Drug Actions in the CNS- Craviso Flashcards
1
Q
What is an important factor in CNS pharm?
A
the blood brain barrier (BBB)
2
Q
What does the BBB do?
A
maintains brain homeostasis and transport of endogenous and exogenous compounds by controlling their selective and specific uptake, efflux, and metabolism in the brain
3
Q
What will the BBB allow to go through channels from the blood to the brain?
A
Small ions and water
K+, Cl-, Na+, H20
4
Q
What will the BBB allow to go through membrane transport (passive diffusion) from the blood to the brain?
A
small lipophilic molecules (o2, co2, anesthetics, barbiturates, ethanol, nicotine, caffeine)
5
Q
What will the BBB allow to go through carrier-mediated transport (solute carriers)?
A
Energy transport systems (glucose, monocarboxylates, lactate, pyruvates (MCT1) creatine)
Amino acid transport systems
6
Q
What will the BBB allow to go through receptor-mediated transport?
A
insulin, transferrin, leptin, IgG, TNFalpha
7
Q
What will the BBB allow to go through the adsorption-mediated transcytosis systems?
A
histone, albumin
8
Q
What will the BBB allow to go through the active efflux transporters?
A
P-glycoprotein****
BRCP
MRP
9
Q
What is P-glycoprotein?
A
it is an active efflux transporter that pumps many foreign substances out of cells (i.e it can kick out drugs, toxins and stuff out of the brain)
10
Q
What is this:
belongs to a family of membrane transporters that modulate drug distribution
A
P-glycoprotein (P-gp)
11
Q
Capillary endothelial cells of the BBB express high levels of (blank) as compared to other tissues
A
P-gp
12
Q
What are some substrates that the active efflux transporter P-gp will transport?
A
- chemotherapeutic agents (vinka alkaloids, doxorubicin)
- antibiotics such as rifampicin
- anti-epileptic drugs
13
Q
What is the clinical significance of P-gp?
A
a drug that is a substrate for active efflux transporters result in VERY LOW levels of the drug in the brain
14
Q
It has been proposed that (blank) of P-gp plays a role in drug refractory epilepsy and multidrug resistance in general
A
overexpression
15
Q
Membrne transport of drugs by passive diffusion depends on the (Blank) of the drug
A
lipid solubility
16
Q
The greater the lipid solubility, the (slower/faster) a drug enters the CNS
A
faster
17
Q
In general, the oil-water partition coeffcient indicates the relationship between lipid solubility and brain uptake. However there are exceptions, what are they and why?
A
glucose and L-dopa are not lipidphilic however they have transporters in the brain so get taken up in the brain quickly
Phenobarbital and phenytoin are highly lipidphiic but get metabolized quickly and bind to plasma binding proteins so do not get taken up by the brain
18
Q
What are the regions where the BBB is more permeable?
A
- area postrema
- median eminence
- pituitary gland
- pineal gland
- choroid plexus capillaries
19
Q
(blank) and (blank) cause an increase in BBB permeability
A
Bacterial and viral infections
20
Q
What is the most promising route for global drug delivery to the brain? WhY?
A
vascular route
Because each neuron has its own capillary (for oxygen, ridding of waste, and nutrients)
21
Q
Can you directly and locally deliver a drug to a particular part in the brain?
A
yes
22
Q
Psych drugs act by doing what (generally speaking)?
A
enhancing or inhibiting neural excitability usually by targeting a specific transmitter system
23
Q
What are drugs targeting pre-synaptically?
A
-effects on synthesis, storage, release, reuptake and/or degradation of neurotransmitters; agonist or antagonist activity at nerve terminal autoreceptors
24
Q
What are drugs targeting post-synaptically?
A
receptor agonist, antagonist, or modulatory activity, degredation of neurotransmitters
25
How else can drugs influence behavior and neural excitability?
1. effects on voltage-gated ion channels
| 2. non-selective effects on membranes
26
What do you target in antiemetic therapy?
blocking chemoreceptor trigger zone, at afferent inputs to the emetic center and in emetic center
27
Where do you find the chemoreceptor trigger zone?
area postrema
28
What directly affects the chemoreceptor trigger zone?
blood borne emetics (cytotoxic drugs etc)
29
What indirectly affects the chemoreceptor trigger zone?
local irritants
blood borne emetics
vagal and sympathetic afferents
30
What directly affects the emetic center (found in medulla)?
chemoreceptor trigger zone, solitary tract nucleus, cereblellum (inner ear motion), higher centers (memory, fear, anticipation)
31
How do you prevent nausea and vomiting?
suppress emetic center
32
What are the major neurotransmiters involved with nausea and vomiting?
