It is important to remember this because patients have died in the hands of doctors who have forgotten or been ignorant of it.3 Adrenoceptor agonists Table 22.1 + effects, nonselective:
Trang 1Adrenergic mechanisms and drugs
SYNOPSIS
Anyone who administers drugs acting on
cardiovascular adrenergic mechanisms requires
an understanding of how they act in order to
use them to the best advantage and with safety.
Adrenergic mechanisms
Classification of sympathomimetics: by mode
of action and selectivity for adrenoceptors
Individual sympathomimetics
Mucosal decongestants
Shock
Chronic orthostatic hypotension
Adrenergic mechanisms
The discovery in 1895 of the hypertensive effect of
adrenaline (epinephrine) was initiated by Dr Oliver,
a physician in practice, who conducted a series of
experiments on his young son into whom he injected
an extract of bovine suprarenal The effect was
confirmed in animals and led eventually to the
iso-lation and synthesis of adrenaline in the early 1900s
Many related compounds were examined and, in
1910, Barger and Dale invented the word
sympatho-mimetic1 and also pointed out that noradrenaline
(norepinephrine) mimicked the action of the
sympathetic nervous system more closely than did
adrenaline
Adrenaline, noradrenaline and dopamine are formed in the body and are used in therapeutics The natural synthetic path is:
tyrosine —> dopa —> dopamine —> noradrenaline —> adrenaline
Classification of sympathomimetics
BY MODE OF ACTION
Noradrenaline is synthesised and stored in adrenergic nerve terminals and can be released from these stores
by stimulating the nerve or by drugs (ephedrine, amfetamine) These noradrenaline stores may be replenished by i.v infusion of noradrenaline, and abolished by reserpine or by cutting the sympathetic neuron
Sympathomimetics may be classified as those that act:
1 directly: adrenoceptor agonists, e.g adrenaline,
1 'Compounds which simulate the effects of sympathetic nerves not only with varying intensity but with varying precision a term seems needed to indicate the types of action common to these bases We propose to call it
"sympathomimetic" A term which indicates the relation of the action to innervation by the sympathetic system, without involving any theoretical preconception as to the meaning of that relation or the precise mechanism of the action/ Barger
G, Dale H H 1910 Journal of Physiology XLI: 19-50.
447
Trang 222 A D R E N E R G I C M E C H A N I S M S A N D D R U G S
noradrenaline, isoprenaline (isoproterenol),
methoxamine, xylometazoline, oxymetazoline,
metaraminol (entirely); and dopamine and
phenylephrine (mainly)
2 indirectly: by causing a release of noradrenaline
from stores at nerve endings, e.g
amphetamines, tyramine; and ephedrine
(largely)
3 by both mechanisms (1 and 2, though often
with a preponderance of one or other): other
synthetic agents.
Tachyphylaxis (rapidly diminishing response to
repeated administration) is a particular feature of
group 2 drugs It reflects depletion of the 'releasable'
pool of noradrenaline from adrenergic nerve
ter-minals that makes these agents less suitable as, for
example, pressor agents than drugs of group 1
Longer-term tolerance (see p 95) to the effects direct
sympathomimetics is much less of a clinical
problem and reflects an alteration in adrenergic
receptor density or coupling to second messenger
systems
Interactions of sympathomimetics with other
vasoactive drugs are complex Some drugs block
the reuptake mechanism for noradrenaline in
adre-nergic nerve terminals and potentiate the pressor
effects of noradrenaline e.g cocaine, tricyclic
anti-depressants or highly noradrenaline-selective
re-uptake inhibitors such as roboxetine Others
de-plete or destroy the intracellular stores within
adrenergic nerve terminals (e.g reserpine and
guanethidine) and thus block the action of indirect
sympathomimetics
Sympathomimetics are also generally optically
active drugs, with only one stereoisomer conferring
most of the clinical efficacy of the racemate: for
instance laevo-noradrenaline is at least 50 times as
active as the dextro- form Noradrenaline, adrenaline
and phenylephrine are all used clinically as their
laevo-isomers
History Up to 1948 it was known that the peripheral
motor (vasoconstriction) effects of adrenaline were
preventable and that the peripheral inhibitory
(vasodilatation) and the cardiac stimulant actions
were not preventable by the then available
antag-onists (ergot alkaloids, phenoxybenzamine) That
same year, Ahlquist hypothesised that this was due
