Ios 8 Test #4 Kuma

Front 1

sedative definition

Back 1

decreases activity, moderates excitement, calms

induces calmness at constant levels regardless of expernal stimuli

Front 2

hyppnotic definition

Back 2

induces drowsiness, facilitates onset and maintenance of sleep

like normal sleep

Front 3

Anxiolytic: definition

Back 3

induces calming effect without producing drowsiness

Front 4

Benzodiazepines:

Back 4

drugs of choice for sedation and hypnosis e.g. diazepam (VALIUMR); flurazepam (DALMANER)

Front 5

Classification of Benzodiazepines:

Back 5

short acting: < 6 hours half life
*trazoloam

Front 6

graded dose dependent CNS depression

Back 6

Drug A; barbiturate (alcohol)
Drug B: Benzo (safe because the drug response saturates)

Front 7

Classification of Benzodiazepines:

Back 7

short acting: half life < 6 hours
*triazolam
intermediate: 6-24 hour half life
*estazolam
long acting: > 24 hour half life
*flurazepam, diazepam

Front 8

Miscellaneous drugs for sleep

Back 8

Zolpidem (Ambien)- not a benzodiazepine structure, but acts like one
Zaleplon (Sonata)-same as Zolpidem
Buspirone (BusPar)
Older drugs (Meprobamate, chloral hydrate, ethchlorvynol)
Ramelteon (Rozerem)

Front 9

C: Structure Activity Relationship (SAR): Benzodiazepines

Back 9

1,4-benzodiazepines, most contain carboxamide group in 7-membered ring structure
Substituent in 7 position (halogen or nitro group required for sedative-hypnotic action)
Triazolobenzodiazepi-nes (triazole ring in 1,2 position) e.g. triazolam

Front 10

SAR:
Barbiturates
Others

Back 10

1) Barbituric acid nucleus is the pharmacologically active moeity
not sedative-hypnotic, usually used as sodium salts (for injection)
2) Oxy barbiturates - #2 carbon: C=O (most barbiturates except ultra shorts) are oxy
3) Methylated oxybarbiturates -#3 nitrogen: N-CH3
e.g. Methohexital, Mephobarbital-metabolized to phenobarbital
4) Thiobarbiturates #2 carbon: C=S(instead of C=O)-increased lipid solubility. E.g. Thiopental, Thioamylal

Front 11

Benzodiazepines
ADME

Back 11

Completely absorbed
High lipid:water partition coefficient
Bind plasma proteins
Extensively metabolized by P450s
Redistributed (major mechanism which drug action is terminated0
All sedative hypnotics cross the placental barrier during pregnancy

Front 12

picture of the structure of benzos

Back 12

the extra ring on trazolam and alprazalam increase the onset of action

Front 13

Pictures of structures of other barbitiurates

Back 13

Front 14

when a structure has a longer side chain what does that indicate

Back 14

more lipophilic

Front 15

Lipid solubility of benzodiazepine

Back 15

Greater the lipid solubility, faster the onset of action
CNS levels are achieved sooner
E.g. triazolam and diazepam have faster onset of action and greater lipid solubility than lorazepam and chlordiazepoxide, which have a slower onset of action
Decreased duration (because leaves the brain sooner because highly profused)
Increased protein binding (imp for drug interactions): 60-90%
Increased proportion metabolized
Less excreted unchanged in urine
Metabolized by P450s (3A4) and subsequently glucuronide conjugation

Front 16

Bioactivation of Benzodiazepines:

Back 16

Bioactivation: Active metabolites
E.g. diazepam to desmethyl diazepam to oxazepam
Unwanted CNS effects
Cumulative effects of multiple dosing
Daytime sedation
Complicates pharmacokinetics
Elimination t1/2 of parent has little to do with time course of pharmacological effects

the active metabolite makes monitoring more difficult and compliates thinkgs, can also cause the next day hangovers, creastes moe SE

Front 17

Redistribution:

Back 17

Transfer of drug from the CNS to other tissues

Order depends on rate of perfusion of organ:
i.e. skeletal muscle>>adipose tissue
Contributes to termination of major CNS effects

order depends on lipid solubility adn profusion of the organ

want the drug in the CNS for sedative and hypnotic affectes

Front 18

ADME (Barbiturates)
Barbiturates:

Back 18

Rapidly absorbed
High lipid:water partition coefficient
Bind plasma proteins
Extensively metabolized
Redistributed

Front 19

pic of non-benzos

Back 19

Front 20

pic of rozerem

Back 20

Front 21

Bioactivation
of benzos pic

Back 21

Front 22

Biodispositon of a Sedative-Hypnotic Drug

Back 22

the first dotted line= the concentration in the plasma
the first bump= brain, kidney, heart and liver
the second bump= is the skeletal muscle
the las bump= fat tissue

Front 23

Lipid solubility barbiturates

Back 23

Faster onset of action (C=S; long R1 or R2 groups) E.g. Thiopental (very fast onset)
Decreased duration
Increased protein binding (implications for drug interactions)
Increased proportion metabolized
Less excreted unchanged in urine
Metabolized by P450s and subsequently glucuronide conjugation

Front 24

in general do barbiturates have active metabolites

Back 24

nope

Front 25

Bioactivation: barbiturates

Back 25

None (metabolites lack activity)

Front 26

Redistribution:

Back 26

Transfer of drug from the CNS to other tissues
Order depends on rate of perfusion of organ:
Skeletal muscle>>adipose tissue
Contributes to termination of major CNS effects

Front 27

Ionization: barbiturates

Back 27

Behave as weak acids pKa=7.4
Alkalization of urine increases elimination rate

increase the pH--> more drug is ionized so more water soluble (this is important for OD)

Front 28

Other factors affecting biodisposition of sedatives-hypnotics

Back 28

Disease
Old age (less skeletal muscle mass and decreased metabolism)
Drug induced increases or decreases in metabolism (only barbiturates induce drug metabolizing enzymes)

Front 29

Mechanism of Action of Sedatives-Hypnotics: GABA

Back 29

GABA is the major inhibitory neurotransmitter
Structure and function
GABA receptors:
2 types of GABA receptors: GABAA and GABAB
GABAA receptor is a chloride ion channel
GABAB receptor is G-protein linked
GABAA receptor channel is a pentameric complex (a,b g are essential for normal functions)

the 3 subunits are essential for function

activation causes hyperpolarization and increases membrane resistance

Front 30

GABA receptors:

Back 30

2 types of GABA receptors: GABAA and GABAB
GABAA receptor is a chloride ion channel
GABAB receptor is G-protein linked
GABAA receptor channel is a pentameric complex (a,b g are essential for normal functions)

Front 31

what happens to the GABA receptor when a sedative or hypnotic binds

Back 31

increases the affects of gaba

Front 32

can sedatives or hyponotics activate the gaba receptors without gaba

Back 32

nope
gaba is needed fot the actions of benzos, they themselves cannot increase the current of Cl

They potentiate the affects of GABA

Front 33

GABAA receptor channel is a ____________ complex

Back 33

pentimeric

Front 34

Subunits _______ are essential for normal functions
of the GABA receptor

Back 34

a,b g

Front 35

Mechanism of action: Benzodiazepines

Back 35

Potentiate GABAergic inhibition at all levels of the brain and spinal cord
Regions include substantia nigra, cerebellum, cortex, hypothalamus, spinal cord, hippocampus
Increase the GABA-mediated synaptic inhibition (via membrane hyperpolarization). This leads to a decrease in firing rate of neurons in certain brain areas.
Do not substitute for GABA, but enhance its inhibitory actions
In other words, binding of BZs to the GABAAreceptor (g subunit) facilitates channel opening, but does not directly initiate Cl current

