Sympathomimetic Drugs

Wording
• Sympathomimetic drugs
• Adrenomimetic drugs
• Adrenergic agonists
• Adrenoceptor agonists
 Outline
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
 Outline
G. Chemistry, SAR and Pharmacokinetics
H. Organ system effects
I. Clinical application of sympathomimetics
J. Adverse effects of sympathomimetics
K. Drug interactions
 Objectives
1. List tissues that contain sig. No. of alpha
receptors of the  or  type and  or
 receptors.
2. Describe the major organ system effects of a
pure alpha agonist, a pure beta agonist, and a
mixed alpha and beta agonist. Give examples
of each type of drug.
 Objectives
3. Describe a clinical situation in which the
effects of an indirect sympathomimetic would
differ from those of a direct agonist.
4. List the major clinical applications of the
adrenoceptor agonists.
 Suggested Reading
 Katzung BG. Basic & clinical pharmacology. 8t
h
ed., 2001.
 Katzung BG, Trevor AJ. Examination &board
review pharmacology. 5th ed. 1998.
 Goodman&Gilman. Basic pharmacology. 9th
ed., 1996.
 Pharmacology, Lippincott’s Illustrated Review
s 1992.
 A. Review of Sympathetic Activation
• ‘Fight’ or ‘Flight’ on Stress
• Heart
– HR, contractility, conduction velocity
• Vessels (arterioles)
– Skin, cutaneous, visceral : constrict
– Skeletal muscle, coronary: dilate
A. Review of Sympathetic Activation
• Vessels (Vein): constrict
• Eye
– Radial muscle, iris: contract
– Ciliary muscle: relax for far vision
• Lung
– Tracheal and bronchial muscle: relax
A. Review of Sympathetic Activation
• Stomach and intestine
– Motility and tone
– Sphincters : contraction
– Secretion (intestine): inhibition
• Urinary bladder
– Detrusor or bladder wall: relax
– Trigone, sphincter: constrict
A. Review of Sympathetic Activation
• Posterior pituitary: ADH secretion
• Liver: glycogenolysis, gluconeogenesis
• Pancreatic  cells
---stimulate insulin release
• Skeletal muscle
– contractility, glycogenolysis, K+ uptake
A. Review of Sympathetic Activation
• Fat cells: lipolysis
• Uterus
– non-pregnant: relax
• Sweat gland : secretion
• Hair : piloerection
 B. Introduction
• The effects of adrenomimetic drugs are similar t
o sympathetic activation.
• But why each adrenomimetic drug can produce
different responses?
• The differences in affinity to adrenoceptor subt
ypes are responsible for different responses.
 C. Types and subtypes of adrenoceptors
• Adrenergic receptors locate on smooth muscle,
cardiac muscle, exocrine glands, endocrine glan
ds and on nerve terminals.
• the transmitter in all adrenergic neurons was N
E
• When NE and Epi interacted with an adrenocep
tor, in some tissues the response was excitatory
while in other tissues it was inhibitory
C. Types and subtypes of adrenoceptors

• Two subtypes of adrenoceptors ( and )

 - excitatory in most tissues
(except - intestinal smooth muscle)
  - inhibitory in most tissues
(except - heart)
C. Types and subtypes of adrenoceptors
Rank Order of Potency
 receptors
Epi > NE >> Iso
 receptors Iso > Epi > NE
Type of adrenoceptor
 , 
  ,  , 
 DA1, DA2
 C. Types and subtypes of adrenoceptors

 type :Phenylephrine, methoxamine

D

 type :Clonidine, BHT920

 :Oxymetazoline
C 
C. Types and subtypes of adrenoceptors

 type :Isoproterenol

:Dobutamine
:Procaterol, terbutaline
:BRL37344
 Peripheral Dopamine (DA) type :Dopamine
DA1 :Fenoldopam
DA2 :Bromocriptine
C. 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
 Phosphatidylinositol
Ca 2+ -Agonist 4, 5-diphosphate


Cell Membrane
Gq
Phospholipase C
SR IP3

Ca 2+ DAG

Ca 2+ -dependent protein kinase Protein kinase C

 Agonist



Cell Membrane
AC Gi

ATP cAMP

Enzyme-PO4

AC= Adenylyl cyclase No biological effect

 -Agonist



- receptor Cell Membrane



Gs AC


ATP cAMP

Enzyme-PO4

AC= Adenylyl cyclase Biological effect

 Mech. of action of Dopamine

DA1 type
– cAMP
DA2 type
– cAMP
Central Dopamine Receptor -different effect
– D1-like: D1A, D1B, D5
– D2-like: D2, D3, D4
 Ca2+ channels Vascular smooth muscle

Ca2+ (intracellular) ATP

Calmodulin agonists

Ca2+ -calmodulin complex cAMP

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

E. Classification of Sympathomimetics
• By chemistry
– Catecholamines
– Non-catecholamines
• By mode of action
– direct acting
– indirect acting
• By selectivity (to types of receptor)
 E. Classification of Sympathomimetics
I. Catecholamines (CAs)
II. Non-catecholamines
A. Direct acting
• classified by alpha, beta receptor subtypes
• -selective, -selective, nonselective
• -selective -selective , nonselective
B. Indirect acting
-Releasers - Reuptake inhibitors
 F. Mode of action
I. Direct acting
– bind to receptor directly