to two different sorts of adrenoceptors (a and (3) For a further 10 years, only antagonists of a-receptor effects (a-adrenoceptor block) were known, but in
1958 the first substance selectively and competitively
to prevent p-receptor effects ((3-adrenoceptor block), dichloroisoprenaline, was synthesised It was, how-ever, unsuitable for clinical use because it behaved
as a partial agonist, and it was not until 1962 that pronethalol (an isoprenaline analogue) became the first (3-adrenoceptor blocker to be used clinically Unfortunately it had a low therapeutic index and was carcinogenic in mice, and was soon replaced by propranolol (Inderal)
It is evident that the site of action has an important role in selectivity, e.g drugs that act on end-organ
receptors directly and stereospecifically may be highly selective, whereas drugs that act indirectly by
discharging noradrenaline indiscriminately from nerve endings, e.g amfetamine, will have a wider range of effects
Subclassification of adrenoceptors is shown in Table 22.1
Consequences of adrenoceptor activation
All adrenoceptors are members of the G-coupled family of receptor proteins i.e the receptor is coupled
to its effector protein through special transduction proteins called G-proteins (themselves a large protein family) The effector protein differs amongst adreno-ceptor subtypes In the case of [3-adrenoadreno-ceptors, the effector is adenylyl cyclase and hence cyclic AMP is the second messenger molecule For oc-adrenoceptors, phospholipase C is the commonest effector protein and the second messenger here is IP3 It is the cascade
of events initiated by the second messenger mole-cules that produces the variety of tissue effects as shown in Table 22.1 It should be clear that specifi-city is provided by the receptor subtype, not the messengers
Complexity of adrenergic mechanisms
Drugs may mimic or impair adrenergic mechanisms:
• directly, by binding on adrenoceptors: as agonists
(adrenaline) or antagonists (propranolol)
Trang 3C L A S S I F I C A T I O N OF S Y M PAT H O M I M E T I C S 22
TABLE 22 1 Clinically relevant aspects of adrenoceptor functions and actions of agonists
ctj-adrenoceptor effects' ( -adrenoceptor effects
Eye: 2 mydriasis Heart (( , 2 ) 3
increased rate (SA node) increased automaticity (AV node and muscle) increased velocity in conducting tissue increased contractility of myocardium increased O 2 consumption decreased refractory period of all tissues
Arterioles: Arterioles:
constriction (only slight in coronary and cerebral) dilatation ( 2 )
Bronchi ( 2 ): relaxation Anti-inflammatory effect:
inhibition of release of autacoids (histamine, leukotrienses) from mast cells, e.g asthma in type 1
allergy Uterus: contraction (pregnant) Uterus ( 2 ): relaxation (pregnant)
Skeletal muscle: tremor ( 2 ) Skin: sweat, pilomotor
Male ejaculation
Blood platelet: aggregation
Metabolic effect: hyperkalaemia Metabolic effects:
hypokalaemia ( 2 ) hepatic glycogenolysis ( 2 ) lipolysis , )
Bladder sphincter: Bladder detrusor: relaxation
contraction
Intestinal smooth muscle relaxation is mediated by a- and -adrenoceptors.
2 -adrenoceptor effects: 1 2 -receptors on the nerve ending i.e presynaptic autoreceptors mediate negative feedback which inhibits noradrenaline release.
1 For the role of subtypes ( , and 2 ) see prazosin.
2 Effects on intraocular pressure involve both a- and P-adrenoceptors as well as cholinoceptors.
3 Cardiac -receptors mediate effects of sympathetic nerve stimulation Cardiac 2 -receptors mediate effects of circulating adrenaline, when this is secreted at a sufficient rate, e.g following a myocardial infarction or in heart failure Both receptors are coupled to the same 'ntracellular signalling pathway (cyclic AMP production) and mediate the same biological effects.
The use of the term cardioselective to mean , -receptor selective only, especially in the case of -receptor blocking drugs, is no longer appropriate Although in most species the -receptor is the only cardiac -receptor, this is not the case in humans What is not generally appreciated is that the endogenous sympathetic neurotransmitter, noradrenaline, has about a 20-fold selectivity for the -receptor — similar to that of the antagonist, atenolol — with the consequence that under most circumstances, in most tissues, there is little or no 2 -receptor stimulation to be affected by a nonselective -blocker.Why asthmatics should be so sensitive to -blockade is paradoxical: all the bronchial -receptors are 2 , and the bronchi themselves are not innervated by adrenergic fibres; the circulating adrenaline levels are, if anything, low in asthma.
