A. Chemical structure of catecholamines and affinity for a- and ß-receptors
Penetrability through membrane barriers
(Enteral absorbability CNS permeability)
Penetrability through membrane barriers
(Enteral absorbability CNS permeability)
I I Affinity for a-receptors I I Affinity for ß-receptors i—i Indirect action
I I Resistance to degradation I I Absorbability
B. Structure-activity relationship of epinephrine derivatives
Apart from receptors, adrenergic neurotransmission involves mechanisms for the active re-uptake and re-storage of released amine, as well as enzymatic breakdown by monoamine oxidase (MAO). Norepinephrine (NE) displays affinity for receptors, transport systems, and degradative enzymes. Chemical alterations of the catecholamine differentially affect these properties and result in substances with selective actions.
Inhibitors of MAO (A). The enzyme is located predominantly on mitochondria, and serves to scavenge axoplasmic free NE. Inhibition of the enzyme causes free NE concentrations to rise. Likewise, dopamine catabolism is impaired, making more of it available for NE synthesis. Consequently, the amount of NE stored in granular vesicles will increase, and with it the amount of amine released per nerve impulse.
In the CNS, inhibition of MAO affects neuronal storage not only of NE but also of dopamine and serotonin. These mediators probably play significant roles in CNS functions consistent with the stimulant effects of MAO inhibitors on mood and psychomotor drive and their use as antidepressants in the treatment of depression (A). Tranylcypromine is used to treat particular forms of depressive illness; as a covalently bound suicide substrate, it causes long-lasting inhibition of both MAO iso-zymes, (MAOA, MAOB). Moclobemide re-versibly inhibits MAOA and is also used as an antidepressant. The MAOB inhibitor selegiline (deprenyl) retards the cat-obolism of dopamine, an effect used in the treatment of parkinsonism (p. 188).
Indirect sympathomimetics (B)
are agents that elevate the concentration of NE at neuroeffector junctions, because they either inhibit re-uptake (cocaine), facilitate release, or slow breakdown by MAO, or exert all three of these effects (amphetamine, metham-phetamine). The effectiveness of such indirect sympathomimetics diminishes or disappears (tachyphylaxis) when ve-Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
sicular stores of NE close to the axolem-ma are depleted.
Indirect sympathomimetics can penetrate the blood-brain barrier and evoke such CNS effects as a feeling of well-being, enhanced physical activity and mood (euphoria), and decreased sense of hunger or fatigue. Subsequently, the user may feel tired and depressed. These after effects are partly responsible for the urge to re-administer the drug (high abuse potential). To prevent their misuse, these substances are subject to governmental regulations (e.g., Food and Drugs Act: Canada; Controlled Drugs Act: USA) restricting their prescription and distribution.
When amphetamine-like substances are misused to enhance athletic performance (doping), there is a risk of dangerous physical overexertion. Because of the absence of a sense of fatigue, a drugged athlete may be able to mobilize ultimate energy reserves. In extreme situations, cardiovascular failure may result (B).
Closely related chemically to amphetamine are the so-called appetite suppressants or anorexiants, such as fenfluramine, mazindole, and sibutra-mine. These may also cause dependence and their therapeutic value and safety are questionable.
a-Sympathomimetics, a-Sympatholytics a-Sympathomimetics can be used systemically in certain types of hypotension (p. 314) and locally for nasal or conjunctival decongestion (pp. 324, 326) or as adjuncts in infiltration anesthesia (p. 206) for the purpose of delaying the removal of local anesthetic. With local use, underperfusion of the vasocon-stricted area results in a lack of oxygen (A). In the extreme case, local hypoxia can lead to tissue necrosis. The appendages (e.g., digits, toes, ears) are particularly vulnerable in this regard, thus precluding vasoconstrictor adjuncts in infiltration anesthesia at these sites.