NK (neurokinin), Dopamine, 5-HT3
33
What do you use antiemetics drugs for?
- preventon and tx of chemotherapy induced (CTI) nausea and vomiting
- treating radiation induced (RI) and post-operative (PO) emesis
34
How do 5HT3 receptor antagonists work?
block 5ht3 receptors and thus inhibit sodium influx, and block intestinal vagal affarents
35
What are the 2 important 5-HT3 receptor antagonists?
Ondansetron (zofran)
| Granisetron (kytril)
36
How do you give Ondansetron (zofran)?
oral, oral soluble film, IV
37
How do you give Granisetron (Kytril)?
oral, IV, transdermal pathc (Sancuso)
38
What is the important NK1 (Substance P/neurokinin) receptor antagonist?
Aprepitant (Emend)
39
How do you give Aprepitant (emend)?
oral and IV (fosaprepitant)
40
What antiemetic do you give someone before you knock them out in surgery so that when they wake up they wont vomit from the anesthesia?
ondansetron (zofran)
41
What is the best way to give medication to someone who needs antiemetics?
Combine 5HT3 antagonist with a NK1 antagonist
42
Wht besides 5ht3 antagnoists and NK1 antagonists can you use to treat nausea and vomiting (antiemetic)?
- corticosteroids
| - D2 receptor antagnoists
43
What is the important corticosteroid used as an antiemetic?
Dexamethasone
44
How can you give dexamethasone?
oral, IV
45
How do D2 receptor antagonists work as antiemetics?
-act peripherally to enhance GI motility
46
When do you use D2 receptor antagonists?
for treating CTI nausea and vomiting and for treating unproductive nausea and vomiting
47
What is the important D2 receptor antagonist?
Metoclopramide (reglan)
48
How do you give metoclopramide (reglan)?
Oral, IM, IV
49
What are the SEs of D2 receptor antagonists?
Dystonias
Tardive dyskinesia
restlessness, fatigue, headache, insomnia, confusion
50
How do oral cannabinoids work as antiemetics?
work at high cortical centers
51
When do you use oral cannabinoids as antiemetics?
with other antiemetics for treatment of breakthrough or refractory emesis
52
What is the important oral cannabinoid?
Dronabinol (marinol)-synthetic form of THC
53
What are the SEs of oral cannabinoids?
euphoria, dysphoria, hallucinations; abuse potential
54
What else do you use marijuana for?
to decrease pain, inflammation, and spasticity
55
What is breakthrough, refractory emesis?
when you vomit as soon as the antiemesis is removed
56
What are the drugs typically used to control non-productive nausea and vomiting?
D2 receptor antagonists (phenothiazines) and H1 receptor antagonist
57
What is the D2 receptor antagonists (phenothiazines) used to control non-productive nausea and vomiting?
promethazine (phenergan)
58
How do you give promethazine (phenergan)?
oral, suppositories, IM, IV
59
What else can you use promethazine (phenergan) for?
as an antihistamine (blocks histamine H1 receptors)
60
D2 receptor ntagonists also block (blank) receptors
mACh
61
H1 receptor antagonists also block (blank) receptors.
mACh
62
What is the most impoortant H1 receptor antagonist?
Doxylamine plus pyridoxine (Diclegis)
63
What is doxylamine plus pyridoxine (Diclegis) used for?
delayed-release combination for nausea and vomiting of pregnancy
64
What are the side effects of doxylamine plus pyridoxine (Diclegis)?
sedation and antimuscarinic effects
65
What H1 receptor antagonists are used for motion sickness?
- Dimenhydrinate (dramamine)
| - Meclizine (antivert)
66
How do you administer Dimenhydrinate (dramamine)?
oral, IM, IV
67
How do you adminster Meclizine (antivert)? What else can you use Meclizine for?
Orally
| vertigo
68
What are the muscarinic (mACh) receptor antagonists that are used for long-term, sustained control of motion sickness?
Scopolamine (transderm scop)
69
What are the 2 types of drugs used for motion sickness?
- H1 receptor antagonist
| - Muscarinic (mACh) receptor antagonist
70
What are these:
skin patch placed behind the ear that produces less side effects than via the oral route; however, some are highly sensitive to the drowsiness and effects on concentration
Scopolamine (transderm scop)
71
What is the main goal of antiseizure therapy?
involves multiple strategies to prevent excessive synchronized neuronal discharges w/out impeding normal neuronal function
72
One way antiseizure therapy works, is by enhancing (blank) neurotransmission.
GABAergic
73
What are the four ways to enhance GABAergic neurotransmission?
