Contents 3 D.A. Kharkevitch PHARMACOLOGY€¦ · Chapter 4 DRUGS AFFECTING ADRENERGIC SYNAPSES In...

Contents 3

D.A. Kharkevitch

Textbook

for medical students

Translation of

12th edition of Russian textbook

«Pharmacology» (2017)

PHARMACOLOGY

Mосква

Издательская группа «ГЭОТАР-Медиа»

2017

Министерство образования и науки РФРекомендовано ФГАУ «Федеральный институт развития образования»

в качестве учебника для использования в учебном процессе образовательных организаций, реализующих программы высшего

образования по специальностям 33.05.01 «Фармация», 31.05.01 «Лечебное дело», 31.05.02 «Педиатрия»,

32.05.02 «Медико-профилактическое дело», 31.05.03 «Стоматология»

Subject and aims of pharmacology. Its position among other medical disciplines... 123

In the adrenergic synapses the transmission is mediated by

norepinephrine. Within the peripheral nervous system norepi-

nephrine participates in the transmission of impulses from the

adrenergic fibres to the effector cells (see Fig. 2.2).

Adrenergic axons, approaching the effector cell, divide

into a thin net of fibres with varicosities, that function as nerve

terminals. The latter participate in the formation of synaptic

contacts with the effector cells (Fig. 4.1). Varicosities contain

vesicles with neurotransmitter norepinephrine.

The biosynthesis of norepinephrine from tyrosine occurs

in the adrenergic neurons with a number of enzymes being in-

volved. Formation of DOPA and dopamine takes place in the

cytoplasm of neurons, and norepinephrine is formed in the

vesicles. Below are the biosynthesis pathways of dopamine,

norepinephrine and epinephrine (Fig. 4.2).

Nerve impulses induce the release of norepinephrine into

the synaptic gap, followed by its interaction with the adreno-

ceptors of the postsynaptic membrane. Adrenoceptors, pres-

Chapter 4DRUGS AFFECTING ADRENERGIC SYNAPSES

In this Сhapter:4.1. Drugs stimulating adrenoceptors (adrenomimetics) 4.1.1. Drugs stimulating α- and β-adrenoceptors (α-, β-adrenomimetics) 4.1.2. Drugs stimulating mostly α-adrenoceptors (α-adrenomimetics) 4.1.3. Drugs stimulating mostly β-adrenoceptors (β-adrenomimetics)4.2. Drugs blocking adrenoceptors (adrenoceptor antagonists) 4.2.1. Drugs blocking α-adrenoceptors (α-adrenoblockers) 4.2.2. Drugs blocking β-adrenoceptors (β-adrenoblockers) 4.2.3. Drugs blocking α- and β-adrenoceptors (α-, β-adrenoblockers)4.3. Drugs of presynaptic action 4.3.1. Sympathomimetics (adrenomimetics of indirect action) 4.3.2. Sympatholytics (drugs inhibiting the transmission from adrenergic fiber terminals)

124 PHARMACOLOGY Special pharmacology Chapter 4

ent in the body, have unequal sensitivity to chemical compounds. Due to this, adreno-

ceptors are divided into α- and β-subtypes. The main α-adrenoceptors include α1- and

α2-adrenoceptors. α

1-Adrenoceptors have postsynaptic localization; α

2-adrenoceptors

are located presynaptically and beyond the synapses. The physiologic role of the presyn-

aptic α2-adrenoceptors is their involvement in the system of negative feedback, control-

ling the release of norepinephrine. Stimulation of these receptors by norepinephrine (or

other drugs with α2-adrenomimetic activity) inhibits norepinephrine release from the

varicosities1.

Fig. 4.1. Adrenergic synapse. MAO — monoamine oxidase; COMT — catechol O-methyltrans-

ferase; PreAR — presynaptic adrenoceptors.

1 It is supposed that α2-adrenoceptors, located on the terminals of postganglionic cholinergic

fibers, have the analogous role (their stimulation lowers acetylcholine release).

Drugs affecting adrenergic synapses 125

α2-Adrenoceptors are also located on the membranes of the effector cells beyond the

synapses (extrasynaptic receptors). It is likely that in vessels they are localized in the nonin-

nervated (internal) layer. They must be stimulated by the epinephrine circulating in the blood

(α1-adrenoceptors are mostly activated by the norepinephrine mediator; Fig. 4.3).

Among post- and extrasynaptic β-adrenoceptors there are β1-adrenoceptors (for ex-

ample, in the heart), β2-adrenoceptors (bronchi, vessels, uterus) and β

3-adrenoceptors

(fatty tissue). Predominant localization of one or the other β-adrenoceptors is men-

tioned to simplify the issue. At the same time in a lot of tissues, different types of recep-

tors coexist. Thus, it is shown, that the heart of a human and a number of animals has

β1-adrenoceptors, β

2-adrenoceptors and β

3-adrenoceptors. Bronchial adrenoceptors in-

clude β2-adrenoceptors and β

1-adrenoceptors. Norepinephrine mostly affects innervated

β1-adrenoceptors (postsynaptic receptors), whereas epinephrine, present in the blood, af-

fects β2-adrenoceptors, not having innervation (extrasynaptic receptors). This explains

why neurotropic effects are mainly realized through β1-adrenoceptors by means of nor-

epinephrine, whereas humoral effects, for example, of circulating epinephrine, are reali-

zed via the β2-adrenoceptors. β

3-Adrenoceptors are activated by catecholamines in higher

concentrations than β1- and β

2-adrenoceptors. There are also presynaptic β-adrenoceptors

(β2-adrenoceptors). Unlike analogous α-adrenoceptors they perform positive reverse

feedback, stimulating norepinephrine release. It can be confirmed that β-agonists facili-

tate the release of the norepinephrine mediator, and β-antagonists inhibit it. Functionally,

the inhibitory effect of presynaptic α2-adrenoceptors is more important.

Fig. 4.2. Biosynthesis pathways of dopamine , norepinephrine and epinephrine.


There are drugs that selectively affect different types of adrenoceptors. This refers

both to agonists and antagonists (Table 4.1 and 4.2).

The stimulation of certain postsynaptic adrenoceptors is associated with effects that

are typical for their activation (Table 4.3). Thus, stimulation of α-adrenoceptors leads to

an increase in the effectors function (except for

the intestines, where muscular tone subsides).

Stimulation of β2-adrenoceptors usually leads

to a decrease in the innervated organ function.

Stimulation of β1- and β

2-adrenoceptors of the

heart is associated with an increase in the force

and rate of cardiac contractions, increases in

automatism and facilitation of atrioventricular

conduction. Activation of β3-adrenoceptors

lowers the force of ventricular contractions of

the heart.

Platelets contain α2-adrenoceptors, the

stimulation of which increases aggregation,

and β2-adrenoceptors, which have the opposite

function (their activation increases concentra-

tion of cAMP).

