CHAPTER 16

ADRENERGIC AGENTS
SHENGQUAN LIU
CHAPTER OVERVIEW
 examines biochemical basis for adrenergic action, adrenoceptors and then discusses the agents that affect the synthesis, storage,
uptake, metabolism, or release of the adrenergic NTs and especially those that act directly on the various types of adrenoceptors
Adrenergic Drugs
 Exert principal pharmacological and therapeutic effects by enhancing or reducing activity of various components of sympathetic
division of autonomic nervous system.
Sympathomimetics or adrenergic stimulants
 substances produce effects similar to stimulation of sympathetic nervous activity

Sympatholytics, antiadrenergic or adrenergic – blocking agents

 decrease sympathetic activity

 Act on adrenergic receptors (adrenoceptors, ARs) or affect the life cycle of adrenergic neurotransmitters (NTs), including
norepinephrine (NE, noradrenaline), epinephrine (E, adrenaline), and dopamine (DA).
NTs modulate vital functions
 rate and force of cardiac contraction
 constriction
 dilation of blood vessels and bronchioles,
 release of insulin
 breakdown of fat.
 Constitute a broad class of agents, including albuterol (a bronchodilator), atenolol (an antihypertensive), and many common over-
the-counter (OTC) cold remedies (Table 16.1).
ADRENERGIC NEUROTRANSMITTERS
Structure and Physicochemical Properties
Chemically Catecholamines (CAs)
NE
E
DA
which refer to all organic compounds that contain a catechol nucleus (ortho-dihydroxybenzene) and an ethylamine group (Fig.
16.1)
physiological context DA and its metabolites NE and E. E contains one secondary amino group and three hydroxyl groups.
One expect molecule is polar and soluble in water using polyfunctional solubilizing potential and calculated log P(-0.63) of E
Using the polyfunctional solubilizing potential and calculated log P (- 0.63) of E, one would expect the molecule is polar and
soluble in water, and, indeed, this turns out to be the caseE
weak base (pKa = 9.9) because of aliphatic amino group
weak acid (pKa = 8.7) because of phenolic hydroxyl group
predicted ionized species (the cation form) at physiological pH is predominant (log D at pH 7 = -2.75) that largely accounts for the
high water solubility as well as other CAs.
poor absorption and poor central nervous system (CNS) penetratiuon if log P with value of 0 to 3 is optimal window for absorption
E and NE
 undergo oxidation in presence of oxygen (air) and other oxidizing agents to produce quinone
analog, which undergoes further reaction to give mixtures of colored products, one of which is
adrenochrome (Fig. 16.2)
 solutions often stabilized by addition of antioxidant (reducing agent) such as Ascorbic acid and
Sodium bisulfide
 possess chiral carbon atom that exist as enantiomeric pair of isomers
R configuration
 with enantiomeric pair biosynthesized by body and possess biological activity
 contributes to high affinity to corresponding adrenoceptors
BIOSYNTHESIS
CA biosynthesis
 with physiological regulation in neuroendocrine cells has been reviewed.
Summary view of events and life cycle of NE
CAs in neuroendocrine cells
state of constant flux that continuouslysynthesized, released, and metabolized, maintain remarkable constant level in tissues.
Biosynthesis invoves a sequence of enzymetic reaction
 
 
Steps in Biosynthesis of Cas and related enzyme inhibitors
Steps in CA Biosynthesis
3Decar with side-chain and N-methylation)
1.3’s – hydroxylation of amino acid L – tyrosine to form L –
dihydroxyphenylalanine (L-DOPA)
2.Decarboxylation of L- DOPA to give DA
3.CA biosynthesis is side-chain β- hydroxylation of DA to give NE
4.CA biosynthesis is N – methylation of NE to give E in adrenal medulla
 
