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72 Cards in this Set
- Front
- Back
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What are the features of Parkinsonism
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"BRIM"
Bradykinesia Resting tremor Impairment of balance Muscular rigidity |
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What is the cause of Parkinson's?
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Cause is unknown (idiopathic).
Loss of neurons in the substantia nigra pars compacta which provide dopaminergic innervation to the striatum. |
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What is the dopamine precursor? What is the rate limiting enzyme?
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AA precursor tyrosine
Tyrosine hydroxylase |
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How does tyrosine get to the brain?
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Phenylalanine, tyrosine, leucine are
transported by SYSTEM L across the BBB in a Na+ independent manner. |
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Give important molecules in
the pathway to Dopamine. |
L-Tyrosine-->tyrosine hydroxylase
L-DOPA--> DOPA decarboxylase Dopamine |
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How much L-DOPA is found in the brain?
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L-DOPA-->dopamine is so rapid that
L-DOPA levels in the brain are negligible |
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How do you dramatically enhance dopamine formation?
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give more substrate (L-DOPA) +
dopamine carboxylase |
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How is dopamine stored?
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Dopamine is stored in storage vesicles
via vesicular monoamine transporter 2 (VMAT2). |
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How is dopamine released?
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Release is is by exocytosis from presynaptic
membranes triggered by depolarization leading to Ca++ entry. |
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How is dopamine action terminated?
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1. Reuptake into presynaptic nerve terminal
2. Uptake into postsynaptic nerve terminal |
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How is dopamine metabolized?
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Sequential actions of COMT, MAO,
and aldehyde dehydrogenase |
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What is the principal metabolite of dopamine?
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HVA
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what are the important dopamine
receptors? |
D1 and D2 in the striatum
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what is the second messenger for D1?
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increase adenylyl cyclase via Gs
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what is the second messenger for D2?
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decrease adenylyl cyclase via Gi
increase K+ conductance decrease Ca++ conductance |
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What is the most prominent receptor for antiparkinson drugs?
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mostly on stimulation of D2 receptors
thought D1 may provide some benefit |
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How is the stratum connected to the substantia nigra?
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by neurons that secrete inhibitory GABA
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What is the source of dopaminergic neurons?
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Substantia nigra is the source.
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Where do the dopminergic neurons terminate?
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In the striatum and secrete inhibitory dopamine.
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What is the dopaminergic motor pathway?
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The nigrostriatal pathway from the substantia nigra to the striatum is a mutual inhibitory pathway that maintains a degree of inhibition over both the striatum and substantia nigra.
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How do the dopaminergic neurons fire?
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Tonically, sustaining influence on motor activity.
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What is destroyed in parkinson's?
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Neurons of the nigrostriatal pathway responsible for secreting dopamine in the striatum.
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How many neurons are destroyed?
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At least 70% are destroyed by the time
sx first appear (BRIM). 95% destroyed by autopsy. |
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What is secondary parkinsonism?
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*ANTIPSYCHOTICS (major action is to block dopamine receptors)
*following viral illness (rare) *multiple vascular lesions (rare) |
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What is the strategy of tx?
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*Restoring dopaminergic input in the basal ganglia
*Antagonizing the excitatory effect of cholinergic neurons *Reestablishing the correct dopamine/ACh balance |
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What drugs are dopamine precursors?
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Levodopa
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What drugs are dopamine receptor agonists?
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Ergot Dopamine Agonists
* BROMOCRIPTINE Non Ergot Dopamine Agonists "Ro, Ro, the Apo Pram" * PRAMIPEXOLE * ROPINIROLE * ROTIGOTINE * APOMORPHINE |
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What are the inhibitors of dopamine metabolism?
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MAOI
"Giline" * SELEGILINE * RASAGILINE Catechol-O-Methyltransferase Inhibitors "Capone" * Tolcapone * Entacapone |
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What class is Amatadine in?
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It does not belong in any class but has the same purpose as the previous drugs: to restore dopamine actions.
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What are the ACh antagonists?
