Pharmacology III

Hebron University
Faculty of Pharmacy and Medical sciences
Hebron University 2022
Drugs affecting CNS
By: Muamar Shaheen, MSc., RPH, GCC, Lect.
Drugs for Neurodegenerative Diseases
 Introduction to CNS therapy

* Most drugs that affect the CNS act by altering some step in
the neurotransmission process.
❖ 1. they may act presynaptically by influencing the
production, storage, release, or termination of action of
neurotransmitters.
❖ Other agents may activate or block postsynaptic receptors.
❖ We will focus on those neurotransmitters that are involved in
the actions of the clinically useful CNS drugs.
 CNS vs. ANS
CNS
* More complex circuitry of the CNS
* number of synapses is far greater.
* contains networks of inhibitory
neurons constantly active in
modulating the rate of neuronal
transmission
* communicates through the use of
multiple NTs
ANS
* Simple one direction circuits
* One or 2 synapses
* Inhibitory neurons in the spinal
cord only
* uses only two primary
neurotransmitters, acetylcholine,
and norepinephrine.
Similarities between CNS & ANS

* Transmission of information in both the CNS and in the

peripheral NS involves:
* Release of NTs diffusion across the synaptic cleft to
bind to specific receptors on the postsynaptic neuron.
* In both systems, the recognition of the neurotransmitter
by the membrane receptor of the postsynaptic neuron
triggers intracellular changes.
 Drugs affecting CNS
Neurodegenerative diseases

* Neurotransmission in the CNS is sophisticated and more

complex than that in the ANS.
* The electrical circuits, NT nature, receptors, Neurons and the
areas responsible for initiating the stimulus are numerous and
multifunctional.
* A single impulse to a neuron can exert, excitatory, inhibitory,
or modulatory effect for the same function
* Though these processes are similar in many aspects to those in
the ANS such as NT involvement, pre-and post-synaptic
receptor-NT or drug interactions, drugs affecting the storage,
release or synthesis of the NT, etc….
 Synaptic potential:

* NTs in the CNS are either excitatory, inhibitory or

both(such as serotonin.)
* EPSP, IPSP, combined EPSP & IPSP
* This depends on the nature of the receptor & the ion
channels connected with this receptor (Na+ or Cl-)
* Some neurons receive EPSP only, IPSP only, but most
neurons receive both. The resultant action is the
summation of the individual IPSP`s and EPSP`s.
* Fig 8.2, Fig 8.3: NT, Excitatory vs. inhibitory
receptor-ligand interactions
EPSP
IPSP
 Neurodegenerative diseases

- Parkinson`s disease
- Alzheimer`s disease
- Huntington`s, MS
- Amyotrophic lateral sclerosis
- These diseases are result of neuronal death, loss or
decreased in the function of certain neurons responsible
for specific function in the brain.
 Parkinson`s diseases (PK)

* Pk: is a slowly progressive degenerative neurological dz. charac.

by tremor, rigidity, bradykinesia (sluggish NM response), and
postural instability. ‘Shaking palsy’ or paralysis agitans. Dr.
James Parkinson 1817.
* Etiology: it is correlated with destruction of dopaminergic
neurons in the Substantia Nigra (SN) with a consequence
reduction of dopamine actions in the corpus striatum
(Basal Ganglia System involved in motor control)
* This will leave the Acetch. excitatory actions in
neostriatum area unopposed.
 Pk/cont.

* Pathogenesis: PK is associated with depigmentation of

the SN and the loss of dopaminergic input to the basal
ganglia (extrapyramidal system) which leads to
distinctive motor disability.
* The basal ganglia are responsible for initiating,
sequencing, and modulating motor activity.
1. In healthy individuals, dopamine is produced by neurons
that project from the SN to the neostriatum (NS)(which
include caudate and putamen) & globus pallidus where
dopamine acts as inhibitory NT.
 PK/Cont.

