Week 4: Parkinsons, Dementia Flashcards
parkinsonism
any disordewr presenting with classic signs and symptoms; usually secondary to some other factor
parkinson disease
idiopathic form of parkinsonism
PAtho of parkinsons disease
dopamine deficiency
causes imbalance btw. inhibitory dopamine and excitatory acetylchaline
2 primary patho features:
*loss of dopamine producicing cells in substantia niagara
*formation of lewy bodies in remianing substantia niagara
requires 80% of nigral cell death before disease manifests clinically
dx of parkinsons disease
bradykinesia: slowness and difficulty initiating voluntary movement …
and atleats 2 of the following
rigidity: usually begins unilateraly and then progresses
resting tremor
pustural instability: stooped forward
other causes of parkinsonism
drug induced: such as APS.
other neurodegenerative conditions
toxins: CO poisening, manganeses, hydrogen sulfide
neoplasms, stroke
bradykinesia
early signs may be isolated to distal muscles.
might start out with having trouble writing etc.
facial masking
motor acts become increasingly difficult
freezing can occur
clinical presentations of parkinsons disease besides primary
autonimic:
bladder and anal sphincter
constipation
diaphoresis
mental changes:
confusion
dementia
psychosis
main aproaches to parkinsons disease treatment
increase endogenous dopamine
decrease cholinergic activity
activate dopamine receptors using synthetic agonists
Anticholinergics used in Parkinsons disease
examples
indication
MOA
AE
examples: Benztropine (cogentin), Trihexylphenidyl (artane)
indication: used to decrease tremors in Parkinsons disease
MOA: antimuscuranic
AE: ANTIcholinergic SE
blind as a bat (mydriasis)
dry as a bone: (dry skin)
hot as a hare (fever)
mad as a hatter (depressed/altered mental status)
red as a beet (flushed skin)
MEdications that increase endogenous dopamine
Levodopa
Carbidopa
COMT inhibitors
MAOB-I
Amantadine
LEvodopa
examples
dosing
indication
MOA
pk/pd
CI
AE
ddi
examples
dosing: start 200-300mg/day in divided doses, 100 BID or TID
indication:
MOA:precursor to dopamine, crosses BBB
pk/pd: extensively broken down in periphery, carbidopa prevents breakdown
CI: breast feeding, closed angle glaucoma, melanoma??
AE:
*dyskenisia: choreiform and dystonic reactions, esp. at high doses or prolonged use
*“on-off phenomena, decreased effectiveness overtime
*GI effects(due to activation of dopamine receptors in the gut)
*orthostatic hypotension
*saliva, sweat, or urine discoloration
*Neuroleptic malignant syndrome (NMS) w. abrucpt d/c
DDI: dopamine antag (metoclopramide, APS)
non selective MAOI’s
high protein intake decrease absorption
iron salts
pyridoxine
Levedopa considerations for parkinsons
Gold standard for parkinsons treatment
precursor to dopamine
AE: dyskenesia, decreased efficacy over time, ortho HTN, saliva, sweat, urine discoloration
DDI: dop. antag such as metaclopramide, non selective MAO’s decreased absorp. w. high protein intake, iron salts, pyroxidine
CArbidopa
examples
dosing
indication
MOA
pk/pd
CI
AE
ddi
examples: CArbidopa/Levadopa (Sinemet, Sinement CR)
dosing: maintain carbidope dose 70-100mg/day
*available ratios: 1:10 or 1:4
indication
MOA: noncompetative dopa decarboxylase inhibitor: inhibits peripheral l-dopa metabolism
pk/pd: does not cross BB
CI: pregnancy, lactation
AE
ddi
Sinemet CR considerations
decrease “off time” and decreased dosing frequency
decreased bioavailability
delayed onset of affect, esp. when taken in morning: time to peak 2hrs vs 30 min for IR: can dose IR and CR in the morning , or set alarm 30-60 min
or can haelp w. morning rigidity if taken at bedtime
Inbrija Considerations
levadopa powder for inhalation
indication: used for treatment of off episodes in pts. being treated with sinemet
NOT a replacement
COMT inhibitor considerations
moa: prevents breakdown of levadopa
no acitivty in absense of levadopa
Entacapone(Comtan)
*no CI
*same SE as levadopa: dyskenesia, decreased efficacy over time, ortho HTN, saliva, sweat, urine discoloration
*may produce brown/orange urine
stalevo is carbi/levo/enta drug: 1:4:200mg
Tolcapone (Tasmar)
*CI in hepatic disease
*no diff in effectiveness btw. entacapone and it.
