1. Antiparkinson Drugs Flashcards
A Parkinson patient enters your dental office with:
• severe motor disturbances
• ____ of the hands
• random muscle activity
• ____ (drooling) from disease or xerostomia from drugs
• difficulty complying with your needs
• Prescribed ____, Dopamine Agonists, antimuscarinics, MAO and COMT inhibitors
• potential for drug:drug interactions
tremors
sialorrhea
L-DOPA
The basic problem in Parkinsonism: • a progressive neurodegenerative disorder • imbalance of \_\_\_\_ • especially in the \_\_\_\_ • \_\_\_\_ has a critical role
CNS neurotransmitters
basal ganglia
dopamine
Major symptoms of Parkinsonism
• ____ (difficulty in starting a movement; basically a locomotion disorder)
• ____ (slow gait; shuffles)
• ____ at rest; “pill rolling”
• muscle ____; mask-like facial expression
• ____
akinesia
bradykinesia
tremor
rigidity
More historical highlights
• anticholinergics for excessive ____; tremor improves.
• animal studies show high concentrations of dopamine in the ____.
• autopsies of Parkinson patients show depletion of dopamine in cells of the ____.
• the ____ are implicated
• dopamine ____ is not effective
• ____ provides transient remission.
salivation basal ganglia substantia nigra basal ganglia administration L-dopa
The basal ganglia are comprised of five subcortical nuclei (clusters of neurons): – \_\_\_\_ (caudate + putamen) – \_\_\_\_, external segment – \_\_\_\_, internal segment – \_\_\_\_ – \_\_\_\_
striate cortex globus pallidus globus pallidus substantia nigra subthalamic nucleus
• To review, blue oval is the caudate nucleus and the putamen
• Other blue circle is the globus pallidus
• Orange- thalamus. This is like the ____ part of our brain. By the way, when we
did some of our brain scanning studies on analgesics effects. One of the things we consistently saw (and we don’t know if it’s a mechanism of the drug or not) but not only did cerebral blood flow in the thalamus DECREASE, but it ____. We would see pts after 3rd molar pain, the right side would be hotter than the left side. Blood flow correlates very closely with neuroactivity. Then when they got pain relief, blood flow ____ and now right and left had the same amount of blood flow.
• Red- Substantia nigra. This is where most of the ____ is getting depleted.
• POINTS TO LOCUS COERULEUS and DORSAL RAPHE NUCLEUS- which are important in ____ pathways. So pathways from there actually descend and go from central to more peripheral. They turn off the release of ____ and excitatory amino acids in the dorsal Horn of the spinal cord and the medulla. These are sort of like analgesic pathways. We think opioids stimulate these.
primitive normalized diminished dopamine descending analgesic substance p
Causes of parkinsonism
____…causes unknown
____ disease…such as flu iatrogenic…as with ____ neurotoxin…as with ____
MPTP provides a breakthrough in cause of PD, as well as in its treatment
idiopathic
postencephalic
halperidol
MPTP
- This MPTP, this was the contaminate. (Its full name is on the slide.)
- MPTP readily crossed the ____, and readily got into neurons. Very lipophilic. But in the neurons, there was ____. This is inside the neuronal cytoplasm.
- MAO-A is a predominantly the MAO that you find in the periphery but it’s not like absolute.
- once this contaminant crossed into the neuron→ because of this interaction by MAO-B it got converted to ____. (What do you know about charge vs. charge molecules, as far as getting in and out of things? Charged species get ____. Ex: local anesthetics when you inject at a low pH & inflammation it’s tough to get him numb. why? because the molecules charged, it has a hard time penetrating the nerve.) This is kind of the opposite it → it penetrates and now it cannot get ____. This (points to the red circle on MPP+) targets the mitochondria and kills the neuronal cell. It is very selective for neuronal cells that contain ____.
BBB MAO-B MPP+ trapped out dopamine
Pharmacology of MPTP
- MPTP penetrates the ____ neurons in the SN
- biotransformed into ____
- charged molecule unable to exit cell
- attacks the ____
- disturbs the “powerhouse”
- cells degenerate
doapminergic
MPP+
mitochondria
A synthetic neurotoxin
- They developed animal models of this MPTP stuff. They gave rodents MPTP and the rodents got Parkinson’s disease. A rat with Parkinson’s disease.
- if you pretreated the animals with an ____, Selegiline, they DID NOT get it! because why? the MPTP couldn’t get converted to ____
- probably the major benefit of MAO-B Inhibitors in Parkinson’s is that -one of the ways that dopamine is degraded is by MAO. so it increases ____ levels in the central nervous system.
- by the way eventually these drugs are not going to work. why? because as Parkinson’s progresses, you will eventually have no ____ left. That’s why I-dopa went is sometimes only good for about 7-8 yrs, bc the nerve terminals that you need to contain the dopamine are not there anymore.