2. In Pk., the loss of dopamine-producing neurons in

SN results in an imbalance between dopamine
(inhibitory NT) and the excitatory NT Acetylcholine.
- GABA is also involved in the process.
- Signs and symptoms: 1. tremor:
a. tremor at rest and with low frequency movement,
pill-rolling tremor
b. Action tremor (most evident during activity)
2. Limb rigidity(cogwheeling)
 PK/cont.

* 3. Akinesia or bradykinesia, masked face

* 4. gait and postural difficulties
* Changes in mental status; depression 50%, dementia
25%, psychosis
* PK scale:
- Early
- Early middle
- Late middle
- late
 PK treatment:

* We have to restore the imbalance between inhibitory

neurons(dopaminergic) and excitatory neurons
(acetylcholine)
* There still has to be some functioning dopaminergic neurons
in the patient`s brain
* Dopamine itself doesn`t pass Blood Brain Barrier, so we
can`t use it as therapy
* Levodopa on the other hand is a precursor for dopamine, it is
actively transported into the CNS, and converted to
dopamine in the brain.
 PK/contin.

* Levodopa: is largely decarboxylated to dopamine in the

periphery, so large doses is needed where side effects as
N/V, cardiac arrhythmia and hypotension will ensue.
* carbidopa: a dopa-decarboxylase inhibitor, enhance
greatly the effects of levodopa on the CNS if
co-administered with levodopa.
* Carbidopa doesn`t cross BBB, it inhibits levodopa
metabolism in the GIT & in the periphery.
Fate of Levodopa
 Levo/carbi combo

* So cabidopa ↓ the dose needed of levodopa to 4-5 folds

and so ↓ the severity of it`s side effects.
* Actions of levodopa:↓ rigidity, tremors and other
symptoms of PK.
* Given on an empty stomach, avoid large protein meals.
Protein will compete for transport sites.
* AE: anorexia, nausea(Chemoreceptor trigger zone
activation of medulla), tachycardia(dopamine on the
heart), hypotension, mydriasis, saliva and urine brown
coloration(melanin), psychiatric problems
 Levodopa / cont.

* Interactions: - pyridoxine(B6) increases peripheral break

down of levodopa.
- MAO-I/(phenelzine)HTN crises
- Increase psychoses symptoms
- Glaucoma/↑ IOP
- Cardiac arrhythmia c cardiac patients/monitor
- Antipsychotics block dopamine and worsen PK
 Selegiline/rasagiline/safinamide

* MAO-I Type B:prevent the metabolism of dopamine or

levodopa once converted to dopamine in the brain without
affecting NE or Serotonin metabolisms which are
metabolized by MAO type- A. This will ↓dose of levodopa.
* They lose their selectivity at high doses and might lead to
hypertensive crises like nonselct. MAO-I
* Rasagiline is 5 X stronger, is not metab. to
methamphe-tamine & amph/no insomnia if given
afternoon/irreversible.
 Entacapone/tolcapone

* Carbidopa→ inhibits dopamine decarboxylase

→↑3-O-methyldopa → competes with levodopa for
active transport into CNS → ↓ activity of levodopa.
* If we inhibit COMT by Entacapone or Tolcapone, we
can reverse this process.
* These agents were introduced to reduce the symptoms of
``wearing off`` (fading or decreasing the response) of
levodopa-carbidopa combo. Fig 8.11
* Hepatic necrosis c Tolcapone/monitor liver
Effect of entacapone on dopa conc. In the CNS
 Dopamine receptor agonists
Bromocriptine, pramipexole, ropinerole, rotigotine

* Longer acting than levo/carbi.

* For patients who suffer fluctuations in response to the previous
combo.
* Bromo, prami, ropi are all effective for advanced PK
complicated with motor fluctuations and dyskinesias
* They are ineffective in patients who show no response to
Levodopa./look like after a while even the receptors are gone
or down regulated after dopaminergic neurons are damaged.
* Apomorphine is also used as a dopamine agonist in severe and
advanced stages of the dz. as injectable.
 PK/Dopamine agonists/Bromocriptine:

* Bromo. is an ergot alkaloid/ergotamine deriv.

