Sedative hypnotics

Dr. Majdi BkhaitanDr. Majdi Bkhaitan

SEDATIVE/HYPNOTICSEDATIVE/HYPNOTICSS

ANXIOLYTICSANXIOLYTICSDr. Majdi Bkhaitan

Dr. Nashwa IbrahimDepartment Of Pharmaceutical

chemistry [email protected]

mailto:[email protected]

mailto:[email protected]

On successful completion of this chapter students should be able to :

Describe anxiety and Insomnia.Describe anxiety and Insomnia. Describe state of lifeDescribe state of life classify anxiolytic drugs.classify anxiolytic drugs. Explain anxiolytic drugs MOA.Explain anxiolytic drugs MOA. Interpret and predict anxiolytic drugs SAR.Interpret and predict anxiolytic drugs SAR. Recognize hypnotic non anxiolytic agents.Recognize hypnotic non anxiolytic agents. Differentiate between addictive and non- Differentiate between addictive and non-

addictive hypnotics.addictive hypnotics.



AnxietyAnxiety feeling of helplessnessfeeling of helplessness difficulty in concentratingdifficulty in concentrating irritability & insomniairritability & insomnia GI disturbancesGI disturbances muscle tensionmuscle tension excessive perspirationexcessive perspiration palpitations palpitations dry mouthdry mouth impending doomimpending doom dreaddread


Clinical DisordersClinical Disorders

• Panic disorder• Obsessive-compulsive disorder• Post-traumatic stress disorder• Social phobia• Social anxiety disorder• Generalized anxiety disorder• Specific phobias

Anxiolytic sedative, minor tranquilizers, antianxiety, tensiolytics, are used to control neuroses and stress. Strategy for treatment

– Reduce anxiety without causing sedation.


NormalNormal

Relief from AnxietyRelief from Anxiety

_________ _________ _________________ _________________SEDATIONSEDATION

(Drowsiness/decrease reaction time)(Drowsiness/decrease reaction time)

HYPNOSISHYPNOSIS

Confusion, Delirium, AtaxiaConfusion, Delirium, Ataxia

Surgical AnesthesiaSurgical Anesthesia

Depression of respiratory and vasomotor center Depression of respiratory and vasomotor center

in the brainstemin the brainstem

COMACOMA

DEATHDEATH


AnxiolyticsAnxiolytics

1)1) Benzodiazepines (BZDs).Benzodiazepines (BZDs).2)2) Barbiturates (BARBs).Barbiturates (BARBs).3)3) 5-HT5-HT1A 1A receptor agonists.receptor agonists.

4)4) 5-HT5-HT2A2A, 5-HT, 5-HT2C 2C & 5-HT& 5-HT3 3 receptorreceptor

antagonists.antagonists. If ANS symptoms are prominentIf ANS symptoms are prominent::

• ß-Adrenoreceptor antagonists. ß-Adrenoreceptor antagonists. ∀ αα22-AR agonists (clonidine).-AR agonists (clonidine).


AnxiolyticsAnxiolytics Other Drugs with anxiolytic activity.Other Drugs with anxiolytic activity.

– TCAs (Fluvoxamine). Used for Obsessive TCAs (Fluvoxamine). Used for Obsessive compulsive Disorder.compulsive Disorder.

– MAOIs. Used in panic attacks.MAOIs. Used in panic attacks.– Antihistaminic agents. Present in over the Antihistaminic agents. Present in over the

counter medications. counter medications. – Antipsychotics (Ziprasidone). Antipsychotics (Ziprasidone).

Novel drugsNovel drugs. . (Most of these are still on clinical trials).(Most of these are still on clinical trials).

– CCKCCKBB (e.g. CCK (e.g. CCK44).).– EAA's/NMDA (e.g. HA966).EAA's/NMDA (e.g. HA966).



