Drugs for Neurodegenerative
Disorders
Munir Gharaibeh, MD, PhD, MHPE
School of Medicine, The University of Jordan,
January, 2019
Corrected by: Rana J. Rahhal
Neurodegenerative Disorders
Parkinson’s disease. ( A disease of the basal ganglia)
Huntington’s disease, excessive and abnormal
movements resulting from the loss of a specific
subset of striatal neurons.
Alzheimer’s disease, an injury in the
hippocampus and cortex.
Amyotrophic lateral sclerosis (ALS), a
progressive weakness and muscle atrophy due to
degeneration of spinal, bulbar, and cortical neurons.
January 19 Munir Gharaibeh, MD, PhD, MHPE 2
ParkinsonismParalysis Agitans , which is the most
famous feature of the degenerative
disease of the brain and it was
described early in 1817 .
It is characterized by :
- Gait ; like reduced arm swinging,
shuffling gait with short steps, and
forward tilt of trunk.
- Bradykinesia = Poor movements,
Mask- like Facies (expressionless
facies/ don’t know if the patient
happy or not, angry or not..)
- Resting Tremor. ( occurs at rest while the patient is not
doing any movement )
- Rigidity: Cog-wheel type. (rigidity all over the
movement unlike Clasp-knife rigidity الموس الكباس ..for example
if you want to flex the arm there will be rigidity all over the
movement, usually during a neurological examination).
- Later in the disease;
Cognitive decline, depression,
and dementia.
Etiology of Parkinsonism- Most Of the cases can be contributed to an unknown causes Idiopathic; Multifactorial, genetic factors, Aging.
- Postencephalitic.
- Arterioselerotic.
- Autoimmune
- Poisoning:Free radicals, CO, Mn++, Wilson's Disease. MPTP;
a synthetic byproduct of a
meperidine analog, is a protoxin converted into MPP+
which leads to cell death and premature parkinsonism.
- Drugs:Antipsychotics.
Reserpine. (antihypertension drug)
α-Methyl Dopa (antihypertension drug) 4
Munir Gharaibeh,MD, PhD,MHPE January19 6
Pathology of Parkinsonism
Munir Gharaibeh,MD, PhD,MHPE January19 7
Neuron destruction in Globus Pallidus
Dark pigmentation of Substantia Nigra.
Reduced basal ganglia levels of Dopamine and
5HT. ( the most important one in pharmacology)
The presence of inclusion bodies ”Lewy
Bodies”.
Biochemistry and Pharmacologyof
Movement Disorders.
Munir Gharaibeh,MD, PhD,MHPE January19 8
Cholinergic ------------- Dopaminergic
(Facilitatory) (Inhibitory)
Parkinsonism:
Loss of dopaminergic neurons in Substantia nigra, which normally inhibit the output of GABAergic cells in the corpus striatum.
Huntington’s Chorea:
Loss of cholinergic neurons and greater loss of GABAergic cells that exit the corpus striatum.
Munir Gharaibeh,MD, PhD,MHPE January19 9
Munir Gharaibeh,MD, PhD,MHPE January19 10
L-Dopa or Levodopa
Munir Gharaibeh,MD, PhD,MHPE January19 11
The most reliable and effective drug used inthe
treatment of parkinsonism.
Considered a form of replacement therapy.
The precursor of dopamine.
Used to elevate dopamine levels in the neostriatum of
parkinsonian patients.
Dopamine itself does not cross BBB.
Levodopa, is transported into the brain where it is
converted to dopamine.
L.Dopa or Levodopa
Munir Gharaibeh, MD,PhD, MHPE January19 11
Rapidly absorbed from g.i.t., delayed by food.
Dietary amino acids can compete for absorption
and for transport into the brain.
Levodopa is rapidly metabolized in the brain to
Dopamine by Decarboxylase.
Levodopa
Munir Gharaibeh, MD,PhD, MHPE January19 13
Levodopa is also Alpha, Beta1 and Dopa
receptor agonist.
D2 presynaptic receptor stimulationinhibits NE
release, so --------- Hypotension(Neurogenic
Postural Hypotension).
Carbidopa and Benserazid
Munir Gharaibeh, MD,PhD, MHPE January19 14
Can not cross BBB.
Inhibit (LAAD)L- Amino Acid Decarboxylase,
peripherally.
When combined with levodopa, the daily
required dose of levodopa is reduced by 75% and
its peripheral conversion to dopamine and
toxicity is reduced.
