The document discusses sympathomimetic drugs, which mimic the effects of sympathetic nervous system stimulation. It defines various adrenergic receptor subtypes and describes their signal transduction pathways. It also explains the mechanisms of action and effects of direct-acting, indirect-acting, and mixed-acting sympathomimetics. Examples are provided of commonly used drugs in each class and their therapeutic applications.

1. SYMPATHOMIMETICS
Dr. Mallappa Shalavadi
DEPARTMENT OF
PHARMACOLOGY,
H.S.K. COLLEGE OF PHARMACY,
BAGALKOT

2. Deffinitions:
• Mimic the effects of sympathetic nervous stimulation of
organs & structures that contain adrenergic receptors.
• sympathomimetics
• Adrenomimetic drugs
• Adrenergic drugs
• Α & β agonists

3. Adrenergic Receptors– Transduction Pathway: There are 2 main
groups, with
several subtypes:
1). α- receptors:
♦ α1 - receptor:
α1A, α1B, α1D
-Gq coupled
♦ α2 - receptor:
α2A, α2B, α2C
-Gi coupled
2). β - receptors:
Gs coupled
♦ β1
♦ β2
♦ β3

5. What do the receptors do?
Activation of  receptors leads to smooth muscle contraction
Activation of 2 receptors leads to smooth muscle relaxation
Activation of 1 receptors leads to smooth muscle
contraction (especially in heart)

7. • NA synthesized in the
sympathetic nerves & stored
in storage vesicles.
• When sufficiently stimulated,
the vesicles migrate to the
end of the nerve and release
NA into the synaptic cleft.
• NA binds to the adrenergic
receptors and stimulates
thermogenesis.

8. Synthesis
of
CAs

9. • Next in the chain of events there
is metabolism, which involves
two uptake mechanisms.
• Uptake 1: After stimulating the
adrenergic receptors, 85-90% of
NA is taken back up into the
sympathetic nerve (uptake 1)
and stored in vesicles or
metabolized by MAO(MAO-A) in
the mitochondria.
• Uptake 2: Some of the NA
diffuses away from the receptors
& is transported by extra-
neuronal cells by uptake 2 and
metabolized by catechol-O-
methyl-transferase (COMT).
COMT plays a much smaller role
in CA dynamics than MAO.
COMT exists in both a soluble
and a membrane-bound form.

11. Sympathetic Transmitter Substances
• NA is the mediator at synapses of the
2nd neuron. This 2nd neuron does not
synapse with only a single cell in the
effector organ; rather, it branches out,
each branch making en passant
contacts with several cells.
• At these junctions the nerve axons
form enlargements (varicosities)
resembling beads on a string. Thus,
excitation of the neuron leads to
activation of a larger aggregate of
effector cells although the action of
released NA may be confined to the
region of each junction.
• Excitation of preganglionic neurons
innervating the adrenal medulla causes
a liberation of Ach. This, in turn, elicits
a secretion of Adr into the blood, by
which it is distributed to body tissues
as a hormone.

12. Activation of the
sympathetic
division can be
considered a
means by which
the body
achieves a state
of maximal work
capacity as
required in fight
or flight
situations.

13. CLASSIFICATION:

14. 20-Jun-23 14
• THERAPEUTIC CLASSIFICATIOIN OF ADRENERGIC DRUGS
1. Pressure agent:-
Noradrenalin, Ephedrine, Dopamine, Phenylephrine, Methoxamine, Mephentermine
2. Cardiac stimulant:-
Adrenaline , Dopamine , Isoprinosine
3. Bronchodilator:-
Adrenaline , Terbutamine , Isoprenaline, Salbutamol, Salmetrol, Formoterol
4. Nasal decongestants:-
Phenylephirine, Naphazoline, Oxylometazoline, Pseudoephdrine,
phenylpropanolamine
5. CNS stimulant:-
Amphetamine, Methamphetamine, Dexamphetamine
6. Anorectics:-
Fenfluramine , Sibutramine , Dexfenfluramine
7. Uterine relaxant & vasodilators:-
Ritodrine ,Salbutamol , Insoxsuprine , Terbutaline

15. PHARMACOLOGICAL ACTIONS OF
SYMPATHOMIMETICS

16. 20-Jun-23 16
Epinephrin binds its receptor, that associates with an heterotrimeric G protein. The
G protein associates with adenylate cyclase that converts ATP to cAMP, spreading the signal .
MECHANISM
Contraction
of smooth
muscle
Inhibition of
Transmitter
release
Contraction
Of smooth
muscle
Contraction of
Heart muscle,
Relaxation of
Smooth muscle,
glycogenolysis

