Lecture 14a Flashcards
CNS drugs part I (87 cards)
1
Q
What is neuropharmacology?
A
study of how drugs affect the function of the central nervous system
2
Q
What are most CNS disorders mediated by?
A
biochemical imbalance
3
Q
What are neurons?
A
excitable cells in the brain that act to process and transmit signals and information
4
Q
what type of signalling do neurons use to transmit information?
A
electrical and chemical
5
Q
What is the process a neuron goes through to transmit information?
A
- dendrite receives a signal from another neuron
- causes action potentials (electrical signalling) to propagate along the axon of the neuron
- action potential reaches pre-synaptic nerve terminal causing release of neurotransmitters (chemical signalling)
- neurotransmitters pass signal along via synapse to the next neuron
6
Q
How do action potentials work?
A
- cell starts at resting membrane potential (inside of cell is negative wrt outside)
- depolarization: Na+ ions enter cell through voltage gated Na+ channels
- repolarization: Na+ channels close and K channels open allowing K to leave the cell
- the current overshoots resting membrane potential and returns to baseline
7
Q
What occurs at a synapse?
A
- action potential reaches pre-synaptic nerve terminal causing influx of Ca
= vesicles containing neurotransmitters to fuse with the pre-synaptic membrane
= vesicles release neurotransmitters into the synaptic cleft (space btwn neurons) - neurotransmitters bind to receptors on post-synaptic nerve membrane & signal continues
8
Q
What are neurotransmitters?
A
chemicals that transmit a signal across a synapse
9
Q
What are the 3 classes of neurotransmitters?
A
- monoamines
- amino acids
- other
10
Q
What are the different types of monoamine neurotransmitters?
A
- norepinephrine (depression & anxiety)
- epinephrine (anxiety)
- dopamine (Parkinson’s and Schizophrenia)
- Serotonin (depression and anxiety)
11
Q
What are the different types of amino acid neurotransmitters?
A
- excitatory: glutamate, aspartate; (Alzheimer’s)
- Inhibitory: GABA, glycine (Anxiety)
12
Q
What are some Other neurotransmitters?
A
- Acetylcholine (Alzheimer’s and Parkinson’s)
13
Q
In what ways can drugs act to treat CNS disorders?
A
- Replacement (replace neurotrans. that are low in diseases)
- agonists/Antagonists (bind receptors on the post-synaptic mem)
- inhibiting neurotransmitter breakdown (neurotrans. metabolism blocked)
- blocking reuptake (reuptake into the pre-synaptic neuron blocked)
- nerve stimulation (stimulates nerve causing neurotrans. release)
14
Q
What is Parkinson’s disease caused by?
A
a progressive loss of dopaminergic neurons (imbalance of acetylcholine and dopamine) (70%-80%) in the substantia nigra of the brain
- progresses in 5-10 yrs to state where patients cannot care for themselves
15
Q
What are the symptoms of PD?
A
- tremor
- rigidity
- bradykinesia (slowness of movement, slow to initiate movement)
- masklike face (no facial expression, hard to blink/swallow)
- postural instability
- Dementia
16
Q
What are the 3 reasons PD symptoms arise?
A
- dopamine release is decreased, so not enough dopamine to inhibit GABA release
- relative excess of acetlycholine = increased GABA release
- excess GABA release causes the movement disorders
17
Q
What is the main cause (etiology) of PD?
A
largely idiopathic (unknown)
18
Q
What are some factors thought to be associated with PD development?
A
- drugs
- genetics
- environmental toxins
- brain trauma
- oxidative stress
19
Q
Why are drugs a factor in PD development?
A
street drug synthesis produces the compound MPTP which kills dopaminergic cells
20
Q
Why are genetics a factor in PD development?
A
mutations in 4 genes (alpha synuclein, parkin, UCHL1, and DJ-1) predispose patients to PD
21
Q
Why are environmental toxins a factor in PD development
A
certain pesticides associated in pd
22
Q
Why is brain trauma a factor in PD development?
