Pharmacology

WHAT IS • It is the process by which signaling molecules called neurotransmitters are released by a presynaptic neuron
NEUROTRANSMISSION? → bind to and activate receptors of the postsynaptic neuron

DIVISIONS OF THE
NERVOUS SYSTEM

THE AUTONOMIC What are the features of the autonomic nervous system?
NERVOUS SYSTEM • Also called the visceral, vegetative, or involuntary nervous system
• Regulates autonomic function without conscious control
• In the periphery, it consists of nerves, ganglia, and plexuses
• Innervate the heart, blood vessels, glands, other visceral organs, and smooth muscles in various tissues

Differences between autonomic and somatic nerves:

Autonomic Nerves Somatic Nerves
The efferent nerves supply all innervated The efferent nerves supply skeletal muscle
structures of the body except skeletal muscle
Contain ganglia that lie outside the Contain no peripheral ganglia; synapses are
cerebrospinal axis located entirely within the cerebrospinal axis
Form extensive peripheral plexuses Plexus networks are absent
Postganglionic autonomic nerves are generally Motor nerves to skeletal muscles are
unmyelinated myelinated
When the spinal efferent nerves are interrupted, Denervated skeletal muscles are paralyzed
spontaneous activity is retained

NEUROTRANSMISSION: ANS AND SNS Karrel C.

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AFFERENT & EFFERENT Afferent vs. Efferent fibers
DIVISION OF ANS (1) Visceral afferent fibers
• conduct sensory impulses (usually pain or reflex sensations)
• input from viscera, glands, and blood vessels is conducted to the CNS
(2) Efferent fibers
• conduct information from the CNS (brain and spinal cord) to muscles and organs throughout the body

Afferent side – Information is transmitted to the CNS through 2 main sensory systems:
Cranial Nerve (Parasympathetic) Spinal (Sympathetic)
Carries mechanoreceptor and chemosensory Carries sensations of temperature and tissue
information injury of mechanical or thermal origin
The information enters the CNS via: Information ascend via:
o CN V (Trigeminal) → face and head o Spinothalamic tract
o CN VII (Facial) → tongue o Spinoreticular tract
o CN IX (Glossopharyngeal) → hard palate o Dorsal column
and upper oropharynx
o CN X (Vagus) → lower oropharynx,
larynx, trachea, esophagus, thoracic
abdominal organs

Efferent side – consists of two large divisions:

(1) Sympathetic or thoracolumbar outflow (2) Parasympathetic or craniosacral outflow

Neurotransmitters:
o all preganglionic fibers
Acetylcholine o most postganglionic
(Ach) parasympathetic nerves
o few postganglionic
sympathetic nerves
o “cholinergic”
o some postganglionic
Nitric Oxide parasympathetic nerves
(NO) o “nitrergic”
o most postganglionic
Norepinephrine sympathetic nerves
(NE) o “adrenergic”
o also called noradrenaline
or levarterenol

THE SYMPATHETIC • Preganglionic fibers

NERVOUS SYSTEM o Lie mainly in the intermediolateral columns of the spinal cord
o Extend from T1 to L2 or L3 segment
o Their axons are carried in the ventral nerve roots → synapse with neurons in sympathetic ganglia
• Sympathetic ganglia are found in 3 locations:
o 22 pairs
o Connected to each other by nerve trunks
o Connected to the spinal nerves via rami communicantes
o White rami
1 - restricted to segments of thoracolumbar outflow
Paravertebral Ganglia - carry preganglionic myelinated fibers that exit the spinal cord by
anterior spinal roots
o Gray rami
- arise from the ganglia
- carry postganglionic fibers back to the spinal nerves for
distribution to sweat glands, pilomotor muscles, and blood
vessels of skeletal muscle and skin

NEUROTRANSMISSION: ANS AND SNS Karrel C.

