1. Adrenergic Nervous System Lec 1-3By
Nohad AlOmari Atrushi

2. SYMPATHOMIMETIC
Sympathomimetic drugs mimic the effects of sympathetic nerve stimulation
Also adrenergic agonists
Adrenergic receptors

3. Striated muscle Effector organs
Summary of the neurotransmitters released and the types of receptors
found within the autonomic and somatic nervous system.
(according to Lippincott´s
Pharmacology, 2006)
AUTONOMIC SOMATIC
Sympathetic innervation
of adrenal medulla
Parasympathetic
Sympathetic
Preganglionic
neuron
Ganglionic
transmitter
Acetylcholine
Acetylcholine
Acetylcholine
No ganglia
Nicotinic
receptor
Nicotinic
receptor
Nicotinic
receptor
Postganglionic
neurons
Adrenal medulla
Neuroeffector
transmitter
Epinephrine release
into the blood
Acetylcholine
Acetylcholine
Norepinephrine
Adrenergic
receptor
Adrenergic
receptor
Muscarinic
receptor
Nicotinic receptor
Striated muscle
Effector organs

4. Adrenergic Agonists Chemical classification Catecholamines
Non-catecholamines

5. Adrenergic Agonists Differences
Catecholamine
Noncatecholamines
Cannot use orally
Cannot cross BBB Short-half live
Examples:
Norepinephrine
Epinephrine
Isoproteronol
Dopamine
Dobutamine
Can use orally
Can cross BBB
Longer half life
Examples:
Ephedrine
Phenylephrine
Terbutaline

6. ENDOGENOUS CATECHOLAMINES
Naturally occurring in body:
Norepinephrine -Sites: postganglionic sympathetic sites (except sweat glands , erector pillorie, hair follicles, )
Epinephrine- Secreted by adrenal medulla
Dopamine- Major transmitter in basal ganglia, CTZ, limbic system, anterior pitutory.

7. BIOSYNTHESIS

9. Catecholamine s Tyrosine ↓ Dopa Dopamine Norepinephrine Epinephrine
In dopaminergic neurons, synthesis stops here
In noradrenergic neurons, synthesis stops here
Final step only in adrenal medulla and CNS neurons

11. STORAGE, RELEASE, UPTAKE
L-Phenylalanine
Hepatic hydroxylase

14. Adrenergic Receptors These are mainly 2 types (α) Alfa (β) Beta
These are again subdivided into various types

16. ADRENERGIC RECEPTORS

17. ADRENERGIC DRUGS Symphathomimetics
DIRECT SYMPHATHOMIMETICS
Adrenaline
Noradrenaline
Isoprenaline
Phenylephrine
Methoxamine
Salbutamol
Xylometazoline
INDIRECT SYMPHATHOMIMETICS
Tyramine
Amphetamine
MIXED SYMPHATHOMIMETICS
Ephedrine
Dopamine
Mephenteramine

18. THERAPEUTIC CLASSIFICATION OF ADRENERGIC DRUGS
Pressor agents
Noradrenaline Phenylephrine
Ephedrine Methoxamine
Dopamine Mephentermine
Cardiac stimulants Adrenaline Dobutamine Isoprenaline
Bronchodilators Adrenaline Terbutaline Isoprenaline Salmeterol Salbutamol Formoterol (Albuterol) Bambuterol
THERAPEUTIC CLASSIFICATION OF ADRENERGIC DRUGS

19. Uterine relaxant and vasodilators Ritodrine Salbutamol
Nasal decongestants Phenylephrine Naphazoline Xylometazoline Pseudoephedrine Oxymetazoline Phenyl propanolamine
CNS stimulants
Amphetamine Dexamphetamine Methamphetamine
Anorectics
Fenfluramine Dexfenfluramine Sibutramine
Uterine relaxant and vasodilators Ritodrine Salbutamol
Isoxsuprine Terbutaline

20. PHARMACOLOGICAL ACTIONS
Cardiac effects
Positive chronotropic effect
An action that increases heart rate
Positive dromotropic effect
An action that speeds conduction of electrical impulses (↑ conduction velocity through AV node)
Positive inotropic effect
An action that increases the force of contraction of cardiac muscle

21. Cardiac effects of epinephrine
Cardiac output is determined by heart rate and stroke volume
Epi→ β1receptors at SA node→↑HR
Epi→ β1receptors on ventricular myocytes→
↑ force of contraction
CO = HR x SV

22. vascular smooth muscleα1
In blood vessels supplying skin, mucous membranes, viscera and kidneys, vascular smooth muscle has almost exclusively alpha1-adrenergic receptors
Also biphasic response