A
increases the risk
23
Q
Why is oxidative stress a factor in PD?
A
reactive O2 species known to cause degeneration of dopaminergic neurons
link btwn diabetes induced oxidative damage and PD
24
Q
How does drug treatment of PD improve the dopamine -acetylcholine balance?
A
- increasing dopamine
2. decreasing acetylcholine
25
What are the 5 different major classes of drugs that act by increasing dopamine neurotransmission?
1. dopamine replacement
2. dopamine agonist
3. dopamine releaser
4. catecholamine-O-Methyltransferase Inhibitor
5. monoamine oxidase (MAO-B) inhibitor
26
What drug is used in dopamine replacement?
Levodopa (L-dopa)
27
Why not just give dopamine?
- does not cross the blood brain barrier
| - has a very short half-life in blood
28
How does L-dopa work?
- crosses the BBB by an active transport protein
- activated when converted to dopamine in dopaminergic nerve terminals mediated by decarboxylase enzymes
- cofactor pyriodoxine (vit B6) speeds up this rxn
- most effective drug for treating PD
- beneficial effects decrease overtime as disease progresses
29
What are the adverse effects of L-Dopa?
- nausea and vomiting
- dyskinesias (abnormal involuntary movements)
- cardia dysrhythmias (accidental activation of cardiac beta 1 receptors)
- orthostatic hypotension (rapid drop in BP when standing up)
- psychosis
30
How much L-Dopa reaches the brain on its own and why?
- only ~ 1% bc its metabolized in the peripheral tissue (mostly in intestine) b4 reaching the brain
31
What is L-Dopa usually given with?
- carbidopa (decarboxylase inhibitor)
- inhibits peripheral metabolism of L-dopa
- lets about 10% total L-dopa reach the brain
32
What are other benefits of combining L-dopa with carbidopa?
- allows lower dose of DOPA to be administered
| - decreases incidence of cardiac dysrhythmias, nausea and vomiting
33
What two types of loss of effect can be experienced when taking LDOPA?
1. wearing off (gradual loss)
| 2. on-off (abrupt loss)
34
When does wearing off usually occur?
- at the end of the dosing interval
| - indicates that drug levels might be low
35
How can wearing off be minimized?
1. shortening the dosing interval
2. give a drug that inhibits LDOPA metabolism
3. add a dopamine agonist to the therapy
36
When does on-off occur?
- can occur even if drug levels are high
37
How can on-off be minimized?
1. dividing the medication into 3-6 doses per day
2. using a controlled release formulation
3. moving protein-containing meals to the evening
38
How do dopamine agonists produce effects?
- directly activating dopamine receptors on the post-synaptic cell membrane
- not as effective as LDOPA but often used at first line treatment for patients with milder symptoms
39
What are the adverse effects of dopamine agonists?
1. hallucinations
2. daytime drowsiness
3. orthostatic hypotension
40
How do dopamine releasers produce their effect?
- stimulate release of dopamine from dopaminergic neurons
- also block dopamine reuptake into pre-synaptic nerve terminals
- also block NMD receptors (thought to decrease dyskinesia side effect of LDOPA)
- 2-3 days to kick in
- usually used in combo with LDOPA
41
What are the adverse effects of dopamine releasers?
- dizziness
- nausea
- vomiting
- lethargy
- anticholinergic
42
How do COMT inhibitors produce their effect?
- COMT adds a methyl group to dopamine and to LDOPA making them inactive and able to activate dopamine receptors
- inhibiting COMT = greater amnt of LDOPA available to be converted to dopamine
- moderately effective and usually + LDOPA
43
What are the adverse effects of COMT inhibitors?
- nausea
- orthostatic hypotension
- vivid dreams
- hallucinations
44
How do MAO-B inhibitors produce their effect?
