Autonomic nervous system

1. Dr.K.Chandrakala
Professor and HOD
Guntur Medical College

7. Efferent (motor) nerves
 Two systems
 Autonomic nerves (unconscious)
 Eg cardiac output, respiration, etc
 Somatic nerves (voluntary)

8. Functions of the Sympathetic System
 Though continually active to some degree (e.g.
in maintaining the tone of vascular beds), the
sympathetic division has the property of
adjusting in response to stressful situations,
such as trauma, fear, hypoglycemia, cold, or
exercise
 1- Effects of stimulation of sympathetic
division
 2- Fight or flight response
 Sympathetic system is not essential to life

10. Functions of the parasympathetic system
 Parasympathetic division maintains essential
bodily functions, such as digestive processes and
elimination of wastes, and is required for life.
 It usually acts to oppose or balance the actions of
the sympathetic division and is dominant over the
sympathetic in “rest and digest” situations.
 Parasympathetic system is not a functional entity
as such and never discharges as a complete system.
If it did, it would produce massive, undesirable,
and unpleasant symptoms. Instead, discrete
parasympathetic fibres are activated separately,
and the system functions to affect specific organs,
such as stomach or eye.

12. Role of CNS in autonomic control of viscera
 1- Reflex arcs (Baroreceptors for BP control)
 2-Emotions and ANS (Rage, fear or pleasure)
 3-Innervation by ANS
 A-Dual innervation
 B-Organs receiving only sympathetic innervation:
adrenal medulla, kidney, pilomotor muscles, sweat
glands and also blood pressure control
 Somatic NS: to skeletal muscle Ach is the
neurotransmitter without interrupting ganglia

13. Chemical signaling between cells
 A- Local mediators: (histamine, PG’s). They act on the cells
in their immediate environment. They are rapidly
destroyed or removed, thus they do not enter the blood.
 B- Hormones: specialized endocrine cells secrete
hormones into blood stream, exerting their effect on distal
organs.
 C- Neurotransmitters: Ach, NE, and Epinephrine
 Second messenger system in intracellular response:
 1. Actions on membrane receptors
 2. Regulation involving second messenger molecules

14. ANS branches
 cholinergic fibres - acetylcholine
 adrenergic fibres noradrenaline (norepinepherine
NE)

15. Functions and origins of the ANS

16. Action of ANS drugs
 Drugs to block ANS chemical transmission
 Drugs to mimic ANS action
 ANS drugs can modify a variety of effector tissues
 Cardiac muscle
 Blood pressure
 Exocrine glands

17. Cholinergic transmission
 Acetylcholine is at motor neuron and CNS
nerve terminals
 Synthesized from
 Acetyl coA (mitochondria)
 Choline (dietary)
 Catalyzed by choline acetyl transferase (ChAT)
 Release is dependent on Calcium (Ca2+)
 Causes muscle contraction

18. Acetylcholine
 Identified 1921
 Present at all NMJ and also CNS
 Synthesized in the axon terminal
 Diffuses across synaptic cleft
 Two receptor subtypes
 Nicotinic ACh receptors
 Muscarinic ACh receptors

19. The discovery of vagusstoff
E.Chudler 2001

20. Neuromuscular Junction
Synaptic End Plate
T.Caceri Veterinary Histology 2003
1999 Sinauer Associates Inc

21. Characteristics of a neurotransmitter
 Synthesized in (or transported to) presynaptic
terminal
 Stored in vesicles
 Regulated release
 Receptor located on postsynaptic membrane
 Termination of action

22. Presynaptic events
 Calcium influx releases synaptic vesicles from
microtubules
 Movement of synaptic vesicles to sites of action
 Interaction of specific proteins
 Vesicle docking
 Membrane fusion
 Calcium dependent exocytosis

23. Fusion proteins regulate neurotransmitter
release
 Vesicle proteins
 Synaptobrevin
 Presynaptic membrane proteins
 Syntaxins
 SNAP-25

24. Vesicular transport of NT – drug
implications
 Toxins targeting neurotransmitter release
 Spider venom (excess ACh release)
 Botulinum (blocks ACh release)
 Tetanus

25. Postsynaptic events
 Boutons have multiple nerve terminals
 Simultaneous release
 Stimulation of contraction via AP
 Acetylcholine degraded after action
 ACETYLCHOLINESTERASE (AChE)

