pharmacology of CNS

Question 1

Which are the signal molecules in the CNS?

Answer 1

 Neurotransmitters
 Neuromodulators
 Neurotrophins

Question 2

What are the types of neurotransmitters in the CNS?

Answer 2

 Typical (e.g. ACh, NE etc.) and atypical (e.g. NO, arachidonic acid
and derivatives)

 Fast (e.g. glutamate) and slow (e.g. dopamine)

 By chemical nature – amino acids, biogenic amines, peptides, gases,
lipids, etc.

Question 3

What are the receptors for NTs in the CNS?

Answer 3

 Ligand-operated ion channels = ionotropic receptors

 G-protein-coupled receptors (GPCR) = metabotropic receptors

Question 4

What are the Changes in the postsynaptic membranes – local postsynaptic
potentials (PSP)?

Answer 4

 Excitatory PSP (EPSP), leading to excitatory effects

 Inhibitory PSP (IPSP), leading to inhibitory effects

Question 5

What are the types of ion channels in the CNS?

Answer 5

1. Voltage-gated
2. Ligand-gated ion channels
3. Membrane-delimited metabotropic ion channel
4. diffusible second messenger metabotropic ion channel

Question 6

What is an EPSP?

Answer 6

Local postsynaptic potentials

 EPSP are produced by stimuli
causing membrane
depolarization
 By opening Na+ channels
 By closing K+ or Cl- channels
 EPSP are capable of inducing action potential (AP)
 AP is generated when the
EPSP reaches the threshold
potential

Question 7

What is an IPSP?

Answer 7

Local postsynaptic potentials

 IPSP are produced by stimuli
causing membrane hyperpolarization
 By opening K+ or Cl- channels
 By closing Na+ and Ca++ channels
 IPSP can not generate AP since it
drives the membrane potential
away from the threshold value.
 IPSP will prevent an EPSP to
induce an AP

Question 8

What are neuromodulators?

Answer 8

 Neuronal or glial origin
 Extrinsic or intrinsic (co-transmitters)
 Extrinsic modulators are usually
released from neuronal varicosities
 Reach the receptors by diffusion
 Act relatively slow (GPCR)

 May modulate:
 Short-term phenomena:
 Release of NT
 Interaction with receptors
 Long-term phenomena:
 Gene regulation

Question 9

What are neutrophins?

Answer 9

 Proteins secreted by target cells/glia

 Act in a retrograde mode to:
 Promote and guide axonal
growth and differentiation
 Support neuronal survival
 Role in synaptic plasticity
 Induce dendritic sprouting
and new synapse
formation.

 Families
 Of neuronal origin:
 NGF, BDGF, NT3,
NT4/5
 Of glial origin (GDNF
family):
 GDNF, artemin,
persephin

 Dual receptor system:
 Tyrosine kinase receptor (Trk)
 High-affinity
 Specific for each neurotrophin
 P75 neurotrophin receptor (TNF-R type)
 Non-specific, low affinity
 Modulation (↑ affinity of Trk)

 Typical expression
 NGF – primarily in forebrain,
sympathetic and sensory neurons
 BDNF and NT3 – mainly in cortex and
hippocampus

 Therapeutic potential of neurotrophins
 Antidepressants increase BDNF
 Local administration (in vision, hearing
loss)
 Systemic administration? (PK issues,
ADRs)

Question 10

What is the cellular organization of brain function?

Answer 10

 Hierarchical Systems
 Local (intra-regional) inter-neurons
 Diffuse (nonspecific) neuronal systems

Question 11

What are Hierarchical systems?

Answer 11

 Projection neurons with long axons are
sequentially connected to transmit signals
over long distances

 Long ascending and descending pathways
involved directly in sensory perception
and motor control

 The axons are myelinated nerve fibers
with high velocity of conduction (~50
m/sec)

 The neurotransmitter involved is almost
exclusively the excitatory amino acid
glutamate

 A lesion at any level of the system will
incapacitate it as a whole

Question 12

What are Inter-neurons
(local circuits neurons)
?

Answer 12

 Short axons

 Inhibitory NT (e.g. GABA, glycine, opioids)

 Modulate the function of the hierarchical
systems by:
 Feed back inhibition
 Feed forward inhibition
 Axo-axonic inhibition

Question 13

What is an example of acidic AA as a neurotransmitter?

Answer 13

 Acidic AA: Glutamate
 The most abundant excitatory
NT in vertebrates

 Receptors:
 Ionotropic excitatory
 NMDA (↑ Na+, K+, Ca++)
 AMPA, Kainate (↑ Na+, K+)
 Metabotropic (GPCR):
 Pre- and postsynaptic
 Inhibitory and excitatory effect

 Physiological role:
 Synaptic plasticity (LTP 
memory, learning)

 Pathogenic role:
 Excitatory neurotoxicity
(ischemic diseases, stroke,
epilepsy, neurodegenerative
diseases)
 Pathological LTP (e.g., in
chronic pain, addiction)

Question 14

What is an example of neutral AA as a neurotransmitter?

