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Block 8 week 1 > Drug action in the CNS - Craviso > Flashcards

Drug action in the CNS - Craviso Flashcards

1
Q

Why is it difficult to predict the effects of drugs on the CNS?

A

Neuronal interconnection is complex and the effect of any given drug depends on the relative strength of the various excitatory and inhibitory synaptic connections. Effects also depend on the influence of glial cells, the BBB and a range of secondary adaptive responses that may take up to weeks to develop. For some drugs the mechanism of action is unknown and this is another reason its hard to predict effects.

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2
Q

Which type of compounds cross the BBB more easily?

A

Lipophilic

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3
Q

What is the function of BBB transport systems?

A

They maintain brain homeostasis and transport endogenous and exogenous compounds by controlling their selective and specific uptake, efflux and metabolism in the brain.

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4
Q

What passes through channels in the BBB?

A
  1. water

2. small ions such as sodium, potassium and chloride

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5
Q

What types of molecules get through the BBB via passive diffusion?

A

Small lipophilic molecules such as:

  1. oxygen
  2. CO2
  3. anesthetics
  4. barbituates
  5. ethanol
  6. nicotine
  7. caffeine
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6
Q

What types of compounds get through the BBB via carrier-mediated transport?

A
  1. glucose - via GLUT-1
  2. monocarboxylates - via MCT1
  3. lactate - via MCT1
  4. pyruvate - via MCT1
  5. creatinine - via CrT
  6. large, neutral amino acids - i.e. by LAT1
  7. nucleosides - via OATP
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7
Q

What types of compounds get through the BBB via receptor-mediated transport?

A
  1. insulin
  2. transferrin
  3. leptin
  4. IgG
  5. TNF-a
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8
Q

What are some types of active efflux transporters?

A
  1. P-glycoprotein
  2. BRCP
  3. MRP
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9
Q

What are some adsorption-mediated transcytosis systems?

A
  1. histone

2. albumin

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10
Q

Describe P-glycoprotein.

A
  1. belongs to a family of membrane transporters that modulate drug distribution
  2. capillary endothelial cells of the BBB express high levels of as compared to other tissues
  3. some substrates of P-glycoprotein are - vinca alkaloids like doxorubicin, antibiotics like rifampicin and various anti-epileptic drugs
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11
Q

What is the clinical significance of active efflux transporters?

A

Any drug that is a substrate of these transporters will exhibit very low levels of drug in the brain. It is thought that over expression of P-glycoprotien plays a role in drug refractory epilepsy and multi drug resistance in general.

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12
Q

What is important about drugs that pass through the BBB via passive diffusion?

A

The amount of these drugs that reach the brain would depend on the lipid solubility of the drug. The greater the lipid solubility, the faster the drug enters the CNS.

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13
Q

Lipid solubility is not the only factor in access to the CNS by a drug. What else needs to be considered?

A
  1. how the drug is metabolized - it may be very lipid soluble but very little will reach the brain if it gets metabolized before it can reach the BBB
  2. extent to which the drug binds to plasma proteins - unbound drug is free to act so affinity for plasma proteins is important
  3. whether or not the drug is a substrate for an efflux protein
  4. whether or not the drug has a carrier protein
  5. for example phenobarbitol and phenytoin (high lipid solubility) and glucose and L-dopa (low lipid solubility) all have similar concentrations in the brain. They are all affected by other factors in addition to their lipophilicity
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14
Q

What are some areas of the brain where the BBB is more permeable and less protective?

A
  1. Area postrema
  2. median eminence
  3. pituitary gland
  4. pineal gland
  5. choroid plexus capillaries
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15
Q

What can cause an increase in BBB permeability?

A

Bacterial and viral infections.

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16
Q

What is the most promising route for global drug delivery?

A

The vascular route. Each neuron has its own capillary for oxygen supply and nutrient/waste exchange.

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17
Q

What is a promising new area of drug delivery?