26. Motor
neuron
innervating
skeletal
muscle

27. Cholinergic receptors
 Two classes for acetylcholine
 Nicotinic and muscarinic
 Nicotinic are ion channels
Ionotrophic
 Muscarinic are G-protein coupled
Metabotrophic

28. Nicotinic AChR are sodium channels
1999 Sinauer Associates Inc

29. Ionotropic AChR
 Consist of five polypeptide subunits
 Receptors vary in:
 subunit structure
 agonist sensitivity
 distribution
 Mediate fast synaptic transmission

30. Muscarinic AChR activate G-proteins
1999 Sinauer Associates Inc

31. Metabotropic AChR
 Five muscarinic AChR subtypes
 G protein coupled
 Slower synaptic transmission via
intracellular signaling cascade

33. Mode of cholinergic drug action
 Cholinomimetics
 agonist
 antagonist
 Cholinesterase inhibitors
 Clinical applications

34. Cholinomimetics
Katzung, 2001

35. AChR agonists and antagonists
 Nicotinic AChR agonists
 Nicotine
 Nicotinic AChR antagonists
 Strychnine
 Snake toxins
 Bungarotoxin
 Muscarinic AChR agonist
 Muscarine
 Muscarinic AChR antagonists
 Atropine

36. Adrenergic transmission
 Catecholamines-
 Noncatecholamines
 Through sympathetic/adrenergic
neurons

37. NE and E are
released at
nerve terminals
and secreted by
the adrenal
medulla

39. Norepinephrine and epinephrine
 Catecholamines
 Synthesized from dopamine
 Present in CNS and sympathetic
nerves
 Widely distributed, general
behavioral arousal eg raise blood
pressure etc
 Stress increases release of
norepinephrine

40. Synthesis of norepinephrine (NA)

41. Synthesis of epinephrine (adrenaline)

42. Adrenergic receptors
 Four receptor subtypes
 a1, a2, b1, b2
 G protein linked
 Bind either norepinephrine or epinephrine

44. Sympathetomimetic drugs
 Can act directly or indirectly
 Direct binding to receptors
 Epinepherine, dopamine (CNS and renal)
 Indirectly
 Drugs targeting synthesis and release of NE and NA
eg DBH inhibitors, reserpine - depletes stores
 Drugs targeting reuptake at synapse eg cocaine,
Tricyclic antidepressants

46. NE and E are
released at
nerve terminals
and secreted by
the adrenal
medulla

47. Norepinephrine and epinephrine
 Catecholamines
 Synthesized from dopamine
 Present in CNS and sympathetic
nerves
 Widely distributed, general
behavioral arousal eg raise blood
pressure etc
 Stress increases release of
norepinephrine

48. Synthesis of norepinephrine (NA)

49. Synthesis of epinephrine (adrenaline)

50. Adrenergic receptors
 Four receptor subtypes
 a1, a2, b1, b2
 G protein linked
 Bind either norepinephrine or epinephrine

51. Sympathetomimetic drugs
 Can act directly or indirectly
 Direct binding to receptors
 Epinepherine, dopamine (CNS and renal)
 Indirectly
 Drugs targeting synthesis and release of NE and NA
eg DBH inhibitors, reserpine - depletes stores
 Drugs targeting reuptake at synapse eg cocaine,
Tricyclic antidepressants

52. Importance of sympathetomimetic drugs
 Cardiovascular system
 Regulation of smooth muscle affects heart and blood
pressure
 beta blockers
 Respiratory tract
 Smooth muscle relaxation – bronchodilation
 Isoproterenol, albuterol (asthma)
 Metabolic effects
 Liver effects, insulin secretion
 CNS
 Nervousness, emotional well-being, psychosis etc

53. Adrenergic
Receptors
●
●
●
Adrenergic receptors (or adrenoceptors) are a class of G-
protein coupled receptors that are the target of catecholamines
Adrenergic receptors specifically bind their endogenous ligands –
catecholamines (adrenaline and noradrenline)
● Increase or decrease of 2ndmessengers cAMP or IP3/DAG
Many cells possess these receptors, and the binding of an
agonist will generally cause the cell to respond in a flight-fight
manner.
● For instance, the heart will start beating quicker and the pupils
will dilate

