Sympathomimetics &

Sympatholytics

Hazel Anne L. Tabo

Sympathetic Outflow
S
P
I Paravertebral
N sympathetic Depolarization on
A chain ganglia post-synaptic Adrenoceptor
neuron
L Na
+
Na
+
N Ach
NE NE
NE
E NE
R
K+ K+
V
E Ganglia
Nicotinic Effector organ
cholinoceptor
Sympathetic NS
Excitation of preganglionic neurons innervating the adrenal medulla causes a
liberation of acetylcholine or nicotine. This, in turn, elicits a secretion of
epinephrine (= adrenaline) into the blood and into body. Liberated norepinephrine
reacts with adrenoceptors:
a) pre-synaptically on the membrane of Varicosities (nerve axons form
enlargements resembling beads on a string.).
b) post-synaptically on the membrane of effector cells or

Activation of presynaptic α2-receptors inhibits NE release. By this negative

feedback, release can be regulated.

METABOLISM: The effect of released norepinephrine wanes quickly, because

approx. 90 % is actively transported back into the axoplasm then back to storage
vesicles (neuronal re-uptake). Small portions of norepinephrine are inactivated by
the enzyme catechol-O-methyltransferase (COMT, present in the cytoplasm of
postjunctional cells, to yield normetanephrine), and Monoamine oxidase (MAO,
present in mitochondria of nerve cells and postjunctional cells, to yield 3,4-
dihydroxymandelic acid).
• The liver is richly
endowed with COMT and
MAO; it contributes
significantly to the
degradation of
circulating
norepinephrine and
epinephrine.
• The end product of the
combined actions of
MAO and COMT is
vanillylmandelic acid.
Distribution of Adrenergic
Receptors: Tissue (Actions)
• α1
- Vascular smooth muscles (constriction)
- Pupillary dilator muscle (dilates pupil)
- Arrector pili / pilimotor smooth muscle (erects hair)
- Rat liver (glycogenolysis)
• α2
- Postsynaptic CNS adrenoceptors (mutiple effects)
- Adrenergic & cholinergic nerve terminals (inhibition of transmitter release)
- Platelets (aggregation)
• β1
- Heart, Adipocytes, CNS (activates Adenylyl cyclase, stimulates fast cardiac activity)
β2
- Respiratory, Uterine & Vascular smooth muscle (activates adenylyl cyclase, relaxation of
smooth muscles or bronchodilation)
• Β3 – urinary bladder (relaxation) - controls frequency & urgency
• Dopa1 – Renal vessels, CNS - activates A-cyclase
• Dopa2 – Nerve terminals, CNS - Inhibition of A-cyclase
• Activation of α1 receptors by catecholamines
Adrenoceptors and
Catecholamine Actions
• Three major groups: α1, α2, and β
1. Smooth muscle effects – Figure A
2. Vasoconstriction –
Local α-sympathomimetics
-Nasal decongestion (naphazoline, tetrahydrozoline, xylometazoline).
Systemic sympathomimetic
- Epinephrine- tx:anaphylactic shock (allergies) for combating hypotension

3. Bronchodilation - β2-Adrenoceptor, tx of bronchial asthma (Ex: terbutaline, fenoterol,

or salbutamol)
4. Tocolysis - The uterine relaxant effect of β2-adrenoceptor agonists can be used to
prevent premature labor, such asterbutaline or fenoterol. Vasodilation with a resultant
drop in systemic blood pressure results in reflex tachycardia (partial effect of drug to β1-
receptors)
5. Cardiostimulation – β1-receptors by Ad-cyclase and cAMP production,
catecholamines augment all heart functions systolic force (positive inotropism),
velocity of shortening (clinotropism), sinoatrial rate (chronotropism), conduction
velocity (p. dromotropism), and excitability (bathmotropism). In pacemaker fibers,
diastolic depolarization is hastened, so that the firing threshold for the action
potential is reached sooner (positive chronotropic effect, B). The cardiostimulant
effect of β-sympathomimetics such as epinephrine, for tx. Of cardiac arrest. Use
of β- sympathomimetics in heart failure carries the risk of cardiac arrhythmias.

