Adrenoreceptor Blockers

Term Competitive blocker Covalently bound inhibitor Epinephrine reversal Intrinsic sympathomimetic activity (ISA) Irreversible blocker Membrane stabilizing activity (MSA) Orthostatic hypotension Partial agonist Pheochromocytoma Definition A surmountable antagonist; one that can be overcome by increasing the dose of agonist An antagonist that binds irreversibly to its receptor or other binding site Conversion of the pressor response (typical of large doses of epinephrine) to a blood pressure-lowering effect; caused by alpha-blockers Partial agonist action by adrenoceptor blockers; an effect of several beta-blockers, eg, pindolol, acebutol An insurmountable inhibitor, usually because of covalent bond formation; eg, phenoxybenzamine Local anesthetic action; typical of several beta blockers, eg, propranolol Hypotension that is most marked in the upright position; caused by venous pooling or inadequate blood volume; typical of alpha blockade A drug (eg, pindolol) that produces a smaller maximal effect than a full agonist and therefore can inhibit the effect of a full agonist A tumor that resembles the adrenal medulla; consisting of cells innervated by sympathetic preganglionic neurons and releasing norepinephrine and epinephrine into the circulation A receptor located on the presynaptic nerve terminal; the receptor modulates transmitter release from the terminal

Presynaptic receptor

CONCEPTS Alpha- and beta-blocking agents are divided into primary subgroups on the basis of their receptor selectivity (Figure 1.) Because they differ markedly in their clinical applications, these drugs are considered separately in the following discussion. ALPHA-BLOCKING DRUGS A. Classification: Subdivisions of the alpha-blockers are based on selective affinity for 1 versus 2 receptors. Other features used to classify the alpha-blocking drugs are their reversibility and duration of action. 1. Irreversible, long-acting: Phenobenzamine is the prototypical long-acting, irreversible alpha-blocker. It is slightly 1-selective. 2. Reversible, shorter-acting: Phentolamine (nonselective) and tolazoline (slightly 2selective) are competitive, reversible blocking agents.

Figure 1. Subgroups of adrenoceptor-blocking drugs. Adrenoceptor antagonists -Blockers 2-Selective 1-Selective Nonselective Reversible Irreversbile -Blockers 2-Selective 1-Selective Nonselective

3. Alpha1-selective: Prazosin is a selective, reversbile pharmacologic 1-blockers. Doxazosin and terazosin are newer drugs with similar properties. The advantage of 1 selectivity is discussed below. 4. Alpha2-selective: Yohimbine and reuwolscine are alpha2-selective competitive pharmacologic antagonists. They are used primarily in research applications. B. Pharmacokinetics: These drugs are all active by the oral as well as parenteral routes, although phentolamine and tolazoline are rarely given orally. Phenoxybenzamine has a short elimination half-life but a very long duration of action-about 48 hours-because it binds covalently to its receptor. Phentolamine and tolazoline have durations of action of 24 hours when used orally and 20-40 minutes when given parenteraly. Prazosin acts for 810 hours. C. Mechanism of Action: Phenoxybenzamine binds covalently to the alpha receptor, thereby producing an irreversible (insurmountable) blockade. The other agents are competitive pharmacologic antagonists - ie, their effects can be surmounted by increased concentrations of agonist. This difference may be important in the treatment of phenochromocytoma, because massive releases of catecholamines from the tumor may overcome a reversible blockade. D. Effects: 1. Nonselective blockers: These agents cause a predictable blockade of alpha-mediated responses to sympathetic nervous system discharge and exogenous sympathomimetics (ie, the alpha responses listed in Table 2.). The most important effects of nonselective alphablockers are those on the cardiovascular system: a reduction in vascular tone with a reduction of both arterial and venous pressures. There are no significant direct cardiac effects. However, the nonselective alpha-blockers do cause baroreceptor reflex-mediated tachycardia as a result of the drop in mean arterial pressure. This tachycardia may be exaggerated because on adrenergic nerve terminals the alpha2 receptors, which normally reduce the net release of norepinephrine, are also blocked. Epinephrine reversal is a predictable result of the use of this agonist in a patient who has received an alpha-blocker. The term refers to a reversal in the blood pressure effect of moderate-to-large doses of epinephrine, from a pressor response (mediated by alpha-receptors) to a depressor effect

