C. Ulens
Overview
Transmission systems in the peripheral and autonomous nervous system
- Afferent sensory signals to CNS
- Efferent
o autonomic NS (or visceral NS)
parasympathetic NS
Pre- and postganglionic fibers
orthosympathetic NS
not all tissues are innervated by both ortho- and parasympathetic NS
enteric NS
the activity of the preganglionic neurons of the ortho- and parasympathetic NS is regulated by
descending pathways from the brain => therefore, many pharmaceutical drugs that influence
the central NS also influence the ortho- and parasympathetic NS.
o motor NS
α- and γ-motor neurons that project from the ventral spinal cord to the
skeletal muscles => neuromuscular junction
In this part of the course we will discuss the medicines that interact with the efferent part of the
peripheral NS. This interaction amounts to direct or indirect influence with the NTs of the peripheral
NS.
- Acetylcholine (Ach)
CHOLINERGIC & ADRENERGIC transmission
- Norepinephrine (NE)
There are other, so-called ‘non-adrenergic-non-cholinergic transmittors’ or NANC transmitters, e.g.,
dopamine, serotonin, purines, neuropeptides, ATP, NO.
Co-transmission = neurons release more than one NT or modulator. It is possible that these
components are inactivated or removed at different rates, causing a different balance depending on
the situation.
Denervation hypersensitivity = due to nerve dissection but also due to long term pharmacological
blockade, abolishing the blockade can lead to rebound effects.
- Proliferation of receptors
- Loss of mechanisms for NT-removal
- Increased post-synaptic sensitivity
Presynaptic modulation = presynaptic receptors regulate NT-release through modulation of Ca2+-influx
in the nerve ending. Most presynaptic receptors are GPCRs.
Synaptic transmission
1. Depolarisation phase: Sodium channels open following the
electro-chemical gradient influx (cell more negative intracell.)
2. Repolarisation phase: Potassium channels open following
the electro-chemical gradient efflux (cell positive intracell.)
3. Hyperpolarisation phase sodium-potassium-pump
against electro-chemical gradient, costs E in form of ATP.
Synaptic transmission in 2 parts = electrical action potential +
chemical component NTs released by Ca2+.
1
, C. Ulens
Ach = Acetylcholine
Drugs affecting cholinergic transmission
NA = Noradrenaline
2 types of Ach-receptors: nicotinic and
muscarinic, both are activated by Ach but the
nicotinic is also specifically activated by nicotine
and the muscarinic also specifically activated by
muscarine.
BBB = Blood Brain Barrier for drugs to pass
through they need to hydrophobic!
Nicotine nicotiana tabacum (plant)
Muscarine amanita muscaria (mushroom)
Synthesis release and reuptake of Ach
Ach is synthesized in Choline AcetylTransferase (CAT), which
transfers an acetylgroup from acetyl-CoA to choline.
Following depolarization of the presynaps, Ach is released into
the synaptic cleft through exocytosis. Ach binds to postsynaptic
Ach-receptors stimulated.
To end its effect in the synaptic cleft Ach is hydrolized to choline
by the enzyme choline-esterase (ChE) which is bound to the
post-synaptic membrane. The choline is then taken up into the
presynaptic nerve through active transport.
If Ach remains bound to receptor -> results in desensitization. Important that Ach gets broken down
by ChE!
Nicotinic = fast only need to open ion channel with conformational change
Muscarinic = slow full blown cascade as it is GPCR
2
, C. Ulens
G-protein = α-subunit + β-subunit + γ-subunit
This is a Gi-protein = α-subunit has inhibitory
characteristics
GDP is exchanged for GTP wen Ach binds to
receptor and triggers a conformational change.
3 different muscarinic receptors
EXCITATORY
INHIBITORY
EXCITATORY
Different nicotinic receptors
α & β are the
different subunits
only binding site in between 2 different subunits! So α4β2 is a nicotinic receptor consisting of both α4
& β2 subunits, the binding sites are in between both subunits.
Homopentamere is also possible e.g., α7, whole nicotinic receptor consisting of 5 the same subunits!
