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M2-2 > PharmacologyCNS > Flashcards

PharmacologyCNS Flashcards

1
Q

Some NT of CNS

A 
Norepinephrine
Epinephrine
Dopamine
Acetylcholine
Serotonin
Gamma amino butyric acid (GABA)
Glutamate
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2
Q

Rank type of drugs from central sedative to central stimulative

A
  • general anesthetics
  • hypnotics
  • sedatives* ,neuroleptics
  • anxiolytics*
  • antiepileptics/anticonvulsants
  • antidepressives*
  • Analeptics*
  • psychoactives
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3
Q

What are less common CNS drugs

A

With medical indication 症状:

  • central muscle relaxants, opiates and central α2-agonists
  • Drugs against Parkinson

Without med. Indication
e.g. LSD, cannabinoids, (but med. indication CB-antagonists

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4
Q

Drugs with CNS side effect but are non-CNS drugs

A

antihistaminics, local anesthetics, antiarrhythmics, antihypertensive drugs

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5
Q

Pre-condition for central action

A
  • passage BBB (lipophil, active transport)
  • interaction with central structures like
    • receptors (pre-, postsynaptic)
    • transporter
    • enzymes (e.g. delayed degradation of neurotransmitters)
    • ion channels (Na+, K+, Ca++)
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6
Q

Type of NT and its % in CNS synapse

A

gamma amino butyric acid 30-40% (inhibitory)
glutamate 30-40% (excitatory)
acetylcholine ca. 10
dopamine ca. 1%
norepinephrine ca. 1%
serotonin (5-hydroxytryptamine= 5-HT) ca. 1%

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7
Q

CNS drugs are difficult because

A
  • main effects and side effects are hard to differentiate

- BBB limits the drugs to be lipid soluble agents or drugs by specific transport systems

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8
Q

Understanding the effects of drugs on individual neurons

A

does not predict the effect on the whole organ

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9
Q

Projection of 5HT

A

everywhere

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10
Q

Projection of DA

A

mostly frontal lobe

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11
Q

Projection of Ach

A

everywhere except cerebellum

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12
Q

Projection of NA

A

everywhere

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13
Q

Benzodiazepines

A

main CNS drugs

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14
Q

BZD mess with…

A

GABA!
BDZ receptor linked to GABA-A receptor complex (bound to Cl channels).
GABA: an inhibitory neurotransmitter
BDZ increase the affinity of the receptor for GABA, and thus increase Cl­- conductance and hyperpolarizing current
Therefore, BDZ are indirect GABA-agonists

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15
Q

Therapeutic use of BZD

A 
Sedative-hypnotic
Anxiolytic
Muscle relaxants
Anticonvulsants
Alcohol withdrawal
Premenstrual syndrome
Psychoses (only supportive) 
Adjunct in mania of bipolar disorder
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16
Q

Patterns of use of BZD

A 
45% of Use <30 days
80% of Use <4 months
15% of Use >12 months (7-18% Europe)
Women, twice the rate as men
<40% of Anxiety Diagnosis Treated
>40% of Panic Disorder Treated
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17
Q

Sedative/Hypnotic effect of BZD

A
  • Transient - lowest effective dose- time-limited
  • Insignificant decrease in sleep latency-1 hour
  • increase in sleep duration
  • ? effect on sleep architecture ( REM, stages 3 and 4)
  • Rebound insomnia - worsening of sleep - worse than before trying benzos.
  • Daytime drowsiness, dizziness, lightheadedness
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18
Q

Anxiety effect of BZD

A
  • benzos good for immediate symptom relief-faster than SSRI’s for panic.
  • long-acting, low potency preferred (clonazepam or chlordiazepoxide)
  • best used for exacerbations of anxiety-short term vs continuous use
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19
Q

Adverse Effects of BZD

A 
-Sedation, CNS Depression
worse if combined with EtOH
-Behavioural Disinhibition
irritability, excitement, aggression (<1%), rage
-Psychomotor &amp; Cognitive Impairment
coordination, attention (driving)
poor visual-spatial ability (not aware of it)
ataxia, confusion
-Overdose:  Rare fatalities if BZD alone
- Severe CNS &amp; Respiratory Depression if combined with:
alcohol
barbiturates
narcotics
tricyclic antidepressants
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20
Q

