Module 14a Flashcards
Stud of how drugs affect the function of the CNS.
Neuropharmacology
There are many disorders in the CNS, and most of them have a component that is mediated by a ________ imbalance. We treat this imbalance with _____.
Unfortunately, these only treat the ________ of disease, not the ______.
biochemical
drugs
symptoms
cause
Cells in the brain that act to process and transmit signals and information.
Neurons
The start of information transfer in the neuron begins at the ________, which receives a signal from another neuron.
dendrite
The resting membrane potential of cells is approximately ____. This means that the inside of the cell is _______ with respect to the outside.
-70mV
negative
During depolarization of a neuron, positively charged ____ ions enter the cell through these.
Na+
voltage-gated Na+ channels
During repolarization of a neuron, these ions leave the neuron.
potassium
Only a few potassium channels are open. Potassium can freely move in and out of cells. The membrane potential does not change.
Resting potential.
IF a depolarizing stimulus is received, it opens a few sodium channels. This allows sodium to enter the cell, until this point is reached.
Threshold
If threshold is achieved, other sodium channels open and sodium rushes in. the membrane potential increases further.
rising phase
Sodium channels close and potassium channels open. Potassium rushes out of the cell and the membrane potential decreases. As the membrane potential approaches resting potential even more potassium channels open.
Falling phase
The membrane potential undershoots the RMP due to excess potassium leaving the cell
Hyperpolarization
Describe the transmission of the chemical signal from one neuron, to another.
The action potential reaches the pre-synaptic nerve terminal.
This induces calcium influx into the neuron.
Calcium causes vesicles to fuse with the pre-synaptic membrane, and release NTs into the synpatic cleft.
NTs travel through the synaptic cleft and bind to receptors on the post-synaptic membrane, inducing an action potential in the post-synaptic neuron
What are the major NT classes?
Monoamines (Epinephrine, NE, Dopamine, Serotonin)
Amino acids (Glutamate, GABA, aspartate, glycine)
Other (ACh)
What NTs fall in the monoamine class?
Serotonin, Epinephrine, NE, Dopamine
What NTs fall in the amino acid class?
Glutamate, GABA, aspartate, glycine
What NT falls in the other class?
ACh (acetylcholine)
Excitatory amino acid NTs.
Glutamate, aspartate
Inhibitory amino acid NTs
GABA, glycine
5 ways in which drugs that treat CNS disorders may act.
Replacement Agonists/Antagonists Inhibiting NT breakdown Blocking reuptake Nerve stimulation
The drug acts to replace NTs that are low in diseases
Replacement
A drug that directly binds to receptors on the post-synaptic membrane
Agonists/Antagonists
NT metabolism is inhibited
Inhibiting NT breakdown
NT reuptake into the pre-synaptic membrane is blocked
Blocking reuptake
The drug directly stimulates the nerve causing it to release more NT
Nerve stimulation
Parkinson’s was first described in 1817 by ______ Parkinson.
James
PD is caused by a progressive loss of _________ neurons in the ________ _______ of the brain.
dopaminergic
substantia nigra
Is progressive loss of dopaminergic neurons a normal process of aging?
yes, however in PD, this number is very elevated
There are distinct symptoms of Parkinsons, these are? (6)
Tremor Rigidity Bradykinesis Masklike face Postural instability Dementia
Slowness of movement, especially slow to initiate movements
Bradykinesia
Patient’s cannot show facial expression and have difficulty blinking and swallowing
Masklike face
Balance is impaired; patients have difficulty balancing while walking
Postural instability
Pd is a chronic movement disorder that is caused by an imbalance between ____ and _______ in the brain.
ACh, dopamine
In healthy patients (i.e. without PD, there is a normal balance of ACh and dopamine which results in normal ________ release.
GABA
Describe the NT imbalance, the result of this imbalance and the overall manifestation as a result of the imbalance, in PD.
Decreased dopamine release, thus Ach release exceeds it greatly
GABA release is not inhibited by dopamine, but stimulated by ACh.
Excess GABA release causes the movement disorders of PD
________ inhibits GABA release; _______ stimulates GABA release.
Dopamine
ACh
The etiology of PD is largely _______.
idiopathic
Describe how drugs may play a role in development of PD.
A by-product of illlicit street drug synthesis is MPTP - which causes irreversible death of dopaminergic neurons
Genetics plays a role in predisposing patients to PD, mutations in these 4 genes have been implicated.
Alpha synuclein, parkin, UCHL1, DJ-1
Certain environmental toxins, ________, have been associated with PD
Pesticides
Trauma to the brain predisposes patients for PD.
_____ are known to cause degeneration to dopaminergic neurons. There is a link between _______ induced ______ damage. and Parkinson’s.
ROS
diabetes
oxidative
The main treatment modality in Parkinson’s is what?