II. Indirect acting

– cause the release of stored catecholamines
– inhibit reuptake of catecholamines by nerve
terminals (uptake 1)
• increase transmitter in synapse
 List of Adrenomimetic Drugs
A. General agonists
– Direct ( ,  ,  ,  )
: Epinephrine*, Ephedrine
– Indirect, releasers:
: Tyramine*, Amphetamine, Ephedrine
– Indirect, uptake inhibitors
: Cocaine*, Tricyclic antidepressants (TCAs)
 List of Adrenomimetic Drugs
B. Selective agonists
 ,  ,  : Norepinephrine*
 >  : Phenylephrine*, methoxamine, m
etaraminol, midodrine
 > 
:Clonidine*, methylnorepinephrine, apracloni
dine, brimonidine
 =  : Isoproterenol*
 List of Adrenomimetic Drugs
B. Selective agonists
 >  : Dobutamine*
  >  : Terbutaline*, albuterol, metaprot
erenol, ritodrine

 Dopamine agonist: Dopamine*, bromocript

ine
G. Chemistry, SAR and Pharmacokinetics

OH (para)

OH (meta)
Catechol

C 

C 
Ethylamine
N

Chemical structure of parent compound of Catec

holamines
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
 Pharmacokinetics of sympathomimetics

Other sympathomimetics
Drug Oral activity Duration
Amphetamine, Yes Hours
Ephedrine Yes Hours
Phenylephrine Poor Hours
Albuterol, Yes Hours
metaproterenol, terbutaline
 Pharmacokinetics of sympathomimetics

Other sympathomimetics
Drug Oral activity Duration
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)
 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
 1. Vascular system effects
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.

 1. Vascular system effects
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)
 1. Vascular system effects
D. Dopamine agonists (eg, dopamine)
• DA1 receptor
– locate at smooth muscle of renal, coronary,
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)
Distribution and Effect of Peripheral D
opamine DA2 Receptor
DA2 group
: locate at presynaptic adrenergic nerve e
ndings, sympathetic ganglia --inh NE rel
ease
: adrenal cortex ---inh AII-mediated aldos
terone secretion
: pituitary gland---inh prolactin release
: emetic center of medulla---emesis
 2. Cardiac effects
 agonists
• eg, isoproterenol
• predominantly receptor(also  )
• activation of which produces an increase in
– the rate of cardiac pacemakers (normal and ab
normal)
– force of contractions
– AV node conduction velocity
 3. Net cardiovascular actions

and  agonists

– eg, norepinephrine
– may cause a reflex increase in vagal outf
low (due to BP increase) --> reflex brady
cardia
– This reflex often dominates any direct b
eta effects on the heart rate.
3. Net cardiovascular actions

and  agonists (cont’d)

• If reflex is blocked (eg, by ganglion blocke
rs), NE can cause tachycardia ( )
Pure alpha agonists
• eg, phenylephrine
• will routinely slow heart rate via the baror
eceptor reflex
 3. Net cardiovascular actions
Pure beta agonists
– eg, isoproterenol
– almost always increases the heart rate
Net effect on Blood Pressure
• Diastolic blood pressure (DBP) is affected
mainly by PVR and HR
• Alpha and  receptors have the greatest e
ffects on PVR
 3. Net cardiovascular actions
Net effect on Blood Pressure (cont’d)
• Systolic blood pressure (SBP) = DBP + puls
e pressure (PP)
• Pulse pressure is determined mainly by stro
ke volume (SV), which is influenced by  r
eceptors (and venous return)
• Cardiac output (CO) = HR x SV
• So, alpha and beta selectivity determine SB
P, DBP and PP
 Effect of NE to intact CVS
Mean arterial pressure
(MAP) = DBP + 1/3 of (S
BP-DBP)

 ,  , 

 Effect of Epi to intact CVS

 ,  ,  , 

 Effect of Iso to intact CVS

 , 
 Effect of DA to intact CVS

• DA1, Beta1
• Moderate Dose
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)
• Ciliary muscle: relaxation for far vision ()
 6. Gastrointestinal tract
• alpha and beta receptors locate on smooth muscle
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: const
rict ()
• Uterus
– non-pregnant: relax ()
– pregnant: contract(), relax ()
8. Metabolic and hormonal effects
• Kidney
– renin release ()

• Pancreatic  cells
– inhibit insulin release ()

– stimulate insuline release ()

• Glycogenolysis in liver and skeletal muscle (

)
8. Metabolic and hormonal effects

• Glucose out of liver associated with initial

ly 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 aggressi
veness, 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 par
tial  effect: Dobutamine
– cardiogenic shock from MI, CHF or septic shock :
Dopamine
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 tr
eatment of acute asthmatic bronchoconstriction (Epi a
nd Iso also)
• Emphysema, bronchitis

3. Anaphylaxis
• Epinephrine is drug of choice for immediate treatment
of anaphylactic shock ( ,)
• sometimes supplemented with antihistamines and corti
costeroids
 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 (paralysis of accommod
ation)
• Epi and prodrug, dipivefrin, sometimes used for gl
aucoma. Phenylephrine also
 5. Genitourinary Tract Application

• Beta2 agonists (ritodrine, terbutaline) used in p

remature labor, but cardiac stimulant effect m
ay be hazardous to both mother and fetus.
• Ephedrine (long-acting)
: sometimes used to improve urinary continen
ce in children with enuresis and in the elderl
y (contract 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.
Other sympathomimetics
• Phenylisopropylamines
– mild to severe CNS toxicity depending on do
sage
– small dose: nervousness, anorexia, insomnia
 J. ADRs of Sympathomimetics
• Phenylpropylamines (PPA)
– higher dose: anxiety, aggressiveness, paranoid,
convulsion
• Peripherally acting agents: predictable toxicity
  agonists: hypertension, bradycardia (reflex)
–  agonists: palpitation, sinus tachycardia, ser
ious arrhythmias
–  agonists: skeletal muscle tremor
 J. ADRs of Sympathomimetics
• 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 catechol
amines in vesicles.
 Tyramine is a releaser of catecholamines
 may occur hypertensive crisis due to massive l
evels 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
 Can you predict the resulting effects ?
Thank you for your attention