Labetalol (NORMODYNE,TRANDATE, others) is a competitive antagonist at both a1and b receptors.
The pharmacological properties of labetolol are complex, because each of four isomers displays
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Summary of Adrenergic Agonists and Antagonists
Prominent Principal Therapeutic
Class Drugs Pharmacological Actions Applications Untoward Effects Comments
Direct-acting Epinephrine Increase in heart rate Open-angle glaucoma Palpitation Not given orally nonselective (a1, a2, b1, b2, b3) Increase in blood pressure With local anesthetics to Cardiac arrhythmias Life saving in
agonists Increased contractility prolong action Cerebral hemorrhage anaphylaxis or
Slight decrease in PVR Anaphylactic shock Headache cardiac arrest Increase in cardiac output Complete heart block or Tremor
Vasoconstriction (viscera) cardiac arrest Restlessness Vasodilation (skeletal muscle) Bronchodilator in asthma
Increase in blood glucose and lactic acid
Norepinephrine Increase in systolic and Hypotension Similar to Epi Not absorbed orally (a1, a2, b1, >> b2) diastolic blood pressure Hypertension
Vasoconstriction Increase in PVR
Direct increase in heart rate and contraction
Reflex decrease in heart rate Breceptor agonists
Nonselective Isoproterenol IV administration Bronchodilator in asthma Palpitations Administered by
(b1+ b2) Decrease in PVR Complete heart block or Tachycardia inhalation in asthma
Increase in cardiac output cardiac arrest Headache
Tachyarrhythmias Shock Flushed skin
Bronchodilation Cardiac ischemia in
patients with CAD
b1-selective Dobutamine Increase in contractility Short-term Increase in blood Use with caution in Some increase in heart rate treatment of cardiac pressure and patients with Increase in AV conduction decompensation after heart rate hypertension or
surgery, or patients with cardiac arrhythmias
CHF or MI Used only IV
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b2-selective Albuterol Relaxation of bronchial Bronchodilators for Skeletal muscle tremor Use with caution in
(intermediate- Bitolterol smooth muscle treatment of asthma Tachycardia and patients with CV
acting) Fenoterol Relaxation of uterine and COPD other cardiac effects disease (reduced by
Isoetharine smooth muscle Short/intermediate- seen after systemic inhalational Metaproterenol Activation of other b2 acting drugs for acute administration administration) Procaterol receptors after systemic bronchospasm (much less with Minimal side effects
Terbutaline administration inhalational use)
Ritodrine
(Long-acting) Formoterol Best choice for prophylaxis Long action favored
Salmeterol due to long action for prophylaxis
AReceptor agonists
a1-selective Methoxamine Vasoconstriction Nasal congestion (used Hypertension Mephentermine and
Phenylephrine topically) Reflex bradycardia metaraminol also act
Mephentermine Postural hypotension Dry mouth, sedation, indirectly to release NE
Metaraminol rebound hyper- Midodrine is a prodrug
Midodrine tension upon converted in vivo to
abrupt withdrawal an active compound a2-selective Clonidine Decrease sympathetic outflow Adjunctive therapy in shock Apraclonidine and
Apraclonidine from brain to periphery Hypertension brimonidine used
Guanfacine resulting in decreased To reduce sympathetic topically for glaucoma
Guanabenz PVR and blood pressure response to withdrawal and ocular hypertension
Brimonidine Decrease nerve-evoked release from narcotics, alcohol, Methyldopa is converted
a-methyldopa of sympathetic transmitters and tobacco in CNS to a-methyl NE,
Decrease production of Glaucoma an effective a2agonist
aqueous humor
Indirect-acting Amphetamine CNS stimulation Treatment of ADHD Restlessness Schedule II drugs
Methamphetamine Increase in blood pressure Narcolepsy Tremor Marked tolerance occurs Methyphenidate Myocardial stimulation Obesity (rarely) Insomnia Chronic use leads to
(releases NE Anxiety dependence
peripherally; NE, Tachycardia Can result in hemorrhagic
DA, 5-HT centrally) Hypertension stroke in patients with
Cardiac arrhythmias underlying disease Long-term use can cause
paranoid schizophrenia (Continued)
Summary of Adrenergic Agonists and Antagonists (Continued)
Prominent Principal Therapeutic
Class Drugs Pharmacological Actions Applications Untoward Effects Comments
Mixed-acting Dopamine (a1, a2, b1, Vasodilation (coronary, renal Cardiogenic shock High doses lead to Important for its ability to
D1; releases NE) mesenteric beds) vasoconstriction maintain renal blood flow
Increase in glomerular Congestive heart failure Administered IV filtration rate and natriuresis
Increase in heart rate and Treatment of acute renal
contractility failure
Increase in systolic blood pressure
Ephedrine (a1, a2, Similar to epinephrine Bronchodilator for Restlessness Administered by all routes b1, b2; releases NE) but longer lasting treatment of asthma Tremor Not commonly used
