Color Atlas of Pharmacology (Part 9): Systems Pharmacology

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Color Atlas of Pharmacology (Part 9): Systems Pharmacology

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Drugs Acting on the Sympathetic Nervous System of the sympathetic division can be considered a means by which the body achieves a state of maximal work capacity as required in fight or flight situations. In both cases, there is a need for vigorous activity of skeletal musculature. To ensure adequate supply of oxygen and nutrients, blood flow in skeletal muscle is increased; cardiac rate and contractility are enhanced, resulting in a larger blood volume being pumped into the circulation. Narrowing of splanchnic blood vessels diverts blood into vascular beds in muscle. Because digestion of food in the intestinal tract...

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  1. Systems Pharmacology Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  2. 80 Drugs Acting on the Sympathetic Nervous System Sympathetic Nervous System of the sympathetic division can be con- sidered a means by which the body In the course of phylogeny an efficient achieves a state of maximal work capac- control system evolved that enabled the ity as required in fight or flight situa- functions of individual organs to be or- tions. chestrated in increasingly complex life In both cases, there is a need for forms and permitted rapid adaptation vigorous activity of skeletal muscula- to changing environmental conditions. ture. To ensure adequate supply of oxy- This regulatory system consists of the gen and nutrients, blood flow in skeletal CNS (brain plus spinal cord) and two muscle is increased; cardiac rate and separate pathways for two-way com- contractility are enhanced, resulting in a munication with peripheral organs, viz., larger blood volume being pumped into the somatic and the autonomic nervous the circulation. Narrowing of splanchnic systems. The somatic nervous system blood vessels diverts blood into vascular comprising extero- and interoceptive beds in muscle. afferents, special sense organs, and mo- Because digestion of food in the in- tor efferents, serves to perceive external testinal tract is dispensable and only states and to target appropriate body counterproductive, the propulsion of in- movement (sensory perception: threat testinal contents is slowed to the extent response: flight or attack). The auto- that peristalsis diminishes and sphinc- nomic (vegetative) nervous system teric tonus increases. However, in order (ANS), together with the endocrine to increase nutrient supply to heart and system, controls the milieu interieur. It musculature, glucose from the liver and adjusts internal organ functions to the free fatty acid from adipose tissue must changing needs of the organism. Neural be released into the blood. The bronchi control permits very quick adaptation, are dilated, enabling tidal volume and whereas the endocrine system provides alveolar oxygen uptake to be increased. for a long-term regulation of functional Sweat glands are also innervated by states. The ANS operates largely beyond sympathetic fibers (wet palms due to voluntary control; it functions autono- excitement); however, these are excep- mously. Its central components reside tional as regards their neurotransmitter in the hypothalamus, brain stem, and (ACh, p. 106). spinal cord. The ANS also participates in Although the life styles of modern the regulation of endocrine functions. humans are different from those of The ANS has sympathetic and hominid ancestors, biological functions parasympathetic branches. Both are have remained the same. made up of centrifugal (efferent) and centripetal (afferent) nerves. In many organs innervated by both branches, re- spective activation of the sympathetic and parasympathetic input evokes op- posing responses. In various disease states (organ malfunctions), drugs are employed with the intention of normalizing susceptible organ functions. To understand the bio- logical effects of substances capable of inhibiting or exciting sympathetic or parasympathetic nerves, one must first envisage the functions subserved by the sympathetic and parasympathetic divi- sions (A, Responses to sympathetic ac- tivation). In simplistic terms, activation Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  3. Drugs Acting on the Sympathetic Nervous System 81 CNS: drive Eyes: alertness pupillary dilation Saliva: little, viscous Bronchi: dilation Heart: Skin: rate perspiration force (cholinergic) blood pressure Fat tissue: lipolysis fatty acid liberation Liver: glycogenolysis Bladder: glucose release Sphincter tone detrusor muscle GI-tract: peristalsis sphincter tone blood flow Skeletal muscle: blood flow glycogenolysis A. Responses to sympathetic activation Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  4. 