pharmacology

Pharmacology: Sedative-Hypnotic-Anxiolytic Drugs | 1

PHARMACOLOGY Sedative-Hypnotic-Anxiolytic Drugs Lecturer: Deo L. Panganiban, MD, FPSECP

I. Sedative-Hypnotic

II. The Drugs

III. Benzodiazepines

a. Diazepam

IV. Newer Sedative Hypnotics

a. Zolpidem

b. Buspirone

V. Barbiturates

a. Phenobarbital

VI. Ethanol

VII. Pharmacotherapy of Alcoholism

a. Disulfiram

Sedative

• Decreases activity

• Moderates excitement

• Calming or tranquilizing effect

• Used as pre-medication for surgical procedures

Hypnotic

• Produces drowsiness

• Facilitates the onset and maintenance of sleep

that resembles natural sleep and from which the

person can be aroused easily

I. SEDATIVE-HYPNOTIC DRUGS

• CNS depressants

• depress the CNS in a dose dependent manner,

progressively producing sedation, sleep,

unconsciousness, surgical anesthesia, coma and

ultimately fatal depression of respiratory and

cardiovascular function

**Shows that the effects of sedative-hypnotics are dose-

dependent; the greater the dose, the “wilder” the effect

II. THE DRUGS

1. Benzodiazepines

• Diazepam

• Midazolam: more water soluble than

Diazepam; less painful when injected IV

2. Non-Benzodiazepines

• Zolpidem

• Buspirone

3. Barbiturates

• Phenobarbital

• Amobarbital

• Thiopental

4. Alcohol

• Ethanol

5. Chloral dervatives** (older sedative-hypnotic)

• Chloral hydrate

6. Carbamates** (older sedative-hypnotic)

• Meprobamate

7. Piperidinediones

• Glutethimide

• Thalidomide: (kakasawa na to haha; initially

prescribed as a sedative for pregnant women,

until they eventually realized that it was a

teratogenic; now it can be used as an

immunosuppressant/anti-cancer drug)

8. Antihistamines: the older antihistamines; because

the newer ones were developed para hindi

antukin (Finals review! 1st generation

Antihistamines make you drowsy, eg.

Diphenhydramine; while 2nd and 3rd generation

Antihistamines do not, eg. Loratadine (2nd),

Cetirizine(2nd), Desloratadine (3rd))

• Diphenhydramine

• Hydroxyzine

• Benzodiazepines were first introduced in 1960’s

with the synthesis of the 1st benzodiazepine,

Chlordiazepoxide

• As a class, they all have similar CNS effects and

adverse effects; while they only differ in their

onset and duration of action.

• Composition: a benzene ring fused to a 7-

membered diazepine ring structure.

• A halogen or nitrogen

substituent in the 7

position – sedative-

hypnotic effect

Transcriber: Cj Editor: MGB Number of pages: 9

III. BENZODIAZEPINES

→Potentiate GABA effects

→Increase FREQEUNCY of Cl- Channel opening

→Have no GABA mimetic properties

→Act through Benzodiazepine receptors

→These receptors are part of GABAA complex

Bz1 – mediates sedation

Bz2 –mediates anti-anxiety and cognitive functions


• Relatively wide margin of safety

• Prolonged, daily use may produce dependence

• Have little effect on respiratory or cardiovascular

function compared to the Barbiturates

• Fatality from overdose is rare except when taken

with alcohol or other CNS depressants

• Exert qualitatively similar clinical effects

• Low capacity to produce fatal CNS depression

• Coma may occur at very large doses

• Has displaced other agents as first line Sedative

hypnotics.

Classification according to duration of action:

1. Short-acting (T½ <6 hours): makes good pre-

anesthetic drugs due to short action

• Triazolam

• Midazolam

Zolpidem (2hrs) and zopiclone (5-6 hrs) –

non benzodiazepines but are active at the

benzodiazepine receptor

2. Intermediate acting (T½ 6-24 hours)

• Lorazepam: The “date-rape” drug :> **24

hours of anterograde amnesia :>

• Chlordiazepoxide

• Alprazolam

• Estazolam

• Flunitrazepam

• Temazepam

3. Long acting (>24 hours): usually used for longer

sedation periods

• Flurazepam

• Quazepam

• Diazepam** (prototype)

Benzodiazepine Receptors

1. Bz1 or Omega 1

• mediate sedative, hypnotic action

2. Bz2 or Omega 2

• mediate cognition, memory, motor control

3. Bz3

• outside CNS; abundant in the kidneys

Characteristics of Benzodiazepine Receptors:

