1
Q
Precursor molecule to dopamine?
A
Tyrosine
2
Q
Where/how are dopamine molecules stored?
A
Stored in vesicles by VMAT2
3
Q
Mechanism of dopamine synthesis and storage
A
- Tyrosine is taken up into dopamine nerve terminals via tryosine transporter
- Conversion into DOPA via tyrosine hydroxlyase (TOH)
- DOPA –> dopamine via DOPA decarboxylase (DDC)
- Dopamine is packaged into synaptic vesciles via vesicular monamine transporter (VMAT2)
- Stored until its release into the synapse during neurotransmission
4
Q
DOPA decarboxylase (DDC)
A
Turns DOPA –> dopamine
5
Q
tyrosine hydroxlyase (TOH)
A
converts tyrosine into DOPA
6
Q
Mechanism of clearing dopamine once released from snaptic vesicles
A
- DAT (dopamine transporter) - reuptake transporter
- catechol-O-methyl-transferase (COMT) - breaks down dopamine extracellularly
- MAO-A or MAO-B (monoamine oxidase A/B) - present in mitochondria within the presynaptic neurons, breaks down dopamine
7
Q
receptor responsible for reuptake of dopamine from the synaptic terminal
A
DAT (dopamine transporter)
8
Q
responsible for the breakdown of dopamine extracellularly
A
catechol-O-methyl-transferase (COMT)
9
Q
What breaks down dopamine intracellularly and where does it happen?
A
monoamine oxidase A/B - located within mitochondria of the presynaptic neuron
10
Q
Where is the majority of the dopamine produced? (what area of the brain)
A
substantia nigra
Ventral tegmentum also produces a small amount but majority is in the substantia
11
Q
What dopamine pathway controls movement?
A
Nigrostriatal (substantia nigra to striatum) pathway
12
Q
Nigrostriatal (substantia nigra to striatum) pathway
A
controls motor function and movement
13
Q
What happens if the nigrostriatal dopamine pathway is dying or inhibited/blocked?
A
Parkinson-like symptoms
This is the pathway that is insufficient in Parkinsons disease
14
Q
mesolimbic dopamine pathway
A
Midbrain ventral tegmental area –> nucleus accumbens
Controls behaviors such as:
- pleasurable sensations
- the powerful euphoria of drugs of abuse
- delusions and hallucinations of psychosis
15
Q
Which dopamine pathway controls reward and perception?
A
mesolimbic dopamine pathway
16
Q
Which pathway is associated with the mesolimbic dopamine pathway?
A
mesocortical dopamine pathway
Also projects from the midbrain ventral tegmental area, but sends axons to areas of the prefrontal cortex where they play roles in mediating symptoms of schizophrenia
- cognitive symptoms (via the dorsolateral prefrontal cortex (DLPFC))
- affective symptoms (via the ventromedial prefrontal cortex (VMPFC))
17
Q
mesocortical dopamine pathway
A
Projects from the midbrain ventral tegmental area, but sends axons to areas of the prefrontal cortex where they play roles in mediating symptoms of schizophrenia
- cognitive symptoms (via the dorsolateral prefrontal cortex (DLPFC))
- affective symptoms (via the ventromedial prefrontal cortex (VMPFC))
Overall: controls executive function
18
Q
Where does the mesocortical dopamine pathway project from and to?
A
From: ventral tegmental area
To:
dorsolateral prefrontal cortex – cognitive symptoms
ventromedial prefront cortex – affective symptoms
19
Q
tuberoinfundibular dopamine pathway
A
projects from the hypothalamus to the anterior pituitary gland and controls prolactin secretion
20
Q
Which dopamine pathway controls pituitary prolactin secretion?
A
tuberoinfundibular dopamine pathway
21
Q
Major Dopamine pathways
A
- Nigrostriatal – controls movement
- Mesolimbic – controls reward and perception
- Mesocortical – controls executive function
- Tuberoinfundibular – controls pituitary prolactin function
- Thalamic – function unknown. arises from multiple sites projecting onto the thalamus.
22
Q
What occurs if there is hypo/hyper functioning of the mesolimbic dopamine pathway?
A
Hypo – amotivation, apathy
Hyper – addiction, hallucinations
23
Q
What occurs if there is hypo/hyper functioning of the mesocortical dopamine pathway?
A
Hypo – inattention
hyper – hypervigilance
24
Q
What occurs if there is hypo/hyper functioning of the nigrostriatal dopamine pathway?
A
Hypo – dyskinetic movement, parkinsonism
hyper – dyskinetic movement
25
What occurs if there is hypo/hyper functioning of the tuberoinfundibular dopamine pathway?
Hypo -- hyperprolactinemia
hyper -- hypoprolactinemia
Remember: dopamine naturally inhibits the secretion of prolactin, hence the negative correlation
26
Schizophrenia - what is occuring (in terms of brain activity) in the pre-frontal cortex?