54. How Many of them
????
Alpha (α) Beta (β)
Adenoreceptors
α
1
β
3
β
2
β
1
α
2
α
2B α
2C
α
2A
α
1A α
1B α
1D

55. Differences - Adrenergic
Receptors (α and β) !
● Alpha (α) and Beta (β)
●
● Agonist affinity of alpha (α):
● adrenaline > noradrenaline > isoprenaline
● Antagonist: Phenoxybenzamine
● IP3/DAG, cAMP and K+ channel opening
Agonist affinity of beta (β):
● isoprenaline > adrenaline > noradrenaline
● Propranolol
● cAMP and Ca+ channel opening

56. Potency of catecholamines on
Adrenergic Receptors
NA
NA
Iso
Log Concentration
Bronchial relaxation
Iso Adr
Aortic strip contraction
Adr
α β

57. Differences
- α Vs β
● α Receptors:
● IP3/DAG
● cAMP
● K+ channel opening
● β Receptors:
● cAMP
● Ca+ channel opening

58. Recall: Adenylyl cyclas
pathway
PKA Phospholamban
Increased
Interaction with
Ca++
Faster relaxation
Troponin
Cardiac
contractility
Other
Functional
proteins
e: cAMP
PKA alters the functions of many
Enzymes, ion channels,
transporters
and structural proteins.
Faster sequestration of
Ca++ in SR

59. PKc
Also Recall: Phospholipase
C: IP3-DAG pathway

60. Beta
receptors
●
●
All βreceptors activate adenylate cyclase, raising the intracellular cAMP
concentration
Type β1:
●
●
These are present in heart tissue, and cause an increased heart rate by
acting on the cardiac pacemaker cells
Type β2:
●
●
●
●
These are in the vessels of skeletal muscle, and cause vasodilatation, which
allows more blood to flow to the muscles, and reduce total peripheral
resistance
Beta-2 receptors are also present in bronchial smooth muscle, and cause
bronchodilatation when activated
Stimulated by adrenaline, but not noradrenaline
Bronchodilator salbutamol work by binding to and stimulating the β
2
receptors
● Type β3:
● Beta-3 receptors are present in adipose tissue and are thought to have a
role in the regulation of lipid metabolism

61. Differences between β1, β2 and β3
Location
Beta-1
Heart and JG cells
Beta-3
Adipose
tissue
Agonist
Antagonist
Dobutamine
Metoprolol, Atenolol
Beta-2
Bronchi, uterus,
Blood vessels,
liver, urinary tract,
eye
Salbutamol
Alpha-methyl
propranolol
-
-
Action on
NA
Moderate Weak Strong

62. Clinical Effects of β-receptor
stimulation
● β1: Adrenaline, NA and Isoprenaline:
●
●
●
●
Tachycardia
Increased myocardial contractility
Increased Lipolysis
Increased Renin Release
● β2: Adrenaline and Isoprenaline (not NA)
●
●
●
●
●
●
Bronchi – Relaxation
SM of Arterioles (skeletal Muscle) – Dilatation
Uterus – Relaxation
Skeletal Muscle – Tremor
Hypokalaemia
Hepatic Glycogenolysis and hyperlactiacidemia
● β3: Increased Plasma free fatty acid – increased O2 consumption -
increased heat production

63. Adrenergic receptors -
alpha
● Type α1
●
●
● Blood vessels with alpha-1 receptors are present in the
skin and the genitourinary system, and during the fight-or-
flight response there is decreased blood flow to these
organs
Acts by phospholipase C activation, which forms IP3 and
DAG
In blood vessels these cause vasoconstriction
● Type α2
●
●
These are found on pre-synaptic nerve terminals
Acts by inactivation of adenylate cyclase, cyclic AMP levels
within the cell decrease (cAMP)

64. Differences between α1 and
α2
Location
Alpha-2
Prejunctional
Function
Alpha-1
Post junctional – blood vessels
of skin and mucous
membrane, Pilomotor muscle
& sweat gland, radial muscles
of Iris
Stimulatory – GU,
Vasoconstriction, gland
secretion, Gut relaxation,
Glycogenolysis
Agonist
Antagonist
Phenylephrine, Methoxamine
Prazosin
Inhibition of transmitter
release, vasoconstriction,
decreased central symp.
Outflow, platelet
aggregation
Clonidine
Yohimbine