Drug ChoicesDrug ChoicesOlder:Older: Barbiturates (drugs ending in “barbital”)Barbiturates (drugs ending in “barbital”) Alcohols / Choral HydrateAlcohols / Choral HydrateNewer:Newer: Benzodiazepines (drugs name ending in “lam” or Benzodiazepines (drugs name ending in “lam” or

“pam”)**“pam”)** Benzodiazepine “Like” (zolpidem & zaleplon)Benzodiazepine “Like” (zolpidem & zaleplon) 5-HT5-HT1A1A partial agonist (buspirone) partial agonist (buspirone)

** The most commonly used anxiolytics


Mechanism of ActionMechanism of Action• “Most” sedative-hypnotics exert effects on GABAA R’s• GABA - the major inhibitory NT in the CNS• GABAA receptors - heteromultimeric structure

– 5 transmembrane polypeptide subunits per receptor/channel complex– α,β,δ,ε,γ,π polypetide subtypes– muliple isoforms for each (e.g. α1-6)

• GABA binding stimulates Cl- current - hyperpolarizing effect - inhibitory effect on neuronal excitability


GABAergic SYNAPSEGABAergic SYNAPSE

GABA

glutamate

glucose

Cl-

GAD


BarbituratesBarbiturates

BarbituratesBenzodiazepines

GABA

Multiple mechanisms1) Bind to GABAA receptors at different site

• Don’t compete for BNZ binding & are not blocked by flumazenil• Increases the duration of Cl- channel openings


Barbiturate Barbiturate Multiple MOAMultiple MOA

1.1. Increase GABA effect (increased duration Increase GABA effect (increased duration of openings)of openings)

2.2. Directly activate GABADirectly activate GABAAA channels at channels at high high

concentrationsconcentrations

3.3. Block glutamate NT* effectsBlock glutamate NT* effects

4.4. Block Na channelsBlock Na channels

* Glutamate is an excitatory NT


Barbiturates modify the mechanism of Barbiturates modify the mechanism of synaptic transmission, they reduce the synaptic transmission, they reduce the excitability of post-synaptic cell by altering excitability of post-synaptic cell by altering the permeability of the cell membrane. the permeability of the cell membrane. They exert their action on the central They exert their action on the central synaptic transmission process of the synaptic transmission process of the reticular activating system, and the reticular activating system, and the cerebral cortex becomes deactivated cerebral cortex becomes deactivated (antidepolarizing blocking agents). (antidepolarizing blocking agents). Barbiturates act also upon the limbic, Barbiturates act also upon the limbic, hypothalamic, and thalamic synaptic hypothalamic, and thalamic synaptic system.system.


Physical dependence may be induced by Physical dependence may be induced by various doses of the drugs. various doses of the drugs. As a rule, drug As a rule, drug dependence is followed by tolerance, dependence is followed by tolerance, in in which increased doses are required to which increased doses are required to obtain the same pharmacological effect. obtain the same pharmacological effect.

Barbiturates don’t induce natural sleep.


HN NH

O

OO

R1 R2

R( )1

23

45

6

Barbiturates: SAR

In order to posses good hypnotic activity, a barbiturate must be a weak acid and must have a lipid /water partition coefficient between certain limits.

SAR: 5,5,-disubstituted & 1,5,5-

trisubstituted are active

1,3-disubstituted or 1,3,5,5-

tetrasubstituted are inactive or

produce convulsions

All other substitution ► inactive

* Replacement of C-2 O by S → ↑ lipid solubility. Thiopental used as IV

anesthetics due to rapid onset & quick brain levels achieved.