Levodopa + Carbidopa = "Sinemet"
10/100(Levodopa/Carbidopa) , 25/100, 25/250
Munir Gharaibeh,MD, PhD,MHPE January19 14
Clinical Use of Levodopa+Carbidopa
Munir Gharaibeh, MD,PhD, MHPE January19 16
Very useful for 3-4 years.
Does not stop the progression of the disease, but lowers the mortality.
One third of the patients respond very well and one third less well.
Remainder either are unable to tolerate the drug or do not respond at all.
Responsiveness may ultimately be lost completely, perhaps because of the disappearance of dopaminergic nigrostriatal nerve terminals, or some direct pathologic process of the receptors.
Side Effects of Levodopa
Gastrointestinal Effects:
Anorexia, Nausea, Vomiting:
Munir Gharaibeh, MD,PhD, MHPE January19 17
Due to stimulation of CTZ (chemoreceptor trigger zone), but do not give
phenothiazines (because it can inhibit
dopamine receptors).
Occur in 80%. So, give after meals or in divided doses
or give antacids.
Cardiovascular Effects: Postural Hypotension
(due to inhibits NE release), tachycardia, extrasystoles,
atrial fibrillation, hypertension with high doses or with
MAO inhibitors.
Side Effects of Levodopa
January19 17
Dyskinesias: 80%
Choreoathetosis of the face and distal extremities is the most common. Variable among patients.
Behavioral Effects:
Depression, anxiety, agitation, delusions, hallucinations, confusion, disorientation, insomnia, somnolence, nightmares, euphoria, and others.
May be precipitated by intercurrent illness orsMuunirrGhgaraeiberh,MyD., PhD,MHPE
Side Effects of Levodopa
Munir Gharaibeh,MD, PhD,MHPE January19 18
Fluctuations in Response:
Wearing –off Reactions or End-of-DoseAkinesia.
On-off Phenomenon:
Marked dykinesia alternating over the course of
a few hours with on-periods of improved
mobility.
Mechanism unknown.
Apomorphine injection might help.
Side Effects of Levodopa
Munir Gharaibeh,MD, PhD,MHPE January19 19
Miscellaneous Effects:
Mydriasis might lead to acute glaucoma.
Blood dyscrasias, hemolysis, +ve Coomb’sTest
Hot flushes, Gout, abnormalities of smell or taste,
brownish discoloration, priapism, high urea,
transaminases, AlkPhase and bilirubin.
Levodopa
Munir Gharaibeh,MD, PhD,MHPE January19 20
Drug Holidays ( stops the treatment then term back to it
after certain period of time)
No longer recommended.
May temporarily improve responsiveness to
levodopa and alleviate some of its adverse effects,
but not the on-off phenomenon.
However, carries the risks of aspiration
pneumonia, venous thrombosis, pulmonary
embolism and depression.
Levodopa
Munir Gharaibeh, MD,PhD, MHPE January19 21
Contraindications:
Psychotic patients.
Angle-closure glaucoma.
Active peptic ulcer disease.
History of melanoma or undiagnosed skin lesion.
Dopamine ReceptorAgonists
Munir Gharaibeh,MD, PhD,MHPE January19 23
Directly stimulate dopamine receptors in the
brain and do not depend on the formation of
dopamine from levodopa.
None is superior to others.
Variable response of patients.
Lower incidence of fluctuations and dyskinesias.
Dopamine ReceptorAgonists
Considered as the first approach to therapy.
Less effective than levodopa but are often used
early in the disease to delay initiation of levodopa
therapy.
Have long duration of action.
Less likely to cause dyskinesia than levodopa.
Can be used as an adjunct to levodopa in
advanced stages, to improve the condition and
reduce dose of levodopa.
Munir Gharaibeh,MD, PhD,MHPE January19 24
Dopamine ReceptorAgonists
Munir Gharaibeh,MD, PhD,MHPE January19 24
Bromocriptine:
D2 agonist.
Ergot derivative.
Can cause pulmonary & retroperitoneal fibrosis.
Pergolide:
D2 and D1 agonist.
Also ergot derivative.
Valvular heart disease.
Dopamine ReceptorAgonists
Munir Gharaibeh,MD, PhD,MHPE January19 25
Pramipexole:
D3>D2 agonist, non ergot.
Ropinirole:
D3>D2 agonist, non ergot .
May ameliorate affective symptoms.
Possible neuroprotective action: scavenge
hydrogen peroxide.
Adverse Effects of Dopamine Receptor Agonists
Gastrointestinal Effects:
Anorexia, nausea, vomiting, constipation, dyspepsia, reflux esophagitis, bleeding ulcer.
