Sympathomimetics 260722

Sympathomimetic agents
A. Review of sympathetic activation

B. Introduction
C. Types and subtypes of adrenoceptors
D. Mechanism of action
E. Classification of sympathomimetic drugs
F. Mode of action
G. Therapeutic Use
C. Types and subtypes of adrenoceptors
Rank Order of Potency
 receptors Epi > NE >> Iso
 receptors Iso > Epi > NE
Type of adrenoceptor
 , 
  ,  , 
 DA1, DA2
Types and subtypes of adrenoceptors
• Generally
 ---Contraction of smooth muscle
 ---Relaxation of smooth muscle
---Stimulation in heart
 ---Inhibition, for GI tract ---Relaxation
D. Mech. of action of Adrenomimetic drugs
 via coupling protein Gq

 via coupling protein Gi
 ,  ,  via coupling protein Gs
Ca2+ channels Vascular smooth muscle
Calmodulin ATP
Ca2+ (intracellular)
agonists
cAMP
Ca -calmodulin complex
2+
Proteinkinase A
MLCK* Myosin-LC kinase (MLCK) MLCK-(PO4)2
Myosin light chain ( Myosin-LC- PO4 Myosin-LC
Myosin-LC)
Actin
Contraction Relaxation
Heart
-Agonist

Ca 2+

Vagus
M
-receptor


Gs AC Gi
kinase
ATP
cAMP
Ca 2+
Heart rate Contraction Conduction

Structure-Activity Relationship (SAR) of A
drenomimetics
• Responsible for
– different receptor selecitvity of sympa
thomimetics
– different distribution of drugs --> diff
erent actions
– different duration
Pharmacokinetic differences between CAs
and NonCAs
Catecholamines
– cannot be given orally
– short half-life, short duration
– not cross blood-brain barrier (BBB)
reasons: due to having catechol group
– Rapid destruction by MAO and COMT
– MAO, COMT locate at gut wall, liver
– High polarity
Pharmacokinetics of sympathomimetics
Drug Oral activity Duration

Catecholamines
Epinephrine No minutes
Norepinephrine No minutes
Isoproterenol Poor minutes
Dopamine No minutes
Dobutamine No minutes
Other sympathomimetics
Amphetamine, Yes Hours
Ephedrine Yes Hours
Phenylephrine Poor Hours
Albuterol, Yes Hours
metaproterenol, terbutaline
Oxymetazoline, Yes Hours
xylometazoline
Cocaine No
Minutes to
Hours
H. Organ System Effects
1. Vascular system
2. Heart
3. Net cardiovascular actions
4. Bronchi
5. Eye
6. Gastrointestinal tract (GI tract)
7. Genitourinary tract (GTU tract)
8. Metabolic and hormonal effects
9. Central nervous system (CNS)
2. Cardiac effects
 agonists
• eg, isoproterenol
• predominantly receptor(also  )
• activation of which produces an increase i
n
– the rate of cardiac pacemakers (normal and a
bnormal)
– force of contractions
– AV node conduction velocity
1. Vascular system effects
A.  agonists
– eg, phenylephrine (pure alpha agonist)
– constrict skin, cutaneous, visceral(splanchnic
), pulmonary, renal blood vessels
– constrict veins
– consequently a rise in BP and an increase in p
eripheral vascular resistance (PVR or TPR)
– Often evoke a compensatory reflex bradycar
dia
B.  agonists
– eg, terbutaline (pure beta agonist)
– dilate arterioles in skeletal muscle, coronary
arteries
– consequently reduce PVR and BP.
– [Voluntary muscle ----> tremor ()]
– Low dose of Epi: Beta2 activation is dominant.

C.  agonists
– eg, clonidine (antihypertensive drugs)
– when given orally, reduce sympathetic ou
tflow from CNS and consequently decreas
e BP
– cause vasocontriction when given IV or to
pically (nasal spray)
D. Dopamine agonists (eg, dopamine)

• DA1 receptor
– locate at smooth muscle of renal, coronar
y, cerebral, mesenteric arteries
• relaxation
– tubule of kidney
• inhibit Na+/K+ ATPase pump
• --> natriuresis, diuresis
Dopamine
• Low dose (0.5-2 mcg/kg/min): activate D
opamine receptors
• Intermediate dose(2-10): activate Beta re
ceptors
• High dose(>10): activate Alpha receptor
• Very useful in treatment of renal failure
associated with shock (low to moderate d
ose)
Effect of Catecholamines to intact CVS
4. Respiratory System
agonists
– eg, terbutaline
– produce relaxation of tracheal
and bronchial muscle
5. Eye
• Radial muscle, iris (pupillary dilator)
– contraction () --> mydriasis
– topical phenylephrine and similar alpha agonist
s
– accommodation is not significantly affected
– outflow of aqueous humor may be facilitated
--> reduce intraocular pressure (IOP)
6. Gastrointestinal tract
• alpha and beta receptors locate on smooth muscl
e and on neurons of enteric nervous system
• Stomach and intestine
– Motility and tone: (,)
– Sphincters : contraction ()
– Secretion (intestine): inhibition ()
: inhibit salt and water secretion
7. Genitourinary tract
• Urinary bladder
– Detrusor or bladder wall: relax ()
– Trigone, sphincter, prostate gland: constrict
()
• Uterus
– non-pregnant: relax ()
– pregnant: contract(), relax ()
• Kidney
– renin release ()
• Pancreatic  cells
– inhibit insulin release ()
– stimulate insuline release ()