* Introduction of more sulfur atoms (2,4-dithio derivatives) destroys

potency, due to decreased hydrophilic character beyond required limits.17




Barbiturates: SAR


HN N

O

OR1 R2

OH

HN N

O

OR1 R2

O

N N

O

R1 R2O-

O-

-

K1K2

AcidityAcidity ::pKa of unsubstituted barbituric acid equals 4.12, while pKa of unsubstituted barbituric acid equals 4.12, while pKa of 5,5 disubstituted barbituric acid equals 7.1-8.1. pKa of 5,5 disubstituted barbituric acid equals 7.1-8.1. So, salts of the 5,5 disubstituted barbituric acid can be So, salts of the 5,5 disubstituted barbituric acid can be obtained with bases such NaH. A second ionization can obtained with bases such NaH. A second ionization can occur with pKa values 11.7-12.7. It is possible to occur with pKa values 11.7-12.7. It is possible to assume that dialkali metal salts could be prepared. assume that dialkali metal salts could be prepared.



Barbiturates - Metabolism

Oxidation of substituent at C- 5by CYP450’s

Most Barbiturates

Aromatic Hydroxylation

PhenobarbitalMephobarbital

Slide 6

Glucuronide and sulfate conjugates

An ultimate (ω) or penultimate ( ω -1) oxidation of C-5 substituents


Desulfuration

Thiobarbiturates

N-Methylbarbiturates

N-Dealkylation

Slide 7

mephobarbital phenobarbital

Desulfuration of 2-thiobarbiturates to yield more hydrophilic barbiturates


hepatic metabolic inactivation

N-oxidation

Hydrolysis

Most Barbiturates

Most Barbiturates

Slide 5

OC2H5

OC2H5

O

O

R

R

NH2

NH2

XC2H5OH

NH

NH

O

O

X

R

R+

Disubstituteddiethylmalonate

X=O in ureaX=S in thiourea

X=O in X=S in thio

barbituratesbarbiturates

-2

Synthesis of Barbiturates

27

Barbiturate Abuse:

•Prolonged use leads to habituation, (tolerance to increased doses and

physical dependence).

•Monooxygenase enzyme synthesis is increased by repeated dose of

phenobarbital (enzyme induction), therefore the drug will be rapidly

metabolized leading to tolerance.


Benzodiazapines

Many derivatives of the 1,4-benzodiazepine series Many derivatives of the 1,4-benzodiazepine series display:display:

TranquilizingTranquilizing Muscle relaxantMuscle relaxant Anticonvulsant andAnticonvulsant and Sedative effects.Sedative effects.

No 1,4-benzodiazepin can be selected exclusively No 1,4-benzodiazepin can be selected exclusively as a hypnotic agent in preference to other as a hypnotic agent in preference to other benzodiazepins.benzodiazepins.

Benzodiazepins that are rapidly metabolized and Benzodiazepins that are rapidly metabolized and eliminated (e.g. temazepam) have gained popularity eliminated (e.g. temazepam) have gained popularity as sleep inducers, because of lack of toxicity neither as sleep inducers, because of lack of toxicity neither through neither accumulation nor hangover.through neither accumulation nor hangover.


Benzodiazepine MOABenzodiazepine MOA

GABA

GABA +diazepam

Pressure

5 mV 1sec

• CNS BNZ receptors: thalamus, limbic system, cerebral cortex.

• BNZs - increase the frequency of Cl- channel openings in presence of GABA



GABA

Benzodiazepine Mechanism of ActionBenzodiazepine Mechanism of Action• GABAA receptor composition varies in different regions• BNZs bind to receptors with alpha & gamma subunits.• BNZ binding “enhances” the effect of GABA on the Cl- current• BNZs exert no effect in the absence of GABA



GABA

Benzodiazepine Mechanism of ActionBenzodiazepine Mechanism of Action• BNZ effect & binding blocked by flumazenil (BNZ antagonist)• Not all BNZs are identical (may be due to differences in effects on different GABAA R isoforms)• BNZs - high doses commonly produce anterograde amnesia more common with BNZs vs. other hypnotics)






N

NO

X

R

1 23

45

N

NO

Cl

CH3

N

N

Cl

O

N

CH3

H

N

NO

Cl

CH3

OH

N

N

Cl

NNCH3

N

N

Cl

NCH3

F

DIAZEPAM

CHLORDIAZEPOXIDE OXAZEPAM

ALPRAZOLAMMIDAZOLAM


SAR:SAR: Presence of an electron-Presence of an electron-

withdrawing group in withdrawing group in position position 7 7 is required for is required for activity. More the activity. More the electron-withdrawing electron-withdrawing more will be the activity.more will be the activity.

