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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
Q

What are the 3 feed-ins to the solitary tract nucleus that can then signal the emetic center?

A

chemoreceptor trigger zone
vagal & sympathetic afferents
glossopharyngeal & trigeminal afferents

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26
Q

What are the 2 places the vagal & sympathetic afferents signal?

A

chemoreceptor trigger zone & solitary tract nucleus

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27
Q

What are the receptors present in the small intestine? What does the SI signal?

A

5-HT3, NK1, D2

signals the vagal & sympathetic afferents.

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28
Q

How does gagging the pharynx cause vomiting?

A

it signals CN9 & CN5. They signal the solitary tract nucleus, which triggers the emetic center in the medulla.

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29
Q

If you have bad emetic drugs in the blood…how does this cause vomiting?

A

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.

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30
Q

What are the main anti-emetic drugs?

A

5-HT3 receptor antagonists

NK1 receptor antagonists

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31
Q

5-HT3 receptors are ___ channels. Which areas of the body will this affect to prevent emesis?

A

Na+ channels
chemoreceptor trigger zone has 5-HT3 receptors.
Also the solitary tract nucleus & SI vagal afferents.

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32
Q

Why would an NK1 receptor antagonist be helpful?

A

found on the chemoreceptor trigger zone & the SI. Also in the solitary tract nucleus.

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33
Q

Give 2 5-HT3 receptor antagonists used to treat emesis & tell their admin.

A

Ondansetron (zofran)-oral, oral soluble film, IV

Granisetron (kytril)-oral, IV transdermal patch

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34
Q

Give a NK1 receptor antagonist used to treat emesis. How is it administered?

A

aprepitant (emend)-oral or IV

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35
Q

How can corticosteroids hop on the anti-emesis bus?

A

don’t know how

seem to augment effects of other anti-emetic agents

36
Q

Give an example of a corticosteroid used for anti-emesis?

A

dexamethasone (methylprednisone). Given orally or by IV.

37
Q

D2 receptor antagonists are also used for anti-emesis. Explain why.

A

these receptors are found in the chemoreceptor trigger zone, SI, solitary tract nucleus
**may enhance GI motility

38
Q

Give an example of a D2 receptor antagonist used to treat nausea & vomiting.

A

Metoclopramide (reglan)-oral, IM, IV

phenothiazines: promethazine (phenergan)-oral, suppository, IM, IV

39
Q

What is special about phenothiazines antagonism? What is special about promethazine’s antagonism?

A

phenothiazines are D2 receptor antagonists & mACH receptor antagonists.
promethazine also blocks histamine H1 receptors.

40
Q

What are the possible negative side effects of metoclopramide?

A

restlessness, fatigue, headache, insomnia, confusion,

most serious: dystonias and tardive dyskinesia

41
Q

How do oral cannabinoids (synthetic analogs of THC) work in anti-emesis?

A

act in higher cortical centers at cannabinoid receptors
good for breakthrough refractory emesis
**can also smoke marijuana–decreases pain, inflammation, spasticity

42
Q

Give an example of an oral cannabinoid & its side effects? Note: same side effects as smoking marijuana.

A

dronabinol (marinol)

Side effects: euphoria, dysphoria, hallucinations; abuse potential

43
Q

What are the drugs typically used to control non-productive nausea & vomiting?

A

D2 receptor antagonists, promethazine

H1 receptor antagonist

44
Q

H1 receptor antagonists also typically block ____ receptors. Give an example.

A

mACH receptors

doxylamine (diclegis)

45
Q

doxylamine is used often to treat what? what are the side effects?

A

nausea in pregnancy

side effects: sedation, antimuscarinic effects

46
Q

What are the most popular drugs for short term, immediate relief of motion sickness?

A

H1 receptor antagonists
dimenhydrinate (dramamine)-oral, IM, IV
meclizine (antivert)-used for vertigo, oral.

47
Q

What is a motion sickness treatment for more long term sustained control?

A

scopolamine (transdermal skin patch)

48
Q

What are the 3 main strategies for anti-seizure therapy?

A
  1. enhance GABAergic neurotransmission
  2. attenuate glutaminergic neurotransmission
  3. modify ion conductance through channels
49
Q

What are the mechanisms by which GABA neurotransmission is enhanced in anti-seizure therapy?

A

enhance GABA synthesis
block degradation
block reuptake into neurons & glial cells
enhance post-synaptic GABAa receptor activity

50
Q

How do you down regulate glutaminergic neurotransmission?

A

bind calcium channels to stop the fusion & release of NT

work on the AMPA & NMDA receptors to block them!

51
Q

Which channels are blocked in anti-seizure medications?

