Drugs Acting on

The Autonomic Nervous System

Dr. Irfan Ahmad KhanAssistant Professor

Dept. of Pharmacology

Autonomic Drugs:

• Drugs that produce their primarytherapeutic effect by Mimicking oraltering functions of the ANS.

AUTOMATIC NERVOUS SYSTEM (ANS)

• major involuntary portion of NS

• responsible for automatic, unconsciousbodily function➢ control of HR and BP ➢ GIT and GUT functions.

Nervous System

Two main divisions

I. CNS

• Brain & spinal cord

II. PNS

1. Afferent (sensory)

2. Efferent (motor)• Somatic & ANS

CENTRAL NERVOUS SYSTEM (CNS)

• Brain and spinal cord

• receives and processes incoming sensory information

• responds by sending out signals that initiate or modify a process

Peripheral Nervous System (PNS)

• Includes all neurons and ganglia found outside CNS

• Afferent: sensory input to CNS

• Afferent neurons carry sensory input from periphery to CNS and modify motor output through reflex arc.

• Efferent: motor output from CNS

• Efferent neurons carry motor signals from CNS to peripheral areas of body.

Efferent Neurons

1. Somatic (SNS): one motor neuron innervatesskeletal muscles and control voluntary(consciously) functions; movement, respiration and posture.

2. Automatic nervous system (ANS)

ANS is divided into 2 main divisions:

1. Parasympathetic ANS (PANS)• dominates in sleep

2. Sympathetic ANS (SANS)• Dominates during activity; fight & flight.

3. Enteric NS

• located in GIT

• send sensory input to both PANS & SANS

• receive motor output from them

• Myenteric plexus (plexus of aurbach)

• Submucous plexus (plexus of Meissner)

NEUROHUMORAL TRANSMISSION

• Nerves transmit their message across synapses and neuroeffector junctions by release of humoral (chemical) messengers

1. Should be present in presynaptic neurone (usually along with enzymes synthesizing it)

2. Should be released in medium following nerve stimulation

3. Application should produce responses identical to those produced by nerve stimulation

4. Effects should be antagonized or potentiated by other substances which similarly alter effects of nerve stimulation.

Steps in neurohumoral transmission

PEPTIDASES

Cotransmission

Location of Ganglia

• Both PANS and SANS haverelay station, or ganglia,between CNS and endorgan, but somatic systemdoes not

• ANS, carries nerve impulses by• a preganglionic fiber that

leaves CNS,• a postganglionic fiber

that innervates effector

SOMATIC vs AUTONOMIC NS

Central roots of origin

•

•

•

Parasympathetic Division Sympathetic Division

• craniosacral division

• Preganglionic fibers: cranial nerve nuclei III, VII, IX, and X and sacral region(usually S2-S4) of spinalcord

• synapse in ganglia close to effector organ.

• Preganglionic fibers are long, and postganglionic ones are short.

• thoracolumbar division

• Preganglionic fibers: thoracic (T1-T12) and lumbar (L1-L5) regions of spinal cord

• synapse in paravertebral ganglia close and parallel to vertebral column.

• Postganglionic axons leadto an effector organ.

Adrenal medulla

• like sympathetic ganglia, receivespreganglionic fibers from sympathetic system

• Lacks axons

• in response to stimulation by Ach, influencesother organs by secreting epinephrine andlesser amounts of Nor-epinephrine into blood

SYMPATHETIC vs PARASYMPATHETIC ANS

SYMPATHETIC AND PARASYMPATHETIC NS & EFFECTOR ORGANS

12

Functions of Sympathetic Nervous System

• Is normally active, even at rest; however, it assumes dominant role when body becomes stressed (trauma, fear, hypoglycemia, cold or exercise).

• Fight or Flight – Protective mechanisms designed to help person cope with stress or get away from it

• For example, if you sense danger: Your heart rate increase, BP rises, eyes dilates, blood sugar rises, bronchioles expand and blood flow shift from skin to skeletal muscles.

Functions of Parasympathetic Nervous System

1. Rest and digest: maintains essential body functions; digestive process and elimination of wastes

2. Save energy

3. Dilation of blood vessels in skin

4. Decrease heart rate (bradycardia)

5. Increase secretion of digestive enzymes

6. Constriction of smooth muscle of bronchi

7. Contraction of smooth muscles of urinary bladder

Sympathetic NS

• Sympathetic NS function as a unitand it often discharge as a completesystem.

• These reactions are triggered both by

1. direct sympathetic activation of effector organs,

2. stimulation of adrenal medulla to release epinephrine.

• Not a functional entity and never discharges as a complete system.

• Else would produce massive, undesirable and unpleasant symptoms.

• Instead, discrete parasympathetic fibers are activated separately and system functions to affect specific organs, such as stomach or eye.

