10.9 PD, HD, MS, ALS Flashcards
Parkinsonism
bradykinesia or hypokinesia,
Akinesia (marche a petite pas)
poor arm swing,
micrographia,
facial hypomimia (mask like facies),
dec eye blinking rate (inc schiz),
resting tremors (pill rolling in hand, head titubation),
volition abolishes rest tremors with cortical over-red,
muscle rigidity (cogwheel or lead pipe),
impairment of pstural balance;
Propulsion,
retropulsion falls forward or back when pushed,
gait: shuffling or festinant gait (in a hurry),
dementia and depression and usually found in association with PD
Extrapyramidal motor system
outside the pyramidal (corticospinal) motor pathways —for control of movement and balance,
EPS important: antigravity and posture maintenance (phylogenetically older moter system, more prominent after attainment of bipedalism in hominids/great apes)
Extrapyramidal motor system (EPS) vs Corticospinal
corticospinal/corticobulbar – monosynaptic direct motor activation which synapses with lower motor neuron LMN,
EPS indirect (multisynaptic) motor activation pathway–no synpase with LMN, cerebral cortex communicates with basal ganglia and vv (CS, GP)
–> thalamus that communicates with cerebral cortex and vv - spinal cord,
Role –coordination of movement force, velocity, agonist/antagonist muscle actions
Nigrostriatal dopaminergic pathways
gultamate induced excitotoxicity (inc Ca),
oxidative stress (ROS),
apoptosis,
lead to dopamine neuron loss in SN,
Pathway to striatum,
mitochondrial defects in MPTP –PD,
this stratal cholinergic overactivity –impaired control of fine movement basal ganglia, (
n-methyl1234-phenyltetrahydor pyridine) a “street drug” produced accidentally in attempted synthesis of meperidien –severe, sudden irreversible
Micrographia and deterioratinc had writing
due to hypkinesia and poor control of distal muscles
biochemical basis of Parkinsonism
a balance btw excitatory cholinergic and inhibitory dopamine is essential for motor control,
apoptotic degeneration of nigrostriatal dopamine pathway causes imbalance btw dopamine (dec) and ach (inc) activites causing a striatal cholinergic excess,
an imbalance btw the two, result in movement disorder, loss of force, velocity, agonist/antagonist muscle contraction regulation
Pharmacotherapy aimed at
increasing dopaminergic activity,
decreasing cholinergic activity or both
Levodopa
replacement of dopamine
bromocriptine
D1 D2 agonist
selegaline
MAO B inhibitor, dec catabolism of neuronal dopamine)
Entacapone
COMT inhibitor, dec met
Anticholinergics
dec striatal Ach
Miscellaneous durgs
glutamate antagonists, Vit-E, Amantidine – release DA
Levodopa (L-dopa)
a levorotatory isomer of dopa and a prodrug,
corsses the BBB and taken up by surviving dopaminergic neurons in the striatum,
then converted to DA by
AAAD (aromatic amino acid decarboxylase) or
dopa decarboxylase to restore DA activity
in the corpus striatum
Levodopa in the CNS
dopamine in the CNS interacts with postjucntional dopamine D2 and D3 receptors and activate inhibitory G proteins (Gi coupled), inhibits adenylyl cyclase, decrease cAMP, and open postassium channel (K),
so levodopa thereby increases the amount of dopamine release by these neurons in pts with parkinson’s and it serves as a form of replacement therapy
Levodopa pharmakokinetis
orrally absorbed and metabolized in the intestine by MAO and decarboxylation (90%) metabolized in the periphery by COMT and decarboxylation (99%), so only about 1% enters the brain
Absorbtion of levodopa
absorbed rapidly from the small intestine in empty stomac (food decreases bioavailability, F),
high protein food interferes with the absorption and also transport of levodopa into the CNS,
should be taken on an empty stomach (usually 45 min before a meal)
Half life of Levodopa
has an extremely short half-life (1-2 hours), hence causes fluctuations in plasma concentration,
leading to “on-off” phenomenon, (high peath to through = inc cmax/cmin conc ratio)
Carbidopa
inhibits the peripheral metabolism of levodopa and increases the CNS bioavailability of the drug
administration of Levodopa
levodopa is always administered with peripheral decarboxylation inhibitor.
