Pharmacology of Neurodegenerative diseases, epilepsy and migraine Flashcards
what are the someone symptoms for parkinsons disease
progressive disease
tremor of rest
bradykinesia, rigidity
postural defect: tendency to stoop
what is the mortality of parkinsons disease
due to complications of severe rigidity
what is the pathophysiology of parkinsons
progressive degeneration of neurons in the substantia nigra: loss of DA transmission
leads to imbalance of input to the cortex - DA/ACh balance
what medication can quickly produce parkinsonian symtpoms
injection of MPTP
(a neurotoxin that kills dopamine-producing neurons)
what are the classes of dopamine receptors
D1 receptors (excitatory) and D2 receptors (inhibitory)
what is the effect of D1 receptor class
Excitatory
Increase cAMP
PIP hydrolysis
Ca2+ mobilization and PKC activation
what is the effect of D2 receptor class
Inhibitory
decrease cAMP
increase K+ currents
decrease Ca2+ currents
what does parkinsons inhibit
the thalamus and reduces thalamic stimulation of the cortex
What is the goal of Parkinson therapy
re-establish balance of striatal signaling
increase DA signaling and Decrease mACh signaling
what type of medication is levodopa
DA precursos
what is the MOA of levodopa
crosses the BBB
actively taken up into neurons (amino acid transporter)
converted to DA by DA decarboxylase
what are the adverse effects of Levadopa
dyskinesia
hallucinations/confusion (cautiously treat psychosis with antipsychotics)
peripheral effects: Nausea, hypotension, arrhythmia
why can Levadopa cause Nausea
DA receptors in the gut are affected
What is Carbidopa
adjunct therapy - peripheral inhibitor of levadopa (l-aa decarboxylase)
what is the purpose of Carbidopa
prevents conversion to DA in periphery
does NOT cross the BBB
reduces peripheral side effects (nausea) and allow more drug to reach the brain
what is the mainstay treatment for parkinsons disease
Levodopa-Carbidopa
what is Entacapone
a levodopa adjunct therapy - inhibits COMT enzyme mostly in the periphery
prevents degradation of Levodopa
what is COMT
catechol-o-methyl transferase
secondary pathway to metabolize levodopa as well as DA and NE
what are the adverse effects of Entacapone
dyskinesia, nausea and diarrhea
what is the efficacy of levodopa
extremly effective early in treatment
overtime one may develop motor flunctuation
how is motor fluctuation effect reduced
by increasing number of dosages
what is the benefit of increasing the number of levodopa dosages
to decrease motor fluctuation
what is the MOA Selegiline
Beta inhibitor that prevents metabolism of DA
selective for striatum, mild effect
reduced the dose of devodopa needed
what is another beta inhibitor that can be used for parkinsons treatment
Rasagiline
what are the adverse effects of selegiline
some amphetamine - like side effects (partly metabolized to amphetamine)
possibility of serotonin syndrome
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
what is a dopamine receptor agonist medication
Bromocriptine
Ropinerole
(pramipexole, perogolide, apomorphine)
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
what are the side effects of Bromocriptine
more risk of psychotic effects and risk of cardiac valve fiborsis in long-term use
what is Ropinerole
dopamine receptor agonist
less selective than bromocriptine has D2, D3, D4 receptor agonist receoptos
what is ropinerole also beneifical in treating
restless leg syndrome
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
the agnoism of D3 is linked to what
increased risky behavior (gambling, hypersexuality)
what are non-DA parkinson treatments
MACh receptor agonists and antivirals
what is trihexyphenidyl
mACh receptor agonists
effective at reducing dyskinetic movements and spastic contractions - often given in combination with DA agonists
what is another option for mACh receptor agonists that is less commonly used
Benztropine
what are the adverse effects of trihexyphenidyl
anticholinergic side effects: sedation, confusion, constipation, urinary retention
pharmacokinets: excreted unchanged
what is amantadine
anti-viral drugmechanism by increaseing DA release and blocking NMDA gluamate receptors
less effective than levodopa
what may amatadine casue
confusion/psychosis
what is huntinggtons disease
dominant inherited disorder characterized by involunatary movements, personality changes and bradykinesia
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
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
what is the psychosis treatment for huntingtons
neuroleptic D2 blockers such as Haloperidol
what is the chorea treatment for huntingtons
inhibitor of neurotransmitter storage such as Deutetrabenazine
what is Deutetrabenazine
inhibitor of VMAT-2
prevents storage of neurotransmitter in vesicles
reduced uncontrolled hyperkinetic movements
where is Deutetrabenzine metabolized
P450 (CYP2D6)
some patient sare poor metabolizers
long half-life relative to tetrabenazine
what are the side effects of deutetrabenzine
similar to antipsychosis
Akathisia, drowsiness, tremor, depression
when is deutetrabenazine contraindicated
with MAO inhibitors and uncontrolled depression (suicide risk)
what are other conditions that deutetrabenzine is useful for
tourettes and tardive dyskinesia
what are the drug types for alzheimers
cholinesterase inhibitor and NMDA antagonists
what are cholinesterase inhibitor drugs used in the treatment of alzheimers
DONEPEZIL (aricept)
rivastigmine
galantamine
what are the NMDA antagonist drugs used in treatment to Alzheimers
MEMANTINE (nemenda)
typcially used in combination with Donepezil
what is the pathophysiology of Alzheimers dementia
neuritic plaques, containing beta-amyloid
neurofibrillary tangles
selective neuronal loss in Hippocampus and Cortex
CHOLINERGIC DAMAGE
What is lost with Cholinergic Damage in connection to Alzheimers Dementia
loss of enzymes for ACh synthesis
loss of cholinergic neurons in basal forebrain
what is the goal of Donepezil
raise ACh levels in damaged areas of the brain
readily enters CNS, relatively long lasting
what are other affects of Donepezil
may increase ACh synthesis and release
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
what is the metabolism of Donepezil
metabolism is through acetylcholinesterase activity, thus no major drug interactions
what is the mechanism of Memantine
NMDA receptor antagonists
blocks pathological activation of NMDA receptors
thought to reduce excitotoxicity
what are the common side effects of Memantine
Dizziness, headache, constipation, confusion
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
what antioxidants are used in the treatment of Alzheimers
Vitamin E and Selegeline
why is Vitamin E important
lipid soluble antioxidant
scavenges damaging free radicals
limited effectiveness, difficult to monitor
what is selegeline
MAO inhibitor in Striatum
has neuroprotective effect (antioxidant?)