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o Lie in the abdomen and the pelvis near the ventral surface of the bony
vertebral column
2 o Consists of:
Prevertebral Ganglia (1) celiac ganglia
(2) superior mesenteric ganglia
(3) aorticorenal ganglia
(4) inferior mesenteric ganglia
o Few in number
o Lie near the organs they innervate
3 o Include:
Terminal Ganglia (1) ganglia connected with the urinary bladder and rectum
(2) cervical ganglia in the region of the neck

• Chromaffin cells of the adrenal medulla:

o Resemble a collection of postganglionic sympathetic nerve cells
o Derived from neural crest
o Innervated by typical preganglionic fibers (which release Ach)
o Release epinephrine

THE PARASYMPATHETIC • Regions of central origin: midbrain, medulla oblongata, and sacral part of spinal cord
NERVOUS SYSTEM (1) Midbrain or tectal outflow
- consists of fibers from Edinger-Westphal nucleus of CN 3 going to the ciliary ganglion
(2) Medullary outflow
- consists of parasympathetic components of CN VII, IX, X
Fibers of CN VII (Facial nerve)
o form the chord tympani → innervate ganglia lying the submaxillary and sublingual glands
o form greater petrosal nerve → innervate sphenopalatine ganglion
Fibers of CN IX (Glossopharyngeal nerve)
o innervate the otic ganglia
o supply sphincter of iris, ciliary muscle, salivary and lacrimal glands, mucous glands of nose, mouth,
and pharynx
Fibers of CN X (Vagus nerve)
o preganglionic fibers do not synapse until they reach the many small ganglia of the viscera of thorax
and abdomen (e.g., myenteric and submucosal plexus)
In parasympathetic ANS, preganglionic fibers are very long, whereas postganglionic fibers are very short.

(3) Sacral outflow

- consists of axons that arise from S1-S4
- proceed as preganglionic fibers to form the pelvic nerves (nervi erigentes)
- synapse in the ganglia lying near or within the bladder, rectum, and sexual organs

The vagal and sacral outflows provide motor and secretory fibers to thoracic, abdominal, and pelvic organs).

ENTERIC NERVOUS • Locally controls the processes of mixing, propulsion, and absorption of nutrients
SYSTEM • Comprises components of the sympathetic and parasympathetic nervous system
• Involved in sensorimotor control → consists of afferent sensory neurons, motor nerves, and interneurons
Two nerve plexuses:
Myenteric (Auerbach) Submucosal (Meissner)
Plexus Plexus
o located between o involved with:
the longitudinal a) secretory and
and circular absorptive functions
muscle layers of the GI epithelium
o plays important b) local blood flow
role in contraction c) neuroimmune
and relaxation of activities
GI smooth muscle

NEUROTRANSMISSION: ANS AND SNS Karrel C.

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COMPARISON OF Sympathetic Parasympathetic Somatic
SYMPATHETIC, ▪ Terminal ganglia far from effector ▪ Terminal ganglia near or within the ▪ Innervate skeletal muscle
PARASYMPATHETIC, cells organ innervated without ganglionic relay
AND MOTOR NERVES ▪ Ratio of preganglionic axons to ▪ Ratio of preganglionic axons to ▪ Neurotransmitter: Ach
ganglion cells → 1:20 or more ganglion cells → 1:1 (in myenteric acting on nicotinic receptor
▪ Preganglionic neurotransmitter: ACh plexus 1:8000)
▪ Postganglionic neurotransmitter: NE ▪ Preganglionic neurotransmitter: Ach
▪ Postganglionic neurotransmitter:
Ach acting on muscarinic receptors

Responses of effector organs to autonomic nerve impulses:

• The sympathetic and parasympathetic neurotransmitters are often functional antagonists
• Their activities on specific structures may be either be:
a) discrete and independent
b) integrated and interdependent

Effect on heart and iris: functional antagonism in controlling heart rate and pupillary aperture

Effect on male sexual organs: complementary and integrated to promote sexual function

GENERAL FUNCTIONS • Primary regulator of the constancy of the internal environment of the organism
OF THE AUTONOMIC
(1) Sympathetic system + associated adrenal medulla
NERVOUS SYSTEM
▪ not essential to life but important under circumstances of stress
(2) Parasympathetic system
▪ conserved with conservation of energy and maintenance of organ function during periods of
minimal activity
▪ elimination is not compatible with life

NEUROTRANSMISSION: ANS AND SNS Karrel C.

