Post traumatic stress disorder

Social phobia
Social Anxiety disorder
Generalized Anxiety disorder
Specific phobias

SEDATIVE-HYPNOTICS
What is the purpose of giving anxiolytic/ sedative
agent?
- To relax the patient
- To calm the patient
What about the hypnotic agents/ drugs?
- To induce sleep
Ang problema lamang with the hypnotic sedative
drugs, if you give in large amount it can cause
respiratory depression, cardiovascular depression,
coma, even death.
Sedative/Anxiolytic Agent
Reduce anxiety
Exert a calming effect
Mild CNS depression (psychomotor and cognitive
function): minimum consistent with therapeutic
efficacy
Dose-dependent anterograde amnesia
Anterograde amnesia
- caused by BENZODIAZEPINES
- while having the medication, the patient cannot
recall what had happened
MANIFESTATIONS OF ANXIETY
Pervasive feeling of apprehension
Feeling of helplessness
Difficulty in concentrating
Irritability / Insomnia
GIT disturbance / Muscle tension
Excessive perspiration / HR/ RR
Nausea, palpitations, dry mouth
ANXIETY DISORDERS
Panic disorders
Obsessive compulsive disorder

Hypnotic Drug
Produce drowsiness
Encourage the onset and maintenance of a state
of sleep can cause:
latency of sleep (time to fall asleep
reduced)
duration of stage 2 NREM sleep
duration of REM sleep
duration of stage 4 NREM slow-wave
sleep
Pronounced depression of the CNS
WHY DO WE NEED TO SLEEP?
RESTORATIVE function
Allows the body to recover from all the work
that it did while it was awake
REM sleep: memory and learning (helps
process & strengthens memories)
ADAPTIVE function
The need of the animals to protect
themselves
Search for food & water during the day
Save energy, avoid getting eaten
Avoid falling off a cliff
PHASES OF SLEEP
NREM & REM
3-6 cycles per night
Lasts approximately 1.5 2 hours per cycle
NREM
Occurs at the onset of sleep
4 stages
STAGE 1
The individuals body movements lessen
HR and eye movements slow down
BP goes down
The person would still be aware of voices of
people and noises around him
easily awakened
Lasts for 1-7 minutes
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 STAGE 2 (also called QUIET SLEEP)

The brain activity slows down
Body temperature decreases
Lasts for 10-25 minutes
STAGES 3 and 4 (called SLOW WAVE or DEEP SLEEP)
EEG dominated by delta waves
Persons muscles are totally relaxed
BP and HR: lowest point
Provide the refreshing phase
Stage 3 lasts for few minutes
Stage 4 lasts for 20-40 minutes
REM (PARADOXICAL SLEEP)
Sleep is deep
Total muscle relaxation is observed
Skeletal muscle atonia
Brain is active
Characterized by EEG activation
Burst of autonomic activity is present
Episodic rapid eye movements
Dreams/ Nightmares take place
Play a role: convert short-term memory to
long-term memory
INSOMNIA : A DISEASE OR A SYMPTOM?
PRIMARY INSOMNIA
Difficulty initiating or maintaining sleep for at
least one month
Significant distress and/or impairment in
daytime functioning
Cannot be accounted for by other primary
disorders
If more than 4 months of INSOMNIA:
- usually PSYCHOLOGICAL in nature.
SLEEP DISORDERS THAT CAUSE INSOMNIA
Sleep apnea
Paranomnias
Somnambulism (sleep walking)
Somniloquy (sleep talking)
Bruxism (teeth gnashing)
Nightmares (sleep terrors)
Unfamiliar or non-conducive sleep environments
Extreme heat or cold
Stress, Conditions associated with pain
Alcohol, caffeine, prohibited drugs
Psychiatric disorders (insomnia > 4 weeks)

