Section 4 Pharmacology

Peripheral Nervous System

Peripheral Nervous system
 Autonomic: Activities not under direct conscious control, primarily visceral functions (e.g. cardiac output, blood
flow to organs, digestion)
 Somatic: Consciously controlled functions (e.g. movement, respiration, posture)

Anatomy of the Autonomic Nervous System

 Sympathetic (thoracolumbar) division
o Origin in nuclei within CNS
o Preganglionic efferent fibres are short and exit CNS via thoracic and lumbar spinal nerves
 Terminate in ganglia mostly located in paravertebral chains (on either side of the vertebral
column), remainder in prevertebral ganglia (in front of the vertebrae)
 Parasympathetic (craniosacral) division
o Origin in nuclei within CNS
o Preganglionic efferent fibres exit CNS via cranial nerves - especially III (occulomotor), VII (facial), IX
(glossopharyngeal), X (vagus) - and S3-4 sacral spinal roots
 Some terminate in parasympathetic ganglia outside the organs innervated (e.g. ciliary,
pterygopalatine, submandibular, otic, and several pelvic ganglia)
 Most terminate on ganglion cells diffusely distributed in the innervated organ
 In addition, there are large numbers of afferent fibres that run from the periphery to integrating centres (including
enteric plexuses in the gut, the autonomic ganglia, and the CNS)

 The enteric nervous system (ENS) is a large and highly organised collection of neurons located in the walls of the
gastrointestinal system. It is sometimes considered a third division of the ANS.
o Includes the myenteric plexus (plexus of Auerbach) and the submucous plexus (plexus of Meissner)
o They receive:
 Preganglionic fibres from the parasympathetic system
 Postganglionic sympathetic axons
 Sensory input from within the wall of the gut
o Fibres from the cell bodies in the plexuses travel to:
 Smooth muscle of the gut (control motility)
 Secretory cells
 Table 10-2 (Bryant): Differentiating characteristics between PNS and SNS
Characteristic Parasympathetic NS Sympathetic NS
Origin Craniosacral Thoracolumbar
Innervation Cardiac muscle, smooth muscle, glands, viscera Cardiac muscle, smooth muscle, glands, viscera
Autonomic ganglia Near or within the wall of the effector Near the CNS
Length of fibres Preganglionic – long Preganglionic – short
Postganglionic – short Postganglionic – long
Ratio of pre- to postganglionic fibres Minimal branching (1:4) High degree of branching (1:11, 1:17)
Chemical transmitter at ganglion ACh ACh
Chemical transmitter at nerve ending ACh Noradrenaline (usually), ACh for sweat glands

Table 6.3 - Effects of autonomic nerve activity on organ systems

Effect
Organ Sympathetic Activity Parasympathetic Activity
Action Receptor Action Receptor
Eye
Iris radial muscle Contracts α1 ... ...
(Dilation)
Iris circular muscle ... ... Contracts M3
(Constriction)
Ciliary muscle [Relaxes] Contracts M3
Heart
Sino-atrial node Accelerates β1, β2 Decelerates M2
Ectopic pacemakers Accelerates β1, β2 ... ...
Contractility Increases β1, β2 Decreases (atria) M2
Blood vessels
Skin, splanchnic vessels Contracts α ... ...
Relaxes β2 ... ...
Skeletal muscle vessels [Contracts] α ... ...
Relaxes3 M ... ...
Endothelium (drug effect) Releases EDRF M3, M5
Bronchiolar smooth muscle Relaxes β2 Contracts M3
Gastrointestinal tract
Smooth muscle
Walls Relaxes α 2, β2 Contracts M3
Sphincters Contracts α1 Relaxes M3
Secretion ... ... Increases M3
Genitourinary smooth
muscle
Bladder wall Relaxes β2 Contracts M3
Sphincter Contracts α1 Relaxes M3
Uterus, pregnant Relaxes β2 ... ...
Contracts α Contracts M3
Penis, seminal vesicles Ejaculation α Erection M
Skin
Pilomotor smooth muscle Contracts α ... ...
Sweat glands ... ...
Eccrine Increases M ... ...
Apocrine (stress) Increases α ... ...
Metabolic functions
Liver Gluconeogenesis β2, α ... ...
Liver Glycogenolysis β2, α ... ...
Fat cells Lipolysis β3 ... ...
Kidney Renin release β1 ... ...