1. enhance synthesis
2. block degredation
3. block reuptake
4. enhance postsynaptic GABA-A receptor activity
74
How does Tigabine work?
blocks GABA reuptake
75
How does Benzodiazepines and Phenobarbital work?
Enhances postsynaptic GABA-A receptor activity
76
How does Vigbatrin work?
it blocks GABA degredation
77
What can you attentuate to work as an antiseizure therapy?
glutaminergic neurotransmission
78
How does gabapentin and pregabalin work ?
blocks L-type calcium channels resulting in decreased Glutamate release ALSO upreguates GABA acting as an agonist
i.e attenuates gluatminergic neurotransmission.
79
How does Levetiracetam work?
Modulates release of glutamate----attenuates glutaminergic neurotransmission
80
How does Felbamate work?
blocks the NMDA receptor thus reduces glutaminergic neurotransmission
81
How does topiramate work?
blocks AMPA and Kainate receptors and thus attenuates glutaminergic neurotransmission
82
What drugs modify ion conductance through channels presynaptically and are used as antiseizure therapies?
Phenytoin, carbamazepine, lamotrigine, retigabine
83
What drugs modify ion channels postsynaptically and are used as antiseizure therapies?
ethosuximide, valproate
84
What neurotransmitter is deficient in Alzheimers?
Acetylcholine (ACh)
85
In Alzheimers disease, what do you lose that causes the loss in acetylcholine (ACh)?
loss of hippocampal pyramidal neurons and basal forebrain cholinergic neurons
86
What will the loss of hippocampal neurons cause deficits in?
memory and cognition
87
How do you treat alzheimers?
increasing ACh levels using cholinesterase inhibitors
AND
open channel blocker of NMDA receptors
88
What are the cholinesterase inhibitors you use to treat alzheimers?
Donepezil (aricept)
| Ravistigmine (excelon)
89
What low affinity open channel blocker of NMDA receptors do you use to treat alzheimers?
Memantine (namenda)
90
In alzheimers, the NMDA receptor opens pathoglocially this is why Memantine works. T OR F
T
91
What neurotransmitter is deficient in parkinson's disease?
dopamine
92
How does parkinsons's happen?
you get a progressive loss of dopaminergic (DM) neurons in the substantia nigra, leading to a shortage of DM in the extrapyramidal movement circuit
93
What is the primary treatment for parkinson's disease?
L-dopa and DM agonists
94
Do the drugs that treat Alzheimer's disease and Parkinson's disease stop the progression of the disease?
no they just slow the process
95
What can be a side effect of memenatine?
can cause exocitoxicity
96
What is an inherited disorder due to a mutation in the protein hutingtin (htt)?
huntington's disease (HD)
97
What is chorea and what disease is characterized by this?
irregular, unpredictabe involuntary muscle jerks at different parts of the body that impair voluntary activity that is the result of a loss of neurons from structures of the basal ganglia, imbalances both in GABA functions (diminished) and dopamine functions (enhanced)
98
How do you treat huntingotns disease (HD)?
- Tetrabenazine (xenazine)
| - D2 receptor antagonists
99
Wht does tetrabenazine (xenazine) do?
a selective and reversible centrally-acting dopamine depleting drug (inhibits VMAT2)
100
What does the D2 receptor antagonist do for huntingtons?
to control abnormal movements and relieve the psychosis that accompanies the disease
101
What are some other classes of drugs that you give to people with huntingtons disease?
Antidepressants for depression
| anxiolytics for anxiety
102
What does VMAT2 do?
causes uptake and storage of dopamine
103
In huntingtons you have too much of the neurotransmitter (blank)
dopamine
104
In Parkinson's disease you have too little of the neurotransmitter (blank)
dopamine
105
What is amyotrophic lateral sclerosis (ALS)?
degeneration of spinal, bulbar and cortical motor neurons
106
What are the clinical manifestations of ALS?
muscle weakness, muscle atrophy, fasciculations, spasticity, dysarthria, dysphagia, and respiratory compromise
107
How do you treat ALS?
You inhibit glutamate release by blocking NMDA and kainate glutamate receptors, and inhibiting voltage dependent Na+ channels
108
What drug can block NMDA and kainate glutamate receptors and inhibit Na+ voltage gated ion channels and thus inhibit glutamate release? WHat do you use this drug in?
Riluzole (rilutek)
| ALS
109
What drugs are used to treat the spasticity associated with ALS?
Baclofen (Lioresal)
| Tizanidine (Zanflex)
110
How does Baclofen (Lioresal) work?
