DRUGS ACTING ON AUTONOMIC NERVOUS SYSTEM - ANATOMICAL AND PHYSIOLOGICAL BASIS OF NERVOUS SYSTEM

DRUGS ACTING ON AUTONOMIC NERVOUS SYSTEM

ANATOMICAL AND PHYSIOLOGICAL BASIS OF NERVOUS SYSTEM

            Nervous system is the one which receives information with regard to the changes in the environment (external and internal) of the body and in response regulates appropriate function. It coordinates activities that require rapid control. The mammalian nervous system is divided into subsections, the central nervous system and the peripheral nervous system.. 

 

Organization of Nervous system

1.      Central nervous system:

A.     Brain

B.     Spinal cord

C.      

2.      Peripheral Nervous system:

A.     Efferent (Motor)

i)                    Somatic – Skeletal muscle

ii)                  Autonomic – Cardiac muscle, smooth muscle & exocrine gland.

B.     Afferent (Sensory)

i)                    Somatic

ii)                  Visceral

The central nervous system is divided into brain and spinal cord. A series of protective bones surround the entire central nervous system. The skull surrounds the brain, and the series of cervical, thoracic and lumbar vertebrae and ligaments surround the spinal cord.

The peripheral nervous system is divided into motor (efferent) and sensory (afferent) sub systems. Within the motor peripheral nerves are somatic motor neurons, which carry action potential commands from the central nervous system to synaptic junctions at skeletal muscles; and the autonomic nervous system’s motor neurons, which carry action potentials through an intermediate synapse to synapses at smooth muscles, cardiac muscle and some exocrine glands. Sensory peripheral nerves bring action potential messages to the central nervous system from peripheral receptors. Sensory nerves carrying action potentials from receptors such as the photoreceptors of the eye, auditory receptors of the ear, or stretch receptors of the skeletal muscles would be classified as somatic sensory peripheral nerves. Receptors located with in the chest and abdomen send action potentials to the central nervous system along visceral sensory peripheral nerves.

 

AUTONOMIC NERVOUS SYSTEM

This is the visceral component of the nervous system. The nerve fibres are distributed to the viscera, blood vessels, glands and unstriped muscles. The sensations of autonomic nervous system are not brought in to consciousness. They work at sub conscious or unconscious level. It regulates such subconscious body functions as blood pressure, heart rate, intestinal motility and the diameter of the eye’s pupil. It is not absolutely autonomous because it is partially regulated by central nervous system, and they also use somatic system as their afferent path.

            Organization: - consists of 2 neuron systems

a)      Preganglionic neurons: - Cell body in spinal cord or brain; - modulated by brain and spinal reflexes; - leaves spinal cord and synapses with post-ganglionic neurons in ganglia (relay-centres)

b)      Post ganglionic neurons: -sends axons to effector organs; - most activity takes place at junctions of pre- and post- ganglionic nerves or at neuro-effector junction.

Differences between autonomic nervous system and somatic nervous system

	Somatic nervous system	Autonomic nervous system
1. Target organ	Skeletal muscles.	Smooth muscles, cardiac muscle & some glands.
2. No. of nerves in peripheral nervous system	One nerve whose cell body is located in the central nervous system and whose axon extends, uninterrupted to the skeletal muscle, where the first peripheral chemical synapse occurs.	Two peripheral nerves: first called pre-ganglionic nerve whose cell body is in central nervous system but its axon innervates a second neuron in the chain called post-ganglionic nerve. Its cell body in a peripheral structure called a ganglion.
3. Nerve fibres	Nerve fibres are covered by myelin sheaths.	Post-ganglionic fibres are non-myelinated.
4. Neurotransmitter	Acetylcholine.	Acetylcholine,  norepinephrine and nitric oxide.
5. Peripheral plexus	Absent.	Present.
6. Nerve section	Paralysis & atrophy.	Activity maintained.

            On structural and functional grounds the efferent component of the autonomic nervous system is divided in to sympathetic and parasympathetic systems.

Sympathetic nervous system :

           

Sympathetic nervous system generally has short pre ganglionic axon and long post ganglionic axons. Pre ganglionic axons leave the spinal cord by way of the ventral roots of the first thoracic through the 3^rd/4^th lumbar spinal nerves – Thoraco-lumbar system. These pre ganglionic axons enter the para vertebral ganglion via white rami communicans, where most synapse with a post ganglionic neuron. These post ganglionic neurons then extend to one of the hollow visceral organs / re-enter the spinal nerves to extend to more distal structures. A few pre ganglionic neurons pass through the para vertebral ganglia to synapse with post ganglionic neurons in more distal pre vertebral ganglia. A few sympathetic pre ganglionic axons extend all the way to the adrenal medulla, where they synapse with rudimentary postganglionic neurons that make up the adrenal medullary secretary cells. These vestigial post ganglion neurons secrete their transmitter substance directly in to the circulating blood.