Front 36

do benzos directly bind the gaba receptor

Back 36

nope they are allosteric activators

modulators

Front 37

GABA A Receptor

Back 37

Benzodiazepines act on GABAA, not GABAB receptors
Site of benzodiazepine interaction with the GABAA receptor is distinct from GABA
Benzodiazepines are allosteric agonists. I.e. they bind GABAA receptor at a distinct site and increase the affinity of GABA (agonist) for its receptor (GABAA receptor)

the fact that benzos are allosteric agonis tdictates there safety

Front 38

Biodispositon of a Sedative-Hypnotic Drug graph

Back 38

the dotted line= plasma
first bump= brain, kidneys, heart, liver
second bump= skeletal muscle
third bump= fat

Front 39

pic of gaba receptor

Back 39

Front 40

Benzodiazepine and Barbiturate Action on GABA Currents

Back 40

phenobarbital causes the channels to stay open for a longer duration, does not increase frequency

Front 41

what happens to the frecuency of the Cl channel with benzos

Back 41

Benzodiazepines result in increased frequency of GABAAreceptor channel opening

Benzodiazepines do not substitute for GABA, but enhance GABA’s effects without directly opening the GABA receptor chloride channel

Benzodiazepines increase the efficiency of GABA mediated synaptic inhibition by increasing chloride influx and membrane hyperpolarization

Front 42

what do barbiturates do Cl channels

Back 42

increase duration of opening

Front 43

Mechanism of action:Barbiturates

Back 43

Facilitate the actions of GABA at multiple CNS sites
In contrast with benzodiazepines, they increase the duration of GABA receptor channel openings
In contrast with benzodiazepines, at high doses of barbiturates directly open GABAA activated chloride channels (therefore benzodiazepines are safer)
Bind the GABAA receptors at sites distinct from benzodiazepines
Also exert non-synaptic effects (membrane actions)-basis anesthetic actions

Front 44

do barbiturates directly activate the gaba receptor

Back 44

yep
In contrast with benzodiazepines, at high doses of barbiturates directly open GABAA activated chloride channels (therefore benzodiazepines are safer)

Front 45

Mechanism of Action (summary) of benzos and barbiturates

Back 45

Both classes potentiate GABAergic inhibition
Benzodiazepines result in increased frequency of GABAAreceptor channel opening
Barbiturates increase the duration of GABA receptor channel openings and directly activate channel opening at high doses

Front 46

Benzodiazepine receptor ligands

Back 46

Agonists: Zolpidem (Ambien): NOT STRUCTURALLY SIMILAR TO BENZODIAZEPINES
Antagonists: (Flumazenil):Blocks the action of benzodiazepines and zolpidem, but not barbiturates, ethanol or meprobamate
Clinically used to treat overdose of benzodiazepines and zolpidem

Front 47

Ideal hypnotic:

Back 47

1)short acting
2)no hangover
3) should not affect REM sleep
4) no physical dependence

Front 48

Sedation

Back 48

Defined as suppression of responsiveness to a constant level of stimulation, with decreased spontaneous activity
Disinhibition (relieve punishment-suppressed behavior or antianxiety effects)
Anterograde amnesic effect (inability to remember events occurring during the drug’s actions) at sedative doses
=

Front 49

Hypnosis

Back 49

Induces sleep at higher doses
Cyclic sleep stages: 2 stages (REM:~25%, NREM:~75%)
REM sleep: recallable dreams occur
NREM sleep: 4 stages (1-4), 50% in stage 2. Stage 3,4 (delta or slow wave sleep) is associated with night terrors, sleep walking

Front 50

Effects of sedative-hypnotics on sleep stages:

Back 50

Latency to onset of sleep is decreased (time to fall asleep)
Duration of stage 2 NREM sleep is increased
Duration of REM sleep is decreased
Duration of slow –wave sleep is decreased

Front 51

Anesthesia
(benzos and barbiturates)

Back 51

Higher doses will depress the CNS to stage III of general anesthesia
Barbiturates are useful e.g. lipid soluble thiopental and methohexital
Benzodiazepines less useful (postanesthetic respiratory depression)

Front 52

Anticonvulsant effects-most (benzos and barbiturates)

Back 52

inhibit the development and spread of seizure activity

Front 53

Muscle relaxation- (benzos and barbiturates)

Back 53

due to inhibition on polysynaptic reflexes

Front 54

Respiration (Benzodiazepines)

Back 54

No effect of hypnotic doses on NORMAL people, but special care in children, people with impaired liver function eg. Alcoholics
Higher doses (as used for preanesthetic medication) for endoscopy, they depress alveolar ventilation and cause respiratory acidosis. This is exagerated in COPD patients
Hypnotic doses worsen sleep-related breathing disorders by interfereing with control of upper airway muscles or decreasing ventilatory response to CO2

Front 55

(benzos and barbiturates)

Back 55

No significant effects in normal people
Cardiovascular depression in disease states that impair cardiac function e.g. congestive heart failure
Toxic doses cause depression of myocardial contractility and vascular tone leading to circulatory collapse

Front 56

Adverse Effects: Benzodiazepines

Back 56

Very safe (contrast with barbiturates)
Dose dependent CNS depression (drowsiness, impaired judgment, decreased motor skills, driving ability etc)
Anterograde amnesia: useful in endoscopy (preanesthetic use) but liable to abuse -(Rohypnol or flunitrazepam- date-rape drug)
Hangover: common with long elimination t1/2s
Elderly individuals: doses approximately half of younger adults, confusion
Respiratory problems: exacerbation of breathing problems in COPD, sleep apnea

Front 57

Adverse Effects: Benzodiazepines (Cont’d)
Tolerance

Back 57

Psychological and physiological dependence
Tolerance is common. I.e. decrease responsiveness to a drug following repeated exposure
Benzodiazepines cause tolerance due to downregulation of CNS BZ receptors (pharmacodynamic tolerance)
Cross tolerance and cross dependence-with ethanol

Front 58

Dependence:

Back 58

Have ability to produce true physical dependence and withdrawal (most prescribed as Schedule III or IV drugs)

Front 59

Adverse Effects: Barbiturates
CNS effects

Back 59

Residual effects: Drowsiness lasts few hours, residual CNS depression can last the following day
Impaired judgment, decreased motor skills, driving ability etc
Vertigo, nausea, diarrhea or overt excitement
Paradoxical excitement (in some)
Pain especially in psychoneurotic patients with insomnia, delirium and restlessness

Front 60

Adverse Effects: Barbiturates

Back 60

Skin hypersensitivity: localized swellings, exfoliative dermatitis
Respiration: severe depressants

Front 61

contraindications of barbiurates

Back 61

Porphyrias (barbiturates enhance porphyrin synthesis)

porphyrins are part of proteins (hem groups)

Front 62

Adverse Effects: Barbiturates
tolerance

Back 62

To sedation partly due to induction of liver enzymes (metabolic tolerance)
Cross tolerance and cross dependence-with ethanol

Front 63

Flumanezil

Back 63

Flumanezil reverses the sedative actions of benzodiazepines

antagonist

Front 64

Drug interactions benzos and barbiturates

Back 64

CNS depressants (additive effects):
Alcohol, opioid analgesics, anticonvulsants, phenothiazines
Drug metabolizing enzyme system:
(only barbiturates) increase metabolism of phenytoin, dicumarol, digitalis, etc

Front 65

Therapeutic Uses
benzos and barbiurates

Back 65

Sedation and amnesia before medical and surgical procedures
Hypnosis-treatment of insomnia
Anesthesia-by increasing dose
Other-(only some) anticonvulsant, muscle relaxant, antianxiety, control of withdrawal symptoms

Front 66

Newer drugs:Buspirone

Back 66

Relieves anxiety without major sedation
Unlike BZs, no muscle relaxing, anticonvulsant or hypnotic actions
Does not work via GABA receptors, but 5HT1A
No rebound anxiety or withdrawal symptoms
Minimal abuse potential
Takes at least a week to work, therefore better suited for generalized anxiety states
Less motor impairment (driving skill not affected like BZs)
Does not potentiate CNS depressant effects e.g. alchohol and other sedative-hypnotic drugs
Side effects include tachycardia, palpitations, nervousness, GI disturbances, pupillary vasoconstriction

Front 67

Novel Benzodiazepine Receptor Agonists

Back 67

Drugs in this class include Zolpidem (Ambien), Zaleplon (Sonata), Indiplon
Eszopiclone (Lunesta)

Structurally unrelated to benzodiazepines

Therapeutic effects are due to action on GABA receptors

Front 68

agonist

Back 68

Binds to specific site on receptor and produces a full tissue response

Front 69

antagonist

Back 69

Competitive: Drug competes with agonist for binding site, lacks intrinsic efficacy but has affinity for receptor.
Non-competitive: Antagonists that dissociate so slowly from the receptor that the effect is essentially irreversible and maximal effect of agonist is decreased.