DorsolateralPrefrontalCortext (DLPFC) is hypoactive.
VentromedialPrefrontalCortex (VMPFC) is hyperactive.
27
What happens to dopamine levels in ADHD? Where does it mainly take place?
Loss of dopamine activity in anterior cingulates
28
catechol-O-methyl-transferase (COMT)
responsible for the majority of the breakdown of dopamine **extracellularly**
29
Dopamine enhancing drugs
Levodopa -- precursor to dopamine (DA) and is freely able to cross the blood-brain barrier
Carbidopa -- an agent often combined with levodopa to help reduce the side effects
30
Levodopa
precursor to dopamine (DA) and is freely able to cross the blood-brain barrier
Side effect: -- think of what happen when there is too much DA in your system
* dyskinesias (choreic, quirky, quick, tic-like involuntary movements)
* psychosis, mania
* anxiety/agitation
* fatigue
* nausea
Therapeutics: Parkinson's
31
Levodopa side effects
Side effect: -- think of what happen when there is too much DA in your system
* dyskinesias (choreic, quirky, quick, tic-like involuntary movements)
* psychosis, mania
* anxiety/agitation
* fatigue
* nausea
32
What drug is given to reduce the side effects of levodopa?
Carbidopa - inhibits DOPA Decarboxylase which converts DOPA into DA
Essentially stops the processing of the drug to completion
33
Carbidopa
inhibits DOPA Decarboxylase which converts DOPA into DA
Used often in conjuction with levodopa to lessen the side effects
34
role of methyl-THF and MTHFR
methyl-THF is associated with synthesis of methionine via methylation of homocysteine using the enzyem MTHFR.
MTHFR can also be used to syntehsize more tyrosine (precursor to DA) which can in turn result in increased DA. **Need to double check this**
35
1 carbon cycle nutraceuticals
* **L-methylfolate** -- increase activity of MTHFR
* **s-adenosyl methionine** -- increase homocysteine (which in turn drives formation of L-methylfolate)
Both these drugs in the end drive the production of more tyrosine.
36
Buproprion
**Class**: NDRI (norepinephrine-dopamine reuptake inhibitors)
**Mech**: blocks the dopamine transporter (DAT) -- leaves more DA in the synapse to increase DA activity in the mesocortical pathway (can also lower depression symptoms)
**Side effects:**
* DA SEs -- insomnia, jitteriness/hypervigilance, seizures.
* Also blocks NE reuptake --\> increase sympathetic stimulation --\> insomnia, anxiety, agitation, nausea, sweating, palptiations, mild increases in BP
Therapeutics: antidepressants
37
Buproprion - side effects
Less severe than levodopa, but still get the same dyskinetic movements. In addition, patient also has increased NE in the synapse and will get increased stimulation of the sympathics
* DA SEs -- insomnia, jitteriness/hypervigilance, seizures.
* NE SEs --\> increased sympathetic stimulation --\> insomnia, anxiety, agitation, nausea, sweating, palptiations, mild increases in BP
38
amphetamines (drug)
* dextroamphetamine
* mixed amphetamine salts
* lisdexamfetamine
**Class**: amphetamines -- stimulants
**Mech**:
1. blocks DAT like bupropion, and may even reverse it.
2. increases vesicular monoamine transport (VMAT2) --\> ejects more DA from nerve terminals
**Therapeutics**: ADHD
39
What class of drugs is similar to amphetamines, but do not reverse the transporter?
Methylphenidate products
Blocks the DA transporter (DAT), but do not have any chance of reversing it. Less aggressive than amphetamines.
40
Methylphenidate drugs
Blocks DAT (DA transporters) --\> blocks reuptake of DA
Does not have any chance of reversing it.
Similar to amphematines but less aggressive --\> less side effects
41
Most useful metric for determining what type of headache a patient has?
