Systems Pharmacology
B. Autoinhibition of norepinephrine release and ! -sympatholytics
!-Agonist
O2 supply < O2 demand O2 supply = O2 demand After
Before
O2 supply = O2 demand
NE
!2 !2 !2
nonselective
!-blocker
!1 #1 !1 #1 !1 #1
!1-blocker
!1-blocker e.g., terazosin
H3CO
O O
H3CO
NH2 N
N N
N
High blood pressure Benign
prostatic hyperplasia
Inhibition of
!1-adrenergic stimulation of
smooth muscle Neck of bladder, prostate Resistance
arteries
!-Sympatholytics (!-Blockers)
!-Sympatholytics are antagonists of norepiphephrine and epinephrine at !-adrenoceptors; they lack affinity for "-receptors.
Therapeutic effects. !-Blockers protect the heart from the oxygen-wasting effect of sympathetic inotrop-ism (p. 306) by blocking cardiac !-re-ceptors; thus, cardiac work can no long-er be augmented above basal levels (the heart is “coasting”). This effect is uti-lized prophylactically in angina pectoris to prevent myocardial stress that could trigger an ischemic attack (p. 308, 310).
!-Blockers also serve to lower cardiac rate(sinus tachycardia, p. 134) and ele-vated blood pressuredue to high cardiac output (p. 312). The mechanism under-lying their antihypertensive action via reduction of peripheral resistance is un-clear.
Applied topically to the eye, !-blockers are used in the management of glaucoma; they lower production of aqueous humor without affecting its drainage.
Undesired effects. The hazards of treatment with !-blockers become ap-parent particularly when continuous activation of !-receptors is needed in order to maintain the function of an or-gan.
Congestive heart failure:In myocar-dial insufficiency, the heart depends on a tonic sympathetic drive to maintain adequate cardiac output. Sympathetic activation gives rise to an increase in heart rate and systolic muscle tension, enabling cardiac output to be restored to a level comparable to that in a healthy subject. When sympathetic drive is eliminated during !-receptor blockade, stroke volume and cardiac rate decline, a latent myocardial ciency is unmasked, and overt insuffi-ciency is exacerbated (A).
On the other hand, clinical evidence suggests that !-blockers produce favor-able effects in certain forms of conges-tive heart failure (idiopathic dilated car-diomyopathy).
Bradycardia, A-V block:Elimination of sympathetic drive can lead to a marked fall in cardiac rate as well as to disorders of impulse conduction from the atria to the ventricles.
Bronchial asthma: Increased sym-pathetic activity prevents broncho-spasm in patients disposed to paroxys-mal constriction of the bronchial tree (bronchial asthma, bronchitis in smok-ers). In this condition, !2-receptor blockade will precipitate acute respira-tory distress (B).
Hypoglycemia in diabetes mellitus:
When treatment with insulin or oral hy-poglycemics in the diabetic patient low-ers blood glucose below a critical level, epinephrine is released, which then stimulates hepatic glucose release via activation of !2-receptors. !-Blockers suppress this counter-regulation; in ad-dition, they mask other epinephrine-mediated warning signs of imminent hypoglycemia, such as tachycardia and anxiety, thereby enhancing the risk of hypoglycemic shock.
Altered vascular responses: When
!2-receptors are blocked, the vasodilat-ing effect of epinephrine is abolished, leaving the "-receptor-mediated vaso-constriction unaffected: peripheral blood flow # – “cold hands and feet”.
!-Blockers exert an “anxiolytic“
action that may be due to the suppres-sion of somatic responses (palpitations, trembling) to epinephrine release that is induced by emotional stress; in turn, these would exacerbate “anxiety” or
“stage fright”. Because alertness is not impaired by !-blockers, these agents are occasionally taken by orators and musi-cians before a major performance (C).
Stage fright, however, is not a disease requiring drug therapy.
92 Drugs Acting on the Sympathetic Nervous System
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Drugs Acting on the Sympathetic Nervous System 93
C. “Anxiolytic” effect of !-sympatholytics A. !-Sympatholytics: effect on cardiac function
B. !-Sympatholytics: effect on bronchial and vascular tone Stroke
volume 100 ml
!-Receptor
!-Blocker blocks receptor
Heart failureHealthy
1 sec
!1-Blockade !1-Stimulation
!2-Blockade !2-Stimulation
HealthyAsthmatic
!2-Blockade !2-Stimulation
" !2 " !2
"
1 sec
!-Blockade
Types of !-Blockers
The basic structure shared by most sympatholytics is the side chain of !-sympathomimetics (cf. isoproterenol with the !-blockers propranolol, pindo-lol, atenolol). As a rule, this basic struc-ture is linked to an aromatic nucleus by a methylene and oxygen bridge. The side chain C-atom bearing the hydroxyl group forms the chiral center. With some exceptions (e.g., timolol, penbuto-lol), all !-sympatholytics are brought as racemates into the market (p. 62).
Compared with the dextrorotatory form, the levorotatory enantiomer pos-sesses a greater than 100-fold higher af-finity for the !-receptor and is, there-fore, practically alone in contributing to the !-blocking effect of the racemate.
The side chain and substituents on the amino group critically affect affinity for
!-receptors, whereas the aromatic nu-cleus determines whether the com-pound possess intrinsic sympathomi-metic activity (ISA), that is, acts as a partialagonist (p. 60) or partial antago-nist. In the presence of a partial agonist (e.g., pindolol), the ability of a full ago-nist (e.g., isoprenaline) to elicit a maxi-mal effect would be attenuated, because binding of the full agonist is impeded.
However, the !-receptor at which such partial agonism can be shown appears to be atypical (!3or !4subtype). Wheth-er ISA confWheth-ers a thWheth-erapeutic advantage on a !-blocker remains an open ques-tion.
As cationic amphiphilic drugs, !-blockers can exert a membrane-stabi-lizing effect, as evidenced by the ability of the more lipophilic congeners to in-hibit Na+-channel function and impulse conduction in cardiac tissues. At the usual therapeutic dosage, the high con-centration required for these effects will not be reached.
Some !-sympatholytics possess higher affinity for cardiac !1-receptors than for !2-receptors and thus display cardioselectivity (e.g., metoprolol, ace-butolol, bisoprolol). None of these blockers is sufficiently selective to
per-mit its use in patients with bronchial asthma or diabetes mellitus (p. 92).
The chemical structure of !-block-ers also determines their pharmacoki-netic properties. Except for hydrophilic representatives (atenolol), !-sympatho-lytics are completely absorbed from the intestines and subsequently undergo presystemic elimination to a major ex-tent (A).
All the above differences are of little clinical importance. The abundance of commercially available congeners would thus appear all the more curious (B). Propranolol was the first !-blocker to be introduced into therapy in 1965.
Thirty-five years later, about 20 different congeners are being marketed in differ-ent countries. This questionable devel-opment unfortunately is typical of any drug group that has major therapeutic relevance, in addition to a relatively fixed active structure. Variation of the molecule will create a new patentable chemical, not necessarily a drug with a novel action. Moreover, a drug no longer protected by patent is offered as a gener-icby different manufacturers under doz-ens of different proprietary names.
Propranolol alone has been marketed by 13 manufacturers under 11 different names.
94 Drugs Acting on the Sympathetic Nervous System
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Drugs Acting on the Sympathetic Nervous System 95
TalinololSotalol
!1 !2