6. Metabolic effects - β-Receptors mediate (glycogenolysis) in both liver and skeletal

muscle. In adipose tissue, triglycerides are hydrolyzed to fatty acids (lipolysis,
mediated by β3-receptors). The metabolic effects of catecholamines are not
amenable to therapeutic use.
The CATECHOLAMINES
Classification of Drugs
• Catechol –presence of OH- at phenyl ring (trivial name for O-
hydroxyphenol)
• Amino group – species of drugs
1. Catecholamines – endogenous and non-endogenous
2. Non-catecholamines – non-endogenous

OH
-CATECHOL, phenyl ring
(aromatic)
OH CH2 – CH2 – NH2
- AMINO GROUP., ethylamine
Direct sympathomimetics (agonists) mimic the actions of the
naturally-occurring catecholamines, norepinephrine and epinephrine,
and are used for various therapeutic effects:

Catecholamines
• 1. Endogenous (adrenal medullary hormones) – E, NE,
Dopamine
• 2. Non-endogenous – Isoproterenol, Dobutamine

Non-catecholamines (non-endogenous)
• Amphetamine – resists COMT: high adrenergic effect
• Phenylephrine
• Ephedrine
• Albuterol
• Terbutaline
• Ritodrine
Mechanism of Action

- Directly reacts with adrenergic receptors as Selective or Non-

Direct-acting selective drugs

- Bring the effect but does not directly react with receptors
Indirect-acting (Amphetamine); resistant to COMT/MAO or enzyme
inhibitors (e,g. MAO-Inhibitors)

- Mimics an endogenous drug and at the same time release the

Mixed endogenous forms (Ephedrine)
I. Direct-acting: Selective Drugs

• Specific receptor – alpha 1, alpha 2, beta 1, beta 2, dopa1, dopa2

• EPINEPHRINE: Due to its equally high affinity for all α-and β-receptors, epinephrine
does not permit selective activation of a particular receptor subtype. Like most
catecholamines, it is also unsuitable for oral administration.
NOREPINEPHRINE: differs from epinephrine by its high affinity for α-receptors and
low affinity for β2-receptors. In contrast, ISOPROTERENOL - has high affinity for β-
receptors, but virtually none for α-receptors
• DOPAMINE is the immediate precursor in the synthesis of NE (regulates Na+ & renal
fxn.); CNS neurotransmitter; Vasodilator; reward stimulus relevant to addiction; Low
levels – Parkinson’s Dse; Anti-psychotic drugs (dopa receptors)
• Norepinephrine α, β1
• Epinephrine α, β1, β2
• Isoproterenol β1, β2
Direct
Sympathomimetics
MOA: affected by their structure
affinity relationship; typically
share a phenylethylamine
structure.
The side chain β-hydroxyl group
confers affinity for α- and β-
receptors. Substitution on the
amino group reduces affinity for
α-receptors, but increases it for β-
receptors (exception: α-agonist
phenylephrine)
II. Indirect-acting:
MAO inhibitors
• Apart from receptors, adrenergic neurotransmission involves mechanisms for
the active re-uptake and re-storage of released amine, as well as enzymatic
breakdown by monoamine oxidase (MAO). Norepinephrine (NE) displays
affinity for receptors, transport systems, and degradative enzymes. Chemical
alterations of the catecholamine differentially affect these properties and result in
substances with selective actions.

• Inhibitors of MAO enzyme – MAO is abundant at mitochondria and serves to

scavenge axoplasmic free NE (norepinephrine). Inhibition of the enzyme causes
free NE concentrations to rise. Likewise, dopamine catabolism is impaired,
making more of it available for NE synthesis  the amount of NE stored in
granular vesicles will increase  high amine release per impulse
Indirect-acting Sympathomimetics on
CNS effect
• In the CNS, inhibition of MAO affects neuronal storage not only of NE but also of
dopamine and serotonin  stimulant effects in mood and psychomotor drive, and
used as anti-depressants.

Ex: Tranylcypromine - for depressive illness; as a covalently bound suicide

substrate, it causes long lasting inhibition of both MAO isozymes, (MAOA, MAOB).
Moclobemide - reversibly inhibits MAO-A; used as antidepressant.
Selegiline (deprenyl) – MAO-B inhibitor retards the catabolism
of dopamine; used in the treatment of parkinsonism

Cocaine – indirect-acting; NE uptake inhibitor (more NE at the synapse)

• Amphetamine –
high adrenergic
stimulation
(sympathomimetic)
-blocks MAO & NE
transport

• Cocaine – blocks
the transport
system, lower
adrenergic
stimulation (local
anesthetics);
blocks NE
transport
Indirect Sympathomimetics : MOA

• Agents that elevate the concentration of NE at neuroeffector

junctions, because they either inhibit re-uptake (cocaine), facilitate
release, or slow breakdown by MAO, or exert all three of these
effects (amphetamine, methamphetamine).

Tachyphylaxis – effectiveness of these sympathomimetics diminishes

when vesicular NE becomes depleted at axolemma.
Effects of Indirect
Sympathomimetics
• Penetrate the blood-brain barrier and evoke such CNS effects as a
feeling of well-being, enhanced physical activity and mood (euphoria),
and decreased sense of hunger or fatigue. Subsequently, the user may
feel tired and depressed.