Pharmacokinetics of BZD

A

Lipid-soluble:
fast cross blood-brain-barrier: rapid onset of action.
Persist longer in high fat-to-lean body mass (obese and elderly )
Abuse liability (Valium)

Biotransformation & Half-Life:
Hepatic oxidation: long-t1/2, active metabolites
Glucuronidation: short-t1/2, no active metab.

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21
Q

absorbtion distribution, metabolism and excretionof BZD

A

Well absorbed,
peak plasma concentrations approx. 1 hour
Several pharmacologically active intermediates

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22
Q

IG: Interactions of BZD with other drugs

A
  • CNS Depressants
  • p450 2C9 (TCAs, warfarin, phenytoin)
  • p450 3A4 (triazolam, midazolam, alprazolam, CBZ, quinidine, terfenadine, erythromycin)
  • Disulfiram & Cimetidine increaseBZD levels
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23
Q

Other sedative-hypnotics than BZD

A

-Barbiturates - pentobarbital,phenobarbital,
secobarbital, butalbital (Fiorinal)
-Barb-like: glutethimide, chloral hydrate, ethhchlorvynol (Placidyl), meprobamate (carisoprodol/Soma)
-Azapirone: buspirone (2-10 mg TID - max 60 mg/d)
-slow onset of action (1-3 wks)
-not abused, no withdrawal
-effective for anxiety disorders-not for acute
-does not block benzo withdrawal
-not sedating, anticonvulsant or mm relaxing
-no resp dep/ cognitive/psychomotor impair

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24
Q

IG: Non-Benzo Hypnotics

A
  • Zolpidem (Ambien) imadozopyridine
  • Zaleplon (Sonata) pyrazolopyrimidine
  • Bind to specifically to BZ-1 sites
  • Both rapid onset (1h-2.5 h) - short action/1/2 life
  • Decrease sleep latency, increase REM sleep
  • 5-20 mg dose range
  • Safe in older adults, metab in liver, no active metabolites
  • Potentiate ETOH impairment
  • Both reinforcing, potentially abusable, and performance-impairing
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25
Q

Parkinson disease

A

a degenerative disorder of the CNS caused by death of neurons that produce the brain neurotransmitter dopamine @substantia nigra. It is the most common degenerative disease of the nerves
Parkinson’s disease is a disorder of the extrapyramidal system associated with disruption of neurotransmissions within the striatum; A disruption of neurotransmission within the striatum (proper function requires balance between dopamine and acetylcholine

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26
Q

Dyskinesias of Parkinson’s disease are

A 
Tremor at rest
Rigidity
Postural instability
Bradykinesia (slow movement)
Akinesia (complete absence of movement)
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27
Q

Therapeutic goal of PD

A
  • Improve Activity of Daily Living’s
  • Restore balance between DA and ACH by activating DA receptors or blocking ACH receptors
  • Drug selection and dosages are determined by activities of daily living performance
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28
Q

Classification of Drug Therapy for Parkinson’s Disease

A

Dopaminergic agents

  • Promote activation of dopamine receptors
  • Levodopa (Dopar)

Anticholinergic agents

  • Prevent activation of cholinergic receptors
  • Benztropine (Cogentin)
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29
Q

Mechanism of action for PD drugs

A 
Dopaminergic Agents:
Promotion of dopamine synthesis
Prevention of dopamine degradation
Promotion of dopamine release
Direct activation of dopamine receptors (D2)

Anticholinergic Agents:
Blockade of muscarinic cholinergic receptors in the striatum

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30
Q

Drug Therapy for Parkinson’s Disease

A 
May take a while for effect to show
Levodopa
Carbidopa
Amantadine
Bromocritine
Pergolide
Selegiline
Benztropine
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31
Q

Epilepsy

A

Group of disorders characterized by excessive neuron stimulation within the central nervous system