Peripheral decarboxylation inhibitors are
carbidopa and
benserazide.
These are incapable of crossing BBB.
Pyridoxine
dopa decarboxylation is pyridoxine (Vit B6) dependent and Vit B6 may decrease the effectiveness of L-dopa
carbidoap with Levodopa helps in
reduction of dose of l-dopa, decreased incidnece of nausea, vomiting, orthostatic hyptension, and cardiac arrhythmia, if DC inhibitor is used approx 10% of L-dopa enters the brain (if not inhibitor then only 1% of l-dopa reaches the brain)
ratio of Carbidopa to L-dopa
ratio of 1:4 or 1:10 soooo__. 25:100 mg
adverse effects of L-dopa
dyskinesias, peripheral nausea, vomiting, abdominal cramps, on off effect, psychosis, postural hypotension, cardiac arrhythmia, pathological gambling
dyskinesias
major limiting factor in therapy, characterized by a variety of repetitive involuntary abnormal movements (dystonia, tics, ballisms, tremor, myoclonus (repetitive jerks) affecting the face, trunk and limb, occurs in 70% of pts, may be relived by decreasing the dose of levodopa
Peripheral effects
nausea, vomiting, abdominal cramps, palpiations, –due to inc l-dopa metabolism peripherally —if these are common,
increased carbidopa does helps (to reduce L-dopa conc in tissues) C/LD 25/100 mg or controled release tab
central effects
nightmares, orthostatic hypotension, dissiness, hallucinations,
psychosis (clozapine/quetiapine treated),
haloperidol worsens the PD if used to treat psychosis
on-off effect
a rapid fluctuation btw showing no beneficial effects of levodopa and showing beneficial effects with dyskinesias, may be a sign of the later stage of dopamine neuron degeneration, clinical improvement can be obtained with continuous IV infusion and in some instances, with sustained release formualtions of levodopa/carbidopa
psychosis
hallucinations, vivid dreams and distorted thinking (with chronic use), probably due to excessive dopamine concentrations in mesolimbic pathway
Postural hypotension
due to activation of vascular dopamine receptors D1
Nausea and vomiting
in 80% of pts, attenuated if l-dopa given along with carbidopa, with food, in divided doses, or with nonphenothiazine antiemetics, this effect is due to the direct effects of dopamine on the CTZ in the CNS and also on the GIT
Cardiac arrhythmia
due to dopaminergic action on the heart
Pathological gambling and other effects
gambling is more common with dopamine agonists, compulsive shopping, binge eating, hypersexual behaviour, or compulsive repetitive behaviors such as endless writing, singing or talking have also been associated with levodopa therapy
Drug holiday
in the treatment, helps alleviating neurological and behavioural adverse effects
—range from 3-21 days,
efficacy–mainly dec bradykinesia rigidity, less effect on tremors, bed ridden pts may be ambulatory
drug interactions with L-dopa
drugs that delay gastric emptying (anticholinergics) delay its absorption,
while drugs which promote gastric emptying such as antacids, cisapride may increase levodopa bioavailability,
Vit B6 (pyridoxine) increases the peripheral breakdown of levodopa and decreases its effectiveness
Levodopa should not be given with
MAO inhibitors (Phenelzine, Traylocypromine) as can cause severe hypertensive crisis, Antipsychotic drugs block dopamine receptors and may reduce the effectiveness of levodopa
Limitations of Levodopa
for the first 2-5 years of treatment, levodopa produces a sustained response, but as the disease progresses, the duration of benefit from each dose becomes shorter (the wearing off effect) and still later some pts develop sudden unpredictable fluctuations btw mobility and immobility (the “on-off” effect),
after about 5-8 yrs, the majority of pts have dose-related clinical fluctuations and dose-related dyskinesias (chorea, dystonia),
as the disease progresses, levodopa-resistant motor problems including difficulties with balance, gait, speech and swallowing and non-motor symptoms including autonomic, cognitive and psychiatric difficulties become more prominent.
