Sedative Hypnotics

Sedative – Hypnotics Dr. Arlene M. Diaz, M.D. MHAM - SWU

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 – Hypnotics 1. Barbiturates 2. Benzodiazepine hypnotics 3. Miscellaneous group A. Chloral Hydrate B. Paraldehyde C. Ethchlorvynol D. Ethinamate E. Glutethimide

F. Methyprylon G. OTC products containing: Diphenhydramine or Doxylamine (Antihistamines) H. Buspirone, Zolpidem, Zaleplon

Barbiturates:

0=C

H l N l H H l N l H UREA

O ll HO - C +

C

H

H HO–C ll O Malonic Acid

N 1

O= C2

C

H (R1 )

6

5 3

N l H

4

C ll O

Barbituri c Acid

C

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

O= C2

l N

ll C

N l (R3)

C ll O

5

(R1 )

C (R2 )

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.

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.

The Barbiturates and

Barbiturates

Classification of Barbiturates  Are classified on the basis of their onset and duration of action. 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 hypnotics C. 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.

Duration of Action

Barbiturate

Substituents in Position 5 R1 R2

A. Ultra – Short (Contains sulfur at position 2 instead of 0xygen). Thiobarbiturates

Thiopental (Pentothal) Thiamylal (Surital)

Ethyl ;

Hexabarbital (Evipal)

Methyl;

cyclohexe nyl

Allyl;

l-methyl butyl

0.1 – 0.2 g

l-methyl butyl

0.1 g

B. Short – Acting Secobarbital (Seconal)

Allyl ;

Pentobarbital Ethyl; (Nembutal)

Hypnotic Dose

l-methyl butyl l-methyl butyl

C. Intermediate Acting

D. Long Acting

Butabarbital Ethyl; (Butisol)

Seebutyl

0.1 -0.2 g

Amobarbital (Amytal)

Ethyl;

Iso amyl

0.05 - 0.2 g

Vinbarbital (Delvinal)

Ethyl;

l-methyl l-butenyl

0.1 – 0.2 g

Phenobarbital

Ethyl;

phenyl

0.1 – 0.2 g

(Luminal)

Mephobarbital Ethyl;

(Mebaral)

Barbital (Verome)

phenyl (CH3 group is attached to a Nitrogen Atom)

0.1 – 0.2 g

Ethyl;

0.3 – 0.5 g

ethyl

Pharmacokinetics behaviour of three barbiturate in relation of their lipid solubility. Characteristics Phenobarbital Secobarbital Thiopental Lipid to water partition coefficient

3

52

580

Absorption from stomach

Slow

Rapid

Not used orally

Plasma Protein binding

2%

44 %

65 %

Rate of entry into CNS

Slow

Rapid

Very Rapid

Renal excretion of unchanged drug

30 %

Negligible

Negligible

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. 2. 3. 4. 5.

Other sedative – hypnotics General anesthetics Neuromuscular blocking agents Alcohol 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 hemodialysis 3. 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 & Hypnosis 2. Anticonvulsant & Antiepileptic (Phenobarbital) 3. Preanesthetic Medication (Pentobarbital ,Secobarbital ; Amobarbital) 4. Treatment of Hyperbilirubinemia and Neonate 5. Anesthetics – ultra – short acting

Members of Benzodiazepines Short acting 3 – 8 hrs

Intermediate acting 10 - 20 hrs.

Long – acting 1 – 3 days

a. Triazolam (Halcion)

a. Lorazepam (Ativan)

a. Chlorazepate (Tranxene)

b. Oxazepam (Serapax)

b. Alprazolam (Xanor)

b. Chlordiazepoxide (Librium)

c. Midazolam (Dormicom)

c. Temazepam (Temaze) d. Estazolam (Esilgan)

c. Diazepam (Valium) d. Flueazepam (Dalmane) e. Quazepam

Actions / Effects of Benzodiazepines 1. Reduction of Anxiety 2. Sedative and Hypnotic Action 3. 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. 4. Triazolam – short duration is effective in patients who have difficulty of going to sleep 5. Midazolam – benzodiazepine.

is

a

short

acting

,

sleep-inducing

 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 sleep has 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 hypnotic 2. 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 Group

A. 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 ulcer Clinical 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

E. Glutethimide – resembles pentobarbital in its hypnotic effect.  If has high addiction liability, severe withdrawal symptoms. 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. 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 Melatonin is derived from serotonin within the pineal gland and the retina, where the necessary Nacetyltransferase 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.

Comparison of plasma levels of melatonin

Natural medicines

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.

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.