Answer 14

 Neutral AA: GABA, Glycine

 Inhibitory effects
 GABA – the most common
inhibitory NT (~ 30% of all
neurons)
 Receptors
 GABA-A, a Clionophore complex
 Integrated BDZ and barbiturate
binding sites
 GABA-B, a GPCR (↓ cAMP, Ca++
,↑ K+)
 GABA-C, an ionotropic receptor
 GABA-ergic pathways
 Interneurons – at supraspinal
and spinal level
 Long pathways (in striatum and
cerebellum)

 Glycine
 Renshaw cells (recurrent
inhibition on spinal motor
neurons)

Question 15

What are Diffuse neuronal systems?

Answer 15

 Origin – one or more groups of
neurons (often located in brainstem)

 Diffuse branching and projections to
many different brain structures

 Fine and non-myelinated axons, firing
at low velocity (~ 0.5 m/sec)

 Numerous varicosities along the nerve
fiber, often with no immediate synaptic
contacts (neurotransmitters diffuse at
long distances)

 A disruption of the system at a given
level does not disturb the function as a
whole

 Variety of functions under control:
autonomic, endocrine, behavioral

 Neurotransmitters – various, mainly
amines, with both excitatory and
inhibitory effects

Question 16

What is acetylcholine?

Answer 16

 Diffuse systems in:
 Forebrain and septo-hippocampal
pathways
 Brain stem (reticular formation)
 Interneurons in C. striatum

 Receptors
 Metabotropic: M
 M1
-like: M1
, M3
and M5
\: Gq (mainly
postsynaptic)
 M2
-like: M2 and M4
\: Gi (pre- and
postsynaptic)
 Ionotropic: Nn
( Na+) (mainly
presynaptic, homo- and hetero-)

 Physiological functions:
 Attention, memory and learning
 Wakefulness and sleep (initiation of
REM phase)
 Locomotion

 Pathogenic role in:
 Dementias, e.g. Alzheimer’s disease
 Parkinson’s disease

Question 17

What are the receptors, physiological functions, and pathogenic role of noradrenaline? (Biogenic amines as NT)

Answer 17

 Cell bodies located mainly in locus
coeruleus (LC) in the pons and in the
reticular formation

 Receptors (GPCR)
 Alpha1,2 – pre (α2) and postsynaptic
 Beta1,2 – pre (beta2) and postsynaptic

 Physiological functions:
 Psychological response to stress
 Active wakefulness and sleep-wake
cycle (arousal from sleep)
 Mood & emotions (fear, anxiety)
 Autonomic reactions
 Analgesia

 Pathogenic role in:
 Depression
 Attention deficit hyperactivity disorder
(ADHD)
 Post-traumatic stress disorder

Question 18

What are the main pathways, receptors, physiological functions, and pathogenic role of dopamine? (Biogenic amines as NT)

Answer 18

 Cell bodies: in midbrain, hypothalamus

 Main pathways:
 Mesocortical and mesolimbic systems
 Nigrostriatal
 Tubero-infundibular

 Receptors (GPCR):
 D1
-like (Gs): postsynaptic
 D2
-like (Gi): pre- and postsynaptic

 Physiological functions:
 Behavior/ motivation (arousal, pleasure)
 Locomotion, stereotypy
 Neuroendocrine: PL inhibition (PIF)
 Vomiting

 Pathogenic role in:
 Parkinson’s disease (dopamine deficiency)
 Schizophrenia (dopamine over-activity)
 Drug dependence
 Neuro-endocrine disorders
 Vomiting

Question 19

What are the receptors, physiologic functions, and pathogenic role of serotonin (5-HT)? (Biogenic amines as NT)

Answer 19

 Cell bodies in Raphe nuclei (brainstem
and pons), sending rostral and caudal
projections

 Receptors:
 Metabotropic (GPCR): 5-HT1-2;4-7
 Ionotropic: 5-HT3
(increased Na+)

 Physiological functions:
 Behavior: mood, fear
 Autonomic (feeding, vomiting) and
neuroendocrine (PL)
 Sensory perception (pain, vision) and
pain control

 Pathogenic role in:
 Depression
 Anxiety disorders
 Obsessive-compulsive disorder
 Eating disorders
 Migraine

Question 20

What are the receptors and physiological functions of histamine?
(Biogenic amines as NT)

Answer 20

 Cell bodies in the tuberomammillary
nucleus (NTM) in ventral posterior
hypothalamus

 Receptors (GPCR):
 H1
(Gq) (postsynaptic)
 H2
(Gs) (pre- and postsynaptic)
 H3
(Gi) (inhibitory autoreceptors)

 Physiological functions:
 Arousal and wakefulness
 Circadian rhythms
 Control of food and water intake
 Vomiting
 Vestibular function

Question 21

What are peptide neurotransmitters (neuropeptides)?