82 Drugs Acting on the Sympathetic Nervous System Structure of the Sympathetic Nervous converted via two intermediate steps to System dopamine, which is taken up into the vesicles and there converted to norepi- The sympathetic preganglionic neurons nephrine by dopamine-!-hydroxylase. (first neurons) project from the inter- When stimulated electrically, the sym- mediolateral column of the spinal gray pathetic nerve discharges the contents matter to the paired paravertebral gan- of part of its vesicles, including norepi- glionic chain lying alongside the verte- nephrine, into the extracellular space. bral column and to unpaired preverte- Liberated norepinephrine reacts with bral ganglia. These ganglia represent adrenoceptors located postjunctionally sites of synaptic contact between pre- on the membrane of effector cells or ganglionic axons (1st neurons) and prejunctionally on the membrane of nerve cells (2nd neurons or sympathocy- varicosities. Activation of presynaptic tes) that emit postganglionic axons "2-receptors inhibits norepinephrine terminating on cells in various end or- release. By this negative feedback, re- gans. In addition, there are preganglion- lease can be regulated. ic neurons that project either to periph- The effect of released norepineph- eral ganglia in end organs or to the ad- rine wanes quickly, because approx. renal medulla. 90 % is actively transported back into the axoplasm, then into storage vesicles Sympathetic Transmitter Substances (neuronal re-uptake). Small portions of norepinephrine are inactivated by the Whereas acetylcholine (see p. 98) enzyme catechol-O- methyltransferase serves as the chemical transmitter at (COMT, present in the cytoplasm of ganglionic synapses between first and postjunctional cells, to yield normeta- second neurons, norepinephrine nephrine), and monoamine oxidase (= noradrenaline) is the mediator at (MAO, present in mitochondria of nerve synapses of the second neuron (B). This cells and postjunctional cells, to yield second neuron does not synapse with 3,4-dihydroxymandelic acid). only a single cell in the effector organ; The liver is richly endowed with rather, it branches out, each branch COMT and MAO; it therefore contrib- making en passant contacts with several utes significantly to the degradation of cells. At these junctions the nerve axons circulating norepinephrine and epi- form enlargements (varicosities) re- nephrine. The end product of the com- sembling beads on a string. Thus, excita- bined actions of MAO and COMT is van- tion of the neuron leads to activation of illylmandelic acid. a larger aggregate of effector cells, al- though the action of released norepi- nephrine may be confined to the region of each junction. Excitation of pregan- glionic neurons innervating the adrenal medulla causes a liberation of acetyl- choline. This, in turn, elicits a secretion of epinephrine (= adrenaline) into the blood, by which it is distributed to body tissues as a hormone (A). Adrenergic Synapse Within the varicosities, norepinephrine is stored in small membrane-enclosed vesicles (granules, 0.05 to 0.2 µm in dia- meter). In the axoplasm, L-tyrosine is Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  5. Drugs Acting on the Sympathetic Nervous System 83 Psychic or physical stress stress First neuron First neuron Second Adrenal neuron medulla Epinephrine Norepinephrine A. Epinephrine as hormone, norepinephrine as transmitter Presynaptic "2-receptors s or pt ce Re 3.4-Dihydroxy- mandelic acid " O MA rs pto !1 ce Re !2 Normeta- nephrine COMT Norepinephrine B. Second neuron of sympathetic system, varicosity, norepinephrine release Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  6. 84 Drugs Acting on the Sympathetic Nervous System Adrenoceptor Subtypes and with a resultant drop in systemic blood Catecholamine Actions pressure results in reflex tachycardia, which is also due in part to the "1-stim- Adrenoceptors fall into three major ulant action of these drugs. groups, designated !1, !2, and ", within Cardiostimulation. By stimulating each of which further subtypes can be "1-receptors, hence activation of ade- distinguished pharmacologically. The nylatcyclase (Ad-cyclase) and cAMP different adrenoceptors are differential- production, catecholamines augment all ly distributed according to region and heart functions, including systolic force tissue. Agonists at adrenoceptors (di- (positive inotropism), velocity of short- rect sympathomimetics) mimic the ac- ening (p. clinotropism), sinoatrial rate tions of the naturally occurring cate- (p. chronotropism), conduction velocity cholamines, norepinephrine and epi- (p. dromotropism), and excitability (p. nephrine, and are used for various ther- bathmotropism). In pacemaker fibers, apeutic effects. diastolic depolarization is hastened, so Smooth muscle effects. The op- that the firing threshold for the action posing effects on smooth muscle (A) of potential is reached sooner (positive !