its about epilepsy

1. Drugs for
Neurodegenerative
Diseases
DR. ZUBAIR AHMAD BHAT.

2. PARKINSONISM
Parkinsonism:- rigidity, bradykinesia,
dyskinesia, tremors, mask like facies and
unstable gait.
Basal ganglia’s output is controlled by
cholinergic and dopaminergic system having
opposite effect.
Nigrostrial pathway damage, dopaminergic
decrease and cholinergic increase.

3. Drug List
Drugs for Parkinson’s Disease
Drugs that increase brain
dopamine levels
Dopamine receptor
agonists
M receptor antagonists
Levodopa
Carbidopa
Selegiline
Entacapone
Amantadine
Bromocriptine
Pramipexole
Benztropine
Drugs for Huntington’s Disease Drugs for Alzheimer’s Disease
Haloperidol
Diazepam
Donepezil

4. The Basal Ganglia in Parkinson’s Disease
Basal ganglia are a group of interconnected subcortical
nuclei that include striatum, substantia nigra, globus pallidus
and subthalamus.
Basal ganglia function via a series of reciprocal innervations
among themselves and the cortex.
In Parkinson’s disease the primary defect is destruction of
dopaminergic neurons in the substantia nigra.
Excitatory cholinergic interneurons are also present in the
striatum. The destruction of dopaminergic neurons in the
substantia nigra leads to excessive cholinergic activity of
these neurons.

5. 1. Levodopa
Chemistry
The amino acid levodopa is the biosynthetic precursor of dopamine.
Mechanism of action
In the brain levodopa is taken up by dopaminergic terminals in the striatum and is
converted to dopamine by levo-aromatic amino acid decarboxylase (DOPA
decarboxylase) (dopamine as such cannot be used since it does not enter the
brain).
Levodopa itself is largely inert. Its effects depend on the increased synthesis of
dopamine in the brain and are mostly related to activation of D2 receptors.

6. Pharmacological effects
The peripheral effects of levodopa are related to the plasma concentration of
dopamine.
Pharmacokinetics
Oral bioavailability: 5% (the firs-pass effect is very large; 95% is metabolized in the
gut wall and in the liver)
Additional amounts are converted into dopamine and therefore only 1% enter
the brain.

7. Adverse effects
CNS
Anxiety, agitation, insomnia or sleepiness, nightmares, euphoria or depression,
confusion, delusions, hallucinations, personality changes. [clozapine is the best
drug to treat these effects]
Dyskinesias (up to 80% of patients treated for more than 3 years): choreoathetosis
of the face and the extremities, tics, myoclonus, tremor. [therapy is unsatisfactory.
A drug holiday can help]

8. Gastrointestinal system
Anorexia, nausea and vomiting (up to 80% of patients),
weight loss.
Tolerance to these effects can occur after several
months.
Cardiovascular system
Palpitations, cardiac arrhythmias (about 10% of ptns)
Postural hypotension (about 25% of patients).
Tolerance can develop in a few months.
Other systems
Leukopenia, agranulocytosis, hemolytic anemia.

9. Levodopa
Drug interactions
High doses of pyridoxine (vit B6) enhances the extracerebral metabolism of
levodopa.
Nonselective MAO inhibitors inhibit dopamine metabolism (an hypertensive crisis
may ensue)

10. Contraindications and Precautions
Melanoma (levodopa is a precursor of melanin and can activate malignant
melanoma)
Cardiac disease
Psychosis
Depression with suicidal ideation
Treatment with nonselective MAO inhibitors

11. Levodopa
Therapeutic Uses
Levodopa ameliorates all signs of parkinsonism.
Bradykinesia is the most sensitive to improvement.
The drug however does not cure the disease and responsiveness fluctuates and
decreases with time.

12. Two main types of fluctuations occur over time:
1. The wearing-off effect (also called end-of-
dose akinesia): each dose improves mobility
for 1-2 hours but akinesia rapidly returns.
2. The on-off effect: ‘off’ periods of marked
akinesia alternate with ‘on’ periods of
improved mobility.