* Same effects like levodopa EXCEPT that:
hallucinations, confusion, delirium, nausea and ortho.
hypo are MORE common/ dyskinesia is less prominent.
* Psychiatric, cardiac, (MI), PVD*, peptic ulcer patients
are all worsening with these drugs
* Pulmonary and retroperitoneal fibrosis
* *PVD: ``Peripheral Vascular Disease``
 Apomorphine, prami, ropi, roti.

* Synthetic dopamine R agonists used in PK.

* Apomorphine is used for acute management of
hypomobility ‘’off’’ phenomena./injec. & patch
* These agents alleviate the motor deficit in early naiive or
late advanced PK.
* They may delay the need for levodopa in early PK or
reduce the dose in late PK.
* SE: Nausea, hallucinations, insomnia, dizziness,
constipation and orth/hypo .
* Dyskinesia is less frequent than with levodopa
 Apomor…./cont.

* Pramipexole & ropinirole don`t exacerbate peripheral

vasospasm nor cause fibrosis.
* Fluoroquinolone AB (such as ciprofloxacin), inhibit
CYP450 1A2, ↓ metab. & enhancing the AUC for
ropinirole by almost 80%.
* Rotigotine: for early PK/ once daily skin patch
* SE: sedation, hallucinations, confusion, Nausea,
hypotension.
 Amantadine

* An antiviral drug for influenza that was discovered by

accident that that it has anti-PK activity
* Activity:↑ dopamine release
* Block cholinergic receptors
* Inhibiting NMDA type glutamate R`s as the primary site
of action at therap. doses
* AE: restlessness, agitation, confusion, hallucin.
 Amantadine /cont.

* At high doses: acute toxic psychoses

* It causes Orthohypo., U retention, edema, dry mouth
also.
* Less efficacious than levodopa /tolerance more
readily/less side Effects
* Has little effects on tremor/more effective than
anticholinergics against rigidity & bradykinesia.
 Antimuscarinic agents

* Less effect than levodopa

* Adjuvant role only in PK
* Benztropine, trihexphenidyl, procyclidine, biperiden
are all similar with little differences interindividually.
- They induce mood changes , dry mouth, visu, disturb.
- Interfere with GIT peristalsis
- C/I: glaucoma, BPH, pyloric stenosis
- AE: pupil dilat., confusion, halluc., sinus tachycardia,
constipation, urine reten. dry mouth like atrpoin HD
 Alzheimer`s disease

* No cure for AZ and all drugs available are only palliative

and can`t change the underlying neuro- degenerative
process.
* Dementia of AZ is charact. by: 1. accumulation of senile
plaques (β-amyloid. ) 2. formation of numerous
neurofibrillary tangles(hyperP tau proteins). 3. loss of
cortical neurons-partic. cholin. N.
* Therapies either improve cholin. transmission or
preventing excitotoxic actions of NMDM-glut type
 Alz./cont.

* Link between loss of cholin. N & transmission within the

cortex to memory loss as the hallmark of AZ.
* CNS acting reversible AChE Inhibitors are used to treat mild
to moderate AZ.
* Donepezile, galantamine, & rivastigmine:-
- All are uncompetitive AChE inhibitors except galanta.(c may
also augment the action of acetylcholine at nicotinic receptors in
the CNS.)
- They have some selectivity to CNS AChE.
- They provide modest reduction in the rate of loss of cognitive
function in AZ.
 AZ/cont.

* Rivastigmine: has no interaction with other drugs

through P450 enzymes
* Others are substrates for P450_ interxns
* AE: nausea, diarrhea, vomiting, anorexia, tremors,
bradycardia, muscle cramps
 NMDA-R antagonists in Az.

* NMDA –glutamate stimulation is critical for certain

memory formation but overstimulation is excitotoxic
leading to apoptosis(programmed cell death)
* Antagonists of this receptor has neuroprotective effect
on the neuron in the CNS
* Memantine: physically block a fraction of NMDA_R-
associated ion channels at therapeutic doses.
* This allows some Ca+ to inter the neuron allowing for
function without achieving cytotoxic levels of Ca+
 Memantine / cont.