23. vascular smooth muscle
In blood vessels supplying skeletal muscle, vascular smooth muscle has both alpha1 and beta2 adrenergic receptors α1
α1 stimulation
β2 stimulation β2

24. Effects of epinephrine on blood vessel caliber
Blood vessels to skin, mucous membranes, viscera and kidneys
Stimulation of α1-adrenergic receptors causes constriction of vascular smooth muscle α1

25. Effects of epinephrine on blood vessel caliber: skeletal muscle
At low plasma concentrations of Epi, β2 effect predominates→ vasodilation
At high plasma concentrations of Epi, α1 effect predominates→ vasoconstriction α1 β2

26. Effects of Epi on arterial blood pressure
Arterial BP = CO x PVR
Epinephrine:
↑ CO
Low doses ↓ PVR (arteriolar dilation in skeletal muscle)
High doses ↑PVR

27. Effects of epinephrine on airways
Epi→β2-adrenergic receptors on airway smooth muscle→ rapid, powerful relaxation→ bronchodilation

28. Effects of epinephrine in the eye
Epi at α1-adrenergic receptors on radial smooth muscle → contraction→ mydriasis
Epi at B2-adrenergic receptors→ relaxation of ciliary muscle α1 β2

29. Mnemonic for therapeutic uses of adrenaline ABCDEG
A- Anaphylactic shock B- Bronchial asthma C- Cardiac arrest D- Delay absorption of local anesthetics E- Epistaxis, Elevate BP G- Glaucoma Others : Reduce nasal congestion, Induces mydriasis

31. Therapeutic uses Shock (moderate doses)
↑ blood flow to kidney and mesentery
↑ cardiac output
Refractory congestive heart failure
Moderate doses ↑ cardiac output without ↑PVR

32. Structures of Norepinephrine and Epinephrine
Epinephrine (Adrenaline)
Norepinephrine
•Belong to chemical class of substances known as the Catecholamines.
•Polar compounds, containing both basic and acidic functional groups.
•Chiral compounds. Natural enantiomer has R-configuration.
•Undergoes oxidation in prolonged exposure to air.
•Limited therapeutic use.

33. Chemical Property of Catecholamines

34. Structures of several important adrenergic agonists
Structures of several important adrenergic agonists. Drugs containing the catechol ring are shown in pink.
(according to Lippincott´s
Pharmacology, 2006)

35. Structure-activity relationships among catecholamines and related compounds
Selective b-agonists
Selective a-agonists
Selective b-antagonists
Non-selective agonist
Indirectly acting sympathomimetic amines HO N
Tyramine
Dopamine OH
Ephedrine
Noradrenaline
Amphetamine
Adrenaline
Metaraminol
a-Me-noradrenaline
Isoprenaline
Salbutamol O
Propranolol

36. Norepinephrine Potent stimulant of both α and β adrenoceptors
Limited therapeutic value
Used to maintain blood pressure in acute hypotensive states
Substrate for MAO and COMT, not effective orally
Chiral compounds. Natural enantiomer has R-configuration. Racemization occurs in heat or acid condition.
Undergoes oxidation in prolonged exposure to air. Sodium bisulfite used as antioxidant in NE preparations
4-((R)- 1-hydroxy-2-amino- ethyl)- 1,2-benzenediol

37. Epinephrine Potent stimulant of both α and β adrenoceptors;
Drug of choice for reversal of acute hypersensitivity reactions (anaphylaxis,
Enhances the action of local anesthetics (restricts local blood flow);
Poor oral absorption. Rapidly metabolized by MAO and COMT;
Degrades on exposure to air and light;
Serious side effects include cerebral hemorrhage and cardiac arrhythmias .

38. ALPHA1 AGONISTS Direct Acting Agents
These are agents which directly active the alpha1 -adrenergic receptor. They are less potent than the endogenous agonists epinephrine or norepinephrine. However, because of structural modifications they are orally active and have longer plasma half-lives. There are 2 structural classes of alpha1 agonists the phenylethylamines which are close structural analogs of epinephrine and norepinephrine and the structurally unrelated imidazolines. The major action of these agents is to produce alpha1-receptor mediated vasoconstriction.

39. SAR of Direct.
general, a primary or secondary aliphatic amine separated by 2 carbons from a substituted benzene ring is minimally required for high agonist activity

40. -OH Substituent: 1. By default must be present at β position to primary amine (i.e. spaced 2 carbons away). 2. being a chiral center the 1 position must be in R configuration for maximum activity (but many drugs sold as racemic i.e. R/S mixture)- exception dobutamine.

