Drugs affecting the sympathetic nervous system

1. Drugs affecting the
sympathetic nervous
system
Dr. Yash N. Panchal
Resident Doctor
Pharmacology Department
AMC MET Medical College
21/02/2022

2. Presentation Layout
 Neurotransmitters of Sympathetic nervous system :
Introduction
Biosynthesis
Storage
Release
Termination of action
Effects
 Directly acting Sympathomimetics :
Endogenous Catecholamines

3. Neurotransmitters in
Sympathetic system
1 - Norepinephrine :
o Major neurotransmitter.
2 - Epinephrine :
o A primary hormone secreted from the adrenal medulla.
3 - Dopamine :
o Metabolic precursor of E and NE.
o Found predominantly in basal ganglia, limbic system, CTZ, anterior
pituitary.
o Have receptors on Splanchnic and renal blood vessels.

4. Catecholamines
• Catecholamines have a
benzene ring and 2 adjacent
– OH groups (Catechol nucleus),
with a side chain containing
amine.
• Norepinephrine lacks one
alkyl group (= NOR).
• Dopamine lacks a –OH group
at β carbon atom.

5. Biosynthesis of catecholamines
Step 1 :
• Starting material is L-phenylalanine.
• Dietary Phenylalanine is absorbed
from the gut.
• In the liver, L-phenylalanine is
converted to L-tyrosine by
Hepatic/Phenylalanine hydroxylase.

6. Step 2 : (Synthesis of L-dopa)
• Circulatory L-tyrosine enters
Adrenergic neuron cytoplasm
by active transport.
• L-tyrosine is hydroxylated to
L-dopa by the cytoplasmic enzyme
Tyrosine hydroxylase.
• Tyrosine hydroxylase can be
inhibited by 2-methyl p-tyrosine,
thus used in Pheochromocytoma.
• Rate limiting step.

7. Step 3 : (Synthesis of
Dopamine)
• L-dopa is decarboxylated
to Dopamine by cytoplasmic
L-dopa decarboxylase.
• In dopaminergic neurons,
in CNS, this is the last step in
biosynthesis.
• Carbidopa prevents peripheral
degradation of L-dopa,
by inhibiting dopa decarboxylase.

8. Step 4 : (Storage of Dopamine)
• Dopamine enters storage
vesicles of axon terminals
by active transport.
• Such, active transport is
blocked by Reserpine.
• Within storage vesicles,
Dopamine β hydroxylase
converts dopamine into Norepinephrine.

9. Step 5 : (Synthesis of epinephrine)
• Formed norepinephrine leaves
storage vesicles by diffusion and
enters adrenal medulla.
• Adrenal medulla contains 2 types
of cells, one with NE containing,
and the other with E.
• Within adrenal medulla cytoplasm,
Phenyl ethanolamine N-methyltransferase
converts norepinephrine to epinephrine.

10. Contd…
• Epinephrine reenters Chromaffin granules and stored until
released.
• Certain amounts of intra-adrenal corticosteroids catalyze the
converting enzyme.
• In adults, about 80% of catecholamines are present as Epinephrine
in the adrenal medulla.

11. Storage
• Endogenous of NE in axon terminal,
stored in synaptic vesicle.
• 4 molecules of ATP + 1 molecule
of NE + Peptides.
• Diffusion of NE from vesicle is
prevented by:
1- Soluble binding protein Chromogranin A
2- Protonation of amino group of NE, due to inside acidic pH.
3- Complexation with ATP prevents excessive osmotic pressure inside
vesicle.

12. Release
• An action potential at axon
terminal, opens calcium channels.
• Calcium influx, promotes
exocytosis of NE, ATP,
Chromogranin A into synaptic cleft.
• Exocytosis is inhibited by
Bretylium and Guanethidine.

13. Contd…
• Release of NE can be promoted by:
1 – Activation of Nn receptor at autonomic ganglia by Nicotine or
DMPP.
2 – Amphetamine and Tyramine – These are transported actively into
cytoplasm of sympathetic neuron , and displace NE from vesicle into
synaptic cleft.
• Spontaneous release of NE :
 Spontaneous migration of vesicle towards axon terminal results in
liberation of NE into synaptic cleft.
 This process is of lesser importance.