Transmitters in the ANS

 Parasympathetic:
o Acetylcholine (ACh): Synthesised by a large number of post-synaptic ANS fibres (‘cholinergic’)
 All preganglionic efferent autonomic fibres
 The somatic (non-autonomic) motor fibres to skeletal muscle
o A significant number of parasympathetic postganglionic neurons utilise nitric oxide or peptides for
neurotransmission.
 Sympathetic:
o Noradrenaline (NA): Synthesised by most postganglionic sympathetic fibres (‘noradrenergic’ =
‘adrenergic’)
o A few sympathetic fibres release ACh (sweat glands) or dopamine (renal vascular smooth muscle).
o Adrenal medullary cells (embryologically analogous to postganglionic sympathetic neurons) release a
mixture of adrenaline and NA.
 Most autonomic nerves also release several transmitter substances in addition to the primary transmitter
(cotransmitters).
 Key features of neurotransmitter function (these are potential targets of pharmacotherapy!):
1. Synthesis
2. Storage
3. Release
 4. Activation of receptors
5. Termination of action

Cholinergic transmission
1. Synthesis
Brief summary:
 In the cytoplasm. Acetyl-CoA + choline (through catalytic action of 1. Synthesis: Acetyl-CoA + Choline
enzyme choline acetyltransferase (ChAT) → ACh. [ChAT] → ACh
 Acetyl-CoA is synthesised in the mitochondria (present in large numbers 2. Storage: In vesicles
in the nerve ending) 3. Release: Action potential → IP, DAG
cascade → Ca2+ influx → Destabilises
 Choline is transported from the extracellular fluid into the neuron terminal storage vesicles → Exocytosis into
by a sodium-dependent membrane carrier (choline transporter). synapse
o This carrier can be blocked by a group of drugs called 4. Activates: ACh receptor
(cholinoceptor)
hemicholiniums 5. Termination: ACh [AChE] → Choline
2. Storage + Acetate
 Once synthesised, ACh is transported from the cytoplasm into the vesicles
by an antiporter that removes protons (vesicle-associated transporter)
o This transporter can be blocked by vesamicol
 The terminals of cholinergic neurons contain:
o Large numbers of small clear vesicles, located near the synaptic portion of the cell membrane, containing
most of the ACh.
o A smaller number of large dense-cored vesicles, located farther from the synaptic membrane, containing a
high concentration of peptide cotransmitters.
3. Release
 Action potential reaches the terminal → Triggers influx of Ca2+ → Destabilises storage vesicles by interacting with
special proteins associated with the vesicular membrane → Vesicular membranes fuse with terminal membrane
(through interaction of proteins in both membranes (vesicular associated membrane proteins (VAMPs), synaptosome-
associated proteins, SNAPs) → Exocytotic expulsion of ACh into synaptic cleft.
o The ACh vesicle release process is blocked by botulinum toxin (through enzymatic removal of two amino
acids from the fusion proteins)
 Several cotransmitters are released at the same time.
4. Receptors
 ACh binds to and activates an ACh-receptor
(cholinoceptor).
o Nicotinic receptors are present in skeletal
neuromuscular junction and autonomic ganglia
(and the CNS)
 Pentameric ligand-gated ion channel.
Subunits consist of 2α, 1β, 1δ, 1ε.
 When the 2 ligands bind (one to each α-
subunit), the channel opens to allow Na+
to diffuse rapidly down its concentration
gradients → Depolarisation of the nerve
cell or neuromuscular end plate
membrane (K+ is also permitted to pass
through the receptor, but net
depolarisation takes place).
 Prolonged agonist occupancy of the
nicotinic receptor → Effector response is
abolished [i.e. postganglionic neuron
stops firing (ganglionic effect) and
skeletal muscle cell relaxes
(neuromuscular end plate effect)].
Furthermore, the continued presence of
the nicotinic agonist prevents electrical
recovery of the post-junctional
membrane (‘depolarising blockade’ →
muscle paralysis).
 2 classifications:
 NN = Neuronal (in the ganglia of PNS and SNS)
 NM = Muscular
o Muscarinic receptors are present on the effector organs of autonomic nervous system (and the CNS)
 G-protein coupled, with multiple different downstream effects, including:
 Activation of the IP3 or DAG cascades (opening of smooth muscle Ca2+-channels, release
of Ca2+ from endoplasmic and sarcoplasmic reticulum)
  Increases in cellular cGMP concentration
 Inhibition of or increases in adenylyl cyclase activity, and altered cAMP levels
 5 distinct types of muscarinic receptor (3 are pharmacologically important):
 M1 = the neural type
 M2 = the cardiac and presynaptic type
 M3 = the glandular and smooth muscle type
5. Termination of action
 ACh is split into choline + acetate (neither of which has significant neurotransmitter effects) by acetylcholinesterase
(AChE), sitting mostly on the post-synaptic membrane.
o Choline is reuptaken by the presynaptic terminal for reincorporation in to ACh

