably lower than those necessary to achieve
inhibition of prostacyclin formation in endothelial cells or analgetic and antipyretic
effects. Following oral administration of aspirin, platelets are exposed to a relatively high
concentration of aspirin in the portal blood. This may further contribute to the relatively
high sensitivity of platelets toward the action of aspirin. Most other tissues are partly
protected by presystemic metabolisation of aspirin to salicylate through esterases in the
liver. Since platelets are the major source of TXA2 production and action, inhibitors of
thromboxane synthase and TXA2 receptor (TP) antagonists are being developed. TXA2
synthesis inhibitors may have some disadvantages as they lead to the accumulation of
cyclic endoperoxides (e.g. PGH2) that are themselves agonists at the TXA2 receptor.

The proteolytic enzyme thrombin is known to play a crucial role in the overall
thrombotic event leading to both, arterial and venous thrombosis by transforming
fibrinogen into fibrin and by serving as a direct platelet activator. Thrombin exerts its
effects on platelets via G-protein-coupled protease-activated receptors (PAR-1 and PAR-
4 in human platelets). Thrombin-dependent receptor activation is achieved by cleaving an
N-terminal extracellular peptide. Exposure of the newly generated N-terminal region
functions as a tethered ligand for the receptor. Substances that directly bind to thrombin
have been developed. The 65 amino acid long protein hirudin, originally isolated from
the medical leech, Hirudo medicinalis, as well as related analogues have been
recombinantly produced. They bind with the stoichiometry of 1:1 to thrombin and
prevent its proteolytic action on fibrinogen as well as its binding to and the activation of
PAR.

ADP is released from activated platelets by the secretion of dense granules and
acts through at least three receptors. These are the ionotropic purinoceptor 2X1 (P2X1)
and two G-protein coupled receptors: the Gq-coupled purinoceptor 2Y1 (P2Y1) and the Gi-
coupled P2Y12 receptor. The latter has also been termed P2TAC or P2cyc and is targeted by
a group of antiplatelet agents -the thienopyridines- such as ticlopidine and clopidogrel.
To become activated, ticlopidine and clopidogrel require biotransformation by the hepatic
CYP-1A enzyme into an active metabolite. The active metabolite irreversibly modifies
the P2Y12 receptor.

Most antiplatelet drugs inhibit platelet activation only partially. In contrast,

blockers of GP-IIb/IIIa interfere at the end of the pathway common to platelet
aggregation. They prevent fibrinogen and vWf from binding to activated GP-IIb/IIIa and
can therefore completely inhibit platelet aggregation. The first GP-IIb/IIIa antagonist
developed was a hybrid human/murine monoclonal antibody. Its Fab fragment, termed
abciximab, is clinically used and functions in a noncompetitive manner. An alternative
approach to block GP-IIb/IIIa involves the use of peptides that mimic short protein
sequences of fibrinogen or vWf. Several peptides (e.g. the cyclic heptapeptide
eptifibatide) or non-peptidic, low molecular weight compounds (e.g. tirofiban, lamifiban)
have been developed and function as competitive antagonists. Prodrugs of
peptidomimetic compounds (e.g. xemilofiban, orbofiban, lefradafiban or sibrafiban) that
are transformed into active metabolites in the body, can be administered orally.

References
•Bennet JS (2001) Novel platelet inhibitors. Annu. Rev. Med. 52: 161-184

•Awtry EH, Loscalzo J (2000) Aspirin. Circulation 101:1206-1218

•Quinn MJ, Fitzgerald DJ (1999) Ticlopidine and clopidogrel. Circulation 100:1667-

1672

•Topol EJ, Byzova TV, Plow EF (1999) Platelet GPIIb-IIIa blockers. Lancet
353:227-231

•George JN (2000) Platelets. Lancet 355:1531-1539