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Sympathomimetic Drugs. Dumrongsak Pekthong M.Sc.(Pharmacology). 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

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sympathomimetic drugs

Sympathomimetic Drugs

Dumrongsak Pekthong


  • Sympathomimetic drugs
  • Adrenomimetic drugs
  • Adrenergic agonists
  • Adrenoceptor agonists

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. Chemistry, SAR and Pharmacokinetics

H. Organ system effects

I. Clinical application of sympathomimetics

J. Adverse effects of sympathomimetics

K. Drug interactions


1. List tissues that contain sig. No. of alpha receptors of the a 1 or a 2 type and b 1 or b 2 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.


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
Suggested Reading
  • Katzung BG. Basic & clinical pharmacology. 8th ed., 2001.
  • Katzung BG, Trevor AJ. Examination &board review pharmacology. 5th ed. 1998.
  • Goodman&Gilman. Basic pharmacology. 9th

ed., 1996.

  • Pharmacology, Lippincott’s Illustrated Reviews 1992.
a review of sympathetic activation
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 activation9
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 activation10
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 activation11
A. Review of Sympathetic Activation
  • Posterior pituitary: ADH secretion
  • Liver: glycogenolysis, gluconeogenesis
  • Pancreatic b cells

---stimulate insulin release

  • Skeletal muscle
    • contractility, glycogenolysis, K+ uptake
a review of sympathetic activation12
A. Review of Sympathetic Activation
  • Fat cells: lipolysis
  • Uterus
    • non-pregnant: relax
  • Sweat gland : secretion
  • Hair : piloerection
b introduction
B. Introduction
  • The effects of adrenomimetic drugs are similar to sympathetic activation.
  • But why each adrenomimetic drug can produce different responses?
  • The differences in affinity to adrenoceptor subtypes are responsible for different responses.
c types and subtypes of adrenoceptors
C. Types and subtypes of adrenoceptors
  • Adrenergic receptors locate on smooth muscle, cardiac muscle, exocrine glands, endocrine glands and on nerve terminals.
  • the transmitter in all adrenergic neurons was NE
  • When NE and Epi interacted with an adrenoceptor, in some tissues the response was excitatory while in other tissues it was inhibitory
c types and subtypes of adrenoceptors15
C. Types and subtypes of adrenoceptors
  • Two subtypes of adrenoceptors (a and b)
    • a - excitatory in most tissues

(except - intestinal smooth muscle)

    • b - inhibitory in most tissues

(except - heart)

c types and subtypes of adrenoceptors16
C. Types and subtypes of adrenoceptors

Rank Order of Potency

1. a receptors Epi > NE >> Iso

2. b receptors Iso > Epi > NE

Type of adrenoceptor

  • a 1 , a 2
  • b 1 , b 2 , b 3
  • DA1, DA2
c types and subtypes of adrenoceptors17
C. Types and subtypes of adrenoceptors
  • a1type :Phenylephrine, methoxamine
    • a1A, a1B a1D
  • a2type :Clonidine, BHT920
    • a2A :Oxymetazoline
    • a2B , a2C
c types and subtypes of adrenoceptors18
C. Types and subtypes of adrenoceptors
  • b type:Isoproterenol
    • b1:Dobutamine
    • b2:Procaterol, terbutaline
    • b3:BRL37344
  • Peripheral Dopamine (DA) type :Dopamine
    • DA1 :Fenoldopam
    • DA2 :Bromocriptine
c types and subtypes of adrenoceptors19
C. Types and subtypes of adrenoceptors
  • Generally
    • a 1---Contraction of smooth muscle
    • b 2 ---Relaxation of smooth muscle
    • b 1---Stimulation in heart
    • a 2---Inhibition, for GI tract ---Relaxation
d mech of action of adrenomimetic drugs
D. Mech. of action of Adrenomimetic drugs
  • a 1 via coupling protein Gq
  • a 2 via coupling protein Gi
  • b 1, b 2 , b 3 via coupling protein Gs