MEDICATIONS ASSOCIATED WITH INSOMNIA

CNS Stimulants
Dextroamphetamine, Methylphenidate, Pemoline
Antihypertensives
Alpha-blockers, Beta blockers, Methyldopa, Reserpine
Respiratory Medications
Albuterol, Theophylline
Chemotherapy
Decongestants
Phenylpropanolamine,Phenylephrine, Pseudoephedrine
Hormones
Corticosteroids, Thyroid medications
Psychotropics
Antidepressants, Selective Serotonin Reuptake Inhibitors
TREATMENT OF INSOMNIA
3 Main Goals:
Treat the underlying cause
Improve nighttime sleep
Improve daytime functioning
SEDATIVE-HYPNOTIC DRUGS
I. BENZODIAZEPINES
II. BARBITURATES
III. MISCELLANEOUS DRUGS:
- BUSPIRONE/ZOLPIDEM/ZALEPLON
- RAMELTEON, ESZOPICLONE
Other Miscellaneous S/H Drugs
CHLORAL HYDRATE
PARALDEHYDE
ETHCHLORYNOL
PIPERIDINEDIONES:
GLUTETHIMIDE, METHYPRYLON
CARBAMATES: MEPROBAMATE
BENZODIAZEPINE CLASSIFICATION (nice to know daw)
Anxiolytic Benzodiazepines
Aprazolam, Diazepam, Oxazepam
Chlordiazepoxide, Halazepam, Prazepam
Clorazepate, Lorazepam, Temazepam
Clonazepam, Midazolam, Triazolam
Hypnotic Benzodiazepines
Nitrazepam
Flurazepam

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BENZODIAZEPINE CLASSIFICATION
I. SHORT ACTING (3-8 hrs)
Midazolam (x)
Triazolam (x)
Oxazepam (xxx)
II. INTERMEDIATE ACTING (10-20 hrs)
Alprazolam
Lorazepam
Estazolam
Temazepam (XXX)
III. LONG ACTING (1-3 days)
Diazepam
Flurazepam (x), Clorazepate (X)
Halazepam (XX)
Chlordiazepoxide (XX)
CHEMICAL CLASSIFICATION
Benzodiazepines
1, 4 benzodiazepines
Contain a carboxamide group in the 7- member
heterocyclic ring structure
Substituent in the 7 position( a halogen or nitro):
needed for sedative-hypnotic effect
Triazole
ring
at
the
1,2
position
(triazolobenzodiazepines) :
triazolam & alprazolam
The chemical structure of Benzodiazepines lacks sedative
hypnotic property but with the presence of nitro and
alkyl group, this will have the hypnotic/ sedative
properties.
BARBITURATES CLASSIFICATION
LONG-acting (1-2 days)
Phenobarbital, Mephobarbital
Barbital, Metharbital
INTERMEDIATE-acting
Amobarbital, Butabarbital
SHORT-acting (3-8hrs)
Pentobarbital, Secobarbital
ULTRA-SHORT-acting (20 minutes)
Thiopental, Hexobarbital,
Methohexical, Thiamylal
BARBITURATE STRUCTURE

- Dun sa position 2, mayroong OXYGEN don (refer to

Katzung), it should be replaced by SULFUR to become
MORE LIPID SOLUBLE itong THIOPENTAL. Kaya if there is
substitution of sulfur to that oxygen, this Thiopental will
become highly lipid soluble. And this lipid can penetrate
in the BRAIN BARRIER and use also as ANESTHETIC
AGENT.
CHEMICAL CLASSIFICATION Newer Drugs
Zolpidem an imidazopyridine
Zaleplon a pyrazolopyridine
Eszopiclone a cyclopyrrolone
Ramelteon a melatonin receptor agonist
Buspirone slow onset anxiolytic agent

PHARMACOKINETICS
ABSORPTION AND DISTRIBUTION
Rates: differ # of factors: lipophilicity
Triazolam: extremely rapid
Diazepam & active metabolite of clorazepate:
more rapid
Clorazepate active form: desmethyldiazepam
(nordiazepam) by acid hydrolysis in the stomach
Barbiturates & newer hypnotics: rapidly into the
blood
Lipid solubility
onset of CNS effects
Triazolam
Thiopental undergoes redistribution
Eszopiclone
Zaleplon
Zolpidem
All cross the placental barrier
Also detectable in breast milk
CHLORDIAZEPOXIDE
DIAZEPAM
PRAZEPAM
CHLORAZEPATE
- is converted to their active metabolite
DESMETHYLDIAZEPAM
has a half-life of about 40 hours
Lalo na yung CHLORDIAZEPOXIDE has LONGER half life
kasi mas napupunta sya sa ibang substance/compound
that would lead to DYSMETHYLDIAZEPAM.
converted to
OXAZEPAM
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and then will undergo CONJUGATION that will make

these drugs easily eliminated into the urinary system.