CNS stimulations Nasal congestion Insomnia
Treatment of hypotension Anxiety
and shock Tachycardia
Hypertension Ablockers
Nonselective Phenoxybenzamine Decrease in PVR and Treatment of catecholamine Postural hypotension Cardiac stimulation due (classical Phentolamine blood pressure excess (e.g., pheochro- Failure of ejaculation to initiation of reflexes
ablockers) Tolazoline Venodilation mocytoma) and to enhanced release
of NE via a2receptor blockade
a1-selective Prazosin Decrease in PVR and Primary hypertension Postural hypotension Phenoxybenzamine Terazosin blood pressur Increase urine flow in BPH when therapy produces long-lasting
Doxazosin instituted a-receptor blockade
Trimazosin Relax smooth muscles in and at high doses can
Alfuzosin neck of urinary block neuronal and
Tamsulosin bladder and in prostate extraneuronal uptake
of amines
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a1-selective (Continued)
Prazosin and related quinazolines are selective for a1receptors
but not among a1subtypes Tamsulosin exhibits
some selectivity for a1Areceptors bblockers
Non-selective Nadolol Decrease in heart rate Angina pectoris Bradycardia Pharmacological effects
(1st generation) Penbutolol Decrease in contractility Hypertension Negative inotropic effect depend largely on Pindolol Decrease in cardiac output Cardiac arrhythmias Decrease in cardiac degree of
Propranolol Slow conduction in atria CHF output sympathoadrenal tone
Timolol and AV node Pheochromocytoma Bradyarrhythmias Bronchoconstriction
Increase refractory period, Glaucoma Reduction in (of concern in AV node Hypertropic obstructive AV conduction asthmatics and COPD) Bronchoconstriction cardiomyopathy Bronchoconstriction Hypoglycemia (concern
Prolonged hypoglycemia Hyperthyroidism Fatigue in hypoglycemics
Decrease in plasma FFA Migraine prophylaxis and diabetics)
Reduction in HDL Acute panic symptoms Sleep disturbances Membrane stabilizing cholesterol Substance abuse (insomnia, nightmares) effect (propranolol,
Increase in LDL withdrawal Prolongation of acebutolol, carvedilol,
cholesterol and Variceal bleeding in portal hypoglycemia and betaxolol only) triglycerides hypertension Sexual dysfunction ISA (strong for pindolol;
Hypokalemia in men weak for penbutolol,
Drug interactions carteolol, labetalol, and betaxolol)
b1-selective Acebutolol (2nd generation) Atenolol
Bisoprolol Esmolol Metoprolol
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(Continued)
184
Summary of Adrenergic Agonists and Antagonists (Continued)
Prominent Principal Therapeutic
Class Drugs Pharmacological Actions Applications Untoward Effects Comments
Nonselective Carteolol Membrane stabilizing Vasodilation seen in 3rd
(3rd generation) Carvedilol effect generation drugs;
vasodilators Bucindolol ISA multiple mechanisms
Labetalol Vasodilation (a1antagonism; b2
agonism; release of
b1-selective Betaxolol NO; Ca2+channel
(3rd generation) Celiprolol blockade; opening of
vasodilators Nebivolol K+channels; others)
ADHD, attention-deficit/hyperactivity disorder; AV, atrioventricular; BPH, benign prostatic hypertrophy; CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; DA, dopamine; D1, subtype 1 dopamine receptor; Epi, epinephrine; FFA, free fatty acids; 5-HT, serotonin; ISA, intrinsic sympathomimetic activity;
MI, myocardial infarction; NE, norepinephrine; NO, nitric oxide; PVR, peripheral vascular resistance.
CHAPTER 10 Adrenergic Agonists and Antagonists
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different relative activities. The properties of the racemic mixture include selective blockade of a1receptors (as compared with the a2subtype), blockade of b1and b2receptors, partial agonist activity at b2receptors, and inhibition of neuronal uptake of NE (cocaine-like effect). The potency of the mixture for b receptor blockade is 5–10× that for a1receptor blockade. Actions of labetalol on both a1and b-receptors contribute to the fall in blood pressure observed in patients with hyper-tension. b1receptor blockade leads to relaxation of arterial smooth muscle and vasodilation, par-ticularly in the upright position. b1Blockade contributes to a fall in blood pressure, in part by blocking reflex sympathetic stimulation of the heart. In addition, intrinsic sympathomimetic activ-ity of labetalol at b2receptors may contribute to vasodilation.
Although labetalol is completely absorbed from the gut, there is extensive first-pass clearance;
bioavailability may be increased by food intake. The rate of hepatic metabolism of labetalol is sensitive to changes in hepatic blood flow. The various isomers have different elimination kinet-ics.
Two forms are available, an oral form for therapy of chronic hypertension, and an intravenous formulation for hypertensive emergencies. Labetalol has been associated with hepatic injury in a limited number of patients.