Pharmacology and Therapeutics Lecture #6

INTRODUCTION TO AUTONOMIC PHARMACOLOGY

Dr. D. Esquivel | October 7, 2020

● Ganglia are found in:

- 2 paravertebral chains that lie along the sides
OUTLINE: of the spinal column in the thorax and abdomen
AUTONOMIC NERVOUS SYSTEM
(most)
ANATOMIC ASPECTS OF THE ANS
- anterior aspect of abdominal aorta (few)
NEUROTRANSMITTER ASPECTS OF THE ANS
Cholinergic Transmission
Adrenergic Transmission FIBERS SANS PANS
Cotransmitters
ANS RECEPTORS
Cholinoceptors Preganglionic short long
Adrenoceptors
Dopamine Receptors Postganglionic long short
EFFECTS OF ACTIVATING AUTONOMIC NERVES
NANC TRANSMISSION
SITES OF AUTONOMIC DRUG ACTION
INTEGRATION OF AUTONOMIC FUNCTION SANS PANS
Local Integration
Systemic Reflexes Preganglionic ACh ACh
Complex Organ Control: The Eye
References
Postganglionic NE, ACh, ACh
Dopamine

AUTONOMIC NERVOUS SYSTEM *Somatic NS: ACh (motorneuron)

● Major involuntary automatic portion of the
nervous system NEUROTANSMITTER ASPECTS OF THE ANS
● Contrasts with somatic (voluntary) nervous system
CHOLINERGIC TRANSMISSION

● ACETYLCHOLINE
- primary transmitter in all autonomic ganglia and
at the synapses between parasympathetic
postganglionic neurons and their effector cells.
- at postganglionic sympathetic neurons to the
thermoregulatory sweat glands.
ANATOMIC ASPECTS OF THE ANS - at the somatic (voluntary) skeletal muscle
● Motor (efferent) portion of the ANS: major neural neuromuscular junction
pathway for information transmission from CNS to
involuntary effector tissues 1) SYNTHESIS AND STORAGE
● Two major subdivisions: Parasympathetic ANS
and Sympathetic ANS ● 𝑨𝒄𝒆𝒕𝒚𝒍 − 𝑪𝒐𝑨 + 𝒄𝒉𝒐𝒍𝒊𝒏𝒆 →
● Enteric Nervous System: semiautonomous 𝑨𝒄𝒆𝒕𝒚𝒍𝒄𝒉𝒐𝒍𝒊𝒏𝒆
part of the ANS located in the gastrointestinal Enzyme: Choline acetyltransferase
(GI) tract, with specific functions for the control of ● Rate limiting step: Transport of choline into the
this organ system. nerve terminal (inhibited by: Hemicholinium)
● Neuron cell bodies of the ENS are located in the: ● ACh is actively transported into its vesicles by
- myenteric plexus (plexus of Auerbach) the vesicle associated transporter, VAT (inh.
- submucous plexus (plexus of Meissner) by: Vesamicol)

PARASYMPATHETIC ANS 2) RELEASE OF ACETYLCHOLINE

● Requires the entry of calcium through calcium
● Vegetative and recuperative functions channels and triggering of an interaction
● Craniosacral outflow (preganglionic motor fibers between SNARE proteins.
originate in:) ● SNARE proteins include:
- Cranial Nerve Nuclei (III, VII, IX, X) - VAMPS (vesicle-associated)
- Sacral Segments (S2 - S4) - SNAPS (associated with nerve
● Most ganglia are found in supplied organs terminal membrane)

SYMPATHETIC ANS
● VAMPS + SNAPS interaction → Docking of
● Fight or flight functions vesicle to terminal membrane → Influx of
● Thoracolumbar outflow (preganglionic motor fibers calcium → Fusion of vesicles with nerve ending
originate in:) membranes → Opening of Pores → Release of
- T1 - T12 NT
- L1 - L5

CANO, CJ & TAYABAN, DESS
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 Pharmacology and Therapeutics Lecture #6
INTRODUCTION TO AUTONOMIC PHARMACOLOGY
Dr. D. Esquivel | October 7, 2020

● Botulinum toxins: inhibit release by altering

docking or fusion proteins (VAMPs)

3) TERMINATION OF ACTION
● 𝑨𝒄𝒆𝒕𝒚𝒍𝒄𝒉𝒐𝒍𝒊𝒏𝒆 → 𝑨𝒄𝒆𝒕𝒂𝒕𝒆 +
𝒄𝒉𝒐𝒍𝒊𝒏𝒆
Enzyme: Acetylcholinesterase (inh. by
Donepezil, Rivastigmine, Galantamine)
● Products are not excreted but are recycled in
the body.

