Tài liệu Color Atlas of Pharmacology (Part 9): Systems Pharmacology pptx

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme... Lüllmann, Color Atlas of Pharmacology © 2000 Thieme... Lüllmann, Color Atlas of Pharmacology © 2000 Thieme... Structure – Activity

Sympathetic Nervous System

In the course of phylogeny an efficient

control system evolved that enabled the

functions of individual organs to be

or-chestrated in increasingly complex life

forms and permitted rapid adaptation

to changing environmental conditions

This regulatory system consists of the

CNS (brain plus spinal cord) and two

separate pathways for two-way

com-munication with peripheral organs, viz.,

the somatic and the autonomic nervous

systems The somatic nervous system

comprising extero- and interoceptive

afferents, special sense organs, and

mo-tor efferents, serves to perceive external

states and to target appropriate body

movement (sensory perception: threat

!response: flight or attack) The

auto-nomic (vegetative) nervous system

(ANS), together with the endocrine

system, controls the milieu interieur It

adjusts internal organ functions to the

changing needs of the organism Neural

control permits very quick adaptation,

whereas the endocrine system provides

for a long-term regulation of functional

states The ANS operates largely beyond

voluntary control; it functions

autono-mously Its central components reside

in the hypothalamus, brain stem, and

spinal cord The ANS also participates in

the regulation of endocrine functions

The ANS has sympathetic and

parasympathetic branches Both are

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

of the sympathetic division can be sidered a means by which the bodyachieves a state of maximal work capac-ity as required in fight or flight situa-tions

con-In both cases, there is a need forvigorous activity of skeletal muscula-ture To ensure adequate supply of oxy-gen and nutrients, blood flow in skeletalmuscle is increased; cardiac rate andcontractility are enhanced, resulting in alarger blood volume being pumped intothe circulation Narrowing of splanchnicblood vessels diverts blood into vascularbeds in muscle

Because digestion of food in the testinal tract is dispensable and onlycounterproductive, the propulsion of in-testinal contents is slowed to the extentthat peristalsis diminishes and sphinc-teric tonus increases However, in order

in-to increase nutrient supply in-to heart andmusculature, glucose from the liver andfree fatty acid from adipose tissue must

be released into the blood The bronchiare dilated, enabling tidal volume andalveolar oxygen uptake to be increased.Sweat glands are also innervated bysympathetic fibers (wet palms due toexcitement); however, these are excep-tional as regards their neurotransmitter(ACh, p 106)

Although the life styles of modernhumans are different from those ofhominid ancestors, biological functionshave remained the same

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Fat tissue:

lipolysisfatty acidliberation

Bladder:

Sphincter tonedetrusor muscle

Skeletal muscle:

blood flowglycogenolysis

A Responses to sympathetic activation

Structure of the Sympathetic Nervous

System

The sympathetic preganglionic neurons

(first neurons) project from the

inter-mediolateral column of the spinal gray

matter to the paired paravertebral

gan-glionic chainlying alongside the

verte-bral column and to unpaired

preverte-bral ganglia. These ganglia represent

sites of synaptic contact between

pre-ganglionic axons (1st neurons) and

nerve cells (2ndneurons or

sympathocy-tes) that emit postganglionic axons

terminating on cells in various end

or-gans In addition, there are

preganglion-ic neurons that project either to

periph-eral ganglia in end organs or to the

ad-renal medulla

Sympathetic Transmitter Substances

Whereas acetylcholine (see p 98)

serves as the chemical transmitter at

ganglionic synapses between first and

second neurons, norepinephrine

(= noradrenaline) is the mediator at

synapses of the second neuron (B) This

second neuron does not synapse with

only a single cell in the effector organ;

rather, it branches out, each branch

making en passant contacts with several

cells At these junctions the nerve axons

form enlargements (varicosities)

re-sembling beads on a string Thus,

excita-tion of the neuron leads to activaexcita-tion of

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

converted via two intermediate steps todopamine, which is taken up into thevesicles and there converted to norepi-nephrine by dopamine-!-hydroxylase.When stimulated electrically, the sym-pathetic nerve discharges the contents

of part of its vesicles, including nephrine, into the extracellular space

norepi-Liberated norepinephrine reacts with adrenoceptors located postjunctionally

on the membrane of effector cells orprejunctionally on the membrane ofvaricosities Activation of presynaptic

"2-receptors inhibits norepinephrinerelease By this negative feedback, re-lease can be regulated