• These after effects are partly responsible for the urge to re-administer the
drug (high abuse potential).
•
• To prevent their misuse, these substances are subject to governmental
regulations (e.g., Food and Drugs Act: Canada; Controlled Drugs Act:
USA) restricting their Rx and distribution.
Amphetamines
• Amphetamine-like substances are misused to enhance athletic
performance (doping) Risk: Dangerous physical overexertion.
Because of the absence of a sense of fatigue, a drugged athlete
may be able to mobilize ultimate energy reserves. In extreme
situations, cardiovascular failure may result.

• Closely related to amphetamine are “appetite

suppressants or anorexiants” (fenfluramine, mazindole, and
sibutramine). These may also cause dependence
and their therapeutic value and safety are questionable.
• α1 – vascular smooth
tone (local bld
vessels)

• α2- nerve terminals’

CNS blood vessels

• 1 – reflex
vasoconstriction
(heart)
Take home Quiz: (ELGA
Grouping)
Discuss the general mechanism of action
of: (give example of drugs at least 2)

• alpha and beta sympathomimetics

• alpha and beta sympatholytics
• beta blockers? Why are they called such.
• adrenergic drugs
SYMPATHOLYTICS
α-Sympatholytics . The interaction of NE with α-adrenoceptors can be inhibited
by α-sympatholytics (α-adrenoceptor antagonists, α-blockers). This inhibition
can be put to therapeutic use in antihypertensive treatment (vasodilation
peripheral resistance ↓, blood pressure ↓).

Non-selective α- blockers/sympatholytics: Phenoxybenzamine, Phentolamine -

inhibit the NE action at both post- and pre-synaptic α-adrenoceptors. Presynaptic
α2-adrenoceptors are sensors of NE release concentration outside the
axolemma, its regulation is through local feedback mechanism. When presynaptic
α2-receptors are stimulated, further release of NE is inhibited (negative feedback
mechanism). Conversely, blockade of α2-adrenoceptors leads to overt
enhancement of sympathetic effects, at β1-adrenoceptor-mediated myocardial
neuroeffector junctions (since it receives uncontrolled NE release)  tachycardia
and tachyarrhythmia.
• α1 – vascular smooth
tone (local bld
vessels)

• α2- nerve terminals’

CNS blood vessels

• 1 – reflex
vasoconstriction
(heart)
Selective α-Sympatholytics or α-
blockers
• Prazosin; Terazosin and Doxazosin (longer-acting)
• Suppress α1-receptors activation w/o associated NE release; Lack affinity
for presynaptic α2-adrenoceptors.
• TX: Used in HPN (prevent reflex vasoconstriction); Can cause postural
hypotension with pooling of blood in lower limb capacitance veins during
change from the supine to the erect position (orthostatic collapse: ↓ venous
return, ↓ cardiac output, fall in systemic pressure, ↓ blood supply to CNS,
syncope).
• For benign hyperplasia of the prostate, α-blockers (terazosin, alfuzosin)
may serve to lower tonus of smooth musculature in the prostatic region
and thereby facilitate micturition (urination).
• Reversible
– Phentolamine &
Prazosin
• Irreversible
– Phenoxybenzamine
β-Sympatholytics / β-blockers

• Antagonists of NE and E at β-adrenoceptors; no affinity for α-receptors.

• Therapeutics: Protects the heart from the O2 - wasting
effect of sympathetic inotropism by blocking cardiac β-receptors; thus, cardiac
work can no longer be augmented above basal levels (the heart is
“coasting/gliding”). This effect is utilized prophylactically in angina pectoris to
prevent myocardial stress that could trigger an ischemic attack.

• Lower cardiac rate (sinus tachycardia) and elevated BP due to high cardiac
output. The mechanism underlying their antihypertensive action via reduction
of peripheral resistance is unclear.

• Applied topically to the eye, β-blockers are used in the management of

glaucoma; they lower production of aqueous humor without affecting its
drainage (enhanced parasympathetic resp.)
Undesirable effects /
Side effects
• The hazards of treatment with β-blockers become apparent
particularly when continuous activation of β-receptors is needed
in order to maintain the function of an organ.
• 1. Congestive heart failure (CHF) - In myocardial insufficiency,
the heart depends on a tonic sympathetic drive to maintain
adequate cardiac output, ↑HR and systole tension. Β-blockers
eliminate β-receptor sympathetic drive leading to stroke volume
and cardiac rate decline, a latent/covert myocardial insufficiency
is exposed, and overt insufficiency is exacerbated or intensified.

• 2. Bradycardia, A-V block: Decline of sympathetic drive can

lead to a marked fall in cardiac rate and lead to A-V d/o of
impulse conduction.
Undesirable effects of β-blockers

• 3. Bronchial asthma: Increased sympathetic activity prevents bronchospasm in

patients disposed to paroxysmal (spastic) constriction of the bronchial tree
(bronchial asthma, bronchitis in smokers). In this condition, β2-receptor blockade
will precipitate acute respiratory distress (ARDs).
Undesirable effects…
• 4. Hypoglycemia in D. mellitus: Insulin or oral hypoglycemics in the
diabetic patient lowers blood glucose below a critical level, epinephrine is
released, which then stimulates hepatic glucose release via activation of β2-
receptors. β-Blockers suppress this counter-regulation; in addition, they
mask other epinephrine-mediated warning signs of imminent hypoglycemia,
such as tachycardia and anxiety, thereby enhancing the risk of hypoglycemic
shock.