Parasympathetic NS

I. Opposite effects on...

• Myocardium: ▪ Sympathetic= tachycardia▪ Parasympathetic= bradycardia

• Intestinal smooth muscle: ▪ Sympathetic= decreased motility▪ Parasympathetic= increased motility

• Pupil muscles of iris: ▪ Sympathetic= radial muscle →mydriasis ▪ Parasympathetic= circular muscle →miosis

II. Innervated by one division of ANS

• Blood vessels: Sympathetic= Constriction

• Sweat glands: Sympathetic= increase secretion

• Ciliary muscle: Parasympathetic= accommodation reflex

• Pancreas and Stomach: Parasympathetic= increased secretion

2

Hormonal Feedback Loop

22

Similarities between ANS & endocrine system

• ANS, along with endocrine system, coordinates regulation and integration of body functions

• Nervous system has several properties in common with endocrine system:

1. High level integration in brain

2. Ability to influence processes in distant regions of body

3. Extensive use of negative feedback

4. Both systems use chemical for transmission ofinformation

Difference between ANS/Endocrine system

ANS Endocrine system

• Rapid response • Slower response

• Brief duration • Long duration

• Transmission of electrical impulsesover nerve fibers

• Sends signals to targettissue by varying levelof hormone through blood

Drugs affecting ANS

• The cholinergic drugs act on receptors activated by acetylcholine

• The adrenergic drugs act on receptors stimulated by norepinephrine or epinephrine

The cholinergic neuron

• All preganglionic fibers of both sympathetic andparasympathetic divisions.

• All parasympathetic postganglionic.

• Few sympathetic postganglionic fibers (sweat gland).

• All Somatic (non autonomic) fibers to skeletal muscle

The adrenergic neuron

• Most sympathetic postganglionic fibers releasenorepinephrine; are noradrenergic or simplyadrenergic.

• Some peripheral sympathetic fibers release dopamine (dopaminergic).

• Adrenal medulla, a modified sympathetic ganglion, receives sympathetic preganglionic fibers and releases epinephrine (~85%) and to a lesseramount norepinephrine (15%) into blood.

Receptor types

• Parasympathetic – cholinergic receptors:– muscarinic (M1 to M5)

– nicotinic receptors (NM & NN)

• Sympathetic – adrenergic receptors:– alpha (α1, α 2),

– beta (β1 to β 3),

– dopamine (D1 to D5) receptors.

NEUROTRANSMITTERS INVOLVED IN PARASYMPATHETIC SYSTEM

❑In parasympathetic system main neurotransmitter is Acetylcholine(Ach).

❑Some other neurotransmitter also involve in parasympathetic system like

i. NO

ii. VIP

iii. ATP

Above have very minor role.

Cholinergic Neurotransmission

1. synthesis

2. storage

3. release

4. binding

5. degradation

6. recycling of choline

SYNTHESIS OF ACETYLCHOLINE

• Materials required:- AcetylCoA, Choline

• Enzymes required:-Choline acetyl transferase(ChAT) & Acetylcholinesterase(AchE)

• Rate limiting step:-Uptake & availability of Choline.

• Site:-Cytoplasm

ATP + Acetate + CoEn-A

⬇

• Botulism & Tetanus toxins block release of Ach.

• Black widow spider toxin causes massive release of Ach.

• After release of Ach into synaptic cleft degraded by Acetylcholinesterase (AChE).

• Degradation prevent activation of adjacent receptors.

Locations of Cholinergic receptors

•

1. M1 :gastric parietal cells,

2. M2 : cardiac cells and smooth muscle,

3. M3 : bladder, exocrine gland, and smooth muscle.

• Neurons: all five subtypes (M1-M5) have been found

G-protein coupled

Ligand gated cation channel

Mechanisms of Ach signal transduction

• M1, M3 & M5:Gq→ activates phospholipase C → hydrolysis of PIP2

→ IP3, DAG→ increase in intracellular Ca2+ this cation can then interact to:➢ stimulate or inhibit enzymes, or cause

hyperpolarization, secretion, or contraction.

• M2 :Gi → inhibits adenylyl cyclase and increase K+

conductance.

32

Nicotinic receptors

Locations of nicotinic receptors: nicotinic

receptors are located in the:– CNS,– adrenal medulla,– autonomic ganglia,– neuromuscular junction.

33

Mechanisms of action• Ligand-gated ion channel.• 2 Ach → conformational change → entry of Na+ ions→

depolarization of effector cells.

Mechanisms of action

M1 & M3 Gq Coupled ↑DAG & IP3

→↑intracellular Ca2+

M2 Gi Coupled ↓ adenylyl cyclase→↓cAMP

NN & NM No 2nd

messengersActivation (opening) of Na/K channels

Key steps in neurotransmission