Module 14 Flashcards
1
Q
What is neuropharmacology
A
study of how drugs affect the function of the central nervous system
2
Q
How do drugs affect neuropharmacology?
A
treat the symptoms not the cause
3
Q
What is the brain composed of?
A
millions of neurons
4
Q
what are neurons
A
cells in the brain that act to process and transmit signals and information
5
Q
How do neurons function
A
excitable cells that transmit information by electrical and chemical signalling
6
Q
where does start of information transfer begin?
A
the dendrite
7
Q
what are action potentials
A
electrical signalling that propagate along the axon of the neuron
8
Q
how does action potential transmit from presynaptic nerve terminal?
A
release of neurotransmitters (chemical signalling) to pass across the synapse
9
Q
Action potentials role
A
cell-to-cell communication
10
Q
what is the resting membrane potential of cells
A
-70mV
11
Q
What is depolarization
A
positively charged Na+ ions enter the cell through voltage gated Na+ channels
12
Q
What is repolarization
A
Na+ channels close and potassium channels open allowing potassium to leave the cell during repolarization (current overshoots)
13
Q
Synapse
A
junction between a presynaptic and postsynaptic neuron
14
Q
What happens once an action potential reaches a synapse? (4)
A
1) influx of calcium
2) calcium causes vesicles containing neurotransmitters to fuse with the pre-synaptic membrane
3) vesicles release neurotransmitters into the synaptic cleft (the space between the neurons)
4) neurotransmitters bind to receptors on the post-synaptic nerve membrane and the signal continues
15
Q
Classes of neurotransmitters (3)
A
- monoamines
- amino acids
- other
16
Q
4 monoamines
A
- norepinephrine
- epinephrine
- dopamine
- serotonin
17
Q
Norepinephrine (associated disease, type)
A
- depression and anxiety
- monoamine
18
Q
Epinephrine (associated disease, type)
A
- anxiety
- monoamine
19
Q
Dopamine (associated disease, type)
A
- parkinson’s and schizophrenia
- monoamine
20
Q
Serotonin (associated disease, type)
A
- depression and anxiety
21
Q
4 Aminoacids
A
- Glutamate
- Asparate
- GABA
- Glycine
22
Q
Excitatory amino acids
A
- glutamate
- aspartate
23
Q
Inhibitory amino acids
A
- GABA
- Glycine
24
Q
Glutamate (associated disease, type)
A
- alzheimer’s
- excitatory amino acid
25
Aspartate (associated disease, type)
- Alzheimer's
| - excitatory amino acid
26
GABA (associated disease, type)
- anxiety
| - inhibitory amino acid
27
Glycine (associated disease, type)
- anxiety
| - inhibitory amino acid
28
Acetylcholine (associated diseases)
alzheimer's and Parkinson's
29
Basic mechanisms of CNS drug action (5)
1) replacement
2) agonists/antagonist
3) inhibiting neurotransmitter breakdown
4) blocking reuptake
5) nerve stimulation
30
Replacement (CNS drug action)
the drug acts to replace neurotransmitters that are low in diseases
31
Agonists/Antagonist (CNS drug action)
a drug that directly binds to receptors on the post-synaptic membrane
32
Inhibiting neurotransmitter breakdown (CNS drug action)
neurotransmitter metabolism is inhibited
33
Blocking reuptake (CNS drug action)
neurotransmitter reuptake into the pre-synaptic neuron is blocked
34
Nerve stimulation (CNS drug action)
the drug directly stimulates the nerve causing it to release more neurotransmitter
35
Parkinson's disease
- progressive loss of dopaminergic neurons in the substantia nigra of the brain
- normal to lose some, but patients with PD lose 70-80% of dopaminergic neurons
36
Parkinson's disease - prognosis
- without treatment = progresses in 5-10 years to a state where patients are unable to care for themselves
37
Symptoms of Parkinson's disease (6)
1) Tremor - mostly in the extremities including hands, arms, legs, jaw, face
2) Rigidity (joint stiffness and increased muscle tone)
3) bradykinesia (slowness of movement/slow to initiate movemnts)
4) masklike face (cant show face expression and have difficulty blining and swallowing)
5) postural instability (balance impaired)
6) dementia (later in disease)
38
Pathophysiology of Parkinson's disease
1) dopamine release is decreased, so there is not enough dopamine present to inhibit GABA release
2) there is a relative excess of acetylcholine compared to dopamine, which results in increased GABA release
3) excess GABA release causes the movement disorders
39
Etiology of Parkinsons (6)
- largely idopathic (aka unknown) but there are 5 factors
1) drugs - a by product of ilicit street durgs synthesis produces MPTP, which causes irreversible death of dopaminergic neurons
2) genetics (mutations in 4 gens = alpha synuclein, parkin, UCHL1 and DJ-1)
3) Environmental Toxins (certain pesticides)
4) brain trauma
5) oxidative stress (ex diabetes induced oxidative damage and PD)
40
4 mutations to lead to parkinsons
- alpha synuclein, parkin, UCHL1, DJ-1
41
Drug treatment for Parkinson's disease (2)
- ideal = reverse degeneration of dopaminergic
- either....