A

Direct, local delivery via implant that releases drug.

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18
Q

CNS pharmacological agents principally target what?

A

Neurotransmitters - drugs that influence behavior and improve the functional status of patients with neuro or psych diseases act by enhancing or blunting neural excitability, usually by targeting specific transmitter systems.

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19
Q

CNS pharmacological agents can act where?

A
  1. pre-synaptic neurotransmitters - may effect their synthesis, storage, release, reuptake and or degradation, and agonist or antagonist activity at the nerve terminal auto receptors
  2. post-synaptic neurotransmitters - may effect receptor agonist, antagonist or modulatory activity and may affect degradation of neurotransmitters
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20
Q

What are 2 ways that drugs can also influence behavior and neural excitability?

A
  1. They may have effects on voltage-gated ion channels

2. They may have non-selective effects on membranes

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21
Q

Anti-emetic drug action involves what?

A

Blocking of neurotransmission at the chemoreceptor trigger zone, at afferent inputs to the emetic center and in the emetic center.

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22
Q

What is the emetic center?

A

This is an area of the brain that controls vomiting. The drugs that block it are important in surgery, chemotherapy, migraine patients, patients with severe GI tract infections and in pregnant patients experiencing severe nausea and vomiting. Many pathways feed into the emetic center.

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23
Q

What are some areas of the brain that send signals to the emetic center and what neurotransmitters do they use?

A
  1. The inner ear detects motion and feeds into the cerebellum which feeds into the emetic center via histamine and muscarinic neurons
  2. the area postrema contains the chemoreceptor trigger zone which feeds into the emetic center via dopamine, serotonin and muscarinic neurons
  3. The stomach and small intestine feed into the vagal and sympathetic afferents via serotonin, NK and dopamine in response to local irritants and blood borne emetics. The vagal and sympathetics feed into the area postrema which then feeds into the emetic center
  4. The solitary tract feeds into the emetic center via dopamine, serotonin, muscarinic and Nk (substance P or neurokinin) neurons. These neurons get stimulated by vagal and sympathetic afferents
  5. higher brain centers also feed into the emetic center in response to sensory input and emotion
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24
Q

What antiemetic drugs are used for prevention and treatment of emesis during chemotherapy, radiation therapy and post -operatively?

A
  1. Serotonin receptor antagonists like:
    * Ondansetron (Zofran - oral, oral soluble film, IV)
    * Granisetron (Kytril - oral, IV, transdermal patch called Sancuso)
    * Dolasetron (Anzemet)
    * Alosetron (Lotronex)
    * Palonosetron (Aloxl)
  2. NK receptor antagonists like Aprepitant (Eend - oral or IV called fosaprepitant)
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25
Q

What drugs are often used to augment the antiemetic effects of other agents for Chemo, radiation and post operative vomiting?

A

Corticosterioids such as:

  1. Dexamethasone - oral, IV
  2. methylprednisone
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26
Q

What are D2 receptor antagonists and what are they used for?

A

These are substituted benzamides that are used alone or in combo for treating chemo induced nausea and vomiting and also for treating unproductive nausea and vomiting. These drugs may also act peripherally to enhance GI motility.

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27
Q

Name two D2 receptor antagonists used.

A
  1. Metochlopramide or Reglan - oral, IM and IV preparations

2. Trimethobenzamide or Tigan

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28
Q

What side effects do the D2 receptor antagonists have?

A
  1. restlessness
  2. fatigue
  3. headache
  4. insomnia
  5. confusion
  6. dystonias and tardive dyskinesia
    These side effects can sometimes be irreversible.
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29
Q

What oral cannabinoids used for?

A

Oral cannabinoids are used as anti emetics. They are thought to act in higher cortical centers but the mechanism is unknown. They are approved in patients not responding to other antiemetic agents or for treatment of breakthrough or refractory emesis.