A GABA-B receptor agonist (oral or via intrathecal admin)
111
How does Tizanidine (Zanflex) work?
an alpha 2 arenergic receptor agonist
112
What is this:
| reduced drug effect with repeated use and higher doses required to produce the same effect
Tolerance
113
What are some ways you can get tolerance?
- pharmacokinetic i.e altered metabolism (induction)
| - physiologic (long term alterations), more or less receptors, messed up synapses
114
What is this:
tolerance to a drug in one class (e.g sedative-hypnotics) will lead to tolerance to others in the SAME class (sedative-hypnotics)
Cross-tolerance
115
What is this:
Repeated, compulsive use of a drug that deviates from the social norms of a given culture; disregard of harmful interpersonal or social consequences (e.g ethanol, opiate analgesics, cocaine and other recreational drugs)
Dependence
116
What is the psychologic reason behind substance use disorder (SUD)? What is the physiologic?
- drug use primarily to receive rewarding effects; craving (e.g cocaine)
- drug use to avoid withdrawal
117
What is this:
drugs within a pharmacological class (e.g. opiate analgesics) support individuals physically dependent on other drugs in the same class- useful property for detox
Cross-dependence
118
How are drugs ranked?
according to abuse potential
119
What is a controlled (scheduled) drug?
one whose use and distribution is tightly controlled because of its abuse potential or risk.
120
The drugs with the highest abuse potential are placed in schedule (Blank) and those with the lowest abuse potential are in the schedule (blank)
I
| V
121
What defines a schedule I drug?
-all non-research use illegal under federal law (highest abuse potential)
122
What defines a schedule II drug?
-no telephone prescriptions, no refills
123
What defines a schedule III drug?
prescription must be rewritten after 6 months or 5 refills
124
What defines a schedule IV drug?
prescription must be rewritten after 6 months or 5 refills; differs from schedule III in penalties for illegal possession
125
What defines a schedule V drug?
no need for prescription
126
What are the categories of schedule I drugs?
- Stimulants
- Depressants
- Hallucinogens
- Narcotics
- Marijuana
127
What are some schedule I stimulants?
MDMA (ecstacy) and related drugs (MDA,MMDA), mephedrone (bath salts)
128
What are some schedule I depressants?
GHB (but approved to treat narcolepsy)
129
What are some schedule I hallucinogens?
LSD, STP, DMT, DET, mescaline, peyote, psilocybin, phencyclidine (PCP- angel dust)
130
What are some schedule I narcotics?
Heroin and many non-marketed synthetic narcotics (e.g. fentanyl congeners-"china white")
131
What are the categories of schedule II drugs?
Opoids
| Stimulants
132
What are the opoids that are schedule II drugs?
```
morphine
hydromorphone
oxymorphone
oxycodone (dihydroxycodeinone, a component of percodan, percocet)
codeine
```
designated synthetic drugs: meperidine, methaone, levorphanol, fentanyl
133
What are the schedule II stimulants?
```
Cocaine
Amphetamine
Amphetamine complex
Amphetamine salts
Dextroamphetamine
Methylphenidate
```
134
Some drugs can have CNS effects and cause psychiatric symptoms.... what can ACE inhibitors cause?
Mania, anxiety, hallucinations, depression, psychosis
135
Some drugs can have CNS effects and cause psychiatric symptoms ....What can acetazolamide cause?
depression, delirium, confusion, stupor (elderly very prone)
136
Some drugs can have CNS effects and cause psychiatric symptoms...what can clarithromycin cause?
mania
137
Some drugs can have CNS effects and cause psychiatric symptoms...what can digoxin cause?
delirium, depression, psychosis, mania, visual hallucinations (elderly at high risk)
138
Some drugs can have CNS effects and cause pyschiatric symptoms....what can mefloquine cause?
vivid dreams or nightmares
139
Some drugs can have CNS effects and cause pyschiatric symptoms....what can metronidazole cause?
depression, agitation, confusion
140
What are some pharamcokinetic considerations when prescribing CNS drugs?
- Lipophilicity
- High degree of plasma protein binding
- Metabolism via the liver
141
What will a high degree of plasma protein binding potential cause with your drugs?
displacement of drug
142
What will displacement lead to?
increased side effects cuz you have basically increased the effective concentrations of that drug.
143
Whats up with carbomezopene?
it metabolizes itself so you have to up the dosage to compensate
144
What are some concerns for prescribing CNS drugs for the elderly?
- dimished hepatic and renal function
- paradoxical reactions
- polypharmacy
- greater susceptibility to SEs (some may be life-threatening)
145
Antipsychotics in elderly patients have a high risk of (blank)
death