Adrenoceptors participate in the control of

carbohydrate and fat metabolism. Their sti-

mulation by adrenomimetics is associated with

the activation of adenylyl cyclase, which leads

to glycogen breakdown and the release of free

fatty acids from fatty tissues.

One of the important localizations of re-

cently discovered β3-adrenoceptors is in the

U.S. von EULER (1905–1983).

Swedish pharmacologist and physi-

ologist.Discovered sympathetic nerves’

transmitter norepinephrine (1946).

Nobel Prize winner (1970).

Fig. 4.3. Main actions of norepinephrine (NE) and epinephrine (EPI) on presynaptic (α2, β

2) and

postsynaptic (α1, α

2, β

1, β

2) adrenoceptors.

Plus — stimulating action; minus — inhibiting action.

membranePostsynaptic


adipocytes of the fatty tissue. The agonists of this subtype of receptors stimulate lipolysis

and thermogenesis in the fatty tissue. They act in the following way1:

Table 4.1. Drugs, affecting different types of α-adrenoceptors

Adrenoceptors Agonists Antagonists

α1

Phenylephrine (mesatonum) Prazosin

α2

Clonidine (clophelinum) Yohimbine

α1 + α

2Epinephrine , norepinephrine Phentolamine

Table 4.2. Drugs, affecting different types of β-adrenoceptors

Adrenoceptors Agonists Antagonists

β1

Dobutamine Metoprolol , atenolol

β2

Salbutamol , fenoterol , terbutaline Butoxamine

β1 + β

2Isoprenaline (isadrinum), orciprenaline Propranolol (anaprilinum)

β3

BRL 37344 SR 59230

β1 + β

2 +

β

3Isoprenaline (isadrinum) Bupranolol

Table 4.3. Main effects, associated with stimulation of postsynaptic and extrasynaptic α- and

β-adrenoceptors

α-Adrenoceptors β-Adrenoceptors

Constriction of vessels (especially vessels of the

skin, kidneys, intestine, coronary, etc.)

Dilation of vessels (especially vessels of the

skeletal muscles, liver, coronary, etc.)

Contraction of the radial muscle

of the iris (mydriasis)

Increase in rate and force of cardiac contrac-

tions*

Decrease of motility and tone of the intestine Decrease of the bronchial muscle tone

Contraction of sphincters of the gastrointesti-

nal tract

Decrease in motility and tone of the intestine

Decrease in the tone of myometrium

Contraction of the spleen capsule Glycogenolysis

Contraction of myometrium Lipolysis

* The activation of β3-adrenoceptors lowers the force of ventricular contractions of the heart.

1 (+) — stimulating action; (↑) — increase.


β3-Adrenoceptors are innervated by the adrenergic fibres. They are more sensitive to

norepinephrine than to epinephrine.

β3-Adrenoceptors are also found in the heart and blood vessels, smooth muscles of

the digestive tract, gallbladder, prostate gland and skeletal muscles. Their physiologic

role has not been studied completely.

Agonists of β3-adrenoceptors are promising drugs for the management of obesity, as

well as for the complex therapy of diabetes mellitus. The first drugs of this group are

undergoing clinical trials.

The quantitative ratio of α- and β-adrenoceptors in tissues varies. Thus, in the ves-

sels of the skin, kidneys, intestine, sphincters of the gastrointestinal tract and in splenic

trabecules α-adrenoceptors prevail. In the heart, bronchial muscles, vessels of the skel-

etal muscles β-adrenoceptors are mainly present. The effect of adrenergic (sympathetic)

nerves, as well as the reaction to adrenomimetics that stimulate α- and β-adrenoceptors,

is determined by the localization and ratio of α- and β-adrenoceptors.

The structure of adrenoceptors has not been studied fully. There is an evidence that β1- and

β2-adrenoceptors are functionally (by means of G-proteins) interrelated with adenylyl cy-

clase, which is localized in the membrane of effector cells and enables the synthesis of cAMP

(Fig. 4.4 and 4.5). α1-Adrenoceptors activate G-proteins, coupled with phospholipase C.

The action of norepinephrine on adrenoceptors is short-term. It is mainly caused by

the swift uptake, up to 75–80%, of mediator present in the synaptic gap by the terminals

of the adrenergic fibres, followed by its storage.

Catabolism of free norepinephrine in the adrenergic terminals is controlled by MAO

enzyme, mainly localized in mitochondria and, also, in the membranes of the vesicles.

MAO promotes oxidative deamination of norepinephrine. The metabolism of norepi-

nephrine released from the nerve terminals, as well as circulating catecholamines, is

mainly performed by the cytoplasmic enzyme of the effector cells — catechol O-methyl-

transferase. Under the effect of this enzyme O-methylation of catecholamines occurs.

Small amounts of mediators undergo extraneuronal uptake by the effector cells

(smooth muscles, etc.). In extraneuronal uptake norepinephrine is rapidly metabolized

by catechol O-methyltransferase and MAO.

Thus, the norepinephrine balance depends on its synthesis, storage, neuronal and

extraneuronal uptake, as well as enzymatic transformation.

The possibilities of pharmacological effect on the adrenergic transmission are rather

variable. The direction of action of different drugs can be as follows: 1) effect on norepi-

nephrine synthesis; 2) impairment of norepinephrine storage in the vesicles and cytoplasm

of the presynaptic terminals; 3) inhibition of enzymatic inactivation of norepinephrine;

4) effect on the release of norepinephrine from the terminals; 5) impairment of the process

of norepinephrine reuptake by the presynaptic terminals; 6) inhibition of the extraneu-

ronal uptake of norepinephrine; 7) direct effect on adrenoceptors.

Thus, norepinephrine synthesis is inhibited by α-methyl-p-tyrosine (inhibits tyrosine

hydroxylase). By blocking the transport systems of the vesicular membranes, reserpine

inhibits penetration of dopamine into the vesicles and norepinephrine reuptake by the

vesicles. Due to this concentration of norepinephrine, deposited in the vesicles, is de-

creasing. A reduction of norepinephrine concentrations in the presynaptic terminals is

also observed after the administration of guanethidine.

Nialamide is a nonselective MAO inhibitor; catechol O-methyltransferase activity

can be inhibited by entacapone and tolcapone.


The process of norepinephrine release from the presynaptic terminals can be altered.

Some drugs stimulate its release (for example, tyramine, ephedrine), others reduce

(guanethidine, bretylium).

Neuronal uptake of norepinephrine by the adrenergic endings is inhibited after the

administration of imipramine or cocaine (at the same time the concentration of media-

tor in the synaptic gap increases); extraneuronal uptake of norepinephrine is inhibited

by metanephrine and phenoxybenzamine.

Drugs that affect adrenoceptors are most often used in medical practice. Drugs that

stimulate adrenoceptors are called adrenomimetics, while drugs that inhibit them are

called adrenoblockers.

Fig. 4.4. Main directions of action of adrenomimetics on postsynaptic receptors. Note.

