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37 Cards in this Set
- Front
- Back
Catacholamines include (3)
Precursor? Rate limiting step? |
Norepineprine
Epinephrine Dopamine Tyrosine oxidation of tyrosine to L-DDPA |
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What do catecholamines do?
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Affect mood, attentiveness and emotion by effecting the function of point to point neurotransmission.
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Review figure 12-1
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Golan Page 186
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What is required to get DA into synaptic vesicles? (2)
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Proton ATPase to concentrate protons in the vesicle
Electropositive vesicle interior (VMAT) |
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DAT
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The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that binds the neurotransmitter dopamine; DAT provides the primary mechanism through which dopamine is cleared from synapses, transporting dopamine from the synapse into a neuron. DAT is present in the peri-synaptic area of dopaminergic neurons in areas of the brain where dopamine signaling is common.
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Once dopamine is released into the postsynaptic cleft, what may occur (2)?
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Dopamine may be reabsorbed by the presynaptic neuron or it is broken down by MAO or COMT
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Where does MAO work, CNS or PNS?
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Both CNS (MAO-B) & PNS (MAO-A)
* MAO-B is often used in the CNS, however, MAO-A retards the breakdown of ALL central and peripheral catecholamines which can be life-threatening. |
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The sequential action of the COMT and MAO degrades DA to the stable metabolite __________ ____ (HVA) which is excrreted in the _______
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Homovanillic acid
urine |
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_________ is expressed in the brain, liver, kidney and heart, and it inactivates catecholamines by adding a methyl group to the hydroxyl group at the 3 position of a benzene ring.
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COMT
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D1 Class receptors
vs D2 Class receptors (Golan page 189) |
D1 lead to increased cAMP (2 receptors 1,5)
D2 class receptors inhibits cAMP generation (3 receptors 2,3,4) |
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Dopamine receptors in striatum, playing a role in motor control by basal ganglia and nucleus accumbens and olfactors tubercle.
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D1 and D2
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Dopamine receptors in anterior pituitary gland lactotrophs, regulate prolactin.
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D2
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What is required for synaptic vesicle trafficking to and fusion with the presynaptic membrane.
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Ca++
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Drugs that block dopamine ___ receptors are used to treat nausea and vomiting.
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D2
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BASAL GANGLIA
Primary input Primary output |
Striatum (caudate and putamen)
Globus pallidus pars interna and substantia nigra pars reticula |
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Cortical inputs to basal gangial are _________ and use ___________ as a transmitter.
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excitatory
glutamate (medium spiny neurons) |
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The medium spiney neurons release the inhibitory transmitter GABA and send their projections to tow downstream targets.
Direct pathway- Indirect pathway- |
Direct pathway-(D1) stimulates movement
Indirect pathway-(D2) - inhibits the thalamus therefore inhibiting movement. |
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Increased levels of dopamine in the striatum tend to activate D1 expressing neurons of the direct pathway while inhibiting the D2 expressing movement. So,
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both of these effects promote movement.
**It is the opposite in Parkinson's (it is thought that the indirect pathway is overactive- surgery to subthalamic nucleus) |
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In parkinson's disease there is a selective loss of dopaminergic neurons in the
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substantia nigra pars compatcta
(70% of neurons lost by time of onset of symptoms, 95% loss on autopsy) |
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Typical presentation of parkinson's diesease:
May be due to exposure to: |
Bradykinesis (slow movement)
Rigidity Impaired postural balance Tremor when limbs are at rest Certain pesticides, mutations, mostly unknown multifactorial |
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Treatment of Parkinson's Disease:
Current goal is: |
Mainly symptomatic control, safe, but disease will take its course especially cognitively (dimentia)
Neuroprotective and neurorestorative |
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3 categories of Parkinson's Disease therapeutic treatment:
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1 DA precursors
2 DA receptor agonists 3 Inhibitors of DA degradation |
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Most effective treatment for PD is:
How come DA cannot be used? |
Levodopa
DA cannot cross the BBB, but L-DOPA can is is converted to DA by AADC once in the CNS. |
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Why must Levodopa be co-administered with carbidopa?
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Carbidopa will inhibit AADC so Levodopa has a chance to cross the BBB before it is made into DA, but still only 10%. However, this decreases adverse effects of peripheral DA (nausea)
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Problems with Levodopa
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Effects at early stage
Patients develop tolerance thus requiring larger doses *Cause dyskinesias of head and trunk @ max levodopa concentrations Chronic therapy causes adaptations in post syn neurons in striatum (pg 194 golan) |
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Explain on and off periods due to Levodopa
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ON: normal to dyskinetic, shortly after administration, can be overcome by lowering dose
OFF: Periods of freezing and increased rigidity, occur as plasma levels of levodopa decrease. Symptoms get worse over time |
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Dopamine precursor: transported across BBB by neutral AA transporter and then made into DA by AADC via decarboxylation.
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Levodopa
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DA receptor agonist advantages:
Disadvantages are excessive sedation, vivid dreams, and hallucinations. |
Delay onset of "off" periods
Nonpeptide, so do not compete with Levodopa to cross BBB Do not require AADC so remain effective late in disease process Longer 1/2 life than Levodopa (less frequent dosing and more uniform response to drug) |
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Dopamine Receptor Agonists (4):
Ergot derivatives bind to and activate postsyn dopamine receptors directly. |
Bromocriptine (ergot derivative:*n/v, edema, HTN)
Pergolide (ergot derivative:*n/v, edema, HTN) Pramipexole (used more often than ergot derivatives) Ropinirole (used more often than ergot derivatives) |
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Clinical applications of Pramipexole &
Ropinirole, and adverse effects. |
PD
Restless Leg Syndrome (Extrapyramidal movements, somolence, dizziness, hallucinations, dream disorder, asthenia, amnesia) *don't use with other sedating meds |
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Adverse effects and contraindications of Levodopa
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AE: Dyskinesia, heart disease, orthostatic hypotension, psychotic disorder, loss of appetite, n/v
contrain: Hx of melenoma, narrow angle glaucoma, simultaneous use of MAO inhibitors. |
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Inhibitors of Levodopa or Dopamine metabolism (4): Inhibits breakdown of DA in CNS by inhibiting MAO-B or COMT, or inhibits breakdown by COMT in periphery
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Rasagiline (CNS)
Selegiline (CNS) Tolcapone (periphery) Entacapone (periphery) |
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Misc Anti-PD medications (3):
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Amantadine
Trihexyphenidyl Benztropine |
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Amantidine is used for PD and _________.
This drug is contraindicated if there is a: |
Influenza A
Hypersensitivity to Amantidine |
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Adverse effects of amantidine:
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Neuroleptic malignat syndrome, exacerbations of mental disorder, insomnia, dizziness, hallucinations, agitation, orthostatic hypotension, pertipheral edema, dyspepsia, livedo reticularis (vascular prob characterized by purplish mottling of skin)
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What are the treatments for parkinsons's disease?
(1) (1&2) (1,2&3) |
L-dopa
Carbidopa Bromocriptine bromocriptine is also marketed for amenorrhea |
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Amantidine is more effective than anticholinergics and less effective than L-dopa. It is also used to treat:
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A2 influenza prophylactically
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