Drugs affecting the Central Nervous System

Drugs used in the management of Neurodegenerative diseases

Neurodegenerative diseases: neuronal damage in certain brain areas.
Causes of neuronal damage:
1. Excessive excitotoxicity (excess glutamate acts on N methyl aspartate receptors
NMDA).
2. Stroke, head trauma.
3. Oxidative stress reactive oxygen species (ROS) free radical as OH..
4. Apoptosis (programmed cell death).
Q. why is it difficult to treat neurodegenerative diseases?
As CNS neurons CANNOT divide or regenerate once they are damaged they cannot be
regenerated so treatment is symptomatic not alter progression of disease.
Examples of neurodegenerative diseases: Parkinsons disease, Alzheimer, Huntington,
Multiple sclerosis.
PARKINSON'S DISEASE "Paralysis Agitans" Management
Overview of Parkinsons disease
Definition: It is a progressive neurological disorder of muscle movement, characterized by
the triad: Tremors, Muscular rigidity, Bradykinesia (slowness in initiating & carrying out
voluntary movement). Abnormal posture and gait. It occurs mainly in elderly people over the
age of 65. It was first described by James Parkinson.
Etiology: in the inhibitory dopaminergic (DA) neurons relative to excitatory
cholinergic (Ach) neurons in the basal ganglia (Dopamine is formed in the Substantia
nigra, dopaminergic neurons are connected to the striatum which contains cholinergic
neurons).

Classification:
Primary (Idiopathic) Parkinsons disease (PD):
due to degeneration of > 80% of dopaminergic neurons secreting dopamine in the
substantia nigra imbalance between the excitatory cholinergic neurons (Ach) & the
inhibitory dopaminergic neurons (DA) i.e DA & Ach.
N.B. Oxidative stress formation of free radicals in the substantia nigra degeneration
of dopaminergic neurons.
Secondary Parkinsonism Parkinsons Syndrome:
The imbalance between Ach & DA ( DA & Ach) is due to:
Disease-induced viral encephalitis, atherosclerosis
Drug-induced Dopamine blockers (e.g: antipsychotics).
Poisons manganese, carbon monoxide poisoning
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Treatment
Treatment goal: restoring the balance between Ach. & DA. DA & Ach.
Treatment leads to temporary relief of symptoms and slow but not prevent progression of
disease (symptomatic treatment).
Anti-Parkinsonian drugs
DA
Ach.
1. Dopaminergic drugs e.g. l-dopa.
- Anticholinergic drugs.
2. Dopamine receptor agonists.
3. Dopamine releasers.
4. Selective MAOB inhibitors.
I. Dopaminergic drugs
1. Levodopa (l-dopa):
MOA:
Dopamine itself does not cross the BBB, but its precursor levodopa is readily
transported into the CNS and is converted to dopamine in the brain by the enzyme
dopa decarboxylase thus restoring DA & Ach balance.
Number of surviving DA neurons should be adequate for conversion of l-dopa to
DA (80% of the Dopaminergic neurons are degenerated so the remained 20% should
be intact to convert l-dopa to DA so that drug gives effect).
L-dopa

Dopa decarboxylase

Required
Dopamine

CNS=Basal ganglia
DA

NOT required
Peripherally
Q: Large doses of levodopa (l-dopa) are required why?
Because most of the drug (>90%) is decarboxylated to dopamine in the periphery resulting in
peripheral adverse effects.
Peripheral dopa decarboxylase inhibitors: Carbidopa or Benserazide:
Selective peripheral (extra-cerebral) dopa decarboxylase inhibitor that does not
cross the blood-brain barrier.
l-dopa + carbidopa or Benserazide
Availability of l-dopa to the CNS.
Dose of l-dopa to 1/5.
S.Es of the peripheral formed DA.
Levodopa/Carbidopa combination produces good control on disease symptoms but
this effect starts to decline from the 3rd to 5th year.
L-dopa