Phosphatidylinositol 4, 5-diphosphate

Ca 2+

Cell Membrane


Phospholipase C




Ca 2+

Ca 2+ -dependent protein kinase

Protein kinase C


a2 - Agonist


No biological effect


Cell Membrane





AC= Adenylyl cyclase


b -Agonist

b - receptor

Cell Membrane






AC= Adenylyl cyclase

Biological effect

mech of action of dopamine
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

Vascular smooth muscle

Ca2+ channels

Ca2+ (intracellular)



b 2 agonists

Ca2+ -calmodulin complex


Proteinkinase A


Myosin-LC kinase (MLCK)



Myosin light chain (Myosin-LC)

Myosin-LC- PO4







Ca 2+










Ca 2+

Heart rate



e classification of sympathomimetics
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 sympathomimetics28
E. Classification of Sympathomimetics

I. Catecholamines (CAs)

II. Non-catecholamines

A. Direct acting

  • classified by alpha, beta receptor subtypes
  • a 1 -selective, a 2 -selective,nonselective
  • b 1 -selective, b 2-selective , nonselective

B. Indirect acting

-Releasers - Reuptake inhibitors

f mode of action
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
List of Adrenomimetic Drugs

A. General agonists

  • Direct (a 1 , a 2 , b 1 , b 2)

: Epinephrine*, Ephedrine

  • Indirect, releasers:

: Tyramine*, Amphetamine, Ephedrine

  • Indirect, uptake inhibitors

: Cocaine*, Tricyclic antidepressants (TCAs)

list of adrenomimetic drugs32
List of Adrenomimetic Drugs

B. Selective agonists

  • a 1 , a 2 , b 1 : Norepinephrine*
  • a 1 > a 2 : Phenylephrine*, methoxamine, metaraminol, midodrine
  • a 2 > a 1

:Clonidine*, methylnorepinephrine, apraclonidine, brimonidine

  • b 1 = b 2 : Isoproterenol*
list of adrenomimetic drugs33
List of Adrenomimetic Drugs

B. Selective agonists

  • b 1 > b 2 : Dobutamine*
  • b 2 > b 1 : Terbutaline*, albuterol, metaproterenol, ritodrine
  • Dopamine agonist: Dopamine*, bromocriptine
g chemistry sar and pharmacokinetics
G. Chemistry, SAR and Pharmacokinetics

Chemical structure of parent compound of Catecholamines

structure activity relationship sar of adrenomimetics
Structure-Activity Relationship (SAR) of Adrenomimetics
  • Responsible for
    • different receptor selecitvity of sympathomimetics
    • different distribution of drugs --> different actions
    • different duration
pharmacokinetic differences between cas and noncas
Pharmacokinetic differences between CAs and NonCAs


  • 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
Pharmacokinetics of sympathomimetics

Drug Oral activity Duration


Epinephrine No minutes

Norepinephrine No minutes

Isoproterenol Poor minutes

Dopamine No minutes

Dobutamine No minutes

pharmacokinetics of sympathomimetics38
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 sympathomimetics39
Pharmacokinetics of sympathomimetics

Other sympathomimetics

Drug Oral activity Duration

Oxymetazoline, Yes Hours


Cocaine No Minutes to Hours

h organ system effects
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
1. Vascular system effects

A. a 1agonists

  • 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 peripheral vascular resistance (PVR or TPR)
  • Often evoke a compensatory reflexbradycardia
1 vascular system effects42
1. Vascular system effects

B. b 2agonists

  • eg, terbutaline (pure beta agonist)
  • dilate arterioles in skeletal muscle, coronary arteries
  • consequently reduce PVR and BP.
  • [Voluntary muscle ----> tremor (b 2)]
  • Low dose of Epi: Beta2 activation is dominant.
1 vascular system effects43
1. Vascular system effects

C. a 2agonists

  • eg, clonidine (antihypertensive drugs)
  • when given orally, reduce sympathetic outflow from CNS and consequently decrease BP
  • cause vasocontriction when given IV or topically (nasal spray)
1 vascular system effects44
1. Vascular system effects

D. Dopamineagonists (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
  • Low dose (0.5-2 mcg/kg/min): activate Dopamine receptors
  • Intermediate dose(2-10): activate Beta receptors
  • High dose(>10): activate Alpha receptor
  • Very useful in treatment of renal failure associated with shock (low to moderate dose)
distribution and effect of peripheral dopamine da 2 receptor
Distribution and Effect of Peripheral Dopamine DA2 Receptor