The effect of released rine wanes quickly, because approx

norepineph-90 % is actively transported back intothe axoplasm, then into storage vesicles

(neuronal re-uptake) Small portions of

norepinephrine are inactivated by the

enzyme catechol-O-methyltransferase

(COMT, present in the cytoplasm ofpostjunctional cells, to yield normeta-

nephrine), and monoamine oxidase

(MAO, present in mitochondria of nervecells and postjunctional cells, to yield3,4-dihydroxymandelic acid)

The liver is richly endowed withCOMT and MAO; it therefore contrib-utes significantly to the degradation ofcirculating norepinephrine and epi-nephrine The end product of the com-bined actions of MAO and COMT is van-illylmandelic acid

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B Second neuron of sympathetic system, varicosity, norepinephrine release

A Epinephrine as hormone, norepinephrine as transmitter

First neuron

SecondneuronAdrenal

medulla

NorepinephrineEpinephrine

Normeta-First neuron

Adrenoceptor Subtypes and

Catecholamine Actions

Adrenoceptors fall into three major

groups, designated !1, !2, and ", within

each of which further subtypes can be

distinguished pharmacologically The

different adrenoceptors are

differential-ly distributed according to region and

tissue Agonists at adrenoceptors

(di-rect sympathomimetics) mimic the

ac-tions of the naturally occurring

cate-cholamines, norepinephrine and

epi-nephrine, and are used for various

ther-apeutic effects

Smooth muscle effects The

op-posing effects on smooth muscle (A) of

!-and "-adrenoceptor activation are

due to differences in signal transduction

(p 66) This is exemplified by vascular

smooth muscle (A) !1-Receptor

stimu-lation leads to intracellular release of

Ca2+via activation of the inositol

tris-phosphate (IP3) pathway In concert

with the protein calmodulin, Ca2+can

activate myosin kinase, leading to a rise

in tonus via phosphorylation of the

con-tractile protein myosin cAMP inhibits

activation of myosin kinase Via the

for-mer effector pathway, stimulation of

!-receptors results in vasoconstriction;

via the latter, "2-receptors mediate

va-sodilation, particularly in skeletal

mus-cle — an effect that has little therapeutic

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

with a resultant drop in systemic bloodpressure results in reflex tachycardia,which is also due in part to the "1-stim-ulant action of these drugs

Cardiostimulation By stimulating

"1-receptors, hence activation of nylatcyclase (Ad-cyclase) and cAMPproduction, catecholamines augment all

ade-heart functions, including systolic force (positive inotropism), velocity of short- ening (p clinotropism), sinoatrial rate (p chronotropism), conduction velocity (p dromotropism), and excitability (p.

bathmotropism) In pacemaker fibers,

diastolic depolarizationis hastened, sothat the firing threshold for the actionpotential is reached sooner (positive

chronotropic effect, B) The

cardiostim-ulant effect of "-sympathomimeticssuch as epinephrine is exploited in thetreatment of cardiac arrest Use of "-sympathomimetics in heart failure car-ries the risk of cardiac arrhythmias

Metabolic effects "-Receptors

me-diate increased conversion of glycogen to glucose (glycogenolysis) in both liver

and skeletal muscle From the liver, cose is released into the blood, In adi-pose tissue, triglycerides are hydrolyzed

glu-to fatty acids (lipolysis, mediated by

"3-receptors), which then enter the blood

(C) The metabolic effects of

catechola-mines are not amenable to therapeuticuse

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Membrane potential (mV)

Time

B Cardiac effects of catecholamines

A Vasomotor effects of catecholamines

Glucose

Lipolysis

Fatty acidsGlycogenolysis

Structure – Activity Relationships of

Sympathomimetics

Due to its equally high affinity for all

!-and "-receptors, epinephrine does not

permit selective activation of a

particu-lar receptor subtype Like most

cate-cholamines, it is also unsuitable for oral

administration (catechol is a trivial

name for o-hydroxyphenol)