Vasoconstriction induced by an a-sympathomimetic is followed by a phase of enhanced blood flow (reactive hyperemia, A). This reaction can be observed after the application of a-sympa-thomimetics (naphazoline, tetrahydro-zoline, xylometazoline) to the nasal mucosa. Initially, vasoconstriction reduces mucosal blood flow and, hence, capillary pressure. Fluid exuded into the interstitial space is drained through the veins, thus shrinking the nasal mucosa. Due to the reduced supply of fluid, secretion of nasal mucus decreases. In coryza, nasal patency is restored. However, after vasoconstriction subsides, reactive hyperemia causes renewed exudation of plasma fluid into the interstitial space, the nose is "stuffy" again, and the patient feels a need to reapply decon-gestant. In this way, a vicious cycle threatens. Besides rebound congestion, persistent use of a decongestant entails the risk of atrophic damage caused by prolonged hypoxia of the nasal mucosa.
a-Sympatholytics (B). The interaction of norepinephrine with a-adreno-ceptors can be inhibited by a-sympath-olytics ( a-adrenoceptor antagonists, ablockers). This inhibition can be put to therapeutic use in antihypertensive treatment (vasodilation ^ peripheral resistance 4, blood pressure 4, p. 118). The first a-sympatholytics blocked the action of norepinephrine at both post-
and prejunctional a-adrenoceptors (non-selective a-blockers, e.g., phen-oxybenzamine, phentolamine).
Presynaptic a2-adrenoceptors function like sensors that enable norepi-nephrine concentration outside the axolemma to be monitored, thus regulating its release via a local feedback mechanism. When presynaptic a2-re-ceptors are stimulated, further release of norepinephrine is inhibited. Conversely, their blockade leads to uncontrolled release of norepinephrine with an overt enhancement of sympathetic effects at Pi-adrenoceptor-mediated myocardial neuroeffector junctions, resulting in tachycardia and tachyar-rhythmia.
Selective a-Sympatholytics a-Blockers, such as prazosin, or the longer-acting terazosin and doxazosin, lack affinity for prejunctional a2-adren-oceptors. They suppress activation of ai-receptors without a concomitant enhancement of norepinephrine release.
a1-Blockers may be used in hypertension (p. 312). Because they prevent reflex vasoconstriction, they are likely to cause postural hypotension with pooling of blood in lower limb capacitance veins during change from the supine to the erect position (orthostatic collapse: I venous return, I cardiac output, fall in systemic pressure, I blood supply to CNS, syncope, p. 314).
In benign hyperplasia of the prostate, a-blockers (terazosin, alfuzosin) may serve to lower tonus of smooth musculature in the prostatic region and thereby facilitate micturition (p. 252).
P-Sympatholytics are antagonists of norepiphephrine and epinephrine at P-adrenoceptors; they lack affinity for a-receptors.
Therapeutic effects. P-Blockers protect the heart from the oxygen-wasting effect of sympathetic inotrop-ism (p. 306) by blocking cardiac P-re-ceptors; thus, cardiac work can no longer be augmented above basal levels (the heart is "coasting"). This effect is utilized prophylactically in angina pectoris to prevent myocardial stress that could trigger an ischemic attack (p. 308, 310). P-Blockers also serve to lower cardiac rate (sinus tachycardia, p. 134) and elevated blood pressure due to high cardiac output (p. 312). The mechanism underlying their antihypertensive action via reduction of peripheral resistance is unclear.
Applied topically to the eye, P-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 P-blockers become apparent particularly when continuous activation of P-receptors is needed in order to maintain the function of an organ.
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 P-receptor blockade, stroke volume and cardiac rate decline, a latent myocardial insufficiency is unmasked, and overt insufficiency is exacerbated (A).
On the other hand, clinical evidence suggests that P-blockers produce favorable effects in certain forms of congestive 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 sympathetic activity prevents broncho-spasm in patients disposed to paroxysmal constriction of the bronchial tree (bronchial asthma, bronchitis in smokers). In this condition, p2-receptor blockade will precipitate acute respiratory distress (B).
Hypoglycemia in diabetes mellitus: When treatment with insulin or oral hypoglycemics in the diabetic patient lowers blood glucose below a critical level, epinephrine is released, which then stimulates hepatic glucose release via activation of p2-receptors. p-Blockers suppress this counter-regulation; in addition, 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 p2-receptors are blocked, the vasodilat-ing effect of epinephrine is abolished, leaving the a-receptor-mediated vasoconstriction unaffected: peripheral blood flow I - "cold hands and feet".
p-Blockers exert an "anxiolytic" action that may be due to the suppression 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 p-blockers, these agents are occasionally taken by orators and musicians before a major performance (C). Stage fright, however, is not a disease requiring drug therapy.
ß-Blocker bIocks receptor
ß-Blocker bIocks receptor
Stroke volume ik A
1 sec ß1-Blockade
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