13. 2. Carbidopa
Carbidopa is a DOPA decarboxylase inhibitor that does not cross the blood-brain
barrier.
When given with levodopa, the peripheral metabolism of levodopa is reduced
with the following consequences:
1. The half-life of levodopa is increased.
2. More levodopa is available for entering the
brain (this reduces by about 75% the daily
requirement)

14. 3. Gastrointestinal and cardiovascular
effects of levodopa are substantially
reduced.
4. CNS adverse effects are increased.
Levodopa is usually given in combination with carbidopa

16. 3. Other drugs that increase
dopamine levels
A. Selegiline
Selegiline is a selective inhibitor of MAO B (the enzyme that metabolizes
dopamine) so preventing the oxidation of dopamine to 3, 4-
dihydroxyphenylacetic acid (DOPAC) and hydrogen peroxide.
This increases brain dopamine levels and prevents the formation of hydroxide
radicals, that may play a role in the degeneration of nigrostriatal neurons.

17. Selegiline may reduce the ‘wearing-off’ and the ‘on-off’ effects.
Adverse effects are related to increased levels of dopamine both centrally
(insomnia, mood changes, dyskinesias) and peripherally (nausea, hypotension).
It is used as a single agent in mild Parkinson’s disease or, more often, as an
adjunct to levodopa, so allowing a reduction of levodopa dose.

18. Other drugs that increase dopamine
levels
B. Catechol-O-methyltransferase inhibitors
Entacapone and tolcapone are inhibitors of Catechol-O-methyltransferase, the
enzyme that transforms methyldopa into 3-Omethyldopa in the gut and the
liver.

19. Since 3-O-methyldopa competes with levodopa for active transport into CNS,
this metabolite may contribute to the wearing-off and on-off effects.
By inhibiting the enzyme, more levodopa can enter the brain.
Adverse effects are related (in part) to increased levels of dopamine.
Entacapone (which is preferred because it has not been associated with
hepatotoxicity) is used as an adjunct to levodopa.

20. Other drugs that increase dopamine
levels
C. Amantadine
The drug is an antiviral agent that probably works by
increasing the release and inhibiting the reuptake of
dopamine on nigrostriatal neurons.
Adverse effects are related in part to increased levels
of dopamine. It can also cause livedo reticularis (a
reddish-blue mottling of the skin with edema)
It is used as a single agent in mild Parkinson’s disease
or, more often, as an adjunct to levodopa.

22. 4. Dopamine Receptor Agonists
Drugs
Bromocriptine (ergot derivative), pramipexole.
Mechanism of action
Bromocriptine is a partial agonist at central and peripheral D2- receptors (the
activation in mammotroph cells of the pituitary blocks prolactin secretion).
Pramipexole is an agonist at D2 and D3 receptors in brain.

23. Pharmacological effects
(All are related to activation of central and peripheral D2 receptors)
Reduction of plasma prolactin levels (within hours from administration).
Stimulation of GH release in normal subjects but blockade (for unknown reasons) of
release in acromegalic subjects.
Pharmacokinetics and administration
Oral bioavailability: bromocriptine 6 % (extensive first-pass effect)
Administration: oral.

24. Dopamine Receptor Agonists
Adverse effects
Dopamine-related
Anorexia, nausea and vomiting (up to 50%), stypsis
(constipation).
Postural hypotension (common), cardiac arrhythmias.
Dyskinesias (after long-term use of high doses).
Headache, insomnia, nightmares, confusion, delusions,
hallucinations)

25. Ergot-related
Digital vasospasm (after long-term use)
Erythromelalgia (hot, red, tender, and painful feet or hands) (rare)
Pulmonary or retroperitoneal fibrosis (rare)
Contraindications and precautions
Psychotic disorders.
Cerebrovascular disorders

27. Dopamine Receptor Agonists
Therapeutic uses
Prolactin-secreting adenomas (unfortunately expansion of
tumor often occurs if the drug is discontinued).
Idiopathic hyperprolactinemia and associated dysfunctions
(amenorrhea-galactorrhea syndrome, infertility,
hypogonadism).
Parkinson's disease.
Acromegaly

28. 5. Antimuscarinic Drugs in
Parkinsonism
Drugs
Benztropine and trihexyphenidyl and are centrally acting antimuscarinic drugs
used for the treatment of Parkinson’s disease.

29. Mechanism of action
They likely act within the striatum on cholinergic striatal excitatory interneurons.
All subtypes of muscarinic receptors are likely present in the striatum.
The competitive blockade of these receptors decrease the cholinergic tone that is
abnormally high in Parkinson’s disease, due to lack of the inhibitory activity of
dopamine.