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Antimuscarinics
"Tri Ben's muscle" * Benzotropine * Trihexyphenidyl |
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What is levodopa's purpose?
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To restore dopamine levels in the extrapyramidal (EP) centers.
**note: Levadopa is a precursor to dopamine AND NE |
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What are levadopa's limitations?
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1. In early disease, enough neurons are present for dopamine conversion and storage.
2. Yes, since levodopa only works with residual dopaminergic neurons in the substantia nigra to convert levadopa to dopamine, then the further along the disease, the less likely it can help, as more and more neurons are destroyed. 3. Late in the disease, the relief provided by levadopa is only symptomatic and only works while the drug is present in the body. |
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What happens to levadopa when it is administered on its own?
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Decarboxylated to dopamine in the periphery resulting in nausea, vomiting, cardiac arrhythmias, and hypotension.
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What is levadopa usually given with?
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carbidopa
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What is carbidopa?
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Dopa decarboxylase inhibitor that does not cross the BBB.
It helps to decrease the metabolism of levodopa in GI and periphery. It lowers the levodopa dose needed 4-5x and decreases peripheral side effects. |
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What is sinemet?
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A dopa preparation containing carbidopa and levodopa in fixed proportion.
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What about levadopa PK?
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*absorbed rapidly in GI
*food delays absorption *AA compete w/levadopa for GI absorption *AA also compete w/levadopa for transport into the brain via System L transport *So, DON'T eat a STEAK |
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How much levodopa makes it to the brain?
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1-3%
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What are levodopa's clinical use?
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*PD
*efficacy decline in 3-5th year *use may be lost completely d/t disappearance of nigrostriatal neurons *does not stop progression of PD but does lower risk of death from PD |
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What are the CNS effects of levodopa?
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*visual and auditory hallucinations
*dyskinesia (Opposite of Parkinsonism and reflect overactivity of dopamine receptors in the basal ganglia) |
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What is the wearing off reactions?
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Fluctuations related to the timing of
levodopa intake (end of dose akinesia) |
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What is the on-off phenomenon?
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Fluctuations NOT related to the timing of levodopa intake (mechanism unknown)
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What to do with pt with severe OFF periods?
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If unresponsive to levodopa, APOMORPHINE SC is the rescue tx.
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How does vitamin B6 affect levodopa?
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It is a co-factor for L-dopa
decarboxylase, therefore, Vit B6 increases peripheral metabolism of levodopa. |
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When is levodopa CI or other restriction?
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*CI in melanoma as levodopa is a precursor to melanin
*CI in CLOSED-ANGLE GLAUCOMA *CI w/antipsychotics since they block dopamine receptors and cause a parkinsonism syndrome on their own. *CI in psychotics d/t exacerbation of sx. *Cautious monitoring in CV dx patients due to arrhythmias. *Caution with MOAI d/t HYPERTENSIVE CRISIS *Caution w/pre-existing peptic ulcer d/t bleeding |
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what do dopamine receptor agonists do?
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Work as an adjunct to dopamine.
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what are the advantages of D-R agonists?
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Do not require enzymatic conversion to an active metabolite.
Have no toxic metabolites. Don't compete with other substances for transport into the blood and BBB. Lower incidence of response fluctuations and dyskenesias which occur with LT levodopa tx. |
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what are the 2 types of D-R agonists?
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Ergot derivatives
*BROMOCRIPTINE Nonergot derivatives *PRAMIPEXOLE, ROPINIROLE, ROTIGOTINE, APOMORPHINE |
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What is the role of D-R agonists?
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They are FIRST-LINE Tx along with dopaminergic tx (either start both at the same time or start DR agonists a little later).
They can be given for END-of-DOSE AKINESIA or ON-OFF phenomenon. They don't really work if the person has never responded to levodopa. |
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When to use BROMOCRIPTINE?
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D2 agonist and endo disorder (hyperprolactinemia)
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When are NONERGOTs used?
