This document discusses sedative/hypnotic drugs and anxiolytics. It begins by introducing Dr. Majdi Bkhaitan and Dr. Nashwa Ibrahim from the Department of Pharmaceutical Chemistry at UQU. The document then discusses the objectives of learning about anxiety, insomnia, classifying anxiolytic drugs, and their mechanisms of action. It describes anxiety symptoms and clinical disorders treated by anxiolytics like benzodiazepines and barbiturates. It explains the mechanisms of action of these drugs as enhancing GABA effects in the brain. The document provides details on drug choices, metabolism, and structure-activity relationships of various sedative/hypnotic and anxiolytic agents.
Impurities in pharmaceutical substancesShaliniBarad
Impurities definition
Sources of impurities
Effect/ type of impurities
Limit test definition
Limit test Importance,
Principle & procedure of Limit test for iron, chloride, sulphate, arsenic & heavy metals.
Impurities in pharmaceutical substancesShaliniBarad
Impurities definition
Sources of impurities
Effect/ type of impurities
Limit test definition
Limit test Importance,
Principle & procedure of Limit test for iron, chloride, sulphate, arsenic & heavy metals.
ELIXIR: ELIXIR
LINCTUSES
EMULSION
SUSPENSION
DRY POWDER FOR RECONSTITUTION
LINCTUSES:Linctuses are viscous, monophasic liquid preparation containing a high concentration of syrup that are used for relief of cough
EMULSION
SUSPENSION
DRY POWDER FOR RECONSTITUTION
Formulation of these product
Advantages, Disadvantages, Storages,
It is generally accepted that for ophthalmic and parenteral administration, isotonic solutions are better tolerated by the patient than those at the extremes of hypo- and hypertonicity. Most ophthalmic preparations are formulated to be isotonic. Injections that are not isotonic should be administered slowly and in small quantities to minimize tissue irritation, pain, and cell fluid imbalance.
Important questions of Pharmaceutical organic Organic chemistry-1Payaamvohra1
This ppt gives you an idea about important Organic chemistry concepts and frequently asked questions .Do checkout other ppt for more info about other pharmacy subjects
The drugs which are obtained from marine organisms are know as marine drugs. these marine drugs are used since ancient times. chines and japanes are very famous to use these resources. And interstingly,innumarable products derived from the marine organisms in several 'crude forms' have been widely used across the globe by the traditional practitioners for thousands of years.
ELIXIR: ELIXIR
LINCTUSES
EMULSION
SUSPENSION
DRY POWDER FOR RECONSTITUTION
LINCTUSES:Linctuses are viscous, monophasic liquid preparation containing a high concentration of syrup that are used for relief of cough
EMULSION
SUSPENSION
DRY POWDER FOR RECONSTITUTION
Formulation of these product
Advantages, Disadvantages, Storages,
It is generally accepted that for ophthalmic and parenteral administration, isotonic solutions are better tolerated by the patient than those at the extremes of hypo- and hypertonicity. Most ophthalmic preparations are formulated to be isotonic. Injections that are not isotonic should be administered slowly and in small quantities to minimize tissue irritation, pain, and cell fluid imbalance.
Important questions of Pharmaceutical organic Organic chemistry-1Payaamvohra1
This ppt gives you an idea about important Organic chemistry concepts and frequently asked questions .Do checkout other ppt for more info about other pharmacy subjects
The drugs which are obtained from marine organisms are know as marine drugs. these marine drugs are used since ancient times. chines and japanes are very famous to use these resources. And interstingly,innumarable products derived from the marine organisms in several 'crude forms' have been widely used across the globe by the traditional practitioners for thousands of years.
Introduction:
SEDATIVES CNS depressant drugs , reduce excitement & tension, & produce calmness & relaxation.
HYPNOTICS drugs that produce sleep similar to that of natural arousal sleep.
Both sedative & hypnotic action may reside in the same drug.
A small dose may act as sedative, whereas a large dose of the same drug may act as a hypnotic.