↔ at neuromuscular junction the receptor is obligatory a heteropentamere! You need 5 ≠ subunits.
biological effects mediated through muscarinic receptors
Pupil narrowing
3
, C. Ulens
Biological effects mediated through nicotinic receptors
Ganglia of the automatic NS
- Alternating ortho- and parasympathetic effects. In cardiovascular system usually the ortho
effects predominate, causing tachycardia, vasoconstriction, and BP↗
- High doses can cause a depolarization block (= blockade of the neurotransmission due to
constant depolarization) BP↘, shock, and muscle paralysis.
Neuromuscular junction
- Normal dose: no effect in normal people, however in patients suffering from myasthenia gravis
(causes muscle weakness) it causes an increase in muscle strength
- Higher dose: muscle fasciculations (i.e. uncoordinated contractions of individual muscle fibers)
or muscle contractions (i.e. contractions of the entire muscle)
- Very high dose: depolarization block with limp muscle paralysis (=’cholinergic crisis)
Myasthenia gravis is an autoimmune disease that targets nicotinic receptors
leading to muscle weakness
MIR = Main Immunogenic Region very accessible Ag for Ab’s
Drugs acting on cholinergic receptors
Ach ↗ - Agonists mAChR (muscarine)
- Agonists nAChR (nicotine)
- AChE inhibitors (physostigmine)
Ach ↘ - Antagonists mAChR (atropine)
- Antagonists nAChR (d-tubocurarine)
Agonist = binds to receptor and activates fully
Partial agonist = binds to receptor and activates partially, EC50 higher efficacy
Antagonists = binds to receptor and no activation
Affinity (conc drug EC50)
Agonists mAChR
Not selective for specific M1, 2 or 3 subtype, some agonists even bind the nicotinic receptor.
- Acetylcholine (Ach): very short plasma half-life and is degraded in the plasma by non-specific
esterases, so called ‘pseudocholinesterases’. Therefore Ach is not used systemically, only used
locally in ophthalmologic surgery to induce miosis.
- Pilocarpine: longer duration of action as it is degraded more slowly. It is uncharged and thus
can pass through the BBB causing central effects. Used to cause miosis (locally) and treat dry-
mouth (centrally)
Agonists nAChR
Nicotine is very toxic!
4
Overview
Transmission systems in the peripheral and autonomous nervous system
- Afferent sensory signals to CNS
- Efferent
o autonomic NS (or visceral NS)
parasympathetic NS
Pre- and postganglionic fibers
orthosympathetic NS
not all tissues are innervated by both ortho- and parasympathetic NS
enteric NS
the activity of the preganglionic neurons of the ortho- and parasympathetic NS is regulated by
descending pathways from the brain => therefore, many pharmaceutical drugs that influence
the central NS also influence the ortho- and parasympathetic NS.
o motor NS
α- and γ-motor neurons that project from the ventral spinal cord to the
skeletal muscles => neuromuscular junction
In this part of the course we will discuss the medicines that interact with the efferent part of the
peripheral NS. This interaction amounts to direct or indirect influence with the NTs of the peripheral
NS.
- Acetylcholine (Ach)
CHOLINERGIC & ADRENERGIC transmission
- Norepinephrine (NE)
There are other, so-called ‘non-adrenergic-non-cholinergic transmittors’ or NANC transmitters, e.g.,
dopamine, serotonin, purines, neuropeptides, ATP, NO.
Co-transmission = neurons release more than one NT or modulator. It is possible that these
components are inactivated or removed at different rates, causing a different balance depending on
the situation.
Denervation hypersensitivity = due to nerve dissection but also due to long term pharmacological
blockade, abolishing the blockade can lead to rebound effects.
- Proliferation of receptors
- Loss of mechanisms for NT-removal
- Increased post-synaptic sensitivity
Presynaptic modulation = presynaptic receptors regulate NT-release through modulation of Ca2+-influx
in the nerve ending. Most presynaptic receptors are GPCRs.
Synaptic transmission
1. Depolarisation phase: Sodium channels open following the
electro-chemical gradient influx (cell more negative intracell.)
2. Repolarisation phase: Potassium channels open following
the electro-chemical gradient efflux (cell positive intracell.)
3. Hyperpolarisation phase sodium-potassium-pump
against electro-chemical gradient, costs E in form of ATP.