• Benzodiazepine receptor is a part of the GABAA

receptor

• Upon binding, this will cause an allosteric change

in the GABAA receptor

• GABAA receptors are responsible for most

inhibitory neurotransmission in the CNS

• Benzodiazepine binding enhances coupling of

GABA to its receptor

• High affinity

• Saturable and stereospecific; a certain dose will

occupy all the receptors

GABAA receptor:

• An Oligomeric glycoprotein (α, β, δ, γ, ε,π, ρ etc)

• Major player in inhibitory synapses

• A Cl- channel

• Binding of GABA causes the channel to open and

Cl- to flow into the cell with the resultant

membrane hyperpolarization

• Various receptors are actually part of the GABAA

receptor, with each receptor accommodating a

specific ligand

A. DIAZEPAM

Mechanism of Action:

• Interaction of Benzodiazepine with

Benzodiazepine receptor in the Chloride

ionophore (ionophore: substance that is able to

transport particular ions across a lipid membrane

in a cell.)

• This leads to an allosteric change in the GABAA

receptor, causing enhanced binding of GABA

• This enhanced binding of GABA leads to an

increase in Cl- conductance

• Hyperpolarization of neuronal membrane

(increases the FREQUENCY of channel opening)

Pharmacologic actions and effects:

1. CNS

• Sedation – calming effect

• Hypnosis – facilitate onset and maintenance

of sleep

• Anticonvulsant

• Muscle relaxation; not as marked as when

neuromuscular blockers are used

• Anterograde amnesia

2. Respiratory system

• hypnotic dose has no effect in normal

individuals

• caution in children, elderly and patients with

impaired hepatic function (I.e. alcoholics)


• hypnotic doses worsen sleep-related

breathing disorders by decreasing muscle

tone in the upper airway muscles or by

decreasing the ventilator response to CO2

Eg. Obstructive sleep apnea (OSA)

**OSA - a contraindication to the use of alcohol or any

sedative-hypnotic agent, including a benzodiazepine;

**Partial airway obstruction of those who snore regularly

may be converted to OSA under the influence of these drugs.

• exaggerated effects in patients with

pulmonary disease

Eg. COPD

**As dose is increased, effects are also increased in

progression. Benzodiazepines however, don’t reach the peak

of this curve. They cannot produce respiratory depression,

but can still induce coma. They are safer compared to

barbiturates, pero not really that safe, kasi nakakapagcause

din ng coma. Lesser evil lang.

**Ethanol can cause respiratory depression. A friendly

post-evals encouragement/reminder :D

3. CVS

• negative inotropic effect

• Coronary vasodilatation on IV administration

• decrease BP and increase heart rate

4. GIT

• Decrease nocturnal gastric secretion

• Relieves anxiety-related GI disorders

Pharmacokinetics:

• completely absorbed from the GIT

o All the benzodiazepines are absorbed

completely, except clorazepate

• very high lipid solubility → high rate of entry into

CNS → rapid onset, short duration

o ~99% lipid solubility: conc’n in the CSF is

approx equal to the conc’n of free drug in

plasma

• Peak plasma concentration in 30-90 minutes after

oral intake

• onset after IM administration is variable, but

faster than oral

• Biphasic plasma concentration time curve:

o An initial rapid and extensive

distribution phase (half-life 3 hrs.)

o Prolonged elimination phase (half-life 20-

48 hrs.)

• Elimination half-life may be prolonged in the

newborn, elderly, patients with hepatic or renal

disease

• High protein binding (99%)

• readily crosses the blood brain barrier

• CNS concentration approximates plasma

concentration

• crosses the placenta and secreted in breast milk

**Diazepam IV reaches therapeutic concentration at a faster

time + less dose compared to PO, since PO route goes

through hepatic first-pass effect

• Benzodiazepines are metabolized by CYP3A4 and

CYP2C19 to active metabolites, Nordazepam and

Temazepam; then both metabolites are further

metabolized to Oxazepam (see the following

diagram)

• Temazepam and Oxazepam subsequently

undergoes glucuronidation

• do not induce activity of hepatic microsomal

enzymes

• Drug and its metabolites are excreted in urine.