- is present in both periphery and brain
- MAO-B metabolizes dopamine and dopa via oxidation making them inactive
- inhibiting MOA-B allows more LDOPA conversion to dopamine + more dopamine to remain in nerve terminals and be released
- moderately effective and + LDOPA
45
What are the adverse effects of MOA-B inhibitors?
- insomnia
- orthostatic hypotension
- dizziness
46
What does the relative excess of acetylcholine in PD cause?
- diaphoresis (excess sweating)
- salivation
- urinary incontinence
47
What are anticholinergic drugs and how do they produce their effect?
- block the binding of acetylcholine to its receptor
- also called cholinergic antagonists
- increase effectiveness of LDOPA which decreased incidence of diaphoresis, salivation, and incontinence
48
What are the adverse effects of anticholinergic drugs?
- dry mouth
- blurred vision
- urinary retention
- constipation
- tachycardia
- hallucination, confusion, delirium (in elderly patients)
49
What is alzheimer's disease?
- irreversible form of progressive dementia (and most common form)
50
What are the symptoms of alzheimers?
- memory loss
- problems with language
- judgement
- behaviour
- intelligence
- confusion
- problems conducting routine tasks
51
What is the pathophysiology of alzheimers?
- degeneration of cholinergic neurons in the hippocampus early in disease
- followed by degeneration of neurons in the cerebral cortex
- so linked to decrease cholinergic nerve function (controls/excrete acetylcholine release)
52
When can alzheimers be diagnosed?
- not definitively until after death when brain sample can be analyzed
53
What are the hallmarks of alzheimers?
- neurofibrillary tangles
| - neuritic plaques
54
What are neurofibrillary tangles?
- form inside neurons when microtubule arrangement is disrupted
= abnormal production of Tau (protein) which is responsible for forming cross-bridges between microtubules keeping their structure
55
What are neuritic plaques?
- found outside neurons
- composed of protein beta amyloid which killed hippocampal cells and caused alzheimer like symptoms when injected into monkeys
56
What are the causes of Alzheimers?
- mostly unknown
- 20% genetically determined (ex. 2 copies of apolipoprotein E4 = increased risk bc APO E4 promotes formation of neuritic plaques by binding to beta amyloid promoting deposition) (ex. increased risk in those with mutations in the amyloid precursor protein gene)
- mutations in DN may cause it
- head injury increases risk
57
What are the 2 classes of drugs we have to treat Alzheimers?
- cholinesterase inhibitors (inhibit breakdown of acetylcholine)
- NMDA receptor antagonists (block NMDA mediated increases in intracellular calcium)
58
How do cholinesterase inhibitors produce an effect?
- inhibit metabolism of acetylcholine by the enzyme acetylcholinesterase
= more acetylcholine to remain in the synaptic cleft to exert its actions
- can only enhance cholinergic neurotransmission in remaining healthy neurons
- minimal benefits of some measures of memory
- somewhat effective
59
What are the adverse effects of cholinesterase inhibitors?
- nausea and vomiting
- diarrhea
- insomnia
60
What is the NMDA receptor?
- is a calcium channel that is blocked by magnesium at rest
- glutamate binds to NMDA receptor = magnesium dissociates = calcium can enter post-synaptic neuron
- glutamate leaves receptor = magnesium returns = blocks entry of calcium
61
What happens with the NMDA receptor and Alzheimer's disease?
- excess glutamate release = NMDA receptor open allowing excess calcium to enter the cell
62
How is excess calcium detrimental?
1. detrimental to learning and memory (overpowers the normal calcium signal)
2. causes degradation of neurons (too much calcium is toxic)
63
What do NMDA receptor antagonists do?
block calcium influx into the post-synaptic neuron
64
What are the adverse affects of NMDA receptor antagonists?
- they are well tolerated
65
What is schizophrenia?
- makes it hard to tell between real and unreal experiences, to think logically, have normal emotional response, and behave normally in social situations
- do not usually have multiple personalities and are not usually violent
- common mental disease
66
when does schizophrenia usually begin?
- adolescence or early adulthood
67
what is the difference between positive and negative schiz?