Front 70

Zolpidem

Back 70

Hypnotic drug structurally unrelated to BZs
Binds selectively with BZ site at GABAA receptors and facilitates GABA mediated inhibition
Unlike BZ, minimal muscle relaxing and anticonvulsant effect
Unlike BZ, minimal effects on sleep stages, but higher doses suppress REM sleep

cleared in approximatley 4 half lives so 8 hours of sedative affects

Front 71

Zolpidem (cont’d)

Back 71

Respiratory depression at high doses with CNS depressants like alcohol
Potential for tolerance and dependence is less than BZs
Half-life is 2 hr, therefore sufficient to last through 8-hour sleep-period
Effective in relieving sleep-onset insomnia. Approved for use up to 7-10 days at a time
Zolipidem and Zaleplon have similar degrees of efficacy
Abuse potential of Zolpidem and Zaleplon is similar to BZs

Front 72

Unlike BZ, Zolpidem produces minimal _________ and _________

Back 72

muslce relaxation
anticonvulsant effects

Front 73

Zaleplon

Back 73

Hypnotic drug structurally unrelated to BZs
Binds selectively with BZ1 site at GABAA receptors and facilitates GABA mediated inhibition
Decreases sleep latency but not total sleep time or sleep stages (architecture)
Potentiates CNS depressant effects of alcohol

Front 74

half life of zaleplon

Back 74

1 hour

Front 75

metabolism of Zaleplon

Back 75

Metabolism:
Metabolized by hepatic aldehyde oxidase and CYP3A4.
Dose should be reduced in patients with liver impairment and elderly.
Metabolism inhibited by cimetidine. Drugs that induce CPY3A4, increase zaleplon clearance.

Front 76

half life of zolpidem

Back 76

2 hours

Front 77

Eszopiclone (Lunesta)

Back 77

Hypnotic drug structurally unrelated to BZs
Cyclopyrrolone class
Binds selectively with benzodiazepine site at GABAA receptors and facilitates GABA mediated inhibition
Potentiates CNS depressant effects of alcohol

Front 78

half life of Eszopiclone (Lunesta)

Back 78

6 hours

Front 79

metabolism of Eszopiclone (Lunesta)

Back 79

Metabolism:
Metabolized by CPY3A4 and CYP2E1
Dose should be reduced in patients with liver impairment and elderly.

Front 80

SE Eszopiclone (Lunesta)

Back 80

Adverse effects include viral infection, dry mouth, dizziness, hallucinations, infection, rash, and unpleasant taste.

Front 81

Eszopiclone (Lunesta)
________ and labeled for long-term use

Back 81

approved

Front 82

Benzodiazepine Receptor Antagonist

Back 82

Flumazenil (Romazicon)
It is a specific benzodiazepine receptor antagonist.
Binds with high affinity to specific sites and competitively antagonizes the binding and allosteric effects of benzodiazepines and other ligands. Effects of agonists are antagonized.
Available for only intravenous administration
Used for the management of benzodiazepine overdose and reversal of their sedative effects during general anesthesia

Front 83

Ramelteon MOA

Back 83

Binds (agonist) to melatonin type 1 (MT1) and type 2 (MT2) receptors in the suprachiasmatic nucleus

Front 84

Ramelteon PK

Back 84

Absorption – affected by high-fat meal
t1/2 = 1-2.6 hrs

Front 85

SE Ramelteon

Back 85

Minimal abuse potential or behavioral impairment
Somnolence and dizziness
Nausea and headache
Severe allergic reactions

Front 86

indications for ramelteon

Back 86

Useful in the treatment of insomnia characterized by difficulty falling asleep

Front 87

_______ are safer than ________

Back 87

Benzos
barbiturates

Front 88

summary of insomnia stuff

Back 88

Sedative (decreases activity and produces calmness)
Hypnotic: (drowsiness, sleep)
B. Chemical classification:BZ and barbiturates (duration)
C. Structure activity relationship
D. ADME :lipid solubility, redistribution, metabolism
E. Mechanism of Action: Potentiate GABA inhibition
BZ: increase frequency of channel opening and chloride influx
Barbiturates: increase duration and directly open channels
F. Pharmacological Actions: Sedation, hypnosis (latency decreased, NREM increased, REM decreased, delta decreased), anesthesia, anticonvulsant action, muscle relaxation, respiration, cardiovascular
G.Adverse Effects: BZ are much safer than barbiturates
BZ: CNS depression, anterograde amnesia (Rohypnol), hangover, elderly, respiration, tolerance (p.dynamic) and cross tolerance
Barbs:CNS, residual, pain, skin, respiration, tolerance, cross
H. Drug Interactions:CNS depressants, metabolism (Barbs)
I. Therapeutic Uses : sedation, hypnosis, anesthesia, anticonvulsant, muscle relaxants, antianxiety, alcohol withdrawal
J. Preparations :

Front 89

1)The following is TRUE regarding an ideal hypnotic:
a.It should be long acting
b.It should affect REM sleep
c.It should not produce physiological dependence
d.All of the above

Back 89

c.It should not produce physiological dependence

Front 90

3). Fluoxetine (ProzacR) produces the following side effect(s) by activation of 5HT3 receptors:
a)Nausea
b)Vomiting
c)Sexual dysfunction
d)All of the above

Back 90

d)All of the above

Front 91

Two major changes in schizophrenia are

Back 91

1)decreased inhibitory interneurons (loss of inhibition) and 2) loss of cortical neuropil I.e. dendrites and axons.

Front 92

The decrease in pyramidal neuron connectivity and interneurons that store and process information further decreases

Back 92

the ability of the brain to sort the incoming information into what is known and what is unknown. Therefore, schizophrenics experience the world as “overwhelming” and form delusions.

Front 93

The neurons that store and process information, such as the pyramidal neurons found cerebral cortex, are regulated by inhibitory interneurons that....

Back 93

nhibitory interneurons monitor and inhibit pyramidal-neuron activity. The activity of both pyramidal and inhibitory neurons is further modulated by dopaminergic neuron

Front 94

a schizophrenic brain

Back 94

a brain that is hypersensitive to stimuli and unable to regulate its response through normal inhibitory mechanisms.

Front 95

Phenothiazine derivatives: 3 subfamilies:

Back 95

a) Aliphatic derivatives (chlorpromazine)
b) Piperidine derivatives (thioridazine)
c) Piperazine derivatives (trifluoperazine)-

Front 96

Thioxanthene derivatives

Back 96

(thiothixene).

Front 97

Butyrophenone derivatives

Back 97

(haloperidol)-

Front 98

Miscellaneous (heterocyclics):

Back 98

newer drugs (clozapine).

Front 99

Highlights of ADME:

Back 99

High lipid solubility, highly protein-bound, large Vd, accumulates in brain, lung and tissues with high blood supply; extensively metabolized by CYPs and conjugation, enter fetal circulation/breast milk, first-pass effect. Elimination t1/2s typically 20-40 hr, therefore allow one day dosing. Longer duration than predicted from t1/2s due to high lipid solubility. Slow removal of drugs from body, which results in slow exacerbation (exaggeration) of psychosis months after drug is stopped.

Front 100

Dopamine Hypothesis of Schizophrenia is based on

Back 100

circumstantial evidence that excessive or increased dopaminergic activity underlies schizophrenia. It has some drawbacks.

Most antipsychotic drugs block postsynaptic D2 receptors in the CNS (mesolimbic system).

