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Block 8; Week 1 > Drug Action in CNS-Craviso > Flashcards

Drug Action in CNS-Craviso Flashcards

1
Q

What are the different mechanisms by which molecules can get past the BBB?

A 
Channels
Membrane Transport (passive diffusion)
Carrier Mediated Transport
Receptor Mediated Transport
Adsorption-Mediated Transcytosis Systems
Active Efflux Transporters
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2
Q

WHat do the active efflux transporters do?

A

They take drugs from the brain & kick them out!
Ex: p-glycoprotein
also: BRCP & MRP

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3
Q

What is transported across the BBB by channels?

A

small ions & water

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4
Q

What is transported across the BBB by membrane transport (passive diffusion)?

A

small lipophilic molecules

includes oxygen etc & ethanol nicotine etc.

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5
Q

Which things are transported across the BBB by carrier mediated transport (solute carriers)?

A

energy transport (glucose, creatine)
amino acid transporters
nucleosides

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6
Q

Which things are transported across the BBB by receptor mediated transport?

A 
insulin 
transferrin
leptin
IgG
TNFalpha
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7
Q

What is transported across the BBB by adsorption mediated transcytosis systems?

A

histone

albumin

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8
Q

Where do you find p-glycoprotein efflux transporters? What is the clinical significance of this?

A

this is found in all tissues, but especially in capillary endothelial cells of the BBB
if a drug is a substrate for p-glycoprotein it won’t be able to stay in the brain at high levels
people w/ drug refractory epilepsy or multi drug resistance may have high p-gp levels.

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9
Q

Which types of drugs are common substrates for p-gp?

A

chemotherapeutic agents: vinca alkaloids, doxorubicin

antibiotics: rifampicin, anti-epileptic drugs

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10
Q

What is the main factor that affects whether a drug can cross the BBB by passive diffusion?

A

its lipid solubility

the more like oil the better!

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11
Q

Some drugs are lipophilic but still don’t cross the BBB well by passive diffusion. Give 2 examples & explain why.

A

Phenytoin & Phenobarbital–>metabolized quickly

Don’t have time to get into the brain. May be bound to drug carrier proteins.

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12
Q

Glucose & L-DOPA are not lipophilic, but they get past the BBB just fine. Why?

A

b/c they have their own transporters!

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13
Q

Where is the BBB more permeable?

A 
Area postrema
Median eminence
Pituitary gland
Pineal gland
Choroid plexus capillaries
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14
Q

Give another factor that increases the permeability of the BBB.

A

bacterial & viral infections.

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15
Q

What is the best route for global drug delivery?

A

vascular route b/c each neuron has its own capillary

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16
Q

How is local, direct drug delivery possible in the brain?

A

intracerebral implant
it delivers the drug.
doesn’t even have to cross the BBB!

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17
Q

Give several ways by which drugs target the CNS & alleviate psychiatric diseases & neural excitability.

A

Presynaptic: affects NT release; agonist or antagonists on nerve terminal auto receptors
Postsynaptic: receptor agonist, antagonist. degradation of NT
Voltage-gated ion channels targeted
Non-selective effects on membranes

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18
Q

Why is it important to have good anti-emetic drugs?

A
  • *surgery: anesthetics used can cause nausea & vomiting
  • *chemo can cause nausea
  • *migraines
  • *GI tract infection–sometimes nonproductive vomiting
  • *pregnancy
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19
Q

Where is the emetic center located?

A

in the medulla

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20
Q

What are the 4 feed ins to the emetic center? Which is the most predominant?

A

Most Important: Chemoreceptor Trigger Zone in area prostrema

  • *Higher Centers
  • *Cerebellum
  • *Solitary Tract Nucleus
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21
Q

What are the receptors found in the chemoreceptor trigger zone?

A

5-HT3, D2, M1, NK1

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22
Q

What are the 2 feed-ins to the higher centers that can signal the emetic center?

A

Thoughts of memory, fear, dread

Sensory input, such as pain or bad smells

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23
Q

What is the main feed-in to the cerebellum that can signal the emetic center & cause vomiting?

A

inner ear. Motion.

Triggers the H1 & M1 receptors on the cerebellum.

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24
Q

What are the receptors found in the solitary tract nucleus?