1)3’ -hydroxylation of amino acid L-tyrosine to form L- dihydroxyphenylalanine
(L-DOPA)
Rate limiting in CA viosynthesis that inhibitors of TH markedly reduce:
Endogenous NE and DA in brain
NE in heart, speelen, and other sympathetically innervated tissues
 Enzyme involved: Tyrosine hydrogenase (TH, Thyrosine – 3 – monooxygenase)
 adrenergic neuron where 3’-hydroxylation of L- Tyrosine normally present in circulation and transported activity
 plays key role in equation of CA biosynthesis and logical target of some drugs
 Effective TH inhibitors
 3
1. methyl – p – tyrosine
 Methyrosine,Demser
 Methyl ester
 have TH inhibitors most widely used to demonstrate effect of:
 Exercise
 Stress
 various drugs on turnover of Cas and to lower NE information in patients with pheochromocytoma and malignant hypertension
 

1. methyl – 3’ -iodotyrosine
  – 5 – nydroxytryptophan
2. methyl
0000— See in Figure 16.4 —-0000
 
 stereospecific and requires molecular:
 O2
 Fe2+
 Tetrahydropteridine cofactor
 TH hydroxylation
 usual for first enzyme in biosynthetic pathway which rate-limiting step in biosynthesis of NE
  
 specific phenotypic maker of CA-producing cells in CNS and PNS that activity is carefully controlled
 Example:
 Adrenergic nerve stimulation leads to activation of a protein kinase that phosphorylates TH, thereby increasing its activity.3 In addition, through end-product
inhibition, NE markedly reduces TH activity. The basis of this feedback inhibition is believed to be a competition between the CA product and the pterin
cofactor.
 Adrenergic nerve stimulation leads to activation of a protein
kinase that phosphorylates TH, thereby increasing its activity.3
In addition, through end-product inhibition, NE markedly
reduces TH activity. The basis of this feedback inhibition is
believed to be a competition between the CA product and the
pterin cofactor.
2.) Decarboxylation of L -DOPA to give DA
 Important of NT and drug in its own right in Chapter 13
Enzyme involved:
a.) DOPA decarboxylase
 Remove carboxyl group only from L-DOPA
 Demonstrate study of purified enzyme preparations and specific inhibitors that act on all naturally occurring aromatic
L-amino acid including:
 L -histidine (precursor in biosynthesis of histamine)
 L – tyrosine-
(Precursor in biosynthesis of 5-HT)
 L-trytophan-
 L – phenylalanine addition both L-DOPA and L-aromatic amino acid decarboxylase
b.) AADC (L-aromatic amino decarboxylase
 High doses result many adverse systemic effect needed to achieve desired result because relatively higher concentration
in peripheral system than in brain
 Found in:
 Catecholaminergic neirons
 High concentrations in many other tissues, including liver and kidney
 Parkinsonism
 DA deficiency in brain that ameliorate symptoms which increasing level ameliorate symptoms
 Direct Parenteral (DA) administration
 Useless because compound does not penetrate blood-brain barrier (BBB)
 Oral – dosing with L-DOPA (Levodopa, Dupar)
 act as prodrug because it entered in brain (on specific carrier) and decarboxylated to DA
 L-DOPA
 Effective and decreases tremor and rigidity
Inhibition of Peripheral AACD activity
 By coadministration of at peripheral decarboxylase inhibitor:
 Carbidopa (charged at physiological pH
 Increase proportion of levodopa that crosses BBB (See on Chapter 13)
 3.) CA biosynthesis is side-chain hydroxylation of DA to give NE
 
Enzyme involved:
Dopamine β-hydrogenase (DBH)
 Dopamine β-monooxygenase
 Where vesicular monoamine transporter (VMAT) that activity transported store vesicles by 12-helix-
memebrane-spannning proton antporter which DA formed in cytoplasm of neuron and then hydroxylated
stereospecifically
o NE formed
 Stored in vesicle until depolarization of neuron initiates process of vesicle fusion with plasma memebrane
and extrusion of NE into synaptic cleft
o DBH
 Rather low substrate specificity and act in vitro on various substrates besides DA, hydroxylating almost any
phenylethylamine to corresponding phenylethanolamine
Example: Ttramine to octopamine, methyldopamine to methylnorephirine
o Number of resultant
 Structurally analogs metabolites can replace NE at noradrenergic nerve endings and function as false NTS
4.) CA biosynthesis is N-methylation of NE to give E in adrenal medulla
 