Norepi-nephrine differs from epiNorepi-nephrine by its

high affinity for !-receptors and low

af-finity for "2-receptors In contrast,

iso-proterenol has high affinity for

"-recep-tors, but virtually none for !-receptors

relationships has permitted the

syn-thesis of sympathomimetics that

dis-play a high degree of selectivity at

adrenoceptor subtypes

Direct-acting sympathomimetics

(i.e., adrenoceptor agonists) typically

share a phenylethylamine structure The

side chain "-hydroxyl group confers

af-finity for !- and "-receptors

Substitu-tion on the amino groupreduces affinity

for !-receptors, but increases it for

"-re-ceptors (exception: !-agonist

phenyl-ephrine), with optimal affinity being

seen after the introduction of only one

isopropyl group Increasing the bulk of

the amino substituent favors affinity for

"2-receptors (e.g., fenoterol,

salbuta-mol) Both hydroxyl groups on the

aro-matic nucleus contribute to affinity;

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, terbuta(orciprena-line, 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-catecholamine congeners can be givenorally and can exert CNS actions; how-ever, this structural change entails a loss

An altered position of aromatic droxyl groups (e.g., in orciprenaline, fe-noterol, or terbutaline) or their substi-tution (e.g., salbutamol) protects

hy-against inactivation by COMT (p 82)

In-droduction of a small alkyl residue atthe carbon atom adjacent to the aminogroup (ephedrine, methamphetamine)

confers resistance to degradation by MAO(p 80), as does replacement on theamino groups of the methyl residuewith larger substituents (e.g., ethyl inetilefrine) Accordingly, the congenersare less subject to presystemic inactiva-tion

Since structural requirements forhigh affinity, on the one hand, and oralapplicability, on the other, do notmatch, choosing a sympathomimetic is

a matter of compromise If the high finity of epinephrine is to be exploited,absorbability from the intestine must beforegone (epinephrine, isoprenaline) Ifgood bioavailability with oral adminis-tration is desired, losses in receptor af-finity must be accepted (etilefrine)

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B Structure-activity relationship of epinephrine derivatives

A Chemical structure of catecholamines and affinity for !- and "-receptors

Epinephrine

Receptor affinity

O-methyltransferase

Catecholamine-Monoamine oxidase

(Enteral absorbability

CNS permeability)

Metabolic stability

Etilefrine Ephedrine MethamphetamineEpinephrine Orciprenaline Fenoterol

Affinity for !-receptors

Affinity for "-receptors

Resistance to degradationAbsorbability

Indirectaction

Penetrability

through

membrane

barriers

Indirect Sympathomimetics

Apart from receptors, adrenergic

neu-rotransmission 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

al-terations of the catecholamine

differen-tially affect these properties and result

in substances with selective actions

Inhibitors of MAO (A) The enzyme

is located predominantly on

mitochon-dria, and serves to scavenge axoplasmic

free NE Inhibition of the enzyme causes

free NE concentrations to rise Likewise,

dopamine catabolism is impaired,

mak-ing 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

af-fects neuronal storage not only of NE

but also of dopamine and serotonin

These mediators probably play

signifi-cant roles in CNS functions consistent

with the stimulant effects of MAO

inhib-itors on mood and psychomotor drive

and their use as antidepressants in the

treatment of depression (A)

Tranylcy-promineis 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 MAOAand 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 juncconcentra-tions,

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-sicular stores of NE close to the

axolem-ma are depleted

Indirect sympathomimetics canpenetrate the blood-brain barrier andevoke such CNS effects as a feeling ofwell-being, enhanced physical activity

and mood (euphoria), and decreased

sense of hunger or fatigue

Subsequent-ly, the user may feel tired and pressed These after effects are partlyresponsible for the urge to re-adminis-ter the drug (high abuse potential) Toprevent their misuse, these substancesare subject to governmental regulations(e.g., Food and Drugs Act: Canada; Con-trolled Drugs Act: USA) restricting theirprescription and distribution.When amphetamine-like substanc-

de-es are misused to enhance athletic

per-formance (doping), there is a risk of

dan-gerous physical overexertion Because

of the absence of a sense of fatigue, adrugged athlete may be able to mobilizeultimate energy reserves In extremesituations, cardiovascular failure may

result (B).

