Sympathomimetics

1. Sympathomimetics
Dr.M.Usman Khalid
DPT,MS-NMPT

2. Sympathomimetics
O A drug that mimics stimulation of the
sympathetic autonomic nervous system.

3. CLASSIFICATION

4. Mode of Action
O Sympathomimetic agonists may directly
activate their adrenoceptors, or they may
act indirectly to increase the concentration
of endogenous catecholamine transmitter
in the synapse.

5. Types of adrenoceptors, some of the peripheral
tissues in which they are found, and their
major effects

6. CHEMISTRY &
PHARMACOKINETICS
O The endogenous adrenoceptor agonists
(epinephrine, norepinephrine, and
dopamine) are catecholamines and are
rapidly metabolized by COMT and MAO.
O If used as drugs, these adrenoceptor
agonists are relatively inactive by the oral
route and must be given parenterally.
O Short duration of action.

7. MECHANISMS OF ACTION
O A. Alpha-Receptor Effects: Alpha-
receptor effects are mediated primarily by
the trimeric coupling protein Gq. When Gq
is activated, the alpha moiety of this
protein activates the enzyme
phospholipase C, resulting in the release
of inositol-1,4,5-trisphosphate (IP3) and
diacylglycerol (DAG) from membrane
lipids.

8. B. Beta-Receptor Effects
O All β receptors (β1, β2, and β3) stimulate
adenylyl cyclase via the coupling protein
Gs, which leads to an increase in cyclic
adenosine monophosphate (cAMP)
concentration in the cell.

9. C. Dopamine-Receptor
Effects
O Dopamine D1 receptors activate adenylyl
cyclase via Gs and increase cAMP in
neurons and vascular smooth muscle.
O Dopamine D2 receptors are more
important in the brain but probably also
play a significant role as presynaptic
receptors on peripheral nerves.
O These receptors reduce the synthesis of
cAMP via Gi.

10. ORGAN SYSTEM EFFECTS
O A. Central Nervous System: Sympathomimetics
that do enter the CNS (eg, amphetamines,
cocaine) have a spectrum of stimulant effects,
beginning with mild alerting or reduction of fatigue
and progressing to anorexia, euphoria, and
insomnia.
O Repeated dosing of amphetamines results in the
rapid development of tolerance and dependence.
O Very high doses of amphetamines lead to marked
anxiety or aggressiveness, paranoia, and, less
commonly, seizures.
O Overdoses of cocaine very commonly result in
seizures.

11. B. Eye
O The smooth muscle of the pupillary dilator
responds to topical phenylephrine and
similar α agonists with contraction and
mydriasis.
O Accommodation is not significantly
affected.

12. C. Bronchi
O The smooth muscle of the bronchi relaxes
markedly in response to β2 agonists, eg,
isoproterenol and albuterol. These
agents are the most efficacious and
reliable drugs for reversing
bronchospasm.

13. D. Gastrointestinal Tract
O The gastrointestinal tract is well endowed
with both α and β receptors, located both
on smooth muscle and on neurons of the
enteric nervous system.
O Activation of either α or β receptors leads
to relaxation of the smooth muscle.
Alpha2 agonists may also decrease salt
and water secretion into the intestine.

14. E. Genitourinary Tract
O The genitourinary tract contains α receptors in
the bladder trigone and sphincter area; these
receptors mediate contraction of the
sphincter.
O In men, α1 receptors mediate prostatic
smooth muscle contraction.
O Sympathomimetics are sometimes used to
increase sphincter tone.
O Beta2 agonists may cause significant uterine
relaxation in pregnant women near term, but
the doses required also cause significant
tachycardia.

15. F. Vascular System
O Different vascular beds respond
differently, depending on their dominant
receptor type:
O 1. Alpha1 agonists—
O Alpha1 agonists (eg, phenylephrine)
contract vascular smooth muscle,
especially in skin and splanchnic blood
vessels, and increase peripheral vascular
resistance and venous pressure. Because
these drugs increase blood pressure, they
often evoke a compensatory reflex
bradycardia.