-and "-adrenoceptor activation are chronotropic effect, B). The cardiostim- due to differences in signal transduction ulant effect of "-sympathomimetics (p. 66). This is exemplified by vascular such as epinephrine is exploited in the smooth muscle (A). !1-Receptor stimu- treatment of cardiac arrest. Use of "- lation leads to intracellular release of sympathomimetics in heart failure car- Ca2+ via activation of the inositol tris- ries the risk of cardiac arrhythmias. phosphate (IP3) pathway. In concert Metabolic effects. "-Receptors me- with the protein calmodulin, Ca2+ can diate increased conversion of glycogen to activate myosin kinase, leading to a rise glucose (glycogenolysis) in both liver in tonus via phosphorylation of the con- and skeletal muscle. From the liver, glu- tractile protein myosin. cAMP inhibits cose is released into the blood, In adi- activation of myosin kinase. Via the for- pose tissue, triglycerides are hydrolyzed mer effector pathway, stimulation of !- to fatty acids (lipolysis, mediated by "3- receptors results in vasoconstriction; receptors), which then enter the blood via the latter, "2-receptors mediate va- (C). The metabolic effects of catechola- sodilation, particularly in skeletal mus- mines are not amenable to therapeutic cle — an effect that has little therapeutic use. use. Vasoconstriction. Local application of !-sympathomimetics can be employed in infiltration anesthesia (p. 204) or for nasal decongestion (naphazoline, tetra- hydrozoline, xylometazoline; pp. 90, 324). Systemically administered epi- nephrine is important in the treatment of anaphylactic shock for combating hy- potension. Bronchodilation. "2-Adrenocep- tor-mediated bronchodilation (e.g., with terbutaline, fenoterol, or salbutamol) plays an essential part in the treatment of bronchial asthma (p. 328). Tocolysis. The uterine relaxant ef- fect of "2-adrenoceptor agonists, such as terbutaline or fenoterol, can be used to prevent premature labor. Vasodilation Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  7. Drugs Acting on the Sympathetic Nervous System 85 Phospholipase C !1 "2 !2 Ad-cyclase Ad-cyclase Gi Gs Gi IP3 Ca2+ + cAMP - u lin od m al C Myosin kinase Myosin Myosin-P A. Vasomotor effects of catecholamines "1 " Ad-cyclase Ad-cyclase Gs Gs cAMP + cAMP + Force (mN) Glycogenolysis Lipolysis Glucose Time Glycogenolysis Membrane potential (mV) Fatty acids Glucose Time B. Cardiac effects of catecholamines C. Metabolic effects of catecholamines Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  8. 86 Drugs Acting on the Sympathetic Nervous System Structure – Activity Relationships of catecholamine congeners can be given Sympathomimetics orally and can exert CNS actions; how- Due to its equally high affinity for all !- ever, this structural change entails a loss and "-receptors, epinephrine does not in affinity. permit selective activation of a particu- Absence of one or both aromatic lar receptor subtype. Like most cate- hydroxyl groups is associated with an cholamines, it is also unsuitable for oral increase in indirect sympathomimetic administration (catechol is a trivial activity, denoting the ability of a sub- name for o-hydroxyphenol). Norepi- stance to release norepinephrine from nephrine differs from epinephrine by its its neuronal stores without exerting an high affinity for !-receptors and low af- agonist action at the adrenoceptor (p. finity for "2-receptors. In contrast, iso- 88). proterenol has high affinity for "-recep- An altered position of aromatic hy- tors, but virtually none for !-receptors droxyl groups (e.g., in orciprenaline, fe- (A). noterol, or terbutaline) or their substi- norepinephrine !, "1 tution (e.g., salbutamol) protects epinephrine !, "1, "2 against inactivation by COMT (p. 82). In- isoproterenol "1, "2 droduction of a small alkyl residue at Knowledge of structure–activity the carbon atom adjacent to the amino relationships has permitted the syn- group (ephedrine, methamphetamine) thesis of sympathomimetics that dis- confers resistance to degradation by play a high degree of selectivity at MAO (p. 80), as does replacement on the adrenoceptor subtypes. amino groups of the methyl residue Direct-acting sympathomimetics with larger substituents (e.g., ethyl in (i.e., adrenoceptor agonists) typically etilefrine). Accordingly, the congeners share a phenylethylamine structure. The are less subject to presystemic inactiva- side chain "-hydroxyl group confers af- tion. finity for !