A

sodium & potassium

52
Q

Which drugs work on the sodium channels for anti-seizure therapy?

A

phenytoin

carbamezepine

53
Q

Which drugs work on calcium N channels? Anti-seizure

A

lamotrigine

54
Q

Which drugs work on K+ channels? Anti-seizure

A

retigabine

55
Q

Which drugs work on calcium T channels? Anti-seizure

A

ethosuximide

valproate

56
Q

What do you lose in Alzheimer’s disease?

A

hippocampal pyramidal neurons
basal forebrain cholinergic neurons–memory & cognition
deficiency of acetylcholine

57
Q

What are the typical treatments for alzheimer’s disease?

A

increase the Ach levels!!
reversible cholinesterase inhibitors
Donepezil (aricept)
Ravistigmine (excelon)-patch

58
Q

One treatment for Alzheimer’s involves blocking a channel…explain.

A

low affinity open channel blocker of NMDA receptors

memantine (namenda)

59
Q

What do you lose in Parkinson’s Disease?

A

dopaminergic neurons in the substantia nigra

too few in the extrapyramidal movement circuit

60
Q

What are the drugs used for Parkinson’s disease?

A

increase dopamine!
L-DOPA
dopamine agonists

61
Q

How is Huntington’s disease inherited?

A

huntingtin protein from genetic mutation

too much dopamine!

62
Q

What characterizes huntington’s disease?

A

chorea
from loss of neurons in basal ganglia
diminished GABA
enhanced dopamine

63
Q

What is the treatment for huntington’s disease?

A

tetrabenazine–selective, reversible dopamine depleting drug (inhibits VMAT2)
D2 receptor antagonist-controls movement & relieves psychosis

64
Q

What are some supportive drugs used in Huntington’s disease?

A

antidepressants

anxiolytics

65
Q

What is ALS?

A

amyotrophic lateral sclerosis
degeneration of motor neurons (spinal, bulbar, cortical)
muscle weakness, muscle atrophy, fasciculations, spasticity, dysarthria, dysphagia, respiratory compromise

66
Q

How do you treat ALS?

A

inhibit glutamate release
block NMDA & kainate glutamate receptors
inhibit voltage-gated Na+ channels
Drug: Riluzole (Rilutek)

67
Q

What are 2 drugs used to treat spasticity in ALS? What is their MOA?

A

BACLOFEN (Lioresal) – a GABAB receptor agonist (oral or via intrathecal administration)
TIZANIDINE (Zanflex) – an alpha2-adrenergic receptor agonist

68
Q

What are 4 special problems associated with CNS drugs?

A
  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
Q

What is a substance use disorder that is psychologic? Physiologic?

A

Psychologic: use to receive rewarding effects
Physiologic: use to avoid withdrawal

70
Q

Why is cross dependence helpful for detox?

A

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
Q

What is the basic structure of the schedule of controlled drugs?

A

Schedule I (highest abuse potential, illegal)–>Schedule V (OTC)

72
Q

Which schedule does marijuana fall into?

A

Schedule I, federally illegal

73
Q

Where does cocaine (anesthetic) & morphine fall into?

A

schedule II

74
Q

What is the possible psychiatric reaction to ACE inhibitors?

A

mania, anxiety, hallucinations, depression, psychosis

75
Q

What is the possible psychiatric reaction to acetazolamide?

A

depression, delirium, confusion, stupor

76
Q

What is the possible psychiatric reaction to clarithromycin?

A

mania

77
Q

What is the possible psychiatric reaction to digoxin?

A

delirium, depression, psychosis, mania, visual hallucinations

78
Q

What is the possible reaction to mefloquine?

A

vivid dreams & nightmares

79
Q

What is the possible reaction to metronidazole?

A

depression
agitation
confusion

80
Q

If a drug is super lipophilic what’s the deal?

A

it can cross the CNS more easily

it can get deposited in fat & be slowly released

81
Q

What happens if a CNS drug has a high degree of plasma protein binding?

A

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
Q

When a CNS drug is metabolized by the liver…what do you have to consider?

A

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
Q

What’s the deal with phenytoin metabolism?

A

variable rates of metabolism of this drug

need to figure out if the patient is a rapid or slow metabolizer

84
Q

What are zero order saturation kinetics?

A

once they get saturated, slow rate of metabolism & drug build up
side effects
Ex: ethanol, phenytoin

85
Q

What happens in benzos metabolism?

A

metabolized by the liver

metabolites excreted, but are active & have their own effects

86
Q

What are you concerned about when you prescribe CNS drugs for the elderly?

A

diminished hepatic & renal function
paradoxical reactions: benzos could cause more confusion
side effects greater!

Block 8; Week 1 (13 decks)

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