16. O 2. Alpha2 agonists—
O Alpha2 agonists (eg, clonidine) cause
vasoconstriction when administered
intravenously or topically (eg, as a nasal
spray), but when given orally they
accumulate in the CNS and reduce
sympathetic outflow and blood pressure.

17. O 3. Beta agonists—Beta2 agonists (eg,
albuterol, metaproterenol, terbutaline)
and nonselective β agonists (eg,
isoproterenol) cause significant reduction
in arteriolar tone in the skeletal muscle
vascular bed and can reduce peripheral
vascular resistance and arterial blood
pressure.
O Beta1 agonists have relatively little effect
on vessels.

18. O 4. Dopamine—
O Dopamine causes vasodilation in the
splanchnic and renal vascular beds by
activating D1 receptors.
O This effect can be useful in the treatment
of renal failure associated with shock.
O At higher doses, dopamine activates β
receptors in the heart and elsewhere; at
still higher doses, α receptors are
activated.

19. G.Heart
O The heart is well supplied with β1 and β2
receptors.
O The β1 receptors predominate in some
parts of the heart; both β1 and β2
receptors mediate increased rate of
cardiac pacemakers (normal and
abnormal), increased atrioventricular node
conduction velocity, and increased cardiac
force.

20. Net Cardiovascular Actions
O Sympathomimetics with both α and β1 effects
(eg, norepinephrine) may cause a reflex
increase in vagal outflow because they
increase blood pressure and evoke the
baroreceptor reflex.
O This reflex vagal effect may dominate any
direct beta effects on the heart rate, so that a
slow infusion of norepinephrine typically
causes increased blood pressure and
bradycardia .
O If the reflex is blocked (eg, by a ganglion
blocker or antimuscarinic drug),
norepinephrine will cause a direct β1-
mediated tachycardia.

21. Metabolic and Hormonal
Effects
O Beta1 agonists increase renin secretion.
O Beta2 agonists increase insulin secretion.
O All β agonists appear to stimulate lipolysis
via the β3 receptor.

22. CLINICAL USES
A. Anaphylaxis
O Epinephrine is the drug of choice for the
immediate treatment of anaphylactic shock.
B. Central Nervous System
O The phenylisopropylamines such as
amphetamine are widely used and abused
for their CNS effects. Legitimate indications
include narcolepsy and, with appropriate
adjuncts, weight reduction.
O Cocaine is abused for its mood-elevating
effect. These drugs have a high addiction
liability.

23. C. Eye
O The α agonists, especially phenylephrine
and tetrahydrozoline, are often used to
reduce the conjunctival itching and
congestion caused by irritation or allergy.
O Newer α2 agonists are in current use for
glaucoma and include apraclonidine and
brimonidine.

24. D. Bronchi
O The β agonists, especially the β2-
selective agonists, are drugs of choice in
the treatment of acute asthmatic
bronchoconstriction.
O The short-acting β2-selective agonists
(eg, albuterol, metaproterenol,
terbutaline) are not recommended for
prophylaxis, but they are safe and
effective and may be lifesaving in the
treatment of acute bronchospasm.

25. E. Cardiovascular Applications
1. Conditions in which an increase in
blood flow is desired: Beta1 agonist
2. Conditions in which a decrease in
blood flow or increase in blood pressure
is desired: Alpha1 agonists
3. Conditions in which acute cardiac
stimulation is desired: Epinephrine

26. O Genitourinary Tract:
Beta2 agonists (ritodrine, terbutaline) are
sometimes used to suppress premature
labor, but the cardiac stimulant effect may
be hazardous to both mother and fetus.

27. TOXICITY
O Excessive vasoconstriction
O Cardiac arrhythmias
O myocardial infarction
O hemorrhagic stroke
O Pulmonary edema or hemorrhage