Pharmacology Lectures 1-2 (3) Benzodiazepines

Front 1

A mixed opiod which at first was thought to be non-addictive, but now is a controlled substance

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Talwin (Pentazocine)

Front 2

Talwin is a _ receptor agonist,
and a _ receptor antagonist

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k, mu

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0.3 mg of this drug is equivalent to 10 mg or morphine; it must be administered parenterally

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Buprenorphine, (Buprenex)

Front 4

30-60 mg of this drug are equivalent to 10 mg of morphine

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Talwin NX

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number of mg to achieve desired effect

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potency

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degree of effect achieved by a drug

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efficacy

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respiratory depression in mixed opiods differs from true opiods in that

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it is not directly proportional to the dose which is administered (reaches a plateau)

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dose of morphine where you begin to see respiratory depression

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20-30 mg

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Pentazocine and Naloxone

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Talwin NX

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receptor which affects resp. depression

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mu

Front 11

receptor which affects degree of analgesia

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k

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initally, __ were used as sedatives in the treatment of anxiety

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barbiturates

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decrease activity, moderate excitement and calms

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sedatives

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produces drowsiness and facilitates onset and maintenance of sleep

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hypnotics

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ideally would induce sleep rapidly, increase sleep time and give the patient a sense of well-being with low ADRs

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hypnotics

Front 16

all benzodiazepines have __ effects

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sleep-inducing

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not all benzodiazepines are ideal __

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hypnotics

Front 18

Flurazpam, Temasepam, Triazolam are

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hypnotics

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Ambien and Sonatal are

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hypnotics

Front 20

may induce REM rebound on w/d

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benzodiazepines

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Provides insight into neural activity associated with different phases of sleep

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EEG

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Appears similar in some ways to wakefulness

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REM

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Alpha waves – 8-12 Hz

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Drowsiness

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Frequency of a-waves

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8-12 Hz

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Theta waves – 3-7 Hz

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Stage 1 sleep

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Frequency of Theta waves

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3-7 Hz

Front 27

Sleep spindles and K complexes – 12-14 Hz

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Stage 2 sleep

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Frequency of Sleep spindles and K complexes

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12-14 Hz

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Delta waves – 0.5-2 Hz

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Deep sleep

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Frequency of Delta waves

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0.5-2 Hz

Front 31

Low voltage fast

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REM sleep and wakefulness

Front 32

Release is increased in REM sleep

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ACh

Front 33

parasympathetic tone refers to the way

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ACh enhances sleep

Front 34

May help entrain circadian rhythm

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ACh

Front 35

Drowsiness associated with this action on this receptor

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H1 antagonists

Front 36

chemical important for wakefulness

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Histamine

Front 37

promotes sleep through regulation of activity in midbrain cholinergic pathways

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Adenosine

Front 38

inhibits adenosine receptor activity, promoting wakefulness

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Caffeine

Front 39

Decreases sleep through inhibition of reticular activating system

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Seratonin

Front 40

prevent sleep, yet produce REM-like symptoms

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5-HT2 agonists

Front 41

Locus coeruleus activation is associated with

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wakefulness

Front 42

Sleep deprivation associated with increased risk of

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psychiatric illness

Front 43

Insomnia affects 25-30% of population and most prevalent in the

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elderly

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The effects of insomnia are serious in % of the population

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17

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Individuals with less than 6 hours of sleep per night have a % higher mortality rate

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70

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sleep > 50 % of time

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Newborns

Front 47

occupies roughly 50 % of sleep time

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REM sleep

Front 48

Sleep levels are especially low in the

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elderly

Front 49

Involuntary muscle contractions

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Myoclonus

Front 50

Flurazepam

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Dalmane

Front 51

Temazepam

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Restoril

Front 52

Triazolam

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Halcion

Front 53

Quazepam

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Dorval

Front 54

Estazolam

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ProSom

Front 55

Zolpidem

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Ambien

Front 56

Zaleplon

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Sonatal

Front 57

Shorten slow wave (deep) sleep, REM cycle

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hypnotics

Front 58

Increase total sleep time (stage 2)

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hypnotics

Front 59

Increase number of REM cycles (total REM increases)

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hypnotics

Front 60

May induce REM rebound on withdrawal

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hypnotics

Front 61

Gives sense of deep, refreshing sleep
with a decrease in sleep latency

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hypnotics

Front 62

increase chloride (Cl-) conductance through interaction with GABAA receptors

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Benzodiazepines

Front 63

GABAa receptors are of this type

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ligand gated Cl- channels

Front 64

Benzodiazepines __ cells, thereby reducing neuronal activity

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hyperpolarize

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__ is complete for most benzodiazepines (except flurazepam and zaleplon)

