Pharmacology of Neurodegenerative diseases, epilepsy and migraine Flashcards
1
Q
what are the someone symptoms for parkinsons disease
A
progressive disease
tremor of rest
bradykinesia, rigidity
postural defect: tendency to stoop
2
Q
what is the mortality of parkinsons disease
A
due to complications of severe rigidity
3
Q
what is the pathophysiology of parkinsons
A
progressive degeneration of neurons in the substantia nigra: loss of DA transmission
leads to imbalance of input to the cortex - DA/ACh balance
4
Q
what medication can quickly produce parkinsonian symtpoms
A
injection of MPTP
(a neurotoxin that kills dopamine-producing neurons)
5
Q
what are the classes of dopamine receptors
A
D1 receptors (excitatory) and D2 receptors (inhibitory)
6
Q
what is the effect of D1 receptor class
A
Excitatory
Increase cAMP
PIP hydrolysis
Ca2+ mobilization and PKC activation
7
Q
what is the effect of D2 receptor class
A
Inhibitory
decrease cAMP
increase K+ currents
decrease Ca2+ currents
8
Q
what does parkinsons inhibit
A
the thalamus and reduces thalamic stimulation of the cortex
9
Q
What is the goal of Parkinson therapy
A
re-establish balance of striatal signaling
increase DA signaling and Decrease mACh signaling
10
Q
what type of medication is levodopa
A
DA precursos
11
Q
what is the MOA of levodopa
A
crosses the BBB
actively taken up into neurons (amino acid transporter)
converted to DA by DA decarboxylase
12
Q
what are the adverse effects of Levadopa
A
dyskinesia
hallucinations/confusion (cautiously treat psychosis with antipsychotics)
peripheral effects: Nausea, hypotension, arrhythmia
13
Q
why can Levadopa cause Nausea
A
DA receptors in the gut are affected
14
Q
What is Carbidopa
A
adjunct therapy - peripheral inhibitor of levadopa (l-aa decarboxylase)
15
Q
what is the purpose of Carbidopa
A
prevents conversion to DA in periphery
does NOT cross the BBB
reduces peripheral side effects (nausea) and allow more drug to reach the brain
16
Q
what is the mainstay treatment for parkinsons disease
A
Levodopa-Carbidopa
17
Q
what is Entacapone
A
a levodopa adjunct therapy - inhibits COMT enzyme mostly in the periphery
prevents degradation of Levodopa
18
Q
what is COMT
A
catechol-o-methyl transferase
secondary pathway to metabolize levodopa as well as DA and NE
19
Q
what are the adverse effects of Entacapone
A
dyskinesia, nausea and diarrhea
20
Q
what is the efficacy of levodopa
A
extremly effective early in treatment
overtime one may develop motor flunctuation
21
Q
how is motor fluctuation effect reduced
A
by increasing number of dosages
22
Q
what is the benefit of increasing the number of levodopa dosages
A
to decrease motor fluctuation
23
Q
what is the MOA Selegiline
A
Beta inhibitor that prevents metabolism of DA
selective for striatum, mild effect
reduced the dose of devodopa needed
24
Q
what is another beta inhibitor that can be used for parkinsons treatment
A
Rasagiline
25
what are the adverse effects of selegiline
some amphetamine - like side effects (partly metabolized to amphetamine)
possibility of serotonin syndrome
26
what is the metabolism of selegiline
metabolized in the liver by CYP450 enzymes
possible serotonin syndrome induced by foods containing tyramine or combining with SSRIs or CYP450 substrates
27
what is a dopamine receptor agonist medication
Bromocriptine
Ropinerole
(pramipexole, perogolide, apomorphine)
28
what is Bromocriptine
DA receoptor agnoist: ergot alkaloid - D2 receptor agnoists
some avitivty at D1, D3 and 5-HT receptors
used to delay the need for using levodopa and also for advanced parkinsons
29
what are the side effects of Bromocriptine
more risk of psychotic effects and risk of cardiac valve fiborsis in long-term use
30
what is Ropinerole
dopamine receptor agonist
less selective than bromocriptine has D2, D3, D4 receptor agonist receoptos
31
what is ropinerole also beneifical in treating
restless leg syndrome
32
what are the adverse effects of ropinirole
metabolized by CYP450 thus could cause drug interaction