• But at least for now we think a lot of the activity of these drugs is blocking dopamine metabolism
MAO inhibitor
MPP+
dopamine
dopamine
Simplified View of Motor Neurophysiology
• There is dopaminergic input from the ____ that is key.
• maybe what’s going on is that this dopamine is acting as a brake on the production of
acetylcholine
• if this (points to dopamine) gets knocked out then there’s no ____ and there’s an
alternate pathway where ____ can be formed.
- you can see from this schematic (and I don’t want to get into what every one of these things are doing), you can see that ____ is involved (going to speak a lot about GABA when we speak about benzodiazepines)
- and to make things even more complex, there’s a direct pathway from the striatum to the motor cortex where it seems to be the key neurotransmitter is ____.
- Again, things that interact w/ glutamate and GABA does not seem to clinically ____ those w/ Parkinson’s disease
substantia nigra
dopamine
acetylcholine
GABA
glutamate
help
The ____ is the major focus in Parkinson’s disease
substantia nigra
Transmitters in the basal ganglia • \_\_\_\_ • \_\_\_\_ • \_\_\_\_ • \_\_\_\_
dopamine
acetylcholine
gamma amino butyric acid
glutamate
The transmitter DA can produce different actions on the same neural structure by ____ at DA receptor ____.
selective actions
subtypes
Dopamine receptor nomenclature
- Family
- D
- Sub-family
- D1 and D2
- Receptor sub-types
- D(1) D(2) D(3) D(4) D(5)
• you can have a ____ of dopamine, this is kind of like your relatives → D (dopamine) receptor
• There are ____, this is like the children —> D1 & D2 receptors (we think the we think the benefit of most of the dopamine stimulating anti-Parkinson drugs are on the ____ receptor)
• receptor sub-types—> D1, D2, D3, D4, D5
◦ *D2→ D2, D3, D4
◦ *D1→ D1, D5
family
sub-family
D2
In the caudate-putamen, the D2 receptor subtype is ____ and the D1 receptor subtype is ____.
inhibitory
excitatory
In Parkinson’s disease: we are very heavy on the ____ and we’re very light on the ____. That that pretty much tells you how to treat the disease
acetylcholine
dopamine
Medication • L-dopa \_\_\_\_ • Carbidopa \_\_\_\_ • Apomorphine \_\_\_\_ • Bromocriptine \_\_\_\_ • Pramipexole \_\_\_\_ • Amantadine \_\_\_\_ • Entacapone \_\_\_\_ • Benztropine \_\_\_\_ • Trihexyphenidyl \_\_\_\_ • Selegiline \_\_\_\_ • Vitamin E \_\_\_\_
Dopamine precursor inhibits decarboxylation of dopa Agonist (non-ergot) Agonist (ergot derivative) Agonist (non-ergot) Indirect Agonist (release enhancer) COMT inhibitor Anticholinergic Anticholinergic MAO-B inhibitor Antioxidant
- L-dopa is a dopamine precursor→ KEY DRUG, especially early on. It gets decarboxylated in the CNS, by an enzyme known as ____ ( some people call it amino acid decarboxylase) to dopamine. The problem with L-dopa alone is that a lot of it becomes dopamine (more than 95%) before it even gets to the brain. So you got to give ____ doses of it and you get tons of peripheral dopamine floating around and you also get some dopamine side effects in the PNS and CNS (____, hallucinations, etc.)
- Carbidopa→ actually inhibits the ____ of dopa to dopamine. But the special property is that IT DOES NOT CROSS THE ____. Only works in the periphery. But cannot be used by itself. Use L-dopa and Carbidopa together.
dopa decarboxylase huge nausea decarboxylation BBB
- Apomorphine→ sounds like morphine and has an opioid like structure. But one of the first ____ receptor agonist. Major use today is to induce ____ when child overdoses. It stimulates dopamine receptors and indirectly stimulates them because it is an opioid.
- Bromocriptine→ major drug today in Parkinson’s disease. It stimulates ____ receptors in the brain. Also, it is a ____, derivative of like a fungal product.
- Pramipexole→ this is another ____ receptor Agonist
- Amantadine→ if you look at this durg in 3D, it’s ____ on both sides. The major use of amantadine today is an ____ prophylaxis but it’s a dopamine releaser. by the way, one of the side effects is pt acts ____ b/c it is releasing dopamine in the brain
D2 vomiting D2 fungus dopamine symmetric influenza loopy
- Entacapone→ ____ receptor antagonist, we think it mainly works in the periphery. one of the other ways, l-dopa can go to dopamine but it can also go to ____ or methyldopa and methyldopa is inactive. So we think that COMT Inhibitors again increase the amount of ____ that’s probably it’s major mechanism of action. By the way, it can interact with ____ but we are not sure. (No money, no research)
- Benztropine, Trihexyphenidyl → ____. Blocking the heavy side of the seesaw
- Selegiline→ ____ inhibitor. By the way, some Parkinson’s patients are on Benadryl (____), which is an antihistamine,H1 receptor blocker. Why? It is anticholinergic.