L-dopa

dopamine

Dopa decarboxylase
Peripherally

Inhibited by

Dopa decarboxylase
Centrally

Carbidopa
Or
Benserazide

dopamine

COMT inhibitors: Entacapone & Tolcapone:

l-dopa undergoes O-methylation by COMT to inactive metabolite (3-O-methyldopa);
minor pathway for levodopa metabolism. However, when peripheral dopamine
decarboxylase is inhibited by carbidopa, a significant concentration of 3-O-methyldopa
is formed that competes with l-dopa for active transport into the CNS.
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 A peripheral COMT inhibitor is given together with l-dopa to protect it from

destruction by COMT.
l-dopa + Entacapone or Tolcapone
degradation of l-dopa
side effects
doses required.
availability of l-dopa to the CNS.
Treatment= l-dopa + Carbidopa + Entacapone
Carbidopa: peripheral dopa decarboxylase inhibitor.
Entacapone: peripheral COMT inhibitor
Availability of l-dopa in CNS
Greater more l-dopa crosses the BBB More constant (sustained) Dopaminergic
Pharmacokinetics:
stimulation in the brain symptoms of the disease.
1. Short
t (1-2 hrs)
fluctuations
in plasma concentration.
S.Es
of ! peripherally
formed
dopamine.
Fluctuations in plasma concentration "on-off phenomenon" due to short half life of
l-dopa Motor fluctuations.
a. ON no symptoms of parkinsons i.e parkinsons free period.
b. OFF parkinsons symptoms appear
How to overcome the on-off phenomenon?
1- Giving more frequent dose of levodopa or a sustained-release preparation
2- Combined treatment with a direct dopamine receptor agonist.

Wear-off phenomenon End of dose means patients do not respond to

treatment, because all dopaminergic neurons are degenerated
i.e. complete degeneration of dopaminergic neurons 100%.

Food (high protein diet) Absorption of l-dopa from small intestine so

take 30 minutes before a meal. l-dopa is transported & absorbed from GIT as
aminoacids, so if protein is taken compete with l-dopa absorption of ldopa.

DA centrally & peripherally

1. Central side effects
a. Dyskinesia: Excessive abnormal involuntary movements develop usually within 2 years
of starting l-dopa therapy.
b. DA in the mesolimbic Delusions, Hallucinations & psychosis, vivid dreams,
confusion, mood changes, anxiety & depression (CI in psychosis).

Adverse effects of l-dopa:

2. Peripheral side effects

1. dopamine in CTZ in medulla nausea, vomiting & anorexia.
2. 1 tachycardia and arrthymia.
3. Postural hypotension due to
a. -ve feedback of NA releaseNA release
b. Dopamine is a venodilator.
c. V.D. of renal blood vessels (D 1 receptor)RBF Renin Aldosterone.
4. Catecholamine oxidation melanin pigment Brown saliva and urine.
5. Mydriasis stimulate -receptor on radial muscle in high doses only (CI in acute
angle closure glaucoma).

Drug interactions:
1. Vit B6 (pyridoxine) peripheral decarboxylation of l-dopa to dopamine efficacy
of l-dopa.
2. Levodopa + Phenelzine (MAO inhibitor) catecholamine accumulation BP
(hypertensive crisis).
3. Anti-psychotics (D2-blockers) cause parkinsonian syndrome so CI in PD patients.
4. Cardiac patients should be monitored because of risk of cardiac arrhythmias.
Drug holiday: transient withdrawal of levodopa may improve the complications of its chronic
use.
II. Dopamine receptor agonists
Dopamine receptor agonists are used as initial therapy in patients who have mild PD and a
younger age of onset or as adjuncts to levodopadopa decarboxylase inhibitor combinations
in patients with severe motor fluctuations (onoff phenomena). They decrease the dose of ldopa in advanced PD.
Adverse effects: Similar to l-dopa
1- dopamine in CTZ in medulla nausea, vomiting.
2- Confusion, psychomotor excitation, hallucination (N.B. Neuropsychiatric disorders are
more frequent than with levodopa monotherapy).
3- Orthostatic hypotension
1. Bromocriptine (Ergotamine derivative)
Drugdisease interactions:
1. Worsening of patient with peripheral vascular disease (due to vasoconstriction as it
is ergotamine derivative)
2. Serious cardiac problems in patients with history of myocardial infarction.
3. In psychiatric illness, bromocriptine and l-dopa may cause mental condition to
worsen.
2. Non ergot drugs: Apomorphine, Pramipexole, Ropinirole. Rotigotine
Apomorphine as s.c injection is used for acute management of off periods, but it causes
severe nausea must be preceded by antiemetic.
III. Drugs inducing dopamine release
Amantadine: "Antiviral against influenza virus"
- release and reuptake of dopamine in surviving neurons.
- Anticholinergic action (block M) Ach.
Its less effective than l-dopa, its actions with time and tolerance develops rapidly to its
use. Used in early disease, especially in younger patients.
S.Es: those of l-dopa + urinary retention & dry mouth.
About 95% is eliminated by the kidneys and it should not be used in patients with renal failure
IV. Monoamine oxidase B inhibitors (MAOB inhibitors)
1. Selegiline (Deprenyl)
- Irreversible selective inhibitor of MAOB DA in brain (No effect on MAOA which
metabolizes NE and 5-HT)
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Uses: combined (adjunct) with l-dopa l-dopa action, l-dopa required