(mediated by 2 receptors) (Figure 2). The effect is occasionally seen as an unexpected (but predictable) effect of drugs for which alpha blockade is an adverse effect (eg, some phenothiazine tranquilizers, antihistamines). 2. Selective alpha-blockers: Because prazosin blocks vascular 1 receptors much more effectively than the 2-modulatory receptors associated with cardiac sympathetic nerve endings, this drug causes a much less marked tachycardia than the nonselective alphablockers when reducing blood pressure. E. Clinical Uses: 1. Nonselective alpha-blockers: Nonselective alpha-blockers have limited clinical applications. The best documented application is in the presurgical management of pheochromocytoma. Such patients may have severe hypertension and reduced blod volume, which should be corrected before subjecting the patient to the stress of surgery. Pehnoxybenzamine is usually used during this preparatory phase; phentolamine is sometimes used during surgery. Phenoxybenzamine also has serotonin receptor-blocking effects, which justify its occasional use in carcinoid tumor, and H1 antihistamine effects, leading to its use in mastocytosis. Accidental local infiltration of potent alpha agonists such as norepinephrine may lead to tissue ischemia and necrosis if not promptly reversed; infiltration of the ischemic are with phentolamine is sometimes used to prevent tissue damage. Overdose with drugs of abuse such as amphetamine, cocaine, or phenylpropanolamine may lead to severe hypertension because of their indirect sympathomimetic actions. This hypertension will usually respond well to alpha-blockers. Raynauds phenomenon sometimes respond to phenoxybenzamine or phentolamine, but their efficacy is not well documented in this condition. Phentolamine or yohimbine are sometimes used by direct injection to cause penile erection in men with impotence. 2. Selective alpha-blockers: Prazosin and other 1 blockers are used in hypertension. Selective 1-blockers have also found increasing use in the management of urinary hesitancy and prevention of urinary retention in men with prostatic hypertrophy. F. Toxicity: The most important toxicities of the alpha-blockers are simple extensions of their alpha-blocking effects. The main manifestations are orthostatic hypotension and for the nonselective agents, reflex tachycardia. In patients with coronary disease, angina may be precipitated by the tachycardia. Oral administration of any of these drugs can cause nausea and vomiting. Prazosin is associated with an exaggerated orthostatic hypotensive response to the first dose in some patients. Therefore, the first dose is usually small and taken just before goint to bed. BETA-BLOCKING DRUGS A. Classification, Subgroups and Mechanisms: All of the clinically used beta-blockers are competitive pharmacologic antagonists. Propranolol is the prototype. Drugs in this group are usually classified into subgroups on the basis of 1 versus 2 selectivity, partial agonist activity, local anesthetic action, and lipid solubility (Table 2.). 1. Receptor selectivity: Beta1 receptor selectivity (1 block > 2 block), is a property of metoprolol, atenolol, acebutol, and other beta-blockers. This property may be an advantage when treating patients with asthma. Butoxamine, a 2-selective drug, is used only in research. Labetalol is an unusual agent with combined alpha- and beta-blocking action. This drug has four diastereomers; the alpha-blocking activity resides in the SR enantiomer

and the beta-blocking action in the RR enantiomer. The other two enantiomers (RS and SS) are practivally inactive. 2. Partial agonist activity: Partial agonist activity (intrinsic sympathomimetic activity) may be an advantage in treating patients with ashma because, even at maximum dosage, these drugs, eg, pindolol, acebutolol, will cause some bronchodilation. In contrast, the full antagonists such as propranolol may cause severe asthma in patients with airway disease. Table 2. Properties of several beta-receptor-blocking drugs.1 Partial Local Agonist Anesthetic Selectivity Activity Action Yes Yes 1 No No 1 No No 1 3 None Yes Yes No Yes 1 None No No None Yes3 Yes None No Yes None No No Lipid Solubility Low Low Low Moderate Moderate Low Moderate High Moderate Approximate Elimination Bioavailability Half-life (%) 3-4 h 50 6-9 h 40 10 min ... 5h 30 3-4 h 50 14-24 h 33 3-4 h 90 3.5-6 h 304 4-5 50

Drug Acebutolol Atenolol Esmolol Labetalol2 Metoprolol Nadolol Pindolol Propranolol Timolol