• indirectly, by discharging noradrenaline stored in • by preventing the destruction of noradrenaline (and
• by preventing reuptake into the adrenergic nerve oxidase inhibitors)
ending of released noradrenaline (and • by depleting the stores of noradrenaline in nerve
dopamine) (cocaine, tricyclic antidepressants endings (reserpine)
and noradrenaline-selective reuptake inhibitors • by preventing the release of noradrenaline from
such as roboxetine) nerve endings in response to a nerve impulse
(guanethidine)
2 Fatal hypertension can occur when this class of agent is • fy activation of adrenoceptors on adrenergic
taken by a patient treated with monoamine oxidase inhibitor nerve endings that inhibit release of
Trang 422 A D R E N E R G I C M E C H A N I S M S A N D D R U G S
noradrenaline ( 2~autoreceptors)
(clonidine)
• by blocking sympathetic autonomic ganglia
(trimetaphan)
All the above mechanisms operate in both the
central and peripheral nervous systems This
dis-cussion is chiefly concerned with agents that
influence peripheral adrenergic mechanisms
SELECTIVITY FOR ADRENOCEPTORS
The following classification of sympathomimetics
and antagonists is based on selectivity for receptors
and on use But selectivity is relative, not absolute;
some agonists act on both a- and -receptors, some
are partial agonists and, if enough is administered,
many will extend their range The same applies to
selective antagonists (receptor blockers), e.g a 1
-selective adrenoceptor blocker can cause severe
exacerbation of asthma (a 2 effect) even at low
dose It is important to remember this because
patients have died in the hands of doctors who
have forgotten or been ignorant of it.3
Adrenoceptor agonists (Table 22.1)
+ effects, nonselective: adrenaline is used as a
vasoconstrictor (a) with local anaesthetics, as a
mydriatic and in the emergency treatment of
anaphylactic shock, for which condition it has the
right mix of effects (bronchodilator, positive cardiac
inotropic, vasoconstriction at high dose)
otj effects: noradrenaline (with slight effect on heart)
is selectively released physiologically where it is
wanted; as therapeutic agents for hypotensive
states (excepting septic shock) dopamine and
dobutamine are preferred (for their cardiac
inotropic effect) Also having predominantly 1
effects are imidazolines (xylometazoline,
oxymeta-3 While it is simplest to regard the selectivity of a drug as
relative, being lost at higher doses, strictly speaking it is the
benefits of the receptor selectivity of an agonist or antagonist,
which are dose-dependent A 10-fold selectivity of an agonist
at the 1 -receptor, for instance, is a property of the agonist
that is independent of dose, and means simply that 10 times
less of the agonist is required to activate this receptor
compared to the 2 -subtype.
zoline), metaraminol, phenylephrine, phen-ylpropanolamine, ephedrine, pseudoephedrine: some are used solely for topical vasoconstriction (nasal decongestants)
2 effects in the central nervous system: clonidine.