Front 101

Action on dopamine receptors:

Back 101

Here are 4 major dopaminergic projections.
1)Mesolimbic system responsible for the antipsychotic effects.
2)Nigrostriatal system responsible for the extrapyramidal effect
3)Hypothalamic system in which dopamine normally inhibits prolactin release. Blockade of dopamine receptors by antipsychotics therefore relieves (or lessens) dopamine’s inhibition on prolactin. Consequently, an increase in prolactin release occurs. This results in the hyperprolactinemia side effect associated with dopamine antagonists.Periventricular system is involved in eating behavior. May be responsible for the changes in food intake following antipsychotics.

Front 102

Mesolimbic system responsible for

Back 102

the antipsychotic effects.

Front 103

Nigrostriatal system responsible for

Back 103

the extrapyramidal effect

Front 104

Therapeutic effect of most antipsychotics correlates with__________ of D2 dopamine receptors

Back 104

inhibition

Front 105

Heterocyclic drugs such as clozapine are more effective inhibitors of ______, ______, and _______ receptors

Back 105

of D4, alpha1, 5HT2A receptors

Front 106

Action on dopamine receptors:

Back 106

Here are 4 major dopaminergic projections.
1)Mesolimbic system responsible for the antipsychotic effects.
2)Nigrostriatal system responsible for the extrapyramidal effect
3)Hypothalamic system in which dopamine normally inhibits prolactin release. Blockade of dopamine receptors by antipsychotics therefore relieves (or lessens) dopamine’s inhibition on prolactin. Consequently, an increase in prolactin release occurs. This results in the hyperprolactinemia side effect associated with dopamine antagonists.Periventricular system is involved in eating behavior. May be responsible for the changes in food intake following antipsychotics.

Front 107

Mesolimbic system responsible for

Back 107

the antipsychotic effects.

Front 108

Nigrostriatal system responsible for

Back 108

the extrapyramidal effect

Front 109

Therapeutic effect of most antipsychotics correlates with__________ of D2 dopamine receptors

Back 109

inhibition

Front 110

Heterocyclic drugs such as clozapine are more effective inhibitors of ______, ______, and _______ receptors

Back 110

of D4, alpha1, 5HT2A receptors

Front 111

endocrine effects of antipsychotics

Back 111

Endocrine Effects: Hyperoprolactinemia
Mechanism: Blockade of dopamine’s tonic inhibition of prolactin secretion

Front 112

CV of antipsychotics

Back 112

Orthostatic hypotension due to alpha adrenergic receptor blockade.
Abnormal electrocardiogram effects: Especially with thioridazine

Front 113

Chemoreceptor trigger zone (CTZ) of antipsychotics

Back 113

Action of antipsychotic drugs here is responsible for their antiemetic effects.
Look up major advantages/disadvantages of drugs i.e. which have more/less sedation, extrapyramidal effect (see table provided from Katzung (Lange) in class) or if you want, look up Goodman and Gilman.

Front 114

SE of antipsychotics

Back 114

sedation
postural hypotension
EPS

MAJOR SE
parkinson's syndrome
akathisia
tardive dyskinesia
seizures
metabolic endocrine effects
DM

Front 115

sedation and antipsychotics

Back 115

is due to blockade of histamine H1 receptors and tolerance develops to this.

Front 116

postural hypotension and antipsychotics

Back 116

is due to alpha adrenergic blockade

Front 117

EPS and antipsychotics

Back 117

effects is due to dopamine receptor blockade in the nigrostriatal pathway.

Front 118

Neurological effects
Parkinson’s syndrome and antipsychotics

Back 118

Due to the blockade of nigrostriatal dopamine receptors. It can be treated with anti-Parkinson's drugs or antimuscarinic drugs.
Akathisia (uncontrollable restlessness)

Front 119

tardive dyskinesia and antipsychotics

Back 119

Late occurring syndrome of abnormal choreoathetoid movements. This is one of the most important side effects of antipsychotics. Its incidence was 20-40% of all chronically treated subjects prior to ther introduction of newer drugs such as risperidone, clozapine, olanzapine and quetiapine. It is very important to recognize it early, since advanced cases are difficult to reverse.
Mechanism: Thought to occur due to excessive function of dopamine due to dopamine receptor supersensitivity (supersensitivity means exquisite or extreme sensitivity). Chronic dopamine receptor blockade over years can lead to adaptive increases in dopamine receptor numbers/sensitivity and thereby result in tardive dyskinesia (see glossary for meaning and syndrome).
Time course: It occurs after months or years of treatment with antipsychotics (especially the dopamine receptor blockers).
Treatment involves discontinuation of antipsychotic, reducing dose.

Front 120

seizures and antipsychotics

Back 120

Older drugs (Chlorpromazine) and newer (Clozapine). Mechanism: Involves lowering of seizure threshold (i.e. makes the brain more sensitive to seizures). Should be used with extreme caution (or not at all) in patients with untreated epilepsies and people undergoing withdrawal of from alcohol, barbiturates, or benzodiazepines. Some atypical drugs such as qeutiapine and risperidone can be used safely in epileptic patients.

Front 121

metabolic and endocrine effects of antipsychotics

Back 121

These include weight gain, hyperprolactinemia in women resulting in amenorrhea-galacterrohea syndrome and infertility and hyperprolactenimia in men resulting in loss of libido, impotence, and infertility. Most antipsychotics increase appetite and result in weight gain especially clozapine and olanzapine.

Front 122

DM and antipsychotics

Back 122

Increasing reported in patients treated > 5 years with second-generation drugs. Cholesterol levels increase ~10% after 14 weeks of olanzapine treatment. Ziprasidone and amisulpride cause less weight gain compared other antipsychotic drugs. Maybe due to weight gain and/or insulin resistance.

Front 123

Toxic or allergic reactions and antipsychotics

Back 123

jaundice
agranulocytosis
blood disorders
effects on the eye
cardio toxicty
neuroleptic malignant syndome

Front 124

jaundice and antipsychotics

Back 124

May be due to hypersensitivity reaction.

Front 125

agranulocytosis and antipsychotics

Back 125

Incidence with clozapine is small (1-2%), but significant. It is a serious fatal effect that can develop rapidly between 6th and 18th week of therapy. Not known if this is an immune reaction. It is reversible upon discontinuation of drug. This is the reason for mandatory weekly blood counts of patients on clozapine.

Front 126

other blood disorder and antiphyschotics

Back 126

Mild leukocytosis, leukopenia and eosinophilia can occur occasionally with antipsychotics, especially with clozapine. These effects are less common with low potency phenothiazines.

Front 127

effects on the eye and antiphyschotics

Back 127

Deposits in the anterior portion of the eye (cornea and lens) are a common complication of chlorpromazine. Thioridazine causes retinal deposits (retinitis pigmentosa), which is associated with browning of vision.

Front 128

cardiac toxicity and antiphyschotics

Back 128

Postural hypotension occurs and discussed above. Chlorpromazine and other low potency drugs have direct negative inotropic effect on the heart. They can produce antiarrhythmic effects. ECG changes have been reported with several antipsychotics. Thioridazine in doses more than 300 mg daily is associated with minor abnormalities of T waves (reversible). Overdoses associated with major ventricular arrhythmias, cardiac conduction block and sudden death.

Front 129

neuroleptic malignant syndomre and antiphyschotics

Back 129

This is a life threatening disorder that occurs in patients who are extremely sensitive to extrapyramidal effects of antipsychotics. The symptoms include muscle rigidity, high fever, leukocytosis, altered pressure, pulse rate. A severe form of the extrapyramidal syndrome (Parkinson’s syndrome) may be seen.
Treatment: Early: antiparkinsonism drugs for extrapyramidal syndrome, muscle relaxants (especially diazepam and others such as dantrolene) or dopamine agonists (bromocriptine because it occurs due to excessive dopamine receptor blockade).

Front 130

drug interactions and antiphyschotics

Back 130

Anticholinergics, sedative/hypnotic agents and antiadrenergic agents together with the antipsychotics will result in additive effects i.e. increased sedation, hypotension etc.