17. 20-Jun-23 17
ACTIVATION OF alpha1 RESPONSE
Agonist Extra cellular
PtdIns4,5-p2
DAG
alpha1
receptor Protein activated
Phospholipase C kinase C PKC
GDP
GTP
IP3 Intracellular
calcium dependent
protein kinase
free calcium stored calcium
activated protein kinase
βγ
αq
α*q
+
+
+
+
Stimulation of α1 receptors by catecholamine leads to the activation of a Gq coupling protein. The α
subunit of this G protein activates the effector, phospholipase C, which leads to the release of IP3 and
DAG from PtdIns 4,5 P2. IP3 stimulates the release of sequestered stores of Ca 2+ leading to an
increased conc. cytoplasmic Ca 2+ .Calcium may then activate Ca 2+ -dependent protein kinase, which
in turn phosphorylate their substrates. DAG activates protein kinase C

18. 20-Jun-23 18
αs
βγ
αi
Agonist
Gs
βγ
Β-receptor
GTP
αs* αi*
+
α2 receptor
Gi
GDP
_
Agonist
ATP cAMP
GTP GDP GDP GTP
R2C2 Protein kinase
2C
2R
Enzyme
Enzyme PO4
Biological effect
ATP
ADP
GTP
+
Adenyl cyclase
GDP
+
ACTIVATION AND INHIBITION OF ADENYL CYCLASE RESULTS…….
R-regulatory sub unit of cAMP dependent proteinkinase.
C- active catalytic sub units-that phosphorylate specific protein
substrate

19. Mechanism of Action:
Direct-acting sympathomimetics:
• Binds directly to the receptor and causes a physiologic
response.

20. DIRECTLY ACTING:
DRUG MAIN
ACTION
USES/FUCTION Adv.EFFECTS PHARMACOKINETIC
ASPECTS
NE α/β
agonist
Clinically not used,
Neurotransmitter at
postganglionic symp.
neurons
Hypertension,
tachycardia,
ventricular
dysrhythmias
Not orally, rapid
removal by tissues,
metabolized by
MAO&COMT,
plasma t1/2≈2min
Epi α/β
agonist
Asthma, anaphylactic
shock, cardiac arrest,
added to LA solutions,
main hormone of adrenal
medulla
As NE As NE, given i.m. or
s.c. or 0.5% aerosol.
Iso β agonist
(non-
selective)
Asthma tachycardia,
dysrhythmias
Some tissue uptake,
inactivation by
COMT, plasma t1/2
≈2h
Dobutamine β1agonist
(non-
selective)
Cardiogenic shock dysrhythmias plasma t1/2≈2min,
given i.v.

21. Salbutamol β2 agonist Asthma,
premature
labour
Tachycardia,
dysrhythmias,
tremor,
Orally, aerosol,
excrete unchanged,
plasma t1/2≈4h
Salmeterol,
Formeterol
β2 agonist Asthma As salbutamol Aerosol, long acting
Terbutaline β2 agonist Asthma, delay
of parturation
As salbutamol Poor orally, aerosol,
unchanged excrete,
plasma t1/2≈4h
Clenbuterol β2 agonist Anabolic action
to increase
muscle stength
As salbutamol Orally, long acting
Ritodrine β2 agonist delay of
parturation
As salbutamol Poor orally, i.v.,
Phenylephrine α1 agonist Nasal
decongestion
Hypertension, reflex
bradycardia
Intranasally,
metabolized by MAO,
short plasma t1/2
Methoxamine α agonist Nasal
decongestion
As Phenylephrine Intranasally, plasma
t1/2≈ 1h
Clonidine α2 Partial
agonist
Hypertension,
migraine
Drowsiness,
orthostatic
hypotension,
oedema,weight gain,
orally; unchanged
excretion; & as
conjugate
Plasma t1/2 ∼12 h