**Diagram of the text


Therapeutic uses of Diazepam:

1. Anxiety

2. Insomnia

3. Seizure disorders

• Status epilepticus and spasms due to tetanus

• Lorazepam as alternative

4. Anesthesia

• Pre-anesthetic medication (Lorazepam as

alternative)

• Induction agent – Midazolam

5. Muscle spasticity

• Reflex muscle spasm due to trauma to

muscles, bones and joints

• Spasticity due to upper motor neuron lesions

6. Control signs and symptoms of withdrawal from

alcohol

• acute agitation

• tremors

• impending or acute delirium tremens

• hallucinosis

Adverse Effects:

• Sedation and impairment of performance

o motor incoordination

o impairment of mental and motor function

o increased reaction time

o residual daytime sedation

• Memory impairment

o anterograde amnesia – may be associated

with inappropriate behaviour

o dose-related

o tolerance may develop

• Increase risk of respiratory depression in patients

with chronic respiratory insufficiency

• Increase arterial carbon dioxide tension and

decrease oxygen tension in patients with chronic

obstructive pulmonary disease

• Increase frequency of seizures in patients with

epilepsy

• Disinhibition (paradoxical) reactions (dose realted):

o restlessness, agitation, irritability

o Aggressive, inappropriate behavior

o delusions, hallucinations

o hostility, acute rage

• Pregnancy and Lactation

o Teratogenic

o Fetal respiratory depression

o “Floppy infant syndrome”

hypothermia

hypotonia, poor sucking

respiratory depression

Abuse and Dependence:

• Abuse potential decreased when properly

prescribed and supervised BUT CAN STILL HAPPEN

• dependence may occur at therapeutic doses taken

on regular basis for prolonged periods

• Shorter acting Benzodiazepines produce the

greatest dependence; since they’re short acting,

they have a shorter effect, and after the short

effect you want more, so you take multiple short

effect drugs.

Withdrawal syndrome:

• similar in character with those of barbiturates and

alcohol

• occurs after abrupt discontinuation of drug

• withdrawal symptoms may include temporary

intensification of the problems that originally

prompted their use (e.g. insomnia, anxiety)

• other symptoms include dysphoria, palpitations,

panic attacks, hypersensitivity to light, sound and

touch

• major syndrome includes convulsions, confusional

state, hyperthermia; death can occur

• can be prevented by gradually tapering the dose

before stopping treatment

• abuse by the pregnant mother can result in

withdrawal syndrome in the newborn

IV. THE NEWER SEDATIVE HYPNOTICS

A. ZOLPIDEM

• an imidazopyridine

• structurally unrelated to Benzodiazepines but

binds to the Bz1 receptor

• shortens sleep latency and prolongs total sleep time

• currently approved for short term treatment of

insomnia (7-10 days)

• rarely produce residual daytime sedation or

amnesia

• do not produce respiratory depression even at

large doses


• binds selectively to Bz1 receptors

• Facilitates GABA-mediated neuronal inhibition

• Actions can be antagonized by Flumazenil

Pharmacokinetics:

• readily absorbed from the GIT

• first pass hepatic metabolism results in an oral

bioavailability of about 70%. (lower when the drug

is ingested with food)


• Peak plasma concentration in 2-3 hrs (may be

increased n those with cirrhosis and in older

patients; adjustment of dose is necessary)

• plasma half-life is approx. 2 hours

• rapidly metabolized by liver enzymes into inactive

metabolites

• dosage should be reduced in the elderly, in

patients with hepatic dysfunction, patients taking

Cimetidine and other drugs that inhibit drug

metabolizing enzymes

B. BUSPIRONE


• Acts as partial agonists at the serotonin (5-HT1-A)

receptor, thereby reducing release of 5-HT &

other mediators

***(More serotonin mas happy; Buspirone

acts as a substitute for serotonin, so by

negative feedback, decreased yung release ng

serotonin, kasi yung Buspirone, acts like

serotonin aka partial agonist)

• Clinically, partial agonists (in this case, Buspirone)

can activate receptors to give a desired

submaximal response when inadequate amounts

of the endogenous ligand (Serotonin) are present

• Has affinity for brain Dopamine (DA2) receptors:

o Ipsapirone, Gepirone - related anxiolytics

o Anxiolytic effects of buspirone takes more

than a week to become established

o Not anticonvulsant or muscle relaxant

• Used to treat generalized anxiety disorders (GAD)