- Vitamin E→ an add on drug. Maybe because it is an ____ that is scavenging some sort of neurotoxin that’s also there.
COMT alpha-methyldopa L-dopa epinephrine anticholinergic MAO-B diphenhydramine antioxidant
L dopa & Dopamine
L dopa is the dopamine precursor
◦ It is converted to dopamine via ____ (amino acid decarboxylase) in the brain
◦ The issue is that more than 95% of L dopa gets converted to dopamine outside the CNS
We will also talk about 3 Hydroxy-Methyldopa (top right molecule)
◦ This is not inactive
◦ This is why you will see some people now on the triple combination
‣ ____, ____ inhibitor, ____ inhibitor
This is mainly a ____ COMT inhibitor BTW, the reason I said Epi might be a concern for someone on a ____ inhibitor, is that one of the major pathways of Epi degradation is through COMT
L dopa COMT peripheral dopa decarboxylase peripheral COMT
L-dopa rationale: • dopamine doesn’t penetrate the \_\_\_\_ • its precursor, L dopa, is taken up from g.i. tract, but there is... • a significant \_\_\_\_ effect • 95% \_\_\_\_ outside CNS • only 5% penetrates the brain, & is... • converted to dopamine in \_\_\_\_ • excess peripheral DA causes \_\_\_\_
brain first-pass decarboxylated CNS AEs
L-dopa • Levodopa (Larodopa®;Dopar®) • precursor of dopamine • mainly reduces \_\_\_\_ • a precursor of other neurotransmitters... • therefore, has many side effects, such as... – \_\_\_\_, tachycardia, nausea, vomiting – \_\_\_\_ &... – \_\_\_\_ disturbances (dyskinesia)
rigidity
hypotension
behavioral
motor
The search for ways to increase the amount of oral L dopa that can get to the brain led to the discovery of ____.
carbidopa
Carbidopa enhances L dopa • a \_\_\_\_ derivative of a methyldopa • does not penetrate the \_\_\_\_, but ... • blocks \_\_\_\_ outside CNS • L dopa + carbidopa= SINEMET® • the combination leads to \_\_\_\_ doses of L-dopa & fewer side effects
hydrazine
blood-brain barrier
decarboxylation
lower
L-dopa metabolism
• Again, this is where carbidopa is blocking, IN THE ____! [points to AAD] ◦ Not in the brain! If it happened in the brain, L dopa would not work
◦ Carbidopa does not penetrate the BBB
brain
APOMORPHINE
• one of the early ____ dopamine postsynaptic
agonists
• also has high affinity for the ____ receptor family (effect is not established)
• used as a “____” drug during the period when L-dopa dose is waning.
• given ____; ____ half-life (30 to 90min.)
• a potent ____; adverse ____ effects
D2 D1 rescue iv/sc short emetic personality
• Apomorphine hits here because it’s ____-like
• And it actually directly stimulates here too (pointing to ____ receptors)
• BTW, one of the breaks on the vomiting center is ____ input (pointing to NE)
• Thats why people that go up in space are given an
____ and an ____-like drug. Amphetamines increase NE release and block reuptake
opioid dopamine noradrenergic anticholinergic amphetamine
BROMOCRYPTINE (PARLODEL®)
• ____ derivative (fungus that infected bread)
• DA agonist at ____ receptor
• has many side effects, including: ____ changes, decreased ____ levels (babies died in 1700s because mothers were not able to produce breast-feeding milk)
ergot
postsynpatic D2
neuropsychiatric
prolactin
PRAMIPEXOLE (MIRAPEX®; ROPINIROLE®) • \_\_\_\_ • high selectivity for \_\_\_\_ receptors • \_\_\_\_ • \_\_\_\_ and vomiting • \_\_\_\_
agonist D2 sleepiness nausea dizziness
AMANTADINE (SYMMETREL®) • \_\_\_\_; non ergot • enhances the synaptic release of \_\_\_\_ • reduces \_\_\_\_ • fewer side effects than \_\_\_\_ • not \_\_\_\_ choice • used mainly as \_\_\_\_ • prophylactic vs influenza virus
• Has some activity against the influenza virus
◦ Inhibits viral ____
◦ Used after onset of first flu symptoms, there is a better version of this called ____ that
has fewer side effects
agonist DA rigidity levodopa first adjunct encoding rimantidine
ENTACAPONE (COMTAN®) • selective, \_\_\_\_ inhibitor of \_\_\_\_ • acts only outside the c.n.s. can’t cross the \_\_\_\_ • blocks methylation of \_\_\_\_ • extends the half-life of \_\_\_\_ • allows a more continuous supply of \_\_\_\_ • minimizes “off time” • maximizes “on time” • less \_\_\_\_
• Minimizes “off time,” this means the time when the drug is not working, and it maximizes “on time” or
the time when the drug is working. So it extends the ____ of L dopa
• Again, probably because you now need less L dopa, you get less dyskinesias
reversible COMT BBB L-dopa L-dopa dopamine dyskinesia duration
ANTICHOLINERGICS
• ____
• ____ (Artane®)
• ____ (Cogentin®)
– ADVERSE REACTIONS • \_\_\_\_ • \_\_\_\_ • \_\_\_\_ • \_\_\_\_
atropine
trihexyphenidyl
benztropine
urinary retention
constipation
xerostomia
memory & visual disturbances
DIPHENHYDRAMINE (BENADRYL®) • \_\_\_\_ (H1 blocker) • \_\_\_\_ • mainly reduce \_\_\_\_ • \_\_\_\_ mouth • forced \_\_\_\_ (severe drowsiness) • \_\_\_\_, urinary retention, tachycardia
antihistaminic anticholinergic tremors dry sleep constipation
SELEGILINE (DEPRENYL, ELDEPRYL®)
• an ____ inhibitor (beta class in c.n.s.)