Effect on varicosities indicates the sympathomimetic effect of drugs.


Depending on the predominant localization of effect the drugs that affect transmis-

sion in the adrenergic synapses, are subdivided into the following groups.

• Drugs, acting directly on adrenoceptors

◊ A d r e n om i m e t i c s o f t h e d i r e c t a c t i o n

∨ Norepinephrine

∨ Epinephrine

∨ Isoprenaline (isadrinum)

◊ Adrenoblockers

∨ Phentolamine

∨ Propranolol

• Drugs of presynaptic action, affecting release and (or) storage of norepinephrine

◊ S y m p a t h om i m e t i c s o r a d r e n om i m e t i c s o f i n d i r e c t a c t i o n 1

∨ Tyramine

∨ Ephedrine 2

◊ S y m p a t h o l y t i c s

∨ Guanethidine (octadinum)

∨ Reserpine

Fig 4.5. The pathways of coupling of various subtypes of arenoceptors with the effector under the

effect of epinephrine.

IP3 — inositol triphosphate, DAG — diacylglycerol.

1 They affect varicosities of the adrenergic fibers, promoting the release of norepinephrine from

them, which stimulates adrenoceptors.2 Ephedrine, moreover, has a slight direct stimulating effect on adrenoceptors.


Depending on the receptor affinity of adrenomimetics and adrenoblockers to α- and

β-adrenoceptors, they can be systematized in the following way.

• Adrenomimetics1

◊ S t i m u l a t i n g α - a n d β - a d r e n o c e p t o r s

∨ Epinephrine (β1, β

2, α

1, α

2)

∨ Norepinephrine2 (α1, α

2, β

1)

◊ S t i m u l a t i n g m o s t l y α - a d r e n o c e p t o r s

∨ Phenylephrine (mezatonum) (α1)

∨ Naphazoline (naphthizinum) (α2)

∨ Xylometazoline (halazolinum) (α2)

◊ S t i m u l a t i n g m o s t l y β - a d r e n o c e p t o r s

∨ Isoprenaline (isadrinum) (β1, β

2)

∨ Salbutamol (β2)

∨ Fenoterol (β2)

∨ Terbutaline (β2)

∨ Dobutamine (β1)

• Adrenoblockers

◊ B l o c k i n g α - a d r e n o c e p t o r s

∨ Phentolamine (α1, α

2)

∨ Tropodifene (tropaphenum ) (α1, α

2)

∨ Dihydroergotoxin (α1, α

2)

∨ Prazosin (α1)

∨ Tamsulosin (α1)

◊ B l o c k i n g β - a d r e n o c e p t o r s

∨ Propranolol (anaprilinum) (β1, β

2)

∨ Oxprenolol (β1, β

2)

∨ Metoprolol (β1)

∨ Talinolol (β1)

∨ Atenolol (β1)

∨ Bisoprolol (β1)

◊ B l o c k i n g α - a n d β - a d r e n o c e p t o r s

∨ Labetalol (β1, β

2, α

1)

∨ Carvedilol (β1, β

2, α

1)

See Figures 4.7, 4.10, 4.12.

4.1. DRUGS STIMULATING ADRENOCEPTORS (ADRENOMIMETICS)

4.1.1. DRUGS STIMULATING α- AND β-ADRENOCEPTORS (α-, β-ADRENOMIMETICS)

The most typical representative of this group is epinephrine (adrenaline). According

to its chemical structure it belongs to the phenylalkylamines (Fig. 4.7). Epinephrine is a

biogenic catecholamine3. It is stored in chromaffin cells, mainly in the adrenal medulla.

1 In parentheses there is the main effect on the receptors subtypes.2 It also stimulates β

3-adrenoceptors, though data on this subtype of adrenoceptors are rather limited.

3 Catechol is O-dioxybenzol.


In medical practice salts of L-epinephrine are used. Epinephrine is obtained syntheti-

cally or can be derived from the adrenal glands of livestock.

Epinephrine has a direct stimulating effect on α- and β-adrenoceptors (Fig. 4.4)1. All

the effects, mentioned in Table 4.3 are observed with epinephrine administration.

Epinephrine has an especially marked effect on the cardiovascular system, and pri-

marily on the level of arterial pressure (Fig. 4.6). By stimulating the β-adrenoceptors

of the heart, epinephrine increases the force and rate of cardiac contractions and this

in turn causes the stroke and minute volume of the heart to increase. At the same time

the consumption of oxygen by myocardium is increased. Hypertensiv reaction usually

induces reflex bradycardia from the mechanoceptors of the blood vessels, though this is

a short-term effect. Depending on the dose of epinephrine, total peripheral resistance

can be decreased, increased or remain unchanged. Most often the administration of

epinephrine in moderate doses decreases total peripheral resistance (it is manifested by

a decrease of the diastolic pressure), which is associated with the predominant excita-

tion of β2-adrenoceptors of the vessels of muscles and other areas and their dilation.

Nevertheless, mean arterial pressure increases due to a rise in the systolic pressure. In

high doses epinephrine can also increase total peripheral resistance. Pressor action of

epinephrine is usually alternated with slight hypotension. The latter is associated with

more prolonged excitation of β2-adrenoceptors.

Epinephrine dilates the pupils (due to the contraction of the radial muscle of the

iris — m. dilatator pupillae, where α-adrenoceptors are located), and decreases intraocu-

lar pressure (production of the intraocular fluid is decreased).

1 On Fig. 4.4 and 4.11 innervated β-adrenoceptors are shown. At the same time it is known that

most β-adrenoceptors lack innervation. Thus, in resistive vessels α1-adrenoceptors are in close con-

tact with varicosities of the adrenergic fibers, and β-adrenoceptors are located away from them.

Fig. 4.6. Effect of catecholamines on the cardiovascular system in humans. The drugs were ad-

ministered intravenously: norepinephrine, epinephrine and isoprenaline at the rate of 10 μg/min,

dopamine — 500 μg/min.


Fig

. 4

.7.

Ch

em

ica

l st

ruc

ture

s o

f so

me a

dre

no

mim

eti

cs.

No

te.

Ep

inep

hri

ne,

no

rep

inep

hri

ne a

nd

iso

pre

na

lin

e (

isa

dri

ne)

are

ca

tec

ho

lam

ines.

Ep

inep

hri

ne,

no

rep

inep

hri

ne a

nd

ep

hed

rin

e c

an

be s

yn

thesi

zed

.


Epinephrine has a marked effect on the smooth muscles of the visceral organs. By

stimulating β-adrenoceptors of the bronchi, it relaxes their smooth muscles and elimi-

nates bronchospasm. The tone and motility of the gastrointestinal tract is reduced with

the use of epinephrine (due to excitation of α- and β-adrenoceptors), while sphincter

tone is increased (α-adrenoceptors are stimulated). The sphincter of the bladder is also

contracted; m. detrusor urinae is relaxed.