Enzyme Involved:
Phenyethanolamine – N – methyltransferase (PNMT)
 cytosolic enzyme and methyl donor S – adenosyl methionine (SAM) is required
for N – methylation of NE
 adrenal medullary that has rather low substrate specificity and transfers methyl
group to nitrogen atom on various β – phenylethanolamines that occurs in cell
cytoplasm, and E formed is transported into storage granules of chromaffin cells
 low levels of activity exist in heart and mammalian brain
 regulation in brain has not been extensively studied, but glucocorticoids are
known to regulate activity in adrenal gland
 
 
 
 
 
 

 
STORAGE, RELEASE, UPTAKE, AND
METABOLISM

Storage and Release.

Symphatetic nerve endings and chromaffin cells
located large percentage of NE present with highly specified subcellular particles
(later shown to be synaptic vesicles but colloquially referred to as granules
located much of NE IN cns within similar vesicle that concentration is maintained by
VMAT
BIOSYNTHESIS AND STORAGE IN
GRANULES
 Entrance of Ca+2 into cells results in extrusion of NE by exocytosis NE by exocytosis of granules
 Interaction of highly conserved molecular scaffolding protein when Ca+2-triggered secretions of heading to
docking of granules at plasma membrane
 NE released from sympathetic nerve endings into synaptic cleft , where interact with specific presynaptic and
postsynaptic adrenoceptors, on effector cell, trigelling in biochemical cascade that result in physiologic
response by effector cell
Indirectly Acting and Mixed Sympathomimetics
 Tyramine
 Amphetamines
 Ephedrine
1. capable of releasing stored transmitter from noradrenergic nerve endings by Calcium-independent
2. poor agonist (some are inactive at adrenoceptors but excellent substrate for VMAT
3. avidly taken up into noradrenergic nerve endings by NE reuptake into nerve terminal
Action not require vesicle exocytosis
 in nerve transported by VMAT into vesicle , displacing NE which subsequently
ending expelled into synaptic space by reverse transport via NET
UPTAKE
must mechanism for removing NE from synapse and terminating action at receptors if once NE exerted its effect at adrenergic receptors
Mechanism
Reuptake of NE into presynaptic neuron
(recycling, major mechanism)
by NET and into extraneuronal tissues
Conversion of NE to an inactive metabolite
Diffusion of NE away from synapse
Recycling of NE
termed uptake1 and involves Na +/Cl - -dependent transmembrane (TM) NET that has affinity for NE
reuptake system transport certain amines other than NE into nerve terminal and blocked by:
Cocaine
Some of tricyclic antidepressants (See Chapter 15)
RESPONSIBLE FOR REUPTAKE OF
DA AND 5 - HT (SEROTONIN)
Sim Do Se)
(

a.Similar transporters
b.Dopamine transporter (DAT)
c.Serotonin transporter (SERT)
Transmitters released into neurons
H+-dependent TM VMAT
Transported from cytoplasm intostorage granules that carried out some of NE that reenter symphathetic neuron
Held in stable complex with adenotriphosphate (ATP) and proteins until sympathetic nerve activity or some other stimulus causes it to be released into
the synaptic cleft
Certain drugs, such as reserpine:
block transport
preventing refilling of synaptic vesicles with NE and eventually cause nerve terminals to become depleted of their NE stores that reserpine inhibits
neurotransmission at adrenergic synapses
Uptake – 2
 with relatively low affinity for NE exists an extraneuronal
uptake process to neuronal uptake of NE
 physiological significance unknown
 play role in the disposition of circulating CAs, because CAs
that are taken up into extraneuronal tissues are metabolized
quite rapidly
METABOLISM.
 second mechanism of CA removal

Major mammalian enzymes

 importance in the CA metabolism

1. monoamine oxidase (MAO)

2. catechol-O-methyltransferase (COMT)