• Relieves anxiety without causing marked

sedative, hypnotic or euphoric effects

• Minimal sedation

• Cognitive and psychomotor dysfunction is low

• Ineffective in control of panic attacks

• Adverse effects :

o headaches, nervousness, dizziness but

not sedation or loss of consciousness

C. FLUMENAZIL: Benzodiazepine antagonist

• Structure similar with benzodiazepines but with

replacement of keto function at position 5 and a

methyl substituent at position 4

• Management of suspected Benzodiazepine

overdose

o Cumulative dose of 5 mg should produce

response

• Reversal of sedative effects of Benzodiazepine

during either general anesthesia, or diagnostic or

therapeutic procedures

• Antagonism of benzodiazepine-induced

respiratory depression is less predictable

• Available only for IV administration with short t½

of (0.7 – 1.3 hours) because benzodiazepines

have a longer duration of action, there is a need

to repeat administration of flumanezil

• Adverse effects: agitation, confusion, dizziness,

and nausea. Seizure and cardiac arrhythmias on

px with tricyclic antidepressant

• most commonly used drug for sedation and

hypnosis before the advent of Benzodiazepines

• toxic and highly addictive

• abrupt withdrawal can cause death

• poisoning accounted for a great number of deaths

from sedative hypnotics

• low degree of selectivity (whether you give it for

anxiety, it may still produce sedation or coma)

• Low therapeutic index (finals review. Haha

therapeutic index is a measure of how safe a drug

is. TI = . LD = lethal dose, ED = effective dose.

The lower the therapeutic index, the more

dangerous the drug is.)

• less selective than Benzodiazepines

• produce strong physiological dependence on long

term use

• depresses the medullary respiratory center

• also produce loss of brainstem vasomotor control

and myocardial depression

Classification according to duration of action:

1. Long acting

• Phenobarbital** (prototype)

2. Intermediate acting

• Amobarbital

3. Short acting

• Pentobarbital

• Secobarbital

4. Ultrashort acting

• Thiopental: used for induction of

anesthesia

V. BARBITURATES

→Prolong GABA activity

→Increase DURATION of Cl- channel opening

→Have GABA mimetic property at high doses

→Do not act through Benzodiazepine receptors

→Have their own binding sites on the GABA complex

→Also inhibit complex 1 of electron transport chain


A. PHENOBARBITAL


• Binds to Barbiturate receptor in the GABAA

receptors

• Enhance binding of GABA to GABAA Receptor

• Increase Chloride conductance

• Hyperpolarization of neuronal membrane

(increases the DURATION of channel opening)


1. Central nervous system

• Mild sedation to deep coma

• Hypnotic doses decrease sleep latency and

increase total sleep time

• Over dosage can produce death due to

respiratory depression

• mood alteration

• anticonvulsant at low doses

• Sub-anesthetic doses may increase reaction

to painful stimuli aka paradoxical excitement

2. Peripheral Nervous structures

• selectively depress transmission in autonomic

ganglia and reduce nicotinic excitation by

choline esters


• Depress both the respiratory drive and the

mechanisms responsible for the rhythmic

character of respiration.

• hypnotic doses produced same degree of

respiratory depression during physiologic

sleep

• Degree of respiratory depression is dose

dependent

• Hypostatic pneumonia

• Coughing, sneezing, hiccoughing and

laryngospasm esp. for very acute use of

Thiopental

4. Gastrointestinal tract

• decrease tone and amplitude of intestinal

contraction→ constipation

• Hypnotic doses does not significantly delay

gastric emptying time

• The relief of various GI symptoms by sedative

doses is probably largely due to the central-

depressant action.

5. Liver

• does not impair normal hepatic function

• Induction of liver enzymes at high doses

(CYP450, delta aminolevulinic acid synthetase,

aldehyde dehydrogenase, etc.)

• Acutely, it may inhibit the biotransformation

of some drugs and endogenous substrates,

such as steroids

6. Cardiovascular system

• hypnotic dose produce slight decrease in BP

and heart rate

• Myocardial depression at toxic doses

7. Uterus

• Decrease tone and frequency of contractions

8. Abuse and dependence potential

• the barbiturates may have euphoriant effects

Pharmacokinetics:

• weak acid

• rapid absorption following oral administration

• Sodium salts are more rapidly absorbed from GIT

• available in tablet, liquid, parenteral and rectal

formulations

• onset of action: 10 mins to 60 mins

• presence of food decreases rate of absorption

• distributed rapidly to all tissues and body fluids

• low lipid solubility

• low plasma protein binding

• Long duration of action; plasma half-life is 53-118

hrs.