Position 6,8 and 9 should Position 6,8 and 9 should not be substituted.not be substituted.

N

NO

X

R

1 23

45

67

8

9


A phenyl ring in position 5 A phenyl ring in position 5 promotes activity, activity promotes activity, activity is increased when the is increased when the phenyl is ortho or diortho phenyl is ortho or diortho substituted with electron-substituted with electron-withdrawing groups. withdrawing groups. Substitution in para Substitution in para position brings about position brings about decrease in activity.decrease in activity.

Saturation of the N4-C5 Saturation of the N4-C5 double bond or its shifting double bond or its shifting to other positions to other positions decreases activity.decreases activity.

N

NO

X

R

1 23

45

67

8

9


Substitution with alkyl group at Substitution with alkyl group at position 3 decreases activity, position 3 decreases activity, substitution with OH group substitution with OH group doesn’t. This hydroxyl affects the doesn’t. This hydroxyl affects the pharmacokinetic of the drug, pharmacokinetic of the drug, truly, compounds that doesn’t truly, compounds that doesn’t posses OH in 3 are non-polar, posses OH in 3 are non-polar, and have long duration of action, and have long duration of action, and undergo hepatic oxidation, and undergo hepatic oxidation, whereas, compounds whereas, compounds possessing the 3-OH group are possessing the 3-OH group are more polar and are readily more polar and are readily conjugated and excreted.conjugated and excreted.

N

NO

X

R

1 23

45

67

8

9


2-carbonyl function is 2-carbonyl function is optimal for the activity, as is optimal for the activity, as is the nitrogen atom at the nitrogen atom at position 1, the N- position 1, the N- substituent should be small. substituent should be small. On the other hand there On the other hand there were obtained compounds were obtained compounds with a fused triazole ring with a fused triazole ring represented by “triazolam” represented by “triazolam” and alprazolam, also and alprazolam, also midazolam, with a fused midazolam, with a fused imidazole ring. In these imidazole ring. In these latter mentioned cases the latter mentioned cases the presence of the 7- electron-presence of the 7- electron-withdrawing group is not withdrawing group is not required for the activity.required for the activity.

N

NO

X

R

1 23

45

67

8

9


Pharmacokinetics of BenzodiazepinesPharmacokinetics of Benzodiazepines

• Hepatic metabolism. Almost all BDZs Hepatic metabolism. Almost all BDZs undergo microsomal oxidation (N-undergo microsomal oxidation (N-dealkylation and aliphatic hydroxylation) dealkylation and aliphatic hydroxylation) and conjugation (to glucoronides).and conjugation (to glucoronides).

• Rapid tissue redistribution Rapid tissue redistribution long acting long acting long half lives and elimination half lives long half lives and elimination half lives (from 10 to > 100 hrs).(from 10 to > 100 hrs).

• All BDZs cross the placenta All BDZs cross the placenta detectable detectable in breast milk in breast milk may exert depressant may exert depressant effects on the CNS of the lactating infant.effects on the CNS of the lactating infant.


Pharmacokinetics of Benzodiazepines

• Many have active metabolites with half-lives Many have active metabolites with half-lives greater than the parent drug.greater than the parent drug.

• Prototype drug is diazepam (Valium), which has Prototype drug is diazepam (Valium), which has active metabolites (desmethyl-diazepam and active metabolites (desmethyl-diazepam and oxazepam) and is long acting (t½ = 20-80 hr).oxazepam) and is long acting (t½ = 20-80 hr).