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*Used increasingly as FIRST LINE
tx for younger patients INSTEAD of levodopa d/t their favorable side effect profile overall. Older patients start levodopa d/t adverse cognitive effects of DR agonists. *Also used as adjuncts |
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When is pramipexole used?
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*Can be monotherapy for mild parkinsons or adjuncts
*Preference for D3 receptors |
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When is ropinirole used?
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**Can be monotherapy for mild parkinsons or adjuncts
*Preference for D3 receptors *Metabolized by cyt P450. |
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When is rotigotine used?
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Transdermal - discontinued
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When is apomorphine used?
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RESCUE tx for ON-OFF episodes of akinesia in pt w/dopaminergic tx.
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What are apomorphine AE in CI?
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AE:
*EMETOGENIC, pretreat w/TRIMETHOBENXAMIDE (antiemetic) *QT prolongation *Dyskinesia *Drowsiness *Sweating *Hypotension *Bruising at injection site CI: 5HT receptor antagonists are CI as the combination can cause profound HYPOtension and loss of consciousness. |
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What are the AE of DR agonists?
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GI (anorexia, N, V)
CV (postural HYPOtension) Dyskenesias Mental disturbances (confusion, hallucinations, delusions) ONLY BROMO: Pulmonary infiltrates, pleural fibrosis, retriperitoneal fibrosis, erythromelalgia (red, tender painful swollen feet, maybe hands). ONLY PRAM, ROPIN, ROTI: Somnolence (uncontrolled urge to sleep) |
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What is the mechanism of action of MAOIs?
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Inhibits dopamine metabolism by inhibiting monoamine oxidase.
2 drugs: Selegiline, Rasagiline |
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What does Selegiline and Rasagilline do?
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Selectively and irreversibly inhibits MAO-B (which metabolizes dopamine) but NOT MAO-A (which metabolizes NE and E - so no HYPERtensive crisis)
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When to use Selegiline and Rasagiline?
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Use BEFORE levadopa (monoTx) to delay initiation of levopda.
Use as as ADJUNCT to levodopa to lower levodopa dose. |
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What are Catechol-O-methyltransferase inhibitors?
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Tolcapone and Entacapone
Outside in the periphery, carbidopa inhibits dopa decarboxylase action on levodopa (which allows more levodopa to cross the BBB) but that activates of other pathways of peripheral and CNS levodopa metabolism (COMT - which is not good) which metabolizes levodopa into plasma 3-O-methyldopa (3-O-MD), in the periphery and in the CNS. 3-O-MD also competes w/levodopa for the GI/BBB carrier. TOLCAPONE blocks COMT in the periphery and CNS and ENTACAPONE blocks only in the periphery. |
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How are COMT inhibitors used?
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Useful in response fluctuations from levodopa l/t smoother respoinse, more prolonged on-time, and reducing levodopa dose.
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What are COMT AE?
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*BOTH: orthostatic HYPOtension, ORANGE URINE.
*TOLCAPONE - DEATH from HEPATIC FAILURE or increase in liver enymes (liver function monitoring necessary) ENTACAPONE preferred. |
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What does amatadine do?
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Increases synthesis, release, or re-uptake of dopamine from surviving neurons.
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What are amatadine AE?
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LIVEDO RETICULARIS
skin blotchiness - goes away after about a month of ceasing drug. |
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What are the uses of antimuscarinics?
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*Adjuvant
*May improve tremor and rigidity |
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What are the antimuscarinic AE and CI?
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Mood changes
Xerostomia Pupil dilation Confusion Hallucination Urinary retention Dry mouth NOT FOR USE IN: glaucoma, prostate hypertrophy, pyloric stenosis. |
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FINAL THOUGHTS:
DOC? |
Levodopa + carbidopa
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NEXT DOC?
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Dopamine-R agonists
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REDUCE MOTOR FLUCTUATIONS in ADVANCED Dx?
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COMT inhibitor or MAO-B inhibitor
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CONTROL TREMOR AND DROOLING?
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ANTIMUSCARINICS
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RESCUE PATIENTS IN OFF EPISODES?
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APOMORPHINE
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