Front 131

therapeutic uses of antipsychotics

Back 131

1)Psychiatric indications:
a.Schizophrenia (primary indication) and bipolar affective disorder (manic episode requires treatment with antipsychotics).
b.Non manic excited states also managed by antipsychotics, often with benzodiazepines
c.Tourettes’s syndrome (see definition in glossary).

2)Non-psychiatric indications:
a.Antiemetic effect (most older antipsychotics except thioridazine). Prochlorperazine is sold solely as an antiemetic.

Front 132

lithium

Back 132

Absorption: Virtually complete within 6-8 hrs; peak plasma levels in 30 min to 2 hrs
Distribution: Water soluble (not lipid soluble). Gets into brain quite slowly due to low lipid solubility. It resides in total body water (vascular compartment) and has a low volume of distribution. It does not bind proteins
Metabolism: It is not metabolized.
Excretion: Entirely in urine. Its plasma half life is ~20 hrs

Front 133

litium effects on electrlytes and ion transport

Back 133

Lithium is closely related to sodium.
It can substitute for sodium. It inhibits Na+-Na+ exchange across the membrane by Na+-Li+ substitution. It does not affect Na+-Ca++ or Na+/K+ ATPase at therapeutic concentrations.
Bottomline: It can substitute for sodium at cellular sites

Front 134

lithium effects on 2nd messengers

Back 134

The best-defined action of lithium is on inositol phosphates (IP).
Inhibits the normal recycling of phosphoinositides.
This results in depletion of PIP2, the precursor of IP3 and diacylglycerol.
Over time, decrease in neurotransmitter dependent phosphoinositide pathways.
Therefore, lithium can inhibit “overactive” circuits that may underlie the manic state.
Also targets GSK3

Front 135

SE lithium

Back 135

Neurological and psychiatric effects: Tremor is the most frequent adverse effect, occurs at therapeutic dosage levels. Treatment: propranolol and atenolol. This is based on the use of some beta blockers for treatment of catecholamine-induced tremor.
Other neurologic abnormalities include choreoathetosis, motor hyperactivity, ataxia, dysarthria, and aphasia (see glossary for the meanings of these terms).
Renal: Polydipsia and polyuria probably due to blockade of antidiuretic hormone (ADH) action. Patients should avoid dehydration.
Edema: Effect of sodium retention.
Toxic reactions: Acute intoxication characterized by vomitting, profuse diarrhea, tremor, ataxia, coma and convulsions. Treatment: no specific antidote, supportive therapy.

Front 136

Chlorpromazine actions

Back 136

a1=5-HT2>D2>D1

Front 137

Haloperidol actions

Back 137

D2>D1=D4>a1>5-HT2

Front 138

Clozapine actions

Back 138

D4=a1>5-HT2> D2=D1

Front 139

Differences among antipsychotic drugs:

Back 139

The degree of D2 receptor blockade in relation with other receptors varies considerably

Chlorpromazine: a1=5-HT2>D2>D1

Haloperidol: D2>D1=D4>a1>5-HT2

Clozapine: D4=a1>5-HT2> D2=D1

Front 140

Neuroleptic syndrome:

Back 140

Neuroleptic” refers to the effects of chlorpromazine and reserpine on the behavior of animals and psychiatric patients
Suppression of spontaneous movements and complex behavior, but not spinal reflexes and unconditioned avoidance behavior

Front 141

what are reserpines effects on monoamines

Back 141

depletes them

Front 142

barbiturates vs. phenothiazines

Back 142

phenothiazine group may not avoid the noxious stimulus, but they are able to escape becasue not sedated
as for the barbitute gourp they inhibited both the escape and the avoidence

Front 143

Psychological effects and behavioral effects antipsychotics

Back 143

In non-psychotic people, antipsychotics cause unpleasant effects characterized by sleepiness, restlessness, antonomic effects

Front 144

Conditioned avoidance behavior and antipsychotics

Back 144

is selectively inhibited by antipsychotic drugs, whereas unconditioned escape or avoidance responses are not

Front 145

Effects on motor activity: antipsychs

Back 145

Diminish spontaneous motor activity
Akathisia
Cataleptic immobility (animals) resembling catatonia in humans ( have ability ti be placed in strange positions, distinct affects of these meds from D2 receptors)
Rigidity and bradykinesia (less voluntary movement)

Front 146

cerebral cortex and antipshys

Back 146

Interfere with dopaminergic projections to the cortex
Seizure threshold: Lower seizure threshold and produce EEG abnormalities (especially clozapine and low potency phenothiazines e.g. chlorpromazine)

Front 147

mesolimbic system and antipshys

Back 147

Dopaminergic projections from the midbrain regions to the temporal and prefrontal cortex
Site of antipsychotic actions

Front 148

basal ganglia and antipshys

Back 148

(including the caudate nucleus, putamen, globus pallidus, which control posture and extrapyramidal aspects of movement)
Extrapyramidal effects (becaue there is a decrease in DA)

Front 149

do 1st or 2nd generation antipsys produce more EPS

Back 149

1st

Front 150

Endocrine Effects: antipsys

Back 150

Amenorrhea-galactorrhea, increased libido (women), decreased libido (men), gynecomastia (men).
Mechanism: Blockade of dopamine’s tonic inhibition of prolactin secretion and peripheral conversion of androgens to estrogens.

Front 151

Chemoreceptor trigger zone (CTZ):antipsys

Back 151

Responsible for antiemetic action of most antipsychotics

Front 152

Diabetes mellitus: antipsys

Back 152

Increasing reported in patients treated > 5 years with second-generation drugs
Cholesterol levels increase ~10% after 14 weeks of olanzapine treatment
Ziprasidone and amisulpride cause less weight gain compared other antipsychotic drugs
Mechanism: Weight gain and/or insulin resistance

Front 153

what is DM produced by form antipsys

Back 153

weight gain and insulin resitance

Front 154

CV toxicity and antipsys

Back 154

Orthostatic hypotension (alpha adrenergic blockade)
Abnormal electrocardiogram effects (especially with thioridazine)
Increased risk of arrhythmias (newer drugs)

Front 155

table of representative antipsys drugs

Back 155

Front 156

weight gain hypothesis for antipsys

Back 156

a decrease in D2 receptor activity decreases reward and saity
5Hts (antoagonism0 processing of leptin is altered
decrease in insulin secretion

Front 157

SE antipsys

Back 157

Sedation (tolerance develops to this) (H1)
Neurological
Extrapyramidal effects (D2)
Hypotension (alpha 1)

Front 158

neurological effects of antipsys

Back 158

PD syndrome: treated with anti-Parkinson's drugs or antimuscarinic drugs. Maybe self limiting
Akathisia (uncontrollable restlessness)
Seizures: Older drugs (Chlorpromazine) and newer (Clozapine)
tardive dyskinesia

Front 159

what can you give to treat EPS

Back 159

antimuscurinics (antihistamine)

Front 160

do 1st or 2nd gen produce more weight gain

Back 160

2nd
on average 40 lbs

Front 161

tardive dyskniesia

Back 161

Late occuring syndrome of abnormal choreoathetoid movements. Most important side effect of antipsychotics. 20-40% of chronically treated subjects prior to risperidone, clozapine, olanzapine and quetiapine. Early recognition is important, advanced cases difficult to reverse. Treatment: discontinuation of antipsychotic, reducing dose
Mechanism: Supersensitivity of dopamine receptors (increase in recepto #s, up regulation, increased sensitivity to Da. This is due to the fact that the receptors are being blocked by the antipshys

not easily controlled
stop therapy if develop

Front 162

metabolic and endocrine effects antipsys

Back 162

Weight gain
Hyperprolactinemia in women resulting in amenorrhea-galacterrhea syndrome and infertility
Hyperprolactenimia in men resulting in loss of libido, impotence, and infertility

Front 163

Toxic or allergic reactions
antipsys

Back 163

Agranulocytosis, cholestatic jaundice, and skin eruptions occur rarely with high potency antipsychotics currently used. (clozapine)
Agranulocytosis:
Incidence with clozapine is small (1-2%), but significant
Serious fatal effect can develop rapidly between 6th and 18th week of therapy
Not known if immune reaction
Reversible upon discontinuation of drug
Requires mandatory weekly blood counts of patients on clozapine
(stop drug if happens)