The administration of epinephrine induces the contraction of the splenic capsule.

It has a favorable effect on neuromuscular transmission, especially if muscular fa-

tigue is experienced. It is associated with an increase in acetylcholine release from the

presynaptic terminals, as well as with a direct action of epinephrine on the muscles.

It increases the secretion of the salivary glands (thick, sticky saliva is produced).

Epinephrine has a characteristic effect on the metabolism. It stimulates glycogenoly-

sis (hyperglycaemia occurs, blood concentration of lactic acid and potassium ions in-

creases) and lipolysis (increase of blood plasma concentration of free fatty acids due to

their release from the fat depot).

Glycogenolytic action of epinephrine may be associated with the stimulating effect

on β2-adrenoceptors of the muscles, liver and activation of the membrane adenylyl cy-

clase (Fig. 4.8). It leads to the accumulation of cyclic 3’,5’-AMP, which successively

activates protein kinase and phosphorylase and catalyzes the conversion of glycogen

into glucose-1-phosphate (see below). Lipolysis is associated with the stimulation of

β3-adrenoceptors and the subsequent activating effect of the accumulating cAMP on

triglyceride lipase. Glycerin and fatty acids are formed from triglycerides. In general,

epinephrine stimulates the metabolism and increases oxygen consumption.

When epinephrine affects the CNS, excitatory effects predominate. They are very

mild. Thus, the administration of epinephrine can cause anxiety, tremor, trigger stimu-

Fig. 4.8. Effect of drugs stimulating β-adrenoceptors on the energy metabolism. β-AR —

β-adrenoceptors; plus — stimulating action.


lation of the vomiting center, etc. EEG shows signs of awakening (desynchronization of

EEG occurs).

After oral administration epinephrine is broken down (in the gastrointestinal tract

and liver). Therefore it is used parenterally (subcutaneously, intramuscularly and some-

times intravenously) and topically. Epinephrine has a short-term action (after intrave-

nous administration — about 5 min, after subcutaneous administration — 30 min) due

to its rapid neuronal uptake as well as enzymatic breakdown with catechol O-methyl-

transferase and, partially, MAO. The metabolic products of epinephrine (and norepi-

nephrine) are 3-methoxy-4-oxymandelic acid (vanillylmandelic acid), 3-methoxy-4-

oxyphenylglycol, as well as normetanephrine and metanephrine (in the form of sulphates

and glucuronides). The kidneys eliminate metabolites and small amounts of unchanged

epinephrine.

Epinephrine is administered for anaphylactic shock and other allergic reactions of

the immediate type. It is effective as a bronchial spasmolytic for the treatment of acute

bronchial asthma attacks. It is used for hypoglycaemic coma, caused by antidiabetic

drugs (insulin, etc.). Sometimes it is administered as a pressor drug (although norepi-

nephrine and phenylephrine are used more often for this purpose). Epinephrine is added

to lokal anesthetic solutions (see Chapter 1.1). Vasoconstriction at the site of epineph-

rine injection intensifies local anesthesia and reduces resorptive and, possibly, the toxic

effect of anesthetics. Epinephrine can be used to eliminate atrioventricular block, as well

as to treat cardiac arrest (intracardial administration). It is used in ophthalmology to

dilate the pupil and in the open-angle glaucoma.

Epinephrine can lead to cardiac rhythm disorders. Most marked arrhythmias (espe-

cially, ventricular extrasystoles) occur after the administration of epinephrine along with

drugs that sensitize the myocardium to it (for example, on the background of action of

halothane ).

L-norepinephrine is also a representative of the group of drugs, stimulating α- and

β-adrenoceptors. It is contained in adrenergic neurons, as a mediator, as well as in the

adrenal medulla (up to 15%). The main stages of norepinephrine biosynthesis are shown

in Fig 4.2.

Norepinephrine (levarterenol, noradrenaline) has a direct stimulating effect on

α-adrenoceptors, as well as on β1-adrenoceptors (and a insignificant effect on β

2-adre-

noceptors).

The main effect of norepinephrine is a marked but short-term (for several minutes)

increase in arterial pressure, associated with its effect on α-adrenoceptors of the vessels

and with an increase of the peripheral resistance of blood vessels. Unlike epinephrine,

norepinephrine does not cause a decrease in arterial pressure, since it has a very slight

effect on β2-adrenoceptors of the vessels. Veins become constricted under the effect of

norepinephrine.

The heart beats slows down after norepinephrine is injected. Sinus bradycardia occurs

as a result of a reflex from vascular mechanoceptors in response to hypertension. Vagus

nerves are the efferent pathways of this reflex. Due to this, norepinephrine-induced bra-

dycardia can be prevented by the administration of atropine . Reflex mechanisms balance

the stimulating effect of norepinephrine on β1-adrenoceptors of the heart. As a result of

this, cardiac output (minute volume) does not change or even decrease while the stroke

volume increases.


Norepinephrine affects the smooth muscles of the visceral organs, metabolism and

the CNS in the same way as epinephrine. However, it yields to epinephrine in the inten-

sity of these effects.

After oral administration norepinephrine is broken down (in the gastrointestinal tract

and liver). After subcutaneous administration it induces vascular spasm at the site of the

injection and that is why it is poorly absorbed and can cause necrosis of the tissue. The

intravenous route of administration is most commonly used. After a single injection the

effect of norepinephrine is short-term, which is why a drop-by-drop intravenous infusion

is used. The rate of intravenous infusion is determined by the increase in arterial pressure

up to a certain required level. In the body norepinephrine is quickly inactivated due to

the above-mentioned mechanisms (neuronal uptake, enzymatic transformations). Kid-

neys eliminate metabolites and an insignificant part of unchanged norepinephrine.

Norepinephrine is used for the treatment of conditions that are associated with acute

decreases in blood pressure (injuries, surgeries).

For cardiogenic and hemorrhagic shock with marked hypotension norepinephrine is

not recommended since it causes a spasm of arterioles that further impairs blood supply

to the tissues. In such cases α-adrenoblockers and, possibly, β-adrenomimetics can have

a useful effect. Blood substitutes are used to help increase blood pressure.

Side effects caused by the administration of norepinephrine occur rarely. These may

include respiratory disorders, headache, cardiac arrhythmias which may occur when

norepinephrine is given in combination with drugs that increase the excitability of the

myocardium. The possibility of tissue necrosis at the site of norepinephrine injection has

to be considered. It is associated with the introduction of the latter into the surrounding

tissues and spasms of the arterioles. Intravenous administration of norepinephrine by

means of catheter, the use of heat pads, varying the site of introduction, and other mea-

sures can be used to minimize the possibility of this complication.

4.1.2. DRUGS STIMULATING MOSTLY α-ADRENOCEPTORS (α-ADRENOMIMETICS)

Phenylephrine (mezatonum) has a predominant effect on α1-adrenoceptors. It

also belongs to the group of phenylalkylamines (see Fig. 4.7). Along with a direct ac-

tion phenylephrine insignificantly favours the release of norepinephrine from presynap-

tic terminals.