PHARMACODYNAMICS

Same with ALPRAZOLAM and TRIAZOLAM. These 2

directly undergoes elimination. Also has SHORT HALF
LIFE.
BIOTRANSFORMATION
Benzodiazepines
Hepatic metabolism
- Phase I and phase II
Barbiturates
Hepatic metabolism
Oxidation alcohol, acids, ketones
Elimination t1/2:
18-48 hrs Secobarbital & Pentobarbital
4-5 days Phenobarbital
Newer Hypnotics
Zolpidem
PPC: 1.6 hours
Elimination t1/2: 1.5-3.5 hours
Zaleplon
t1/2: 1 hour
Cimetidine INHIBITS aldehyde hydrogenase
& CYP3A4
Eszopiclone
Elimination t1/2: 6 hours
Ketoconazole INHIBITS CYP3A4
Rifampicin INDUCE CYP3A4
EXCRETION
Kidney
Barbiturates (Phenobarbital): enhanced by
alkalinization of the urine
CLORAZEPATE LONGEST
Elimination Half-life: 50-100 hrs.
ZALEPLON SHORTEST Peak Blood Level: <1 hr
Elimination Half-life: 1-2 hrs

So this is the receptor where Benzodiazepines, the

Barbiturates and Newer Hypnotics bind. So ngayon,
kailangan magbind yung GABA. Ano nga yung GABA?
What is the function of GABA? Bukod sa opening of the
chloride channel, ano ang nangyayari pag nagopen?
Decrease ang excitability kasi INHIBITORY ang function
ng GABA diba. So ngayon, this is the binding of GABA.
Ngayon ang binding of Benzodiazepines is between this
GAMMA and ALPHA part of this GABA receptor. Once na
nagbind yung BENZODIAZEPINE, mag oopen yung GABA
Receptor, papasok yung Chloride Channel. Syempre naiinhibit yung DEPOLARIZATION, so ano ang nangyayari?
HYPERPOLARIZATION OF THE CELL.
Ngayon ang ginagawa ng GABA dyan, frequent OPENING
of the GABA Receptor bukas ng bukas ng bukas. Tandaan.
Bubuka ang bulaklak, papasok ang Chloride Hindi
papasok ang Reyna. Bubuka ng bubuka. Tapos ano
ngayon ang difference naman? Andito lang din yan.
Barbiturates naman, nandito naman ngayon yung
binding site ng Barbiturate. Ang gagawin naman ng
Barbiturate na pagkanagbind sya dyan, mag oopen yung
GABA receptor, papasok yung Chloride, inhibiting
depolarization and would lead to HYPERPOLARIZATION
of the cell. Kapag sinabing Hyperpolarization, Relaxation
yun diba. So walang excitation. Yung excitability, nawala.
So ngayon ano ang mangyayari kapag nagbind naman
yung Barbiturates? PROLONGED naman yung OPENING
ng GABA Receptor. So pasok naman ng pasok yung
Chloride.
So kung ang Benzodiazepine ay BUKA ng BUKA ng BUKA
INCREASED FREQUENCY of the OPENING of GABA
Receptor. Etong Barbiturates, PROLONG the OPENING of
GABA Receptor. OK. Then action would take place.
sweetpotatoMD - 4

BENZODIAZEPINES: Increase frequency of the

opening of GABA chloride channel
BARBITURATES: Prolong the duration of the
opening of the GABA chloride channels

We have the LIGANDS:

- AGONIST
- ANTAGONIST (Flumazenil)
- INVERSE AGONIST (B-carbolines n-butyl-carboline-3-carboxylate (-CCB)
Ano ang functions ng mga LIGANDS?
Once we say
AGONIST BIND & ACTIVATE
ANTAGONIST BLOCKS THE EFFECTS OF
BENZODIAZEPINES
- FLUMAZENIL - Antagonist for Benzodiazepine
Overdosage
Kung halimbawa, na-overdose yung patient
nagkaroon
ng
Respiratory
Depression,
Cardiovascular Depression, you give FLUMAZENIL to
bring back to normal function yung nadepress.
INVERSE AGONIST BLOCKS THE EFFECTS OF
BENZODIAZEPINES

BUSPIRONE
5HT1A RECEPTOR AGONISTS
Has affinity for brain D2 receptors
No rebound or withdrawal signs
No sedation, no motor in coordination, no withdrawal
effects
May cause nausea, dizziness, headache & restlessness
Rifampin t1/2
Erythromycin, ketoconazole, grapefruit juice,
nefazodone t1/2
Used to treat ANXIETY, the advantage of this is
against the Benzodiazepines is that there is NO
REBOUND or WITHDRAWAL SIGNS