Parasympathetic nervous system:

It arises from the brainstem and spinal cord. This generally has long pre ganglionic and short postganglionic axons. The pre ganglionic efferent fibres emerge from some cranial and some sacral spinal nerves and from cranio-sacral outflow. The cell bodies of postganglionic neurons are situated in the structures; they innervate, i.e. peripherally.

(The cranial nerves which transmit the pre ganglionic para sympathetic efferent fibres are i. Oculomotor, ii. Facial, iii. Glossopharyngeal and iv. Vagus )

Differences between sympathetic and parasympathetic nervous system

	Sympathetic nervous system	Parasympathetic nervous system
1. Origin	Dorso-lumbar (Thoraco-lumbar).	Cranio-sacral.
2. Distribution	Wide.	Limited to head, neck, and trunk.
3. Ganglia	Away from organs.	On / close to the organ.
4. Post ganglionic fibres	Long.	Short.
5. Pre to post ganglionic fibre ratio	1:20 to 1:100.	1:1 to 1:2.
6. Transmitter	Pre ganglionic – Acetylcholine. Post ganglionic – Norepinephrine	Acetylcholine at all levels.
7. Stability of the transmitter	Norepinephrine – stable; diffuses for wider actions.	Acetylcholine – rapidly destroyed; locally.
8. Important function	Tackling stress and emergency (for fight or flight).	Assimilation of food (conservation of energy).
9. Control	Controlled by posterior part of hypothalamus.	Controlled by anterior part of hypothalamus.

            Important functions:

           

            Parasympathetic nervous system: One preganglionic parasympathetic fiber synapses with only one post ganglionic fibre and therefore its actions are accurate and localized. On stimulation this system produces following effects:

1.      Inhibition of heart rate.

2.      Fall in blood pressure.

3.      Constriction of pupil.

4.      Constriction of bronchi & bronchioles.

5.      Promotion of secretomotor & peristaltic activity of gut.

6.      Relaxation of spinchtors of gut and

7.      Evacuation of bladder and rectum.

Sympathetic nervous system : One preganglionic neuron of sympathetic nervous system usually makes synapse with twenty or more post ganglionic sympathetic neurons and thereby makes wide spread response and produce the following effects:

1.      Vasoconstriction of cutaneous blood vessels.

2.      Vasodilatation of coronary and skeletal muscle providing more blood to the heart muscles and brain and increases heart rate, blood sugar and blood pressure.

3.      Dilate the pupil, bronchi and bronchioles.

4.      Decreases peristalsis, glandular secretion and absorption of gut.

5.      Spichtor muscles of the gut is stimulated.

6.      Sweat glands are stimulated and perspiration is increased. This leads to  fall of body temperature and produce goose flesh appearance.

Thus sympathetic system works for energy mobilization and therefore catabolic. It works in emergency and may be considered a nerve for today. The parasympathetic system works for energy storage and therefore anabolic. It works for tranquility & considered as a nerve for tomorrow. The sympathetic and parasympathetic components are antagonistic but complementary to each other. Some times they work synergistically. Ex. Salivary secretion – mucous component is regulated by sympathetic and serous component is regulated by parasympathetic system.

                                    CNS                PERIPHERY

           

The general outlay of autonomic nervous system. The transmitter released and the primary postjunctional receptor subtype is shown at each synapse/neuroeffector junction

N = Nicotinic,   M = Muscarinic,   α = α adrenergic,    β = β adrenergic

Effects of Autonomic Nerves on some Organ Systems

Criteria	Sympathetic		Paraympathetic
Functional	Action	R	Action	R
General Homeostasis	-stress response (fight or flight) -expends energy		-maintains homeostasis -saves energy
Heart
-SA, AV nodes -cardiac muscle	­ rate/conduction ­ contractility	b1 b1	¯ rate ¯ contractility	M M
Smooth muscle
Blood vessels             -skin             -skeletal           muscle.	-constriction -dilation	a1 b2,
Spleen	-contraction	a
Bronchi	-dilation	b2	constriction	M
GI tract           -walls             -sphincters	-¯ motility -contraction	a, b2 a1	-­ motility -relaxes	M M
GU tract         -bladder wall             -sphincter             -penis	-relaxation -contraction -ejaculation	b2 a1 a	-contraction -relaxation -erection	M M M
Glands
-salivary	­ secretion (viscous, minimal)	a1	­ secretion (watery, profuse)	M
-sweat             -eccrine (thermoregul’n)             -apocrine (stress)	­ secretion ­ secretion	M a
Metabolism
-liver	-glycogenolysis	a, b2
-adipose tissue	-lipolysis	b3
-kidney	-renin release	b1
Eye
Iris     Ciliary muscle	-dilation	a1	-constriction -contraction	M M

R=receptor

NEURO TRANSMISSION

Nerve impulses elicit responses in smooth, cardiac and skeletal muscles and post synaptic neurons through liberation of specific chemical neurotransmitters.