Sudden discontinuation or abrupt reduction of Levodopa dosage for several days may cause a severe return of parkinsonisma symptoms
Dopamine receptor agonist in basal ganglia – Ergot derived agonists
bromocriptine,
Pergolide (D1, D2 receptors)
Dopamine receptor agonist in basal ganglia – nonErgot derived agonists
ropinirole,
pramipexole,
rotigotine
Dopamine receptor agonists
no decarboxylation required,
used as an adjunct to levodopa in advanced disease,
they may permit a reduction in levodopa dosage,
less effective than levodopa for motor symptoms of PD,
but are less likely to cause dyskinesia or motor fluctionations,
ineffective in pts who have shown no therapeutic response to levodopa
Bromocriptine and Pergolide
are ergot alkaloids – D2 agonist,
pergolide is more potent,
these ergot compounds are known to cause pulmonary cardiac valvular and retroperitoneal fibrosis,
bromocriptine is mainly used in Hyperprolactinemia (for suppression of lactation) and acromegaly,
Bromocriptine is still marketed in the US;
pergolide was taken off the market bc its used was associated with cardiac-valve regurgitation
COMT inhibitors
block the conversion of L-dopa to 3-O-methyldopa (3-O-MD) in the gut and liver,
extens the effect of L-dopa (prolonging the half life of Levodopa and decrease parkinsonian disability, reduce the “wearing off” and “on off” effects with Levodopa bc they reduce formation of 3-o-MD wich competes with levodopa for transport into brain tissue
the combination of Levodopa and COMT
can however increase dyskinesia, a reduction in levodopa dosage may be required to avoid dyskinesia
COMT inhibitors
Entacapone and
Tolcapone
(cause dyskinesia, nausea, diarrhea (more often with Tolcapone))
Tolcapone
long acting, more potent COMT inhibitor, Fatal hepatotoxicity can occur, hence reserved for pts with fluctuations who have not responded to Entacapone, not available in Canada
Entacapone
short acting preferred over tolcapone as no risk of hepatotoxicity
use of tolcapone
requires pt written concent and hepatic monitoring twice per month for the first 6 monts and periodically thereafter,
since these drugs are used in combination with levodopa, the levodopa dose may have to be decreased in pts who develop dyskinesia, nausea or hallucinations
MAO-B inhibitors
Rasagiline, Selagiline
MAO-B is predominantly seen in the
CNS
MAO-B inhibitors fn
decrease dopamine metabolism in the CNS and prolong its synaptic action,
used as initial treatment and also as adjunct to levodopa,
used as montherapy in early disease, it cana delay initiation of levodopa treatment
MAO-B adverse effects
dyskinesia and psychosis,
mild amphetamine-like stimulating action (selegiline is metabolized to amphetamine),
nausea and orthostatic hypotension
MAO-B precaution
in pts taking SSRIs,
TCAs and meperidine
(chance of “serotonin syndrome”)
what will be the effect of selagiline on prolactin secretion and nausea and vomiting?