- and "-receptors. Substitu- Since structural requirements for tion on the amino group reduces affinity high affinity, on the one hand, and oral for !-receptors, but increases it for "-re- applicability, on the other, do not ceptors (exception: !-agonist phenyl- match, choosing a sympathomimetic is ephrine), with optimal affinity being a matter of compromise. If the high af- seen after the introduction of only one finity of epinephrine is to be exploited, isopropyl group. Increasing the bulk of absorbability from the intestine must be the amino substituent favors affinity for foregone (epinephrine, isoprenaline). If "2-receptors (e.g., fenoterol, salbuta- good bioavailability with oral adminis- mol). Both hydroxyl groups on the aro- tration is desired, losses in receptor af- matic nucleus contribute to affinity; finity must be accepted (etilefrine). high activity at !-receptors is associated with hydroxyl groups at the 3 and 4 po- sitions. Affinity for "-receptors is pre- served in congeners bearing hydroxyl groups at positions 3 and 5 (orciprena- line, terbutaline, fenoterol). The hydroxyl groups of catechol- amines are responsible for the very low lipophilicity of these substances. Pola- rity is increased at physiological pH due to protonation of the amino group. De- letion of one or all hydroxyl groups im- proves membrane penetrability at the intestinal mucosa-blood and the blood- brain barriers. Accordingly, these non- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  9. Drugs Acting on the Sympathetic Nervous System 87 Norepinephrine Epinephrine Isoproterenol A. Chemical structure of catecholamines and affinity for !- and "-receptors Receptor affinity Catecholamine- O-methyltransferase Penetrability through Metabolic membrane stability barriers (Enteral absorbability CNS permeability) Monoamine oxidase Epinephrine Orciprenaline Fenoterol Etilefrine Ephedrine Methamphetamine Affinity for !-receptors Indirect Resistance to degradation action Affinity for "-receptors Absorbability B. Structure-activity relationship of epinephrine derivatives Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  10. 88 Drugs Acting on the Sympathetic Nervous System Indirect Sympathomimetics sicular stores of NE close to the axolem- ma are depleted. Apart from receptors, adrenergic neu- Indirect sympathomimetics can rotransmission involves mechanisms penetrate the blood-brain barrier and for the active re-uptake and re-storage evoke such CNS effects as a feeling of of released amine, as well as enzymatic well-being, enhanced physical activity breakdown by monoamine oxidase and mood (euphoria), and decreased (MAO). Norepinephrine (NE) displays sense of hunger or fatigue. Subsequent- affinity for receptors, transport systems, ly, the user may feel tired and de- and degradative enzymes. Chemical al- pressed. These after effects are partly terations of the catecholamine differen- responsible for the urge to re-adminis- tially affect these properties and result ter the drug (high abuse potential). To in substances with selective actions. prevent their misuse, these substances Inhibitors of MAO (A). The enzyme are subject to governmental regulations is located predominantly on mitochon- (e.g., Food and Drugs Act: Canada; Con- dria, and serves to scavenge axoplasmic trolled Drugs Act: USA) restricting their free NE. Inhibition of the enzyme causes prescription and distribution. free NE concentrations to rise. Likewise, When amphetamine-like substanc- dopamine catabolism is impaired, mak- es are misused to enhance athletic per- ing more of it available for NE synthesis. formance (doping), there is a risk of dan- Consequently, the amount of NE stored gerous physical overexertion. Because in granular vesicles will increase, and of the absence of a sense of fatigue, a with it the amount of amine released drugged athlete may be able to mobilize per nerve impulse. ultimate energy reserves. In extreme In the CNS, inhibition of MAO af- situations, cardiovascular failure may fects neuronal storage not only of NE result (B). but also of dopamine and serotonin. Closely related chemically to am- These mediators probably play signifi- phetamine are the so-called appetite cant roles in CNS functions consistent suppressants or anorexiants, such as with the stimulant effects of MAO inhib- fenfluramine, mazindole, and sibutra- itors on mood and psychomotor drive mine. These may also cause dependence and their use as antidepressants in the and their therapeutic value and safety treatment of depression (A). Tranylcy- are questionable. promine 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 inhibi- tor 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 concentra- tion 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- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  11. Drugs Acting on the Sympathetic Nervous System 89 Inhibitor: Moclobemide MAO-A Selegiline MAO-B M M AO AO Nor- epinephrine Norepinephrine transport system Effector organ A. Monoamine oxidase inhibitor § § Pain stimulus Local anesthetic effect Controlled Substances Act regulates use of Amphetamine cocaine and Cocaine amphetamine M M AO AO "Doping" Runner-up B. Indirect sympathomimetics with central stimulant activity and abuse potential Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  12. 