dose, reduce the end-of-dose deterioration in advanced disease.
S.Es: Deprenyl is metabolized into amphetamine & methamphetamine
insomnia, & anxiety if the drug is administered later than midafternoon.
Contraindications:
- Unlike non selective MAO inhibitors NO hypertension crisis when combined
tyramine-containing food. BUT at high doses (six times the therapeutic dose),
selectivity is lost, inhibit both MAOA & MAOB hypertensive crisis.

2. Rasagiline: Irreversible selective inhibitor of MAOB, 5 times more potent than

selegiline. It is not metabolized to an amphetamine like substance.
V. Anticholinergics
e.g. Benztropine, Trihexyphenidyl, Procyclidine, Orphenadrine, & Biperiden
- Restore the balance between dopamine and ACh in the Neostriatum.
- Pharmacological actions: Tremors, Rigidity only so used as adjuvant therapy
(effect l-dopa). Drug of choice for PD caused by D2 blockers Why??
- Side effects: Atropine like side effects: mydriasis, blurred vision, urinary retention,
xerostomia, decreased GIT motility (constipation) & decreased memory and
concentration, confusion with visual hallucination.
- Contraindications: glaucoma, prostatic hypertrophy.
DA level or effect in the Striatum
Adv: treat all signs & symptoms including
bradykinesia
S.Es: Nausea, Vomiting, Anorexia
Tachycardia=arrhythmia.
Postural hypotension.
Psychosis (centrally).
e.g. l-dopa, Bromocriptine, Amantadine,
Deprenyl.

Ach level or effect in the Striatum

Adv: Tremors & Rigidity only (adjuvant
only)
S.Es: Atropine S.Es

e.g. Benztropine, Trihexyphenidyl &

Biperiden

Adverse effects of:

levodopa
dopamine agonists

Alzheimers Disease
Alzheimer's disease is a common age-related dementia.
Symptoms: Dementia, loss of intellectual ability & learning deficit.
Etiology:
1. Plaques (-amyloid), neurofibrillary tangles mainly in hippocampus.
2. Loss of cholinergic neurons ( Ach) in the cortex.
Treatment:
No effective therapy is available.
1. Acetylcholinesterase inhibitors: Donepezil, Galantamine, and Rivastigmine
They have some selectivity for AChE in the CNS, as compared to the periphery. Used in mild
to moderate cases.
Rivastigmine is the only agent approved for the management of dementia associated
with Parkinsons disease and also the only AChE inhibitor available as a transdermal
formulation. It has no interactions with drugs that alter the activity of CYP450 enzymes. The
other agents are substrates for CYP450 and have a potential for such interactions.
Adverse effects: nausea, vomiting, diarrhea, anorexia, tremors, bradycardia, and muscle
cramps.
Treatment of overdose: Atropine
2. NMDA receptor antagonist (used in moderate to severe cases)
Stimulation of glutamate receptors in the CNS is critical for memory. However,
overstimulation of glutamate receptors, particularly of the NMDA type, assists in the opening
of an ion channel that allows Ca2+ to enter the neuron. Excess intracellular Ca2+ results in
excitotoxic effects on neurons, which in turn results in neurodegenerative or apoptotic
(programmed cell death) processes.
Memantine is an NMDA receptor antagonist indicated for moderate to severe Alzheimers
disease. It blocks the NMDA receptor and limits Ca2+ influx into the neuron. It is often given in
combination with an AChE inhibitor.

Adverse effects of ACHE inhibitors