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32
Q

Seizure types/epilepsy

A

Generalized seizures:
Convulsive (tonic-clonic)/Grand Mal
Nonconvulsive (absence)/Petite Mal

Partial (focal)Seizures:
Simple partial
Complex partial

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33
Q

Antiepilectic Drugs

A

Suppress neuronal discharge at the seizure’s focus and brain
Mechanism of action
-Suppression of sodium influx
-Suppression of calcium influx

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34
Q

Therapeutic Considerations for epilepsy

A 
Treatment goal
Diagnosis
Drug Selection
Plasma drug levels
Compliance 服薬順守
Withdrawal
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35
Q

IG: Phenytoin

A

-Drug for Partial and tonic-clonic seizures
-Mechanism of action-selective inhibition of sodium channels
-Varied oral absorption
-Half-life 8-60 hours
-Adverse effects:
Nystagmus
Sedation
Ataxia
Diplopia
Cognitive Impairment
-Drug interactions:
Decreases effect of oral contraceptives, warfarin, glucocorticoids
Increases levels of diazepam,isoniazid,cimetidine,alcohol, valproic acid

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36
Q

IG: Phenobarbital

A

-Drug for Partial and generalized tonic-clonic seizures
-Promotes sleep and sedation
-Adverse Effects:
Physical dependence/porphyria
Nystagmus/Ataxia
CNS Depression

37
Q

IG: Carbamazepine

A

-Drug for Partial and tonic-clonic seizures, Bipolar disorders, Trigeminal Neuralgias
-Adverse Effects:
CNS symptoms-nystagmus, ataxia
Anemia,leukopenia, thrombocytopenia

38
Q

IG: Valproic Acid

A 
-Uses:
Absence seizures
Other seizures
Migraine
-Adverse Effects:
Hepatoxicity
Teratogenic effects
-potential use:
neuroprotective, e.g. better rehabilitation after ischemic stroke (decreased excitation – more reserves?)
39
Q

Migraine headaches

A

Migraine Headaches
-Inflammation and dilation of intracranial blood vessels

Types:
With aura (classic migraine)
Without aura (common migraine)
40
Q

Drugs for Migraine headaches

A

To abort ongoing attack

  • To eliminate headache pain
  • Suppress nausea and vomiting

To prevent attacks
-Prophylaxis

To abort an attack

  • Aspirin-like analgesics
  • Opioid analgesics
  • Ergot alkaloids: α-agonist vasoconstructive
  • Serotonin agonists (Sumatriptan)
41
Q

IG: Drugs for prophylaxis for Migraine headaches

A 
予防薬
Beta blockers (atenolol)
Calcium channel blockers (verapimil)
Tricyclic antidepressant (amitryptyline)
42
Q

Opioid (Narcotic) Analgesics

A

Opiod:
Drug similar to morphine
Derived from opium

Analgesic鎮痛剤:
Relieves pain without loss of consciousness

43
Q

Opioid Receptors

A

Mu- Pure opioid agonists: activation cause analgesia, respiratory depression, euphoria, and sedation
Kappa: activation cause analgesia and sedation
Delta: activation does not interact with opioid

44
Q

Increased activation of K+ channel causes

A

hyperpolarisation, excitation decrease

45
Q

Decreased activation of v-gated Ca2+ channel causes

A

less ca influx leading to less NT release

46
Q

endogenous opioids and their receptor preference

A

Endorphins: mu and delta
Dynorphins: delta over mu and kappa
Enkephalins: kappa over mu and delta
Nociceptin: ORL-1

47
Q

Morphine

A

Used for relief of moderate and severe pain
Decreases sensation of pain
Decreases the emotional reaction to pain

48
Q

Adverse effects of morphine

A 
Respiratory depression
Constipation
Orthostatic 起立性のhypotension
Urinary Retention
Cough suppression
Emesis嘔吐
49
Q

What is tolerance

A
  • Increasing doses to obtain same response
  • Develops with analgesia, euphoria, sedation, respiratory depression
  • Cross-tolerance to other opioid agonists
50
Q

What is physical dependence

A

-Abstinence syndrome occurs if drug abruptly stopped
-Abstinence syndrome is dependent on:
Half life of drug
Degree of physical dependence

51
Q

Opioid Overdose leads to

A

Classic Triad:
Coma
Respiratory depression
Pinpoint pupils

Can be treated by Ventilatory support and/or Opioid antagonist

52
Q

What is Pain

A
  • Unpleasant sensory and emotional experience associated with tissue damage
  • Patient’s pain description is the cornerstone of pain assessment
53
Q

What are the types of pain?