Show comparison of two enzymes

E and NE

b oth orally inactive and have sho rt duratio ns of action because o f their:

 hig h hydrop hilicity

 ionization

 extensive first-pass metab olic d eactivation b y COMT and MAO

 metab olism manifested lack of sub strate sp ecifity o f COMPT and MAO

 acts on metabolites produced by the other

Show Lack of Substrate Specificity of COMT and MAO

Manifested in metabolism of NE and E
Catecho ls

 d rug s that sub ject to metabo lism by COMT, whereas d rug s with unsub stituted o r seco nd ary N -

methylamino amino g ro up s are o ften sub strates fo r MAO

MAO

 first enzyme imp o rtant in metab o lism o f CAs in ad renerg ic neuro ns of human b rain and p erip heral

tissues

 o xid atively d eaminate CAs to their corresp o nd ing aldehyd es, which are rap id ly o xid ized to the

co rresp o nding acid b y the enzyme ald ehyd e d ehydro g enase (AD).

Ald ehyd e reductase (AR)

 red uced to the glyco l

Exa m p le :

NE d e a m ina te d o xid ative ly b y MAO to g ive 3,4 -d ihyd ro xyp he nylg lyco lalde hyd e (DOPGA), which the n re d uce d

b y AR to 3,4-d ihyd ro xyp he nyle thyle ne g lyco lwhich p rim arily this g lyco l m e ta b o lite tha t is re le a se d into the

circula tio n, whe re it und e rg o e s m e thyla tio n b y the COMT tha t it e nco unte rs in no nne uro na l tissue s.

The p ro d uct o f m e thyla tio n, 3-m e tho xy-4-hyd ro xyp he nyle thyle ne g lyco lo xid ize d b y a lco ho l d e hyd ro g ena se

a nd AD to g ive 3-m e tho xy-4-hyd ro xym a nd elic a cid which m e ta b olite co m m only is re fe rre d to a s

vanillylmandelic acid (VMA), a nd is the m a jo r e nd p ro d uct o f se ve ra l p a thwa ys o f NE m e ta b o lism .

Estim a te o f CA turno ve r

 ca n b e o b ta ine d fro m la b o ra to ry a na lysis o f to ta l m e ta bo lite s (so m e tim es re fe rre d to a s VMA a nd

m e ta ne p hrine s) in 24-ho ur urine sa m p le .

Extra ne uro na l Site s (live r)

 Oxid a tive d e a m inatio n o f NE a nd E

 a ld e hyd e fo rm e d is o xid ize d usua lly b y AD to g ive 3,4 -d ihyd ro xym a nd e lic a cid (DOMA)
MAO inhib ito rs (MAOIs)

 p re ve nt MAO-ca ta lyze d d e a m ina tion o f NE, DA, a nd 5-HT fo llo wing the ir re up ta ke into the ne rve

te rm ina l fro m the syna p tic cle ft tha t re sult, hig he r co nce ntra tio n o f the NTs will b e sto re d in the ve sicle s

a nd b e co m e a va ila b le fo r re le a se fro m the p re syna p tic te rm ina ls o n d e m a nd .

 Antid e p re ssa nts such a s:

 Phe ne lzine (Na rd il) Iso carb o xa zid (Ma rplan),

 Tra nylcyp ro m ine (Pa rna te ).

Two typ e s o f MAOs,

 e xhib it d iffe re nt sub stra te se le ctivity

1. MAO-B p rim a rily m e ta b o lize s DA a nd thus MAO-B inhib ito rs

 wo uld te nd to p re se rve b ra in DA a nd b e e ffe ctive b y the m se lve s a nd / o r p o te ntia te le vod o pa .

Se le g iline

(Eld e p ryl)

 sp e cific typ e MAO-B inhib ito r a nd d o e s e xte nd the d ura tio n a nd incre a se the e ffica cy o f

le vo d o p a .

 Pro m ising d rug p ro b a b ly a s a d junct to le vo d o p a o r in le vo d o p a re fra cto ry p a tients.

Und erstanding of CAs metabo lism

 imp ortant in management of certain drug therap ies and may even aid in diagno sis.