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NEUROCHEMICAL TRANSMISSION
NERVE IMPULSES • Elicit responses in muscles, exocrine glands, and postsynaptic neurons

Neurotransmitters
• Mediate synaptic transmission
• It is once believed that each neuron contains only 1 transmitter substance
• We now find that synaptic transmission may be mediated by more than 1 neurotransmitter
➔ Additional substances have been found in nerve endings along with the classical neurotransmitters
(1) peptides → enkephalin, substance P, NPY, VIP, and SST
(2) purines → ATP and adenosine
(3) small molecules → NO
➔ These additional substances can depolarize or hyperpolarize nerve terminals or postsynaptic cells

STEPS INVOLVED IN
1 AXONAL CONDUCTION
NEUROTRANSMISSION
▪ Conduction: refers to the passage of an electrical impulse along an axon or muscle fiber
▪ In response to depolarization at a threshold level, an action potential is initiated at a local region of
the membrane

Action potential
o Initial phase
Resting potential - rapid increase in permeability and inward movement of
o -70 mV Na+ through voltage-sensitive Na+ channels
o Intracellular ion: K+ - continues to a positive overshoot
o Extracellular ion: Na+ o Second phase
- rapid inactivation of the Na+ channel
- delayed opening of K+ channel permits outward
movement of K+ to terminate depolarization

NEUROTRANSMISSION: ANS AND SNS Karrel C.

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▪ This results to propagation of action potential without decrement along the axon
▪ In myelinated fibers: jumping or saltatory conduction along the nodes of Ranvier

Few drugs modify axonal conduction in the doses employed therapeutically:

Tetrodotoxin (from puffer fish) and saxitoxin (from shellfish)
➔ selectively block the voltage-sensitive Na+ channel, thereby preventing the increase in Na+
permeability associated with the rising phase of the action potential
Batrachotoxin
➔ extremely potent steroidal alkaloid secreted by a South American frog
➔ produces paralysis through a selective increase in permeability of Na+ channel → persistent
depolarization
Scorpion toxins
➔ peptides that also cause persistent depolarization by inhibiting the deactivation process

2 JUNCTIONAL TRANSMISSION
▪ Transmission: refers to the passage of an impulse across a synaptic or neuroeffector junction
▪ The arrival of the action potential at the axonal terminal initiates a series of events that trigger the
transmission of an excitatory or inhibitory biochemical message
▪ Include the following events:
Storage and release of neurotransmitter
➔ largely synthesized in the region of the axonal terminals
➔ stored in synaptic vesicles
- driven by an electrochemical gradient generated by the vesicular ATPase
promotes fusion of exocytosis of
influx of calcium axoplasmic membrane and neurotransmitter
vesicles

Combination of neurotransmitter with post-junctional receptors and

production of the post-junctional potential
➔ transmitter diffuses across the synaptic or junctional cleft and combines with specialize
receptors on the postjunctional membrane → localized increase in ionic conductance
➔ 3 types of permeability change:
(1) Generalized increase in the permeability to cations (Na+ and occasionally Ca2+)
- Result to a localized depolarization of the membrane
- EPSP
(2) Selective increase in permeability to anions
- Result to stabilization or actual hyperpolarization of membrane
- IPSP
(3) Increased permeability to K+
- K+ gradient directed out of the cell leads to hyperpolarization
- IPSP

Initiation of postjunctional activity

➔ EPSP:
- initiates a propagated action potential
- in smooth muscles: Ca2+ release, enhance muscle tone
- in gland cells: Ca2+ mobilization, secretion
➔ IPSP:
- not found in skeletal muscle
- opposes excitatory potentials initiated by other neuronal sources

Destruction or dissipation of the neurotransmitter

o ACh → via acetylcholinesterase or diffusion

o NE → via simple diffusion + reuptake by axonal terminals
o Amino acid → active transport into neurons and surrounding ganglia
o Peptides → hydrolyzed by peptidases and dissipated by diffusion

NEUROTRANSMISSION: ANS AND SNS Karrel C.