ZOLPIDEM
Imidazopyrimidine derivative
Binds to BZ 1 (omega receptors)
Minor effects on sleep architecture
Less tolerance & dependence
T is 1.5 to 3.5 hrs
Rifampin decrease its half life
Headache, dizziness, confusion, ataxia

ZALEPLON
Similar to zolpidem
t: 1 hour
Metabolism inhibited by cimetidine
Decreases sleep latency; Has little effect on total sleep
or sleep architecture
Rapid onset & short duration of action
Back/chest pain, migraine, nervousness, headache,
dizziness

RAMELTEON
Agonist at MT1 & MT2 melatonin receptors at the
suprachiasmatic nuclei of the brain
Reduce the latency (the time of falling asleep) of sleep
w/ no effects on sleep architecture , no rebound
insomnia or significant withdrawal symptoms
Adverse effect: dizziness, somnolence, fatigue,
endocrine changes, decrease in testosterone, increase
in prolactin

RAMELTEON - DRUG INTERACTIONS

CYP1A2 : Ciprofloxacin, Fluvoxamine,

Tacrine, Zileuton
CYP2C9: Fluconazole
Caution in liver dysfunction
Rifampicin induces its metabolism

ORGAN LEVEL EFFECTS

SEDATION

sweetpotatoMD - 5

ALL
- Benzodiazepines
- Barbiturates
- Older Sedative Hypnotic Drugs
can EXERT CALMING EFFECTS. REDUCTION OF
ANXIETY, DEPRESSANT EFFECT ON PSYCHOMOTOR
& COGNITIVE FUNCTION.
But ONLY BENZODIAZEPINES can
DEPENDENT ANTEROGRADE AMNESIA.

cause

DOSE-

ORGAN LEVEL EFFECTS

HYPNOSIS

the skeletal neuromuscular junction

RESPIRATORY FUNCTION
Healthy individual: comparable to changes
during natural sleep
Pulmonary disease: respiratory depression
Dose-related
Depression of the medulary respiratory center
CARDIOVASCULAR FUNCTION
No significant effect at hypnotic dose (healthy
individual)
Cardiovascular depression: hypovolemic states,

actions on the medullary vasomotor centers

Toxic doses: myocardial contractility & vascular
tone: depressed

TOLERANCE & DEPENDENCE

Tolerance decreased responsiveness to a drug
following repeated exposure
REBOUND INSOMNIA: ZOLPIDEM/ZALEPLON
ORGAN LEVEL EFFECTS
ANESTHESIA STAGE III of general anesthesia
Depends mainly on the physiochemical
properties (rapid onset and duration of effects)
ULTRA-SHORT ACTING
THIOPENTAL
METHOHEXITAL
Large doses contribute to persistent
respiratory depression long t1/2 & active
metabolite
DIAZEPAM, LORAZEPAM, MIDAZOLAM
ANTICONVULSANT EFFECTS inhibiting the
development and spread of epileptiform
electrical activity in the CNS
Clonazepam, Nitrazepam, Lorazepam,
& Diazepam
Phenobarbital & Metharbital
MUSCLE RELAXATION
Carbamate (meprobamate)
Benzodiazepines
Exert inhibitory effects on polysynaptic
reflexes and internuncial transmission
High doses: depress transmission at

Dependence altered physiologic state that requires

continuous drug administration to prevent an abstinence
or withdrawal syndrome
BENZODIAZEPINES ANTAGONIST
FLUMAZENIL
Antagonist at BZ binding sites on the GABAA
receptor
t is 0.7 to 1.3 hrs
Rapid hepatic clearance
Agitation, Confusion, Dizziness & Nausea
CLINICAL USES OF SEDATIVE-HYPNOTICS
FOR RELIEF OF ANXIETY
FOR INSOMNIA
FOR SEDATION & AMNESIA BEFORE AND DURING
MEDICAL & SURGICAL PROCEDURES
FOR TREATMENT OF EPILEPSY & SEIZURE STATES
AS A COMPONENT OF BALANCED ANESTHESIA (IV)
FOR CONTROL OF ETHANOL OR OTHER SEDATIVE
HYPNOTIC WITHDRAWAL STATES
FOR
MUSCLE
RELAXATION
IN
SPECIFIC
NEUROMUSCULAR DISORDERS
AS DIAGNOSTIC AIDS OR FOR TREATMENT IN
PSYCHIATRY