Improve the balance between ACh and Dopamine
There are 5 different major classes of drugs that act by increasing dopamine neurotransmission, what are they?
Dopamine replacement - L-DOPA Dopamine agonist Dopamine release Catecholamine-O-Methyltransferase inhibitor Monoamine oxidase-B inhibitor
the most effective drug for PD treatment.
Levodopa
Unfortunately, the beneficial effects of _______ decrease over time as PD progresses.
levodopa
L-DOPA crosses the blood brain barrier by an _______ transport protein.
L-DOPA is ________, but is converted to dopamine in dopaminergic nerve terminals.
Conversion of L-DOPA is mediated by ____________ enzymes in the brain.
The cofactor ________ (vitamin ___) speeds up this reaction
active inactive decarboxylase pyridoxine vitamin B6
What are the reasons why dopamine is not given to treat PD?
Dopamine cannot cross the BBB
Dopamine has a very short half-life in blood
L-DOPA may cause nausea and vomitting due to dopamine mediated activation of the _________ trigger zone in the _______.
chemoreceptor
medulla
Cardiac dysrhythmias may occur when taking L-DOPA, because its conversion to dopamine in the periphery can result in activation of these receptors.
cardiac beta 1 receptors
What are the adverse effects of L-DOPA?
Nausea/vomitting (chemoreceptor trigger zone in the medulla)
Dyskinesias
Cardiac dysrhythmias (dopamine in periphery - cardiac beta 1 receptors)
Orthostatic hypotension
Psychosis
Only approximately _% of the total L-DOPA dose reaches the brain.
The remaining is metabolzied int he peripheral tissues (mostly the _______), before reaching the brain.
Thus, L-DOPA is almost always given with ________, a ________ inhibitor that inhibits the peripheral metabolism of L-DOPA.
In this case, approximately __% of L-DOPA now reaches the brain.
1% intestine carbidopa carboxylase inhibitor 10%
Carbidopa allows a _______ dose of L-DOPA to be administered and _______ the incidence of cardiac dysrhythmias and nausea and vomiting. Explain.
lower
decreases
Lower amount of peripheral metabolism, means there is less dopamine to interact with cardiac beta 1 receptors, and (to a lesser degree), with the chemoreceptor trigger zone int he medulla
There are two types of loss of effects that L-DOPA taking patients may expreince, what are they?
Wearing off - gradual loss of effect
On-off - abrupt loss of effect
Usually occurs at the end of the dosing interval of L-DOPA and indicates that drug levels might be low.
Wearing off
Wearing off of L-DOPA may be minimized by these three methods.
Shortening the dosing interval
Administer with a COMT inhibitor (inhibits L-DOPA metabolism)
Add a dopamine agonist to the therapy
Can occur even when L-DOPA levels are high and is difficult to treat this loss of effect.
On-off
What are the three ways in which on-off may be minimized in L-DOPA treatment?
Divide the medication into 3-6 doses per day
Use a controlled release formulation
Move protein containing meals to the evening
Acts to stimulate release of dopamine from dopaminergic neurons and also blocks dopamine reuptake; also blocks the NMDA receptor.
Dopamine releasers
Dopamine releasers
- Response is ______, usually within - days
Usually used in combination with _______, or alone in the case of ______ PD.
fast, 2-3 days
L-DOPA
mild
The blockade of NMDA receptors by dopamine releasers is thought to decrease this side effect.
Dyskinesia
Side effects of dopamine releasers.
dizziness, nausea, vomiting, lethargy, and anticholinergic side effects
Enzyme that adds a methyl group to dopamine and L-DOPA, making them inactive
COMT
Adverse effects of COMT inhibitors are similar to those of L-DOPA, what are they?
Nausea/vomitting
orthostatic hypotension
vivid dreams and hallucinations
Enzyme that oxidatively metabolizes dopamine and L-DOPA, inactivating them.
Located in these two areas.
Monoamine oxidase-B
Brain and periphery
Inhibiting oxidative metabolism of L-DOPA allows more conversion to dopamine in the brain, and also allows more dopamine to remain in _______ ______ and be released following an action potential.
nerve terminals
Adverse effects of MAO-B inhibitors.
insomnia, orthostatic hypotension, dizziness
Can patients taking MAO-B inhibitors have tyramine containing foods?
Yes, as at therapeutic levels, these drugs do not inhibit MAO-A in the liver. Thus no hypertensive crisis
Excess acetylcholine causes what types of symptoms in PD patients?
Urinary incontinence, salivation, diaphoresis
Block the binding of ACh to its receptor.
Anticholinergic drugs
Anticholinergic drugs may increase the effectiveness of _____. In doing so, these drugs may decrease the incidence of these ACh related symptoms.
L-DOPA
urinary incontinence, diaphoresis, salivation