MAO-B inhibitors
examples
dosing
indication
MOA
pk/pd
CI
AE
ddi
examples: Selegline, Reseligine
dosing
indication: ADJUNCTIVE TO L-dopa for wearing off symptoms
MOA: noncompetitive selective antagonists of monoamine oxidase type b. decreases break down of dopamine. (MAO-A activation causes serious tyramine reactions such as hypertensive crisis, so nonselective maos are not preffered)
pk/pd
CI
AE
ddi
MAO-B considerations
selective MAO-B inhibitors
Rasagiline has potential disease-modifying
when used in combo w. L.dopa, pts can reduce ldopa dose
Selegeline:
*active amphetamine metabolites: insomnia, jitteriness, anorexia
CNS, GI
*htn crisis(at higher doses due to loss of selectivity)
Rasageline
*possible disease modifying
*does not have amphetamine metabolites
*CNS and GI symptoms
*orthostasis
New drug: Safinamide (Xadago)
*same SE and CI
Amantadine considerations
*Symmetrel, Gocovri, Osmolex)
*poorly understood MOA
*DECREASES L-DOPA INDUCED DYSKENESIA as an add on
*renal adjustment
*precautions: exac. CHF, orthostatic hypotension, peripheral edema
AE:ortho htn,dizziness, falls
hallucinations
anticholinergic AE
NMS w. abrupt
*livedo reticularis-mottling of skin w. LE edema
Drugs that act as dopamine agonists
dopamine agonists use considerations
can be used as monotherapy esp. in younger, healthier pts.
START LOW AND GO SLOW
reduced risk of developing motor complications liek bradykinesia
can also be used as adjunctive agents in case ofdeteriationin response to l-dopa
*most common N/V, vivid dreams, daytime sedation, orthostatic hypotension, impulsive behaviors and psychosis
List of dopamine agonists
pramipexole (Mirapex)
Ropinirole (Requip)
Bromocriptine (Parlodel)
Pergolide (Permax) WITHDRAWN
Cabergoline
Rotigotine
Apomorphine (apokyn)
pramipexole considerations
most commmon dopamine agonist
renal adjustment Crcl<60
DI w. cimetidine
START LOW AND GO SLOW with dosing
Ropinirole considerations
*cyp1a2 substrate
*IR&ER formulation
Bromocriptine (Parlodel) considerations
*also used for hyprprolactinemia more so
CI: in breast feeding, eclampsia, ergot alkaloid sensitivity, uncontrolled HTN
DI: *antihypertensive agents (decrease effectiveness)
Ritogotine considerations
*transdermal patch
*should not be worn in an MRI machine, can cause skin burns
*same AE: as other dopamine agonists, also aplication site reaction
Apomorphine (Apokyn)
used in advanced parkinson disease prn for off episodes
needs a 2 mg test dose under medical supervision
monitor BP predose, and 20,40,min and 60 min
*pretreat with antiemetic 3 days before and continue for 2 months. NOT 5HT3 ANTAGONISTS OR ANTIDOPAMINERGIC. CONTRAINDICATEDDDD
*can cause qt prolongation: added
nonpharm treatments of parkinsons disease
phsyical therapy and exercise (boxing and tai chi)
surgery:deep brain stimulation
adequate fluids and fiber can prveent constipation
omega-3 fatty acids
accupational therapy and fall precautions
evaluation a patiens response to levadopa
stage I: patient not aware of variation in the effect of an individual dose
stage II: midafternnoon loff of benefit requirs additional dose
stage 3: good response to levadopa, sleep benefit is lost eaely morning akinesia appears
stage 4: regular “wearing off” q4hrs or more hours then levodopa response gradually worsens
stage 5: wearing off from each dose of levodopa as well as abrupt “off periods’ pts require dosing at intervals of 2 hrs or less
long term complications of levodopa
fluctuations in motor performance
wearing off phenomenom, end of dose deteriation
peak effect dyskinesia
dyskinesia or abnormal involuntary movement
when to start L-dopa?
