Pharm: Mvmt Disorders Flashcards
Levodopa
- Dopa precursor - enters the BBB via L-amino acid transporter (LAT)
MOA: stimulates D2 receptors
PK: only 1-3% of dose reaches brain unaltered where it is metabolized extracerebrally through decarboxylation
– combination w/ dopa decarboxylase inhibitor (carbidopa), reduces peripheral metabolism of levodopa, resulting in higher plasma levels with longer t1/2 and increased availability to enter the CNS – co administration w/ carbidopa decreases daily requirement of Levo by 75%
USE:
- does not stop progression of PD, but may lower mortality w/ early initiation
- Best results obtained in first few years. Benefits diminish after 3-4 years of therapy
- 1/3 of pts. respond very well
ADR’s:
- GI: w/out add’n of carbidopa - 80% have anorexia, nausea, vomiting d/t activation of chemoreceptor trigger zone located in the brainstem outside the BBB
- CV: postural hypotension - tachycardia and A fib
- HTN can occur when combined with MAOIs
- Behavioral: depression, anxiety, agitation, insomnia, confusion, delusions, nightmares, euphoria
- Dyskinesia: occurs in 80% of pts. receiving Levodopa for >10 years: choreathetosis
Carbidopa
- dopa decarboxylase inhibitor which reduces peripheral metabolism of levodopa - resulting in higher plasma levels and increased availability for CNS entry
Carbidopa/Levodopa
- “sinemet”
MOA: stimulates D2 receptors
** PK: – combination w/ dopa decarboxylase inhibitor (carbidopa), reduces peripheral metabolism of levodopa, resulting in higher plasma levels with longer t1/2 and increased availability to enter the CNS – co administration w/ carbidopa decreases daily requirement of Levo by 75%
USE:
- does not stop progression of PD, but may lower mortality w/ early initiation
- Best results obtained in first few years. Benefits diminish after 3-4 years of therapy
- 1/3 of pts. respond very well
ADR’s:
** - GI effects occur in 10 years: choreathetosis
Bromocriptine
- D2 agonist
MOA:
- acts directly on postysynaptic dopamine receptors and does NOT require enzymatic conversion to active metabolite
- no toxic metabolites, don’t compete w/ other substances for transport across BBB
USE:
- ** 1st line therapy for PD - Use assoc. w/ lower incidence of dyskinesias that occur w/ long-term levodopa therapy
- if don’t respond well to levodopa, won’t respond well to this
- can be used w/ carbidopa/levodopa
NOTE: ** also approved for endocrine disorder tx ***
Pramipexole
- D3 agonist
MOA:
- acts directly on postysynaptic dopamine receptors and does NOT require enzymatic conversion to active metabolite
- no toxic metabolites, don’t compete w/ other substances for transport across BBB
USE:
- ** 1st line therapy for PD - Use assoc. w/ lower incidence of dyskinesias that occur w/ long-term levodopa therapy
- if don’t respond well to levodopa, won’t respond well to this
- can be used w/ carbidopa/levodopa
PK; 90% excreted in urine - renal impairement dose adjustment
** NOTE: also approved for RLS tx **
Rasagiline
- Monoamine Oxidase Inhibitor (MAOI’s):decreased metabolization of dopamine
MOA: irreversible inhibitor of MAO-B - more potent!
Use: neuroprotective agent for early symptomatic tx of PD
DDI’s: must NOT be used w/ levodopa d/t HTN crisis (d/t accumulation of NE)
Entacapone
- Catechol-O-Methyltransferase Inhibitor (COMT)
MOA:
- inhibition of dopa decarboxylase (w/ carbidopa) is assoc/ w/ compensatory activation of other pathways of levodopa metaoblism, especially through the COMT pathway which increases levels of 3-O-methyldopa (3OMD)–> this competes w/ levodopa for transport across BBB, resulting in less effective BBB
- ** Entacopone prolongs the action of levodopa by diminishing peripheral metabolism (decreaseing clearance and increasing bioavailability) through inhibiting COMT
USE: useful in pts. who have developed response fluctuations do levodopa/carbidopa
- entacapone has peripheral effects only
ADR’s: increased levodopa exposure; may cause diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, orange colored urine
Benztropine
- antimuscarinic agent
MOA: centrally acting mACHR antagonist
USE: may improve tremor and rigidity of PD but little effect on bradykinesia
** useful if <70 y/o w/ tremor as sole problem
ADRs: sedation, mental confusion, constipation, urinary retention, blurred vision
athetosis
abnormal mvmts which are slow and writhing
dystonia
sustained athetosis; regarded as abnormal postures
DDI’s of Levodopa?