Time course of the headache
42
Migraine headache
Lasts 4-72 hours
occurs sporadically (but usually once or twice a month)
43
Cluster headaches
Occur 15-180 minutes
may occur every other day to many (~8) times per day
These attacks occur in clusters with several months or years between the next bunch of attacks
44
Tension headaches
Most common type of headache
sporadic, non-regular, and last minutes to days depending on underlying etiology
45
First line treatment for headache
NSAIDs
46
Sumatriptan
Class: Triptans
Mech:
* selective 5HT1 agonists
* constriction of extracerebral intracranial vessles
* inhibition of trigeminovascular system
Therapeutics: acute Rx of cluster headaches
SE: flushing, tingling, dizziness, chest discomfort (noncardiac)
47
Ergotamine
Class: Ergot alkaloid
Mech: vasoconstriction possibly; may also act as a 5HT agonist in the trigeminovascular pathway
Therapeutics: acute treatment of migranes
SE: Nausea, dizziness, paresthesia, chest pain, abdominal cramps
48
Verapamil
Mech: calcium channel blocker
Therapeutics: migraine prevention (particularly for prolonged or disabling aura). Long term prevention of cluster headaches
SE: constipation, dizziness
49
Natalizumab
mAb that binds α4 subunit of integrins (VLA-4) expressed on all leukocytes
inhibits the migration of leukocytes across BBB
Therapies: long term management of MS
SE: progressive multifocal leukoencephalopathy (PML), serious systemic hypersensitivity
2ndary treatment b/c of these seriously SEs
50
Natalizumab - major side effect
mAb that binds α4 subunit of integrins (VLA-4) expressed on all leukocytes
inhibits the migration of leukocytes across BBB
SE: progressive multifocal leukoencephalopathy (PML), serious systemic hypersensitivity
2ndary treatment b/c of these seriously SEs
51
Fingolimod
first oral medicine approved. much more effective than low dose IFN
Mech: agonist of the sphinosine-1 receptor (SIP1) --\> induces internalization of receptors --\> sequesters lymphocytes within lymph nodes
SE: cardiac abnormalities (ie bradycardia and heart block)
Therapeutics: Long term management of MS
52
Fingolimod - SE
SIP1 inhibitor
Biggest issue is cardiac concerns ie bradycardia or heart block
53
Teriflunomide
Selective hydro-orotate dehydrogenase inhibitor
blocks pyrimidine synthesis --\> reduce T & B cell proliferation
SE:
* decreased hair density
* GI -- diarrhea
* liver enzyme (hepatotoxicity)
* nausea
* teratogenecity
Therapeutics: Long term MS management
54
Dimethyl fumarate
Mech
* Actives Nrf2 pathway and induces antioxiant production
* protecting oligodendrocytes against free-radical induced cytotoxicity
* also has anti-inflammatory effect (prevents migration)
SE:
* GI pain, N&V -- less symptoms if taken on a full stomach
* flushing -- controlled by aspirin
Therapeutics: Long term MS management
Used to treat psoariasis
55
Alemtuzumab
humanized mAb to CD52 (CD52 function unknown)
primarily effects T&B cells - little effect on innate immunity
* B cells return to normal in 6-9 months
* T cells never return to normal but some recovery
SE:
* infusion reactions
* increased infections
* autoimmunity (ITP, thyroid via both hypo/hyper)
Therapeutics: Long term MS management
56
Treatment of acute attacks in MS
corticosterioids - antiinflammatory via suppression of both B and T cells. May also reduce cytokine release
alternatives: plasmaphoresis, ACTH (stimulates the production of endogenous steroids)
57
mechanism of action of local anesthetics
bind reversibly to _intracellular_ portion of sodium channel --\> abolishing ability to generate an action potential
If the Na+ current is blocked over a critical length of the nerve, propagation across the nerve is no longer possible. May require 2-3 nodes of Ranvier
58
how to tell the effect of local anesthetic is working
More sodium channels in the activated state than the resting or inactivated state
59
differential blockade of local anesthetic
* smaller nerves and myelinated nerves get blocked earlier than larger/unmyelinated ones
* active fibers blocked more than inactive ones
* fibers more proximal to injection site blocked earlier than distal ones
60
Biotransformation of ester anesthetics
* hydrolyzed by an enzyme in plasma: pseudocholinesterase --\> rapid metabolism to water soluble metabolites
* Makes esters relatively safe anesthetic because of its quick metabolism
* CSF lack this enzyme. Esters injected intrathetcally are metabolized by absorption into blood
61
Biotransformation of amide anesthetics
* Transformed by hepatic carboxyl esterases and CYP450 enzymes --\> slow metabolism
* Liver disease may lead to accumulation --\> toxicity
* Low hepatic flow, CHF, vasopressor use prolong effects of these anesthetics
62
local anesthetic toxicities
Associated with drugs such as Procaine and Mepivacaine
Cuases transient pain or dysesthesia linked to use of these drugs as spinal anesthesia
63
Major toxicities associated with local anesthetics
CNS toxicity --\> readily crosses BBB producing dose dependent effects
* High risk for high potency agents
* Factors that contribute to increasing risk
* intrinsic: low protein binding, decreased clearance
* extrinsic: metabolic acidosis (results in more in ionized form --\> dissolves in blood --\> moves to CNS more readidly), increased PCO2 by increased CBF and decreased plasma protein binding
Cardiac toxicity
* much higher doses are required than for CNS toxicity
* occurs via the cardiac Na channel blockade --\> depression of myocardial contractility and reduced refractory period.
* Since most local anesthetics are vaso-dilators (except cocaine and ropivacine) --\> increased demand, but decreased output --\> cardiac arrest
64
Highest cardiac toxicity local anesthetic
Bupivacaine
R+ isomer blocks cardiac sodium channels fast and leaves channels slowly.
65
Ester allergies - what is the allergen?
PABA - para aminobenzoic acid
66
Ester allergies - what can you use instead?
Can use amides as long as the PABA is not used as a perservative
67
Unit 3
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