14. Inactivation of NE and E
• Metabolic degradation is not main way of termination of action.
• Termination of action is by:
1- Uptake 1
 By catecholamine transporter
 Active reuptake into axon terminal
 Subsequent reuptake into storage vesicle by VMAT-2
 80%
 Inhibited by Cocaine and TCA

15. Contd…
2 – Uptake 2
 Active uptake into post synaptic non neuronal cell membrane
 20%
3 – Metabolic degradation
 By enzymes, MAO (Mono-amine oxidase), and COMT (Catechol o-
methyl transferase)

16. Contd…
Characteristics MAO-A MAO-B
Distribution Adrenergic neuron,
Intestine, Liver,
Kidney
Dopaminergic
neuron, Platelets
Specific substrate NE, 5HT DA,
Phenylethylamine
Specific inhibitor Clorgyline,
Moclobemide
Selegiline

17. Contd…
• MAO mainly located intraneuronally, and intracellularly, while
COMT is found only intracellularly in heart, bronchi, intestine,
smooth muscle of vessels.
• Reuptake of catecholamines by Uptake 1 will precedes metabolic
degradations, and so monoamines are used again for
transmission.

18. Contd…

19. Contd…
• Final metabolite of Epinephrine, and Norepinephrine is VMA
(Vanillyl mandelic acid), and
and of Dopamine is HVA (Homo vanillic acid).
• Metabolites are excreted in urine
Normal value for VMA – 2-4 mg in 24 hr urine
Estimation is useful in the diagnosis of Pheochromocytoma

20. Adrenoceptors

21. Adrenoceptors

22. Adrenoceptors
• Epinephrine activates all adrenoceptors (α1, α2, β1, β2, and β3).
• Norepinephrine has weak agonistic action on β2.
• Α α2, and β2 are also located pre-synaptic on the adrenergic
neuron and involved in vesicular neurotransmitter release.

23. α1
• Gq subtype GPCR receptor.
• Secondary messenger – IP3/DAG.
• Effect – Increase in Calcium influx inside effector cell.
• Location – Post-synaptic effector cells.
• On activation, it produces an excitatory response in vascular
smooth muscle, Radial muscle of iris, Lower urinary tract smooth
muscle
Except in Intestine (Inhibitory effect).

24. α2
• Gi subtype GPCR receptor.
• Secondary messenger – cAMP(decrease).
• Located Presynaptically on the sympathetic postganglionic neuron.
• Their activation, inhibits further release of NE.
• In the brain may be located pre or postsynaptic, but their
activation decreases central sympathetic outflow.

25. • Release of NE is
Stimulated by
Activation of
AT1, and β2 receptors
and inhibited by
activation of
α2, and M1 receptors
• Α α2 receptors also located
Presynaptically on cholinergic
nerve terminals of gut, their
activation inhibits further Ach release.

26. β1
• Gs subtype GPCR receptor.
• Secondary messenger – cAMP(increase).
• Located Postsynaptic on Heart, and Kidney.
• Heart – Positive ionotropic, and Chronotropic action.
• Kidney – Stimulate the release of Renin.
• NE has strong agonist action here, than E.

27. β2
• Gs subtype GPCR receptor.
• Secondary messenger – cAMP(increase).
• Located postsynaptic on Bronchi, blood vessels supplying skeletal
muscles, coronary arteries, Cardiac myocytes, Uterus, GIT.
• On activation Smooth muscle relaxation
Except Myocardium.
• Presynaptic ones, stimulates NE release.
• E has strong agonist action here, than NE.

28. β3
• Gs subtype GPCR receptor.
• Secondary messenger – cAMP(increase).
• Located on Adipocytes.
On activation
Lipolysis
Increase in serum free fatty acids
Thermogenesis

29. Desensitization of Beta adrenoceptors
• Desensitization occurs on continuous activation of the receptor by
an agonist.
• Receptor becomes less responsive to an agonist.
• AKA Tolerance, Refractoriness, Tachyphylaxis.
• Develops rapidly, which distinguish it from Down-regulation.
• Mechanism
Continued activation of receptor

30. Contd…
Phosphorylation of serine residue of the receptor by Beta-adrenergic
receptor kinase (β-ARK)
Association of the receptor with protein β arrestin
No Coupling to Gs protein possible
If the agonist is removed, then serine residue is dephosphorylated,
and further signal transduction occurs.
• Example – Desensitization of β2 receptors in bronchial asthma
patients treated with β2 agonists.