Examp le

Changes resulting from drug s indicate success of treatment. The cereb ro spinal fluid (CSF) levels

o f methylhyd ro xyp henylg lycoald ehyd e (MOPEG) are indicative o f NE levels. Just as they can be

related to the intensity of d epressio n, deg ree o f imp ro vement expected with antidepressants

can monitored in the weeks it may take befo re the clinical symptoms imp ro ve. A CSF level of

ho mo vanillic acid (HVA, the major metab olite of b rain DA, which is a co unterpart o f end

metab olite of NE) is understand ab ly low in p arkinsonism.

2. COMT

 second enzyme o f impo rtant in metabo lism o f CAs

 O-methylates 3-OH g ro up o f CAs and rend ers them inactive

Methylatio n by COMT

o ccurs almost exclusively on the meta-OH gro up of the catechol, reg ardless o f whether the catecho l is NE, E,
o r o ne of the metab olic p roducts
 Example:
a. Action of COMT on NE and E gives normetanephrine and metanephrine, respectively. A converging
pattern of the metabolism of NE and E in which 3-methoxy-4-hydroxymandelic acid (VMA) and 3-
methoxy-4-hydroxyphenylethylene glycol are common end products thus occurs, regardless of
whether the first metabolic step is oxidation by MAO or O-methylation by COMT. In patients with
tumors of chromaffin tissue that secrete these amines (a rare cause of high blood pressure), the
urinary excretion of VMA is markedlyexclusively on the meta-OH group of the catechol, regardless
of whether the catechol is NE, E, or one of the metabolic products.

b. The action of COMT on NE and E gives normetanephrine and metanephrine, respectively. A

converging pattern of the metabolism of NE and E in which 3-methoxy- 4-hydroxymandelic acid
(VMA) and 3-methoxy-4-hydroxyphenylethylene glycol are common end products thus occurs,
regardless of whether the first metabolic step is oxidation by MAO or O-methylation by COMT. In
patients with tumors of chromaffin t issue that secrete these amines (a rare cause of high blood pressure),
the urinary excretion of VMA is markedly increased and is used as a diagnostic test for this condition.
ADRENERGIC RECEPTORS
Adrenergic Receptor Subtypes
Density and proportion α- and β-adrenoreceptors
-important factor in the response of any cell or organ to adrenergic d rugs.
Example:

NE has relatively little capacity to increase bronchial airflow, because the receptors in bronchial smoo th muscle

are largely of the β2-subtype. In co ntrast, isoprotereno l (ISO) and E are potent bronchodilators.

The various adrenocep tor typ es and subtypes are not uniformly distributed with certain tissues containing

more of one type than another.

𝒂 1-Ag onists as Vaso co nstrictors and Nasal Decongestants.

Vaso constrictio n-princip al effect in b lo od vessels.

-results in the d ecreased blo od flow during the fight -o r-flight response.

-this accounts for an individ ual’s skin appearing pale when frightened.

- Ag o nists acting selectively on 𝑎 1 recepto rs cause vaso constriction and thus can be used alongside lo cal

anesthetics in dentistry to localize and p rolo ng the effect on the anesthetic at the site o f injectio n.

- Ag o nists acting selectively on 𝑎 1 -recepto rs cause vaso co nstriction and thus can be used along side local

anesthetics in dentistry to localize and p rolo ng the effect on the anesthetic at the site o f injectio n.
𝒂 1 Antag o nists fo r Tre atment o f Hype rte nsio n

𝑎 1 -a nta g o nists wo uld b e e xp ecte d to b e va so d ila tors a nd hyp o te nsive with cle a r im p lications o f tre ating

hyp e rte nsio n. Simila rly, the y sho uld b lo ck 𝑎 1A-re ce p to r in p ro sta te sm o o th muscle and re la x the m uscle with

imp lica tion o f treating b e nig n p ro sta tic hyp erp lasia (BPH).

𝒂1-Ag o nists fo r Tre atme nt o f Hype rte nsio n.