• metabolized primarily in the liver by glucuronide

conjugation

• metabolic products are excreted in the urine

• 25% of Phenobarbital is excreted unchanged in

the kidneys

• Phenobarbital excretion can be increased by

alkalinization of the urine.

• In the elderly and in those with limited hepatic

function, dosages should be reduced.

• Phenobarbital causes auto metabolism by

induction of liver enzymes

Adverse Effects:

1. Hypersensitivity reaction

• Stevens – Johnson syndrome


• drowsiness, residual CNS depression

• paradoxical excitement

• paradoxical dysphoria

• hyperreactivity


• Hypoventilation, manifested as apnea

• Hypostatic pneumonia

• Cough, hiccough/hiccup

• Laryngospasm


• bradycardia

• Hypotension, syncope

5. Gastrointestinal

• Nausea, vomiting

• Constipation


6. Enhance porphyrin synthesis

• may be fatal in patients with acute

intermittent porphyria (disorders of certain

enzymes in the heme bio-synthetic pathway)

7. Toxicity

• acute – unsteady gait, slurred speech,

sustained nystagmus

• chronic – confusion, poor judgment,

irritability, insomnia, somatic complaints

8. Drug Interaction

• Additive CNS depression with ethanol

Dependence:

• Similar to chronic alcoholism

• Arises from repeated administration on a

continuous basis in amounts exceeding usual

therapeutic doses

Withdrawal syndrome:

• Minor withdrawal symptoms appear 8-12 hrs.

after the last dose

o Symptoms appear in the following order:

anxiety, muscle twitching, tremors in

hands and fingers, progressive weakness,

distortion in visual perception, nausea,

vomiting, insomnia, orthostatic

hypotension

• Major withdrawal symptoms such as convulsions

and delirium occur within 16 hrs. and last up to 5

days after abrupt cessation of drug use.

• Symptoms of withdrawal can be very severe and

cause death

• Alcoholics, opiate, sedative-hypnotic and

amphetamine abusers are susceptible to

Phenobarbital abuse and dependence

• Intensity of withdrawal symptoms gradually

declines over a period of approximately 15 days

Tolerance:

• develops with prolonged use

• Amount needed to maintain the same level of

intoxication increases

• Mechanisms:

o Pharmacodynamics

o Pharmacokinetics

• Tolerance to the effects on mood, sedation, and

hypnosis occurs more readily and is greater than

that to the anticonvulsant and lethal effects; thus,

as tolerance increases, the therapeutic index

decreases.

Therapeutic uses of Barbiturates:

1. Seizure disorders

• Grand mal seizures aka Tonic-Clonic seizures

• Benign febrile convulsion

2. Anesthesia

• Pre-anesthetic medication

3. Kernicterus and Hyperbilirubinemia: because

barbiturates induce protein (albumin) synthesis,

thereby increasing hepatic glucuronyl transferase

activity

Contraindications:

• Pregnancy and lactation

• Acute intermittent porphyria or porphyria variegata

• Pulmonary disease

VI. ETHANOL

• widely used for its social value

• tolerance develops after chronic use

• Blood Alcohol Levels in human beings can be

estimated readily by the measurement of alcohol

levels in expired air

• Legally allowed Blood Alcohol Level is set at

below 80 mg % (80 mg ethanol per 100 ml blood;

0.08% w/v),

• Each of the following contains approximately 14 g

Ethanol which will produce a BAL of approximately

30mg% to 70-kg person:

o 12 oz. bottle of Beer

o 5 oz. glass of wine

o 1.5 oz. “shot” of 40% liquor

• BAL is determined by a number of factors,

including the rate of drinking, sex, body weight and

water percentage, and the rates of metabolism and

stomach emptying

Pharmacokinetics:

• Rapidly absorbed after oral administration

• Peak blood levels occur about 30 min after

ingestion when stomach is empty (Correlation:

Kumain kung gusto tumagal)

• Presence of food delays absorption

• undergoes first pass metabolism in the stomach

and liver by alcohol dehydrogenase (ADH)

• Aspirin increases ethanol bioavailability by

inhibiting gastric ADH.