• Glycogenolysis in liver and skeletal muscl
e ()
• Glucose out of liver associated with initia

lly hyperkalemia, then transport into skel
etal muscle resulting in a later hyperkale
mia.
• Lipolysis () : break down of triglyceri
des (TGs) into free fatty acids(FFAs) --> i
ncrease lactate from lipid metabolism
9. CNS effects
• Catecholamines do not produce CNS effects
• eg, Amphetamine have stimulant effects on CNS
• Beginning with mild alerting or reduction of fatigu
e
• Progressing to anorexia, euphoria, and insomnia
• CNS effects probably represent the release of dopa
mine in certain dopaminergic tracts
• Very high doses lead to marked anxiety or aggress
iveness, paranoid, and sometimes convulsions
I. Clinical Application of Sympathomimetics
1. Cardiovascular system
2. Respiratory system
3. Anaphylaxis
4. Eye
5. Genitourinary tract
6. CNS
7. Additional uses
1. Cardiovascular application
A. Increase blood flow
– acute heart failure (), decrease PVR through partia
l  effect: Dobutamine
– cardiogenic shock from MI, CHF or septic shock : Do
pamine
B. Reduce blood flow and increase BP
– Surgery : prolong action of local anesthetics (
– hypotension, during spinal anesthesia (
– congestion ( : oxymetazoline
1. Cardiovascular application (cont’d)
• Shock due to septicemia or myocardial infarcti
on is usually made worse by vasoconstrictors
• chronic orthostatic hypotension due to inadequ
ate sympathetic tone: midodrine ()
C. Cardiac application
– paroxysmal atrial tachycardia (
– complete heart block or cardiac arrest ()
: Epi or Iso
2. Respiratory application
• Especially selective  agonists are drug of choice in
treatment of acute asthmatic bronchoconstriction (E
pi and Iso also)
• Emphysema, bronchitis
3. Anaphylaxis
• Epinephrine is drug of choice for immediate treatme
nt of anaphylactic shock ( ,)
• sometimes supplemented with antihistamines and co
rticosteroids
4. Ophthalmic Application
• Alpha agonists, especially phenylephrine, often use
d topically to
– produce mydriasis, eg, ophthalmologic exam
– reduce the conjunctival itching and congestion c
aused by irritation or allergy
– do not cause cycloplegia
• Epi and prodrug, dipivefrin, sometimes used for gl
aucoma.
5. Genitourinary Tract Application
• Beta2 agonists (ritodrine, isoxsupreme) used

in premature labor, but cardiac stimulant ef
fect may be hazardous to both mother and f
etus.
• Ephedrine (long-acting)
Used to improve urinary continence in chil
dren with enuresis and in the elderly (con
tract trigone, prostate of bladder)
6. CNS Application
• Amphetamine: widely used and abused
• Legitimate indication: narcolepsy, attentio
n deficit hyperkinetic syndrome, weight re
duction
• Metabolism effect ( ) and anorexant
effect
• Misuse or abuse for deferring sleep, for mo
od-elevating, euphoria-producing action
7. Additional uses
Central  agonists

– hypertension
– menopausal hot flushes
– narcotics, alcohol, smoking withdrawal
J. ADRs of Sympathomimetics
Catecholamines
– little CNS toxicity
– high dose: excessive vasoconstriction, cardia
c arrhythmias, MI, pulmonary edema or he
morrhage, tissue necrosis.
• Phenypropylamines
– mild to severe CNS toxicity depending on do
sage
– small dose: nervousness, anorexia, insomnia
• Peripherally acting agents: predictable toxicity
  agonists: hypertension, bradycardia (refle
x)
–  agonists: palpitation, sinus tachycardia, s
erious arrhythmias
–  agonists: skeletal muscle tremor
• No drug are perfectly selective; at high dose,
selectivity will decrease.
• Cocaine:
 special importance: drug of abuse
 cardiac arrhythmias or infarction and co
nvulsions
K. Drug interaction
Tyramine --MAO inhibitors

 tyramine not a drug, found in many foods
 tyramine is rapidly metabolized by MAO.
 MAO inhibitors increase the stores of catech
olamines in vesicles.
 Tyramine is a releaser of catecholamines
 may occur hypertensive crisis due to massiv
e levels of NE
K. Drug interaction
Reuptake inhibitors -- Direct acting sympathomimetics
 eg, Cocaine vs NE
 when cocaine is given before NE -- intensify the ef
fects of NE
Epinephrine reversal
Beta blockers -- Sympathomimetics
Thank you for your attention

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Sympathomimetic agents

A. Review of sympathetic activation

 via coupling protein Gq

Heart rate Contraction Conduction

Drug Oral activity Duration

– Low dose of Epi: Beta2 activation is dominant.

D. Dopamine agonists (eg, dopamine)

– stimulate insuline release ()

• Glucose out of liver associated with initia

• Beta2 agonists (ritodrine, isoxsupreme) used

Central  agonists

Tyramine --MAO inhibitors

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