A

5-HT3, D2, M1, H1, NK1

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25
What are the 3 feed-ins to the solitary tract nucleus that can then signal the emetic center?
chemoreceptor trigger zone vagal & sympathetic afferents glossopharyngeal & trigeminal afferents
26
What are the 2 places the vagal & sympathetic afferents signal?
chemoreceptor trigger zone & solitary tract nucleus
27
What are the receptors present in the small intestine? What does the SI signal?
5-HT3, NK1, D2 | signals the vagal & sympathetic afferents.
28
How does gagging the pharynx cause vomiting?
it signals CN9 & CN5. They signal the solitary tract nucleus, which triggers the emetic center in the medulla.
29
If you have bad emetic drugs in the blood...how does this cause vomiting?
blood can get to the SI. Then that will trigger vagal & sympathetic afferents, which will signal chemoreceptor trigger zone & solitary tract nucleus. Both of these will say hi to the emetic center. Blood borne means it will cover the loose BBB of the area prostrema, directly triggering the chemoreceptor trigger zone, which signals the emetic center.
30
What are the main anti-emetic drugs?
5-HT3 receptor antagonists | NK1 receptor antagonists
31
5-HT3 receptors are ___ channels. Which areas of the body will this affect to prevent emesis?
Na+ channels chemoreceptor trigger zone has 5-HT3 receptors. Also the solitary tract nucleus & SI vagal afferents.
32
Why would an NK1 receptor antagonist be helpful?
found on the chemoreceptor trigger zone & the SI. Also in the solitary tract nucleus.
33
Give 2 5-HT3 receptor antagonists used to treat emesis & tell their admin.
Ondansetron (zofran)-oral, oral soluble film, IV | Granisetron (kytril)-oral, IV transdermal patch
34
Give a NK1 receptor antagonist used to treat emesis. How is it administered?
aprepitant (emend)-oral or IV
35
How can corticosteroids hop on the anti-emesis bus?
don't know how | seem to augment effects of other anti-emetic agents
36
Give an example of a corticosteroid used for anti-emesis?
dexamethasone (methylprednisone). Given orally or by IV.
37
D2 receptor antagonists are also used for anti-emesis. Explain why.
these receptors are found in the chemoreceptor trigger zone, SI, solitary tract nucleus **may enhance GI motility
38
Give an example of a D2 receptor antagonist used to treat nausea & vomiting.
Metoclopramide (reglan)-oral, IM, IV | phenothiazines: promethazine (phenergan)-oral, suppository, IM, IV
39
What is special about phenothiazines antagonism? What is special about promethazine's antagonism?
phenothiazines are D2 receptor antagonists & mACH receptor antagonists. promethazine also blocks histamine H1 receptors.
40
What are the possible negative side effects of metoclopramide?
restlessness, fatigue, headache, insomnia, confusion, | most serious: dystonias and tardive dyskinesia
41
How do oral cannabinoids (synthetic analogs of THC) work in anti-emesis?
act in higher cortical centers at cannabinoid receptors good for breakthrough refractory emesis **can also smoke marijuana--decreases pain, inflammation, spasticity
42
Give an example of an oral cannabinoid & its side effects? Note: same side effects as smoking marijuana.
dronabinol (marinol) | Side effects: euphoria, dysphoria, hallucinations; abuse potential
43
What are the drugs typically used to control non-productive nausea & vomiting?
D2 receptor antagonists, promethazine | H1 receptor antagonist
44
H1 receptor antagonists also typically block ____ receptors. Give an example.
mACH receptors | doxylamine (diclegis)
45
doxylamine is used often to treat what? what are the side effects?
nausea in pregnancy | side effects: sedation, antimuscarinic effects
46
What are the most popular drugs for short term, immediate relief of motion sickness?
H1 receptor antagonists dimenhydrinate (dramamine)-oral, IM, IV meclizine (antivert)-used for vertigo, oral.
47
What is a motion sickness treatment for more long term sustained control?
scopolamine (transdermal skin patch)
48
What are the 3 main strategies for anti-seizure therapy?
1. enhance GABAergic neurotransmission 2. attenuate glutaminergic neurotransmission 3. modify ion conductance through channels
49
What are the mechanisms by which GABA neurotransmission is enhanced in anti-seizure therapy?
enhance GABA synthesis block degradation block reuptake into neurons & glial cells enhance post-synaptic GABAa receptor activity
50
How do you down regulate glutaminergic neurotransmission?
bind calcium channels to stop the fusion & release of NT | work on the AMPA & NMDA receptors to block them!
51
Which channels are blocked in anti-seizure medications?
sodium & potassium
52
Which drugs work on the sodium channels for anti-seizure therapy?
phenytoin | carbamezepine
