Dr. Arlene M. Diaz, M.D.

MHAM - SWU

Sedative – Hypnotics

Sedative – Hypnotics- Are agents that is use as adjuncts in the treatment of organic or emotional disorders in order to produce a calming effect (sedation) or to induce sleep (Hypnosis)

Classification of Sedative – Hypnotics1. Barbiturates

2. Benzodiazepine hypnotics

3. Miscellaneous group

A. Chloral Hydrate F. MethyprylonB. Paraldehyde G. OTC products containing:C. Ethchlorvynol Diphenhydramine orD. Ethinamate Doxylamine (Antihistamines)E. Glutethimide H. Buspirone, Zolpidem, Zaleplon

HlNlH

HlNlH

UREA

Barbiturates:

O llHO - C

+

H O – C ll O Malonic Acid

CH

HO = C2

N 1

3

N lH

4

CllO

C6

5 C

Barbituric

Acid

0 = C

H (R1 )

H (R2)

The majority of the clinically useful barbiturates are obtained by making appropriate substitutions in position 5 of the molecule, in order to have a central depressant activity.

O = C2

Nl

(R3)

CllO

H lN

OllC

(R1 )

(R2 )

Barbiturates with an ethyl group; longer chain; branched chain at position 5 have greater hypnotic activity.

Barbiturates containing a phenyl group in the 5 position are less potent hypnotics, but have enhanced anticonvulsant and antiepileptic activity.

Replacement of Oxygen in the z position by Sulfur (thiobarbiturates) causes a marked increase in the lipid solubility of the drug.

5 C

Mech of Action:

Barbiturates potentiate GABAA – induced chloride influxes into neuronal tissues. GABA is an inhibitory neurotransmitter of the brain. Potentiation of neuronal GABA activity produces a Central depressant action.

Barbiturates

The Barbiturates and

Classification of Barbiturates

A. Ultra -Short Acting = acts within seconds and their duration of action is 30 minutes. They have high lipid solubility which allows rapid transport across the blood – brain barrier. They are use principally as intravenous adjuvants to anesthesia.B. Short – Acting = have a duration of action of about 2 hours; use principally as hypnoticsC. Intermediate Acting = have an effect lasting 3 to 5 hours, they have a “Hangover” liability if use as hypnotics, the result of residual depression of the CNS.D. Long – Acting = have a duration of action greater than 6 hours; the least lipid soluble. They are dose effective hypnotics and sedatives and at a low dose are use as an antiepileptic agents; but they are likely to cause hangover.

Are classified on the basis of their onset and duration of action.

DurationDurationof Actionof Action

BarbituratBarbituratee

Substituents in Substituents in Position 5Position 5R1R1 R2R2

HypnoticHypnoticDoseDose

A. Ultra – ShortA. Ultra – Short (Contains (Contains

sulfur sulfur at position 2 at position 2

instead of instead of 0xygen). Thio-0xygen). Thio-barbituratesbarbiturates

Thiopental Thiopental (Pentothal)(Pentothal)ThiamylalThiamylal(Surital)(Surital)

HexabarbitalHexabarbital(Evipal)(Evipal)

Ethyl ; Ethyl ;

Allyl ;Allyl ;

Methyl;Methyl;

l-methyll-methylbutylbutyll-methyll-methylbutylbutyl

cyclohexcyclohexenyl enyl

B. Short – B. Short – Acting Acting

SecobarbitalSecobarbital(Seconal)(Seconal)

PentobarbitaPentobarbitall(Nembutal)(Nembutal)

Allyl;Allyl;

Ethyl;Ethyl;

l-methyll-methylbutylbutyl

l-methyll-methylbutylbutyl

0.1 – 0.2 g0.1 – 0.2 g

0.1 g0.1 g

C. C. IntermediateIntermediate ActingActing

ButabarbitaButabarbital l (Butisol)(Butisol)

AmobarbitalAmobarbital(Amytal)(Amytal)

VinbarbitalVinbarbital(Delvinal)(Delvinal)

Ethyl;Ethyl;

Ethyl; Ethyl;

Ethyl;Ethyl;

See-See-butylbutyl

Iso amylIso amyl

l-methyl l-methyl l-butenyll-butenyl

0.1 -0.2 g0.1 -0.2 g

0.05 - 0.2 g0.05 - 0.2 g

0.1 – 0.2 g0.1 – 0.2 g

D. Long ActingD. Long Acting PhenobarbitaPhenobarbitall(Luminal)(Luminal)

MephobarbitMephobarbitalal(Mebaral)(Mebaral)

BarbitalBarbital(Verome)(Verome)

Ethyl; phenylEthyl; phenyl

Ethyl; phenylEthyl; phenyl(CH3 group is (CH3 group is attached to a attached to a Nitrogen Atom)Nitrogen Atom)

Ethyl; ethylEthyl; ethyl

0.1 – 0.2 g0.1 – 0.2 g

0.1 – 0.2 g0.1 – 0.2 g

0.3 – 0.5 g0.3 – 0.5 g

Pharmacokinetics behaviour of three barbiturate in relation of their lipid solubility.