effects, nonselective (i.e. 1 + 1): isoprenaline
(isoproterenol) Its uses as bronchodilator ( 2), for positive cardiac inotropic effect and to enhance conduction in heart block ( 1, 2) have been largely superseded by agents with a more appropriately selective profile of effects Other agents with non-selective effects, ephedrine, orciprenaline, are also obsolete for asthma
1 effects, with some a effects: dopamine, used in
cardiogenic shock
1 effects: dobutamine, used for cardiac inotropic
effect
2 effects, used in asthma, or to relax the uterus,
include: salbutamol, terbutaline, fenoterol, pirbuterol, reproterol, rimiterol, isoxsuprine, orciprenaline, rit-odrine
Adrenoceptor antagonists (blockers)
See page 474
Effects of a sympathomimetic
The overall effect of a sympathomimetic depends on
the site of action (receptor agonist or indirect action),
on receptor specificity and on dose; for instance
adre-naline ordinarily dilates muscle blood vessels ( 2; mainly arterioles, but veins also) but in very large doses constricts them (a) The end results are often complex and unpredictable, partly because of the variability of homeostatic reflex responses and partly because what is observed, e.g a change in blood pressure, is the result of many factors, e.g vasodilatation ( ) in some areas, vasoconstriction (a) in others, and cardiac stimulation ( )
To block all the effects of adrenaline and nor-adrenaline, antagonists for both a- and -receptors must be used This can be a matter of practical importance, e.g in phaeochromocytoma (see p 495)
Trang 5C L A S S I F I C A T I O N OF S Y M P AT H O M I M E T I C S 22
Physiological note The termination of action of
noradrenaline released at nerve endings is by:
• reuptake into nerve endings where it is stored
and also subject to MAO degradation
• diffusion away from the area of the nerve ending
and the receptor (junctional cleft)
• metabolism (by extraneuronal MAO and
COMT)
These processes are slower than the very swift
destruction of acetylcholine at the neuromuscular
junction by extracellular acetylcholinesterase seated
alongside the receptors This difference reflects the
differing signalling requirements: almost
instan-taneous (millisecond) responses for voluntary muscle
movement versus the much more leisurely
con-traction of arteriolar muscle to control vascular
resistance
Synthetic noncatecholamines in clinical use have
t// of hours, e.g salbutamol 4h, because they are
more resistant to enzymatic degradation and
conjugation They may be given orally although
much higher doses are required They penetrate the
central nervous system and may have prominent
effects, e.g amphetamine Substantial amounts
appear in the urine
Pharmacokinetics
Catecholamines (adrenaline, noradrenaline,
dopa-mine, dobutadopa-mine, isoprenaline) (plasma t1/2 approx
2 min) are metabolised by two enzymes, monoamine
oxidase (MAO) and catechol-O-methyltransferase
(COMT) These enzymes are present in large amounts
in the liver and kidney and account for most of the
metabolism of injected catecholamines MAO is
also present in the intestinal mucosa (and in nerve
endings, peripheral and central) Because of these
enzymes catecholamines are ineffective when
swallowed, but noncatecholamines, e.g salbutamol,
amphetamine, are effective orally
a result of leakage from i.v infusions The effects on the heart ( 1) include tachycardia, palpitations, cardiac arrhythmias including ventricular tachy-cardia and fibrillation, and muscle tremor (( 2) Sym-pathomimetic drugs should be used with great caution in patients with heart disease
The effect of the sympathomimetic drugs on the pregnant uterus is variable and difficult to predict, but serious fetal distress can occur, due to reduced placental blood flow as a result both of contraction
of the uterine muscle (a) and arterial constriction (a). 2-agonists are used to relax the uterus in pre-mature labour, but unwanted cardiovascular actions can be troublesome Sympathomimetics were parti-cularly likely to cause cardiac arrhythmias ( 1 effect)
in patients who received halothane anaesthesia (now much less used)
Sympathomimetics and plasma potassium.
Adrenergic mechanisms have a role in the physio-logical control of plasma potassium concentration The biochemical pump that shifts potassium into cells is activated by the ( 2-adrenoceptor agonists (adrenaline, salbutamol, isoprenaline) and can cause hypokalaemia. 2-adrenoceptor antagonists block the effect
The hypokalaemia effects of administered ( 2) Sympathomimetics may be clinically important, particularly in patients having pre-existing hypo-kalaemia, e.g due to intense adrenergic activity such as occurs in myocardial infarction,4 in fright (admission to hospital is accompanied by transient hypokalaemia), or with previous diuretic therapy, and taking digoxin In such subjects the use of a sympathomimetic infusion or of an adrenaline-containing local anaesthetic may precipitate a cardiac arrhythmia Hypokalaemia may occur during treatment of severe asthma, particularly where the 2-receptor agonist is combined with theophylline
-adrenoceptor blockers, as expected, enhance the hyperkalaemia of muscular exercise; and one of their benefits in preventing cardiac arrhythmias
Adverse effects
These may be deduced from their actions (Table
22.1, Fig 22.1) Tissue necrosis due to intense
vasoconstriction (a) around injection sites occurs as
4 Normal subjects, infused i.v with adrenaline in amounts that approximate to those found in the plasma after severe myocardial infarction, show a fall in plasma K of about 0.8 mmol/1 (Brown M J 1983 New England Journal of Medicine 309:1414).