41. Amine moiety
as the size increases – selectivity for β receptor increases over α receptors. 2. α and β activity is maximum when R1= methyl (e.g. epinephrine). 3. R1= isopropyl (e.g. isoproterenol) – α activity is negligible and only β activity present.

42. Benzene substituted
3′,4′- dihydroxy substitued benzene ring provides excellent receptor activity for both α and β sites. 2. However, there is poor oral bioavailablity due to COMT

43. INDIRECT-ACTING MIXED-ACTING DIRECT-ACTING
Drug enhances release of norepinephrine from vesicles.
Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists.
Neuron
MIXED-ACTING
Drug acts both directly and indirectly.
Synapse
DIRECT-ACTING
Drug directly activates receptor.
Postsynaptic
target cell
membrane
(according to Lippincott´s
Pharmacology, 2006)

45. Phenylethylamines
Phenylephrine
Pseudoephedrine 
Methoxamine,
Imidazolines
Oxymetazoline
Naphazoline
Metaraminol
Tetrahydrozoline

46. α-Adrenergic Receptor Agonists
α1−Selective Adrenergic Agonists:
• Stimulation of vascular smooth muscle.
• Maintenance of blood pressure in hypotension or shock
Phenylephrine
Methoxamine
Metaraminol

47. -Adrenergic Receptor Agonists
Most of the -selective adrenergic agonists are used primarily as bronchodilators in asthma and other constrictive pulmonary conditions.
Isoprenaline
•Highly potent bronchodilator
•Non-selective (β1 and β2) and leads to cardiac stimulation caused by its β1-activity.
•Metabolized primarily by COMT (Poor substrate for MAO)

48. 2-Agonists (Phenylethanolamines)
•Primarily used as bronchodilators in the treatment of asthma
•Selectivity (β1 vs. β2) is poor at high doses
•Administration by inhalation (aerosol，
enhances β2-selectivity (pulmonary)
Specific agents:
Salbutamol, Salmeterol

49. Salbutamol (Albuterol)
2-[(1,1-Dimethylethyl)amino]-1-[4-hydroxy-3- (hydroxymethyl)phenyl]ethanol
Selective β2 agonist
Orally active drugs, also available for inhalation therapy;
Not metabolized by MAO or COMT;
Bronchodilator used for the treatment of asthma, chronic bronchitis, and other breathing disorders

50. The Synthesis of Salbutamol

51. Metabolism of Salbutamol
从胃肠吸收, 在肠壁和肝代谢,
4-O-glucuronide mostly metabolised in dog, rabbit and rat
While for human, 4-O-sulfate

52. Salmeterol •Long lipophilic substituent
•Prolonged duration of action (~ 12 hrs)
•Slow onset (not suitable alone for prompt relief of bronchospasm，

53. 1-Adrenergic Agonists
Dopamine
Dobutamine

54. Dopamine Not strictly an adrenergic drug, acts on dopamine receptors.
Stimulates cardiac 1-AR through both direct and indirect mechanisms.
Used to correct hemodynamic imbalances induced by shock, trauma, or congestive heart failure.
Rapidly metabolized by MAO and COMT. Not effective orally.

55. Indirect Acting Agents
These agents require the presence of endogenous monoamine neurotransmitters (norepinephrine, epinephrine, dopamine, serotonin) to produce their effects. Indirect acting agonists work at the nerve terminal to promote the release and/or block the reuptake of endogenous neurotransmitters. These agents have little activity if these neurotransmitters are depleted. Cocaine and amphetamine interact with cell surface monoamine transporters for dopamine (DAT), serotonin (SERT) and norepipephrine (NET). These transporters are expressed peripherally and in specific brain loci and are the site of action of psychostimulants and antidepressant drugs.

56. Amphetamine: Promotes the release of monoamines from nerve endings from the terminal cytoplasm. There is only a limited amount of neurotransmitter in this pool. Amphetamine also blocks the reuptake of monoamines. Several structural analogs of amphetamine and "amphetamine like" agents are available for clinical use. These include:
Dexamphetamine (the resolved and more potent d-isomer of amphetamine)
Hydroxyamphetamine
Methamphetamine
Methylphenidate

57. Sympathomimetics with Mixed Mechanism of Action
Ephedrine Hydrochloride
(1R,2S)-2-methylamino-1-phenylpropan-1-ol hydrochloride

58. Actions and Uses ① not be affected by COMT, prolonged duration
Decreased molecular polarity, easily enter CNS, cause stimulation.
② ：-methyl group, not be easily affected by MAO. prolonged duration, decreased molecular polarity, increased CNS toxicity.