Not used orally

65 %

Very Rapid

Negligible

Rapid

44 %

Rapid

Negligible

Slow

2 %

Slow

30 %

Absorption from stomach

Plasma Protein binding

Rate of entry intoCNS

Renal excretion of unchanged drug

580523Lipid to water partition coefficient

Thiopental

Secobarbital

Phenobarbital

Characteristics

Pharmacologic Effects:A. CNS – depress all levels in a dose dependent fashion.

REM sleep (Rapid Eye Movement) – paradoxical sleep is reduced, but do not totally obliterate it. “Hangover” may result.

B. Analgesic – they are not analgesics , but comfort maybe achieve by combining with aspirin

C. Anesthesia – capable of producing anesthesia but only the ultra – short acting are useful as intravenous anesthetics.D. All barbiturates – suppress convulsant activity if given in sufficient doses but only the long acting are use as anti-convulsant.E. Cardiovascular – Not significant,but b.p is due inhibition of central neurogenic component of the hypertensives.

F. Respiration – at therapeutic doses resp. depression is similar to that in normal sleep. But in larger doses causes reduction of minute volume and hypoxic drive (respond to CD2) fails. Death from acute barbiturate poisoning is usually due to Respiratory failure

G. Liver – most barbiturates, but esp. phenobarbital are capable of inducing the hepatic drug – microsomal enzyme system this result in:

1. Increased degradation of the barbiturate ultimately leading to barbiturate tolerance.

2. It also cause increase inactivation of other cpds such as anticoagulants , leading to serious problem with drug interactions. (others – tetracycline ; quinidine)

Drug Interactions: Drugs that increases the actions of barbiturates esp. the resp. depressant effect.

1. Other sedative – hypnotics2. General anesthetics3. Neuromuscular blocking agents4. Alcohol5. Anti-anxiety drugs

acute Ethanol intoxication = increases CNS depression, decrease biotransformation of barbiturate Chronic ethanol abuse = decrease effect of Barbiturate due to increase biotransformation)

Toxicity:A. Acute Toxicity – stupor or coma and resp depression (slow or rapid respiration or cheyne – strokes pattern)

1. treatment – removal of the unabsorb drug from the stomach by gastric lavage

2. performing hemodialysis3. preventing complications

B. Chronic Toxicity – similar to alcohol intoxication mental changes include impairment of intellectual activity , defective judgement , loss of emotional control and accentuation of pathological personalities.

Treatment of Chronic Toxicity

Hospitalized patient & stabilize with a low dose, then slowly withdraw for 2 to 3 weeks. Idiosyncrasy – excitement and inebriation ; headache nausea ; vomiting ; diarrhea ; myalgia , neuralgia ; arthralgia. Hypersensitivity : Skin – Exfoliative dermatitis Blood & Blood forming organs – agrarulocytosis , thrombocytopenic purpura

Clinical Uses:1. Sedation & Hypnosis2. Anticonvulsant & Antiepileptic (Phenobarbital)3. Preanesthetic Medication

(Pentobarbital ,Secobarbital ; Amobarbital)4. Treatment of Hyperbilirubinemia and Neonate5. Anesthetics – ultra – short acting

Short acting 3 – 8 hrs

Intermediate acting10 - 20 hrs.

Long – acting 1 – 3 days

a. Triazolam (Halcion)

b. Oxazepam (Serapax)

c. Midazolam(Dormicom)

a. Chlorazepate (Tranxene)

b. Chlordiazepoxide (Librium)

c. Diazepam (Valium)

d. Flueazepam (Dalmane)

e. Quazepam

Members of Benzodiazepines

a. Lorazepam (Ativan)

b. Alprazolam (Xanor)

c. Temazepam (Temaze)

d. Estazolam (Esilgan)

Actions / Effects of Benzodiazepines

1.Reduction of Anxiety2.Sedative and Hypnotic Action3.Anticonvulsant 4.Muscle relaxant

Hypnotic Benzodiazepines

1. Flurazepam – long acting, significantly reduces sleep induction time and number of awakenings, it increases the duration of sleep.

It causes little rebound insomnia, if continually use and then discontinued because its effectiveness is maintained up to 4 weeks, because it is converted to an active metabolite and cause daytime sedation.