22. 20-Jun-23 22
 The overall pharmacological actions are…
1. Heart- increases hrt rate by activating latent pacemakers in AV node and
purkinje fibres.
. Force of cardiac contraction is increased, development of tension as well as
relaxation are accelerated – thus systole is shortened than diastole .
All cardiac actions are predominantly β1 receptor mediated.
2. Blood vessels – both vasoconstriction (α) in cutaneous, mucous membrane
& renal bed and vasodilatation (β2) mainly in sk muscles, liver and coronaries,
depending on the drugs, its dose and vascular bed .
3. BP – the effect depends on the amine its dose and rate of administration
. NA- rise in systolic ,diastolic and mean bp. No vasodilation (no β2 action ).
. Iso – rise in systolic bp (β1),and marked fall in diastolic (β2)
. Adr – when given slow i.v infusion or sc inj. –rise in systolic but fall in
Diastolic bp. Pulse presser is increased
When given iv inj. Marked increase in systolic and diastolic bp (at high conc. Alpha
response predominates)

23. 20-Jun-23 23
4. Respiration – Adr and Iso (but not NA) potent bronchodilators (β2)
5. Eye – Adr : mydriasis due to contractn of radial muscles of iris (α1)
6. GIT – Gut relaxation will occures through activation of both α and β recept.
7. Uterus – effect of Adr varies with species, harmonal and gestational status
eg- non pregnt pregnt
rat relaxtn relxn
rabbit contr contr
cat relxn contr
human contr relxn
8. CNS – clinically Adr does not produce marked CNS effect – as poor
penetration in brain . Inj. In brain –produce excitn followed by depression
. Activation of alpha 2 recpt in brain stem results in decreased sympathetic
outflow – fall in bp .
Receptor Agonist action
α1 - vasoconstritn of ciliary muscle- reduced aq formation
α2 - reduced secretary activity of ciliary epithelium
β2 - enhanced secr. activity of epithelium

24. 20-Jun-23 24
 COMPARATIVE EFFECTS OF Adr , NA and Iso
Adr NA Iso
1.Hrt rate
2.Cardiac output
3.BP- systolic
diastolic
mean
4.Bld flows – sk. Muscle
kidney
coronary
5.Bronchial muscle
6.Intestinal muscle

25. 20-Jun-23 25
Liver
glycogen
Glucose-1-p
Glucose-6-p
glucose
Glycogen
synthase
phosphorylase
phosphatase
Fatty acids
triglycerides
lipases
Fat
Muscle
glycogen
Glucose-1-p
Glucose gucose-6-p
TCA CYCLE
ENERGY
phosphorylase
Glycogen
synthase
+ +
+
-
-
Blood stream
Regulation of energy metabolism by CATECHOLAMINES
The main enzymic steps that are affected by beta adrenoreceptor activation
Are indicated by+ and – signs, denoting stimulation and inhibition resp. The
Overall effect is to mobilise glycogen and fat stores to meet energy demands

26. Dobutamine
• Activates myocardial β1 to increase the force of myocardial
contraction.
• Little effect on heart rate at therapeutic doses - high doses can
induce arrhythmias.
• Causes a decrease in BP & TPR.
• Does not activate dopamine receptors
• Dobutamine used clinically is a racemic mixture
• (+) Dobutamine is a β1 and β2 agonist
• (-) Dobutamine is an α1 agonist.
• Observed clinical profile is due to a combination of these
pharmacological effects.
• Short term treatment of cardiogenic shock and CHF. Its use is
associated with a decrease in LV filling pressure.
• Must be given intravenously.

27. Tocolysis:
• The uterine relaxant effect of β2-adrenoceptor agonists, such as
terbutaline or fenoterol, can be used to prevent premature labor.
• Vasodilation with a resultant drop in systemic BP results in reflex
tachycardia, which is also due in part to the β1-stimulant action of
these drugs.
Vasoconstriction:
• Local application of α-sympathomimetics can be employed in
infiltration anesthesia for prolong the action(Adr);
• or for nasal decongestion (naphazoline, tetrahydrozoline,
xylometazoline).
• Systemically administered epinephrine is important in the
treatment of anaphylactic shock for combating hypotension.

28. Indirect-acting sympathomimetics:
• Causes the release of CA from the storage sites (vesicles) in
the nerve endings.
• The CA then binds to the receptors and causes a physiologic
response.
Mechanism of Action:

29. INDIRECTLY ACTING
Tyramine
NA release No clinical uses
Present in various
foods
As NE metabolized
by MAO in
gut , no BBB
Amphetamine NA release,
MAO inhibitor,
uptake 1 inhibitor,
CNS stimulant
as CNS stimulant in
narcolepsy,
Appetite
suppressant
Drug of abuse
Hypertension,
tachycardia,
insomnia
Acute psychosis
with overdose
Dependence
Orally, BBB,
Excrets
unchanged in
urine
Plasma t1/2
∼12h,
Atomexitine,
Reboxetine
CA reuptake
inhibitors,
CNS stimulant
As NE As NE ----
Modafinil Uptake 2
inhibitor of NE,
Dopamine, 5-HT
To improve
wakefulness in
narcolepsy,
BP & heart rate
increases
----
Sibutramine CA reuptake
inhibitors
Appetite
suppressant-in
obesity
---- ----
DRUG MAIN ACTION USES/FUCTION Adv.EFFECTS P-KINETIC
ASPECTS

30. • Amphetamine enters the nerve
terminal via NA transporter
(uptake1) &
• Enters synaptic vesicles via vesicular
monoamine transporter (VMAT), in
exchange for NA, which accumulates
in the cytosol.
• Some of the NA is degraded by MAO
within the nerve terminal & some
escapes, in exchange for
amphetamine via the uptake1, to act
on postsynaptic receptors.
• Exocytosis is not involved in the
release process, so their actions not
require the presence of Ca2+.
• They are not completely specific in
their actions, & act partly by a direct
effect on receptors, partly by
inhibiting uptake 1 (thereby
enhancing the effect of the released
NA), & partly by inhibiting MAO.

31. Indirect Acting:
• MAO is located in mitochondria, & serves to scavenge axoplasmic
free NE.
• Inhibition of the enzyme causes free NE concentrations to rise.
Likewise, dopamine catabolism is impaired, making more of it
available for NE synthesis.
• Consequently, the amount of NE stored in granular vesicles will
increase, and with it the amount of amine released per nerve
impulse.

32. Mixed Acting:
Ephedrine : as alkaloid
• Non-catechol phenylisopropylamine - has high bioavailability
& long duration of action.
• Excreted unchanged through urine.
• Activate β-receptor– Asthma, as mild stimulant.
• Pseudoephedrine as a precursor for manufacture of
methampetamine.
Phenylpropylamine: as appetite suppressant.
• Not used: hemorrhagic strokes, MOA is unclear.
• Can increase BP in patients with impaired autonoic reflexes.

33. DOPAMINE:
• Dopamine has a
complex
pharmacology. It can
activate at least 4
receptors: β1, DA1, α1
& α2.
• low doses: the DA1
receptors will be
activated
• moderate doses:the
beta1 receptors will
be activated
• high doses:- the
alpha receptors will
be activated.

34. Clinical uses of adrenoceptor agonists:
• Cardiovascular system:
– cardiac arrest: adrenaline
– cardiogenic shock: dobutamine (β1 agonist)
• Anaphylaxis (acute hypersensitivity) : adrenaline.
• Respiratory system:
– asthma: selective β2-receptor agonists (salbutamol, terbutaline,
salmeterol, formoterol)
– nasal decongestion: drops containing xylometazoline or ephedrine for
short-term use.
• Miscellaneous indications:
– adrenaline: with local anaesthetics to prolong their actions.
– premature labour salbutamol.
– α2 agonists (e.g. clonidine): to lower blood pressure and intraocular
pressure; as an adjunct during drug withdrawal in addicts; to reduce
menopausal flushing; and to reduce frequency of migraine attacks.

35. Adverse Effects:
α-adrenergic; β-adrenergic
CNS
Headache, restlessness,
excitement, insomnia,
euphoria
Cardiovascular
Palpitations (dysrhythmias),
tachycardia,
vasoconstriction,
hypertension
Other
Loss of appetite, dry mouth,
nausea, vomiting, taste
changes (rare)
CNS
Mild tremors, headache,
nervousness, dizziness
Cardiovascular
Increased heart rate,
palpitations (dysrhythmias),
fluctuations in BP
Other
Sweating, nausea, vomiting,
muscle cramps

36. REFERENCES:
• Rang H. P., Dale M. M., Ritter J. M., Flower R. J., Rang and
Dale’s Pharmacology, 6th ed. Churchil Livingstone Elsevier
2007: 168-177.
• Katzung B. G., Masters S. B., Trevor A. J., Basic and clinical
pharmacology, 11th ed. Tata Mc Graw-Hill 2009:127-148.
• Laurence L. B., John S. L., Keith L. P. Goodman and Gilman’s-
The Pharmacological basis of therapeutics, 11th ed. Mc Graw
Hill 2005,237-263.
• Barar F. S. K. Essentials of pharmacotherapeutics, 5th ed. S
chand & company Ltd. 2009,193-206.
• www.google.com