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30
Q

Name some oral cannabinoids and their side effects.

A
  1. Dronabinol (marinol) - synthetic form of THC
  2. Nabilone (Cesamet)

Side effects include euphoria, dysphoria, hallucinations and potential abuse.

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31
Q

What is another form of cannabinoid used in states where it is legal?

A

Smoking marijauna can be used as an antiemetic. It is also used to decrease pain, inflammation and spasticity. Side effects include euphoria, dysphoria, hallucinations and potential abuse.

32
Q

What are some medications typically used to control non-productive nausea and vomiting?

A

D2 receptor antagonists such as:

  1. Phenothiazines - block mach receptors too
  2. Promethazine (Phenergan) - oral suppositories, IM,IV, also used as an antihistamine because it blocks H1 receptors
  3. Prochlorperazine (Compazine)- oral,IM, IV and suppositories

H1 receptor antagonists such as:
1. Doxylamine plus pyridoxine (Diclegis) - delayed release combination for nausea and vomiting of pregnancy. side effects include sedation and antimuscarinic effects

33
Q

What is the only antiemetic that is FDA approved for pregnant women?

A

Doxylamine

34
Q

What antiemetic drugs are used for motion sickness?

A

H1 receptors that provide short term relief including:

  1. Dimenhydrinate (dramamine) - oral, IM,IV
  2. Meclizine (Antivert) - also used for vertigo; oral formulation

Muscarinic (mAch) receptor antagonists that provide long term, sustained control including:
1. Scopolamine (Transder Scop) - skin patch, placed behind ear that produces less side effects than oral route. If sensitive may cause drowsiness and affect concentration

35
Q

Antiseizure therapy involves what?

A

Multiple strategies to prevent excessive, synchronized neuronal discharges without impeding normal neuronal function.

36
Q

What are two anti seizure therapy strategies?

A
  1. enhance GABAergic neurotransmission - can do this by enhancing synthesis, blocking degradation, blocking reuptake and enhancing postsynaptic GABA-A receptor activity.
  2. Attenuate glutaminergic neurotransmission
  3. modify ion conductance through channels
37
Q

What drug blocks GABA degradation?

A

Vigabatrin

38
Q

What drug blocks reuptake of GABA?

A

Tiagabine

39
Q

What drugs enhance postsynaptic GABA-A receptor activity?

A

Benzodiazapines and Phenobarbital

40
Q

What drugs attenuate glutaminergic neurotransmission by blocking calcium from going into the nerve terminal?

A

Gabapentin and Pregabalin

41
Q

What drug attenuates glutaminergic neurotransmission by blocking NMDA receptors?

A

Felbamate

42
Q

What drug attenuates glutaminergic neurotransmission by blocking AMPA and Kainate receptors?

A

Topiramate

43
Q

What anti-seizure drugs modify ion conductance through channels located on the nerve terminal?

A
  1. Phenytoin
  2. Carbamazepine
  3. Lamotrigine
  4. Retigabine
44
Q

What anti-seizure drugs modify ion conductance through channels located on the postsyntaptic membrane?

A
  1. ethosuximide

2. valproate

45
Q

What is an underlying mechanism that contributes to Alzheimer’s disease?

A

Loss of hippocampal pyramidal neurons and basal forebrain cholinergic neurons leading to a striking deficiency in acetylcholine. Loss of neurons causes impairment in memory and cognitive ability.

46
Q

What does treatment of Alzheimer’s involve and what drugs are used?

A

Treatment involves increasing Ach levels using reversible cholinesterase inhibitors. Examples are:
1. Donepezil (aricept)
2. Ravistigmine (Excelon)
Treatment also involves blocking NMDA receptors selectively. This inhibits the pathological activation of the receptor. The drug that does this is called Memantine (Namenda).

47
Q

Why is Memantine a good drug for Alzheimer’s treatment?