SAR of Benzodiazepine:
Presence of phenyl ring / pyridyl ring promotes sedative-hypnotic activity at C5-position.
If presence of electron withdrawing group like –Cl or –NO2 (Lorazepam, Clonazepam) at R2’ position, then sedative-hypnotic activity .
Presence of electron withdrawing group like –Cl,
-F, –NO2 at C7 position, activity.
Substitution at 6,8,9 position of carbon atom, activity.
Shifting of double bond present between –N4 & C5 or saturation of double bond activity.
R3 = alkyl group, activity & R3 = -OH or –COOH activity & R1 = -CH3 ,if larger group is present activity.
Sleep is mainly loss of consciousness. Sleep is an architectured cyclic process.
These drugs maintains the sleep-wake cycle.
Insomnia is a symptom & its proper treatment depends on finding the cause of sleeplessness. To treat this type of patient, use sedative-hypnotics.
High dose of the drugs may lead to coma or death.
Basic Presentation on Sedatives & Hypnotics that includes course objectives, course outcomes.
This file also contains Introduction, Classification, Structure Activity Relationship, Synthesis, Therapeutic uses of given topic.
Some questions are also covered in this file.
Palestine last event orientationfvgnh .pptxRaedMohamed3
An EFL lesson about the current events in Palestine. It is intended to be for intermediate students who wish to increase their listening skills through a short lesson in power point.
The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
Embracing GenAI - A Strategic ImperativePeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...Levi Shapiro
Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
harassment and intimidation at the Massachusetts Institute of Technology (MIT). Failing to act decisively to ensure a safe learning environment for all students would be a grave dereliction of your responsibilities as President of MIT and Chair of the MIT Corporation.
This Congress will not stand idly by and allow an environment hostile to Jewish students to persist. The House believes that your institution is in violation of Title VI of the Civil Rights Act, and the inability or
unwillingness to rectify this violation through action requires accountability.
Postsecondary education is a unique opportunity for students to learn and have their ideas and beliefs challenged. However, universities receiving hundreds of millions of federal funds annually have denied
students that opportunity and have been hijacked to become venues for the promotion of terrorism, antisemitic harassment and intimidation, unlawful encampments, and in some cases, assaults and riots.
The House of Representatives will not countenance the use of federal funds to indoctrinate students into hateful, antisemitic, anti-American supporters of terrorism. Investigations into campus antisemitism by the Committee on Education and the Workforce and the Committee on Ways and Means have been expanded into a Congress-wide probe across all relevant jurisdictions to address this national crisis. The undersigned Committees will conduct oversight into the use of federal funds at MIT and its learning environment under authorities granted to each Committee.
• The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
• The Committee on Oversight and Accountability is investigating the sources of funding and other support flowing to groups espousing pro-Hamas propaganda and engaged in antisemitic harassment and intimidation of students. The Committee on Oversight and Accountability is the principal oversight committee of the US House of Representatives and has broad authority to investigate “any matter” at “any time” under House Rule X.
• The Committee on Ways and Means has been investigating several universities since November 15, 2023, when the Committee held a hearing entitled From Ivory Towers to Dark Corners: Investigating the Nexus Between Antisemitism, Tax-Exempt Universities, and Terror Financing. The Committee followed the hearing with letters to those institutions on January 10, 202
Biological screening of herbal drugs: Introduction and Need for
Phyto-Pharmacological Screening, New Strategies for evaluating
Natural Products, In vitro evaluation techniques for Antioxidants, Antimicrobial and Anticancer drugs. In vivo evaluation techniques
for Anti-inflammatory, Antiulcer, Anticancer, Wound healing, Antidiabetic, Hepatoprotective, Cardio protective, Diuretics and
Antifertility, Toxicity studies as per OECD guidelines
Synthetic Fiber Construction in lab .pptxPavel ( NSTU)
Synthetic fiber production is a fascinating and complex field that blends chemistry, engineering, and environmental science. By understanding these aspects, students can gain a comprehensive view of synthetic fiber production, its impact on society and the environment, and the potential for future innovations. Synthetic fibers play a crucial role in modern society, impacting various aspects of daily life, industry, and the environment. ynthetic fibers are integral to modern life, offering a range of benefits from cost-effectiveness and versatility to innovative applications and performance characteristics. While they pose environmental challenges, ongoing research and development aim to create more sustainable and eco-friendly alternatives. Understanding the importance of synthetic fibers helps in appreciating their role in the economy, industry, and daily life, while also emphasizing the need for sustainable practices and innovation.