mostly has replaced bromocriptine therapeutically due to reduced side effects - less risk of cardiac valve fibrosis and D3 agonisms is linked to increased risky behavior
33
the agnoism of D3 is linked to what
increased risky behavior (gambling, hypersexuality)
34
what are non-DA parkinson treatments
MACh receptor agonists and antivirals
35
what is trihexyphenidyl
mACh receptor agonists
effective at reducing dyskinetic movements and spastic contractions - often given in combination with DA agonists
36
what is another option for mACh receptor agonists that is less commonly used
Benztropine
37
what are the adverse effects of trihexyphenidyl
anticholinergic side effects: sedation, confusion, constipation, urinary retention
pharmacokinets: excreted unchanged
38
what is amantadine
anti-viral drugmechanism by increaseing DA release and blocking NMDA gluamate receptors
less effective than levodopa
39
what may amatadine casue
confusion/psychosis
40
what is huntinggtons disease
dominant inherited disorder characterized by involunatary movements, personality changes and bradykinesia
41
what type of vulnerability does huntingtons disease have
selective,
mutant gene expressed throughout brain
neuronal loss is limited to caudate/putamen, striatum and loss of GABA function
42
what is the treatment for huntingtons
very difficult to treat becasuse of its effects on multiple neuronal systems
based on most pronounced symptoms: psychosis and chrea
43
what is the psychosis treatment for huntingtons
neuroleptic D2 blockers such as Haloperidol
44
what is the chorea treatment for huntingtons
inhibitor of neurotransmitter storage such as Deutetrabenazine
45
what is Deutetrabenazine
inhibitor of VMAT-2
prevents storage of neurotransmitter in vesicles
reduced uncontrolled hyperkinetic movements
46
where is Deutetrabenzine metabolized
P450 (CYP2D6)
some patient sare poor metabolizers
long half-life relative to tetrabenazine
47
what are the side effects of deutetrabenzine
similar to antipsychosis
Akathisia, drowsiness, tremor, depression
48
when is deutetrabenazine contraindicated
with MAO inhibitors and uncontrolled depression (suicide risk)
49
what are other conditions that deutetrabenzine is useful for
tourettes and tardive dyskinesia
50
what are the drug types for alzheimers
cholinesterase inhibitor and NMDA antagonists
51
what are cholinesterase inhibitor drugs used in the treatment of alzheimers
DONEPEZIL (aricept)
rivastigmine
galantamine
52
what are the NMDA antagonist drugs used in treatment to Alzheimers
MEMANTINE (nemenda)
typcially used in combination with Donepezil
53
what is the pathophysiology of Alzheimers dementia
neuritic plaques, containing beta-amyloid
neurofibrillary tangles
selective neuronal loss in Hippocampus and Cortex
CHOLINERGIC DAMAGE
54
What is lost with Cholinergic Damage in connection to Alzheimers Dementia
loss of enzymes for ACh synthesis
loss of cholinergic neurons in basal forebrain
55
what is the goal of Donepezil
raise ACh levels in damaged areas of the brain
readily enters CNS, relatively long lasting
56
what are other affects of Donepezil
may increase ACh synthesis and release
57
what are the adverse effects of Donepezil
GI distrubances from chilinergic effects, N/V/D (can be severe due to overactive gut motility)
Sleep distrbances- vivid dreams
58
what is the metabolism of Donepezil
metabolism is through acetylcholinesterase activity, thus no major drug interactions
59
what is the mechanism of Memantine
NMDA receptor antagonists
blocks pathological activation of NMDA receptors
thought to reduce excitotoxicity
60
what are the common side effects of Memantine
Dizziness, headache, constipation, confusion
61
when is Memantine used
it is not as effective as Donepezil, but useful for patients that do not response or cannot tolerate the side effects
can be used in addition to Donepezil
62
what antioxidants are used in the treatment of Alzheimers
Vitamin E and Selegeline
63
why is Vitamin E important
lipid soluble antioxidant
scavenges damaging free radicals
limited effectiveness, difficult to monitor
64
what is selegeline
MAO inhibitor in Striatum
has neuroprotective effect (antioxidant?)