90 Drugs Acting on the Sympathetic Nervous System !-Sympathomimetics, and prejunctional !-adrenoceptors !-Sympatholytics (non-selective !-blockers, e.g., phen- oxybenzamine, phentolamine). !-Sympathomimetics can be used Presynaptic !2-adrenoceptors func- systemically in certain types of hypoten- tion like sensors that enable norepi- sion (p. 314) and locally for nasal or con- nephrine concentration outside the junctival decongestion (pp. 324, 326) or axolemma to be monitored, thus regu- as adjuncts in infiltration anesthesia (p. lating its release via a local feedback 206) for the purpose of delaying the re- mechanism. When presynaptic !2-re- moval of local anesthetic. With local ceptors are stimulated, further release use, underperfusion of the vasocon- of norepinephrine is inhibited. Con- stricted area results in a lack of oxygen versely, their blockade leads to uncon- (A). In the extreme case, local hypoxia trolled release of norepinephrine with can lead to tissue necrosis. The append- an overt enhancement of sympathetic ages (e.g., digits, toes, ears) are particu- effects at #1-adrenoceptor-mediated larly vulnerable in this regard, thus pre- myocardial neuroeffector junctions, re- cluding vasoconstrictor adjuncts in in- sulting in tachycardia and tachyar- filtration anesthesia at these sites. rhythmia. Vasoconstriction induced by an !- sympathomimetic is followed by a Selective !-Sympatholytics phase of enhanced blood flow (reactive hyperemia, A). This reaction can be ob- !-Blockers, such as prazosin, or the served after the application of !-sympa- longer-acting terazosin and doxazosin, thomimetics (naphazoline, tetrahydro- lack affinity for prejunctional !2-adren- zoline, xylometazoline) to the nasal mu- oceptors. They suppress activation of cosa. Initially, vasoconstriction reduces !1-receptors without a concomitant en- mucosal blood flow and, hence, capil- hancement of norepinephrine release. lary pressure. Fluid exuded into the !1-Blockers may be used in hyper- interstitial space is drained through the tension (p. 312). Because they prevent veins, thus shrinking the nasal mucosa. reflex vasoconstriction, they are likely Due to the reduced supply of fluid, se- to cause postural hypotension with cretion of nasal mucus decreases. In co- pooling of blood in lower limb capaci- ryza, nasal patency is restored. Howev- tance veins during change from the su- er, after vasoconstriction subsides, reac- pine to the erect position (orthostatic tive hyperemia causes renewed exuda- collapse: " venous return, " cardiac out- tion of plasma fluid into the interstitial put, fall in systemic pressure, " blood space, the nose is “stuffy” again, and the supply to CNS, syncope, p. 314). patient feels a need to reapply decon- In benign hyperplasia of the pros- gestant. In this way, a vicious cycle tate, !-blockers (terazosin, alfuzosin) threatens. Besides rebound congestion, may serve to lower tonus of smooth persistent use of a decongestant entails musculature in the prostatic region and the risk of atrophic damage caused by thereby facilitate micturition (p. 252). prolonged hypoxia of the nasal mucosa. !-Sympatholytics (B). The interac- tion of norepinephrine with !-adreno- ceptors can be inhibited by !-sympath- olytics ( !-adrenoceptor antagonists, !- blockers). This inhibition can be put to therapeutic use in antihypertensive treatment (vasodilation peripheral resistance ", blood pressure ", p. 118). The first !-sympatholytics blocked the action of norepinephrine at both post- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  13. Drugs Acting on the Sympathetic Nervous System 91 Before !-Agonist After O2 supply = O2 demand O2 supply < O2 demand O2 supply = O2 demand A. Reactive hyperemia due to !-sympathomimetics, e.g., following decongestion of nasal mucosa !2 !2 !2 nonselective NE !-blocker !1-blocker !1 #1 !1 #1 !1 #1 B. Autoinhibition of norepinephrine release and !-sympatholytics !1-blocker Benign High blood pressure e.g., terazosin prostatic hyperplasia O N H3CO N N O N H3CO NH2 Inhibition of !1-adrenergic stimulation of Resistance smooth muscle Neck of bladder, arteries prostate C. Indications for !1-sympatholytics Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  14. 92 Drugs Acting on the Sympathetic Nervous System !-Sympatholytics (!