Front 164

ocular effects of antipsys

Back 164

Deposits in the anterior portion of the eye (cornea and lens) are common complication of chlorpromazine.
Thioridazine causes retinal deposits (retinitis pigmentosa)
Associated with browning of vision

mainly 1st generation

Front 165

cardia toxicity and antipsys

Back 165

Thioridazine in doses more than 300 mg daily associated with minor abnormalities of T waves (reversible)
Overdoses associated with major ventricular arrhythmias, cardiac conduction block and sudden death

increase in QT interval

Front 166

Neuroleptic malignant syndrome

Back 166

Life threatening disorder occurs in patients extremely sensitive to extrapyramidal effects of antipsychotics

inhibits Ca flux in muscles
happens to thos ewho are sensitive to EPS

Front 167

Neuroleptic malignant syndrome
symptoms

Back 167

muscle rigidity, high fever, leukocytosis, altered pressure pulse rate, severe form of extrapyramidal syndrome

Front 168

Neuroleptic malignant syndrome treatment

Back 168

Early: antiparkinsonism drugs for extrapyramidal syndrome, muscle relaxants (especially diazepam and others such as dantrolene) or dopamine agonists (bromocriptine)

Front 169

Psychiatric indications for antipsys

Back 169

Schizophrenia (primary indication)
Bipolar affective disorder (manic episode requires treatment with antipsychotics. Non manic excited states also managed by antipsychotics, often with benzodiazepines
Tourettes’s syndrome

Front 170

Non-psychiatric indications antipsys

Back 170

Antiemetic effect (most older antipsychotics except thioridazine). Prochlorperazine sold solely as antiemetic.

Front 171

common SE of 1st and 2nd generations antipsys

Back 171

Front 172

drugs that effect Da and their MOA, and how SZ symptoms are affected

Back 172

neuroleptics
*antagonize D2
*decrease symptoms

amphetamines
*increase Da in synapse
* increase symptoms

Front 173

drugs that effect glutamate and their MOA, and how SZ symptoms are affected

Back 173

phencyclidine (PCP)
*antagonis of NMDA
*increases symptoms

D-serine and D-cycloserine
*agonist of NMDA
*decrease symptoms

Front 174

drugs that effect seratonin and their MOA, and how SZ symptoms are affected

Back 174

atypical antipsys (clozapine)
*binding 5HT2
*decrease symptoms

Front 175

Reactive
depression

Back 175

Loss (life events)
illness, drugs (antihypertensives, alcohol, hormones), senility

>60% cases
Symptoms: depression, anxiety, tension, guilt. May respond spontaneously

Front 176

Major depression
(Endogenous)

Back 176

Precipitating life events do not explain the level of depression. Unresponsive to changes in life. May occur at any age (childhood-old age). Biologically determined (family history)

25% of all cases. Core syndrome plus “vital” signs: abnormal:abnormal sleep, motor activity, libido, appetite. Responds to antidepressants, ECT. Recurs through life.

Front 177

Bipolar (manic-depressive)

Back 177

Characterized by episodes of mania. Cyclic; mania alone is rare. Depression alone is occasional. Usually observe mania-depression.

10-15% of cases. May be misdiagnosed as endogenous. Lithium stabilizes mood. Mania may require antipsychotic drugs also. Depression managed with antidepressants.

Front 178

PK of lithium

Back 178

Absorption
Virtually complete within 6-8 hrs; peak plasma levels in 30 min to 2 hrs

distirbution
In total body water, Low Vd, No protein binding

metabolism
none

excretion
Entirely in urine. T1/2 ~20 hrs

Front 179

PD of lithium (Effect on electrolytes and ion transport0

Back 179

Lithium is closely related to sodium
It can substitute for sodium in generating action potentials and inhibits Na+-Na+ exchange across the membrane by Na+-Li+ substitution
Does not affect Na+-Ca++ or Na+/K+ ATPase at therapeutic concentrations.
Bottomline: It can substitute for sodium at cellular sites

Front 180

PD of lithium (Effect on second messengers)

Back 180

Best defined action of lithium is on inositol phosphates (IP)
Inhibits the normal recycling of phosphoinositides
This results in depletion of PIP2, the precursor of IP3 and diacylglycerol
Over time, decrease in neurotransmitter dependent phosphoinositide pathways
Therefore, lithium can inhibit “overactive” circuits
Inhibits Glycogen Synthase Kinase b3 (GSKb3) (this is shared by carbomazapine and valproate)

this is the biggest effects of lithium

turning off over active circuit

Front 181

SE of lithium

Back 181

1) Neurological and psychiatric effects:
Tremor is the most frequent adverse effect, occurs at therapeutic dosage levels.
Treatment: propranolol and atenolol
Other neurologic abnormalities include choreoathetosis, motor hyperactivity, ataxia, dysarthria, and aphasia

2) Renal: polydipsia and polyuria. Patients should avoid dehydration
3) Edema: Effect of sodium retention.
Toxic reactions: Acute intoxication characterized by vomitting, profuse diarrhea, tremor, ataxia, coma and convulsions. Treatment: no specific antidote, supportive therapy.

Front 182

Other drugs (mood stabilizers)

Back 182

Valproic acid: Antiepileptic drug demonstrated to have anti-manic effects and widely used for mania. Efficacy similar to lithium.

Carbamazepine: Also antiepileptic drug. Used in acute mania and also for prophylactic therapy.

Front 183

DSM IV Criteria for Schizophrenia

Back 183

Characteristic symptoms
Delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms
Social or occupational dysfunction
Duration
continuous symptoms for 6 months
Exclude schizoaffective and mood disorders
Substance Induced Disorder or General Medical Condition excluded

Front 184

schizoaffectuve disorder

Back 184

1/2 way between bipolar and schizophrenia

Front 185

Positive Symptoms schizoaffectuve

Back 185

Delusions (made up over a long period of time)
False belief
Hallucinations (ususlky hearing voices)
altered senses
Paranoia (seinse others are to to get them)
Loosening of Associations (loss of ability of putting words together and creating meaning)

Positive sx: something is present that shouldn’t be

Front 186

Negative Symptoms schizoaffectuve

Back 186

Poverty of Speech (doesn't answer questions with spontaneous verbage)
Avolition (no goals or dirve)
Affective flattening (no emational presence, underlying lack of affect)
Anhedonia
Isolation

Negative sx: something absent that is normally present

Front 187

Disability due to Schizophrenia

Back 187

Positive symptoms
Delusions
Hallucinations
Disorganized speech

Negative symptoms
Affective flattening
Alogia
Avolition
Anhedonia
Social withdrawal

Cognitive deficits
Attention
Memory
Executive functions(eg, abstraction

Comorbid Conditions
Depression
Anxiety
Aggression
Substance abuse

all the above lead to:
Social / occupationaldysfunction
Work
Interpersonal relations
self-care

COGNITION best correlates with functional attainment in the community

Front 188

Prevalence and Demographics of schizophrenia

Back 188

1% adult population
Men and women equally affected
Onset
men: 15-25 years
women: 25-35 years
Rarely before adolescence or after age 40
Prevalence similar in most cultures

Front 189

Differential Diagnosis for Psychosis

Back 189

Schizophrenia (chronic disorder0
Substance-Induced disorders 9watch for a couple of days to see if recover, when substance wears off)
Mood disorder with psychotic features
Mania
Depression
Dementia/delirium (poor historian and difficultly telling what has been going on with the person)

Front 190

Target Sx for Antipsychotic Therapy in Psychosis expected to imporve

Back 190

Hostility
Agitation/anxiety
Suspiciousness
Hallucinations
Loose associations

Front 191

Target Sx for Antipsychotic Therapy in Psychosis don't expect to imporve

Back 191

“fixed” delusions
Negative sx
Interpersonal rel’t

Front 192

JM is a 28 yom brought to State Hosp by police after claiming to be a prophet on a sacred mission and disrobing in the capitol building. On interview, he is disheveled, foul smelling, speech is rapid and disorganized with shifts from topic to topic. He hears the “voice of God and seventeen angels” who keep him safe from his enemies.

