Download Drugs for Neurodegenerative Diseases

Drugs for Neurodegenerative
Diseases
Kaukab Azim, MBBS, PhD
Drug List
Drugs for Parkinson’s Disease
Drugs that increase
Dopamine receptor
M receptor
brain dopamine
agonists
antagonists
levels
Levodopa
Bromocriptine
Benztropine
Carbidopa
Pramipexole
Selegiline
Entacapone
Amantadine
Drugs for Huntington’s Disease Drugs for Alzheimer’s Disease
Haloperidol*
Diazepam*
Donepezil
Learning Outcomes
By the end of the course the students will be able to
 Explain the mechanism of action of each drug in each group
 Describe the main effects of each drug on different organ systems
 Describe the absorption, distribution and metabolism of levodopa and
carbidopa
 Describe the administration routes of each drug in each class
 Describe the main adverse effects of each drug in each class
 Explain the on/off effect and wearing-off effect of levodopa / carbidopa
 Explain the therapeutic value of combining levodopa with carbidopa in
Parkinson’s disease
 Explain the use of dopamine agonists and antimuscarinic drugs in
Parkinson’s disease
 Explain the use of neuroleptic and benzodiazepines in Huntington’s
disease
 Explain the use of central cholinesterase inhibitors in Alzheimer’s disease
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 levoaromatic amino acid decarboxylase (LAAD) (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.
Medulla
Glucocorticoid
+
Levodopa
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.
Adverse effects
Levodopa
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[A gr of Involantary movement] (up to 80% of patients treated for more than 3
years): choreoathetosis[Jerky Involantary movement] of the face and the extremities, tics[a
repeated & largely Involantary movement] , myoc lonus[a sudden spasm of the Muscle],
tremor. [therapy is unsatisfactory. A drug holiday can help]
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 patients)
Postural hypotension (about 25% of patients). Tolerance can develop in a few months.
Other systems
•
Leukopenia, agranulocytosis, hemolytic anemia.
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)
• Neuroleptics that block D2 receptors reduce the efficacy of levodopa and
can exacerbate motor dysfunctions.
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
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.

Two main types of fluctuations occur over time:

1.
The wearing-off effect (also called end-of-dose akinesia{loss of
muscular tonicity OR responsiveness}): 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.
Levodopa therapy must not discontinued abruptly (a
malignant syndrome can result)
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)
3.
Gastrointestinal and cardiovascular effects of levodopa are
substantially reduced.
4.
CNS adverse effects are increased.
Levodopa is usually given in combination with carbidopa.
Other drugs that increase dopamine levels
Selegiline

Selegiline is a selective inhibitor of MAO B (the enzyme that
metabolizes dopamine) so preventing the metabolism ( oxidation ) of
dopamine.

This increases brain dopamine levels and prevents the formation of
hydroxide radicals, that may play a role in the degeneration of
nigrostriatal neurons.

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.
Other drugs that increase dopamine levels
Catechol-O-methyltransferase inhibitors

Entacapone and tolcapone are inhibitors of Catechol-Omethyltransferase, the enzyme that transforms methyldopa into 3Omethyldopa in the gut and the liver.

Since 3-O-methyldopa competes with levodopa for active transport
into CNS, this metabolite may contribute to the wearing-off and onoff 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.
Other drugs that increase dopamine
levels
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[spot] 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.
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.
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.
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[False misbelief about
others], hallucinations)
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
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

Cocaine detoxification (results are modest, at the best).
Antimuscarinic Drugs in Parkinsonism
Drugs

Benztropine and trihexyphenidyl and are centrally acting
antimuscarinic drugs used for the treatment of Parkinson’s
disease.
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.
Antimuscarinic Drugs in Parkinsonism
Clinical uses
 Antimuscarinic drugs may improve sialorrhea[excessive production of saliva]
 , 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).
Adverse effects
Adverse anticholinergic effects are both:
a.
b.
Central: drowsiness, restlessness, confusion, agitation , delusions, hallucinations.
Peripheral; xerostomia, blurring of vision, urinary retention, constipation,
tachycardia, increased intraocular pressure.
(Elderly people are especially at risk).
Drugs for Huntington’s Disease
Drugs used in Huntington’s disease include:
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[personality disorder] and delusional states that
often accompany the disease.
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).
Drugs for Tourette’s Syndrome
Drugs used
include:
in
Tourette’s
syndrome
1. Neuroleptics (haloperidol, olanzapine, etc.)
2. Clonidine (it is effective in some patients
only)
3. Nn blocking drug (mecamylamine)
Drugs for Alzheimer’s Disease
The ‘cholinergic hypothesis’ which states that a deficiency of
acetylcholine is critical in the genesis of symptoms of AD.
 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.