-Blockers) Bradycardia, A-V block: Elimination of sympathetic drive can lead to a !-Sympatholytics are antagonists of marked fall in cardiac rate as well as to norepiphephrine and epinephrine at !- disorders of impulse conduction from adrenoceptors; they lack affinity for "- the atria to the ventricles. receptors. Bronchial asthma: Increased sym- Therapeutic effects. !-Blockers pathetic activity prevents broncho- protect the heart from the oxygen- spasm in patients disposed to paroxys- wasting effect of sympathetic inotrop- mal constriction of the bronchial tree ism (p. 306) by blocking cardiac !-re- (bronchial asthma, bronchitis in smok- ceptors; thus, cardiac work can no long- ers). In this condition, !2-receptor er be augmented above basal levels (the blockade will precipitate acute respira- heart is “coasting”). This effect is uti- tory distress (B). lized prophylactically in angina pectoris Hypoglycemia in diabetes mellitus: to prevent myocardial stress that could When treatment with insulin or oral hy- trigger an ischemic attack (p. 308, 310). poglycemics in the diabetic patient low- !-Blockers also serve to lower cardiac ers blood glucose below a critical level, rate (sinus tachycardia, p. 134) and ele- epinephrine is released, which then vated blood pressure due to high cardiac stimulates hepatic glucose release via output (p. 312). The mechanism under- activation of !2-receptors. !-Blockers lying their antihypertensive action via suppress this counter-regulation; in ad- reduction of peripheral resistance is un- dition, they mask other epinephrine- clear. mediated warning signs of imminent Applied topically to the eye, !- hypoglycemia, such as tachycardia and blockers are used in the management of anxiety, thereby enhancing the risk of glaucoma; they lower production of hypoglycemic shock. aqueous humor without affecting its Altered vascular responses: When drainage. !2-receptors are blocked, the vasodilat- Undesired effects. The hazards of ing effect of epinephrine is abolished, treatment with !-blockers become ap- leaving the "-receptor-mediated vaso- parent particularly when continuous constriction unaffected: peripheral activation of !-receptors is needed in blood flow # – “cold hands and feet”. order to maintain the function of an or- !-Blockers exert an “anxiolytic“ gan. action that may be due to the suppres- Congestive heart failure: In myocar- sion of somatic responses (palpitations, dial insufficiency, the heart depends on trembling) to epinephrine release that a tonic sympathetic drive to maintain is induced by emotional stress; in turn, adequate cardiac output. Sympathetic these would exacerbate “anxiety” or activation gives rise to an increase in “stage fright”. Because alertness is not heart rate and systolic muscle tension, impaired by !-blockers, these agents are enabling cardiac output to be restored occasionally taken by orators and musi- to a level comparable to that in a cians before a major performance (C). healthy subject. When sympathetic Stage fright, however, is not a disease drive is eliminated during !-receptor requiring drug therapy. blockade, stroke volume and cardiac rate decline, a latent myocardial insuffi- 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). Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  15. Drugs Acting on the Sympathetic Nervous System 93 !-Blocker !-Receptor blocks receptor 100 ml Healthy Stroke volume 1 sec !1-Blockade !1-Stimulation Heart failure 1 sec A. !-Sympatholytics: effect on cardiac function Healthy Asthmatic " " !2 " !2 !2-Blockade !2-Stimulation !2-Blockade !2-Stimulation B. !-Sympatholytics: effect on bronchial and vascular tone !-Blockade C. “Anxiolytic” effect of !-sympatholytics Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  16. 94 Drugs Acting on the Sympathetic Nervous System Types of !-Blockers mit its use in patients with bronchial asthma or diabetes mellitus (p. 92). The basic structure shared by most !- The chemical structure of !-block- sympatholytics is the side chain of !- ers also determines their pharmacoki- sympathomimetics (cf. isoproterenol netic properties. Except for hydrophilic with the !-blockers propranolol, pindo- representatives (atenolol), !-sympatho- lol, atenolol). As a rule, this basic struc- lytics are completely absorbed from the ture is linked to an aromatic nucleus by intestines and subsequently undergo a methylene and oxygen bridge. The presystemic elimination to a major ex- side chain C-atom bearing the hydroxyl tent (A). group forms the chiral center. With All the above differences are of some exceptions (e.g., timolol, penbuto- little clinical importance. The abundance lol), all !-sympatholytics are brought as of commercially available congeners racemates into the market (p. 62). would thus appear all the more curious Compared with the dextrorotatory (B). Propranolol was the first !