31. Heart
• Direct effect mainly results from β1 receptor
(Although β2 and α1 also play a role)
• Sympathetic stimulation:
1 – Increase in heart rate (+ chronotropic) (β1 receptor – SA node)
2 – Increase in conduction (β1 receptor – AV node)
3 – Increase in automaticity (β1 receptor – Purkinje fibres)
4 – Increase in force of contraction (+ Ionotropic)
(β1 receptor - Ventricular myocardium)
5 – Increase in cardiac output
• Large dose of epinephrine – Premature ventricular contraction –
Ventricular arrhythmia.

32. Blood vessels
• Vascular smooth muscle tone is maintained by α1 and β2
receptors.
• α1 receptor activation increase arterial resistance
β2 receptor activation causes smooth muscle relaxation.
• The skin, mucosal, splanchnic, and renal blood vessels have
predominantly α1 receptors.
On sympathetic stimulation, Vasoconstriction occurs
• But, vasodilatation in renal arteries occurs
(D1 receptor effect)

33. Contd…
• Coronary arteries possess α2, β2, and D1 receptors.
• A α2 receptors are located on Endothelial cells of coronaries,
Stimulation of them Vasodilatation
(Nitric oxide mediated).
• Overall effect is Vasodilatation
(Due to predominant β2 receptors on smooth muscle of vessel).

34. Contd…
• Pulmonary blood vessels have both α1 and β2 receptors.
• But, α1 dominates Mild pulmonary vasoconstriction.
• No change in cerebral blood flow and vascular resistance
(α1 = β2).
• No change in tone of systemic veins.
(α1 = β2).

35. Eye
• Radial muscle of iris α1 receptor
On sympathetic stimulation :
1 – Mydriasis (Phenylephrine)
(NE instilled topically, not produce mydriasis, as cant cross
conjunctival membrane)
2 – Increase in aqueous humor outflow, resulting in a decrease in
IOP
• Eyelid smooth muscle also get constricted
(α1 receptor).

36. Salivary and Sweat glands
• Sympathetic stimulation leads to Thick saliva (Vasoconstriction).
• Secretion of sweat in Palm, Sole, and Forehead is increased on
sympathetic stimulation.
(Sympathetic-cholinergic postganglionic fibers supplying M3
receptors).
• Pilomotor erection (α1 receptor),
Increases the perception of the surroundings and helps the body
to cope with fight or flight situation.

37. Lungs
• Bronchial smooth muscle β2 receptor
On stimulation Bronchodilatation.
• Blood vessels of the mucous membrane of the upper respiratory
tract possess α1 receptor
On stimulation Vasoconstriction Decongestion
• Both bronchodilatation, and decongestion decrease bronchial
resistance.
• Epinephrine also inhibits the release of allergic mediators from
mast cells (β2 receptor).

38. Gastro-intestinal tract
• Smooth muscles of GI tract α2 and β2 receptors.
• α2 receptor (Presynaptic on cholinergic nerve terminal )
activation , decrease Ach release.
• β2 receptors activation, also reduces tone and motility of GI tract
(Relaxation is by Hyperpolarization).
• A α1 receptors are located on Sphincters, and their activation
leads to contraction of sphincters.

39. Gastro-intestinal tract
• A α1 receptors also found on GI smooth muscles, but instead of
being excitatory, this are inhibitory in nature
(Reason – Potassium ion mediated hyperpolarization)
• A α2 receptors activation on smooth muscles, also decrease influx
of salt and water into intestinal lumen.

40. Genito-urinary tract
• Sympathetic stimulation causes accumulation of urine in bladder
Relaxation of Detrusor (β3) Contraction of trigone base
and Sphincter (α1)
• Response in uterus depends on state of gestation
(Non-pregnant uterus – Contracts - α1 > β2)
(Pregnant uterus - Relax - β2 > α1)
• In men, ejaculation occurs (α1 activation on vas deferens, seminal
vesicle, and prostate).

41. Metabolic effects
ADIPOCYTES:
• Activation of β3 receptor activates Lipase enzyme
Lipase converts Triglycerides into Free fatty acids
Raise in plasma free fatty acid levels occurs.
LIVER CELLS:
• Activation of β2 receptor catalyse Phosphorylase enzyme
Glycogenolysis Gluconeogenesis
(Glycogen Glucose) (Lactate Glucose)
Hyperglycaemia occurs

42. Contd…
• Release of glucose from liver is accompanied by efflux of K+ ions,
resulting in Hyperkalemia
But, later K+ is taken up by muscle and resulting in Hypokalemia.
SKELETAL MUSCLE CELLS & MYOCYTES:
• Activation of β2 receptor results in Glycogenolysis and Glycolysis,
and produces lactic acid.