Like norepinephrine, phenylephrine mainly affects the cardiovascular system. It

increases arterial pressure (after intravenous administration in approximately 20 min,

after subcutaneous — 40–50 min) and causes reflex bradycardia. It does not affect the

heart. It has an insignificant stimulating effect on the CNS. Unlike norepinephrine,

phenylephrine is more stable. It is effective after oral administration.

Indications for the use of phenylephrine are similar to those of norepinephrine. Phe-

nylephrine is used as a pressor drug. Besides, it is administered locally in rhinitis. The

combination with local anesthetics is possible. Phenylephrine is also indicated for the

treatment of open-angle glaucoma.

According to the chemical structure α2-adrenomimetic naphazoline (naphthizinum,

sanorinum) is substantially different from norepinephrine and phenylephrine. It is a de-

rivative of imidazoline (see Fig. 4.7). Naphazoline, when compared with norepinephrine


and phenylephrine, causes longer-term vasoconstrictive effect. It has an inhibitory effect

on the CNS1. It is used locally in rhinitis.

Xylomethazolin (halazolinum ) is analogous to naphazoline. It also belongs to the gro-

up of imidazoline derivatives. It is used locally in acute rhinitis. It causes local irritation.

4.1.3. DRUGS STIMULATING MOSTLY β-ADRENOCEPTORS (β-ADRENOMIMETICS)

One of the β-adrenomimetics is isoprenaline (isadrinum, isuprel; see Fig. 4.7), which

is a derivative of phenylalkylamines. It has a direct influence on β-adrenoceptors (see

Fig. 4.3). Isoprenaline stimulates β1-, β

2- and β

3-adrenoceptors. Its main effects are di-

rected at the heart and smooth muscles. By stimulating β1-adrenoceptors of the heart,

isoprenaline increases the force and rate of cardiac contractions. At the same time sys-

tolic pressure increases. Moreover, the drug also activate β2-adrenoceptors of the vessels

(especially the skeletal muscle vessels). This leads to a decrease in diastolic pressure. The

mean arterial pressure is also decreased.

Isoprenaline facilitates atrioventricular conduction and increases heart automatism.

It effectively decreases the tone of the bronchi (after inhalation it causes a rapid bron-

cholytic effect, which lasts for 1 h), muscles of the gastrointestinal tract, as well as other

smooth muscles, that have β2-adrenoceptors.

Isoprenaline stimulates the CNS. It has the same effect on metabolism as epineph-

rine but hyperglycaemia, associated with isoprenaline, is less marked.

Isoprenaline is administered to relieve bronchial spasm (it is mainly introduced by

inhalation in the form of spray), as well as for the treatment of atrioventricular block

(sublingual administration).

Adverse effects include tachycardia, cardiac arrhythmias, and headache.

Since these side effects (especially tachyarrhythmia), which occur with isoprenaline

use for bronchial asthma, are associated with β1-adrenomimetic action, drugs with pre-

dominant effects on β2-adrenoceptors have been synthesized. They are salbutamol , terb-

utaline (bricanyl), fenoterol (berotec N, partusisten), etc. They differ from isoprenaline

(isadrinum) in that they have a less marked effect on the β1-adrenoceptors of the heart.

Besides, they are effective after oral administration and they have a more long-term ef-

fect than isoprenaline (especially terbutaline ). The above mentioned drugs are admin-

istered as broncholytic drugs (by inhalation, orally, parenterally), as well as to reduce

contractile activity of the myometrium.

There are also drugs that selectively stimulate β1-adrenoceptors. Dobutamine belongs

to this group of drugs. Its main effect is a marked positive inotropic action. It is admin-

istered as a cardiotonic drug (see Chapter 14.1.2).

1 One of α2-adrenomimetics from the group of imidazoline derivatives — tizanidine (sirdalud)

has properties of a central muscle relaxant. The ability to decrease the muscular tone is explained by

its stimulating effect on the presynaptic α2-adrenoceptors in the spinal cord. This effect leads to a

reduction in the release of excitatory amino acids from the nerve endings. It leads to the inhibition of

spinal neurons and polysynaptic reflexes. Tizanidine also has a moderate analgesic effect. Accord-

ing to the hypotensive activity it is 10–50 times weaker than clonidine (that has a similar chemical

structure and pharmacological spectrum). It is administered to relieve skeletal muscles spasms of

various origins.


4.2. DRUGS BLOCKING ADRENOCEPTORS (ADRENOCEPTOR ANTAGONISTS)

Adrenoblockers block adrenoceptors (Fig. 4.9), preventing the effect of the mediator

(norepinephrine), as well as catecholamines that circulate in the blood and other ad-

renomimetics (Table 4.4). Adrenoblockers do not inhibit norepinephrine synthesis.

4.2.1. DRUGS BLOCKING α-ADRENOCEPTORS (α-ADRENOBLOCKERS)

α-Adrenoblockers reduce the pressor effect of epinephrine or alter it. α-Adreno-

blockers in high doses convert a pressor effect of epinephrine to depressor one (so

called epinephrine reversal). This occurs due to the fact that when α-adrenoceptors are

blocked, the stimulating effect of epinephrine on the vascular β-adrenoceptors leads to

their dilation (the smooth muscle tone is decreased).

Synthetic drugs, blocking α1- and α

2-adrenoceptors, include phentolamine and

tropodifene (tropaphenum) .

Phentolamine (regitine) is an imidazoline derivative. It is characterized by a marked,

but short-term α-adrenoblocking effect (10–15 min after intravenous administra-

tion). Decreases in arterial pressure are linked to its α-adrenoblocking and myotropic

Fig. 4.9. Main directions of action of adrenoblockers and sympatholytics (only postsynaptic ad-

renoceptors are shown).


spasmolytic action. It causes tachycardia (partially due to the block of presynaptic α2-

adrenoceptors). It increases motility of the gastrointestinal tract and secretion of the

gastric glands. Phentolamine does not really change the hyperglycaemic effect of epi-

nephrine. It is poorly absorbed from the gastrointestinal tract. The kidneys eliminate

phentolamine and its metabolites.

Tropodifene (tropaphenum) belongs to the esters of tropine. It combines a rather high

α-adrenoblocking activity and some atropine -like properties that cause arterial pressure

decreases and tachycardia. Tropodifene is the antagonist of α-adrenomimetics. It is re-

markable for its long-term α-adrenoblocking action (measured in hours) and surpasses

phentolamine and dehydrated ergot alkaloids in this regard.

Semisynthetic compounds of dehydrated ergot alkaloids include dihydroergotoxin

and dihydroergotamine.

Dihydrated ergot alkaloids differ from natural ones by their more marked

α-adrenoblocking effect, an absence of stimulating effects on the myometrium (non-

pregnant uterus), less vasoconstrictive action and lower toxicity.