65. adrenoceptors
Clinical effects
● Eye -- Mydriasis
● Arterioles – Constriction (rise in BP)
● Uterus -- Contraction
● Skin -- Sweat
● Platelet - Aggregation
● Male ejaculation
● Hyperkalaemia
● Bladder Contraction
● α
2 adrenoceptors on nerve endings mediate negative
feedback which inhibits noradrenaline release

66. Molecular Basis of Adrenergic
Receptors
Also glycogenolysis
in liver
Inhibition of
Insulin
release and
Platelet
aggregation
Gluconeogen
esis

67. Dopamine
receptors
● D1-receptors are post synaptic receptors
located in blood vessels and CNS
● D2-receptors are presynaptic present in CNS,
ganglia, renal cortex

68. Summary of agents modifying
adrenergic transmission
Step Actions Drug
Synthesis of NA Inhibition α - methyl-p-tyrosine
Axonal uptake Block Cocaine, guanethidine,
ephedrine
Vesicular uptake Block Reserpine
Vesicular NA Displacement Guanethidine
Membrane NA pool Exchange diffusion Tyramine, Ephedrine
Metabolism MAO-A inhibition
MAO-B inhibition
COMT inhibition
Moclobemide
Selegiline
Tolcapone
Receptors α 1
α 2
β1 + β2
β1
Prazosin
Yohimbine
Propranolol
Metoprolol

70. Adrenaline as
prototype
● Potent stimulant of alpha and beta receptors
● Complex actions on target organs

71. Hear
t
●
●
Beta-1 mediated action - Powerful Cardiac stimulant - +ve
chronotropic, +ve inotropic
Acts on beta-1 receptors in myocardium, pacemaker cells and
conducting tissue
●
●
●
●
● Heart rate increases by increasing slow diastolic depolarization of cells
in SAN
High doses cause marked rise in heart rate and BP causing reflex
depression of SAN – unmasking of latent pacemaker cells in AVN and
PF – arrhythmia (sensitization of arrhythmogenic effects by Halothane)
Cardiac systole is shorter and more powerful
Cardiac output is enhanced and Oxygen consumption is increased
Cardiac efficiency is markedly decreased
● Conduction velocity in AVN, atrial muscle fibre, ventricular fibre and
Bundle of His increased – benefit in partial AV block
● Reduced refractory period in all cardiac cells

72. Blood
Vessels
● Seen mainly in the smaller vessels –
arterioles – Vasoconstriction (alpha) and
vasodilatation (beta) – depends on the drug
● Decreased blood flow to skin and mucus
membranes and renal beds – alpha effect (1
and 2) -
● Increased blood flow to skeletal muscles,
coronary and liver vessels - (Beta-2 effect)
counterbalanced by a vasoconstrictor effect
of alpha receptors

73. Blood
Pressure
● Depends on the Catecholamine involved
● NA causes rise in Systolic, diastolic and mean
BP (no beta-2 action) – unopposed alpha action
● Isoprenaline causes rise in systolic but fall in
diastolic BP – mean BP falls (beta-1 and beta-2)
● Adr causes rise in systolic BP, but fall in diastolic
BP – mean BP generally rises (slow injection)
● Decreased peripheral resistance at low conc. Beta
receptors are more sensitive to Adr than alpha
receptors

74. Blood Pressure –
contd.
● Rapid IV injection of Adrenaline marked rise in
Systolic and diastolic BP
● Large concentration alpha action predominates –
vasoconstriction even in skeletal muscle
● But BP returns to normal in few minutes
● A secondary fall in mean BP occurs
● Mechanism – rapid uptake and dissipation of
Adr – at low conc. Alpha action lost but beta
action predominates – Dale`s Vasomotor
reversal phenomenon

75. Dale`s Vasomotor Reversal Phenomenon

76. Actions of
Adrenaline
❑ Respiratory:
●
●
Powerful bronchodilator
Relaxes bronchial smooth muscle (not NA)
● Beta-2 mediated effect
● Physiological antagonist to mediators of
bronchoconstriction e.g. Histamine
❑ GIT : Relaxation of gut muscles (alpha and beta) and constricted
sphincters – reduced peristalsis – not clinical importance
❑ Bladder: relaxed detrusor muscle (beta) muscle but constriction of
Trigone – both are anti-voiding effect
❑ Uterus: Adr contracts and relaxes Uterus (alpha and beta action)
but net effect depends on status of uterus and species – pregnant
relaxes but non-pregnant - contracts