1) increase dopamine
2) decrease acetylcholine
42
5 drugs that increase dopamine neurotransmission
1) dopamine replacement
2) dopamine agonist
3) dopamine releaser
4) catecholamine-O-Methyltransferase Inhibitor
5) monoamine oxidase-B (MAO-B) inhibitor
43
Levodopa
dopamine replacement drug to treat parkinson;s
44
What is the most effective drug for treating parkinson;s disease
- levodopa (dopamine replacement)
| - however beneficial effects of L-DOPA decrease over time as the disease progresses
45
L-DOPA mechanism of action (3)
- L-DOPA is inactive on its own but is converted to dopamine in dopaminergic nerve terminals
- conversion of L-DOPA to dopamine is mediated by decarboxylase enzymes in the brain
- the cofactor pyridoxine (vitamin B6) speeds up this reaction
46
L-DOPA and getting into cells
crosses the blood brain barrier via an active transport protein
47
Why give levodopa instead of dopamine (2)
1) Dopamine does not cross the BBB
| 2) dopamine has a very short half life in blood
48
L-DOPA adverse effects
- nausea and vomiting (dopamine activation of chemoreceptors)
- dyskinesias (abnormal involuntary movements)
- cardiac dysrhythmias (L-DOPA to dopamine in periphery can intervere with cardiac beta 1 receptors)
- orthostatic hypotension
- psychosis (20% of patients will have hallucinations, vivid dreams, paranoid thoughts)
49
L-DOPA - peripheral metabolism
- only 1% of total DOPA dose reaches the brain, as the remaining dose is metabolized in the peripheral tissue (Esp. intestine)
50
L-DOPA - peripheral metabolism - solution
- solution = give L-DOPA with a carbidopa (decarboxylase inhibitors that inhibits peripheral metabolism)
- 10% of L-DOPA reaches the brain
- RESULT = lower dose of L-DOPA administered, decreased risk
51
2 types of loss of effect from L-DOPA
1) wearing off (gradual loss of effect)
| 2 on-off - abrupt effect
52
Wearing off (loss of effect from L-DOPA)
- usually occurs at the end of the dosing interval and indicates that drug levels might be low
53
how to minimize Wearing off (loss of effect from L-DOPA) (3)
1) shortening the dosing interval
2) give a drug that inhibits L-DOPA metabolism (ex a COMT inhibitor)
3) add a dopamine agonist to the therapy
54
On-Off (loss of effect from L-DOPA)
- can occur even when drug levels are high
55
how to minimzie On-Off (loss of effect from L-DOPA) (3)
1) dividing the medication into 3-6 doses per day
2) using a controlled release formulation
3) moving protein-containing meals to the evening
56
Dopamine agonist - Parkinson's disease
- produce their effects by directly activating dopamine receptors on post-synaptic cell membrane
57
Dopamine agonist - use
- not as effective as L-DOPA
| - often used as first line treatment for patients with milder symptoms
58
Adverse effects of dopamine agonist (3)
- hallucinations
- daytime drowsiness
- orthostatic hypotension
59
Dopamine Releaser - action
- acts to stimulate release of dopamine from dopaminergic neurons and in addition, it also blocks dopamine reuptake into pre-synaptic nerve terminals, and blocks NMDA receptors
60
Dopamine Releaser - response time
- rapid, 2-3 days
61
Dopamine releaser - efficacy
not as effective as L-DOPA
62
Dopamine releaser - effect of blocking NMDA
decrease dyskinesia side effect of L-DOPA
63
Dopamine releaser - adverse effects
- dizziness
- nausea
- vomiting
- lethargy
- anticholinergic side effects
64
Catecholamine-O-Methyltransferase (COMT)
- COMT - an enzyme that adds methyl group to dopamine and L-DOPA
- methylated dopamine and L-DOPA = inactive
65
Catecholamine-O-Methyltransferase (COMT) inhibitor
- inhibiting COMT results in a greater fraction of L-DOPA and L-DOPA available to be converted to dopamine
- moderately effective (combine with L-DOPA)
66
Catecholamine-O-Methyltransferase (COMT) inhibitor - adverse effects
- similar to adverse effects of L-DOPA =
- nausea
- orthostatic hypotension
- vivid dreams
- hallucinations
67
Monoamine oxidase-B (MAO-B)
- enzyme that metabolizes dopamine and L-DOPA through oxidation (thus inactivating them)
- present in the periphery and in the brain
68
Monoamine oxidase-B (MAO-B) inhibitor
- inhibiting oxidative metabolism of L-DOPA allows more conversion to dopamine, and allows more dopamine to remain in nerve terminals and be released
69
Monoamine oxidase-B (MAO-B) inhibitor efficacy
moderately effective, often combined with L-DOPA
70
Monoamine oxidase-B (MAO-B) inhibitor adverse effects
- insomnia
- orthostatic hypotension
- dizziness
- *at therapeutic doses, MAO-B inhibitors do not inhibit MAO-B in liver --> dont cause hypertensive crisis when patients eat tyramine-containing foods
71
Acetylcholine excess
- diaphoresis (excess sweating)
- salivation
- urinary incontinence