Cardiovascular Effects:
Postural hypotension, digital vasospasm, arrhythmias, edema, valvopathy.
Dyskinesias.
Mental disturbances:
More than with levodopa.
Others:
Headache, nasal congestion,erythromelalgia, narcolepsy.
Munir Gharaibeh, MD,PhD, MHPE January19 26
Apomorphine
Munir Gharaibeh,MD, PhD,MHPE January19 28
Potent dopamine agonist.
Effective for temporary relief of off-on periods
of akinesia of patients on dopaminergic therapy.
Action starts within 10 minutes of injection
and lasts for up to 2 hours.
Causes nausea, vomiting, dyskinesia,
drowsiness, sweating, hypotension and bruising
at injection site.
MAOInhibitors
Munir Gharaibeh,MD, PhD,MHPE January19 29
Selegilline = Deprenyl: Irriversible inhibitor ofMAO-B.
For newly diagnosed cases who have some endogenous
DA(dopamine).
Also combined with Levodopa --- to decrease the doses and fluctuations.
May retard the progression of the disease by an antioxidant activity.
Inhibits the formation of a toxic product in DAmetabolism.
Also, its metabolite has a neuroprotective effect byan
antiapoptotic mechanism.
Rasagiline:MAO-B inhibitor, more potent.
Neuroprotective.
Monoamine oxidases breakdown dopamine either peripherally or centrally.
COMTInhibitors
Munir Gharaibeh,MD, PhD,MHPE January19 30
Inhibition of dopa decarboxylase is associated
with compensatory activation of COMT
leading to increased 3OMD, which competes
with levodopa for its transport.(this happens in
the peripheral circulation)
So, COMT inhibitors can prolong the action
of levodopa by diminishing its peripheral
metabolism.
Increase the “on-time” .
Reduce the daily dose of levodopa.
COMTInhibitors
Munir Gharaibeh,MD, PhD,MHPE January19 31
Entacapone:
Has peripheral effects.
Tolcapone:
Has central and peripheral effects.
Can cause fulminant hepatic necrosis.
Amantadine
,
31
.
Antiviral (used in elderly people with influenza)
Enhances the synthesis, release or reuptake of DA.
Also has antimuscarinic and NMDAreceptor antagonistic activity.
Effects are short –lived.
Used occasionally, to help in reducing iatrogenic dyskinesias.
Can cause excitement, hallucinations and confusion, edema, livedo reticularis, headache, heart failure
postural hypotension, urinary retention and g.i.tdisturbances.
Munir Gharaibeh,MD, PhD,MHPE January19
Anticholinergic Drugs
BelladonaAlkaloids:
Atropine: Less CNS depression , in high
doses can cause stimulation
Scopolamine: Drowsiness, euphoria.
(they are natural product and not useful in the
treatment)
32
SyntheticAlkaloids:
Trihexylphenidyl
Benztropine
Biperiden
OJranuparyh19enadrineMunir Gharaibeh, MD, PhD,
MHPE
Anticholinergic Drugs
* Mild and early stages.
*Block muscarinic receptors in the striatum.
* For tremor and rigidity more than dyskinesia.
* Good for drug induced parkinsonism.
* Elevate the mood.
* Block sialorrhea.(sialorrhea: Hypersalivation)
* Tolerance, but no cross tolerance.(tolerance to the effects of a
certain drug will not produce tolerance to another drug in the same group).
* Minimal systemic effects: Cycloplegia, Dryness,
suppurative parotitis, Retention, Constipation,
Confusion, Delirium, Hallucinations.Munir Gharaibeh,MD, PhD,MHPE January19
34
Antihistamines
Diphenhydramine
Orphenadrine
Chlorphenoxamine
* Most effective against rigidity
* Mood elevation Euphoria
* Sedation
* Weak peripheral anticholinergic actions
Munir Gharaibeh,MD, PhD,MHPE January1935
Neuroprotective Therapy
Munir Gharaibeh,MD, PhD,MHPE January1936
Antioxidants.
AntiapoptoticAgents.
Glutamate antagonists.
Glial-derived neurotrophic factor.
Coenzyme Q10
Creatine.
Antiinflammatory agents.
GeneTherapy
Trials involved infusion into the striatum of
adeno-associated virus type 2 as the vector for
the gene.
Genes were produced for glutamic acid
decarboxylase (GAD), to facilitate synthesis of
GABA, for aromatic acid decarboxylase (AADC),
and for neurturin (a growth factor that may
enhance the survival of dopaminergic neurons).