77. Actions of Adrenaline –
contd.
● Skeletal Muscle:
● Facilitation of Ach release in NM junction (alpha -1)
● Beta-2 acts directly on Muscle fibres
● Abbreviated active state and less tension in slow
conducting fibres and enhanced muscle spindle firing
– tremor
● CNS: No visible clinical effect in normal doses – as low
penetration except restlessness, apprehension and
tremor
● Activation of alpha-2 in CNS decreases sympathetic outflow and
reduction in BP and bradycardia - clonidine

78. Metabolic
effects
● Increases concentration of glucose and lactic
acid
● Calorigenesis (β-2 and β-3)
● Inhibits insulin secretion (α-2)
● Decreases uptake of glucose by peripheral
tissue
● Simulates glycogenolysis - Beta effect
● Increases free fatty acid concentration in blood
● Hypokalaemia – initial hyperkalaemia

79. ADM
E
● All Catecholamines are ineffective orally
● Absorbed slowly from subcutaneous tissue
● Faster from IM site
● Inhalation is locally effective
● Not usually given IV
● Rapidly inactivated in Liver by MAO and
COMT

80. Clinical
Question!
● Question: A Nurse was injecting a dose of penicillin
to a patient in Medicine ward without prior skin test
and patient suddenly developed immediate
hypersensitivity reactions. What would you do?
● Answer: As the patient has developed Anaphylactic
reaction, the only way to resuscitate the patient is
injection of Adrenaline
●
●
● 0.5 mg (0.5 ml of 1:10000) IM and repeat after 5-10
minutes
Antihistaminics: Chlorpheniramine 10 – 20 mg IM or IV
Hydrocortisone 100 – 200 mg

81. Adrenaline – Clinical
uses
● Injectable preparations are available in dilutions
1:1000, 1:10000 and 1:100000
● Usual dose is 0.3-0.5 mg sc of 1: 10000 solution
● Used in:
●
●
●
●
●
●
Anaphylactic shock…
Prolong action of local anaesthetics
Cardiac arrest
Topically, to stop bleeding
Hyperkinetic children – ADHD, minimal brain dysfunction
Anorectic

82. CPR -
Image

83. ADRs
● Restlessness, Throbbing headache, Tremor,
Palpitations
● Cerebral hemorrhage, cardiac arrhythmias
● Contraindicated in hypertensives,
hyperthyroid and angina poctoris
● Halothane and beta-blockers – not indicated

84. Other Adrenergic
Drugs

85. Other Adrenergic
Drugs

86. Noradrenali
ne
● Neurotransmitter released from
postganglionic adrenergic nerve endings
(80%)
● Orally ineffective and poor SC absorption
● IV administered
● Metabolized by MAO, COMT
● Short duration of action

87. Actions and
uses
● Agonist at α
1(predominant), α
2 and β
1Adrenergic receptors
● Equipotent with Adr on β
1, but No effect on β2
● Increases systolic, diastolic B.P, mean pressure, pulse pressure
and stroke volume
● Total peripheral resistance (TPR) increases due to vasoconstriction -
Pressor agent
●
●
●
Increases coronary blood flow
Decreases blood flow to kidney, liver and skeletal muscles
Uses: Injection Noradrenal bitartrate slow IV infusion at the rate
of 2-4mg/ minute used as a vasopressor agent in treatment of
hypovolemic shock and other hypotensive states in order to raise
B.P
●
●
Problems: Down regulation of receptors, Renal Vasoconstriction
Septic and neurogenic shock (?)