what is the treatment for behavioral effects of alzheimers
antipsychotics
anxiolytics
antidepressants
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
what are the common types of epilepsy
idiopathic and symptomatic
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
how is idiopathic epilepsy treated
with antiseizure drugs or vagal nerve stimulation
what is symptomatic epilepsy
caused by illict drug use, tumor, head injury, hypoglycemia, meningeal infection or withdrawal from alcohol
how is symptomatic epilepsy treated
antiseizure drugs and vagal nerve stimulators used to treat as well as treating the underlying cause
what are the subtypes of seizures
partial and generalized
what are partial seizures
conciousness preseved entirely or partially
simple vs complex
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
what is complex partial seizures
consciousness altered/no memory
exhibits complex sensory hallucinations and mental distortion
what are the categories of generalized seizures
tonic-clonic
absence
myoclonic
status epilepticus
infantile spasm
what is generalized seizures
consciousness lost / no memory
what is generalized tonic - clonic seizures
loss of consciousness, followed by tonic and clonic
what is tonic
continuous contraction
what is clonic
rapid contraction and relaxation phases
what is generalized absence seizures
brief abrupt self limiting loss of consciousness. may stare and exhibit rapid eye blinking lasting 3-5 seconds
what is generalized myoclonic seizures
short episodes of muscle contractions that may recur within several minutes
what is status epilepticus
two or more seizures occur without recovery of full consciousness between them. LIFE THREATENING
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
what is the MOA for Benzodiazepines
bind to GABA inhibitory receptors to reduce firing rate
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
what is the benefit of Lorazepam
shorter half life - but stays in the brain longer than diazepam
what is the benefit of Diazepam
available for rectal administration to avoid or interrupt prolonged generalized tonic-clonic seizures or clusters
what population is diazepam typcially used in
childen and patients with AMS
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
what are carbamazepine used for
effective for treating partial seizures and secondarily generalzied tonic-clonic seizures
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
how is carbamazepine metabolized
absorbed slowly and erratically following oral administration, resulting in large variations of serum concentration
what is Ethosuximide
effective in treating primary generalized absence seizures
what is the MOA for ethosuximide
reduces propagation of abnormal electrical activity in the brain, most likely inhibiting T-type calcium channels
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
what is Gabapentin approved for
approved as adjunct therapy in partial seizures and for treatment of postherpetic neuralgia
when is gabapentin dose reduced
patients with renal disease - does not bind to plasma proteins and is excreted unchanged through the kidneys
what is the MOA for Lamotrigine
blocks sodium channels as well as high voltage dependent calcium channels
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
what other conditions are treated with Lamotrigine
bipolar disorder
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
when lamotrigine is used in combination, what is important to remember
reduce doing if given in combination
what are serious adverse reactions to lamotrigine
SJS
overall tolerated by elderly with partial seizures due to relatively minor effects
what is Levetiracetam approved for
adjunct therapy of partial onset seizures, myoclonic seizures and primary generalized tonic-clonic seizures in adults and children
how is Levetiracetam metabolized
does not interact with CYP or UGT metabolism systems
well absorbed orally and excreted in urine unchanged
what are the side effects of levetiracetam
dizziness, sleep disturbances, headache and weakness
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
what is oxcarbazepine approved for
use in adult and children with partial onset seizures
what are the adverse effects of oxcarbazepine
N/V, headaches, visual disturbances
what is the MOA for phenobarbital
enhancing the inhibitory effects of GABA-mediated neurons
what should phenobarbital be used for
primarily for the treatment of status epilepticus
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
what treatments are phenytoin and fosphenyotin used for
treatment of partial seizures and generalized tonic-clonic seizures and in the treatment of status epilepticus
how are phenytoin and fosphenytoin metabolized
induces drugs metabolized by the CYP2C and CYP3A families and the UGT enzyme system
