CHAPTER 8: NEURODEGENERATIVE DISEASES Flashcards
What does CNS consist of?
brain and spinal cord, meninges, BBB, blood supply to the brain
what are the CNS functions?
sensory, motor, intellect/emotion
common neurotransmitters?
ACh, NE, glutamate, glycine, dopamine, serotonin, Gamma-aminobutyric acid (GABA)
excitatory vs. inhibitory neurotransmission/pathway
- both bind to post synaptic receptor, transiently open ion channels, and alter the post synpatic POTENTIAL
excitatory DEpolarizes, inhibitory HYPERpolarizes post synaptic membrane
why are some pathways meant to be inhibitory?
because certain pathways must remain inhibitory to be kept NORMAL
Excitatory post synaptic potentials (EPSP) are generated by:
- release of neurotransmitters, inc permeability on Na+ ions
- influx Na+, weak depol, and move post syn potential TOWARDS firing threshold
- inc stimulation of excitatory neurons, depol PASSES threshold, and generates “all or none” AP
Inhibitory post synaptic potentials (IPSP) are generated by:
- stimulating inhibitory neurons, releasing neurotransmitters like GABA or GLYCINE—> transient inc permeability for SPECIFIC IONS
GABA induces hyperpol
- influx Cl-, efflux, K+—> weak hyperpolarization, move post syn potential AWAY from firing threshold (less firing)
which specific ions are moving in excitatory vs inhibitory
excitatory: Na+ influx
inhibitory: Cl- influx, K+ efflux
Neurodegenerative Diseases: list and explain what it is
Parkinson’s (PD), Alzheimer’s (AD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS)
- PROGRESSIVE loss of selective neurons in discrete brain areas
- cause characteristic disorders of movement and cognition
PARKINSON’S DISEASE: what is it? age range? cure?
- progressive chronic neurological disorder
- develop in ANY age– most in middl age/past 60
- NO CURE
therapy aims to manage the symptoms/signs not necessarily slow down progression (not possible)
PARKINSON’S: signs and symptoms
- lack of coordination
- rhythmic tremors
- rigidity/weakness
- trouble maintaining position/posture
- bradykinesia—> slow movement
- difficutly walking
- drooling/affect speech
- mask-like expressions
PARKINSON’S: mechanism
- destruction of dopaminergic neurons in SUBSTANTIA NIGRA—> reduces dopamine actions in CORPUS STRIATUM
cells in substantia nigra are destroyed, results in degeneration of nerve terminals that secerete dopamine
dopamine depletion—-> blocks the autoinhibition of ACh and releases MORE in corpus—-> triggers chain of abnormal signaling resulting in motor impairment
SIMPLE: dopamine neurons destroyed, not able to inhibit ACh firing, starts firing like crazy and results in motor impairment
secondary parkinsonism
drugs blocking dopamine receptors in brain may produce Parkinsonism SYMPTOMS
- drugs should be used cautiously in PD patients
Substantia Nigra and Corpus Stratum importance
- these are parts of basal ganglia system that are involved in motor control
Drugs used in PARKINSON’S, categories?
Levodopa w carbidopa
selegiline, rasagiline, safinamide
entacapone and tolcapone
amantadine
MAO-B selective Inhibitors, COMT Inhibitors, Dopamine Agonists, Antimuscarinic Agents
Therapeutic Strategies of treating PARKINSON’S
need to try and reestablish correct dopamine/ACh balance by:
- restoring dopamine in basal ganglia
- antagonizing excitatory effect of cholinergic neurons
restore balance in this CIRCUIT
GOALS of treating PARKINSON’S
drug therapy is aimed at achieving a balance between stimulating cholinergic effects and inhibitory effects of dopamine in basal ganglia
type 1 drugs vs. type 2 drugs
type 1: for inhibition
- inc dopamine conc
- inc dopamine release
- stimulate dopamine receptors
type 2: stimulation
- anticholinergic drugs block stimulant (of cholinergic neurons)
LEVODOPA and CARBIDOPA: MOA
(combination therapy)
levodopa: restore dopaminergic neurotransmission in the neostriatum, ENHANCE synth of dopamine in surviving neurons of susbstantia nigra
carbidopa: diminish metabolism of levodopa in periphery, inc levodopa availability to CNS (gets in through transporter AADC)
neurotransmission L-dopa and carbidopa
PERIPHERY: Carbidopa stops DDC (dopa decarboxylase) inhibits levodopa metabolism, L-dopa turns into DOPA, and crosses BBB into neuron to be turned into dopamine
CNS: tyrosine converted by TH (tyrosine hydroxylase) into L-dopa, AADC (amino acid decarboxylase) makes that into Dopamine
administered levodopa vs. levodopa plus carbidopa
administered levodopa will undergo metabolism in peripheral tissues and GI tract, cause undesirable side effects and result in LOST LEVODOPA (less drug to go to CNS)
levo+carbidopa decreases metabolism in periphery/GI, less side effects, and MORE levodopa to go into CNS (cross BBB)
what does carbidopa do for levodopa?
it blocks the DECARBOXYLASE ENZYME that is trying to metabolize levodopa
LEts CARry the drug to the brain!
LEVODOPA and CARBIDOPA: indications and therapeutic effects, withdrawal?