3. Local anesthetic activity: Local anesthetic activity (membrane stabilizing activity or MSA) is a disadvantage when beta-blockers are used topically in the eye. MSA is absent from timolol and several newer beta-blockers. 4. Pharmacokinetics: The systemic agents have been developed for chronic oral use, but bioavailability and duration of action vary widely (Table 2.). Esmolol is a short-acting beta-blocker that is only used parenterally. Nadolol is the longest acting beta-blocker. Acebutolol and atenolol are less lipid soluble than the older beta-blockers and probably enter the CNS to a lesser extent. B. Effects and Clinical Uses: Most of the organ-level effects of beta-blockers (Table 3) are predictable from blockade of the beta-receptor-mediated effects of sympathetic discharge. Effects of beta blockade not previously emphasized (and not recognized until beta-blockers became widely used) include reduction of aqueous humor formation in the eye and reduction of skeletal muscle tremor. The cardiovascular and ophthalmic applications are extremely important. The treatment of open angle glaucoma involves the use of several groups of autonomic drugs and a diuretic. These agents are listed in Table 4. C. Toxicity: Cardiovascular adverse effects, which are extensions of the beta blockade induced by these agents, include bradycardia, atrioventricular blockade, and congestive heart failure. Patients with airway disease may suffer asthmatic attacks. Premonitory sympatoms of hypoglycemia from insulin overdosage, eg, tachycardia, tremor, and anxiety, may be maked. CNS adverse effects include sedation, fatigue, and sleep alterations. Atenolol, nadolol, and several other less lipid soluble beta-blockers are claimed to have less marked CNS action because they do not enter the CNS as readily as other members of this group.

Table 3. Clinical applications of beta-blockers.

Application Hypertension Angina pectoris Arrhythmia prophylaxis after myocardial infarction Supraventricular tachycardias Hypertrophic cardiomyopathy Migraine Familial tremor, other types of tremor, stage fright Thyroid storm, thyrotoxicosis Glaucoma1
1

Drugs Propranolol, metoprolol, timolol, others Propranolol, nadolol, others Propranolol, metoprolol, timolol

Effect Reduced cardiac output, reduced renin secretion Reduced cardiac rate and force Reduced automaticity of all cardiac pacemakers Propranolol, esmolol, acebutolol Slowed AV conduction velocity Propranolol Slowed rate of cardiac contraction Propranolol Prophylactic, mechanism uncertain Propranolol Reduced 2 alteration of neuromuscular transmission; possible CNS effects Propranolol Reduced cardiac rate and arrhythmogenesis; other mechanisms may be involved Timolol, others Reduced secretion of aqueous humor

See table 4. for additional drugs used in glaucoma.

Table 4. Drugs used in open angle glaucoma1

Group, Drugs Cholinomimetics Pilocarpine, carbachol, physostigmine, echothiophate Alpha agonists Nonselective Epinephrine, dipivefrin Alpha2-selective Apraclonidine Beta-blockers Timolol, betaxolol, carteolol, levobunolol, metipranolol Diuretics Acetazolamide Ethacrynic acid (investigational)
1

Mechanism Cilliary muscle contraction, opening of trabecular meshwork; incrased outflow

Methods of Administration Topical drops or gel; plastic film slow-release insert

Increased outflow, probably via Topical drops the uveoscleral vein Decreased aqueous secretion Decreased aqueous secretion from the ciliary epithelium Decreased secretion due to lack of HCO3-ion Decreased secretion Topical following ocular laser surgery Topical drops Oral; topically active carbonic anhydrase inhibitors in clinical trials Intraocular injection at long intervals, eg, annually

Modified and reproduced, with permission, from Katzung BG (editor): Basic and Clinical Pharmacology, 6th ed. Appleton and Lange, 1995

DRUG LIST The following drugs are important members of the group discussed in this chapter. Prototypes should be learned in detail; the features of major variants should be known well enough to distinguih the variants from prototypes and from each other; the other significant agents should be recognized as belonging to a specific subclass. Subgroup Alpha-blokers Nonselective 1-selective 2-selective Beta-blockers Nonselective 1-selective 2-selective Prototype Phenoxybenzamine1 Prazosin Yohimbine Propranolol Metoprolol Butoxamine Major Variants Phentolamine Terazosin, doxazosin Rauwolscine Timolol, nadolol Atenolol, esmolol Other Significant Agents