Download Neurodegenerative Diseases

Neurodegenerative Diseases
Neurodegenerative diseases of the CNS include Alzheimer's disease, Parkinson's
disease and Huntington's disease. The most prevalent of these disorders is Alzheimer's
disease.
Alzheimer's disease
Alzheimer's disease is characterized by the loss of cholinergic neurons in the
nucleus basalis. the Alzheimer's dementia has three distinguishing features:
1) accumulation of senile plaques.
2) formation of numerous neurofibrillary tangles.
3) loss of cortical neurons particularly cholinergic neuron.
TREATMENT
Current therapies are aimed at either improving cholinergic transmission within the
CNS or preventing excitotoxic actions resulting from overstimulation of N-methyl-Daspartic acid (NMDA)-glutamate receptors in selected brain areas.
Acetylcholinesterase inhibitors
Numerous studies have linked the progressive loss of cholinergic neurons and,
presumably, cholinergic transmission within the cortex to the memory loss that is a
hallmark symptom of Alzheimer's disease. It is postulated that inhibition of
acetylcholinesterase (AChE) within the CNS will improve cholinergic transmission, at
least at those neurons that are still functioning. Currently, four reversible AChE
inhibitors are approved for the treatment of mild to moderate Alzheimer's disease.
They are donepezil , galantamine ,rivastigmine , and tacrine
NMDA-receptor antagonist
Stimulation of glutamate receptors in the CNS appears to be critical for the
formation of certain memories; however, overstimulation of glutamate receptors,
particularly of the NMDA type, has been shown to result in excitotoxic effects on
neurons and is suggested as a mechanism for neurodegenerative or apoptotic
(programmed cell death) processes. memantine has been shown to slow the rate of
memory loss in both vascular-associated and Alzheimer's dementia in patients with
moderate to severe cognitive losses.
PARKINSON DISEASE
PD is a progressive neurodegenerative disease affecting mainly old ages. It is
commonly associated with dementia propably because the degenerative process is not
confined to the basal ganglia but also affects other parts of the brain .
CLINICAL FEATURES
PD is a progressive disorder of movement characterized by:
1-Tremor at rest usually started in the hands (pill-rolling tremor)which tend to
diminish during voluntary activity.
2-muscle rigidity:↑↑resistance in passive limb movement .
3-suppression of voluntary movements (hypokinesia),due partly to muscle rigidity and
partly to an inherent inertia of the motor system sot there will be a difficulty in
initiating and in stopping the movement.
PATHOGENESIS
PD affects the basal ganglia and the neurochemical studies showed that the
dopamine contents of the substantia nigra and corpus striatum were extremely low, it
was found that the PD symptoms appear when the striatal content of dopa. Falls to2040% of normal .the other neurotransmitter involved in PD is ACh. The Ach release is
strongly inhibited by dopa. And it is suggested the hyperactivity of cholinergic
neurons contributes top the symptoms of PD (rigidity and tremor)while hypokinesia is
dueto dopa deficiency.
AETIOLOGY
PD occurs with no obvious underlying cause but it may the result of
1) cerebral ischemia ,viral encephalitis ,or other pathological damage
2) drug induced PD:
a)drug that reduce the amount of dopamine in the brain like reserpine.
b) drugs that block DR like antipsychotics as chlorpromazine .
c)drugs with neurotoxic activity which destroy the dopaminergic nigro
-striatal neurons like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(
MPTP)which appears to be selective in destroying nigrostriatal neurons and not
affects dopa. Neurons elsewhere.
3)rare types of hereditary –early onset PD where several gene mutations have been
identified mostly synuclein and parkin.
TREATMENT
I-Medical treatment:
1-Dopamine agonists and L-dopa:this group is the main group in the treatment of PD.
2-Selective MAO-B inhibitors ex: selegiline(↓ dopa. Break down) .
3-Drugs that release dopa.like amantadine which also↓↓ dopa reuptake
4-muscarinic acetylcholine receptor antagonists like benztropine,biperdine,benzhexol,
procyclidine.
None of the drugs used to treat PD affects the progress of the disease.
II-Surgical treatment: by neural transplantation, but it is still in an experimental phase.
Levodopa
It is the 1st line treatment for PD is combined with a peripheral dopa. decarboxylase
inhibitor carbidopa ,this combination reduces the dose needed by about 10-folds and
diminishes the peripheral SEs.
KINETICS
It is well absorbed from intestine although much of it is inactivated by MAO in the
wall of intestine, food affects its absorption ,so it should be taken on an empty
stomach. the plasma t1/2 is 2 hrs, convesion to dopamine in the periphery is largely
prevented by dopa decarboxylase inhibitor.decarboxylation occurs rapidly within the
brain because the decarboxylase inhibitor doesn't penetrate the BBB.
Therapeutic effectiveness of L-dopa ↓ with the time as the disease advances because
part of its action rely on the presence of dopaminergic
Neurons, so combination of L-dopa with entacapone (an inhibitor of
Catechol-O-methyl transferase{COMT}) is recommended to inhibit its degradation.
SEs: 1- dyskinesia :appears after 2 years of treatment.
2- rapid fluctuations in the clinical state where symptoms worsen
then improved(on-off phenomena).
3-nausea and anorexia .
4-psychological effects.
DRUG INTERACTIONS:
1)Vit. B6 ↑↑breakdown of L-dopa and ↓↓its effectiveness.
2) co administered non selective MAOIs like phenelzine produce hypertensive crisis.
DOPAMINE-RECEPTOR AGONISTS
Bromocriptine
It is a derivative of ergot alkaloids and it is a potent D2-receptor agonist.its plasma
t1/2 6-8hrs.the main SEs are N,V and rarely but seriously peritoneal fibrosis.
Newer dopamine agonists include : lisuride , pergolide , ropinirol , Cabergoline and
pramipexole have longer time of action than L- dopa . They are given 1-2 daily with
less tendency to cause dyskinesia and on-off phenomena. Their main SEs are
confusion ,occasionally delusion and sleep disturbances.
Selegiline
A Selective MAO-B inhibitor , the enz, that predominates in the dopamine
containing regions in the CNS , its inhibition prevents dopamine from intraneuronal
degradation. selegiline was initially used as adjunct therapy to L-dopa ,it is shown
that this combination is more effective than using L-dopa alone in prolonging life and
relieving symptoms. selegiline also shown to be effective in preventing MPTPInduced neurotoxicity by blocking its conversion to the toxic metabolite MPP+ which
is mediated by MAO-B oxidase enz.It is also used to treat depression and as
compared to other non selective MAOIs it lacks the unwanted peripheral side effects
and doesn’t provoke the cheese reaction or interact so frequently with other drugs .
AMANTADINE
An antiviral drug that ↑ release of dopamine and inhibits its reuptake. It is less
effective than L-dopa ,its action ↓ with time ,SEs are considerably less severe
although qualitatively are similar to those of L-dopa.
ACETYLCHOLINE ANTAGONISTS
Muscarinic Ach receptors exert an inhibitory effects on dopaminergic nerve
terminals ,suppression of which compensates for a lack of dopamine. The SEs of
these drugs ( dry mouth , constipation , impaired vision ,urinary retention …) are
troublesome and they are rarely used now except to treat symptoms in patient
receiving antipsychotic therapy.