A

One mechanism thought to contribute to neuronal death is excitotoxicity due to excessive excitation of NMDA receptors. This drug selectively blocks open NMDA channels.

48
Q

Can drugs used to treat Alzheimer’s stop the progression of the disease?

A

No. They just slow the process down and improve symptoms.

49
Q

What is the underlying mechanism involved in Parkinson’s disease?

A

Progressive loss of dopaminergic neurons in the substantial nigra, leading to a shortage of dopamine in the extrapyramidal movement circuit.

50
Q

What is the primary therapeutic strategy in treating Parkinson’s?

A

Treatment involves drugs that increase the levels of dopamine and use of dopamine agonists.

51
Q

Why is L-Dopa used to increase levels of dopamine in the treatment of Parkinson’s?

A

L-dopa is a precursor of dopamine. L-dopa can cross the BBB but dopamine cannot.

52
Q

What is the underlying mechanism involved in Huntington’s disease?

A

An inherited mutation in the Huntingtin protein. The mutation leads to loss of neurons from structures of the basal ganglia, imbalances in both GABA functions (diminished) and dopamine functions (enhanced).

53
Q

Huntington’s disease is characterized by what?

A

Chorea - irregular, unpredictable involuntary muscle jerks at different parts of the body that impair voluntary activity.

54
Q

What pharmacological agents are used to treat Huntington’s?

A
  1. Tetrabenazine (Xenazine) - a selective and reversible centrally-acting dopamine depleting drug. Blocks VMAT2 which causes uptake and storage of dopamine.
  2. D2 receptor antagonists - used to control abnormal movements and relieve psychosis that accompanies disease
  3. drugs used to treat other conditions that accompany Huntington’s such as antidepressants for depression and anxiolytics for anxiety
55
Q

What is the underlying mechanism of Amyotrophic Lateral Sclerosis (ALS)?

A

Degeneration of spinal, bulbar and cortical motor neurons that leads to muscle weakness, muscle atrophy and fasciculations, spasticity, dysarthria, dysphagia and respiratory compromise.

56
Q

Treatment of ALS involves what?

A

Inhibiting glutamate release, blocking NMDA and Kainate glutamate receptors and inhibiting voltage dependent sodium channels. The drug that does this is called Riluzole (Rilutek).

57
Q

What drugs are used to treat spasticity in ALS?

A
  1. Baclofen (Lioresal) - a GABA-B receptor agonist given orally or by intrathecal administration
  2. Tizanidine (Zanflex) - an a2-adrenergic receptor agonist
58
Q

What are some problems associated with the use of CNS drugs?

A
  1. tolerance
  2. cross-tolerance
  3. dependence
  4. cross dependence
59
Q

What is tolerance when applied to CNS drugs?

A

Reduced drug effect with repeated use and higher doses required to produce the same effect.

60
Q

By what 2 mechanisms can tolerance develop?

A
  1. pharmacokinetic - induction of altered metabolism of the drug
  2. physiologic - long term alterations at site where drug acts (i.e. up or down regulation of receptors) or at other synapses for other neurotransmitters
61
Q

What is cross-tolerance when applied to CNS drugs?

A

Tolerance to a drug in one class leading to a tolerance in other drugs in the same class.

62
Q

What is dependence when applied to CNS drugs?

A

Repeated, compulsive use of a drug that deviates from the social norms of a given culture; disregard of harmful interpersonal or social consequences.

63
Q

What disorder is caused by dependence to CNS drugs?

A

Substance use disorder. Can occur via:

  1. physcologic mechanism - drug use is primarily to receive rewarding effects
  2. physiologic mechansim - drug use to avoid withdrawal
64
Q

What is cross dependence when applied to CNS drugs?

A

Drugs within a pharmacological class support individuals physically dependent on other drugs in the same class. This is used as a tool for detox.

65
Q

What is a controlled or scheduled drug?