• Differing times of onset and elimination half-lives Differing times of onset and elimination half-lives (long half-life => daytime sedation).(long half-life => daytime sedation).

Estazolam, oxazepam, and lorazepam, which are directly metabolized to glucoronides have the least residual (drowsiness) effects.

All of these drugs and their metabolites are All of these drugs and their metabolites are excreted in urine.excreted in urine.


Biotransformation of BenzodiazepinesBiotransformation of Benzodiazepines

From Katzung, 1998

Dr. Majdi BkhaitanDr. Majdi BkhaitanMetabolism


Piperidindione: Such as Glutethimide, which is considered the most

active non-barbiturate hypnotic. Like barbituratres it is a rostral reticular depressant and exhibit a potent anticholinergic activity. It is metabolized by hydroxylation at various positions, then it is glucuronated.

N OO

C2H5

H


Nonbenzodiazepine GABAA Agonists

Historically, benzodiazepines have been the mainstay for treatment of sleeping disorders, yet they have many shortcomings. A new group of sedative-hypnotic agents similar to the benzodiazepines—zaleplon, zolpidem, and zopiclone—have been developed with affinity for the GABA receptor complex. This produces a more efficacious clinical profile with fewer side effects than the benzodiazepines.

Zolpidem, zopiclone, and zaleplon (the “Z” drugs) are structurally distinct, and are being used as short-acting sedative-hypnotics in the United States and Europe. They act at the GABAA high-affinity receptors comparable to the benzodiazepines but with different subunit specificity. Because of variation in binding to the GABA receptor subunits



Imidazopyridine:Such as zolpidem (stilnox®) and alpidem., which are non benzodiazepine hypnotic agents. Acting on the high-affinity benzodiazepine receptor subtype in the brain. They have no major effect on sleep stages, have no rebound effect after withdrawal, and used mainly as hypnotic. Zolpidem was the first non-benzodiazepine ω1 “BDZ 1” agonist marketed. It is a hypnotic agent with minimal anticonvulsant and anxiolytic effects

N

N

O

CH3

CH3

CH3

N CH3

Zolpidem (stilnox )


Cyclopyrolone: such as zopiclone (Imovane) a non benzodiazepine hypnotic agent, Acting on the high-affinity benzodiazepine receptor subtype in the brain, at 7.5mg dose. It decreases sleep latency, increase total sleep duration, reduce the number of awakenings and increase sleep efficiency, REM sleep is substantially unaffected by zopiclone. Rebound effect and withdrawal symptoms do not accompany discontinuation of Zopiclone, it is also devoid of abuse and dependence potential.

N

NN

ON

O C

O

N N CH3

Cl

Zopiclone (Imovane)

Pyrazolopyrimidine

ZaleplonIt displays a unique binding profile with GABAA that is distinct from the benzodiazepines but similar to that of zolpidem . Because of it greater potency for GABAA, the starting dose for zaleplon is comparable to that of zolpidem. It is rapidly absorbed, zaleplon. It is rapidly metabolized by the liver, with an elimination half- life of pproximately 1 hour. The oxidative metabolites are inactive, conjugated with glucuronic acid, and eliminated in the urine. zaleplon has been shown to improve sleep quality with minimal adverse effects and no significant rebound insomnia on stopping the drug.



Buspirone “BuSparBuspirone “BuSpar®®””

8- Melatonin Receptor Agonist

It is effective in initiating sleep (shortening sleep latency) but not in maintaining

sleep (has short half-life).

It is a very potent & very selective ligand for the MT1 receptor

used in the treatment of insomnia.

Does not bind with other receptors associated with sleep (GABAA or dopamine).

MT receptor play important role in discovery and approval of ramelteon.

Ramelteon

52

Sedative hypnotics

Education

majdi bkhaitan normal

barbiturates drugs

anxiolytic drugs moa

anxiolytic drugs sar

benzodiazepines drugs

novel drugs

anxiolytic agents

gabaa channels