2. Estazolam - intermediate acting hypnotic benzodiazepine, can also cause daytime sedation.

3. Temazepam – useful in patients who had freq. awakenings.

5. Midazolam – is a short acting , sleep-inducing benzodiazepine.

4. Triazolam – short duration is effective in patients who have difficulty of going to sleep

rapid onset of action (less than 20 mins) short sojourn in the body shortens onset of sleep and prolongs duration of sleep without impairment of REM sleephas also anticonvulsant, anxiolytic and muscle relaxant property wide therapeutic margin, and can be given over a period of up to 150 days without any signs of tolerance or accumulation. On correct discontinuation of the drug, no withdrawal symptoms or rebound insomnia were observed. No accumulation of the active ingredient occurs.

hepatic dysfunction and advance age has no influence on its pharmacokinetics.absorption is more rapid and complete after I.M , I.V and rectal administration.metabolize to an active metabolite which has a shorter half life =Alpha-hydoxy - midazolam, which is then glucuronidated, then eliminated by the kidneys.

USES = 1. As a hypnotic2. A premedication before surgery or diagnostic proceed.

DOSE = 7.5mgs – 15mgs (½ -1 tab) before retiring.ADVERSE EFFECTS OF BENZODIAZEPINES= psychomotor dysfunction : cognitive impairment, ataxia,

daytime drowsiness. = fatigue, amnesia and resp. depression, tolerance

Drug interaction: Produces additive effect -more CNS depression if use with alcohol, antihistaminics,antipsychotics , opioid analgesic, barbiturates and tricyclic anti-depressants.

Miscellaneous GroupA. Chloral hydrate an aldehyde hydrate which has a pungent odor & causes caustic taste – induces sleep in 30 min & may last up to 6 hrs. It is metabolized in the liver by alcohol dehydrogenase to trichloroetharol which is the active metabolite producing the CNS depression. Trichloroethanol (as well as chloral hydrate) are oxidized to trichloroacetic acid which is excreted in the kidney as a glucoronide conjugate The CNS depressant effect is potentiated by alcohol (“ knockout drops “ ; “ Mickey Finn “)This drug should be used cautiously in the presence of severe hepatic, renal or cardiac disease oral administration should be avoiding in pnts with esophagitis, gastritis or duodenal ulcerClinical use – short term treatment of insomnia in elderly and children

B. Paraldehyde – a trimer of acetaldehyde produces sleep in 15 min & last up to 4 – 8 hrs. CNS effect is similar with chloral hydrate & alcohol and barbiturate If is useful in patients with hepatic or renal is because it is eliminated via the lungs.

C. Ethchorvynol – a tertiary alcohol which has sedative

Hypnotic prop; muscle relaxant prop and anti-convulsant prop. Absorbed from GIT & onset of action is 30 min & lasts for % hours Untoward effects include or auditory hallucinations. A daily dose of 2g may cause physical dependence & withdrawal may result to gen. toxic – clonic seizures or psyhotic behaviour

D. Ethinamate – resembles pentobarbital and secobarbital in its effect

F. Methyprylon – resembles secobarbital in its onset and duration of actions

G. Buspirone – has affinity to DA2 (dopamine) & a partil agonist at 5 HT serotonin receptor. It relieves anxiety without sedation and hypnosis. It is use to treat chronic generalized anxiety. It can cause tachycardia and G.I distress.

H. Hydroxyzine – an antihistaminic with anti-emetic and anti-anxiety property.

E. Glutethimide – resembles pentobarbital in its hypnotic effect. If has high addiction liability, severe withdrawal symptoms.

I. Trazodone -a selective serotonin re-uptake inhibitor, highly sedating . It is use also as anti-depressant.

I. Zolpidem – acts on a subset of benzodiazepam receptor. It has no anticonvulsant or muscle relaxing properties. No withdrawal effects and exhibits minimal rebound insomnia

Melatonin is derived from serotonin within the pineal gland and the retina, where the necessary N-acetyltransferase enzyme is found.

The pineal parenchymal cells secrete melatonin into the blood and cerebrospinal fluid. Synthesis and secretion of melatonin increases during the dark period of the day between 2-3a.m and is maintained at a low level during daylight hours.

Melatonin

Comparison of plasma levels of

melatonin

Valerian Root is a perennial herb that is harvested in its natural environment in India and Western Asia, without pesticides, herbicides, or synthetic fertilizers. The pungent root has been used since ancient times for restlessness and nervous disturbances in sleep.

Natural medicines

Exercise

Meditation , Relaxation

Avoidance of Stressors

GOOD NIGHT! SLEEP TIGHT!

DO LET YOUR BEDBUGS BITE

YOU TONIGHT !!!

A computer programmer complains of feeling tired during the day.He says his wife is the cause because she snores too much. She says he stays too late working with his new programs and sleep only 2 hours a day . He claims he had difficulty of falling asleep and when he does sleep he had to wake up many times during the night.