What behavioral sx are present?

Back 192

disrobing in the capitol
speech is rapid

Front 193

JM is a 28 yom brought to State Hosp by police after claiming to be a prophet on a sacred mission and disrobing in the capitol building. On interview, he is disheveled, foul smelling, speech is rapid and disorganized with shifts from topic to topic. He hears the “voice of God and seventeen angels” who keep him safe from his enemies.

What delusions are present?

Back 193

prophet on a sacred mission
who keep him safe from his enemies

Front 194

JM is a 28 yom brought to State Hosp by police after claiming to be a prophet on a sacred mission and disrobing in the capitol building. On interview, he is disheveled, foul smelling, speech is rapid and disorganized with shifts from topic to topic. He hears the “voice of God and seventeen angels” who keep him safe from his enemies

What evidence of hallucinations present?

Back 194

hears the “voice of God and seventeen angels

Front 195

JM is a 28 yom brought to State Hosp by police after claiming to be a prophet on a sacred mission and disrobing in the capitol building. On interview, he is disheveled, foul smelling, speech is rapid and disorganized with shifts from topic to topic. He hears the “voice of God and seventeen angels” who keep him safe from his enemies.

Any other sx of schizophrenia present?

Back 195

disheveled, foul smelling (avolition)
disorganized with shifts from topic to topic (loosening of associations)

Front 196

goals of treatment for schizophernia

Back 196

Prevent aggression: decrease danger to self/others
Decrease target symptoms of psychosis
Hallucinations, paranoia, loosening of associations
Minimize side effects of medications
Prevent tardive dyskinesia
Prevent metabolic side effects

Front 197

treatment Schiz non-pharm

Back 197

secure environment; orienting programming; family counseling

help the family understand the illness

Front 198

treatment Schiz pharmalogical

Back 198

Antipsychotic treatment
Antipsychotics have DIFFERENT side effects and safety profiles
Medication selection must balance risks and benefits

Front 199

Issues in Treating Schizophrenia

Back 199

 70% respond poorly to treatment1
Poor compliance1
discontinuation rate = 74% at 18 months
High relapse rate per year2
treated  25%
untreated/poor compliance  70%
 50% of patients with schizophrenia have history of substance abuse3
 50% of patients attempt suicide at least once3
10–15% complete suicide

Front 200

what is the #1 Issues in Treating Schizophrenia

Back 200

Poor compliance1
discontinuation rate = 74% at 18 months

Front 201

Antipsychotic History

Back 201

50's (conventionals)
Chlorpromazine (D2 blocker)

Thioridazine
Mesoridazine
Trifluoperazine
Haloperidol


80's (atypicals)
clozapine (d2/5HT blocker)

90's
Risperidone
Olanzapine
Quetiapine
Ziprasidone
Asenapine
Iloperidone

aripiprazole (D2 partial agonist)

Front 202

Chlorpromazine

Back 202

conventional

1st antipsychotic; prototype for subsequent drug development
Low potency (100 mg = 2 mg haloperidol)
Dopamine D2 blockade
Also blocks 1, m1, H1
orthostasis, anticholinergic (masks EPS), sedation, weight gain

Front 203

haloperidol

Back 203

conventional

High potency antipsychotic
Blocks dopamine D2 9almost exclusively)
Low activity at other sites
Extrapyramidal Symptoms (EPS) are common and dose related
Long term risk of TD

Front 204

Clinical Consequences of D2 Blockade

Back 204

Dopamine2 Receptor Blockade
Extrapyramidal movement disorders
Akathisia, Pseudoparkinson's, Dystonia
Tardive Dyskinesia
Endocrine changes
Hyperprolactinemia
Amenorrhea, Dysmenorrhea, gynecomastia, lactation
Sexual dysfunction

Front 205

Extrapyramidal Symptoms (EPS) (4 groups)

Back 205

Four Extrapyramidal Symptom groups
dystonia (1st 24-48 hours)
akathisia (1 or more weeks)
pseudoparkinsonism (1 or more weeks)
tardive dyskinesia (>6 months)

Front 206

Dystonia

Back 206

Uncoordinated involuntary sustained contraction of voluntary muscles
Occurs proximal to initiation of treatment
Use of high potency agents, large doses, erratic delivery are risk factors
Requires immediate anticholinergic tx
diphenhydramine
benztropine

this is an emergency

Front 207

Pseudoparkinsonism

Back 207

DOSE RELATED EFFECT; onset within 1 - 2 weeks of initiation or dose increase
Early (mild) symptoms
tremor, decreased arm swing, stiffness
Later symptoms
tremor, loss of arm swing, cog-wheel rigidity, decreased gait, masked face
Treatment
DECREASE DOSE
Switch to Atypical Agent
add anticholinergic

Front 208

Pseudoparkinsonism treatment

Back 208

DECREASE DOSE
Switch to Atypical Agent
add anticholinergic

Front 209

Akathisia

Back 209

Dose related effect; onset within 1 - 2 weeks of initiation or dose increase
Subjective sense of restlessness
Objective increase in psychomotor activity (purposeless movement, pacing, uneasy at rest)
OFTEN MISTAKEN for continued or worsened psychosis or anxiety

Front 210

Akathisia treatment

Back 210

DECREASE DOSE
Switch to different agent
add benzodiazepine or propranolol

Front 211

JM is started on haloperidol 5 mg qid. After 2 days, JM is less intrusive. On the 7th day of therapy, JM complains of feeling stiff and “wired”. On casual observation, while seated, JM exhibits a resting tremor.

What additional questioning/examination
is needed?

Back 211

have patient walk down hallway to look at arm swing
cog-wheel rigidity exam
ask more questions about being wired

Front 212

Tardive Dyskinesia

Back 212

Abnormal involuntary movements with insidious onset
Early symptoms:
Movements seen on close examination
lip pursing/smacking, tongue tremor, writhing movements of tongue, fingers, toes
Late symptoms:
Movements seen by casual observation
choreoathetoid (dance like/snake like) movements of mouth, face, fingers, extremites, trunk
Chewing, tics, grimacing, tongue protrusions

slow and gradual onset

Front 213

tradive dyskinesia risk factors

Back 213

Conventional antipsychotic exposure (duration/dose)
Conventional ~ 5%/year incidence
Atypical ~1%/year incidence
Elderly

Front 214

Antipsychotic withdrawal/dose decrease

Back 214

May unmask TD
Usually slow reversal after antipsychotic withdrawn

Front 215

Clozapine

Back 215

Discovered ~ 1976 testing revealed
Safety Concerns: weight gain agranulocytosis, lower seizure threshold (dose related)
Tolerability Concerns: orthostasis, anticholinergic, sedation, weight gain, hypersalivation
FDA approved in 1990 in US for treatment refractory schizophrenia
Why did this drug launch a revolution in pharmacotherapy of schizophrenia?