- treat PD
effects: - dec rigidity, tremor, and other symptoms
WITHDRAWAL MUST BE GRADUAL
LEVODOPA and CARBIDOPA: absorption/metabolism
- SHORT half-life (1-2 hrs), fluctuates in plasma conc.
- motor fluctuations–> PT may suddenly lose normal mobility, experience tremors, cramps, immobility
when is it best to take levodopa and carbidopa?
on an empty stomach, if you take it after eating there are amino acids present trying to break down/metabolize your food and the DRUG! this will let less drug go to the brain!
eating=harder for L-dopa to get to brain
LEVODOPA and CARBIDOPA: peripheral and CNS effects
PERIPHERAL
- anorexia
- nausea, vomiting
- tachycardia, ventricular extrasystole (DA action on heart)
- possible develop of hypotension
- mydriasis–> adrenergic action
CNS
- visual/auditory hallucinations
- dyskinesia–> abnormal involun movements (overactivity of dopamine in basal ganglia)
- mood changes, depression, psychosis (activation dopamine receptors), anxiety
why don’t we just use dopamine to treat PD?
it does NOT cross the BBB, so we use L-dopa and transporters.
dopamine interferes with ADRENERGIC RECEPTORS as well
LEVODOPA and CARBIDOPA: interactions
- vitamin B6–> inc peripheral breakdown levodopa
- co-administration L-dopa and nonselective MAOIs—> hypertensive crisis (enhanced catecholamine production)
- psychotic PT—> worsens symptoms (build up central catecholamines)
- cardiac PT: monitor for arrhythmia
CONTRAINDICATE: antipsychotic drugs (potently block DA receptors/augment PD symptoms)
MAO INHIBITORS:
what are the differences between MAO-A and MAO-B? (not the inhibition)
MAO type A–> metabolism of NE and 5-HT
MAO type B–> metabolism of DA
MAOB Selective Inhibitors: SELEGILINE
LOW DOSE: REVERSIBLE selective inhibitor MAOB
HIGH DOSE: lose selectivity
- inc dopamine in brain
- metabolize to methamphetamine and amphetamine–> may produce insomnia
MAOB Selective Inhibitors: RASAGILINE
- IRREVERSIBLE, selective MAOB inhibitor
- MORE POTENT THAT SELEGILINE
- inc dopamine in brain
NOT metabolized to amph and meth
MAOB Selective Inhibitors: SAFINAMIDE
REVERSIBLE, selective MAO B inhibitor
- inc dopamine in brain
NOT metabolized to amph and meth
COMT Inhibitors: entacapone and tolcapone
- MOA
- selectively and reversibly inhibit COMT
Entacapone and Tolcapone: therapeutic effects
- inhibit COMT–> dec plasma conc of 3-O-methyldopa—> INC uptake L-dopa—> inc conc brain dopamine
-reduce wearing off symptoms in levi-carbi pts
REMEMBER L-dopa and 3OMD compete for entry into BBB, so we want to dec 3OMD and allow more L-dopa in
explain how COMT inhibitors work step by step
when carbidopa inhibits peripheral DDC (the thing that metabolizes) L dopa, 3-O-methyldopa is created which competes L-dopa for active transport into CNS
inhibiting COMT, decreases conc 3-O-methyldopa and allows inc central uptake L-dopa into brain and therefore inc dopamine in brain!
Entacapone and Tolcapone: adverse effects
- diarrhea
- nausea
- anorexia
- postural/orthostatic hypotension
- dyskinsesias
- hallucinations
- sleep disorders
- suddenly developed hepatic necrosis w TOLCAPONE
entacapone doesn’t exhibit this toxicity, largely replaced tolcapone
Dopamine Agonists: bromocriptine, ropinirole, pramipexole, rotigotine, apomorphine
- routes of administration
bromocriptine (oral), ropinirole (oral), pramipexole (oral), rotigotine (transdermal), apomorphine (injectable for severe/advanced stages)
Dopamine Agonists: MOA
type 1: STIMULATE dopamine receptors
- longer duration of action than L-dopa
- effective in PT exhibiting fluctuations in response to L-dopa
- initial therapy associated w/less risk dyskinesias/motor fluctuations compared to L-dopa
fluctuations in L-dopa, wear off effect, its difficult to maintain a constant level of dopamine so the effect fluctuate throughout the day
Dopamine Agonists: adverse effects
- sedation
- nausea
- confusion
- hallucinations
- hypotension
Antiviral: Amantadine
- therapeutic effects and adverse effects
-accidentally discovered to help PD treatment
therapeutic:
- inc dopamine release
- block cholinergic receptors
- inhibit NMDA (type of glutamate receptor)
ADVERSE:
- restlessness, agitation, confusion, hallucinations
HIGH DOSES: acute toxic psychosis, orthostat hypotension, urinary retention, peripheral edema, dry mouth
Antimuscarinic Agents : benztropine, trihexyphenidyl, biperiden, procyclidine
- main purpose
- therapeutic effects
- adverse effects
- contraindications
INHIBIT PSNS
muss less efficacious than L-dopa, only play ADJUVANT ROLE
therapeutic:
- block cholinergic transmission, correct imbalance of DA/ACh activity
adverse:
- mood change, confusion, xerostomia, constipation, visual problems, GI peristalsis interference
contraindications:
- PT w/ glaucoma, prostatic hyperplasia, pyloric stenosis