Answer 21

 Neuropeptides are synthetized in the soma and transported
to the terminal

 Stored in dense core vesicles and released as main
transmitters or as co-transmitters, acting as modulators

 Tachykinins:
 SP, NKA, NKB
 Receptors: NK1-3
(GPCR)
 Functions:
 Pain perception
 Neurogenic inflammation

 Other peptides:
 Opioids: endorphins, enkephalins, dynorphins
 CCK, bradykinin, TRH, CRH, CGRP, etc.

Question 22

What are opioid ligands?

Answer 22

 Ligands for the opioid
receptors

 Endogenous neuropeptides:
 Beta-endorphin
 Enkephalins
 Dynorphins

 Exogenous:
 The plant alkaloid Morphine

Question 23

How are opioid analgesics classified?

Answer 23

Agonists
 Of natural origin
 Morphine
 Codeine

 Semi-synthetic
 Dihydrocodeine
 Oxycodone

 Synthetic
 Pethidine = Meperidine
 Fentanyl
 Tramadol
 Methadone

Partial agonists
 Buprenorphine

Antagonists
• Naloxone
• Naltrexone
• Methylnaltrexone

Question 24

What is morphine?

Answer 24

The natural alkaloid is derived from
Papaver somniferum
 The milky latex sap dripping from cuts in the
seed capsules of opium poppy contains the
alkaloids

Chemistry
 A phenanthrene alkaloid
 Substitutions in the OH at C3 (codeine,
heroin) →
 PK consequences
 Reduced first-pass metabolism
 Better access across the BBB
 PD consequences
 Reduced affinity to µ receptors
 Replacement of the CH3 moiety at the N
with larger radicals (e.g. allyl) →
 Antagonist activity (Naloxone)

Question 25

What is the PK of morphine?

Answer 25

 Oral absorption
 Low bioavailability (~ 25%) due to first-pass metabolism

 Metabolism
 Conjugation with glucuronic acid
 М6G: analgesic potency > parent compound
 M3G: excitatory effects on CNS (allodynia, myoclonus, seizures)

 Renal and biliary excretion of metabolites
 Dose reduction in renal failure (М6G and M3G tend to accumulate
in renal failure)

 Plasma half-life ~ 3 h

 Routes of administration
 Parenteral: SC, IV
 Oral – in cancer patients, in prolonged release drug forms
 Epidural (in OG); spinal (in surgery)

Question 26

PD of morphine?

Answer 26

 Central effects:

 Analgesia
 Increased pain threshold for
moderate to severe pain
 Reduced emotional (affective)
response to pain
 Euphoria (DA pathway)
 Respiratory paralysis
 Sedation (“Morpheus” – the god
of dreams)
 Cough suppression
 Miosis
 Nausea and vomiting
 Neuroendocrine effects
 ↑ АDH, prolactin
 ↓ FSH, LH; CRF

 Peripheral effects:

 Constipation, biliary spasm
 Urine retention
 Bronchoconstriction
(histamine release)
 Cardiovascular – at high
doses
 Hypotension
 Venodilation
 Immunosuppression (with
long-term administration)

Question 27

Mode and sites of action of opioids?

Answer 27

 Analgesia – simulation of opioid receptors at:

 Supra-spinal level
 Descending pain inhibitory
pathways (enkephalin, NA, 5-HT)

 Spinal cord:
 Presynaptic inhibition of glutamate
and SP release from nociceptive
afferents
 Inhibition of the secondary afferent
neuron
 Gate control: opioid interneuron

 Periphery:
 Reduced excitability of nociceptors
by opioids secreted by immune
cells during tissue inflammation

 Euphoria
 Stimulation of the DA reward
pathway (VTA to NAcc)

 Abstinence
 LC activation (NA)

Question 28

What are the toxicological aspects of morphine?

Answer 28

 Side/toxic drug reactions:

 Constipation
 Requires treatment with
laxatives or methylnaltrexone
 Nausea and vomiting
 Sedation
 Bronchospasm, itching,
urticaria, (histamine release)
 Respiratory depression
 ↑ intracranial pressure (ICP)
 Urine retention
 Tolerance and dependence

 Contraindications:

 Cranial trauma
 ↑ CO2, vasodilation, ↑ ICP
 “Acute abdomen”
(morphine obscures the
clinical picture)
 Bronchial asthma

 Acute intoxication:

 Symptoms:
 Respiratory paralysis
 Pin-point pupils (NB!)
 Coma and death
 Treatment: Naloxone

Question 29

What are the tolerance and dependence of morphine?