Trang 622 ADRENERGIC M E C H A N I S M S A N D DRUGS
Fig 22.1 Cardiovascular effects of noradrenaline (norepinephrine), adrenaline
(epinephrine) and isoprenaline (isoproterenol): pulse rate/min, blood pressure in mmHg (dotted line is mean pressure), peripheral resistance in arbitrary units.The differences are due to the differential a and agonist selectivities of these agents (see text) (By permission,after GinsburgJ,Cobbold A F I960 InrVane J R et al (eds) Adrenergic mechanism Churchill, London)
after myocardial infarction may be due to block of
2-receptor-inducedhypokalaemia
Overdose of sympathomimetics is treated according
to rational consideration of mode and site of action
(see Adrenaline, below)
Individual
sympathomimetics
The actions are summarised in Table 22.1 The classic,
mainly endogenous substances will be described first
despite their limited role in therapeutics, and then
the more selective analogues that have largely
replaced them
CATECHOLAMINES 5
For pharmacokinetics, see above
Adrenaline (epinephrine)
Adrenaline ( - and -adrenoceptor effects) is used:
• as a vasoconstrictor with local anaesthetics (1:80 000 or weaker) to prolong their effects (about 2-fold)
• as a topical mydriatic (sparing accommodation;
it also lowers intraocular pressure)
• for severe allergic reactions, i.m., i.v (or s.c.) The route must be chosen with care For adults, adrenaline 500 micrograms (i.e 0.5 ml of the 1 in
1000 solution) may be given i.m and repeated
5 Traditionally catecholamines have had a dual nomenclature
(as a consequence of a company patenting the name
Adrenalin), broadly European and N American The latter has been chosen by the World Health Organization as International Nonproprietary Names (INN) (see Ch 6), and the European Union has directed member states to use INN Because uniformity has not yet been achieved and because of the scientific literature, we use both.
For pharmacokinetics, see above.
Trang 7at 5-min intervals according to the response
(see Ch 8, p 143) If the circulation is
compromised to a degree that is immediately
life-threatening, adrenaline 500 micrograms
may be given by slow i.v injection at a rate of
100 micrograms/min (i.e 1 ml/min of the
dilute 1 in 10 000 solution) with continuous
monitoring of the ECG This course requires
extreme caution and use of a further x 10
dilution (i.e a 1 in 100 000 solution) may be
preferred as providing finer control and greater
safety The s.c route is generally not
recommended as there is intense
vasoconstriction, which slows absorption
Adrenaline is used in anaphylactic shock because
its mix of actions, cardiovascular and bronchial,
provide the best compromise for speed and
sim-plicity of use in an emergency; it may also stabilise
mast cell membranes and reduce release of
vaso-active autacoids (see p 280) Patients who are
taking nonselective -blockers may not respond to
adrenaline (use salbutamol i.v.) and indeed may
develop severe hypertension (see below)
Adrenaline (topical) decreases intraocular pressure
in chronic open-angle glaucoma, as does dipivefrine,
an adrenaline ester prodrug They are
contra-indicated in closed-angle glaucoma because they
are mydriatics Hyperthyroid patients are intolerant
of adrenaline
Accidental overdose with adrenaline occurs
occasionally It is rationally treated by propranolol
to block the cardiac effects (cardiac arrhythmia)
and phentolamine or chlorpromazine to control the
a effects on the peripheral circulation that will be
prominent when the (3 effects are abolished Labetalol
( + block) would be an alternative p-adrenoceptor
block alone is hazardous as the then unopposed
ot-receptor vasoconstriction causes (severe)
hyper-tension (see Phaeochromocytoma, p 494) Use of
antihypertensives of most other kinds is irrational
and some may also potentiate the adrenaline
Noradrenaline (norepinephrine) (chiefly OL
and , effects)
The main effect of administered noradrenaline is to
raise the blood pressure by constricting the arterioles
I N D I V I D U A L S Y M P A T H O M I M E T I C S
and so raising the total peripheral resistance, with reduced blood flow (except in coronary arteries which have few 1-receptors) Though it does have some cardiac stimulant ( a) effect, the tachycardia
of this is masked by the profound reflex bradycardia caused by the hypertension Noradrenaline is given
by i.v infusion to obtain a gradual sustained response; the effect of a single i.v injection would last only a minute or so It is used where peripheral vaso-constriction is specifically desired, e.g vasodilation
of septic shock Adverse effects include peripheral gangrene and local necrosis; tachyphylaxis occurs and withdrawal must be gradual
Isoprenaline (isoproterenol)