- Pyridoxine (Vit B6) - increases extracerebral metabolism - may prevent therapeutic effect unless peripheral decarboxylase inhibitor also given (carbidopa)
- MAOIs: cause HTN - do NOT give if taking MAOI’s
CI’s of Levodopa?
- angle closure glaucoma (may produce mydriasis)
- psychosis
- active PUD
- malignant melanoma (levodopa is precursor to melanin)
ADR’s of Dopamine agonists?
- Bromocriptine
- Pramipexole
- Ropinirole
- Rotigotine
- Apomorphine
- GI: anorexia, nausea, vomiting
- CV: pstural hypotension
- Dyskinesias: may be reduced by lowering dose
- Mental disturbance: confusion, hallucinations, delusions - disorders of impulse control (i.e. gambling, shopping, sex)
- Miscellaneous: h/a, nasal congestion, increased arousal
CI’s to dopamine agonists?
hx of psychotic illness, recent MMI, active PUD
clinical pharm of PD?
- benefits of levodopa diminish w/ time;
- only begin to tx when sx impact pt. lifestyle
when tx necessary:
1. Use trial of rasagiline (MAOI), amantadine (antiviral) or benztropine (antimuscarinic) in young people
Disease progression reqs dopa therapy….
- dopamine agonist +/- low dose Sinemet
- alternatively just use Sinemet at higher dose
- if have severe disease/ long term problems w/ levodopa therapy try Entacapone (COMT inhibitor) or rasagaline (MAOI)
Patients < 65 years old
- Dopamine agonist
Patients ≥ 65 years old
- Levodopa
MAO B Inhibitors
- Reasonable in early PD; modest benefit as monotherapy
Anticholinergic drugs
Useful if < 70 years old, with tremor without significant bradykinesia or gait disturbance
Amantadine
Relatively weak; may be useful in young patients with early/mild PD
tx of tremor?
- B blockers (to block the B1 receptor) - NOTE: don’t use with asthma or CV disease
- propranolol (nonselective)
- metoprolol (selective: best for pts. w/ lung problems) - antiepileptic drug primidone in small doses
- topiramate anticonvulsant drug
- alprazolam (benzodiazepine) and IM injections of botulinum toxin A
tx of HD?
development of chorea most likely d/t imbalance of dopa, ACh, GABA in basal ganglia ( thus want drugs that decreased dopa)
- Reserpine/tetrabenazine: block the monamine transporter and deplete cerebral dopamine stores!
- Olanzapine, perphazine, haloperidol : all block dopamine receptors
Reserpine
block the monamine transporter and deplete cerebral dopamine stores!
tx for HD
Tetrabenazine
block the monamine transporter and deplete cerebral dopamine stores!
tx for HD, Tics
Olanzapine
blocks dopa receptors: tx for HD
Perphazine
blocks dopa receptors: tx for HD
haloperidol
blocks dopa receptors: tx for HD, Tics
tx of tics?
- neuroepileptic antipsychotics (tetrabenazine, haloperidol, pimozide) - not always first choice d/t w/g, sedation, irribatility, phobias
- alpha adrenergic agents: clonidine: not yet FDA approved
- injection of butulinum A
tx of RLS?
- make sure that iron is corrected if have deficiency
- first line: pramipexole and ropinerole (dopamine agonists)
- respond to dopamine agonists, levodopa, diazepam (benzo), clonazepam, opiates
