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
