Pharm 33 - Movement disorders Flashcards
Goal of AD treatment is to…
improve symptoms and reduce/slow cognitive decline
No available drugs can currently stop or reverse cognitive decline
Drugs approved for AD
three cholinesterase inhibitors: donepezil, galantamine, rivastigmine
memantine: blocks neuronal receptors for N-methyl-D-aspartate
clinical uses of cholinesterase inhibitors
- myasthenia gravis
- reversal of neuromuscular blockade (neostigmine)
- antidote (physostigmine) for poisoning due to muscarininc antagonists (atropine toxicity)
Common/general ADE of cholinesterase inhibitors
- Gastrointestinal:
Nausea, vomiting, dyspepsia, diarrhea. - Dizziness and headache.
- Bronchoconstriction
- Bradycardia, fainting or falls.
Severe acute toxicity of cholinesterase inhibitors
SLUDGE and killer B’s
Salivation Lacrimation Urination Diaphoresis/diarrhea Gastrointestinal cramping Emesis
Bradycardia
Bronchorrhea
Bronchospasm
Donepezil use
mild, moderate, severe AD
MOA of donepezil
reversible inhibition of cholinesterase
ADE of donepezil
N/D
Bradycardia
Fainting, falls, fall-related fractures
mild, moderate, severe AD drug
donepezil
mild to moderate AD
galantamine
MOA of galantamine
reversible cholinesterates inhibitor
ADE of galantamine
N/D/V Weight loss Anorexia Bradycardia Bronchoconstriction Fainting, falls, fall-related fractures
galantamine use
mild to moderate AD
mild, moderate, or severe Alzehimer dementia and parkinson-related dementia
rivastigmine
clinical utilitzation for AD: put these drugs in order of utilization
rivastigmine
donepezil
galantamine
donepezil»_space; rivastigmine > galantamine
MOA Rivastigmine
Irreversible inhibition of cholinesterase.
more likely to cause toxicity; 10 hour duration in CSF
ADE of Rivastigmine
MORE GI effects than the others:
Nausea, vomiting, diarrhea, abdominal pain, anorexia; may cause undesired weight loss.
Worsening of peptic ulcer disease
Also: bradycardia, urinary obstruction, lung disease, fainting, falls, and fall-related fractures
Memantine MOA
An N-methyl-d-aspartate (NMDA) receptor antagonist; reduces the persistent over-activated state in AD
Memantine use
for moderate to severe AD
Better tolerated than cholinesterase inhibitors.
Somewhat irrelevant….
almost always used in combination of cholinesterase inhibitors
Memantine ADE
Dizziness, headache, confusion
Constipation
use of antipsychotic drugs in AD population will result in…
- A 9-fold risk of stroke in the first four weeks of antipsychotic drug use
- Almost a doubling in the risk of mortality
Other approaches to behavioral disturbances that occurs with “sun-downing” AD patients
- lifestyle approaches: activities, reminiscence therapy, social interaction
- antidepressants to reduce agitation/treat apathy
Primary parkinsonism drug MOA’s
- increase dopamine concentration and availability in the brain
- directly stimulate dopamine receptors
- inhibit cholinergic neurotransmission
- adenosine antagonists
Why can you not just give dopamine to treat PD?
- does not readily cross the BBB
- poorly tolerated
- very short 1/2 life as metabolized by COMT, MOA-B, convereted to NE by dopamine hydroxylase
- causes peripheral, dose-limiting pharmacologic effects
Best way to replace dopamine in the brain
give a dopamine precursor, to be converted to dopamine in the brain
L-DOPA MOA
L-DOPA is converted to dopamine by DOPA decarboxylase.
- Peripherally–> gastrointestinal or vascular “side effects.”
- Within the CNS–> therapeutic effects and CNS “side effects.”