53
Which drugs work on calcium N channels? Anti-seizure
lamotrigine
54
Which drugs work on K+ channels? Anti-seizure
retigabine
55
Which drugs work on calcium T channels? Anti-seizure
ethosuximide | valproate
56
What do you lose in Alzheimer's disease?
hippocampal pyramidal neurons basal forebrain cholinergic neurons--memory & cognition deficiency of acetylcholine
57
What are the typical treatments for alzheimer's disease?
increase the Ach levels!! reversible cholinesterase inhibitors Donepezil (aricept) Ravistigmine (excelon)-patch
58
One treatment for Alzheimer's involves blocking a channel...explain.
low affinity open channel blocker of NMDA receptors | memantine (namenda)
59
What do you lose in Parkinson's Disease?
dopaminergic neurons in the substantia nigra | too few in the extrapyramidal movement circuit
60
What are the drugs used for Parkinson's disease?
increase dopamine! L-DOPA dopamine agonists
61
How is Huntington's disease inherited?
huntingtin protein from genetic mutation | too much dopamine!
62
What characterizes huntington's disease?
chorea from loss of neurons in basal ganglia diminished GABA enhanced dopamine
63
What is the treatment for huntington's disease?
tetrabenazine--selective, reversible dopamine depleting drug (inhibits VMAT2) D2 receptor antagonist-controls movement & relieves psychosis
64
What are some supportive drugs used in Huntington's disease?
antidepressants | anxiolytics
65
What is ALS?
amyotrophic lateral sclerosis degeneration of motor neurons (spinal, bulbar, cortical) muscle weakness, muscle atrophy, fasciculations, spasticity, dysarthria, dysphagia, respiratory compromise
66
How do you treat ALS?
inhibit glutamate release block NMDA & kainate glutamate receptors inhibit voltage-gated Na+ channels Drug: Riluzole (Rilutek)
67
What are 2 drugs used to treat spasticity in ALS? What is their MOA?
BACLOFEN (Lioresal) – a GABAB receptor agonist (oral or via intrathecal administration) TIZANIDINE (Zanflex) – an alpha2-adrenergic receptor agonist
68
What are 4 special problems associated with CNS drugs?
1. Tolerance 2. Cross tolerance (tolerance to drugs of the same class) 3. Dependence 4. Cross Dependence (can withdraw by using drug of same class)
69
What is a substance use disorder that is psychologic? Physiologic?
Psychologic: use to receive rewarding effects Physiologic: use to avoid withdrawal
70
Why is cross dependence helpful for detox?
b/c can avoid dangerous withdrawal symptoms by putting a person on a different drug from the same class as the one they are addicted to...
71
What is the basic structure of the schedule of controlled drugs?
Schedule I (highest abuse potential, illegal)-->Schedule V (OTC)
72
Which schedule does marijuana fall into?
Schedule I, federally illegal
73
Where does cocaine (anesthetic) & morphine fall into?
schedule II
74
What is the possible psychiatric reaction to ACE inhibitors?
mania, anxiety, hallucinations, depression, psychosis
75
What is the possible psychiatric reaction to acetazolamide?
depression, delirium, confusion, stupor
76
What is the possible psychiatric reaction to clarithromycin?
mania
77
What is the possible psychiatric reaction to digoxin?
delirium, depression, psychosis, mania, visual hallucinations
78
What is the possible reaction to mefloquine?
vivid dreams & nightmares
79
What is the possible reaction to metronidazole?
depression agitation confusion
80
If a drug is super lipophilic what's the deal?
it can cross the CNS more easily | it can get deposited in fat & be slowly released
81
What happens if a CNS drug has a high degree of plasma protein binding?
another drug that binds same protein could displace the new drug could get a lot of free drug & more side effects & higher effective concentration
82
When a CNS drug is metabolized by the liver...what do you have to consider?
Status of liver function Individual variations in rate of metabolism Saturation kinetics Conversion to an inactive versus an active metabolite Inhibition by other drugs Induction of metabolism by itself or another drug
83
What's the deal with phenytoin metabolism?
variable rates of metabolism of this drug | need to figure out if the patient is a rapid or slow metabolizer
84
What are zero order saturation kinetics?
once they get saturated, slow rate of metabolism & drug build up side effects Ex: ethanol, phenytoin
85
What happens in benzos metabolism?
metabolized by the liver | metabolites excreted, but are active & have their own effects
86
What are you concerned about when you prescribe CNS drugs for the elderly?
diminished hepatic & renal function paradoxical reactions: benzos could cause more confusion side effects greater!

Block 8; Week 1 (13 decks)

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