Read| The latest issue of The Challenger is here! We are thrilled to announce that our school paper has qualified for the NATIONAL SCHOOLS PRESS CONFERENCE (NSPC) 2024. Thank you for your unwavering support and trust. Dive into the stories that made us stand out!
Thesis Statement for students diagnonsed withADHD.ppt
Sedative hypnotics
1. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
SEDATIVE/HYPNOTICSEDATIVE/HYPNOTIC
SS
ANXIOLYTICSANXIOLYTICS
Dr. Majdi Bkhaitan
Dr. Nashwa Ibrahim
Department Of Pharmaceutical
chemistry
mmbakhaitan@uqu.edu.sa
2. 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.
Dr. Majdi BkhaitanDr. Majdi Bkhaitan
3. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
AnxietyAnxiety
feeling of helplessnessfeeling of helplessness
difficulty in concentratingdifficulty in concentrating
irritability & insomniairritability & insomnia
GI disturbancesGI disturbances
muscle tensionmuscle tension
excessive perspirationexcessive perspiration
palpitationspalpitations
dry mouthdry mouth
impending doomimpending doom
dreaddread
4. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
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.
5. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
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 centerDepression of respiratory and vasomotor center
in the brainstemin the brainstem
COMACOMA
DEATHDEATH
6. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
AnxiolyticsAnxiolytics
1)1) Benzodiazepines (BZDs).Benzodiazepines (BZDs).
2)2) Barbiturates (BARBs).Barbiturates (BARBs).
3)3) 5-HT5-HT1A1A receptor agonists.receptor agonists.
4)4) 5-HT5-HT2A2A, 5-HT, 5-HT2C2C & 5-HT& 5-HT33 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).
7. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
AnxiolyticsAnxiolytics
Other Drugs with anxiolytic activity.Other Drugs with anxiolytic activity.
– TCAs (Fluvoxamine). Used for ObsessiveTCAs (Fluvoxamine). Used for Obsessive
compulsive Disorder.compulsive Disorder.
– MAOIs. Used in panic attacks.MAOIs. Used in panic attacks.
– Antihistaminic agents. Present in over theAntihistaminic 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).
9. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
Drug ChoicesDrug Choices
Older:Older:
Barbiturates (drugs ending in “barbital”)Barbiturates (drugs ending in “barbital”)
Alcohols / Choral HydrateAlcohols / Choral Hydrate
Newer:Newer:
Benzodiazepines (drugs name ending in “lam” orBenzodiazepines (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
10. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
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
12. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
BarbituratesBarbiturates
Barbiturates
Benzodiazepin
GABA
Multiple mechanisms
1) 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
13. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
BarbiturateBarbiturate Multiple MOAMultiple MOA
1.1. Increase GABA effect (increased durationIncrease GABA effect (increased duration
of openings)of openings)
2.2. Directly activate GABADirectly activate GABAAA channels atchannels at highhigh
concentrationsconcentrations
3.3. Block glutamate NT* effectsBlock glutamate NT* effects
4.4. Block Na channelsBlock Na channels
* Glutamate is an excitatory NT
14. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
Barbiturates modify the mechanism ofBarbiturates modify the mechanism of
synaptic transmission, they reduce thesynaptic transmission, they reduce the
excitability of post-synaptic cell by alteringexcitability of post-synaptic cell by altering
the permeability of the cell membrane.the permeability of the cell membrane.