DA can then be synthesized and released as a neurotransmitter
purpose of carbidopa (decarboxylase) when combo’d with levodopa
prevents L-DOPA conversion to dopamine in the peripheral to prevent the ADE in the GI tract (NAUSEA)
what is the daily dose of carbidopa to sufficiently inhibit DOPA decarboxylase
Carbidopa doses of 70-100 mg/day
how do you minimize wearing off of the levo-carbidopa (3 ways)
- shorten the dose interval (more frequent dosing)
- give drug that prolong’s plasma 1/2 life
- adding a direct-acting dopamine agonist
an acute loss of effects of levo/carbiodpa can occur. to combat this, give a rescue therapy drug…
apomorphine
what part of the diet inhibits L-DOPA oral absoroption
dietary protein
what dietary component increases DOPA-decarboxylase acitivity
Vitamin B-6: pyridoxine
disadvantages of Carbi/levo
- multiple doses per day
- orthostatic hypotension
- nausea
- high rates of ADE
ADE of carbi/levo
hallucinations nausea vomiting hypotension dizziness
unusal ADE of carbi/levo
- can activate malignant melanoma
- discoloration of urine/stool (harmless)
- problems with impulse control
- drug induced dyskinesia
dopamine receptor agonist classes
ergot derivatives
non-ergot (only group indicated for monotherapy)
advantages of direct dopamine receptor agonism
- active agents do not require metabolic conversion
- longer t1/2 than levodopa (minimizes wearing off)
- can be used as monotherapy or in combo with L-DOPA
- no dietary protein complications
- lower incidence of response failure (if not responsive to L-DOPA)
disadvantages of direct dopamine receptor agonism
- must start at low dose and increase SLOWLY
- same ADE of L-DOPA, plus: increased rates of somnolence, sleep attacks, psychosis, compulsive behavioral activities
bromocriptine
ergot derivative for dopamine receptor agonism
- ADE: high incidence with N/HA/dizziness most common
- very long time to titrate dosing up (at 2-4 week intervals –> can take months)
pramipexole
oral non-ergot DA receptor agonists
- may be used early in therapy as monotherapy
- como’d with Carbi/levo in advanced disease
- renally eliminated
ropinorole
oral non-ergot DA receptor agonists
- may be used early in therapy as monotherapy
- como’d with Carbi/levo in advanced disease
- hepatic eliminated
apomorphine
A derivative of morphine but devoid of typical opioid effects (for example, NO analgesia, euphoria, respiratory depression)
Used clinically as a “rescue” therapy for acute akinesia
apomorphine special property
very strong emetic - severe N/V is common and need to be administered with antiemetics
apormorphine ADE
hypotension
daytime sleep attacks
Most common ADE of dopamine agonists (ergot and non-ergot)
CV: postural hypotension, peripheral edema, dysrhythmias
GI: N/V, anorexia, constipation, dyspepsia
Dyskinesia ESP in combo with L-DOPA
severe mental disturbances: confusion, hallucinations, impulse control disorders, spontaneous sleep
Benefits of COMT inhibitors
add entacapone or tolcapone to prolong the effects of L-DOPA
CANNOT be given as monotherapy
MOA of COMT-I
prevents degradation of L-DOPA, and other monoamines
COMT-I ADE
brownish urine discoloration
diarrhea
liver toxicity
COMT-I monitoring
LFT’s
worse hepatotoxicity of the COMT-I’s
tolcapone > entacapone
MOA-I place in parkinson’s disease treatment
adjunct with carbi-levo, esp. late in disease
can be monotherapy, but usually not selected for this due to greater benefits of carbi-levo
drug names of MAO-I
selegiline
rasagiline
safinamide
ADE of selegiline
metabolites are amphetamine and methamphetamine: can cause anxiety and insomnia
Most commonly used MAO-I
rasagline: dosed once, generic, no amphetamine metabolites, fewer ADE
role of antimuscarinic drugs in PD
used early in disease with younger patients with only/primary manifestation being tremor
will NOT improve bradykinesia with mediocre benefits for rigidity
antimuscarinics worsen what in PD
postural instability
dementia
constipation
then typical antimuscarinic side effects: dry mouth, urinary retention, blurred vision, confusion
amantadine place in PD treatment
response occurs within 2-3 days with a little less efficicay than with L-DOPA or dopamine agonists
responses can diminish in 3-6 months
amantadine role for PD common effects
helpful for dyskinesias caused by levodopa
causes stimulant-like effects to help with fatigue
toxicity of amantadine
renal toxicity –> renal adjustment required
ADE of amantadine
CNS: confusion, anxiety, lightheadness
Peripheral: blurry vision, urinary retention, dry mouth, constipation
Restless leg syndrome (RLS) may be due to…
may be due to IDA
How do you treat RLS?
dopaminergic supplementation or dopamine agonists: pramipexole or ropinirole or carbi/levo
how do you treat tremor
- r/o intentional tremor, rest tremor, drug causes, underlying CNS disorder
tremor pharmacologic treatments
- non-selective beta blocker (if not contraindicated)
- primidone
- topiramate
- gabapentin
- benzos
how to treat huntington’s disease
want to reduce over-activity:
- inhibit dopaminergic activity to alleviate chorea:
1. deplete central monoamines (riserpine)
2. dopamine receptor blockers (haloperiodl)
3. increased dopaminergic activity (levodopa supplementation) tends to exacerbate chorea
only FDA approved drug for treatment of chorea in HD
tetrabenazine
FDA boxed warning: depression and suicidality
treatment of tics
dopamine antagonism: haloperidol, pimozide, fluphenazine
secondly: clonidine, clonazepam, carbamazepine
wilson’s disease treatment
- chelating agents: deplete many minerals and vitamins in addition to copper
- restrict copper
- zinc supplement to decrease copper absorption
**only treated in specialty care
ALS treatment
spasticity: baclofen
first/only disease-modifying drug: riluzole –> prolongs life/time to tracheostomy by ~3months
treating acute attacks of MS
- make sure it’s a real attack and treat with IV high dose steriods 3-5 days (methylprednisolone)
- then oral prednisone or dexamethasone
dosing of steriods in acute attacks of MS
methylprednisolone 500-1000mg per day for 5 days
prednisone (oral) 625-1,250mg per day for 3-7 days
Concomitnat drug therapy with high dose steroids for MS treatment of acute attacks
benzos for bedtime to combat mood changes and insomnia
Li if manic
low salt diet to combat salt retention/HTN
H2RAs or PPIs for gastric distress
common treatments for MS patients in primary care:
- depression
- neuropathic pain
- drugs for spasticity/muscle spasms
- ataxia/tremor
- constipation
- bladder dysfunction
- UTI
- cognitive impairment