DA2 group

: locate at presynaptic adrenergic nerve endings, sympathetic ganglia --inh NE release

: adrenal cortex ---inh AII-mediated aldosterone secretion

: pituitary gland---inh prolactin release

: emetic center of medulla---emesis

2 cardiac effects
2. Cardiac effects

b agonists

  • eg, isoproterenol
  • predominantly b 1 receptor(also b 2 )
  • activation of which produces an increase in
    • the rate of cardiac pacemakers (normal and abnormal)
    • force of contractions
    • AV node conduction velocity
3 net cardiovascular actions
3. Net cardiovascular actions

a and b 1 agonists

  • eg, norepinephrine
  • may cause a reflex increase in vagal outflow (due to BP increase) --> reflex bradycardia
  • This reflex often dominates any direct beta effects on the heart rate.
3 net cardiovascular actions49
3. Net cardiovascular actions

a and b 1 agonists (cont’d)

  • If reflex is blocked (eg, by ganglion blockers), NE can cause tachycardia (b 1)

Pure alpha agonists

  • eg, phenylephrine
  • will routinely slow heart rate via the baroreceptor reflex
3 net cardiovascular actions50
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 b 1 receptors have the greatest effects on PVR
3 net cardiovascular actions51
3. Net cardiovascular actions

Net effect on Blood Pressure (cont’d)

  • Systolic blood pressure (SBP) = DBP + pulse pressure (PP)
  • Pulse pressure is determined mainly by stroke volume (SV), which is influenced by b 1 receptors (and venous return)
  • Cardiac output (CO) = HR x SV
  • So, alpha and beta selectivity determine SBP, DBP and PP
effect of ne to intact cvs
Effect of NE to intact CVS

Mean arterial pressure

(MAP) = DBP + 1/3 of (SBP-DBP)

a 1 , a 2 , b 1

effect of epi to intact cvs
Effect of Epi to intact CVS

a 1 , a 2 , b 1 , b 2

effect of da to intact cvs
Effect of DA to intact CVS
  • DA1, Beta1
  • Moderate Dose
4 respiratory system
4. Respiratory System

b 2 agonists

  • eg, terbutaline
  • produce relaxation of tracheal

and bronchial muscle

5 eye
5. Eye
  • Radial muscle, iris (pupillary dilator)
    • contraction (a 1) --> mydriasis
    • topical phenylephrine and similar alpha agonists
    • accommodation is not significantly affected
    • outflow of aqueous humor may be facilitated

--> reduce intraocular pressure (IOP)

  • Ciliary muscle: relaxation for far vision (b 2)
6 gastrointestinal tract
6. Gastrointestinal tract
  • alpha and beta receptors locate on smooth muscle and on neurons of enteric nervous system
  • Stomach and intestine
    • Motility and tone: (a 2 ,b 2)
    • Sphincters : contraction(a 1)
    • Secretion (intestine): inhibition(a 2)

: inhibit salt and water secretion

7 genitourinary tract
7. Genitourinary tract
  • Urinary bladder
    • Detrusor or bladder wall: relax(b 2)
    • Trigone, sphincter, prostate gland: constrict(a 1 )
  • Uterus
    • non-pregnant: relax(b 2)
    • pregnant: contract(a 1 ), relax (b 2)
8 metabolic and hormonal effects
8. Metabolic and hormonal effects
  • Kidney
    • renin release (b 1)
  • Pancreaticb cells
    • inhibit insulin release (a 2 )
    • stimulate insuline release(b 2)
  • Glycogenolysis in liver and skeletal muscle (b 2)
8 metabolic and hormonal effects62
8. Metabolic and hormonal effects
  • Glucose out of liver associated with initially hyperkalemia, then transport into skeletal muscle resulting in a later hyperkalemia.
  • Lipolysis (b 3) : break down of triglycerides (TGs) into free fatty acids(FFAs) --> increase lactate from lipid metabolism
9 cns effects
9. CNS effects
  • Catecholamines do not produce CNS effects
  • eg, Amphetamine have stimulant effects on CNS
  • Beginning with mild alerting or reduction of fatigue
  • Progressing to anorexia, euphoria, and insomnia
  • CNS effects probably represent the release of dopamine in certain dopaminergic tracts
  • Very high doses lead to marked anxiety or aggressiveness, paranoid, and sometimes convulsions
i clinical application of sympathomimetics
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
1. Cardiovascular application