* It has been shown that it slows the rate of memory loss in

both vascular-associated & Az.-dementia in patients c
moderate to severe cognitive losses.
* Well tolerated with few dose- dependent SE.
* SE: confusion, agitation, restlessness/indistiguishable
from Alzheimer`s symptoms.
* Given with AChE-I/might have neuroprotective effects?
Need further investigations and research
 Drugs used in MS

* Multiple sclerosis is an autoimmune inflammatory

demyelinating disease of CNS.
* Course of MS: - may consist of one or two acute neurologic
episodes.
* - In others, it is a chronic, relapsing, or progressive disease
that may span 10 to 20 years.
* Dexamethasone/prednisone: have been used to treat acute
exacerbations of the disease.
* Chemotherapeutic agents, such as cyclophosphamide and
azathioprine, have also been used.
Disease modifying therapy in MS

* decrease relapse rates/prevent accumulation of

disability.
* modify the immune response by;
* inhibition of white blood cell–mediated inflammatory
processes that eventually lead to myelin sheath damage
and decreased or inappropriate axonal communication
between cells.
Interferon Glatiramer Fingolomid Teriflunomid Natalizumeb
В1a, B1b e
Immunomodu Drugs
oral drugin
synthetic PP that MS
Oral monoclonal
l-atory, help resembles alters pyrimidine antibody
diminish myelin lymphocyte synthesis indicated for
inflam protein & migration, inhibitor that MS in
responses that may act as a resulting in leads to a patients who
lead to decoy to fewer lower conc. of have failed
demyel-inatio T-cell attack. lymphocytes active first-line
n of the axon in the CNS lymphocytes therapies.
sheaths in the CNS.

AE: AE: Post inj. AE: 1st -dose AE: may

Depression, Rxns: bradycardia ., cause elevated
local inj. site flushing, assoc. c an ↑ liver
rxn, ↑hepatic chest pain, risk of enzymes. It
enz., flu like anxiety, infection and should be
symptoms itching/self-li macular avoided in
miting edema. pregnancy.
 Other agents for MS

* Dimethyl fumarate:
* is an oral agent that may alter the cellular response to
oxidative stress to reduce disease progression.
* AE:
* Flushing and abdominal pain are the most common
adverse events.
 Monoclonal antibodies for MS

* Alemtuzumab, daclizumab, natalizumab, &ocrelizumab

* monoclonal antibodies indicated for the treatment of MS.
* Ocrelizumab: first agent to be approved for primary
progressive forms of the disease.
* Significant toxicities of these agents:-
* Natalizumab: progressive multifocal leukoencephalopathy
* Daclizumab /alemtuzumab: serious infections
* Alemtuzumab: autoimmune disorders
* So, keep these agents for patients who have failed other
therapies.
 Symptomatic treatment of MS

* Many different classes of drugs are used to manage

symptoms of MS such as spasticity, constipation,
bladder dysfunction, and depression.
* Dalfampridine : an oral K-channel blocker
* Improves walking speeds in patients with MS.
* It is the first drug approved for this use
 Amyotrophic lateral sclerosis

* ALS is characterized by progressive degeneration of motor

neurons, resulting in the inability to initiate or control
muscle movement
* Riluzole & edaravone: are indicated for management of
ALS.
* Riluzole: is an oral NMDA release inhibitor that is used for
ALS.
* It inhibits glutamate release & blocks Na+ channels.
* It may improve survival time in patients suffering from ALS
* Edaravone: is an IV free radical scavenger and antioxidant
that may slow the progression of ALS.
 ALS

* (ALS): Lou Gehrig's disease, is a form of motor neuron

disease caused by the degeneration of neurons located in the
ventral horn of the spinal cord and the cortical neurons that
provide their afferent input. The disorder is characterized by
rapidly progressive weakness, muscle atrophy and
fasciculations, spasticity, dysarthria, dysphagia, and
respiratory compromise. Sensory function generally is
spared, as is autonomic, and oculomotor activity. ALS is a
progressive, fatal, neurodegenerative disease with most
afflicted patients dying of respiratory compromise and
pneumonia after 2 to 3 years.