In clinical practice, drugs blocking α1- and α

2-adrenoceptors, are used comparatively

rarely. The most important effect of α-adrenoblockers is the dilation of the peripheral ves-

sels. This is why they are mainly used to treat various disorders of peripheral blood circula-

tion (endarteritis, Raynaud's disease, other), including shock (hemorrhagic, cardiogenic),

with spasm of arterioles. The administration of α-adrenoblockers for pheochromocytoma

is quite common1. Sometimes, α-adrenoblockers are used in hypertensive crises.

Table 4.4. Some effects of the drugs, affecting adrenoceptors1

Organs ParameterEffect

Agonists Antagonists

The eye Tone of the radial muscle

of the iris

Intraocular pressure

Increased (mydriasis) (α1)

Decreased (α1, α

2) Decreased2 (β

2)

The heart Rhythm, contractility,

automatism, conduction

Increased (β1, β

2) Decreased (β

1, β

2)

Vessels Tone of the smooth muscle Mainly increased (α1, α

2),

sometimes decreased (β2)

Decreased3 (α1, α

2)

Trachea, bronchi Tone of the smooth muscle Decreased (β2) Increased (β

2)

The stomach

and intestine

Motility and tone of the

smooth muscle

Decreased (α1, α

2, β

1, β

2)

The gallbladder

and bile ducts

Tone of the smooth muscle Decreased (β2)

Bladder Sphincter tone Increased (α1) Decreased (α

1)

Myometrium Contractile activity Decreased (β2)

1

Subtypes of receptors are shown in parentheses.

2 Especially in glaucoma.3 Mechanism of hypotensive action of β-adrenoblockers includes a number of components (see

Chapter 14.5).

1 Pheochromocytoma (tumor of the adrenal medulla) produces large amounts of epinephrine,

which leads to substantial increase of the arterial pressure.


These drugs block both post- and presynaptic α-adrenoceptors (α1 and α

2). It has to

be considered that the block of presynaptic α2-adrenoceptors impairs physiologic auto-

regulation of the release of norepinephrine. Negative feedback is disturbed and, conse-

quently, excessive release of norepinephrine ensues, leading to a recovery of the adren-

Fig. 4.10. Chemical structures of some α-adrenoblockers.

Tamsulosin


Fig. 4.11. Localization of α-adrenoblockers effect.

NE — norepinephrine; α — α-adrenoceptors; β — β-adrenoceptors.

Plus — stimulating action; minus — inhibitory action.

ergic transmission. The latter explains why the block of postsynaptic α1-adrenoceptors

by nonselective antagonists (blockers of α1- and α

2-adrenoceptors) is not stable. Marked

tachycardia is also the result of the increased norepinephrine release. Hence adreno-

blockers, mostly affecting postsynaptic α1-adrenoceptros, are most interesting for clini-

cal practice. Due to the function of presynaptic α2-adrenoceptors the mechanism of

negative feedback is retained, hence, there is no increased norepinephrine release. At the

same time the postsynaptic block of α1-adrenoceptros becomes prolonged. Tachycardia

is not prominent (Fig. 4.11).

Prazosin belongs to the group of drugs that mainly affect postsynaptic α1-adreno ceptors.

According to α1-adrenoblocking activity it surpasses phentolamine by approximately 10

times. The main effect of prazosin is a decrease in arterial pressure. This is caused by a de-

crease in the tone of the arteries and, to a lesser extent veins, and a reduction of the venous

return and decreased cardiac work. Heart rate is slightly changed (there may be a slight

tachycardia). There is evidence indicating that prazosin inhibits phosphodiesterase.

The drug is effective when given orally. Its action starts 30–60 min after intake and

lasts for 6–8 h.

Prazosin may be used as an antihypertensive drug.

α1-Adrenoblockers (tamsulosin , terazosin , alfuzosin , other) are also used to treat

benign hyperplasia of the prostate gland. Tamsulosin (omnic) has a predominant effect


on α1-adrenoceptors of the prostate gland. Unlike other α

1-adrenoblockers, tamsulosin

insignificantly affects systemic hemodynamics.

There are several types of α1-adrenoceptors: α

1A, α

1B and α

1D

1. α1A

-Adrenoceptors are

involved in the control of the smooth muscles of the prostate gland, and α1B

— in the

contraction of muscles of the blood vessels. Of the total amount of α1-adrenoceptors in

the human prostate gland 70% are of the α1A

subtype. Tamsulosin affinity to α1A

recep-

tors is 7–38 times higher than to α1B

-adrenoceptors. Block of α1A

-adrenoceptors reduces

the smooth muscle tone of the prostate gland, neck of the bladder and prostatic part of

the urethra. It leads to an increase in urine flow rate and to a general improvement of its

outflow from the bladder.

Tamsulosin is taken orally once a day. It is almost fully absorbed. It is metabolized

in the liver. The kidneys eliminate the drug and its metabolites (only 10% unchanged).

t1/2

= 12–19 h. Possible side effects are dizziness, ejaculation disorder, headache, palpi-

tation, etc.

Doxazosin (cardura) is a α1-adrenoblocker that is preferentially used to treat pros-

tatic hyperplasia, since it has more long-term action than other drugs of this group. Total

duration of doxazosin action can exceed 36 h. It does not have a selective action on some

subtypes of α1-adrenoceptors.

4.2.2. DRUGS BLOCKING β-ADRENOCEPTORS (β-ADRENOBLOCKERS)

Propranolol (anaprilinum, inderal, obsidan) is a widely used β-adrenoblocker.

It blocks β1- and

β

2-adrenoceptors (of the heart, vessels, bronchi, gastrointestinal

tract, etc.).

Propranolol causes bradycardia and reduces the force of cardiac contractions, due

to which cardiac output is decreased. The drug inhibits atrioventricular conduction and

lowers myocardial automatism.

Propranolol decreases arterial pressure, especially after prolonged use. It also causes

some reduction in cardiac output. General peripheral vascular resistance increases at

first, and then it decreases. Renin production decreases, which also causes a hypotensive

effect. When administered together with propranolol, the pressor action of epinephrine

becomes similar to that of norepinephrine, since the final phase (arterial pressure de-

crease), associated with excitation of vascular β2-adrenoceptors, is eliminated.

Propranolol increases the bronchial tone and can induce a bronchospasm (the result

of bronchial β2-adrenoceptors block). It is an antagonist of epinephrine by its hypergly-

caemic and lipolytic action.

Propranolol is almost fully absorbed from the digestive tract. A substantial part is me-

tabolized in the liver, 90–95% binds with the plasma proteins; t1/2

approximately equals

4 h. The kidneys eliminate propranolol and its metabolites.