88. Noradrenaline -
ADRs
● Anxiety, palpitation, respiratory difficulty
● Acute Rise of BP, headache
● Extravasations causes necrosis, gangrene
● Contracts gravid uterus
● Severe hypertension, violent headache,
photophobia, anginal pain, pallor and
sweating in hyperthyroid and hypertensive
patients

89. Isoprenalin
e
●
●
●
●
Catecholamine acting on beta-1 and beta-2 receptors – negligible
action on alpha receptor
● Therefore main action on Heart and muscle
vasculature
Main Actions: Fall in Diastolic pressure, Bronchodilatation and
relaxation of Gut
ADME: Not effective orally, sublingual and inhalation (10mg tab. SL)
Overall effect is Cardiac stimulant (beta-1)
●
●
Increase in SBP but decrease in DBP (beta-2)
Decrease in mean BP
● Used as Bronchodilator and for treatment of AV block, Stokes-Adam
Syndrome etc. – but not preferred anymore

90. Summar
y

91. Dopamin
e
● Immediate metabolic precursor of
Noradrenalin
● High concentration in CNS - basal ganglia,
limbic system and hypothalamus and also in
Adrenal medulla
● Central neurotransmitter, regulates body
movements ineffective orally, IV use only,
● Short T 1/2 (3-5minutes)

92. Dopamin
e
● MECHANISM:
● Agonists at dopaminergic D1, D2 receptors
● Agonist at adrenergic α1 and β1

93. Dopamin
e
● In small doses 2-5 μg/kg/minute, it stimulates D1-
receptors in renal, mesenteric and coronary vessels
leading to vasodilatation (Increase in cAMP)
● Recall: Renal vasoconstriction occurs in CVS shock due to
sympathetic over activity
● Increases renal blood flow, GFR an causes natriuresis
● Interaction with D2 receptors (present in presynaptic adrenergic
neurones) – suppression of NA release (no alpha effect)

94. Dopamine –
cond.
● Moderate dose (5-10 μg/kg/minute), stimulates β1-
receptors in heart producing positive inotropic and
chronotropic actions actions
● Releases Noradrenaline from nerves by β1-
stimulation
● Does not change TPR and HR
● Great Clinical benefit in CVS shock and CCF
● High dose (10-30 μg/kg/minute), stimulates vascular
adrenergic α1-receptors (NA release) –
vasoconstriction and decreased renal blood flow

95. Why renal and mesenteric
vasodilatation is useful in Shock?
● Increases renal blood flow, GFR an
causes natriuresis
● In CVS shock – excessive sympathetic
activity leading to ischemia of gut,
sloughening and entry of Bacteria to
systemic circulation - septicemia

96. Dobutamine - Derivative of
Dopamine
● MOA:
●
●
●
●
●
● Acts on both alpha and beta receptors but more prominently in beta-1
receptor – increase in contractility and CO
Does not act on D1 or D2 receptors – No release of NA and thereby
hypertension
Predominantly a beta-1 agonist with weak beta-2 and selective alpha-1
activity
Racemic mixture consisting of both (+) and (−)isomers - the (+) isomer
is a potent β
1agonist and α
1antagonist, while the (−)isomer is an α
1
agonist
Overall beta-1 activity and weak beta-2 activity
Increase in force of contraction and cardiac output but no change in
heart rate
●
●
Uses: Clinically give in dose of 2-8 mcg/kg/min IV infusion in Heart
failure in cardiac surgery, Septic and cardiogenic shock, Congestive Heart
failure
ADRs: Tachycardia, hyperension, angina and fatal arrhythmia

97. Adrenergic
agonists
● Selective Alpha-1 Agonists:
● Phenylepherine, Ephederine, Methoxamine,
Metaraminol, Mephentermine
● Selective Alpha-2 Agonists:
● Clonidine, α-methyldopa, Guanfacine and
Guanabenz
● Β
-2 Adrenergic agonists:
● Salbutamol, Terbutaline, Salmeterol,
Reproterol, Oxiprenaline, Fenoterol,
Isoxsuprine, Rimiterol, Ritodrine, Bitolterol and
Isoetharine

98. Therapeutic
Classification
● Pressor agents:
● NA, Phenylephrine, ephedrine, Methoxamine, Dopamine
● Cardiac Stimulants:
● Adr, Dobutamine and Isoprenaline, Dopexamine
● Nasal Decongestants:
● Phenylepherine, Xylometazoline, Oxymetazoline, Naphazoline and
Tetrahydrazoline and Phenylpropanolamine and Pseudoephidrine
● Bronchodilators:
● Isoprenaline, Salbutamol, Salmeterol, Terbutaline, Formeterol
● Uterine Relaxants:
● Ritodrine, Salbutamol, Isoxsuprine
● Anorectics
● Fenfluramine, Dexfenfluramine and Sibutramine
● CNS Stimulants:
● Amphetamine, Methamphetamine