Flashcards in Dopaminergic Pharm Deck (26):
What are the effects of high doses of IV dopamine?
incr. peripheral resistance
What are the effects of low doses of IV dopamine?
vasodilation in kidney, mesentery, heart, and brain from stimulation of dopamine recepors on the smooth muscles of blood vessels in these organs
What are the effects of dopamine on the CNS (4 effects, though you really only need to know first 2)
1. nigrostriatal system (sustantia nigra pars compaction project into the striatu, which is involved in motor control)
2. mesocorticolimbic system (ventral tegmental area project to nucleus accumbens and hippocampus. reward/addition behaviors)
3. hypothalamic control of the pituitary gland
4. odorant perception
What do D1 receptors do?
stimulate adenylyl cyclase via Gs. incr. cAMP formation.
enhance nerve stim via phosphorylation of cation channels, allowing for incr. cation influx
What do D2 receptors do?
inhibit adenylyl cyclase via Gi protein; activated phospholipase C via Gq. decr. formation of cAMP and incr. IP3 and DAG. decreased nerve stim mediated by phopsphorylation of cation channels and by interactions btw channels and G proteins that lead to hyperpolarization
Which dopamine receptors are stimulatory?
D1 and D5
Which dopamine receptors are inhibitory
D2, D3, D4
Which dopamine receptors are found in the striatum?
What are the pathological landmark feature of parkinsons disease? (2 features. both seen only on autopsy)
1. loss of melanin-pigmented dopaminergic neurons in the substantia nigra pars compacta
2. Lewy bodies in the neurons of the substantia nigra pars compacta.
What are 4 main (general) hypotheses for the etiology of PD?
1. dopamine toxicity/ selective susceptibility to oxidative stress (little actual scientific evidence, though)
2. environmental insults (infections, toxins/drugs, brain injury
3. selective vulnerability to excitotoxicity leading to excessive intracellular calcium
4. selective deficiencies in ubiquitin/proteosome pathway and/or apoptosis
What are three major genes that, when mutated, lead to familial forms of Parkinson's disease? What sorts of pathways are these gene products involved in?
tend to be involved in protein degradation pathways (ubiquitin/proteosome) or in signaling activities
What is the main goal of most pharmacological treatment for parkinson's disease?
replacing or substituting dopamine lost in the striatum to reestablish normal homeostatic control of motor function
What is Levo-DOPA? how does it work?
-most effective and widely prescribed drug for treatment of PD
-replaces dopamine in surviving striatal nerve terminals
L-DOPA has a short (1-3 hrs) blood half life, but is effective after that. Why?
it is taken into striatal nerve terminals and converted to DA. DA can be stored and reused for a relatively long period of time.
What kinds of drugs must be given with L-DOPA to make it effective? Why?
L-DOPA is easily degraded by aromatic amino acid decarboxylases. L-DOPA should be given with a peripherally active AADC inhibitor (carbidopa or benserazide) to allow L-DOPA to reach CNS and reduce nausea associated w L-DOPA
What is the primary limitation of L-DOPA treatment?
After 5-6 yrs, L-DOPA becomes less effective: "wearing off" phenomenon. L-DOPA helps for first 1-2 hrs but then PD symptoms return. this is due to the fact that nigrostriatal dopaminergic neurons are continuing to die (remember, we are treating symptoms, not underlying cause here), and at some pt there aren't enough left to store/reutilize dopamine for a sustained period.
What is the on/off phenomenon of parkinson's disease?
late stage of PD
rapid fluctuations btw an off stage, where L-DOPA isn't helping with PD symptoms at all, and the on stage, where L-DOPA side effects are incredibly severe (dyskinesias).
What are major side effects of L-DOPA treatment?
motor dyskinesias, nausea. sometimes hallucinations/confusion
severe hypotension/cardiac arrhytmias bc of dopamine effects on peripheral DA and beta-adrenergic receptors in the blood vessels and heart
What are 4 potential advantages of dopamine receptor agonists in the treatment of PD?
1. direct agonists don't depend on surviving functional dopamine nerve terminals
2. potentially more selective for specific dopamine receptors
3. longer duration than L-DOPA and avoidance of on/off phenomenoa
4. reduces risk of free radical generation during dopamine metabolism
How do newer dopamine agonists differ from older dopamine agonists in terms of side effects?
newer drugs have fewer side effects (severe nausea and blood pressure effects in older drugs mandates slow build up in dosage). but, the newer drugs do run a very rare risk of sleep disorders- sudden sleep attacks during waking hours.
CNS effects resemble those of L-DOPA
speed of action also different.
What is selegiline? Disadvantages? uses (disease stage)?
irreversible selective inhibitor of MAO-B, the MAO form that predominates in the striatum.
no wine, cheese, beer effect seen in other MAO inhbitors; can take in combo with L-DOPA.
uses: early to mid stage PD (exacerbate dyskinesia seen from L-DOPA in advanced pts)
disadvantegs: methamphetamine, which causes insomnia and anxiety, is a metabolite. mat be better with rasagiline, another MAO inhibitor for PD
When are COMT inhibitors useful for PD treatment?
prevent the break down of L-DOPA and allow more L-DOPA to get to the CNS.
disadvantae is sometimes hepatotoxicity- monitor serum enzymes
How are muscarinic acetylcholine receptor antagonists used to treat PD?
unclear how this works- maybe because striatal mAChRs normally respond to intrinsic cholinergic striatal interneurons.
What is amantadine?
anti-viral drug with modest anti-PD effects. unclear why, but appears to incr. DA release from striatal terminals
What is drug-induced parkinsonism?
Some classical anti-psychotics, as well as reserpine (which depletes dopamine) causes reversible PD like symptoms. Esp. seen in elderly pts w fewer dopamine neurons in reserve.