43. Contd…

44. Pancreas

45. Other effects
Central nervous system
• No specific effects, but during stress, there may be Anxiety,
restlessness, and rarely tremors
Kidney
• Renin release from JG apparatus (β1 effect)
• Increase in tone and motility of ureter (α1 effect)
Immunological
• Inhibition of histamine release through mast cell stabilization.
• Inhibition of Lymphocytic activity.

46. Sympathomimetics
• Mimics the action of endogenous catecholamines.
• Based on their mode of action, they can be
1 – Directly acting Sympathomimetics
 Act directly on Pre- or Post synaptic receptors
 Can exhibit effects even after denervation of postganglionic
adrenergic neuron

47. Sympathomimetics
2 – Indirectly acting sympathomimetics
 Enters neuronal cytoplasm and displace NE from vesicle
 Denervation of postganglionic neuron prevents their action.
 Repeated dosing at short interval, leads to tachyphylaxis .
(NE store gets depleted)
 More lipid soluble than NE and E.
3 – Mixed action sympathomimetics
 Mainly act by displacing NE from storage vesicle.
 Also have direct action on receptors.

48. Sympathomimetics

49. Endogenous Catecholamines
CHARACTERISTICS:
 High potency in activating α and/or β receptors.
 Rapid inactivation (Shorter half life), hence given by I.V. infusion
 Inactive Orally (COMT in Gut wall, and MAO in Liver and Gut)
 Poor penetration into CNS

50. Epinephrine
• Mainly secreted as hormone from Adrenal medulla.
• Naturally acting one is optically active, and Levo form more potent
than dextro form.
• Unstable, rapidly oxidized by air and light into colored substance
Adrenochrome
Hence, the Solution is kept in an amber-colored bottle with
reducing agent – Sodium metabisulphite / Ascorbic acid.

51. Contd..
• The relative affinity for epinephrine is:
β2 > β1=α1=α2
• At low dose, β2 effects are predominantly seen.
• But, α and β1 effects are stronger at higher dose, due to fewer
blood vessels endowed with β2 receptors.
(Skeletal muscle vessels only)
• Has weak β3 agonis activity.

52. Effects of Epinephrine
CARDIOVASCULAR EFFECTS:
Epinephrine is potent vasoconstrictor and Cardiac stimulant.
Heart: (β1 and β2 effect)
Increase in heart rate
Increase in conduction velocity
Increase in automaticity
Increase in force of contraction
Increase in stroke volume, and so Cardiac output
Increase in systolic BP

53. Contd..
Vascular effects:
 Constricts blood vessels of skin, mucous membrane, splanchnic ,
and renal vessels (α1 effect)
 Dilatation occurs in blood vessels supplying to skeletal muscles,
Liver, and Coronary arteries (β2 effect)
 Total peripheral resistance decreases
(Vascular β2 receptors are more sensitive than α1 receptors).
 Thus, slight decrease in diastolic BP occurs

54. Contd..
Blood pressure:
Moderate dose produces biphasic response
 Initially rise in BP
(α1 and β1 action)
(Rise in systolic BP than Diastolic BP)
 As the plasma concentration declines, there is Fall in mean BP
occurs
(Unmasking of β2 effect)
(β2 receptors are more sensitive than α1 , and responds at even
lower dose )

55. Contd..

56. Dale’s vasomotor reversal

57. Contd..
Bronchial smooth muscle:
Powerful bronchodilatation (β2 effect)
Decrease in bronchial secretion (α1 effect)
GIT:
Relaxation of gut smooth muscles (α2 and β2 effect)
Contraction of sphincters (α1 effect)
Urinary tract:
Micturition is hindered

58. Therapeutic uses of Epinephrine
1 – Allergy
• Drug of the first choice in Type 1 allergic reactions
(Acute anaphylactic shock)
• Mechanism:
Relieves bronchospasm
Relieves angioneurotic edema of the larynx
Prevents histamine release from mast cells
Maintains BP
• Dose: 0.3-0.5 ml 1:1000 solution I.M.
(Absorption from S.C. route is very poor)

59. Contd..
2 – Bronchial Asthma
• Causes Bronchodilatation and decongestion.
• 0.3-0.5 ml of 1:1000 solution S.C.
3 – Cardiac Resuscitation
• Intracardiac injection of epinephrine 0.1 mg/ml – Sudden cardiac
arrest.
(Drowning and Electrocution).
4 – Epistaxis
• To control local bleeding in epistaxis as a spray.