Closely related chemically to phetamine are the so-called appetitesuppressants or anorexiants, such asfenfluramine, mazindole, and sibutra-mine These may also cause dependenceand their therapeutic value and safetyare questionable

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ControlledSubstancesAct regulatesuse ofcocaine andamphetamine

B Indirect sympathomimetics with central stimulant activity and abuse potential

A Monoamine oxidase inhibitor

Nor-epinephrine

Norepinephrinetransport system

!-Sympathomimetics,

!-Sympatholytics

!-Sympathomimetics can be used

systemicallyin certain types of

hypoten-sion (p 314) and locally for nasal or

con-junctival decongestion (pp 324, 326) or

as adjuncts in infiltration anesthesia (p

206) for the purpose of delaying the

re-moval 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

append-ages (e.g., digits, toes, ears) are

particu-larly vulnerable in this regard, thus

pre-cluding vasoconstrictor adjuncts in

in-filtration anesthesia at these sites

Vasoconstriction induced by an

!-sympathomimetic is followed by a

phase of enhanced blood flow (reactive

hyperemia, A) This reaction can be

ob-served after the application of

!-sympa-thomimetics (naphazoline,

tetrahydro-zoline, xylometazoline) to the nasal

mu-cosa Initially, vasoconstriction reduces

mucosal blood flow and, hence,

capil-lary pressure Fluid exuded into the

interstitial space is drained through the

veins, thus shrinking the nasal mucosa

Due to the reduced supply of fluid,

se-cretion of nasal mucus decreases In

co-ryza, nasal patency is restored

Howev-er, after vasoconstriction subsides,

reac-tive hyperemia causes renewed

exuda-tion 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

!-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-and prejunctional !-adrenoceptors

(non-selective !-blockers, e.g.,

phen-oxybenzamine, phentolamine).Presynaptic !2-adrenoceptors func-tion like sensors that enable norepi-nephrine concentration outside theaxolemma to be monitored, thus regu-lating its release via a local feedbackmechanism When presynaptic !2-re-ceptors are stimulated, further release

of norepinephrine is inhibited versely, their blockade leads to uncon-trolled release of norepinephrine with

Con-an overt enhCon-ancement of sympatheticeffects at #1-adrenoceptor-mediatedmyocardial neuroeffector junctions, re-sulting in tachycardia and tachyar-rhythmia

Selective !-Sympatholytics

!-Blockers, such as prazosin, or the

longer-acting terazosin and doxazosin,lack affinity for prejunctional !2-adren-oceptors They suppress activation of

!1-receptors without a concomitant hancement of norepinephrine release

en-!1-Blockers may be used in tension (p 312) Because they preventreflex vasoconstriction, they are likely

hyper-to cause postural hypotension withpooling of blood in lower limb capaci-tance veins during change from the su-pine to the erect position (orthostaticcollapse: " venous return, " cardiac out-put, fall in systemic pressure, " bloodsupply to CNS, syncope, p 314)

In benign hyperplasia of the tate, !-blockers (terazosin, alfuzosin)may serve to lower tonus of smoothmusculature in the prostatic region andthereby facilitate micturition (p 252)

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C Indications for !1 -sympatholytics

A Reactive hyperemia due to !-sympathomimetics, e.g., following decongestion

of nasal mucosa

B Autoinhibition of norepinephrine release and !-sympatholytics

O2 supply < O2 demand O2 supply = O2 demand

H 3 CO

O O

H 3 CO

NH 2

N

N N NHigh blood pressure Benignprostatic hyperplasia

Inhibition of

!1-adrenergicstimulation ofsmooth muscle Neck of bladder,prostateResistance

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 amarked fall in cardiac rate as well as todisorders of impulse conduction fromthe atria to the ventricles

Bronchial asthma: Increased 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-receptorblockade will precipitate acute respira-

sym-tory distress (B).

Hypoglycemia in diabetes mellitus:

When treatment with insulin or oral poglycemics in the diabetic patient low-ers blood glucose below a critical level,epinephrine is released, which thenstimulates hepatic glucose release viaactivation of !2-receptors !-Blockerssuppress this counter-regulation; in ad-dition, they mask other epinephrine-mediated warning signs of imminenthypoglycemia, such as tachycardia andanxiety, thereby enhancing the risk ofhypoglycemic shock

hy-Altered vascular responses: When

!2-receptors are blocked, the ing effect of epinephrine is abolished,leaving the "-receptor-mediated vaso-constriction unaffected: peripheralblood flow # – “cold hands and feet”

vasodilat-!-Blockers exert an “anxiolytic“

action that may be due to the sion of somatic responses (palpitations,trembling) to epinephrine release that

suppres-is induced by emotional stress; in turn,these would exacerbate “anxiety” or

“stage fright” Because alertness is notimpaired by !-blockers, these agents areoccasionally taken by orators and musi-

cians before a major performance (C).

Stage fright, however, is not a diseaserequiring drug therapy

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