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Non-electrogenic functions

➔ The continual release of neurotransmitters in amounts insufficient to elicit response is

important in transductional control of neurotransmitter action.

CHOLINERGIC Synthesis, storage, and release of acetylcholine

TRANSMISSION

2
11

9 10
5
7
6

1 Uptake of choline by Na+ and Cl--dependent transport system

Can be blocked by hemicholinium
2 Choline + Acetyl moiety of Acetyl CoA = ACh
Catalyzed by choline acetyl transferase (ChAT)
3 ACh transported into storage vesicles by a carrier
Inhibited by vesamicol
4 (Not shown in the illustration)
ACh stored with potential cotransmitters (Co-T), ATP, VIP at neuroeffector junctions
5 Depolarization allows entry of Ca2+
Promotes fusion of vesicular membrane with cell membrane
6 Involves vesicle-associated membrane proteins (VAMPS) and synaptosome-
associated proteins (SNAPS)
7 Release of ACh via exocytosis
Blocked by botulinum toxin
8 ACh interact with muscarinic or nicotinic receptors
Produce characteristic response
9 ACh can also act on presynaptic mAChRs or nAChRs to modify its own release
10 Acetylcholinesterase terminates action of ACh by metabolism to choline and acetate
11 Choline is recycled after reuptake for ACh synthesis (rate-limiting step)

NEUROTRANSMISSION: ANS AND SNS Karrel C.

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Acetylcholine receptors
Nicotinic Muscarinic
o ligand-gated o G protein-coupled
o 5 subunits o Subtypes:
o Subtypes: a) M1, M3, M5 → increase cAMP
a) Muscle type (Nm) → found in b) M2, M4 → decrease cAMP
vertebrate skeletal muscle
b) Neuronal type (Nn) → found in PNS,
CNS, and nonneuronal tissues

ADRENERGIC Synthesis of catecholamines Synthesis, storage, and release of norepinephrine:

TRANSMISSION
1
11

2
4 3
5

6 10

9 8
7

1 Tyrosine transported into the varicosity → converted to DOPA by tyrosine hydroxylase

→ converted to dopamine via aromatic L-amino acid decarboxylase
2 Dopamine taken up into vesicles by VMAT
Blocked by reserpine
3 VMAT can also transport cytoplasmic NE
4 Dopamine converted to NE within the vesicle by dopamine-β-hydroxylase
Stored with NPY and ATP
5 Depolarization → increase Ca2+ → fusion of vesicular membrane with membrane of
varicosity thru interaction with VAMPs and SNAPs
6 Exocytosis → release of NE, NPY, and ATP
7 NE interacts with α and β receptors to produce characteristic response
8 NPY activates NPY receptors (Y1-Y5)
Removed from synapse by peptidases
9 ATP activates P2X and P2Y receptors
Cleared by nucleotidases
10 NE cleared via:
a) neuronal uptake transporter (NET)
b) dilution by diffusion out of the junctional cleft and uptake at extraneuronal sites
by ENT, OCT1, and OCT2
11 NE transported in the cytosol – re-stored in the vesicle or metabolized by monoamine
oxidase (MAO)

NEUROTRANSMISSION: ANS AND SNS Karrel C.

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Metabolic disposition of catecholamines

Adrenergic receptors
α-adrenoceptors β-adrenoceptors
o inhibits NE release o myocardium
α2A o antinociceptive effects, sedation, β1 o epinephrine & NE equipotent
hypothermia, hypotension
o smooth muscles and other sites
β2
α2B o mediates vasoconstriction o epinephrine 10-50x more potent than NE

o modulate dopamine neurotransmission & o adipose tissue

α2C β3
behavioral responses o NE 10x more potent than epinephrine

o produce prostaglandins & leukotrienes

α1
o relaxation of GI smooth muscle

NEUROTRANSMISSION: ANS AND SNS Karrel C.

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PHARMACOLOGICAL
CONSIDERATIONS

NEUROTRANSMISSION: ANS AND SNS Karrel C.