Synaptic transmission in 2 parts = electrical action potential +
chemical component NTs released by Ca2+.
1
, C. Ulens
Ach = Acetylcholine
Drugs affecting cholinergic transmission
NA = Noradrenaline
2 types of Ach-receptors: nicotinic and
muscarinic, both are activated by Ach but the
nicotinic is also specifically activated by nicotine
and the muscarinic also specifically activated by
muscarine.
BBB = Blood Brain Barrier for drugs to pass
through they need to hydrophobic!
Nicotine nicotiana tabacum (plant)
Muscarine amanita muscaria (mushroom)
Synthesis release and reuptake of Ach
Ach is synthesized in Choline AcetylTransferase (CAT), which
transfers an acetylgroup from acetyl-CoA to choline.
Following depolarization of the presynaps, Ach is released into
the synaptic cleft through exocytosis. Ach binds to postsynaptic
Ach-receptors stimulated.
To end its effect in the synaptic cleft Ach is hydrolized to choline
by the enzyme choline-esterase (ChE) which is bound to the
post-synaptic membrane. The choline is then taken up into the
presynaptic nerve through active transport.
If Ach remains bound to receptor -> results in desensitization. Important that Ach gets broken down
by ChE!
Nicotinic = fast only need to open ion channel with conformational change
Muscarinic = slow full blown cascade as it is GPCR
2
, C. Ulens
G-protein = α-subunit + β-subunit + γ-subunit
This is a Gi-protein = α-subunit has inhibitory
characteristics
GDP is exchanged for GTP wen Ach binds to
receptor and triggers a conformational change.
3 different muscarinic receptors
EXCITATORY
INHIBITORY
EXCITATORY
Different nicotinic receptors
α & β are the
different subunits
only binding site in between 2 different subunits! So α4β2 is a nicotinic receptor consisting of both α4
& β2 subunits, the binding sites are in between both subunits.
Homopentamere is also possible e.g., α7, whole nicotinic receptor consisting of 5 the same subunits!
↔ at neuromuscular junction the receptor is obligatory a heteropentamere! You need 5 ≠ subunits.
biological effects mediated through muscarinic receptors
Pupil narrowing
3
, C. Ulens
Biological effects mediated through nicotinic receptors
Ganglia of the automatic NS
- Alternating ortho- and parasympathetic effects. In cardiovascular system usually the ortho
effects predominate, causing tachycardia, vasoconstriction, and BP↗
- High doses can cause a depolarization block (= blockade of the neurotransmission due to
constant depolarization) BP↘, shock, and muscle paralysis.
Neuromuscular junction
- Normal dose: no effect in normal people, however in patients suffering from myasthenia gravis
(causes muscle weakness) it causes an increase in muscle strength
- Higher dose: muscle fasciculations (i.e. uncoordinated contractions of individual muscle fibers)
or muscle contractions (i.e. contractions of the entire muscle)
- Very high dose: depolarization block with limp muscle paralysis (=’cholinergic crisis)
Myasthenia gravis is an autoimmune disease that targets nicotinic receptors
leading to muscle weakness
MIR = Main Immunogenic Region very accessible Ag for Ab’s
Drugs acting on cholinergic receptors
Ach ↗ - Agonists mAChR (muscarine)
- Agonists nAChR (nicotine)
- AChE inhibitors (physostigmine)
Ach ↘ - Antagonists mAChR (atropine)
- Antagonists nAChR (d-tubocurarine)
Agonist = binds to receptor and activates fully
Partial agonist = binds to receptor and activates partially, EC50 higher efficacy
Antagonists = binds to receptor and no activation
Affinity (conc drug EC50)
Agonists mAChR
Not selective for specific M1, 2 or 3 subtype, some agonists even bind the nicotinic receptor.
- Acetylcholine (Ach): very short plasma half-life and is degraded in the plasma by non-specific
esterases, so called ‘pseudocholinesterases’. Therefore Ach is not used systemically, only used
locally in ophthalmologic surgery to induce miosis.
- Pilocarpine: longer duration of action as it is degraded more slowly. It is uncharged and thus
can pass through the BBB causing central effects. Used to cause miosis (locally) and treat dry-
mouth (centrally)
Agonists nAChR
Nicotine is very toxic!
4