controversy
l.dopa therapy associated w. motor complications,
not a clear reference on whether or not to delay ldopa initaition as much as possible until its absolutely needed , or use it early on due to great benefits and relatively inexpensive
motor complications of Parkinson disease and PD treatment
wearing off response
peak effect dyskinesia
delayed onset
off,no on
off period dystonia
diphsaic dystonia
unpredicatble off
bebginning of dose deterioration
freezing
nonmotor complocations of PARkinson disease and PD treatment
psychosis
anxiety and depression
dementia
sleep disturbances
somnolenceorthostatic hypotensino
sweating episodes
sexual dysfunction
constipating
urinary incontinance
mangement of motor complications
“on-Off”
On-Off: Increase frequency dosing before choosing to increase dose
switch to CR
add adjunctive agents such as DA ag/ MAOI/COMT/amantadine
mangement of motor complications
off- no on
look to see possibledelayed absoprtion
take med on empty stomach
increase dose, frequence,
use ODT
a pt w. advance disease
sub q apomorphine
mangement of motor complications
delayed onset
empty stomach, water, avoid protein
if on CR, can consider switching off CR or adding IR
mangement of motor complications
peak efectc dyskenesia
dec dose
inc frequency
add amantadine
use CR sinemet, or switch to DA agonsit(have less risk of bradylinesia)
mangement of motor complications
dsytonia (painful cramping)
often occurs at early morning
give sinement at bedtime
mangement of motor complications
freezing
increase dose
add DA agonist
gait modification/ physical therapy
management of non motor symptoms
depression
pramipexole (clinically useful)
SSRI’s (possibly useful)
venlafaxine (clinically useful)
management of non motor symptoms
dementia and cognitive impairment
ACH: esterase inhibitors such as Rivastigmine
management of non motor symptoms
insomnia
eszopiclone
melatonin
management of non motor symptoms
excessive daytime somnelence
modafnil
management of non motor symptoms
orthostatic hypotension
fluticortisone
midodrine
droxidopa
management of non motor symptoms
sexual dysfunction
sildenifil
management of non motor symptoms
urinary frequency
solifenacin
management of non motor symptoms
drooling
glycopyrrolate
botox
apprach to psychosis in PD
- evaluate hypoxemia, infection, electrolyte disturbance
- simplify regimen
*d/c meds w. highest risk such ass…
a. anticholinergics (benztropine, oxybutinin)
b.taper and d/c amantadine (abrupt withdrawal can cause delerium
c)selegiline (from amphetamine like metabolites)
d. taper and d/c agonists
consider d/c l.dopa
3.consider atypical APS such as
*quetiapine
clozapine
pimavanserin tartrate (nuplazid): specifically indicated for parkinsons related psychosis. inverse agonist of 5HT2A/2C
BBW: increased death in elderly in pts. with dementia
demntia
syndrome characterized by progrressive decline of intellectual ability from a previous attained level
involves varibale deteriation from speech, memory, judgement, and mood
what is alzheimers disease
progressive neurodegenerative disease affecting cognition, behavior
most common form of dementia
AD patho
brain atrophy with ventricular enlargement
degeration of cholinergic and other neurons
absent or minimal vascular disease
signs of AD are first noticed in the entorhinal cortex, then proceed to the hippocampus
memoryloss is the first sign of AD
anyloid plaques and neurofibrillary tangles form as well
mild signs of AD
memory loss, confusion, trouble handling money, poor judgement, mood changes, and increased anxiety
moderate signs of AD
increased memory loss and confusion , problems recognizing ppl, difficulty w. language and thoughts, restlessness, agitation, wandering, and repetitive statements
severe AD
extreme shrinkage of the brain
wieghtloss, seizures, skin infections, groaning moaning, grunting, increased sleeping, loss of bladder and bowel control
differential dx of dementia
alzheimers disease: 70%
multi-infarct dementia-10-20%:
brain tumors: 5%
unkown causes: 10-15%
10 warning signs of alzhemiers disease
problems w. words in speaking or writing
misplacing things and losing ability to retrace steps
decreased poor judgement
withdrawal from work or social acitivites
changes in mood or personality
memory loss that disrupts daily life
challenges in plNNING or solving problems
difficulty completing familiar tasks
confusion with time or place
problems w. visual images and spatial relationships
evaluation for AD
- history
- physical and neurologic examinations