sweetpotatoMD - 6

THERAPEUTIC USES:
1. Anxiety & Agarophobia: ALPRAZOLAM
2. Insomnia: TRIAZOLAM, QUAZEPAM, TEMAZEPAN,
FLURAZEPAM, ESTAZOLAM
3. Anxiety, status Epilepticus, Anesthetic Premedication,
Muscle Relaxation: DIAZEPAM
4. Anxiety, Preanesthetic Medication: LORAZEPAM
5. Pre-anesthetic & intraoperative medication:
MIDAZOLAM
6. Seizure, acute mania, movement disorder:
CLONAZEPAM
7. Ethanol Withdrawal: CHLORDIAZEPOXIDE,
DIAZEPAM, PHENOBARBITAL
8. Delirium Tremens: PARENTERAL LORAZEPAM
9. Central muscle relaxant: MEPROBAMATE and
BENZODIAZEPINES
10. Psychiatric uses (mania control of drug-induced
hyperexcitability states
PHENCYCLIDINE INTOXICATION: BENZODIAZEPINES
Dosages of Drugs Used Commonly
for Sedation and Hypnosis
DRUG DOSAGE FOR
Alprazolam
Buspirone
Chlordiazepoxide
Chlorazepate
Diazepam
Halazepam
Lorazepam
Oxazepam
Phenobarbital
DRUG DOSAGE FOR
Chloral hydrate
Estazolam
Eszopiclone
Lorazepam
Quazepam
Secobarbital
Temazepam
Triazolam
Zaleplon
Zolpidem

SEDATION
0.25 0.5 mg 2-3 x daily
5-10 mg 2-3 x daily
10 20 mg 2-3 x daily
5 7.5 mg twice daily
5 mg twice daily
20 40 mg 3-4 x a day
1 2 mg once or twice/d
15 30 mg 3-4 x a day
15 30 mg 2-3 x a day
HYPNOSIS At Bedtime
500 1000 mg
0.5 2 mg
1 3 mg
2 4 mg
7.5 15 mg
100 200 mg
7.5 30 mg
0.125 0.5 mg
5 20 mg
5 10 mg

CLINICAL TOXICOLOGY OF S/Hs

Results from dose-related depression of CNS
Low doses:
Drowsiness
Impaired judgment
Diminished motor skills
Driving ability
Job performance
Personal relationships
Significant anterograde amnesia (BZ)
Effortful cognitive processes
Date rape
Results from long half-lives
Hangover effects
MIDAZOLAM would NOT manifest HANGOVER effects
Overuse of S/H
Confusional states in elderly
Higher doses
Lethargy or a state of exhaustion
Can exacerbate breathing problem
(COPD/symptomatic sleep apnea)
Overdosage Alprazolam
Severe toxicity
Respiratory depression from central actions
complicated by aspiration of gastric contents
Cardiovascular depression
Ensure airway with mechanical ventilation,
Maintenance of plasma volume,
Renal output, and cardiac function
Use of positive inotropic drugs
Hemodialysis or hemoperfusion
Flumazenil (BZ overdosage)
Not referable to their CNS actions (infrequent)
Hypersensitivity reactions (skin rashes)
Teratogenicity (fetal deformation)
Benzodiazepines
Category D or X
Barbiturates
Category D
Eszopiclone, Ramelteon,
Category C
Zaleplon, Zolpidem
Buspirone
Category B
CONTRAINDICATIONS
Barbiturates
History of acute intermittent porphyria,
Variegate porphyria,
Hereditary coproporphyria, or
Symptomatic porphyria
sweetpotatoMD - 7

DRUG INTERACTIONS
Additive effect enhanced depression: alcohol,
opioid analgesics, anticonvulsants, & Phenothiazines,
antihistamines, antihypertensive agents, tricyclic
antidepressant drugs
P450 inhibitor: cimetidine, oral contraceptives,
prolong BZ t
Cisapride s concentration of Triazolam, Alprazolam,
Midazolam
THE ALCOHOL
Widely consumed
Low to moderate amounts: relieves anxiety and
fosters a feeling of well-being or even euphoria
Most common abused drug alcohol abuse
Alcoholism
END.
I am only one but I am one. I cannot do everything, but I
can do something. What I can do, I ought to do. And with
the grace of God, I will do it.

sweetpotatoMD - 8