Adrenergic transmission
1. Synthesis Brief summary:
 Pathway: 1. Synthesis: Tyr → Dopa → Dopamine
o Tyrosine (Tyr) [Tyrosine hydroxylase] → Dopa [Dopa [dopamine β-hydroxylase] → NA
[Phenylethanolamine-N-
carboxylase] → Dopamine [Dopamine β-hydroxylase] → methyltransferase] → Adrenaline
Noradrenaline [Phenylethanolamine-N-methyltransferase] → 2. Storage: Membrane-bound vesicles
Adrenaline 3. Release: Similar to Ca2+ dependent
 End products: release of cholinergic transmission
(cotransmitters are also released)
o Dopaminergic neurons of the CNS: synthesis terminates with 4. Activates: Adrenoceptors on
dopamine postsynaptic cell
o Most sympathetic postganglionic neurons: Noradrenaline 5. Termination: Mostly simple
o Adrenal medulla and several areas of the brain: noradrenaline is diffusion and reuptake in nerve
terminal; also metabolised by MAO
further converted to adrenaline and COMT → Metanephrines and
 The rate limiting step in catecholamine transmitter synthesis is the VMA
conversion Tyr → Dopa, which can be inhibited by the Tyr analogue
metyrosine.
2. Storage
 The catecholamine transmitters are stored in membrane-bound vesicles, into which they are transported by a carrier,
located in the wall of the storage vesicle.
o This carrier can be inhibited by the reserpine alkaloids; depletion of transmitter stores results.
3. Release
 Similar to the Ca2+-dependent process for
cholinergic terminals.
 In addition to the primary neurotransmitter, the
following are also released into the synapse:
o ATP
o Dopamine-β-hydroxylase
o Peptide cotransmitters
 Indirectly acting sympathomimetics (Examples:
Tyramine, amphetamines) are capable of
releasing stored transmitter from noradrenergic
nerve endings. These drugs are poor agonists
(some are inactive) but they are taken up into
noradrenergic nerve endings, where they may
displace NA from storage vesicles, inhibit MAO,
and have other effects that result in increased NE
activity in the synapse.
4. Receptors
 Adrenoceptors are mostly on the postsynaptic cell
o α-adrenoceptors:
 α1 = CNS (postsynaptic
membrane - excitatory),
peripheral (smooth muscle -
vascular, urinary)
 α2 = CNS (pre- and postsynaptic
membrane - inhibitory, negative-feedback receptors)
o β- adrenoceptors:
 β1 = heart
 β2 = smooth muscle (bronchioles, arterioles, uterine)
 β3 = adipose tissue
5. Termination of action
 NA, adrenaline, and dopamine can be metabolised by several enzymes:
 o Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) → Metanephrines and 3-
methoxy-4-hydroxy-mandelic acid (VMA).
 However, metabolism is not the primary mechanism for termination of action of NA that is physiologically released
from noradrenergic nerves:
o Reuptake into the nerve terminal (main mechanism)
o Simple diffusion away from the receptor site (with eventual metabolism in the plasma or liver)
o Uptake into perisynaptic ganglia or smooth muscle cells