• Ethanol is metabolized largely by sequential

hepatic oxidation, first to acetaldehyde by ADH

and then to acetic acid by aldehyde

dehydrogenase (ALDH)

• Hepatic cytochrome P450 (CYP2E1) and catalase

also contribute to ethanol metabolism

• Zero order kinetics

• 90-95% of ingested Ethanol undergoes hepatic

metabolism to acetate

• small amounts are excreted in urine, sweat and

breath


• chronic alcohol consumption induces activity of

hepatic enzymes

• acute alcohol consumption inhibits activity of

hepatic enzymes

**Sequential hepatic metabolism of Ethanol (also see figure

on the last page)



• Depressant

• Mild depression to general anesthesia

• Death can result due to respiratory

depression

• Behavioral disinhibition

• Neurotoxic


• “French paradox” (is the observation that

French people suffer a relatively low incidence

of coronary heart disease, despite having a

diet relatively rich in saturated fats.)

• Light to moderate amounts may be cardio-

protective

o Increase HDL

o Anti-clotting mechanism

• Cardiac arrhythmias

• Cardiomyopathy

• Hypertension, Hemorrhagic stroke

3. Skeletal muscle

• Decrease muscle strength

• Muscle atrophy

4. Body temperature

• Hypothermia 20 to cutaneous vasodilatation

• increased sweating

5. Kidneys

• Inhibition of ADH release

6. Gastrointestinal tract

• Esophageal dysfunction

• Peptic ulcer disease

• Malabsorption

• Acute and chronic pancreatitis

• Fatty infiltration of the liver, hepatitis and

cirrhosis

7. Vitamin and Mineral Deficiencies

• Peripheral neuropathy

• Korsakoff’s psychosis (a neurological disorder

caused by the lack of thiamine (vitamin B1) in

the brain. Its onset is linked to chronic alcohol

abuse and/or severe malnutrition)

• Wernicke’s encephalopathy (syndrome

characterized by ataxia, ophthalmoplegia,

nystagmus, confusion, and impairment of

short-term memory)

• Osteoporosis

• Hypomagnesemia

8. Sexual function

• Disinhibiting effects initially

• Excessive long term use can lead to

deterioration of sexual function

o Gonadal atrophy, decrease fertility

o Impotence in men

Decrease sexual arousal

Increased ejaculatory latency

Decreased orgasmic pleasure

9. Hematologic and Immunologic

• Anemia

• Thrombocytopenia

• leukopenia

• Immunosuppression

Acute Ethanol Intoxication:

• Blood ethanol concentration of 20-30 mg/dL will

produce

o Increased reaction time

o Impulsive behavior

o Diminished fine motor control

o Impaired judgment

• 50-80 mg/dL intoxicated

• 400 mg/dL can be fatal

Tolerance and Dependence:

• reduced behavioral or physiological response to

the same dose of Ethanol

• Withdrawal syndrome include sleep disruption,

sympathetic activation, tremors and in severe

cases, seizures (physical dependence)

• 2 or more days after withdrawal, delirium tremens

may occur characterized by hallucinations,

delirium, fever and tachycardia

• Delirium tremens can be fatal

• psychological dependence - craving and drug-

seeking behaviour


Teratogenic Effect: Fetal Alcohol Syndrome

• Craniofacial abnormalities

o Microcephaly, long and smooth philtrum

o Shortened palpebral fissures, flat midface

o Epicanthal folds

• CNS dysfunction

o Hyperactivity, attention deficits

o Mental retardation

o Learning disabilities

• Pre and/or post natal stunting of growth

VII. PHARMACOTHERAPY OF ALCOHOLISM

• Disulfiram**

• Naltrexone

• Acamprosate

A. DISULFIRAM

• Inhibits acetaldehyde dehydrogenase, therefore

acetaldehyde accumulates

• Given alone, relatively non-toxic

• Given to persons who ingest alcohol will produce

signs and symptoms of Acetaldehyde poisoning

o Hot and flushed face

o Throbbing headache

o Respiratory difficulty

o Copious vomiting

o Hypotension, chest pains

*** Disulfram - inhibits acetaldehyde dehydrogenase

**Note: DIAZEPAM, ALPRAZOLAM, MIDAZOLAM,

ZOLPIDEM, (Benzodiazepines) PENTOBARBITAL SODIUM,

PHENOBARBITAL SODIUM (Barbiturates) NEED S2

NUMBER, NO REFILL PER Rx IN PRESCRIPTION WRITING.

-Nothing follows-

Hepatic metabolism of

Ethanol

pharmacology

Documents

increased reaction time

produce respiratory depression

newer sedative hypnotics

respiratory depression

rapidly absorbed

partial agonists

aldehyde dehydrogenase

neuronal membrane