30. Antimuscarinic Drugs in Parkinsonism
Clinical uses
Antimuscarinic drugs may improve sialorrhea, tremor and rigidity but have little
effect on bradykinesia
They are less effective than dopaminergic drugs but may be helpful as adjunct
therapy. They can also reduce parkinsonism, acute dystonias and akathisia caused
by neuroleptics and other dopamine antagonists (but they can exacerbate tardive
dyskinesia).

31. Adverse effects
Adverse anticholinergic effects are both:
a. Central: drowsiness, restlessness, confusion,
agitation , delusions, hallucinations.
b. Peripheral; xerostomia, blurring of vision,
urinary retention, constipation, tachycardia,
increased intraocular pressure.
(Elderly people are especially at risk).

32. CONCLUSION….
Classification
1. Drugs affecting brain dopaminergic system
a. Dopamine Precursor : Levodopa (ldopa)
b. Peripheral Decarboxylase Inhibitors : Carbidopa, Benserazide.
c. Dopaminergic Agonists: Bromocriptine, Ropinirole, Pramipexole
d. MAO-B Inhibitor: Selegiline
e. COMT Inhibitors: Entacapone, Tolcapone
f. Dopamine Facilitator: Amantadine.
2. Drugs affecting brain cholinergic system
a. Central Anticholinergics: Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden.
b. Antihistaminics : Orphenadrine, Promethazine.

34. Drugs for Huntington’s Disease
Huntington’s disease (or Huntington’s chorea) is an autosomal dominant hereditary
disorder characterized by choreiform movements and progressive mental
impairment, usually beginning in middle age.
The pathogenesis of the disease is related to the degeneration of GABA neurons in
the striatum which leads to disinhibition of thalamic nuclei and to an increase of
thalamic input to the cortex.

35. Drugs used in Huntington’s disease
1. Dopamine receptor antagonists
Neuroleptics (haloperidol , chlorpromazine) antagonize the excessive
dopaminergic activity in basal ganglia and are also helpful to improve
motor function and to relieve paranoia and delusional states that often
accompany the disease.

36. 2. Amine depleting drugs
Reserpine, which can block the vesicular storage of dopamine
(Benzodiazepines which potentiate central GABA activities should help but the
results have been somewhat disappointing).

37. Drugs for Tourette’s Syndrome
Tourette’s syndrome is a hereditary tic disorder that begins in childhood. It
involves multiple tics including respiratory and vocal ones which begin as
grunting or barking noises and progress into compulsive utterances.
Echolalia is common and coprolalia may occur in some patients.
It is probably an autosomal dominant trait.

38. Echolalia is the automatic repitition of vocalization
made by another person
Coprolalia is involuntary swearing or the
involuntary utterance of obscene words or socially
inappropriate and derogatory remarks
Drugs used in Tourette’s syndrome include:
1. Neuroleptics (haloperidol, olanzapine, etc.)
2. Clonidine (it is effective in some patients only)
3. Nn blocking drug (mecamylamine)

40. Alzheimer's and the Brain
Alzheimer's disease leads to nerve cell death and tissue loss throughout the brain. As the
disease progresses, brain tissue shrinks and the ventricles (chambers within the brain that
contain cerebrospinal fluid) become larger. The damage disrupts communication between brain
cells, crippling memory, speech, and comprehension.

42. Drugs for Alzheimer’s Disease
Alzheimer’s disease (AD) is a type of progressive dementia
characterized by an progressive loss of cognitive functions
associated with an excessive number of senile plaques in the
brain.
In AD there is a progressive atrophy and degeneration of
subcortical cholinergic neurons, particularly those in the basal
forebrain (nucleus basalis of Meynert) that provide cholinergic
innervation of the whole cerebral cortex.
The above mentioned deficit has given rise to the ‘cholinergic
hypothesis’ which states that a deficiency of acetylcholine is
critical in the genesis of symptoms of AD.

43. Donepezil, galantamine and tacrine are cholinesterase inhibitors approved for
treatment of AD.
Donepezil and rivastigmine selectively inhibits cholinesterase in the CNS with less
effect on cholinesterases in peripheral tissues.
These drugs can slow the deterioration of cognitive functions, even if they do not
affect the underlying neurodegenerative process.
Adverse effects include insomnia, nausea, vomiting and diarrhea.