Central Nervous System Pharmacology

Drugs affecting the CNS

- Most drugs affecting CNS by altering some step
in the neurotransmission process:
o May act presynaptically by influencing
the:
Production
Storage
Release
Termination of the action of the
NTs
o Other agents may activate or block
postsynaptic receptors
(((picture of synaptic transmission)))

Neurotransmission in the CNS

- Similarities w/ ANS:
o Transmission of info involves the
release of NTs -> diffusion across the
synaptic space -> bind to specific
receptors (postsynaptic neuron)
-> triggers intracellular changes
- Differences w/ ANS:
o Circuitry more complex in the CNS:
No. of synapses in the CNS is
greater
o CNS contains powerful networks of
inhibitory neurons
o CNS communicates through a network
of multiple NTs, whereas ANS only uses
two main NTs

Identification of Central NTs

- Primary goal of neuropharmacologists- identify
the transmitters in CNS pathways
- FF criteria have been established to consider a
substance as a NT:
o Localization
o Release
o Synaptic mimicry

Known central NTs

- Based on the nature of action elicited:
o Excitatory
o Inhibitory

Excitatory Pathway
- Stimulation of excitatory neurons causes a
movement of ions that results in a weak
depolarization of the postsynaptic membrane
(Excitatory post-synaptic potential or EPSP)
Mechanism
1. Stimulation of an excitatory neuron causes the
release of NTs such as glutamate or
acetylcholine, w/c bind to receptors on the
postsynaptic cell membrane.
a. A transient in permeability of Na+
ions occurs
2. Influx of Na+ causes a weak depolarization, or
EPSP, that moves the postsynaptic potential
toward its firing threshold.
3. More stimulation of excitatory neurons ->
release of more NTs -> the EPSP depolarization
of the postsynaptic cell to pass a threshold ->
all-or-none action potential.
Inhibitory Pathways
- Stimulation of inhibitory neurons causes
movement of ions that results in a
hyperpolarization of the postsynaptic
membrane
Mechanism
1. Stimulation of inhibitory neurons causes NTs
such as GABA or glycine which bind to receptors
on the postsynaptic cell membrane
a. Causes a transient increase in the
permeability of specific ions, such as K+
and Cl-
2. Influx of Cl- and efflux of K+ causes a weak
hyperpolarization, or IPSP, -> moves the
postsynaptic potential away from its firing
threshold.
a. This diminishes the generation of action
potentials
(((picture: diagram of inhibitory pathway))))
Combined effects of EPSP and IPSP
- Most neurons in the CNS receive both EPSP +
IPSP input.
- Thus, several different types of NTs may act on
the same neuron
Neurodegenerative Diseases
- Parkinsonism
- Alzheimers disease
- Multiple sclerosis
Parkinsonism
- Progressive neurological disorder of muscle
movement, characterized by:
o Tremors
o Muscular rigidity
o Bradykinesia (slowness in initiating
voluntary movements)
o Postural and gait abnormalities
- Involve people over the age of 65 Parkinsonism S&S
o Incidence: ~1 in 100 individuals - Tremors
o Resting tremors
Etiology o Pill rolling tremor
- Unknown for most patients o Action tremor
o Correlated w/ destruction of - Limb rigidity
dopaminergic neurons in the substantia - Akinesia
nigra with consequent decrease of - Bradykinesia
dopamine actions in the corpus system - Masked face
- Secondary parkinsonism - Gait and postural difficulty
o Pseudoparkinsonism
o Caused by drugs e.g. phenothiazines
and haloperidol w/c block dopamine
receptors in the brain -> parkinsonian
symptoms