-blocker form, the levorotatory enantiomer pos- to be introduced into therapy in 1965. sesses a greater than 100-fold higher af- Thirty-five years later, about 20 different finity for the !-receptor and is, there- congeners are being marketed in differ- fore, practically alone in contributing to ent countries. This questionable devel- the !-blocking effect of the racemate. opment unfortunately is typical of any The side chain and substituents on the drug group that has major therapeutic amino group critically affect affinity for relevance, in addition to a relatively !-receptors, whereas the aromatic nu- fixed active structure. Variation of the cleus determines whether the com- molecule will create a new patentable pound possess intrinsic sympathomi- chemical, not necessarily a drug with a metic activity (ISA), that is, acts as a novel action. Moreover, a drug no longer partial agonist (p. 60) or partial antago- protected by patent is offered as a gener- nist. In the presence of a partial agonist ic by different manufacturers under doz- (e.g., pindolol), the ability of a full ago- ens of different proprietary names. nist (e.g., isoprenaline) to elicit a maxi- Propranolol alone has been marketed by mal effect would be attenuated, because 13 manufacturers under 11 different binding of the full agonist is impeded. names. However, the !-receptor at which such partial agonism can be shown appears to be atypical (!3 or !4 subtype). Wheth- er ISA confers a therapeutic 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- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  17. Drugs Acting on the Sympathetic Nervous System 95 Isoproterenol Pindolol Propranolol Atenolol !-Receptor !-Receptor !-Receptor Agonist partial Antagonist Antagonist Agonist Effect No effect !1 !1 !1 !1 !2 !1 Cardio- !2 !2 !2 !2 selectivity 100% Presystemic 50% elimination A. Types of !-sympatholytics 1965 1970 Year introduced Tertatolol Carvedilol Esmolol Bopindolol Bisoprolol Celiprolol Betaxolol Befunolol Carteolol Mepindolol Penbutolol Carazolol Nadolol Acebutolol Bunitrolol Atenolol Metipranol Metoprolol Timolol Sotalol Talinolol Oxprenolol Pindolol Bupranolol Alprenolol Propranolol 1975 1980 1985 1990 B. Avalanche-like increase in commercially available !-sympatholytics Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  18. 96 Drugs Acting on the Sympathetic Nervous System Antiadrenergics leased per nerve impulse is decreased. To a lesser degree, release of epineph- Antiadrenergics are drugs capable of rine from the adrenal medulla is also lowering transmitter output from sym- impaired. At higher doses, there is irre- pathetic neurons, i.e., “sympathetic versible damage to storage vesicles tone”. Their action is hypotensive (indi- (“pharmacological sympathectomy”), cation: hypertension, p. 312); however, days to weeks being required for their being poorly tolerated, they enjoy only resynthesis. Reserpine readily enters limited therapeutic use. the brain, where it also impairs vesicu- Clonidine is an !2-agonist whose lar storage of biogenic amines. high lipophilicity (dichlorophenyl ring) Adverse effects. Disorders of extra- permits rapid penetration through the pyramidal motor function with devel- blood-brain barrier. The activation of opment of pseudo-Parkinsonism (p. 88), postsynaptic !2-receptors dampens the sedation, depression, stuffy nose, im- activity of vasomotor neurons in the paired libido, and impotence; increased medulla oblongata, resulting in a reset- appetite. These adverse effects have ting of systemic arterial pressure at a rendered the drug practically obsolete. lower level. In addition, activation of Guanethidine possesses high affin- presynaptic !2-receptors in the periph- ity for the axolemmal and vesicular ery (pp. 82, 90) leads to a decreased re- amine transporters. It is stored instead lease of both norepinephrine (NE) and of NE, but is unable to mimic the func- acetylcholine. tions of the latter. In addition, it stabiliz- Side effects. Lassitude, dry mouth; es the axonal membrane, thereby im- rebound hypertension after abrupt ces- peding the propagation of impulses into sation of clonidine therapy. the sympathetic nerve terminals. Stor- Methyldopa (dopa = dihydroxy- age and release of epinephrine from the phenylalanine), as an amino acid, is adrenal medulla are not affected, owing transported across the blood-brain bar- to the absence of a re-uptake process. rier, decarboxylated in the brain to !- The drug does not cross the blood-brain methyldopamine, and then hydroxylat- barrier. ed to !