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

2. Wording Adrenergic agonists Adrenomimetic drugs Adrenoceptor agonists
Sympathomimetic drugs

3. 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

4. Outline G. Chemistry, SAR and Pharmacokinetics H. Organ system effects
I. Clinical application of sympathomimetics
J. Adverse effects of sympathomimetics
K. Drug interactions

5. Objectives
1. List tissues that contain sig. No. of alpha receptors of the a1 or a2 type and b1 or b2 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.

6. 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.

7. Suggested Reading
Katzung BG. Basic & clinical pharmacology. 8th ed., 2001.
Katzung BG, Trevor AJ. Examination &board review pharmacology. 5th ed
Goodman&Gilman. Basic pharmacology. 9th
ed., 1996.
Pharmacology, Lippincott’s Illustrated Reviews 1992.

8. 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

9. 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

10. 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

11. A. Review of Sympathetic Activation
Posterior pituitary: ADH secretion
Liver: glycogenolysis, gluconeogenesis
Pancreatic b cells
---stimulate insulin release
Skeletal muscle
contractility, glycogenolysis, K+ uptake

12. A. Review of Sympathetic Activation
Fat cells: lipolysis
Uterus
non-pregnant: relax
Sweat gland : secretion
Hair : piloerection

13. 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.

14. 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

15. 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)

16. 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

17. C. Types and subtypes of adrenoceptors
a1 type :Phenylephrine, methoxamine
a1A, a1B a1D
a2 type :Clonidine, BHT920
a2A :Oxymetazoline
a2B , a2C

18. C. Types and subtypes of adrenoceptors
b type :Isoproterenol
b1 :Dobutamine
b2 :Procaterol, terbutaline
b3 :BRL37344
Peripheral Dopamine (DA) type :Dopamine
DA1 :Fenoldopam
DA :Bromocriptine

19. C. Types and subtypes of adrenoceptors
Generally
a 1 ---Contraction of smooth muscle
b Relaxation of smooth muscle
b Stimulation in heart
a 2 ---Inhibition, for GI tract ---Relaxation

20. 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

21. Ca 2+ -dependent protein kinase
Phosphatidylinositol 4, 5-diphosphate
a1 -Agonist
Ca 2+ a1
Cell Membrane Gq
Phospholipase C
IP3 SR
DAG
Ca 2+
Ca 2+ -dependent protein kinase
Protein kinase C

22. AC Gi ATP cAMP a2 - Agonist a2 Cell Membrane Enzyme-PO4
No biological effect
Enzyme-PO4
AC= Adenylyl cyclase

23. AC Gs ATP cAMP Cell Membrane Enzyme-PO4 Biological effect b -Agonist
b - receptor Gs AC
ATP
cAMP
Enzyme-PO4
AC= Adenylyl cyclase
Biological effect

24. Mech. of action of Dopamine
DA1 type
cAMP
DA2 type
Central Dopamine Receptor -different effect
D1-like: D1A, D1B, D5
D2-like: D2, D3, D4

25. Vascular smooth muscle Myosin-LC kinase (MLCK)
Ca2+ channels
Ca2+ (intracellular)
ATP
Calmodulin
b 2 agonists
Ca2+ -calmodulin complex
cAMP
Proteinkinase A
MLCK*
Myosin-LC kinase (MLCK)
MLCK-(PO4)2
Myosin light chain (Myosin-LC)
Myosin-LC- PO4
Myosin-LC
Actin
Contraction
Relaxation

26. Heart Ca 2+ AC Gi M Gs ATP Ca 2+ Vagus kinase cAMP b1-Agonist
b1-receptor M Gs AC Gi
kinase
ATP
cAMP
Ca 2+
Heart rate
Contraction
Conduction

27. E. Classification of Sympathomimetics
By chemistry
Catecholamines
Non-catecholamines
By mode of action
direct acting
indirect acting
By selectivity (to types of receptor)

28. 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

29. F. Mode of action I. Direct acting II. Indirect 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

31. 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)

32. 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*

33. List of Adrenomimetic Drugs
B. Selective agonists
b 1 > b 2 : Dobutamine*
b 2 > b 1 : Terbutaline*, albuterol, metaproterenol, ritodrine
Dopamine agonist: Dopamine*, bromocriptine

34. G. Chemistry, SAR and Pharmacokinetics
Chemical structure of parent compound of Catecholamines

35. Structure-Activity Relationship (SAR) of Adrenomimetics
Responsible for
different receptor selecitvity of sympathomimetics
different distribution of drugs --> different actions
different duration

36. 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

37. Pharmacokinetics of sympathomimetics
Drug Oral activity Duration
Catecholamines
Epinephrine No minutes
Norepinephrine No minutes
Isoproterenol Poor minutes
Dopamine No minutes
Dobutamine No minutes

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

39. Pharmacokinetics of sympathomimetics
Other sympathomimetics
Drug Oral activity Duration
Oxymetazoline, Yes Hours
xylometazoline
Cocaine No Minutes to Hours

40. 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)

41. 1. Vascular system effects
A. a 1 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 peripheral vascular resistance (PVR or TPR)
Often evoke a compensatory reflex bradycardia

42. 1. Vascular system effects
B. b 2 agonists
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.

43. 1. Vascular system effects
C. a 2 agonists
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)

44. 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

45. Dopamine 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)

46. 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

47. 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

48. 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.

49. 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

50. 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

51. 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

52. Effect of NE to intact CVS
Mean arterial pressure
(MAP) = DBP + 1/3 of (SBP-DBP)
a 1 , a 2 , b 1

53. Effect of Epi to intact CVS
a 1 , a 2 , b 1 , b 2

54. Effect of Iso to intact CVS
b 1 , b 2

55. Effect of DA to intact CVS
DA1, Beta1
Moderate Dose

56. Effect of Catecholamines to intact CVS

57. 4. Respiratory System b 2 agonists eg, terbutaline
produce relaxation of tracheal
and bronchial muscle

58. 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)

59. 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

60. 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)

61. 8. Metabolic and hormonal effects
Kidney
renin release (b 1)
Pancreatic b cells
inhibit insulin release (a 2 )
stimulate insuline release (b 2)
Glycogenolysis in liver and skeletal muscle (b 2)

62. 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

63. 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

64. I. Clinical Application of Sympathomimetics
1. Cardiovascular system
2. Respiratory system
3. Anaphylaxis
4. Eye
5. Genitourinary tract
6. CNS
7. Additional uses

65. 1. Cardiovascular application
A. Increase blood flow
acute heart failure (b 1), decrease PVR through partial b 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

66. 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

67. 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

68. 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

69. 5. Genitourinary Tract Application
Beta2 agonists (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)

70. 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

71. 7. Additional uses Central a 2 agonists hypertension
menopausal hot flushes
narcotics, alcohol, smoking withdrawal

72. J. ADRs of Sympathomimetics
Catecholamines
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

73. J. ADRs of Sympathomimetics
Phenylpropylamines (PPA)
higher dose: anxiety, aggressiveness, paranoid, convulsion
Peripherally acting agents: predictable toxicity
a 1 agonists: hypertension, bradycardia (reflex)
b 1 agonists: palpitation, sinus tachycardia, serious arrhythmias
b 2 agonists: skeletal muscle tremor

74. 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

75. 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

76. 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 ?

77. Thank you for your attention