- screening lab studies (CBC, chem panel, TSH, syphillis, UA, b12 and folate levels, chest xray, EKG, CT scan
- neuroimaging (MRI OR CT)- MRI superior. used to rule out other sources of cholinergic hypothesis
anticholinergic effects in alzheimers disease
concentrations of acetylcholine are markedly decreased in AD
anticholinergic effect
blind as a bat (mydriasis)
dry as a bone (dry skin and mouth)
hot as a hare (fever)
mad as a hatter (depressed/agitated mental status)
red as a beet (flushed skin)
other anticholinergic meds
Sleep medications (diphenhydramine)
* Antihistamines (diphenhydramine)
* Certain bladder medications (oxybutynin)
* Certain pain medications (codeine)
* Antiemetics/antivertigo (meclizine, scopolamine, promethazine,
prochlorperazine)
* Medications for Parkinson’s disease (benztropine, trihexphenidyl)
* Gastrointestinal (GI) antispasmotics (belladonna, clindinium,
hyoscyamine, scopolamine)
* Tricyclic antidepressants (TCAs) (cyclobenzaprine, amitriptyline)
* Typical antipsychotics (chlorpromazine, thioridazine)
* Atypical antipsychotics (clozapine)
non pharm treatment for AD
comprehensive techniques (memory books)
environmental adaptations
case manegement
exercise programs, occupatinoal therapy
psych education/ psychotherapeutic approaches, cognitive rehabilitation
caregiver support groups, counseling
alzheimers association
the 36 hr day
respite/day care
advanced directives, power of attorney, living will, DNR orders, healthcare proxy
pharm treatment of AD symptoms
acetylcholinesterase inhibitors
moa:
AE
moa: block acetylcholinesterase, block metabolism of Ach
AE:
cholinergic SE:
SLUDGE
siallorhea
LAcrimation
urination
defacation
GI(emesis, diarrhea)
Emesis
cns: headahce, insomnia, vivid dreams
cardiac: bradycardia, syncope, heartblock, hypotension
CI: in pts with bradycardia/ known conduction system disease
pharm treatment of AD symptoms
Donepezil considerations
*cns selective noncompetative, reversible AchE-i
for mild-severe
indicated for all 3 stages of AD (mild mod. severe)
1 tab @bedtime w. or w.o food
met. by 2d6 and 3a4
lmost likely to be titrated to max dose and least likely to be d/c due to cost
less likely to cause GI effects and more likely to cause sleep sleep disturbances
pharm treatment of AD symptoms
Rivastigmine (Exelon) considerations
*cns selective, non competitve reversible ACHEi
*available in capsules and patches
poor tolerabi;oity
capsule:must start low and titrated slowly to prevent gi disturbances
start at 1.5 mg bid, increase 3 mg q2w
patch dosed 4.6 mg/24 hrs initially and hsould be increased to 9.5 mg/24hrs
can cause site reactions, rotate patch. can be used chest, upper and lower back and upper arms
higher rates of d/c
how to switch from rivastigmine capsule to patch
<6mg of oral R.= exelon patch 4.6 mg/24hrs
6-12 of ral R: exelon 9.5 mg/24hrs
pharm treatment of AD symptoms
Galantamine considerations
cns selective competitive reversible ache-i; modulates nicotinic ach receptor to increase ach from surviging presynaptic nerve
available in tablet, ER capsule, solution
metabolized by cyp2d6 and 3a4
AChE-I
Donezepil
Rivastigmine (Exelon)
Galamantine (Razadyne)
ACHE-I considerations
d/c other anticholinergic drugs
slection based on ease of use, individual tolerability, cost and pt preference
not disease modifying, just for symptomatic improvement
NMDA receptor antagonists
Memantine considerations
NMDA receptor antagonists: nmda sustained low level activation in AD cause neuronal damage and loss, and cholinergic deficit
approved for mod-severe stages
NOT disease modifying
use in caution w. pts with seizure disorders or CV disorders
IR dose :
initial 5 mg: 5mg/wek titration
target dose 20 mg
ER:
start 7 mg
target dose: 28 mg: tmg/day titration’
if renal impairment (5-29mL/min): IR: MDD 5 mg bid
ER: target dose 14 mg qd
AE: cv effects
constipation
Namzeric considerations
Memantine ER+donezepil
taken in evening w. or w.o food
do not divide/crush/chew
pts must be on donezepil 10 mg to be eligible for this combo
management of confusion, agitation and behaviors
non pharm:
*provide structure and routine
*follow regular predicatable routines
*encourage pleasant activities
participate in activities they used to enjoy
keep things simple
pharm treatment
behaviors
*non drug approaches
*antidepressants, anxiolytics, APS, AED
sleep changes
*TCA’s, benzos, sedative/hypnotics, APS
avoid anticholinergic, benzos, sedative hypnotics
emerging therapies for AD
Riluzole: small gutamatergic agent.
antisense technology: IONIS-MAPTRX reduce tau protein production, to decrease
antiinflammatory agents