A. Increase blood flow

  • acute heart failure (b 1), decrease PVR through partialb 2 effect: Dobutamine
  • cardiogenic shock from MI, CHF or septic shock : Dopamine

B. Reduce blood flow and increase BP

  • Surgery :prolong action of local anesthetics(a 1)
  • hypotension, during spinal anesthesia (a 1) : NE
  • congestion (a 2) : oxymetazoline
1 cardiovascular application cont d
1. Cardiovascular application (cont’d)
  • Shock due to septicemia or myocardial infarction is usually made worse by vasoconstrictors
  • chronic orthostatic hypotension due to inadequate sympathetic tone: midodrine (a 1)

C. Cardiac application

    • paroxysmal atrial tachycardia (a 1)
    • complete heart block or cardiac arrest (b 1)

: Epi or Iso

2 respiratory application
2. Respiratory application
  • Especially selective b 2 agonists are drug of choice in treatment of acute asthmatic bronchoconstriction (Epi and Iso also)
  • Emphysema, bronchitis

3. Anaphylaxis

  • Epinephrine is drug of choice for immediate treatment of anaphylactic shock (a 1 ,b 1, b 2)
  • sometimes supplemented with antihistamines and corticosteroids
4 ophthalmic application
4. Ophthalmic Application
  • Alpha agonists, especially phenylephrine, often used topically to
    • produce mydriasis, eg, ophthalmologic exam
    • reduce the conjunctival itching and congestion caused by irritation or allergy
    • do not cause cycloplegia (paralysis of accommodation)
  • Epi and prodrug, dipivefrin, sometimes used for glaucoma. Phenylephrine also
5 genitourinary tract application
5. Genitourinary Tract Application
  • Beta2agonists (ritodrine, terbutaline) used in premature labor, but cardiac stimulant effect may be hazardous to both mother and fetus.
  • Ephedrine (long-acting)

: sometimes used to improve urinary continence in children with enuresis and in the elderly (contract trigone, prostate of bladder)

6 cns application
6. CNS Application
  • Amphetamine: widely used and abused
  • Legitimate indication: narcolepsy, attention deficit hyperkinetic syndrome, weight reduction
  • Metabolism effect (b 2, b 3) and anorexant effect
  • Misuse or abuse for deferring sleep, for mood-elevating, euphoria-producing action
7 additional uses
7. Additional uses

Central a 2 agonists

  • hypertension
  • menopausal hot flushes
  • narcotics, alcohol, smoking withdrawal
j adrs of sympathomimetics
J. ADRs of Sympathomimetics


    • little CNS toxicity
    • high dose: excessive vasoconstriction, cardiac arrhythmias, MI, pulmonary edema or hemorrhage, tissue necrosis.

Other sympathomimetics

  • Phenylisopropylamines
    • mild to severe CNS toxicity depending on dosage
    • small dose: nervousness, anorexia, insomnia
j adrs of sympathomimetics73
J. ADRs of Sympathomimetics
  • Phenylpropylamines (PPA)
    • higher dose: anxiety, aggressiveness, paranoid, convulsion
  • Peripherally acting agents: predictable toxicity
    • a 1 agonists: hypertension, bradycardia (reflex)
    • b 1agonists: palpitation, sinus tachycardia, serious arrhythmias
    • b 2agonists: skeletal muscle tremor
j adrs of sympathomimetics74
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 convulsions
k drug interaction
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 catecholamines in vesicles.
  • Tyramine is a releaser of catecholamines
  • may occur hypertensive crisis due to massive levels of NE
k drug interaction76
K. Drug interaction

Reuptake inhibitors -- Direct acting sympathomimetics

  • eg, Cocaine vs NE
  • when cocaine is given before NE -- intensify the effects of NE

Epinephrine reversal

Beta blockers -- Sympathomimetics

  • Can you predict the resulting effects ?