A

One whose use and distribution is tightly controlled because of its abuse potential or risk. Controlled drugs are rated in the order of their abuse risk and placed in schedules by the DEA. Drugs with the highest abuse potential are placed in Schedule I and those with the lowest abuse potential are in Schedule V.

66
Q

Describe the general schedules used by the DEA?

A

Schedule I - highest abuse potential, use of these drugs is illegal except for those used in research
Schedule II - no telephone Rx, no refills
Schedule III - prescription must be rewritten after 6 months or 5 refills
Schedule IV - prescription must be rewritten after 6 months or 5 refills; differs from Schedule III in penalties for illegal possession
Schedule V - may be dispensed without prescription unless additional state regulations apply

67
Q

List some Schedule I drugs.

A
  1. Stimulants such as Ecstasy and Mephedrone or bath salts
  2. Depressants such as Gamma hydroxybutyrate or GHB - this drug can be used to treat narcolepsy but approval comes with severe restrictions
  3. Hallucinogens such as LSD, STP,DMT,DET, mescaline, peyote, psilocybin, and PCP
  4. Marijuana and synthetic marijuana
  5. Narcotics such as heroin and synthetic narcotics such as ‘China White’
68
Q

List some Schedule II drugs.

A
  1. Opiods such as morphine, hydromorphone, oxymorphone, oxycodone (component of percodan and percocet), codeine, meperidine, methadone, levorphanol, fentanyl
  2. Stimulants such as cocaine, amphetamine, amphetamine complex, amphetamine salts, dextroamphetamine, and methylphenidate
69
Q

Some drugs can have CNS effects and can actually cause psychiatric symptoms. What are these drugs and what symptoms do they cause?

A
  1. angiotensin-converting enzyme inhibitors - mania, anxiety, hallucinations, depression , psychosis
  2. Acetezolamide - depression, delirium, confusion, stupor (elderly very prone)
  3. Clarithromycin - mania
  4. Digoxin - delirium, depression, psychosis, mania, visual hallucinations (elderly at high risk)
  5. Mefloquine - vivid dreams or nightmares
  6. Metronidazole - depression, agitation, confusion
70
Q

What are some pharmacokinetic considerations when prescribing CNS drugs?

A
  1. Lipophilicity - can cause ‘depot effect’ if accumulates in fatty tissue
  2. high degree of plasma protein binding - can be displaced by another drug that also binds to a high degree
  3. Metabolism in the liver - must know liver function status, individuals can vary in rate of metabolism, saturation kinetics important, conversion to another metabolite (can be active or inactive), drug may be inhibited by another drug, drug may cause induction of metabolism of itself or be induced by another drug
71
Q

What might happen if a patient is on two drugs with a high affinity for plasma proteins?

A

One drug may displace the other leading to a higher concentration of drug that is free to act. Can cause increased side effects and toxicity.

72
Q

Why are saturation kinetics of a drug important to know?

A

The body can only get rid of so much drug in a given time. If too high of a dose is given then saturation occurs and the effective concentration of that drug is increased.

73
Q

What might happen if a drug can induce its own metabolism?

A

The effective concentration of that drug may then be below therapeutic dose.

74
Q

What are some concerns when prescribing CNS drugs to the elderly?

A
  1. they may have diminished hepatic and renal function
  2. they have a higher risk of paradoxical reactions
  3. they often are taking multiple drugs - interactions must be considered
  4. they exhibit greater susceptibility to side effects some of which may be life threatening
75
Q

What are some considerations when looking at CNS drug specificity?

A
  1. there may be no established, conclusive mechanism of action - i.e.. ethanol and certain anesthetics
  2. they may be classified according to primary MOA but may also exert a similar therapeutic effect by another mechanism - i.e. anti emetics
  3. classification may be based on a specific therapeutic use when it has other therapeutic uses too - ie. antidepressants can be used to treat anxiety disorders and certain anti seizure meds have multiple uses

Block 8 week 1 (13 decks)

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