Parkinson's Disease Drugs Flashcards
What are some motor symptoms of parkinsons?
Tremor, rigidity, bradykinesia (slowness of movement)
postural instability, speech, swallowing difficulty
What are some non-motor symptoms of parkinsons?
Constipation, restlessness, paraesthesia,
autonomic symptoms: dry mouth, urinary retention, erectile dysfunction, dec libido
Cold/hot intolerance
What are 5 theoretical ways to treat parkinsons?
give DA precursor
DA2 receptor agonist
MAOI + something
Release more DA
Remove Ach
Why does parkinsons occur?
There is an imbalance between DA and Ach, favouring Ach.
Causes excessive cholinergic activity = muscle rigidity, tremor
List the DA agonist types
Dopamine precursor w/ dopa-decarboxylase inhibitors (DDCi)
DA-R agonist
MAO-B inhibitor
COMT inhibitor
Apomorphine
Drugs that release DA
What are the three dopaminergic pathways?
Nigrostriatal pathway = motor control
Mesolimbic/mesocortical pathways (emotion/drug-induced reward)= midbrain to limbic system, inc nucleus accumbens and cortex
Tuberhypophyseal neurons (reg pituitary sec)= from hypothalamus to pituitary gland
What is levodopa?
Gold standard parkinsons treatment, favourable benefit to adverse effect profile (esp. in elderly w/ cognitive impairment)
Improve 2-3 wks, some need it for >6 months for therapeutic effect
What is the role of DOPA decarboxylase>
Responsible for the conversion of DOPA to dopamine in periphery
What is the role of COMT?
COMT is responsible for the breakdown of catecholamines due to the targeting of catechol groups
An important catechol = dopamine, noradrenaline, adrenaline
Why is levodopa given with a DDCi?
When levodope is given orally, DDC and MAO in gut convert (90%) L-DOPA to dopamine and metabolites—> only 10% of original dose (now active) gets into blood
In periphery (tissue plasma) —> DDC and COMT –> Convert further 90% of L-DOPA in DA and metabolites
BB = the presence of DDC will convert the remaining 1% of L-DOPA in DA, which will result in minimal DA binding to CNS DA receptors
List some ADRs associated with Levodopa
Anxiety, agitation, confusion, delusions (D2 hyperstim), hallucinations, depression, somnolence, nightmares
CV = hypotension (DA vasodilator), tachycardia, arrythmia (DA also hits B1)
GI = constipation, severe nausea, vomiting, anorexia, peptic ulcers
Other = dyskinesia, hypersexuality, unpredictable loss of mobility, lactation inhibit
What affect does DA have on prolactin and growth hormone?
A D2 block results in inc prolactin and dec GH
Inc DA –> inc GH, dec prolactin
How do D2 agonist effect impulse control?
2-3 fold inc in risk of impulse control disorders (Addiction)
Compulsive buying, pathologic gambling, binge-eating, compulsive sexual behaviour
What syndrome occurs with abrupt withdrawal of L-DOPA?
Neuroleptic malignant syndrome
Symp = fever, muscle rigidity, rhabdomyolysis, profuse sweating, tachycardia, tachypnoea, agitation
Explain some drug interactions associated with L-DOPA
Dopamine antagonists = antipsychotics (typicals)
Antihypertensive = DA is a vasodilator
MAO-A inhibitor = non-selective metabolite of monoamines
Ferrous sulphate = dec GI absorption
Anticonvulsants
How do antiepileptics work?
Block VGNaC in use dependent manner
Inc GABA
Inhibit glutamate and aspartate
What happens with prolonged L-DOPA therapy? (>2 yrs)
“On-off syndrome” = fluctuations of being symptom free “on” to full-blown parkinsons “off” during therapy (mins to hrs)
Why does on-off syndrome occur?
Dec in delivery of DA centrally
Alteration in sensitivity of DA-R
Variation in amount and rate of drug absorption
DA metabolite interference
What is the ‘waring off’ effect with long-term L-DOPA use?
L-DOPA’s duration of action shortens and patients become less responsive
List the relevant DDCi
carbidopa
Discuss DA-R agonists
Direct stimulate DA-R
differing affinities for DA-R
improve bradykinesia, rigidity
less effective than L-DOPA = due to fast adaption
List the ergot derivative DA-R agonists
Bromocriptine
Pergolide
Cabergoline
List the non-ergot derivative DA-R agonists
pramipexole
Rotigotine
Ropinorole
Which DA-R agonists carry a risk of fibrotic cardiac vulvopathy
pergolide or cabergoline
This is not seen in non-ergot derivates
Which DA-R agonist is associated with pulmonary fibrosis?
bromocriptine
Which DA-R is used to inhibit lactation?
Cabergoline = dec prolactin due to DA stimulus
Discuss Apomorphine
Used as anti-parkinsons drug = DA agonist, not structurally related to ergot alkaloids
Its a morphine derivative w/ little analgesic activity
A potent D2 agonist = extreme N/V and hypotension
Used in severely disabled by motor fluctations in L-DOPA
Which drugs irreversibly inhibit MAO-B?
Selegiline
rasagiline = more potent (5x more potent)
What is the MOA of rasagiline and selegiline?
irreversibly inhibit MOA-B –> indirect dopamine agonism
also blocks DA reuptake, antioxidant
Which drugs interact with Selegiline?
MAOi, SSRI (fluoxetine, sertraline), TCA’s, St Johns wort, linezolid, sumatriptan, pethidine –> inc mania risk, serotonin toxicity
^ need to discontinue selegiline for 2-5 wks before use
L-DOPA = reduce dose due to additive effect
Tyramine rich foods = tyramine reaction, less severe than with MAO-A inhibitors, relatively specific to NA, 5HT and drugs
Name the relevant COMT inhibitor and its MOA
Entacapone = inc lvls of DA and NA
C/I = hepatic failure
Is entacapone used alone?
No, entacapone is usually an adjunct to L-DOPA-carbidopa therapy, should dec L-DOP dose by 10-30%
Name the M-R antagonists used to treat parkinsons
Centrally acting:
Benztropine, benzhexol, biperiden, orphenadrine
List the ADRs of the M-R antagonists used in parkinsons
Atropine ADRs
dry mouth, constipation, urinary retention, blurred vision
cognitive impairment, hallucinations, memory loss
Which drugs can cause parkinsons?
Anything that takes DA
High risk = Antipsychotics, methyldopa, metoclopramide, tetrabenazine
Intermediate risk = verapamil (Take Ca2+ away –> affect C-type Ca2+ channels –> impair movement), valporate (VGNa+C block), lithium (mimic Na+, dec DA)
What is the MOA of local anaesthetics?
Use dependent block of voltage gated Na+ channels –> drug gains more access readily when channel opens
Depth of block inc with action of potential freq
What is the difference between Ester LAs and Amide LAs?
Ester local anaesthetics = cocaine, procaine, tetracaine (too much cause arrythmias and death)
Amide local anaesthetics = Cinchocaine, lidocaine, prilocaine, bupivavaine, benzocaine
Difference = amide LAs have longer half life due to CYP450 metabolism whilst ester LAs undergo metabolism by esterases which are found more abundantly
In which order do LAs block conduction?
Nociceptive/sympathetic transmission blocked first
small myelinated fibred > non-myelinated fibres > large myelinated fibres
less effective in acidic tissue
When considering the MOA of LAs, what is the loss of nerve function orders?
1) pain = fires the fastest
2) temp
3) touch
4) proprioception
5) skeletal muscle tone
as you up the dose`