Steps involved in Neurotransmission :

The sequence of events involved in neurotransmission is of particular importance pharmacologically, since the actions of a large number of drugs are altered directly to the individual steps.

1.      Axonal conduction :

It refers to the passage of an impulse along a nerve fibre.

The resting membrane potential is established by high Potassium (K⁺) permeability of axonal membrane and high axoplasmic concentration of this ion coupled with low sodium (Na⁺) permeability and its active extrusion. Stimulation or arrival of an electrical impulse causes a sudden increase in sodium permeability to the interior in relation to the potassium ion. Thus the membrane potential moves from  -85mv toward 0 and then overshoot to the extend that momentarily the inside of the fibre is positive in relation to the exterior of the cell (Depolarization).

Potassium ion then move out in the direction of their concentration gradient and repolarization occurs. Ionic distribution is normalized during the refractory period by the activation of Na⁺K⁺ pump.

Action potential thus generated sets up local circuit currents which activate ionic channels at the next excitable part of the membrane (next nodes of Ranvier in myelinated nerve – jumping / salutatory conduction) and action potential propagated with out decrements. Thus action potential is self propagating.

2.      Junctional transnission :

The arrival of the action potential at the axonal terminals initiates a series of events that trigger transmission of an excitatory / inhibitory impulse across the synapse or neuro-effctor junction.

a.      Storage and release of the transmitter :

            The non-peptide neurotransmitters are largely synthesized in the region of the axonal terminals and stored there in synaptic vesicles. Where as, peptide neurotransmitters are found in large dense core vesicles, which are transported down the axon from their site of synthesis in the cell body. During the resting state, there is a continuous slow release of isolated quanta of the transmitter which produces electrical responses at the post junctional membrane (Miniature End Plate Potential) that are associated with the maintenance of physiological responsiveness of the effector organ. As the action potential arrives at the nerve terminal, it facilitates an inward movement of Ca⁺⁺ , which triggers the discharge of neurotransmitters from the storage vesicles in to the synaptic cleft by causing the Excitation-secretion coupling phenomena (Influx of Ca⁺⁺ -----into the axonal cytoplasm -----increases the fusion of vesicular and axonal membranes --------Exocytosis of the neurotransmitters and enzymes).

b. Combination of the transmitter with postjunctional receptors and production of post junctional potential:

            The released transmitter combines with specific receptors on the post junctional membrane and depending on its nature induces an EPSP or an IPSP.

EPSP : A generalized increase in the permeability to cations (notably Na⁺ and occasionally Ca⁺⁺), resulting in localized depolarization of the membrane, ie. Excitatory post synaptic potential.

IPSP :  I) a selective increase in permeability to anions, usually Cl^-, resulting in stabilization / actual hyperpolarisation of the membrane, which constitutes an Inhibitory post synaptic potential  (or)

              II) an  increased permeability to K⁺, because K⁺ can then exit the cell, hyperpolarization and stabilization of the membrane potential (IPSP).

MEPP :   In normal cicumstances, when there is no EPSP / IPSP there will be a constant release of small quantitites of the neurohumoral substances in the synaptic as well as neuro-effector junctions to sensitize the post junctional receptors there by they will be ready for the EPSP / IPSP, ie. Miniature endplate potential.

3.      Initiation of post junctional activity :

     

If an EPSP exceeds a certain threshold value, it initiates a propagated action potential in a post synaptic neuron / a muscle action potential in skeletal / cardiac muscle, in which propagated impulses are minimal, an EPSP may cause the rate of spontaneous depolarization and enhance muscle tone; in gland cells, it initiates secretion. An IPSP, which is found in neurons and smooth muscles, but not in skeletal muscles, will tend to oppose excitatory potentials initiated by other neuronal sources at the same time and site. The resultant response depends on the summation of all the potentials.

4.      Destruction / Dissipation of the transmitters :

                  Following its combination with the receptors and the post junctional activity the transmitter is either locally degraded (Ach E --- Ach) or is taken back in to prejunctional neurone by active (NEN) or diffuses away (GABA). Rate of termination of transmitter action governs the rate at which responses can be transmitted across a junction (1-1000/Sec.).