59. Ephedrine Hydrochloride
•Natural product, isolated from various species of Ephedra.
•Long history of use in traditional Chinese medicine (Ma Huang)
Four isomers of Ephedrine
(-)-Ephedrine
(+)-Ephedrine
(+)-Pseudoephedrine
(-)-Pseudoephedrine

60. (+)-Pseudoephedrine • An alkaloid. A diastereoisomer of ephedrine,
• Used as a nasal decongestant (many OTC preparations available)
• To be used with caution in hypertensive individuals
Enantiomer：

61. Synthetic Catecholamines: Isoproterenol
Very powerfully stimulates β1- and β2-adrenergic receptors
No significant effect at α1-adrenergic receptors
SA nodal cells→↑HR β1
AV nodal cells→↑ conduction velocity β1 β1
Ventricular muscle cells→ ↑ force of contraction

62. Synthetic Catecholamines: Isoproterenol
Very powerful β-adrenergic receptor agonist; no effect at α-adrenergic receptors α1
α1 stimulation
β2 stimulation β2

63. ↓arterial BP = ↑CO x ↓↓PVR
Isoproterenol
↓arterial BP = ↑CO x ↓↓PVR
Decreased arterial blood pressure triggers autonomic reflex arc

64. Effects of isoproterenol on airways
Powerfully stimulates β2-adrenergic receptors on airway smooth muscle→ rapid, powerful relaxation→ bronchodilation

65. Synthetic Catecholamines: Dobutamine
It’s a derivative of DA but not a D1 or D2 receptor agonist
Stimulates β1- and β2-adrenergic receptors, but at therapeutic doses, β1-effects predominate
Increases force of contraction more than increases heart rate
↑CO = ↑HR x ↑ ↑ SV

66. Dobutamine: Therapeutic uses
Shock MI
Cardiac surgery
Refractory congestive heart failure

67. Major toxic effects of catecholamines
All are potentially arrhythmogenic
Epi and isoproterenol more arrhythmogenic than dopamine and dobutamine
Some can cause hypertension
Epinephrine, in particular, can cause CNS effects – fear, anxiety, restlessness
Dobutamine can cause vomiting and seizures in cats – must be used at very low doses

68. Adverse effects CNS: CVS: Restlessness Palpitation Anxiety, tremors
Increase BP….cerebral haemmorrhage
Ventricular tachycardia, fibrillation
May precipitate angina or AMI

69. Non-catecholamine direct-acting adrenergic agonists
Ephedrine
Stimulates α1-, β1 and β2-adrenergic receptors and ↑ NE release from noradrenergic fibers
Repeated injections produce tachyphylaxis
It is resistant MAO, orally
Longer acting (4-6), cross BBB

70. Marketed as dietary supplement promoted to aid weight loss, ↑ sports performance and ↑ energy. Ingredient in OTC nasal decongestants and bronchodilators
Uses : Mild chronic Bronchial asthma, hypotension during spinal anaesthesia ,occasionally for postural hypotension
Sale prohibited by FDA in 2004 due to risks of life-threatening cardiac arrhythmias, stroke and death

71. Non-catecholamine direct-acting adrenergic agonists: Phenylpropanolamine (PPA)
Actions much like ephedrine in the PNS
In veterinary medicine, used to treat urinary incontinence in dogs
Available in OTC products for treatment of nasal decongestion and as appetite suppressant
FDA has requested all companies discontinue marketing products containing PPA due to risk of hemorrhagic stroke

72. β2-selective adrenergic agonists
Due to selectivity for β2 receptors at recommended doses, little-to-no direct stimulation of β1 receptors in heart
Inhalant administration maximizes local effect and minimizes systemic effects

73. Mephenteramine Uses: It is mixed sympathomimetic
COP, BP, heart rate are increased
Active orally with longer DOA (2-6 hrs),can crosses BBB
Uses:
To treat hypotension due to spinal anesthesia and surgical procedures
Shock in MI and other hypotensive states

75. Adrenergic Agonists Indirect: Amphetamine Cause NE release only
Example:
Amphetamine
CNS stimulant
Increases BP by alpha effect on vasculature, beta effect on heart

76. Drug affecting neurotransmitter
Summary of blocking
agents and drugs affecting neurotransmitter uptake or release
Adrenergic blockers
a - blockers
Doxazosin
Phenoxybenzamine
Phentolamine
Prazosin
Tamsulosin
Terazosin
b - blockers
Acebutolol
Atenol
Carvediol
Esmolol
Labetalol
Metoprolol
Nadolol
Pindolol
Propranolol
Timolol
Drug affecting neurotransmitter
uptake or release
Cocaine
Guanethidine
Reserpine
(according to Lippincott´s
Pharmacology, 2006)