no idea
Anticholinergics (muscarinic blockers) work to
control mainly resting tremors and drooling
drug of choice in drug induced Parkinsonism (anticholinergics)
benztropine, trihexylphenidyl, diphenhydramine, procyclidine, biperiden, ethopropazine --> these drugs are used in initial stages of mild parkinsonism, often in combination with L-dopa, decrease tremor and rigidity, but have little effect on bradykinesia and postural reflexes
Anticholinergic adverse effects
atropine like
Amantadine
antiviral drug used in prophylaxis and treatment of Influenza,
slightly blocking Dopamine uptake and inc presynaptic release from axoplasm,
also inhibits glutaminergic NMDA receptors,
whose excitation may paly a role in the degeneration of the nigrostriatal system in Parkinson’s disease,
Also has muscarinic blocking action
Amantadine adverse effects
common--confusion, dizziness, dry mouth, hallucination, also causes livedo reticularis (reddish blue molting of the skine with edema around ankel) and other atropine-like adverse effects
Novel therapies for Parkinsonism
NMDA antagonists,
VitE and other antioxidants,
neuronal growth factors,
neuronal transplant
Surgical treatment of Parkinsonism
should be reserved for PD pts with major dyskinesia or clinical fluctuations on Levodopa treatment,
surgery does not help pts who are unresponsive to Levodopa,
deep Brain Stimulation of the subthalamic nucleus or globus pallidus with high frequency electrical stimuli from implanted electrodes is employed for PD
choice treatment for PD
Levodopa combined with carbidopa remains the most effective symptomatic treatment for PD,
dopamine agonists, the next most effectiv drugs after levodopa in decresing symptoms, can be used alone before the introduction of levodopa, or as an adjunct to levodopa,
addition of peripherally -acting COMT inhibitor or an MAO-B inhibitor to levodopa can reduce motor fluctuations in pts with advance disease,
Anticholinergics are rarely used bc of theri side effects, but can be useful addition to levodopa for control of tremor and drooling,
bilateral subthalamic deep brain stimulation is an option for pts with more advanced motor fluctuations and intact cognition
Huntingoton’s disease
abnormal gene on chromosome 4 with polyglutamine expansion
(encoded by CAG repeats)
–> inc huntingtin protein and other molecules
–> glutamate excitotoxicity
–> apoptotic oxidative neuronal damage in cortex + stratum
–> degeneration of GABAergic neurons in the striatum and cortex (path for control of movement). Loss of GABA nurons leads to excessive dopaminergic activity in the basal ganglia.
Huntingtons is characterized
by abnormally expansive or choreo-arthetoid movements (dance-like movements) of limbs, rhythmic movements of tongue and face, and mental deterioration that lead to personality disorders, psychosis, and dementia.
Pts are usually in their late 30s when the disease begins, and progressive respiratory depression usually causes death in 10-15 yrs
no specific treatment exists fo huntingtons but
drugs which block NMDA receptors may block the toxic effects of excess glutamate.
Treatment of Huntingtons includes
tetrabenazine (VMAT inhibitor) for reduction of chorea?,
Dopamine antagonist – Haloperidol,
Gaba facilitatory drugs –like benzodiazepines help in reducing excessive movements?
Multiple Sclerosis
is characterized by the demyelination of neurons in the CNS.
Begins with optic neuritis commonly.
Although etiology unknown; the disease is postualted to have an autoimmune or viral origin.
Demyelination accompanied by inflammatory responses leads to disruption of nerve transmission and formation of plaques in the brain
pathology of MS
disseminated patches of demyelination in the CNS (brain and spinal cord) which occurs at different places at different times (fibrous gliosis),
both sensory and motor dysfunctions occurs,
S/S depends on the part of brain involved – includes visual, ocular palsies, pain, spasticity, weakness, ataxia, problems with speech, gait and bladder function
MS goal
reduce frequency and severity of exacerbations and remissions.
Symptomatic.
Corticosteroidss
(prednisone,
methylprednisolone-IV)
Immuno modulatory agents (IFN-B1b IFNbeta1A, Glatiramer acetate, Natalizumab monthly infusion (dec WBC entry to brain) anti-alpha 4 integrin ab,
Immunosuppressants:
Mitoxanthrone,
Antispastic drugs:
Baclofen (GABAb agonists),
Pain (sensory neuropathy):
Gabapentin, TCA, carbamazepine
ALS – Amyotrophic Lateral Sclerosis
also called Lou Gherig disease, a progressive disorder of the motor nurons characterized by muscle wasting, weakness, and respiratory failure. A defect in the superoxide dismutase enzyme that scavenges super oxide radicals.
ALS treatment
not specific, only treat symptoms,
Riluzole,
Baclofen,
Insulin like growth factors
Riluzole in MS
blocks the sodium channle and decrease the release of glutamate,
protects the motor neurons from the neurotoxic effects of glutamate
Baclofen (gaba B agonist)
to control spasticity