Functional organisation

1. Central integration
 At the level of midbrain and medulla, the two divisions of the ANS and the endocrine system are integrated with each
other, with sensory input, and with information from higher CNS centres.
 Example: Integration of cardiovascular function. Primary controlled variable is mean arterial pressure:
o Autonomic feedback loop: ↓ MAP → ↑ Baroreceptor firing → Vasomotor centre →
 ↓ Parasympathetic NS Activity:
 ↑ HR → ↑ CO → ↑ MAP
 ↑ Sympathetic NS Activity:
 ↑ PVR → ↑ MAP
 ↑ HR → ↑ CO → ↑ MAP
 ↑ Contractility → ↑ SV → ↑ CO → ↑ MAP
 ↑ Venous tone → ↑ Venous return → SV → CO → MAP
o Hormonal feedback loop: ↓ MAP → ↓ Renal blood flow/pressure → ↑ Renin → ↑ Angiotensin → ↑
Aldosterone → ↑ Blood volume → ↑ Venous return → ↑ SV → ↑ CO → ↑ MAP
2. Presynaptic regulation
 Important presynaptic feedback inhibitory control mechanisms have been shown to exist at most nerve endings.
Examples:
o α2-receptor is activated by NA → Activation diminishes further release of NA from these nerve endings
o Presynaptic β-receptor appears to facilitate the release of NA
o Presynaptic receptors that respond to the transmitter substances released by the nerve ending are called
autoreceptors. They are usually inhibitory, but many cholinergic fibres (especially somatic motor fibres)
have excitatory nicotinic autoreceptors.
3. Postsynaptic regulation
 Modulation by the prior history of activity at the primary receptor
o May up- or down-regulate receptor number
 ↓ Activation of receptors ~→ Up-regulation
 ↑ Activation of receptors ~→ Down-regulation
o May also desensitise receptors (see Chapter 2)
 Modulation by other temporally associated events
 o Primary transmitter-receptor is modulated by events evoked by the same or other transmitters acting on
different post-synaptic receptors.
o Example: Ganglionic transmission

Pharmacology of the eye

 The eye is a good example of an organ with multiple ANS functions
o Three muscles in the anterior chamber:
 Pupillary dilator muscle (in the iris)
 Pupillary constrictor muscle (in the iris)
 Ciliary muscle
o Parasympathetic activity causes:
 Contraction of pupillary constrictor
muscle (circular muscle)
 Miosis (reduction in pupil
size)
 Contraction of ciliary muscle
 Accommodation of focus
(for near vision)
 Marked contraction of the
ciliary muscle (cyclospasm)
often occurs after
cholinesterase inhibitor
intoxication
 Contraction of the ciliary muscle also puts tension on the trabecular meshwork, opening the
pores and facilitating outflow of the aqueous humor into the canal of Schlemm → ↓
Intraocular pressure
o This is a desired effect in patients with glaucoma.
 All of these effects are prevented or reversed by muscarinic blocking drugs (Example: Atropine), but
they are accentuated by ↑ muscarinic transmission, as is the case with cholinesterase inhibitors
(Example: Organophosphates)
o SNS α-adrenoceptors cause:
 Contraction of the pupillary dilator muscle (radial muscle) → Mydriasis (enlargement of pupil)
 This occurs in sympathetic discharge and with α-adrenergic drugs (Example: Phenylephrine)
o SNS β-adrenoceptors on the ciliary epithelium facilitate the secretion of aqueous humor.
 β-blockers reduce this secretion → Reduction in intraocular pressure → Another therapy for glaucoma.