They exert their action on the centralThey exert their action on the central
synaptic transmission process of thesynaptic transmission process of the
reticular activating system, and thereticular activating system, and the
cerebral cortex becomes deactivatedcerebral cortex becomes deactivated
(antidepolarizing blocking agents).(antidepolarizing blocking agents).
Barbiturates act also upon the limbic,Barbiturates act also upon the limbic,
hypothalamic, and thalamic synaptichypothalamic, and thalamic synaptic
system.system.
15. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
Physical dependence may be induced byPhysical dependence may be induced by
various doses of the drugs.various doses of the drugs. As a rule, drugAs a rule, drug
dependence is followed by tolerance,dependence is followed by tolerance, inin
which increased doses are required towhich increased doses are required to
obtain the same pharmacological effect.obtain the same pharmacological effect.
Barbiturates don’t induce natural sleep.
16. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
HN NH
O
OO
R1 R2
R( ) 1
2
3
4
5
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.
17. 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
21. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
HN N
O
O
R1 R2
OH
HN N
O
O
R1 R2
O
N N
O
R1 R2
O
-
O
-
-
K1
K2
AcidityAcidity::
pKa of unsubstituted barbituric acid equals 4.12, whilepKa 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 beSo, salts of the 5,5 disubstituted barbituric acid can be
obtained with bases such NaH. A second ionization canobtained with bases such NaH. A second ionization can
occur with pKa values 11.7-12.7. It is possible tooccur 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.
24. Barbiturates - Metabolism
Oxidation of
substituent at C- 5
by CYP450’s
Most Barbiturates
Aromatic Hydroxylation
Phenobarbital
Mephobarbital
Slide 6
Glucuronide and
sulfate conjugates
An ultimate (ω) or penultimate (ω -1) oxidation of C-5 substituents
27. OC2H5
OC2H5
O
O
R
R
NH2
NH2
X
C2H5OH
N
H
N
H
O
O
X
R
R
+
Disubstituted
diethylmalonate
X=O in urea
X=S in thiourea
X=O in
X=S in thio
barbiturates
barbiturates
-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.
28. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
Benzodiazapines
Many derivatives of the 1,4-benzodiazepine seriesMany 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 exclusivelyNo 1,4-benzodiazepin can be selected exclusively
as a hypnotic agent in preference to otheras a hypnotic agent in preference to other
benzodiazepins.benzodiazepins.
Benzodiazepins that are rapidly metabolized andBenzodiazepins that are rapidly metabolized and
eliminated (e.g. temazepam) have gained popularityeliminated (e.g. temazepam) have gained popularity
as sleep inducers, because of lack of toxicity neitheras sleep inducers, because of lack of toxicity neither
through neither accumulation nor hangover.through neither accumulation nor hangover.
29. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
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
30. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
Barbiturates
Benzodiazepine
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
31. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
Barbiturates
Benzodiazepines
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)
36. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
N
N
O
X
R
1 2
3
45
N
N
O
Cl
CH3
N
N
Cl
O
N
CH3
H
N
N
O
Cl
CH3
OH
N
N
Cl
NN
CH3
N
N
Cl
N
CH3
F
DIAZEPAM
CHLORDIAZEPOXIDE OXAZEPAM
ALPRAZOLAMMIDAZOLAM
37. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
SAR:SAR:
Presence of an electron-Presence of an electron-
withdrawing group inwithdrawing group in
positionposition 77 is required foris required for
activity. More theactivity. More the
electron-withdrawingelectron-withdrawing
more will be the activity.more will be the activity.
Position 6,8 and 9 shouldPosition 6,8 and 9 should
not be substituted.not be substituted.
N
N
O
X
R
1 2
3
45
6
7
8
9
38. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
A phenyl ring in position 5A phenyl ring in position 5
promotes activity, activitypromotes activity, activity
is increased when theis increased when the
phenyl is ortho or diorthophenyl is ortho or diortho
substituted with electron-substituted with electron-
withdrawing groups.withdrawing groups.