60. Contd..
5 – To prolong the duration of action of Local anesthetics
• Antagonizes the vasodilating effects of LA
(By its vasoconstricting effect)
• Retards systemic absorption from desired site of the action
• Given S.C or Intradermal in combination with LA.

61. Contraindications
Hyperthyroidism
Upregulation of α receptors of the vasculature, and β receptors in
Heart
A hyperthyroid individual becomes hyper-responsive to Epinephrine
Angina and Hypertension

62. Interactions
TCA
Prevents reuptake of Epinephrine into sympathetic neurons
Halothane group of general anesthetics
Increases sensitivity of myocardium towards catecholamines
MAOIs
Clorgyline
Moclobemide
Selegiline

63. Norepinephrine
• Its l-isomer is more potent than d-isomer
• Is chemical mediator, liberated from
Postganglionic sympathetic neurons
Adrenal medulla (20%)
• Constitutes 97% of the secretions from the tumor
Pheochromocytoma.
• Has predominantly α effect
(Relative affinity: α1= α2>β1> β3>>>β2)

64. Norepinephrine actions
• Raises systolic BP (Cardiac stimulation – β1 effect).
• Raises Diastolic BP (α1 effect)
Total peripheral resistance increases.
• Rise in Mean blood pressure.
• Reflex bradycardia due to compensatory vagal stimulation is seen
If atropine (Blocks vagal transmission) is given prior to NE,
Hypertension is followed by Tachycardia.

65. Contd…
• Increase in coronary blood flow
(Rise in mean pressure + Adenosine production).
• No vasomotor reversal phenomena evident
(Predominant α action, and very little β2 action).

66. Contd..

67. Therapeutic uses of NE
• Cardiogenic shock – NE IV infusion - 0.5-1 ml/min
Injection of NE is dissolved in one liter of 5% glucose.
• Should be used carefully.
(Increase vascular resistance and decrease blood flow to vital
organs – So Dopamine is preferred ).
• Not suitable for S.C, I.M., or undiluted I.V
(Risk of local site necrosis – Powerful vasoconstrictor).

68. Precautions
• Infusion should be tapered gradually to avoid sudden fall in BP
• Extravasation into surrounding subcutaneous tissue should be
carefully watched.
(To avoid tissue necrosis)

69. Dopamine
• Endogenous catecholamine, that is immediate precursor of NE.
• Act as Neurotransmitter in CNS.
• On parenteral administration, cant cross BBB.
• Has dose dependent actions on different receptors.

70. Dopamine dose dependent action
• At low dose (up to 2-5 microgram/kg/min, IV)
Acts on D1 receptors – Renal blood vessels
Increased renal blood flow, GFR rate, and excretion of sodium
• At moderate dose (5-10 microgram/kg/min, IV)
Acts on β1 receptors
Increase in cardiac output, (TPR, and Mean BP unchanged)
(Simultaneous renal vasodilatation – D1)

71. Contd…
• At high dose (> 10 microgram/kg/min, IV)
Acts on α1 receptors
Vasoconstriction, Increase IN TPR

72. Therapeutic uses
• Preferred in the conditions with low cardiac output with
compromised renal functions
1- Cardiogenic shock from MI, Trauma, Surgery
2- Congestive heart failure
Also preferred in Renal failure and Liver failure.
• During treatment, BP, HR, and urine flow should be monitored to
Obtain beneficial effects
Also to adjust doses

73. References
• Goodman, Louis S., Alfred Gilman, Laurence L. Brunton, John
S. Lazlo, and Keith L. Parker. 2017. Goodman & Gilman's the
pharmacological basis of therapeutics. New York: McGraw-
Hill.
• Ritter, J. (2020). Rang and Dale's pharmacology (Ninth
edition) Edinburgh: Elsevier.
• Tripathi, K. D. (2018). Essentials of medical
pharmacology (8th ed.). Jaypee Brothers Medical.
• Principles of Pharmacology by H. L. Sharma and K. K.
Sharma; Paras Medical Publishers, New Delhi.2018
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