A

Nociceptive pain:
Results from injury to tissues
Called somatic or visceral pain

Neuropathic pain:
Results from injury to peripheral nerves
Responds poorly to opioids

54
Q

Clinical Approach to Pain Management

A 
A- Ask and assess
B- Believe
C- Choose
D- Deliver
E- Empower and enable
55
Q

Assessment parameters of pain

A 
Onset and temporal patterns
Location
Quality
Intensity
Modulating Factors
Previous treatment
Impact
56
Q

WHO Analgesic Ladder

A 
Step 1- Mild to moderate pain
Nonopiod analgesic
Step 2- More severe pain
Add opioid analgesic
Step 3- Severe pain
Substitute opioid-morphine
57
Q

Classes of Antidepressants

A 
amines:
amitriptyline
imipramine
doxepin
clomipramine
trimipramin
desipramine
atypical:
maprotiline (Ludiomil)
trazodone (Desyrel)
bupropion (Wellbutrin)
venlafaxine (Effexor)
nefazodone (Serzone)
mirtazapine (Remeron)
58
Q

Classes of Antidepressants (drug types)

A

SSRI/SNRI, MAOIs, psychostimulants

59
Q

IG: SSRI

A 
Antidepressants
Specific serotonin reuptake inhibitors:
fluoxetine (Prozac)
sertraline (Zoloft)
paroxetine (Paxil)
fluvoxamine (Luvox)
citalopram (Celexa)
60
Q

IG: MAOIs

A 
Antidepressants
Monoamine oxidase inhibitors:
phenelzine (Nardil)
isocarboxazid (Marplan)
tranylcypromine (Parnate)
selegiline (Deprenyl)
61
Q

IG: Psychostimulants

A 
Antidepressants
methylphenidate (Ritalin)
dextro-amphetamine (Dexedrine)
dex + amphetamine (Adderall)
methamphetamine (Desoxyn)
modafinil (Provigil)
62
Q

The decision to treat a patient with antidepressants should be based on the following

A
  • Severity of symptoms and ability to identify target symptoms
  • Impairment of functioning
  • Patient’s view of medication
  • Not necessarily the specific diagnosis
63
Q

Predictors of antidepressant response

A
  • Acute onset
  • Severe depressive symptoms
  • Positive previous response to medication
  • Patient’s willingness to accept medication as an aid to successful treatment
64
Q

How to start antidepressants?

A
  • Start low to assess tolerance of side effects
  • Increase dosage rapidly as tolerated
  • Maintain typical dose for at least 4 to 8 weeks
65
Q

Most common reasons antidepressants fail

A

Dosage too low
Duration of trial to short
Poor compliance
Intolerable side effects

66
Q

What is an adequate trial for antidepressants

A

Adequate dose:
5 mg/kg/d
Nortriptyline 100 to 150/d (therapeutic window)
Fluoxetine 20 mg/d

Adequate duration:
4 – 8 weeks

67
Q

Indications for serum levels

A

Unequivocally useful for:
Patients who are not responding to usual doses
Patients who are at increased risk for toxicity, e.g. cardiac patients

May be useful for:
Patients where prompt response is critical
Determining compliance and metabolic availability

68
Q

IG: Therapeutic Blood Levelsfor antidepressants

A

Known:
imipramine
desipramine
nortriptyline

Possibly known:
amitriptyline

Under assessment:
All other antidepressants

69
Q

How Antidepressants Work

A

Most of the important clinical actions of antidepressant drugs cannot be fully accounted for on the basis of “synaptic pharmacology”.
There are two important observations that contribute to this rationale

Many drugs require long term administration to be effective;
Drugs of abuse require repeated administration to produce tolerance and physical dependence;

Clinical effects would appear to result from the slow onset adaptive changes that occur within neurons, not within the synapse. That is, activation of intraneuronal messenger pathway and regulation of neural gene expression play a central role. (drug-induced neural plasticity).