Substitution in paraSubstitution in para
position brings aboutposition brings about
decrease in activity.decrease in activity.
Saturation of the N4-C5Saturation of the N4-C5
double bond or its shiftingdouble bond or its shifting
to other positionsto other positions
decreases activity.decreases activity.
N
N
O
X
R
1 2
3
45
6
7
8
9
39. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
Substitution with alkyl group atSubstitution with alkyl group at
position 3 decreases activity,position 3 decreases activity,
substitution with OH groupsubstitution with OH group
doesn’t. This hydroxyl affects thedoesn’t. This hydroxyl affects the
pharmacokinetic of the drug,pharmacokinetic of the drug,
truly, compounds that doesn’ttruly, 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, compoundswhereas, compounds
possessing the 3-OH group arepossessing the 3-OH group are
more polar and are readilymore polar and are readily
conjugated and excreted.conjugated and excreted.
N
N
O
X
R
1 2
3
45
6
7
8
9
40. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
2-carbonyl function is2-carbonyl function is
optimal for the activity, as isoptimal for the activity, as is
the nitrogen atom atthe nitrogen atom at
position 1, the N-position 1, the N-
substituent should be small.substituent should be small.
On the other hand thereOn the other hand there
were obtained compoundswere obtained compounds
with a fused triazole ringwith a fused triazole ring
represented by “triazolam”represented by “triazolam”
and alprazolam, alsoand alprazolam, also
midazolam, with a fusedmidazolam, with a fused
imidazole ring. In theseimidazole ring. In these
latter mentioned cases thelatter mentioned cases the
presence of the 7- electron-presence of the 7- electron-
withdrawing group is notwithdrawing group is not
required for the activity.required for the activity.
N
N
O
X
R
1 2
3
45
6
7
8
9
41. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
Pharmacokinetics of BenzodiazepinesPharmacokinetics of Benzodiazepines
• Hepatic metabolism. Almost all BDZsHepatic 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 redistributionRapid tissue redistribution long actinglong acting
long half lives and elimination half liveslong half lives and elimination half lives
(from 10 to > 100 hrs).(from 10 to > 100 hrs).
• All BDZs cross the placentaAll BDZs cross the placenta detectabledetectable
in breast milkin breast milk may exert depressantmay exert depressant
effects on the CNS of the lactating infant.effects on the CNS of the lactating infant.
42. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
Pharmacokinetics of Benzodiazepines
• Many have active metabolites with half-livesMany have active metabolites with half-lives
greater than the parent drug.greater than the parent drug.
• Prototype drug is diazepam (Valium), which hasPrototype drug is diazepam (Valium), which has
active metabolites (desmethyl-diazepam andactive 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-livesDiffering 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 areAll of these drugs and their metabolites are
excreted in urine.excreted in urine.
43. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
Biotransformation of BenzodiazepinesBiotransformation of Benzodiazepines
From Katzung, 1998
45. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
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
47. 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
Dr. Majdi BkhaitanDr. Majdi Bkhaitan
48. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
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 )
49. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
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
N
N
O
N
O C
O
N N CH3
Cl
Zopiclone (Imovane)
50. Pyrazolopyrimidine
Zaleplon
It 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. Dr. Majdi BkhaitanDr. Majdi Bkhaitan
52. 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
Editor's Notes
Barbiturates lose their activities through metabolic transformation in the liver. In the course of metabolism the lipophilic character decreases which will diminish the concentration of the barbiturates in the cerebral tissues with loss in depressant activity.
N-demethylation does not proceed rapidly and excreted slowly therefore the produced metabolite accumulates with the N-alkylated barbiturates.
During the course of mephobarbital therapy a definite blood level of phenobarbital has been established
Hydrolytic cleavage of the ring leads to the formation of acetamide or dialkylacetylurea