Isoprenaline (isopropylnoradrenaline) is a non-selective (3-receptor agonist, i.e it activates both Pj-and P2-receptors It relaxes smooth muscle, including that of the blood vessels, has negligible metabolic or vasoconstrictor effects, but a vigorous stimulant effect on the heart This latter is its main dis-advantage in the treatment of bronchial asthma Its principal uses are in complete heart block and occasionally in cardiogenic shock (hypotension)
Dopamine
Dopamine activates different receptors depending
on the dose used At the lowest effective dose it stimulates specific dopamine (Da) receptors in the CNS and the renal and other vascular beds (dilator);
it also activates presynaptic autoreceptors (D2) which suppress release of noradrenaline As dose is raised, dopamine acts as an agonist on P^adrenoceptors in the heart (increasing contractility and rate); at high doses it activates a-adrenoceptors (vasoconstrictor) It
is given by continuous i.v infusion because, like all
catecholamines, its i l / 2 is short (2 min) An i.v in-fusion (2-5 micrograms/kg/min) increases renal blood flow (partly through an effect on cardiac out-put) As the dose rises the heart is stimulated, resulting in tachycardia and increased cardiac out-put At these higher doses, dopamine is referred to
as an 'inoconstrictor'
Dopamine is stable for about 24 h in sodium chloride or dextrose Subcutaneous leakage causes vasoconstriction and necrosis and should be treated
by local injection of an a-adrenoceptor blocking agent (phentolamine 5 mg, diluted)
Trang 822 A D R E N E R G I C M E C H A N I S M S A N D D R U G S
It may be mixed with dobutamine
For CNS aspects of dopamine, agonists and
antagonists: see Neuroleptics, Parkinsonism
Dobutamine
Dobutamine is a racernic mixture of d- and
1-dobutamine The racemate behaves primarily a 1
adrenoceptor agonist with greater inotropic than
chronotropic effects on the heart; it has some
-agonist effect, but less than dopamine It is useful in
shock (with dopamine) and in low output heart
failure (in the absence of severe hypertension)
Dopexamine
Dopexamine is a synthetic catecholamine whose
principal action is as an agonist for the cardiac 2
-adrenoceptors (positive inotropic effect) It is also a
weak dopamine agonist (thus causing renal
vasodilatation) and inhibitor of noradrenaline
uptake thereby enhancing stimulation of cardiac 1
-receptors by noradrenaline It is used occasionally
to optimise the cardiac output, particularly
perioperatively
NONCATECHOLAMINES
Salbutamol, fenoterol, rimiterol, reproterol,
pir-buterol, salmeterol, ritodrine and terbutaline are
fi-adrenoceptor agonists that are relatively selective for
2-receptors, so that cardiac (chiefly 1-receptor)
effects are less prominent Tachycardia still occurs
because of atrial (sinus node) 2-receptor stimulation;
the 2-adrenoceptors are less numerous in the
ventricle and there is probably less risk of serious
ventricular arrhythmias than with the use of
nonselective catecholamines The synthetic agonists
are also longer-acting than isoprenaline because they
are not substrates for catechol-O-methyltransferase,
which methylates catecholamines in the liver They
are used principally in asthma, and to reduce
uterine contractions in premature labour
Salbutamol (see also Asthma)
Salbutamol (Ventolin) (t1/2 4h) is taken orally,
2-4 mg up to 4 times/day; it also acts quickly by
inhalation and the effect can last as long as 4h,
which makes it suitable for both prevention and treatment of asthma Of an inhaled dose < 20% is absorbed and can cause cardiovascular effects It can also be given by injection, e.g in asthma, premature labour 2-receptor) and for cardiac inotropic ( 1) effect in heart failure (where the ( 2 vasodilator action is also useful) Clinically imp-ortant hypokalaemia can also occur (the shift of potassium into cells) The other drugs above are similar
Salmeterol (Serevent) is a variant of salbutamol that has additional binding property to a site adjacent to the 2-adrenoceptor, which results in slow onset and long duration of action (about 12 h) (see p 560)
Ephedrine
Ephedrine (t l / 2 approx 4 h) is a plant alkaloid with indirect sympathomimetic actions that resemble adrenaline peripherally Centrally (in adults) it pro-duces increased alertness, anxiety, insomnia, tremor and nausea; children may be sleepy when taking it
In practice central effects limit its use as a sym-pathomimetic in asthma
Ephedrine is well absorbed when given orally and, unlike most other sympathomimetics, under-goes relatively little first-pass metabolism in the liver; it is largely excreted unchanged by the kidney
It is usually given by mouth but can be injected It differs from adrenaline principally in that its effects come on more slowly and last longer Tachyphylaxis occurs on repeated dosing Ephedrine can be used
as a bronchodilator, in heart block, as a mydriatic and as a mucosal vasoconstrictor, but newer drugs, which are often better for these purposes, are dis-placing it It is sometimes useful in myasthenia gravis (adrenergic agents enhance cholinergic
neuro-muscular transmission) Pseudoephedrine is similar.