𝑎 1 - Ag o nists (e .g ., clo nid ine ) act a t CNS site s to d e cre a se symp athe tic o utflo w to the p e rip he ry, resulting in

d ecrea sed NE release a t sym p athe tic ne rve te rm ina l a nd , the re fo re , re la xe d va scula r sm o o th m uscle.

𝑩 1-Blo cke rs fo r Tre atme nt o f Hype rte nsio n, Ang ina, and Ce rtain Cardiac Arrhythmias.

-Activa tio n o f the 𝐵1 re ce p to rs in he a rt causes a n incre a se in ra te a nd fo rce o f co ntra ctio n and 𝑎 1 -b lo ckers

sho uld b e e xp ected to slo w the he a rt rate a nd d e cre a se the fo rce o f co ntra ctio n.

𝑩 2 -Ag o nists fo r Treatme nt o f Asthma and Pre mature Labo r.

-A m a jo r clinica l use fo r a d re ne rg ic a g o nists is in tre atme nt o f a sthma . Activa tio n o f 𝐵 2 -re ce p to rs re la xes the

smo o th m uscle s in the b ro nchi, thus d ila ting a nd o p e ning a irways. Sim ilarly, a ctivation o f 𝐵2 -re ce p to rs in the

ute rus re la xe s the m uscle , a nd so m e 𝐵 2 -a g o nists a re thus use d to inhib it ute rine co ntra ctio ns.
-ADRENERGIC RECEPTORS
The  subtypes of adrenoceptor and their effector systems
 Early 1970s, the d isco very that certain ad renerg ic ago nists and antag o nists exhib ited vario us d eg rees o f

selectivity for p resynap tic and p o stsynap tic 𝑎-recepto rs led to the prop o sal that p o stsynaptic 𝑎 1 -

recepto rs be desig nated 1 and that p resynap tic 𝑎-recep to rs be referred to as 2.

 Later, a functio nal classificatio n o f the -recepto rs was p ro po sed wherein 𝑎1-recep to rs were d esig nated

as those that were excitato ry, while 𝑎 2 -recep to rs purp o rtedly med iated inhib ito ry resp o nses.

 Further d evelo p ments revealed, ho wever, that b o th 𝑎 1 and 𝑎 2 recepto rs could be either p resynap tic or

p o stsynap tic and either excitato ry o r inhib ito ry in their resp o nses. Ho wever, the p hysio lo g ic sig nificance

o f p o stsynaptic 𝑎 2 recep to rs is less well und ersto od .

 Pharmaco lo gical and mo lecular b io lo gical metho d s have shown that it is p o ssible to subd ivid e the 1and

2-recep to rs into ad d itio nal sub types. The 𝑎 1 and 𝑎 2recepto rs each have b een d ivided into at least three

subtypes, which have b een desig nated 𝑎1A, 𝑎1B, 𝑎1D and 𝑎2A, 𝑎2B, 𝑎2C, resp ectively.
 Both receptor subtyp es b elong to a superfamily o f memb rane recepto rs who se general structure

consists o f 7TM α-helical seg ments. The interactio n o f ad renergic d rugs and the recep to rs alters the

tertiary o r quaternary structure of the recep to r, includ ing the intracellular d o main. These structural

changes are no t sufficient to yield an ap pro p riate respo nse, b ecause they are restricted to a small

numb er o f recep to r molecules in the cell memb rane.

 The info rmation emb o died by CAs or d rug s, which act as primary messeng ers, must b e transd uced into

d ownstream activity that can alter the biochemistry of the cell. The signal–transd uction mechanisms

invo lve co up ling to G proteins. Each G p rotein is a hetero trimer co nsisting of α-, β-, and 𝑦-sub unit and

is classified based on their distinctive subunits. G p ro teins of p articular impo rtance for ad renocep to r

functio n includ e Gs, the stimulato ry G p rotein of ad enylyl cyclase (AC); Gi, the inhibitory G p rotein o f AC;

and Gq , the pro tein co upling recep tors to p ho sp ho lipase C (PLC).