+: exaggerate or distort normal neurological function
| -: loss of normal neurological function
68
What are the positive symptoms of Schiz?
- delusions
- hallucinations
- agitation
- paranoia
- combativeness
- disorganized speech
- disorganized thinking
69
What are the negative symptoms of schiz?
- social withdrawal
- poverty of speech
- poor self care
- poor insight
- poor judgement
- emotional withdrawal
- blunted afect
- lack of motivation
70
What is the cause of schiz?
- largely unknown
71
What are the factors that increase risk for developing shiz?
- family history (genetic component)
- drug abuse ( crystal meth, angel dust, LSD all known to cause shiz)
- low birth weight (<5.5 lbs at risk)
- low IQ (lower the IQ the greater the risk)
72
What are the brain regions that are affected by schizophrenia?
- basal ganglia (paranoia and hallucinations)
- frontal lobe (difficulty planning actions and organizing thoughts)
- limbic system (contributes to agitation)
- auditory system (hallucinations)
- occipital lobe (interpreting images, reading facial expressions, recognizing motion)
- hippocampus (learning and memory decreased)
73
what is the pathophysiology of schiz?
- disorder with increase dopaminergic nerve transmission (drugs that block dopaminergic nerve function decrease some of the +ve symptoms, some PD drugs cause schiz like side effects)
- 5-HT (serotonin): decreased # of 5-HT2A and increased 5-HT1A in frontal cortex
- glutamate: binds to and activates NMDA receptors
74
What things may psychiatrists evaluate before diagnosis of schiz?
1. changes in function from before illness
2. developmental background
3. family history
4. response to medication
5. brain scans (schiz has enlarged ventricles but not definitive diagnosis)
75
How is schiz usually treated?
- blocking dopamine and/or serotonin neurotransmission in the brain
76
What are the two classifications of schiz drugs?
- conventional antipsychotics
- atypical antipsychotics
(differ in their mechanism of action and side effect profile)
77
What are conventional antipsychotics and how do they work?
- primarily block dopamine 2 receptors in the mesolimbic area
- also block receptors for acetylcholine, histamine, and norepinephrine
- potency directly proportional to ability to inhibit D2 receptors
- more affective at treating positive symptoms
- initial effect seen 1-2 days, substantial improvement betwn 2-4 weeks
78
What are the adverse effects of conventional antipsychotics?
- extrapyramidal symptoms
- sudden high fever
- anticholinergic effects
- orthostatic hypotension
- sedation
- skin reaction
79
What are extrapyramidal symptoms?
- movement disorders that resemble the symptoms of PD
| - are due to blockade D2 receptors
80
What are the 4 differently types of EPS?
1. acute dystonia
2. Parkinsonism
3. akathesia
4. tardive dyskinesia
81
What is acute dystonia?
involuntary spasm of the muscles in the face, tongue, neck or back, typically occurs early in the therapy
82
What is parkinsonism?
- bradykinesia, mask-like faces, rigidity, and stooped posture are common
- may treat with an anticholinergic drug to help relieve these symptoms (LDOPA must be avoided)
83
What is akathesia?
pacing, squirming, and a desire to continually be in motion (typically occurs early in treatment)
84
What is tardive Dyskinesia?
- irreversible involuntary twisting and writhing of the face, tongue along with lip-smacking
85
What are atypical antipsychotics?
- block both dopamine D2 receptors and 5-HT1A and 5-HT 2A receptors
- affinity for D2 receptors v low, effects mostly bc of blockade of the 5-HT receptors
86
Compared to conventional antipsychotics, what do atypical antipsychotics have?
1. the same efficacy vs +ve symptoms of schiz
2. a much greater efficacy vs negative symptoms
3. much lower risk of developing EPS (bc less D2 receptors)
87
What are the adverse effects of atypical antipsychotics?
- sedation
- orthostatic hypotension
- weight gain
- risk of developing type II diabetes
- anticholinergic effects