ADRENERGIC TRANSMISSION

● NOREPINEPHRINE
- primary transmitter at the sympathetic
postganglionic neuron-effector cell synapses in
most tissues EXCEPT in a) eccrine sweat
glands and b) skeletal muscle.
- In renal BV, dopamine is a vasodilator while NE
is a vasoconstrictor.

1) SYNTHESIS AND STORAGE

a) 𝑻𝒚𝒓𝒐𝒔𝒊𝒏𝒆 → 𝑫𝑶𝑷𝑨 (rate limiting step)
Enzyme: Tyrosine hydroxylase (inh. by:
Metyrosine)
b) 𝑫𝑶𝑷𝑨 → 𝑫𝒐𝒑𝒂𝒎𝒊𝒏𝒆
Enzyme: DOPA decarboxylase
c) 𝑫𝒐𝒑𝒂𝒎𝒊𝒏𝒆 → 𝑵𝒐𝒓𝒆𝒑𝒊𝒏𝒆𝒑𝒉𝒓𝒊𝒏𝒆
Enzyme: Dopamine β- hydroxylase
● NE and Dopamine are transported into vesicles
by the vesicular monoamine transporter
(VMAT) and are stored there.
● VMAT: inh. by Reserpine

2) RELEASE AND TERMINATION OF ACTION

● Release: same Ca2+ dependent mechanism as
ACh (inh. by Guanethidine)
● Difference with ACh release: lack of receptors
for botulinum & do not transport this toxin into
the nerve terminal
● Termination:
a) Diffusion
b) Reuptake by: Norepinephrine transporter
(NET) & Dopamine transporter (DAT) →
reduce their concentration in the synaptic
cleft. Cocaine: inhibits NE reuptake by
binding to transporter, NET.
c) Metabolism (outside the cleft) by:
Monoamine oxidase (MAO) and Catechol-
O-methyltransferase (COMT) → products of
these enzymatic reactions are excreted.
● MAO Inhibition: ↑stores of catecholamines,
useful as antidepressants
● COMT Inhibition: useful in Parkinson’s disease

CANO, CJ & TAYABAN, DESS
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 Pharmacology and Therapeutics Lecture #6
INTRODUCTION TO AUTONOMIC PHARMACOLOGY
Dr. D. Esquivel | October 7, 2020

COTRANSMITTERS
EFFECTS OF ACTIVATING AUTONOMIC NERVES
● Main role in autonomic function: modulation of
synaptic transmission. Each division of the ANS has specific effects on organ
systems.These effects, summarized in Table 6–3.
ATP Substance P
Dually innervated organs

Enkephalins Neurotensin - receive both sympathetic and parasympathetic

innervation.
- Iris of the eye and sinoatrial node of the heart.
Vasoactive Somatostatin
Intestinal Peptide - When both divisions of the ANS are blocked, the
reaction of each organ will side to its dominant
system.
Neuropeptide Y

ANS RECEPTORS NONADRENERGIC, NONCHOLINERGIC (NANC)

● IMPORTANT: Memorize Table 6.1 and 6.2 TRANSMISSION
especially the locations of the different
Some nerve fibers in autonomic fibers do not show
receptor subtypes
the histochemical characteristics of either cholinergic
CHOLINOCEPTORS or adrenergic fibers. Instead, they have the
characteristics of motor or sensory fibers.
Subdivided as:
1) MUSCARINIC RECEPTORS Motors fibers (purine-evoked or peptidergic)
- G-protein coupled receptors (all subtypes)
- Cause the release of ATP and other purines
- Primarily located in autonomic effector cells
- M1 & M3: regulate intracellular 2nd related to it.
messengers (↑IP3 & DAG) - Puring-evoked responses have been identified in
- M2: activate K+ channels w/ increased flux the bronchi, gastrointestinal tract, and urinary
(↓cAMP) , located in the heart tract.
- Peptidergic release peptides as the primary
2) NICOTINIC RECEPTORS transmitters.
- Mechanism: Na+ - K+ ion channel
- Function: Depolarizes, evokes AP Sensory fibers
- Nn: ANS ganglia - Contain peptides, such as substance P, that are
- Nm: skeletal muscle endplate stored and released from the fiber terminals.
- These fibers have been termed “sensory-efferent”
ADRENOCEPTORS or “sensory-local effector” fibers à they release
transmitter peptides when activated by a sensory
Subdivided as: input.
1) ALPHA RECEPTORS
- 2 subtypes using different G-coupling proteins SITES OF AUTONOMIC DRUG ACTION