Drugs used in parkinsonism

- Levodopa and carbidopa
- Selegiline and rasagiline (MAOi)
- Catechol- o-methyltransferase (COMT)
inhibitors:
o Tolcapone
o Entacapone
- Dopamine receptor agonists
o Bromocriptine
o Apomorphine, pramipexole, ropinirole,
and rigotine
- Amantadine
- Antimuscarinic agents
Levodopa and carbidopa
- Levodpa
o Metabolic precursor of dopamine
o Can cross BBB
o Enhancing the synthesis of dopamine in
the surviving neurons of the substantia
nigra
o Only provides a symptomatic relief
- Carbidopa
o Dopamine decarboxylase inhibitor
Inhibits decarboxylation of
levodopa to dopamine in the
periphery
Increases CNS
bioavailability of
levodopa
Greatly enhances effect
of levodopa
o Cannot cross BBB
Levodopa
- A/E:
o Peripheral effects
Anorexia, N&V occur because of
stimulation of the
chemoreceptor trigger zone
(CTZ)
Tachycardia from dopaminergic
action on heart
Hypotension
o CNS effects
Visual and auditory
hallucinations
Involuntary movements
(dyskinesias) may occur
Effects are the opposite of
parkinsonism symptoms and
reflect overactivity of dopamine
Selegiline and rasagiline
- Selegiline also called deprenyl
o Selectively inhibits MAO type B at low
to moderate doses
o Has little potential for causing
hypertensive crises (unlike nonselective
MAO-Is)
o Metabolized to amphetamine- like
substances that cause insomnia
- Rasagiline
o Irreversible and selective inhibitor of
brain MAO type B
o 5x the potency of selegiline
o Not metabolized to amphetamine- like
substances
- MAOA -> NE and 5-HT (serotonin)
- MAOB -> dopamine
Catechol-O-methyltransferase (COMT) inhibitors
- The methylation of levodopa by COMT to 3-O-
methyldopa is a minor pathway for levodopa
metabolism
o BUT, when peripheral dopamine
decarboxylase activity is inhibited by
carbidopa, a significant conc. of 3-O-
methyldopa is formed that competes
with levodopa for active transport into
the CNS
- Entacapone and tolcapone selectively and
reversibly inhibit COMT
o Leads to decrease in plasma conc. of 3-
O-methyldopa
o Tolcapone has relatively long duration
of action than entacapone but it causes
fulminant hepatic necrosis
Dopamine receptor agonists
- Have long duration of action than levodopa
- Mimic dopamine activity
 - Drugs include:
o Ergot derivatives
Bromocriptine
o Non-ergot
Ropinirole
Pramipexole
Rotigotine
Apomorphine
Bromocriptine
- D2 receptor agonist
- Aka prolactin-inhibiting hormone
- Actions that similar to those of levodopa,
except that hallucinations, confusion delirium,
Nausea and orthostatic hypotension are more
common
- Dyskinesia less prominent
- A/R:
o As an ergot derivative- potential to
cause pulmonary and retroperitoneal
fibrosis
o Assoc. with Livedo reticularis
Pramipexole and Ropinirole
- Orally active agents
- Pramipexole
o Mainly excreted unchanged in the
urine; dosage adjustments needed in
renal dysfunction
Apomorphine
- Injectable D agonist used in severe and
advanced stages of the disease to supplement
oral medications
- Used for acute management of the
hypomobility off phenomenon in advanced
Parkinsons disease
Rotigotine
- Administered as a once-daily TDM patch that
provides even drug levels over 24 hours
Amantadine
- Antiviral drug used to treat influenza
- Current evidence, MOA: inhibition of the N-
methyl-D-aspartate (NMDA) receptors as the
primary action at therapeutic conc.
- Less efficacious than levodopa and tolerance
develops more readily
- Has fewer side effects
- A/E: Livedo reticularis
Antimuscarinic agents
- Correct the imbalance in
dopamine/Acetylcholine ratio
- Less efficacious than levodopa
- Play only an adjuvant role in antiparkinsonism
therapy
- Drugs include:
o Benztropine
o Trihexyphenidyl
o Procyclidine
o Biperiden
Alzheimers disease
- Dementia of the Alzheimer type
- Has three distinguishing features:
o Accumulation of senile plaques (B-
amyloid accumulations)
o Formation of numerous neurofibrillary
tangles
o Loss of cortical neurons, particularly
cholinergic neurons
Drugs used in Alzheimers Disease
- Two goals of current therapies
o Improve cholinergic transmission w/in
CNS
o Prevent excitotoxic actions resulting
from overstimulation of NMDA-
glutamate receptors in the brain
- Only palliative and provides modest short-term
benefit
- Two main types:
o AChE inhibitors- improvement
o NMDA receptor antagonist- prevention
AChE inhibitors
- There is a link b/w loss of cholinergic neurons/
transmission to memory loss
 - Approved for the treatment of mild to Drugs used in MS
moderate Alzheimers disease - Disease- modifying therapies
- Donepezil o Modify the immune response thru
- Galantamine inhibition of WBC- mediated
o Augment action of Ach at nicotinic inflammatory processes that -> myelin
receptors in CNS sheath damage
- Rivastigmine - Drugs include
o TDM patch o Interferon B1a and Interferon B1b
o Only agent approved for the o Glatiramer
management of dementia assoc. w/ o Fingolimod
Parkinsons disease o Teriflunomide
o Dimethyl fumarate
NMDA receptor antagonist o Natalizumab
- Overstimulation of NMDA type, may result in o Mitoxantrone
excitotoxic effects on neurons and is suggested - Symptomatic treatment
as a mechanism for neurodegenerative or o Dalfampridine
apoptotic processes
- Memantine Interferon B1a and Interferon B1b
o An NMDA receptor antagonist indicated - Possess immunomodulatory effects
for moderate to severe Alzheimers o Help to diminish the inflamm.
disease Responses that lead to demyelination of
axon sheaths
Multiple Sclerosis (MS)
- An autoimmune inflammatory demyelinating Glatiramer
disease of the CNS - Synthetic polypeptide that resembles myelin
- The course of MS is variable: protein
o May consist of one or two acute - May act as a decoy to T-cell attack
neurologic episodes
o Or a chronic, relapsing progressive Fingolimod
disease that may span 10-20 years - Oral drug that alters lymphocyte migration ->
o S&S: fewer lymphocytes in the CNS
Blurred/Double vision - A/E:
Clumsiness o May cause first-dose bradycardia
Loss of balance o Assoc. w/ an increased risk of infection
Tingling sensation and macular edema
Constipation Teriflunomide
Spasticity - Oral pyrimidine synthesis inhibitor
Bladder dysfunction - Lead to a decreases conc. of active lymphocytes
Depression in CNS

Dimethyl fumarate
- Oral agent that may alter the cellular response
to oxidative stress to decrease disease
progression
- A/E:
o Flushing and abdominal pain

Nataliumab
- Monoclonal antibody
- Indicated for MS in patients who have failed 1st
line therapies
Mitoxantrone
- Cytotoxic anthracycline analog that kills T cells
- May also be used for MS

Symptomatic treatment
- Used to manage symptoms of MS:
o Spasticity
o Constipation
o Bladder dysfunction
o Depression
- Dalfampridine
o Oral K+ channel blocker
o Improves walking speeds in patients
with MS
1st drug approved for such use