65
what is the treatment for behavioral effects of alzheimers
antipsychotics
anxiolytics
antidepressants
66
what is epilepsy
abnormal electrical activity can result in a variety of events including LOC, abnormal movements, atypical or odd behavior and distorted perceptions that are of limited duration but recur if untreated
67
what are the common types of epilepsy
idiopathic and symptomatic
68
what is idiopathic epilepsy
no specific anatomic cause for the seizure, such as truama or neoplasm, is evident, a patient may be diagnosed with idiopathic or cryptogenic (primary) epilepsy
69
how is idiopathic epilepsy treated
with antiseizure drugs or vagal nerve stimulation
70
what is symptomatic epilepsy
caused by illict drug use, tumor, head injury, hypoglycemia, meningeal infection or withdrawal from alcohol
71
how is symptomatic epilepsy treated
antiseizure drugs and vagal nerve stimulators used to treat as well as treating the underlying cause
72
what are the subtypes of seizures
partial and generalized
73
what are partial seizures
conciousness preseved entirely or partially
simple vs complex
74
what is simple partial seizures
consciousness normal - cauaed by a group of hyperactive neurons exhibiting abnormal electrical activity which are confined to a single locus in the brain
- no LOC
75
what is complex partial seizures
consciousness altered/no memory
exhibits complex sensory hallucinations and mental distortion
76
what are the categories of generalized seizures
tonic-clonic
absence
myoclonic
status epilepticus
infantile spasm
77
what is generalized seizures
consciousness lost / no memory
78
what is generalized tonic - clonic seizures
loss of consciousness, followed by tonic and clonic
79
what is tonic
continuous contraction
80
what is clonic
rapid contraction and relaxation phases
81
what is generalized absence seizures
brief abrupt self limiting loss of consciousness. may stare and exhibit rapid eye blinking lasting 3-5 seconds
82
what is generalized myoclonic seizures
short episodes of muscle contractions that may recur within several minutes
83
what is status epilepticus
two or more seizures occur without recovery of full consciousness between them. LIFE THREATENING
84
What is the MOA of antiseizure drugs
blocking voltage-gated channels (Na+ or Ca2+)
enhancing inhibitory y-aminobutyric acid (GABA)-ergic impulses
interfering with excitatory glutamate transmission
85
what is the MOA for Benzodiazepines
bind to GABA inhibitory receptors to reduce firing rate
86
what are the most common Benzodiazepines
diazepam and lorazepam are most offen used as an adjuctive therapy for myoclonic as well as partial and generalized tonic-clonic seizures
87
what is the benefit of Lorazepam
shorter half life - but stays in the brain longer than diazepam
88
what is the benefit of Diazepam
available for rectal administration to avoid or interrupt prolonged generalized tonic-clonic seizures or clusters
89
what population is diazepam typcially used in
childen and patients with AMS
90
what is the MOA for Carbamazepine
reduces the propagation of abnormal impulses in the brain by blocking sodium channels, thereby inhibits the generation of repetitive action potentials in the epileptic focus and preventing their spread
91
what are carbamazepine used for
effective for treating partial seizures and secondarily generalzied tonic-clonic seizures
92
what patient should not be treated with Carbamazepine
patient with absence seizures becuase it may casue an increase in seizures - inducer of isozyme families CYP1A2, CYP2C, and CYP3A and UGT enzymes
Elderly
93
how is carbamazepine metabolized
absorbed slowly and erratically following oral administration, resulting in large variations of serum concentration
94
what is Ethosuximide
effective in treating primary generalized absence seizures
95
what is the MOA for ethosuximide
reduces propagation of abnormal electrical activity in the brain, most likely inhibiting T-type calcium channels
96
what is the MOA for Gabapentin
analog of GABA, but does not act on GABA receptors and it neither enhances GABA actions not is converted to GABA
MOA is not known
97
what is Gabapentin approved for
approved as adjunct therapy in partial seizures and for treatment of postherpetic neuralgia
98
when is gabapentin dose reduced
patients with renal disease - does not bind to plasma proteins and is excreted unchanged through the kidneys
99
what is the MOA for Lamotrigine
blocks sodium channels as well as high voltage dependent calcium channels
100
what is lamotrigine used for
effective in a wide variety of seizure types including partia, generlized and typical absnse seizures in the Lennox-Gastaut syndrome
101
what other conditions are treated with Lamotrigine
bipolar disorder
102
how is lamotrigine metabolized
through the N-2 glucuronide through the UGT pathway
half life is 24-35 hours and is decreased by enzyme inducing drugs like carbamazepine and phenytoin
103
when lamotrigine is used in combination, what is important to remember
reduce doing if given in combination
104
what are serious adverse reactions to lamotrigine
SJS
overall tolerated by elderly with partial seizures due to relatively minor effects
105
what is Levetiracetam approved for
adjunct therapy of partial onset seizures, myoclonic seizures and primary generalized tonic-clonic seizures in adults and children
106
how is Levetiracetam metabolized
does not interact with CYP or UGT metabolism systems
well absorbed orally and excreted in urine unchanged
107
what are the side effects of levetiracetam
dizziness, sleep disturbances, headache and weakness
108
what is the MOA for Oxcarbazepine
prodrug that is rapidly reduced to 10-monohydroxy (MHD) metabolite responsible for its anticonvulsant activity
MHD blocks sodium channels, preventing spread of abnormal discharge
109
what is oxcarbazepine approved for
use in adult and children with partial onset seizures
110
what are the adverse effects of oxcarbazepine
N/V, headaches, visual disturbances
111
what is the MOA for phenobarbital
enhancing the inhibitory effects of GABA-mediated neurons
112
what should phenobarbital be used for
primarily for the treatment of status epilepticus
113
what is the MOA for phenytoin and fosphenytoin
blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and sling its rate of recovery
114
what treatments are phenytoin and fosphenyotin used for
treatment of partial seizures and generalized tonic-clonic seizures and in the treatment of status epilepticus
115
how are phenytoin and fosphenytoin metabolized
induces drugs metabolized by the CYP2C and CYP3A families and the UGT enzyme system