• 5. Altered vascular responses: When β2-receptors are blocked, the

bronchodilating effect of epinephrine is abolished, leaving the α-receptor-
mediated vasoconstriction unaffected: peripheral blood flow ↓ – “cold hands
and feet”.
• 6. β-Blockers exert an “anxiolytic“ action that may be due to the
suppression of somatic responses (palpitations, trembling) caused by
sympathetic epinephrine release and induce emotional stress; in turn, these
would exacerbate “anxiety” or “stage fright”. Because alertness is not
impaired by β-blockers, these agents are occasionally taken by orators and
musicians before a major performance. Stage fright, however, is not a
disease requiring drug therapy.
Types of β-blockers
• Isoproterenol (sympathomimetic) vs.
• Propanolol (β-blocker)
• Propanolol – 1st β-blocker introduced in therapy (1965)
• Pindolol – is a partial agonist in full agonist e.g. isoprenaline,
thus binds to β receptors and effect of full agonist becomes
impeded.
• Metoprolol, Acebutolol, Bisoprolol – cardioselective (affinity for
cardiac β1 > β2)
• These β- blockers can exert a membrane-stabilizing
effect, as evidenced by the ability of the more lipophilic
congeners to inhibit Na+-channel function and impulse
conduction in cardiac tissues.
Anti-Adrenergics
• Drugs capable of lowering transmitter output from
sympathetic neurons, i.e., “sympathetic tone”. Their
action is hypotensive (indication: Hypertension);
however, being poorly tolerated, they enjoy only
limited therapeutic use.

• Inhibitors of sympathetic tone: Clonidine, Methyldopa,

Reserpine, Guanethidine
Other Anti-adrenergics or
Sympatholytics
• 1. Clonidine is an α2-agonist with high lipophilicity
(dichlorophenyl ring), permits rapid penetration through the blood-
brain barrier. The activation of postsynaptic α2-receptors reduces
the activity of vasomotor neurons in the medulla oblongata,
resulting in a resetting decrease of systemic arterial pressure. In
addition, activation of presynaptic α2-receptors in the Peripheral
NS leads to a decreased release of both NE and Ach.

Side effects (SE). Lassitude (tiredness), dry mouth; rebound

hypertension after abrupt cessation of clonidine therapy
(withdrawal syndrome).
• 2. Methyldopa (dopa = dihydroxyphenylalanine), an amino acid, is transported across the
BBB, decarboxylated in the brain to α-methyldopamine, and then hydroxylated to α-methyl-
NE. Rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter α-
methyl-NE can be stored. However, unlike the endogenous dopamine, methyldopa has a
higher affinity for α2- than α1-receptors and produce SE similar to those of clonidine.
• Inhibition of dopa-decarboxylase  non-conversion of Dopa to Dopamine

• Adverse effects. Fatigue, orthostatic hypotension, extrapyramidal Parkinson-like symptoms,

cutaneous reactions, hepatic damage, immune-hemolytic anemia
• 3. Guanethidine. (+) high affinity for axolemmal and vesicular amine transporters.
It is stored instead of NE, but unable to mimic NE fxns. It stabilizes the axonal
membrane  impeding the propagation of impulses in the sympathetic nerve
terminals. Storage and release of epinephrine from the adrenal medulla are not
affected, owing to the absence of a re-uptake process. The drug is impermeable in
BBB.

• Adverse effects. Risk of Cardiovascular crises : emotional stress of the patient

may cause sympathoadrenal activation with E release. It can increase BP and can
be more marked because persistent depression of sympathetic nerve activity
induces supersensitivity of effector organs to circulating catecholamines.
• 4. Reserpine, an alkaloid from the Rauwolfia plant, abolishes the vesicular
storage of biogenic amines (NE, dopamine (DA), serotonin (5-HT) ) by inhibiting
ATPase required for the vesicular amine pump. Low NE release per nerve impulse,
impaired E release from the adrenal medulla, and higher reserpine dose 
irreversible damage to storage vesicles or “pharmacological sympathectomy”, days
to weeks being required for transmitter re-synthesis. It is permeable to brain 
impaired vesicular storage of biogenic amines.
• Adverse effects. Extrapyramidal motor function D/O with pseudo-Parkinsonism,
sedation, depression, stuffy nose, impaired libido, and impotence; increased
appetite. These adverse effects have rendered the drug practically obsolete.