Answer 29

 Tolerance:

 Develops rapidly (days) but becomes clinically manifest after 2-3
weeks
 Dose escalation up to 30-50 times possible
 No tolerance to:
 Miosis
 Constipation

Opioid dependence:

 Psychological dependence – prominent (in addicts):
 Due to euphoria
 Compulsive drug seeking behavior
 Upon discontinuation – long lasting (months) craving for the drug,
leading eventually to relapse

 Physical dependence – prominent:
 Clear-cut abstinence syndrome upon withdrawal following chronic
administration (piloerection, yawning, lacrimation, chills,
hyperventillation, hyperthermia, mydriasis, diarrhea, anxiety, hostility)
 Precipitated by opioid antagonists and/or partial agonists

Question 30

Morphine analogs - Codeine

Answer 30

Codeine
 Better absorbed by mouth and
easier access to brain
 Partly converted to morphine
(CYP2D6)
 Weaker agonist
 Cough suppression at lower doses
 Weaker dependence and
respiratory depression
 Contraindicated in children under
12/18

Question 31

Morphine analogs - Tramadol

Answer 31

Tramadol
 Weaker analgesic
 Mode of action
 Agonist at opioid receptors
 Inhibitor of 5-HT and NE reuptake
 Suitable for post-operative and
other moderate pains
 Lower addiction liability and
respiratory toxicity

Question 32

Morphine analogs - oxycodone

Answer 32

Oxycodone
 More potent than morphine
 Oral use; CYP-dependent
metabolism
 Abusable

Question 33

Morphine analogs - Meperidine

Answer 33

Meperidine (pethidine):

 Good oral bioavailability and shorter
half-life
 Antimuscarinic (spasmolytic) effects
 Preferred for labor analgesia, renal
colic or biliary spasm
 Local anesthetic activity
 Hypothermia (a kappa effect)
 Used to treat post-operative
shivering
 Excitation up to seizures (convulsive
metabolite)
 Drug interactions with МАОIs
(hyperpyrexia, convulsions) and
SSRIs (serotonin syndrome)

Question 34

morphine analogs - Fentanyl

Answer 34

Fentanyl

 More potent (50-100 x) and
shorter acting agonist
 Routes of administration
 Parenteral (acute)
 Transdermal (chronic)
 Intrathecal (in
anesthesiology)

 Indications
 Malignant pain
 Labor
 Neuroleptanalgesia (in
combination with
droperidol) – in surgery,
cardiology

 Similar drugs:
 Remifentanil, sufentanil

Question 35

morphine analogs - Methadone

Answer 35

Methadone:

 Potent and longer-acting µ agonist
 Also blocks NMDA receptors and monoamine
transporters

 Indications
 Substitution therapy in opioid dependence

 ADR
 Abusable; QT prolongation

Question 36

morphine analogs - Buprenorphine

Answer 36

Buprenorphine
 Potent and long-acting partial µ agonist and
kappa antagonist
 Useful in opioid dependence as a substitution
 Prevents euphoric action of full agonists
 Sublingual administration, CYP3A4 substrate
 Buprenorphine/naloxone combination
 ADR
 Similar to other opioids
 Less sensitive to naloxone

Question 37

What are the clinical uses of opioid analgesics?

Answer 37

 Pain (moderate to severe)
in:

 Cancer patients (morphine,
fentanyl, etc.)
 Post-operative (tramadol,
meperidine)

 Other pain syndromes
 Trauma, burns
 Delivery (meperidine,
fentanil, remifentanil)
 Renal/biliary colic
(meperidine)
 Myocardial infarction
(fentanyl)

 Other indications:

 Cough suppression (codeine)
 Cardiac asthma (morphine, IV)
 Soothing the irritated
respiratory center (?)
 Venodilation
 Diarrhea – peripheral agonists
(loperamide)

Question 38

Treatment of acute opioid intoxication

Answer 38

Acute intoxication:

 Cause of death
 Respiratory depression:
the patient “forgets” to
breathe (“Cheyne-Stokes”
breathing)

 Therapy
 Naloxone IV
 Clinical criterion:
 Dilation of the pupils

Question 39

Treatment of chronic intoxication

Answer 39

Chronic intoxication =
dependence

 Methadone, buprenorphine
 Substitution therapy
 Milder abstinence syndrome

 Naltrexone
 Oral antagonist
 Blocks the effect of morphine
“high” in “detoxicated” users

 Clonidine
 Inhibits stress and reduces
the severity of the abstinence
symptoms (LC)