-methyl-NE. The decarboxylation Adverse effects. Cardiovascular cri- of methyldopa competes for a portion of ses are a possible risk: emotional stress the available enzymatic activity, so that of the patient may cause sympatho- the rate of conversion of L-dopa to NE adrenal activation with epinephrine re- (via dopamine) is decreased. The false lease. The resulting rise in blood pres- transmitter !-methyl-NE can be stored; sure can be all the more marked be- however, unlike the endogenous media- cause persistent depression of sympa- tor, it has a higher affinity for !2- than thetic nerve activity induces supersen- for !1-receptors and therefore produces sitivity of effector organs to circulating effects similar to those of clonidine. The catecholamines. same events take place in peripheral ad- renergic neurons. Adverse effects. Fatigue, orthostatic hypotension, extrapyramidal Parkin- son-like symptoms (p. 88), cutaneous reactions, hepatic damage, immune-he- molytic anemia. Reserpine, an alkaloid from the Rauwolfia plant, abolishes the vesicular storage of biogenic amines (NE, dopa- mine = DA, serotonin = 5-HT) by inhibit- ing an ATPase required for the vesicular amine pump. The amount of NE re- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  19. Drugs Acting on the Sympathetic Nervous System 97 Stimulation of central !2-receptors Suppression of sympathetic !-Methyl-NE impulses in in brain vasomotor center Clonidine Tyrosine Inhibition of Dopa Dopa-decarb- oxylase Dopamine NE !-Methyl-NE !-Methyldopa False transmitter CNS NE 5HT DA Inhibition of biogenic amine storage Peripheral sympathetic activity Reserpine No epinephrine from adrenal medulla Varicosity due to central sedative effect Inhibition of peripheral sympathetic activity Guanethidine Active uptake and storage instead of norepinephrine; not a transmitter Release from adrenal medulla Varicosity unaffected A. Inhibitors of sympathetic tone Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  20. 98 Drugs Acting on the Parasympathetic Nervous System Parasympathetic Nervous System cord. Parasympathetic outflow is chan- nelled from the brainstem (1) through Responses to activation of the para- the third cranial nerve (oculomotor n.) sympathetic system. Parasympathetic via the ciliary ganglion to the eye; (2) nerves regulate processes connected through the seventh cranial nerve (fa- with energy assimilation (food intake, cial n.) via the pterygopalatine and sub- digestion, absorption) and storage. maxillary ganglia to lacrimal glands and These processes operate when the body salivary glands (sublingual, submandib- is at rest, allowing a decreased tidal vol- ular), respectively; (3) through the ume (increased bronchomotor tone) ninth cranial nerve (glossopharyngeal and decreased cardiac activity. Secre- n.) via the otic ganglion to the parotid tion of saliva and intestinal fluids pro- gland; and (4) via the tenth cranial motes the digestion of foodstuffs; trans- nerve (vagus n.) to thoracic and abdom- port of intestinal contents is speeded up inal viscera. Approximately 75 % of all because of enhanced peristaltic activity parasympathetic fibers are contained and lowered tone of sphincteric mus- within the vagus nerve. The neurons of cles. To empty the urinary bladder (mic- the sacral division innervate the distal turition), wall tension is increased by colon, rectum, bladder, the distal ure- detrusor activation with a concurrent ters, and the external genitalia. relaxation of sphincter tonus. Acetylcholine (ACh) as a transmit- Activation of ocular parasympa- ter. ACh serves as mediator at terminals thetic fibers (see below) results in nar- of all postganglionic parasympathetic rowing of the pupil and increased curva- fibers, in addition to fulfilling its trans- ture of the lens, enabling near objects to mitter role at ganglionic synapses with- be brought into focus (accommodation). in both the sympathetic and parasym- Anatomy of the parasympathetic pathetic divisions and the motor end- system. The cell bodies of parasympa- plates on striated muscle. However, dif- thetic preganglionic neurons are located ferent types of receptors are present at in the brainstem and the sacral spinal these synaptic junctions: Localization Agonist Antagonist Receptor Type Target tissues of 2nd ACh Atropine Muscarinic (M) parasympathetic Muscarine cholinoceptor; neurons G-protein-coupled- receptor protein with 7 transmembrane domains Sympathetic & ACh Trimethaphan Ganglionic type parasympathetic Nicotine (!3 "4) ganglia Nicotinic (N) cholinoceptor ligand- gated cation channel formed by five trans- membrane subunits Motor endplate ACh d-Tubocurarine muscular type Nicotine (!12"1#$) The existence of distinct cholino- ses allows selective pharmacological ceptors at different cholinergic synap- interventions. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
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