70
Q

“Synaptic Pharmacology”of antidepressants

A

Acute:
Block reuptake or degradation of monoamines and post-synaptic alpha-1 receptor.
Chronic:
Down regulation of the post-synaptic receptors
Alteration of second messenger systems
Alteration of protein synthesis.

71
Q

Pharmacokinetics of Antidepressants

A 
Absorption is rapid
Metabolism: extensive 1st pass
Oxidation, hydroxylation, demethylation
5% = “slow acetylators”
Protein bound: 90 – 95%
72
Q

Cardiac Side-effectsof tricyclic antidepressants

A

Cardiac conduction delay
Anti-arrhythmic at therapeutic doses
Arrhythmigenic at toxic doses
Minimal effects on cardiac output

Monitoring EKG parameters:
QTc = 450 msec
PR = 210 msec
QRS - >30% above baseline

73
Q

How to choose an antidepressant

A

Choose by side effects, not efficacy

The SSRIs, secondary amines, and atypical antidepressants, are generally better choices considering side effects

74
Q

Norepinephrine uptake blockadePossible clinical consequences

A

Tremors and Tachycardia

75
Q

Serotonin reuptake blockadePossible clinical consequences

A

Gastrointestinal disturbances
Anxiety (dose – dependent)
Sexual dysfunction

76
Q

Dopaminergic uptake blockadePossible clinical consequences

A

Psychomotor activation
Antiparkinsonian effects
Psychoses
Increased attention/concentration

77
Q

Histamine H1 blockadePossible clinical consequences

A

Sedation, drowsiness
Weight gain
hypotension

78
Q

Muscarinic receptor blockadepossible clinical consequences

A 
Blurred vision
Dry mouth
Sinus tachycardia
Constipation
Urinary retention
Memory dysfunction
79
Q

alpha – 1 receptor blockadepossible clinical consequences

A

Postural hypotension
Reflex tachycardia
Dizziness

80
Q

Within the unclear CSN… depression, anxiety and schizo

A

Depression: noradrenaline (norepinephrine) and 5- HT
Anxiety: gammaamino butyric acid (GABA)
SCZ: hyperactivity in dopaminergic pathways???

81
Q

chemical mediators within the brain can

A
  • produce slow and long-lasting effects
  • act rather diffusely, at a considerable distance from their site of release;
  • can produce diverse effects, for example on transmitter synthesis and on the expression of neurotransmitter receptors, in addition to affecting the ionic conductance of the postsynaptic cells
82
Q

A good example for “neuromodulator” dilemma

A

nitric oxide (NO) and arachidonic acid metabolites, which are not stored and released like conventional neurotransmitters and may come from non-neuronal cells as well as neurons

83
Q

In general, neuromodulation relates to

A

synaptic plasticity, including short- term events, such as the regulation of presynaptic transmitter release or postsynaptic excitability, and longer-term events such as neuronal gene regulation

84
Q

Neuromodulator vs neurotrophic factors

A

Neurotrophic factors act over even longer timescales to regulate the growth and morphology of neurons, as well as their functional properties

85
Q

neuromodulators aka

A

neuromediators

86
Q

Neuroactive drugs act on

A

four types of target protein, namely ion channels, receptors, enzymes and transport proteins

87
Q

Current drugs are often designed for?

A

Of the four main receptor types — ionotropic receptors. Gproteincoupled receptors, kinase-linked receptors and nuclear receptors—current drugs target mainly the first two.

88
Q

Complexity of drug action in CNS

A

Wiring diagram: glia cells

Secondary effects: can be counteracting and takes time to see the response of drugs

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