Propranolol is administered for the treatment of angina pectoris (block of

β-adrenoceptors leads to a reduction in cardiac work, thus lowering its oxygen con-

1 α1D

-Adrenoceptors are found in a number of tissues: in the prostate gland, aorta, brain cortex

and hippocampus. Their function is unclear. These receptors may be one of the targets for the effect

of tamsulosin, which has a significant affinity to them.

sumption), hypertension (prolonged adminis-

tration of the drug is associated with gradual and

stable decrease of the arterial pressure). Propra-

nolol is indicated to treat supraventricular arrhyth-

mias, for example, atrial fibrillation (propranolol

reduces automatism and slows conduction from

the atria to the ventricles). Propranolol is used

to eliminate tachycardia of various etiologies (in

mitral stenosis, thyrotoxicosis), as well as in ar-

rhythmia, caused by adrenomimetics or cardiac

glycosides.

Possible side affects are: cardiac failure, car-

diac block, increase in peripheral vessel tone

and bronchospasm. Propranolol is administered

carefully to patients with diabetes mellitus, since

it prolongs hypoglycaemia caused by the drugs.

β1- and β

2-Adrenoceptor blockers also in-

clude oxprenolol (trasicor) and a number of

other drugs.

There are compounds that mainly block β1-adrenoceptors. One of them is metoprolol

(egilok). It has an insignificant effect on the β2-adrenoceptors of the bronchi and vessels.

Metoprolol is absorbed well from the intestine, but a substantial part of it is degraded

while passing the liver. The maximal effect develops approximately in 1.5 h and is retained

for about 5–6 h. The kidneys eliminate metoprolol mainly in the form of metabolites.

It is administered orally in arterial hypertension, cardiac arrhythmia, and angina

pectoris. Possible side effects are headache, fatigue and sleep disturbance. In bronchial

asthma metoprolol can somewhat increase bronchial tone.

Talinolol (cordanum), atenolol (tenormin) and bisoprolol (concor) also mainly affect

β1-adrenoceptors. These drugs can be listed according to the duration of the block of

β1-adrenoceptors: bisoprolol (t

1/2=10–12 h) >atenolol (t

1/2=6–9 h) >talinolol (t

1/2=6.6 h)

>metoprolol (t1/2

=3–3.5 h). Thus, bisoprolol has the longer-term effect (24 h). It is

taken once a day, and other drugs — 2–3 times a day. The main properties of these drugs,

indications for their use and side effects are similar to that of metoprolol.

Nebivolol (nebilet) is an β1-adrenoblocker, which also causes vasodilation. It is used

for the treatment of hypertension.

β-Adrenoblockers play an important role in the management of open-angle glau-

coma1. Their local administration decreases the production of intraocular fluid, leading

to a decrease in intraocular pressure.

J.W. BLACK (b. 1924).

English pharmakologist. Created the

first β-adrenoblockers and histamine

H2-receptors’ blockers.

Nobel Prize winner (1988).

1 Drugs, used to decrease the intraocular pressure in glaucoma, are represented by 3 main

groups:

I. Increasing the intraocular fluid outflow (cholinomimetics — pilocarpine, carbacholine; an-

ticholinesterase drugs — neostigmine, physostigmine, arminum; prostanoid — latanoprost;

osmotic diuretics — mannitol).

II. Decreasing the intraocular fluid production (β-adrenoblockers — timolol, levobunolol,

etc.; carbonic anhydrase inhibitors — acetazolamide (diacarbum, dorzolamide).

III. Drugs of mixed action (I + II; adrenomimetics — epinephrine, dipivefrine, clonidine).



4.2.3. DRUGS BLOCKING α- AND β-ADRENOCEPTORS (α-, β-ADRENOBLOCKERS)

Labetalol (trandate) blocks both types of adrenoceptors (β1, β

2, α

1). It lowers periph-

eral vascular resistance. It is well absorbed after oral administration. A significant part

of labetalol is degraded during the first passage through the liver. The drug works for

8–10 h. Kidneys eliminate it mainly in the form of metabolites. Labetalol is used as an

antihypertensive drug.

Carvedilol (dilatrend) is an adrenoblocker of a mixed type of action. It is an antago-

nist of β- and α1-adrenoceptors. Its blocking effect on β-adrenoceptors is 10–100 times

higher than on α1-adrenoceptors (for labetalol — 1.5–3 times). Besides, this drug has a

marked antioxidant activity.

Fig. 4.12. Chemical structures of some β- and α-, β-adrenoblockers.

Carvedilol

(CH )


The vasodilating affect of carvedilol is associated with a decrease in peripheral vas-

cular resistance. It inhibits the production of renin. Pre- and afterload on the heart is

decreased. The drug also prevents hypertrophy of the left ventricle.

It is taken per os and is well absorbed. Its bioavailability is 25–30%.

The duration of hypotensive action exceeds 15 h, i.e. significantly longer than that

of labetalol.

Carvedilol is useful in the treatment of arterial hypertension, coronary heart disease

and chronic heart failure. Possible side effects include dizziness, headache, broncho-

spasm, fatigue, skin reactions, etc.

4.3. DRUGS OF PRESYNAPTIC ACTION

4.3.1. SYMPATHOMIMETICS (ADRENOMIMETICS OF INDIRECT ACTION)

Ephedrine is contained in different species of the Ephedra plant. It is a sympathomi-

metic (adrenomimetic of indirect action), indirectly stimulating α- and β-adrenoceptors.

Ephedrine , obtained from raw vegetable material, is a sinistrorotatory isomer. The syn-

thetic drug is a racemate, inferior to L-ephedrine in its activity.

Ephedrine has the following effect (see Fig. 4.6). Firstly, it has a presynaptic effect

on the varicosities of the adrenergic fibres, promoting mediator release (norepinephrine).

Secondly, it has a weaker stimulating effect directly on the adrenoceptors.

Ephedrine is similar to epinephrine in its main effects. It stimulates heart function,

increases arterial pressure, causes a broncholytic effect, inhibits intestinal peristalsis,

dilates the pupil (not affecting accommodation or intraocular pressure), increases the

skeletal muscle tone and induces hyperglycaemia.

It differs from epinephrine in that its effect develops gradually and lasts longer (in

regards to the arterial pressure — by 7–10 times).

Ephedrine is significantly inferior to epinephrine in its vasopressor activity (for the

equal pressor effect the dose of ephedrine has to be 50–100 times higher than that of epi-

nephrine).

After repeated frequent (after 10–30 min) administration of ephedrine its pressor ac-

tion rapidly subsides, and tachyphylaxis occurs. It is caused by a progressive reduction

in norepinephrine storage in the varicosities (since ephedrine intensifies norepinephrine

release from them).

Ephedrine has a marked effect on the CNS. In this regard it surpasses epinephrine,

but is inferior to amphetamine .

A substantial difference of ephedrine from other drugs of this group is its efficiency

after oral administration. It is resistant to MAO action. It is partially deaminated in the

liver (due to other enzymes). The kidneys eliminate a substantial part of ephedrine (ap-

proximately 40%) in an unchanged form.