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Systemic absorption

Front 66

Estazolam should be administered

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1-2 hours before bedtime

Front 67

Highly lipophilic, resulting in high CNS penetration

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benzodiazepines

Front 68

Extensive (>90%) binding to plasma proteins

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benzodiazepines

Front 69

benzodiazepines cross placenta during pregnancywhich means they

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are secreted in milk

Front 70

OHylation at position 3 yields

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active compounds

Front 71

N-desalkylation yields

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active compounds

Front 72

Hydroxylation of a-methyl groups on fused rings results in

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active compounds

Front 73

Dependent on hydroxylation

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Glucuronidation

Front 74

Conjugation with glucuronic acid

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Glucuronidation

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Glucuronidation results in

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inactive metabolites

Front 76

Flurazepam is metabolized to

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N-desalkyl derivative

Front 77

Desalkylflurazepam accumulates with

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repetitive dosing

Front 78

Half-life longer in elderly (especially men)

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Flurazepam

Front 79

Flurazepam is subject to hydroxylation here

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3-position

Front 80

Metabolite of flurazepam, has a half-life of ~80 hours

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N-Desalkylflurazepam

Front 81

Sustained effect even after discontinuation; hangover effect after initial doses

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N-Desalkylflurazepam

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No daytime anxiety; daytime somnolence

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N-Desalkylflurazepam

Front 83

Already hydroxylated in the 3-position;
Glucuronidation results in inactivation

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Temazepam

Front 84

Half-life of 13-14 hours

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Temazepam

Front 85

Quazepam is metabolized to

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2-oxo-quazepam

Front 86

Subject to N-desalkylation, resulting in N-desalkyl-flurazepam

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Quazepam AND Flurazepam

Front 87

Net effects similar to N-desalkyl-flurazepam

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Quazepam

Front 88

Metabolized by a-hydroxylation and by 3-hydroxylation then rapid glucuronidation of both hydroxyl groups results in inactivation

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Triazolam

Front 89

Short half-life (1 – 1.5 hours)

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Triazolam

Front 90

Implications of short half-life

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Potential for rebound insomnia and daytime anxiety

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Estazolam is oxidized to

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1-oxoestazolam

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Half-life (10 – 24 hours)

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Estazolam

Front 93

Not benzodiazepines, yet enhance GABAa receptor activity

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Zolpidem and Zaleplon

Front 94

Metabolized by oxidation of methyl groups to carboxylic acids

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Zolpidem

Front 95

Zaleplon is metabolized by oxidation to

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5-oxo-zaleplon

Front 96

Minor oxidation pathway through CYP3A4, resulting in desethylation

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Zaleplon

Front 97

Oxidation of most benzodiazepines is inhibited by

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cimetidine

Front 98

do not induce or inhibit mixed function oxidases

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Benzodiazepines

Front 99

Although NOT a benzodiazepine, oxidation of Zaleplon also is inhibited by cimetidine since

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cimetidine inhibits aldehyde oxidase

Front 100

a dopamine agonist which induces n/v

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apomorphine

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Benzodiazepines have __ abuse potential

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low

Front 102

Headache, irritability, dizziness, abnormal sleep are

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w/d sx from benzodiazepines

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Rebound insomnia is associated with this benzodiazepine

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Triazolam

Front 104

Benzodiazepines, in combination with __ can be fatal

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alcohol

Front 105

a benzodiazepine antagonist that can be used to block adverse effects of benzodiazepines

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Flumazenil

Front 106

Stomach pump, charcoal, hemodialysis are all ways to treat

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benzodiazepine toxicity

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drug of choice for the treatment of insomnia

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Benzodiazepines

Front 108

This benzodiazepine can be used for up to one month with little tolerance

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Flurazepam

Front 109

This benzodiazepine can be used for up to three months with little tolerance

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Temazepam

Front 110

Benzodiazepines should be used for no longer than

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3 – 6 months

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use recommended for benzodiazepines - (frequency of dose)

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Intermittent (every three days)

Front 112

(e.g., flurazepam) produce sustained sleep, but increased risk of daytime somnolence

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Benzodiazepines with long half lives

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may be best for patients with difficulty falling asleep

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Benzodiazepines with short half lives

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May be less effective patients having difficulty maintaining sleep

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Benzodiazepines with short half lives

Front 115

Development of tolerance can produce __ in compounds with with short half lives

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rebound insomnia

Front 116

Levels decline rapidly so withdrawal symptoms are more apparent

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Benzodiazepines with short half lives

Front 117

Shortens sleep latency and prolongs sleep time with low abuse potential

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Zolpidem

Front 118

Less likely to produce w/d symptoms than benzodiazepines;
Rebound insomnia after first night of w/d, but soon resolves

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Zolpidem

Front 119

This hypnotic is often prescribed for patients with insomnia

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Alprazolam (Xanax®)

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Adaptive response to repeated administration of drugs

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Tolerance

Front 121

Repeated doses have diminishing effects and mMore drug required to produce the same effect

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Tolerance

Front 122

Presence of drug required for normal function

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Dependance

Front 123

Usually manifested by emergence of withdrawal symptoms following discontinuation of drug

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Dependance