Munir Gharaibeh,MD, PhD,MHPE January1937
Surgery
Munir Gharaibeh,MD, PhD,MHPE January1938
Ablation of the ventral intermediate nucleus
of the thalamus for tremor.
Ablation of the posteroventral portion of
globus pallidus for dyskinesia.
Electrical stimulation of thalamus,
subthalamic nucleus or globus pallidus.
Fetal substantia nigra transplantation.
Stem cell transplant.
Can result in relative excess of dopamine
from continued fiber growth from the
transplant.
Huntington’s Disease(Chorea)An inherited disease causing progressive
breakdown (degeneration) of nerve cells in
the brain, with an impact on functional
abilities resulting in movement, thinking
(cognitive) and psychiatric disorders.
Signs and symptoms appear in the 30s or 40s.
But the disease may emerge earlier or later in
life.
Juvenile Huntington's disease develops before20Jan’uasry.19 Munir Gharaibeh, MD, PhD, MHPE 38
Munir Gharaibeh, MD,PhD, MHPE January1940
ALZHEIMER’SDISEASE
Munir Gharaibeh, MD,PhD, MHPE January1941
Alzheimer’s disease is the most prevalent form of dementia.
Afflicts approximately 10% of the population over age65.
Loss ofmemory.
Disordered cognitivefunction.
Alterations in behavior and a decline in language function.
In advanced stages, the individual may not recognize spouse or
children, levels of arousal and alertness are severely impaired,
with reduced verbal fluency.
Ultimately, motor function is impaired and the patient mayfall
into a vegetative state.
Death is usually associated with complications of immobility (e.g.,
pneumonia or pulmonary embolism).
Pathology of Alzheimer’sDisease
Munir Gharaibeh, MD,PhD, MHPE January1942
Loss of cholinergic neurons and acetylcholine in the
brain.
Affected brain regions include the entorhinal
cortex (الناصية) ; hippocampus; amygdala;
association cortices of the frontal, temporal and
parietal lobes; and subcortical nuclei that project
to these regions.
Hallmarks are βamyloid and τ tangles )causal or
byproducts).
Drugs for AlzheimerDisease
Acetylcholinesterase Inhibitors: Only palliative, do not cure or prevent thedisease.
Tacrine:
First useful drug.
Many other actions on release and receptors of
MAO, GABA, NE, DA, 5HT.
Only delays further decline.
Hepatotoxic, NVD)nausea
vomiting diarrhea)
Donepezil
Galantamine
Rivastigmine 42
Memantine:
NMDA receptorantagonist.
May slow progression of the disease.
Less toxic.
Future Directions:
Molecules that prevent the proteolytic cleavage
of amyloid precursor protein
Antibodies to remove the β peptides from the cells
and brain.
Antiinflammatory agents and antioxidants.January 19 43Munir Gharaibeh, MD, PhD, MHPE
Drugs for Alzheimer disease
➢ Parkinsonism is due to loss of dopaminergic neurons and excess cholinergic activity.
➢ Levodopa/carbidopa increase the level of dopamine in brain. Unlike dopamine, l-DOPA can cross blood-brain barrier and is converted by dopa decarboxylase in the CNS to dopamine. Carbidopa, a peripheral DOPA decarboxylase inhibitor, is given with l-DOPA to increase the bioavailability of l-DOPA in the brain and to limit peripheral side effects. Side effect (“on-off” phenomenon).
➢ Dopamine agonists , Ergot—Bromocriptine.Non-ergot (preferred)—pramipexole, ropinirole.
➢ Levodopa/carbidopa – ultimate therapy.. but Dopamine agonists might be used initially.
➢ Apomorphine - Potent dopamine agonist.
Summary
➢ Selegiline, rasagiline - block conversion of dopamine into DOPAC by Selectively inhibit MAO-B (metabolize dopamine).. increase dopamine availability. Adjunctive agent to l-DOPA in treatment of Parkinson disease.
➢ Entacapone—blocks conversion of dopamine to 3-methoxytyramine (3-MT) by inhibiting
central COMT.➢ Tolcapone is hepatotoxic.➢ Amantadine, Antiviral, (increases dopamine release and decreases
dopamine reuptake); toxicity (livedo reticularis).➢Benztropine, trihexyphenidyl (Antimuscarinic; improves tremor and
rigidity but has little effect on bradykinesia in Parkinson disease). Park your Mercedes-Benz
➢ Antihistamines - Most effective against rigidity.