Events during neurochemical transmission:

•     electrical impulses from CNS

•     ®­ in Na+ permeability

•     ®local depolarization of neuronal membrane

•     ®­ in K+ permeability and repolarization

•     \ ion currents through distinct channels ® action potential

•     action potential arrives at nerve terminal

•     ® release of stored neurotransmitter by exocytosis

•     neurotransmitter diffuses across synaptic cleft

•     interacts with receptor on postganglionic cell body or effector organ

•     alters ion permeability and initiates action potential in post-ganglionic nerve cell body

•     or mediates a response in the end-organ (response is dependent on transmitter and receptor subtype)

  

Overview of Effect of Pharmacological Agents acting on Autonomic Nervous System

A) Pre-synaptic Actions

1. Drugs which inhibit transmitter synthesis

2. Drugs which interfere with transmitter storage

3. Drugs which inhibit transmitter release

4. Drugs which promote transmitter release

5. Drugs which affect neuronal uptake

6. Drugs which inhibit transmitter metabolism

B) Post-synaptic Actions

7. Ganglionic Blockers

8. Drugs which stimulate autonomic receptors

9. Drugs which block autonomic receptors

1. Drugs which inhibit transmitter synthesis

a)Catecholamines (NE, EP & dopamine)

-a-methyltyrosine inhibits tyrosine hydroxylase

-a-methyldopa inhibits L-aromatic amino acid decarboxylase

-fusaric acid inhibits dopamine-b-hydroxylase

b) Acetyl choline:

-hemicholinium blocks choline transport into nerve terminal

2. Drugs which interfere with transmitter storage

-reserpine blocks uptake of catecholamies into storage vesicles

3. Drugs which inhibit transmitter release

-bretylium and guanethidine block adrenergic neurotransmission by inhibiting  fusion of storage vesicle with neuronal membrane

-botulinus toxin prevents release of ACh from cholinergic nerves

4. Drugs which promote transmitter release

a) ­ NE release from post-ganglionic nerve terminal by:

-activation of nicotinic ganglionic receptors by nicotine

-indirect acting sympathomimetic amines (tyramine, ephedrine, or amphetamine)

b) ­ ACh release from post-ganglionic nerve terminal by:

-activation of nicotinic ganglionic receptors by nicotine

-no drugs displace ACh from neuronal stores

5. Drugs which affect neuronal uptake

-agents which prevent catecholamine reuptake by blocking the amine uptake pump (eg. cocaine, imipramine)

6. Drugs which inhibit transmitter metabolism

-monoamine oxidase inhibitors (eg. pargyline)

-acetylcholinesterase inhibitors (eg. physostigmine)

7. Ganglionic Blockers

-interfere with transmission of nerve impulses from preganglionic nerve terminals to postganglionic cell bodies

-because transmitters (ACh) and receptors (nicotinic) are identical in ganglia of both sympathetic and parasympathetic nerves blockers impede both divisions equally

-end-organ response may show predominant cholinergic or adrenergic effect depending on degree of innervation

-eg. hexamethonium (limited use)

8. Drugs which stimulate autonomic receptors

i) Adrenergic receptors:

-Epinephrine stimulates all adrenergic receptors

-Norepinephrine stimulates a1, a2, b1, b3 receptors (not b2)

-Phenylephrine: a1 receptor agonist

-Clonidine: a2 receptor agonist

-Isoproterenol stimulates all b adrenergic receptors

-Dobutamine: b1 receptor agonist

-Terbutaline: b2 receptor agonist

ii) Cholinergic receptors:

-Acetylcholine activates both muscarinic and nicotinic receptors

-Nicotine and dimethylphenylpiperazinium simulate nicotinic receptors

-Muscarine, pilocarpine and bethanechol stimulate muscarinic receptors

9. Drugs which block autonomic receptors

-a1 & a2 blockers: phenoxybenzamine, phentolamine

-a1 blocker: prazosin

-a2 blocker: yohimbine

-b1 & b2 blocker: propranolol

-b1 blocker: metoprolol

-b2 blocker: butoxamine

-muscarinic blocker: atropine

-nicotinic blocker: i) in skeletal muscle: tubocurarine

                               ii) at ganglionic nicotinic receptor: hexamethonium.

A variety of chemical substances can inhibit the axonal conduction:

1.                  Tetradotoxin from puffer fish and Saxitoxin from some shell fish selectively block axonal conduction by blocking the voltage sensitive Na+ channel and prevent the increase in permeability to Na+.

2.                  Batrachotoxin from South American frog produces paralysis through a selective increase in permeability of the Na+ channel to Na+, which induces a persistant depolarization.

3.                  Scorption poisons also cause persistant depolarization, but they do so by inhibition of the inactivation process.

4.                  Local anaesthetics block conduction by decreasing / preventing the large transient increase in the permeability of excitable membranes to Na+ that normally is produced by a slight depolarization of the membrane.