Phenylpropanolamine (norephedrine) is similar
but with less CNS effect Prolonged administration
of phenylpropanolamine to women as an anorectic has been associated with pulmonary valve abnor-malities and led to its withdrawal in some countries
Amfetamine (Benzedrine) and dexamphetamine
(Dexedrine) act indirectly They are seldom used for their peripheral effects, which are similar to those of
Trang 9S H O C K 22
ephedrine, but usually for their effects on the central
nervous system (narcolepsy, attention deficit in
children) (For a general account of amphetamine,
see p 193)
Phenylephrine has actions qualitatively similar to
noradrenaline but a longer duration of action, up to
an hour or so It can be used as a nasal decongestant
(0.25-0.5% solution), but sometimes irritates In the
doses usually given, the central nervous effects are
minimal, as are the direct effects on the heart It is
also used as a mydriatic and briefly lowers
intraocular pressure
Mucosal decongestants
Nasal and bronchial decongestants (vasoconstrictors)
are widely used in allergic rhinitis, colds, coughs
and sinusitis, and to prevent otitic barotrauma, as
nasal drops or nasal sprays All the sympathomimetic
vasoconstrictors, i.e with a effects, have been used
for the purpose, with or without an antihistamine
(Hj-receptor), and there is little to choose between
them Ischaemic damage to the mucosa is possible if
they are used excessively (more often than 3-hourly)
or for prolonged periods (> 3 weeks) The occurrence
of rebound congestion is also liable to lead to
over-use The least objectionable drugs are ephedrine
0.5% and phenylephrine 0.5% Xylometazoline 0.1%
(Otrivine) should be used, if at all, for only a few
days since longer application reduces the ciliary
activity and will lead to rebound congestion
Naphazoline and adrenaline should not be used,
and nor should blunderbuss mixtures of
vaso-constrictor antihistamine, adrenal steroid and
anti-biotics Oily drops and sprays, used frequently and
long-term, may enter the lungs and eventually
cause lipoid pneumonia
It may sometimes be better to give the drugs
orally rather than up the nose They interact with
antihypertensives and can be a cause of unexplained
failure of therapy unless enquiry into patient
self-medication is made Fatal hypertensive crises have
occurred when patients treated for depression with
a monoamine oxidase inhibitor have taken these
preparations
Shock
Definition Shock is a state of inadequate capillary perfusion (oxygen deficiency) of vital tissues to an extent that adversely affects cellular metabolism (capillary endothelium and organs) causing mal-function, including release of enzymes and vasoactive substances,6 i.e it is a low flow or
hypo-perfusion state.
The cardiac output and blood pressure are low in fully developed cases But a maldistribution of blood (due to constriction, dilatation, shunting) can be sufficient to produce tissue injury even in the presence of high cardiac output and arterial blood pressure (warm shock), e.g some cases of septic shock
The essential element, hypoperfusion of vital organs, is present whatever the cause, whether pump failure (myocardial infarction), maldistribution
of blood (septic shock) or loss of total intravascular volume (bleeding or increased permeability of vessels damaged by bacterial cell products, burns or anoxia) Function of vital organs, brain (consciousness, respiration) and kidney (urine formation) are clinical indicators of adequacy of perfusion of these organs Treatment may be summarised:
• Treatment of the cause: bleeding, infection,
adrenocortical deficiency
• Replacement of any fluid lost from the circulation
• Perfusion of vital organs (brain, heart, kidneys)
and maintenance of the mean blood pressure
Blood flow (oxygen delivery) rather than blood
pressure is of the greatest immediate importance for the function of vital organs A reasonable blood pressure is needed to ensure organ perfusion but peripheral vasoconstriction may maintain a normal mean arterial pressure despite a very low cardiac output Under these circumstances, blood flow to vital organs will be inadequate and multiple organ
6 In fact, a medley of substances (autacoids), kinins, prostaglandins, leukotrienes, histamine, endorphins, serotonin, vasopressin, has been implicated In endotoxic shock, the toxin also induces synthesis of nitric oxide, the endogenous vasodilator, in several types of cells other than the endothelial cells which are normally its main source.