• prevents DA ____
• increases ____ DA concentration
• many drug interactions (build up of normeperidine with meperidine admin)
• its rationale was an outgrowth of the ____ episode
MAO
degradation
tissue
MPTP
BTW, meperidine is a drug that when he went to dental school this was the major opioid used in intravenous sedation
◦ An issue with meperidine is that it has a metabolite called ____ which is metabolized by MAO. If you are on an MAO inhibitor (doesn’t matter whether it is for depression or Parkinson’s), normeperidine can build up and it increases the risk for ____
◦ Boards question: What drug should you absolutely avoid for a pt on an MAO inhibitor? ____
◦ You’ll see a relative
contraindication with other opioids. But with meperirdine, don’t use with an ____ inhibitor or you’re getting sued
• BTW, what’s the other issue with MAO inhibitors? Foods that contain ____ (ex. cheddar cheese)
• It was first tried in patients because of the MPTP episode, probably not the reason it is working, but it
led to looking at MAO inhibitors and Parkinson’s disease
normeperidine seizures meperidine MAO tyramine
VITAMIN E (alpha TOCOPHEROL)
• An ____
• Supplemental drug
antioxidant
Is levodopa neurotoxic?
• If you look at the way L dopa is processed in the body, when you build up a lot of dopamine, it eventually gets broken down into ____ and also generates the cytotoxic hydroxyl ____
◦ Some people are worried that if we keep pumping L dopa into people that we are going to be causing the generation of these ____ that will cause other neuronal damage
• All drugs are poisons and the idea is to put enough molecules into somebody to get a beneficial effect with few side effects
◦ There are no drugs with zero side effects
hydrogen peroxide
free radicals
free radicals
Summary
• If you give L dopa and combine it with Carbidopa, it is a peripheral amino acid or dopa decarboxylase
inhibitor
• Entacapone is the ____ inhibitor, and it also increases the levels of ____
• We think that the MAO inhibitors are mainly working by increasing ____ levels in the brain
• All of these therapies will eventually ____
◦ Once those CNS neurons in the basal ganglia containing dopamine are wiped out, these drugs are really not going to work because there is no ____ and no where to store it
◦ When there is no place to store it, L dopa won’t work anymore
◦ That’s when you get into the dopamine receptor ____ agonists
COMT L-dopa dopamine fail dopamine D2
Principles of management • major drugs (Sinemet®) – ergot DA agonist: \_\_\_\_ – non-ergot agonists:, \_\_\_\_ – \_\_\_\_ with Levodopa
• minor drugs
– ____
– trihexyphenidyl
– benztropine
• prophylactics
– ____
– vitamin E
bromocriptine
ropinirole
entacapone
amantadine
selegiline
lso in the pipeline
• ____ (GAD)
• ____ stimulation (DBS)
– Recent success in decreasing motor disturbances with ____ stimulation
• Triple mixture (____, ____ and ____) This is now approved!!
gene therapy deep-brain subthalamus levodopa carbidopa entacapone
TISSUE TRANSPLANTATION
• ____ cells in humans.
• embryonic ____ cells in experimental animals & humans.
• ____ cells
adrenal medullary
nigral
cultured
Reapproved in 2012 !
Very recent advances
- Rotigotine “patch” (Neupro®)
- ____ selective, non-ergot agonist
- continuous availability ____ “off” time
- useful in ____ Parkinson disease
- used with ____
- FDA approved in 2007, but
- manufacturer withdraws it in 2008 – drug was ____ in patch inhibiting ____ through skin
D2-D3 lowers early L-dopa crystalizing absorption