Ephedrine is used as a broncholytic and sometimes to increase arterial pressure.

It is effective for treating rhinitis (local vasoconstriction lowers secretion of the nasal

mucous membrane). It can be administered to treat atrioventricular block; it is also used

in ophthalmology to dilate the pupil. The stimulating effect of ephedrine on the CNS is

sometimes used in narcolepsy.


4.3.2. SYMPATHOLYTICS (DRUGS INHIBITING THE TRANSMISSION FROM ADRENERGIC FIBER TERMINALS)

Sympatholytics impair transmission on the level of the varicosities of the adrener-

gic fibres, i.e. they act presynaptically (see Fig. 4.9). They do not affect adrenoceptors.

Under the action of these drugs direct adrenomimetic effect does not decrease but even

increases. Thus, sympatholytics and adrenoblockers have a blocking effect on different

stages of the adrenergic transmission of nerve impulses.

Guanethidine (octadinum), reserpine, bretilium (ornidum) belong to the group of sympatho-

lytics. Affecting the varicosities of the adrenergic fibres, these drugs reduce the amount of norepi-

nephrine, released in response to nerve impulses. The drugs of this group weaken the effects of ad-

renomimetics of indirect action (tyramine, ephedrine, amphetamine ). It has to be considered that

the mechanism of action of various sympatholytics is different. Guanidine derivative guanethidine

(octadinum; Fig. 4.13) is an active sympatholytics. When guanethidine accumulates in the vari-

cosities, norepinephrine concentration there is substantially reduced. This is why in response to

the stimuli the amount of the transmitter, released into the synaptic gap falls, the consequence of

which is a reduction in the effector reaction. Concentration of norepinephrine in the heart, vessels

and other organs and tissues decreases.

The main effect of guanethidine is a gradually developing (during several days) stable decrease

of the arterial pressure. This is caused by a reduction in cardiac output, bradycardia and the in-

hibition of the pressor reflexes. Long-term administration of guanethidine leads to a decrease in

peripheral vascular resistance.

At present time guanethidine is not used in clinical practice.

Reserpine has marked sympatholytic properties; it is an alkaloid of the Rauwolfia

plant (Rauwolfia serpentina Benth, etc.). It is a derivative of indole (Fig. 4.13).

Reserpine impairs the process of norepinephrine storage in the vesicles, which leads

to a reduction in its concentration in the varicosities. The main part of norepinephrine,

accumulating in the cytoplasm of the varicosities, is deaminated, since reserpine (as

well as guanethidine) does not inhibit MAO. A small part of norepinephrine is released

Fig. 4.13. Chemical structures of sympatholytics.


unchan ged from the endings. Reserpine does not affect its neuronal uptake. The drug low-

ers norepinephrine concentrations in the heart, vessels, adrenal medulla and other organs.

A decrease in catecholamines (and serotonin) level is also marked in the CNS. As a

consequence of this, reserpine inhibits the CNS. It has a calming (sedative) and slight

antipsychotic effect, due to which it is also mentioned in the group of the antipsychotic

drugs (see Chapter 11.1). Reserpine promotes the development of sleep. It inhibits in-

teroceptive reflexes. It intensifies the effect of hypnotics (non-selective CNS depres-

sants) and general anesthetics. It somewhat inhibits respiration and decreases body

temperature.

Currently reserpine is not used at all as an antipsychotic drug; its hypotensive effect,

induced by its peripheral (sympatholytic) action is useful in clinical practice.

Reserpine causes a gradual decrease in arterial pressure (the maximal effect is observed

after several days). Hypotension that occurs after long-term reserpine administration is

associated with a reduction in cardiac output, as well as with a decrease of peripheral

vascular resistance and pressor reflex inhibition. Reserpine does not have ganglionblock-

ing or adrenoblocking effects. Most authors do not believe that reserpine has an effect on

the vasomotor centers, since experimentally reserpine does not reduce efferent impulsa-

tion in the preganglionic fibres of the adrenergic (sympathetic) innervation.

The inhibition of the adrenergic innervation by reserpine leads to the predominance

of the cholinergic effects. It is manifested by bradycardia, an increase in the secretory

and motor activity of the gastrointestinal tract and miosis.

Monoquaternary ammonium compound — bretilium (ornidum) is another sympatho-

lytic. Its action mechanisms differ from that of guanethidine and reserpine. It mainly blocks

the presynaptic membrane, impairing the release of the mediator. Bretilium inhibits MAO.

Besides, it inhibits norepinephrine reuptake. Short-term administration of bretilium does

not change the concentration of norepinephrine in the varicosities of the adrenergic fibres,

long-term administration causes its reduction. The duration of action of bretilium is sub-

stantially lower than that of guanethidine and reserpine (5–8 h).

Guanethidine and reserpine were used mainly for the treatment of hypertension (see

Chapter 14.5). Guanethidine is more effective than reserpine as a hypotensive drug.

Sometimes guanethidine is administered for glaucoma. Tolerance to guanethidine and

reserpine develops very slowly, which is an advantage of these drugs, since they are usu-

ally administered for a long period.

Bretilium is not used as a hypotensive drug, since it is poorly absorbed from the di-

gestive tract and tolerance develops quickly. In some cases it is administered for cardiac

arrhythmias treatment (Chapter 14.2).

The possible side effects of guanethidine and reserpine are an increase in intestinal

motility (diarrhea occurs relatively often) and the digestive glands secretion (especially

of the stomach), bradycardia; some patients have pain in the area of the parotid gland

and swelling of the mucous membrane of the nose. Fluid retention is often seen. Ortho-

static hypotension can occur with guanethidine administration (but substantially more

rarely than with the administration of ganglionic blockers) but it does not happen when

reserpine is used to treat hypertension.

Reserpine may cause side effects, associated with its effect on the CNS: drowsiness

and general weakness. Long-term administration of the drug in high doses may lead to


depressive conditions and, rarely, extrapyramidal disorders. Increases in appetite also

have a central origin.

The drugs from the atropine group can eliminate increases in the digestive glands’

secretion and bradycardia that can occur due to sympatholytic action. The stimulat-

ing effect on the intestinal motility is levelled by combination with ganglionic blockers,

which reduce motility of the gastrointestinal tract. The antagonists of reserpine’s inhibi-

tory effect on the CNS are MAO inhibitors (nialamide ), which restore the balance of

catecholamines and serotonin in the cerebral tissues1. Extrapyramidal disorders are

treated with drugs effective for the treatment of Parkinsonism [for example, trihexy-

phenidil (cyclodol)].

Sympatholytics are contraindicated in severe cardiovascular disease, marked renal

failure and stomach and duodenum ulcers. Guanethidine is not recommended for ad-

ministration in pheochromocytoma.

During the recent years the use of sympatholytics for the treatment of arterial

hypertension has decreased substantially due to the advent of new improved hypoten-

sive drugs.

1 It is administered after the discontinuation of reserpine treatment.

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