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failure will ensue unless the patient is resuscitated
adequately
The decision how to treat shock depends on
assessment of the pathophysiology:
• whether cardiac output, and so peripheral blood
flow, is inadequate (low pulse volume,
cold-constricted periphery)
• whether cardiac output is normal or high and
peripheral blood flow is adequate (good pulse
volume and warm dilated periphery), but there
is maldistribution of blood
• whether the patient is hypovolaemic or not, or
needs a cardiac inotropic agent, a vasoconstrictor
or a vasodilator
Types of shock
In poisoning by a cerebral depressant or after
spinal cord trauma, the principal cause of
hypo-tension is low peripheral resistance due to reduced
vascular tone The cardiac output can be restored by
simply tilting the patient head-down and by
increasing the venous filling pressure by infusing
fluid Vasoactive drugs (noradrenaline, dobutamine)
may be beneficial
In central circulatory failure (cardiogenic shock,
e.g after myocardial infarction) the cardiac output
and blood pressure are low due to pump failure;
myocardial perfusion is dependent on aortic pressure
Venous return (central venous pressure) is normal
or high The low blood pressure may trigger the
sympathoadrenal mechanisms of peripheral
circu-latory failure summarised below
Not surprisingly, the use of drugs in low output
failure due to acute myocardial damage is
dis-appointing Vasoconstriction (by an
-adreno-ceptor agonist), by increasing peripheral resistance,
may raise the blood pressure by increasing
afterload, but this additional burden on the
damaged heart can further reduce the cardiac
out-put Cardiac stimulation with a 1-adrenoceptor
agonist may fail; it increases myocardial oxygen
consumption and may cause an arrhythmia
Dobutamine, dopexamine or dopamine offer a
reasonable choice if a drug is judged necessary;
dobutamine is preferred as it tends to vasodilate, i.e
it is an 'inodilator' A selective phosphodiesterase
inhibitor such as enoximone may also be effective, unless its use is limited by hypotension
If there is bradycardia (as sometimes complicates myocardial infarction), cardiac output can be increased by vagal block with atropine, which acceler-ates the heart rate
Septic shock is severe sepsis with hypotension that
is not corrected by adequate intravascular volume replacement It is caused by lipopolysaccharide (LPS) endotoxins from Gram-negative organisms and other cell products from Gram-positive organ-isms; these initiate host inflammatory and pro-coagulant responses through the release of cytokines, e.g interleukins, and the resulting diffuse endo-thelial damage is responsible for many of the adverse manifestations of shock, including multi-organ failure First, there is a peripheral vaso-dilatation from activation of nitric oxide by LPS and cytokines, with eventual fall in arterial pressure This initiates a vigorous sympathetic discharge that causes constriction of arterioles and venules; the cardiac output may be high or low according to the balance of these influences There is a progressive peripheral anoxia of vital organs and acidosis The veins (venules) dilate and venous pooling occurs so that blood is sequestered in the periphery and effective circulatory volume falls because of this, and of fluid loss into the extravascular space from endothelial damage caused by bacterial products When septic shock is recognised, appropriate antimicrobials should be given in high dose immediately after the taking of blood cultures (see
p 237) Beyond that, the prime aim of treatment is
to restore cardiac output and vital organ perfusion
by accelerating venous return to the heart and to reverse the maldistribution of blood Increasing intravascular volume will achieve this, guided by the central venous pressure to avoid overloading the heart Oxygen is essential as there is often uneven pulmonary perfusion
After adequate fluid resuscitation has been established, inotropic support is usually required
Noradrenaline is the inotrope of choice for septic
shock: its potent -adrenergic effect increases the mean arterial pressure and its modest 1 effect may raise cardiac output, or at least maintain it as the
peripheral vascular resistance increases Dobutamine
may be added further to augment cardiac output