Front 216

is clozapine 1st line

Back 216

nope used for resistant schiz

Front 217

Clozapine: an ATYPICAL Antipsychotic pharmocology

Back 217

Unique pharmacology:
Serotonin 5-HT2 blockade>dopamine D2
Low affinity Dopamine blockade
Successful treatment of 30% of patients that failed all trials of conventionals

Front 218

does clozapine cause EPS

Back 218

No extrapyramidal side effects
No TD
Reverses TD in some patients

Front 219

What do we mean when we say “Atypical Antipsychotics”

Back 219

Efficacy for treatment resistant
D2/5-HT2 antagonist
No/low risk of EPS
No/low risk of TD
Efficacy for negative sx

Front 220

Second Generation Antipsychotics (SGAs)

Back 220

Clozapine
Risperidone
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
Paliperidone
(9-hydroxyrisperidone)
Iloperidone
Asenapine

Front 221

Risperidone (Risperdal®)

Back 221

Approved in 1994 marketed by Janssen
High affinity D2/5-HT2 blocker
Increases SERUM PROLACTIN
Lower risk of EPS when dosed appropriately (2 - 6 mg/d for SCZ)
RISK of EPS higher with doses > 6 mg/day
Lowest $/tx among atypicals (generic)
Common side effects: orthostasis, weight gain, sedation, prolactin elevation

Front 222

what are dose titrations in anitpsys trying to prevent

Back 222

orthostatic hypotension

Front 223

Olanzapine (Zyprexa®)

Back 223

Approved 1997 marketed by Lilly
Low risk of EPS
monitor for AKATHISIA at higher doses
Potential for elevating triglycerides and FASTING BLOOD GLUCOSE
Dosed 5 - 30 mg/d for SCZ
labeled up to 20 mg/d
Common side effects: WEIGHT GAIN, sedation, anticholinergic effects
Effectiveness trials show slightly superior efficacy to other atypical antipsychotics

Front 224

Quetiapine (Seroquel®)

Back 224

Approved 1998 marketed by Astra-Zeneca
Low affinity D2/5HT-2 antagonist
Often used among GERIATRICS
LOW EPS AT ALL DOSES
Frequently used for psychosis with dementia and for psychosis with Parkinson’s Disease
Frequent off-label use as an anxiolytic or hypnotic; (25 - 200 mg q hs)
Most common side effects: orthostasis, sedation, weight gain

Front 225

Ziprasidone (Geodon®)

Back 225

Approved 2001 marketed by Pfizer
Dosed 20 mg BID to 80 mg BID
Reduced absorption in fasting state (take with food)
Low risk of weight gain
Has NE and 5-HT re-uptake inhibition
Side effects: orthostasis, sedation
EKG changes – dose-related QTc prolongation (avoid combination with other QT-prolonging drugs)

Front 226

what happens when doses >100 mg of Ziprasidone (Geodon®) are used

Back 226

greater risk of cardiac QT porlongation

Front 227

Aripiprazole (Abilify®)

Back 227

Approved 2002, marketed by BMS
D2 Partial Agonist + 5-HT2 antagonist
Dosing 10-30 mg/d
No effect on prolactin
Lower risk of weight gain
Side effects: frequent transient NAUSEA, dose-related akathisia, insomnia, sedation

Front 228

Paliperidone (Invega®)

Back 228

Approved 2007 marketted by Janssen
On oral ingestion, risperidone is rapidly bio-transformed to 9-OH-risperidone
Paloperidone is extended release formulation of 9-OH-risperidone
Safety, tolerability, efficacy appear similar to risperidone
Oral potency appears to be 1/3 of risperidone (i.e. 3 mg paloperidone = 1 mg risperidone)
OROS Technology – pill casing intact in feces
No clear clinical relevance (patent extender)

Front 229

Iloperidone (Fanapt®)

Back 229

Approved 2009, marketted by Vanda
History: HMR  Titan  Novartis  Vanda
July 2008: FDA Non-approvable
May 2009: Approved
Issues: QT prolongation, efficacy
Side effects: dizziness, somnolence, tachycardia, dry mouth, weight gain and nasal congestion
Limited experience in most practices

Front 230

Asenapine (Saphris®)

Back 230

Approved 2009 marketed by Scherring-Plough
Sublingual tabs (only)
BID dosing
Low risk of weight gain
Side effects: orthostatic hypotension, numb mouth, extrapyramidal side effects
Efficacy: poor performance compared to olanzapine
Limited experience in most practices

Front 231

Drug Selection: STEPS

Back 231

Safety
Tardive dyskinesia
Weight gain
QT prolongation/sudden death
Tolerability
Efficacy
Price
Simplicity

Front 232

Metabolic Syndrome

Back 232

Metabobolic Syndrome observed among 42.7% of 689 assessable CATIE participants
Three of five criteria:
Abdominal obesity (waist circ. >40” men, 35” in women (39%)
Fasting TG >150 ng/dl (58.3%)
HDL <40 men, <50 women (26.5%)
BP >130/85 (45.9%)
Fasting Glucose >100 mg/dl (26.5%)

Front 233

Antipsychotics Market Changes

Back 233

IMS Health 2009:
US Sales of Antipsychotics = $14.6 Billion
(55% INCREASE from 2004 = $9.4 Billion)
Pediatric use of antipsychotic increased 20x from 1996 to 2006
Most atypicals have indications in age 10 – 17
PROFOUND WEIGHT GAIN in pedes started on atypicals
Increased scrutiny of antipsychotics among children and adolescents
My editorial: As we appreciate increased risk with antipsychotics, we are treating more people with less disabling conditions

Front 234

increases in market for Antipsychotics due to...

Back 234

drugs such as abilify and seroquel being advertised and directly marketed for depression

Front 235

JAMA 2009: SATIETY Study

Back 235

12 week weight outcomes in youths ages 4 to 17 (n= 205) treated with
antipsychotic for schizophrenia (30.1%), mood disorder (47.8%)
or behavior problem (22.1%)

biggest weight gains seen with zyprexia

abilify which is still supposed to be weight neutral still increased weight

Front 236

Meta-analysis of Antipsychotic-related 10–Week Weight Change

Back 236

biggest changes seen with: olz,

moderate seen with:
rsp, qtrp

least seen with:
zpl

Front 237

Tennessee Medicaid 2009: Sudden Cardiac Death with Antipsychotics

Back 237

Antipsychotic users were 2x more likely to have SUDDEN CARDIAC DEATH than non-users
Former users: no increased risk vs. non-users
Risk of sudden cardiac death increased with increasing dose of antipsychotics
478 events in 166,324 patient years = 2.9 events/1000 pt yrs (1.4 excess events/1000)
Compare to agranulocytosis with clozapine = 6.8 events/1000 pt yrs

Front 238

Antipsychotics in Mood Disorders

Back 238

All SGAs (except clozapine) now approved for short term treatment of bipolar mania
APA guidelines specify maintenance treatment of bipolar is continuation of drugs that patient responded to acutely
Thus SGAs are routinely used as chronic therapy for bipolar disorder
Aripiprazole, olanzapine and quetiapine now have indications in depression
Direct to consumer marketing

Front 239

Antipsychotics in Dementia

Back 239

Boxed warning on all SGAs:
“Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo…”

Is this an absolute contraindication to antipsychotics in elderly patients with dementia?
not efficacious, but maybe the last resort

Front 240

Antipsychotic Selection for Psychotic Disorders safety

Back 240

Long term risk of TD
Weight gain (ziprasidone, aripiprazole, haloperidol)
Lipid/glucose abnormalities (avoid olanzapine, risperidone, quetiapine, clozapine)
EKG/seizure/blood dyscrasia

Front 241

Antipsychotic Selection for Psychotic Disorders tolerability

Back 241

Weight gain, EPS, sedation

Front 242

Antipsychotic Selection for Psychotic Disorders efficacy

Back 242

Clozapine SUPERIOR to other antipsychotics
FGAs = SGAs
Iloperidone and asenapine may be inferior to other SGAs
Patient’s past response to agents

Front 243

Antipsychotic Selection for Psychotic Disorders price

Back 243

Price (affordability)
Risperidone $
Seroquel $$$$
Zyprexa $$$$
Geodon $$$$
Abilify $$$$
Most Medicaid systems don’t have cost-control measures or these are hidden from patients and prescribers

Front 244

Antipsychotic Selection for Psychotic Disorders simplicity

Back 244

Once-daily > BID
Initial titration

Front 245

with antiphys weight needs to be monitored at....

Back 245

weeeks 4, 8, 12 and quaterly therafter

Front 246

with antiphys lipids needs to be monitored at....

Back 246

baseline and then at 12 weeks, then q5 years as indicated

Front 247

barbiturates classifcations

Back 247

ultra shor acting (anesthetics): half life 6 hours, brain half life 30 mins
*thiopental
short intermediate acting: 14-24 hours half life
*pentobrabital, secobarbital
long acting: > 24 hour half life
*Phenobarbital