2) BETA RECEPTORS • CNS centers

- 3 subtypes using the same Gs-coupling protein.
DOPAMINE RECEPTORS
● Subclass of adrenoceptors but with different
distribution & function
● Important in the renal & splanchnic vessels & in
the brain
● D1 – most important, found on peripheral effector
cells
● D2 – found on presynaptic nerve terminals
• Ganglia
• Postganglionic nerve terminals
• Effector cell receptors
INTEGRATION OF AUTONOMIC FUNCTION
Functional integration in the ANS is provided mainly
through the mechanism of negative feedback and is
extremely important in determining the overall response
to endogenous and exogenous ANS transmitters and
their analogs.

A. Local Integration
• Local feedback control has been found out at
the level of the nerve endings in all systems
investigated. The best documented of these is

CANO, CJ & TAYABAN, DESS
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 Pharmacology and Therapeutics Lecture #6
INTRODUCTION TO AUTONOMIC PHARMACOLOGY
Dr. D. Esquivel | October 7, 2020
the negative feedback of norepinephrine upon
its own release from adrenergic nerve
terminals. It is mediated by α2 receptors
located on the presynaptic nerve membrane.
• AUTORECEPTORS
- Are presynaptic receptors that bind the primary
transmitter substance that thereby regulate its
release.
- Sensitive only to neurotransmitters or hormones
released by the cell in whose wall they are
embedded.
• HETERORECEPTORS
- Presynaptic receptor
- are terminal receptors for other transmitters that
may act either to stimulate or inhibit at that
terminal.
- Respond to neurotransmitters, neuromodulators,
neurohormones released from adjacent neurons or
cells.
• Postsynaptic modulatory receptors
- M1 and M2
- Have been found in ganglionic synapses, where
nicotinic transmission is primary.
- These receptors may facilitate or inhibit
transmission by evoking slow excitatory or
inhibitory postsynaptic potentials.
B. Systemic Reflexes
• System reflexes regulate blood pressure,
gastrointestinal motility, bladder tone, airway
smooth muscle, and other processes.
- The control of blood pressure – by the baroreceptor
neural reflex and the renin-angiotensin-
aldosterone hormal response.
- Homeostatic mechanisms maintain mean arterial
blood pressure at a level determined by the
vasomotor center and renal sensors.
CANO, CJ & TAYABAN, DESS
- Any deviation from this blood pressure “set point”
causes a change in ANS activity and renin-
angiotensin-aldosterone (RAA) levels.
• Compensatory mechanism – an action taken by
the body to continue physiological function
despite an alteration in natural function.
For example:
- ↓BP caused by hemorrhage results in increased
Sympathetic ANS (SANS) discharge and renin
release. Consequently, peripheral vascular
resistance, venous tone, heart rate, and cardiac
force are increased by norepinephrine released
from sympathetic nerves.
- This ANS response can be blocked with ganglion-
blocking drugs such as hexamethonium.
- Blood volume is replenished by retention of salt
and water in the kidney under the influence of
increased level of aldosterone.
NOTE: These compensatory responses may be large
enough to overcome some of the actions of drugs.
Example: The chronic treatment of hypertension with a
vasodilator such as hydralazine will be unsuccessful if
compensatory tachycardia and salt and water are not
prevented through the use of additional drugs.
C. Complex Organ Control: The Eye
• Ciliary muscle – muscarinic receptor
• Ciliary epithelium – β-adrenoceptor
• Radial muscle (iris) – α-adrenoceptor
• Circular muscle (iris) – muscarinic receptor
• Pupil
– Via α receptors on the pupillary dilator
muscle (SANS)
– Via muscarinic receptors on the
pupillary constrictor (PANS)
END OF TRANSCRIPTION
REFERENCES
● Trevor, A. J., Katzung, B. G., & Masters, S. B.
(2008). Katzung & Trevor's pharmacology:
Examination & board review (8th ed.). New York:
McGraw Hill Medical.
● Batch Dravergonz Trans ( by: Cuanso & Jaya, RPh)
● Dr. Esquivel Lecture
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 Pharmacology and Therapeutics Lecture #6
INTRODUCTION TO AUTONOMIC PHARMACOLOGY
Dr. D. Esquivel | October 7, 2020

CANO, CJ & TAYABAN, DESS
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 Pharmacology and Therapeutics Lecture #6
INTRODUCTION TO AUTONOMIC PHARMACOLOGY
Dr. D. Esquivel | October 7, 2020

CANO, CJ & TAYABAN, DESS
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