All about drugs in central nervous system and mechanism of action

1. 3. DRUGS ACTING ON CNS

2. • Drugs affecting the CNS provide
• Anesthesia, treats psychiatric disorders, relieve anxiety,
provide sleep or sedation, prevent epileptic seizure, and
suppress movement
• Lipid soluble non-ionized molecules pass readily into
the CNS (BBB)

3. 1. Sedative and hypnotics
• Sedative drugs provide a quieting effect accompanied by
relaxation and rest but not necessarily sleep
• No sharp distinction between the two types
• Also employed as anticonvulsant, muscle relaxant and
anti-anxiety
• Cause transient decrease in the level of consciousness
for the purpose of sleep without lingering effect
• Have no potential for decreasing or arresting respiration
(even at high dose)
• Produce no Abuse , Addiction , Tolerance or Dependence

4. Classification of Sedative-Hypnotics
• The sedative-hypnotics may be divided into three
major groups:
• Barbiturates
• Benzodiazepines
• Miscellaneous:-
• drugs that do not fall into either of the first two groups

5. i. Barbiturate
• Barbituric acid was synthesized from a reaction of
urea with malonic acid, a chemical found in apples.
• But was not used as a drug
• synthesize a therapeutically active "barbiturate" by
substituting two ethyl groups for two hydrogens
attached to carbon no. 5. [sleep inducer]
• Diethyl barbituric Acid (Veronal) was a popular drug.
• Are 5, 5 disubstituted derivatives of barbituric acid

7. ii. Benzodiazepines
• Refers to portion of the structure of benzene fused to
seven membered diazepine ring.
• E.g:
• Substituents at position marked R1, R2, R3
and X result in different drugs

8. • The pharmacological effects of benzodiazepines are
outlined as follows:
• They produce sedation, hypnosis, decreased anxiety,
muscle relaxation, and anticonvulsant activity.
• are not general neuronal depressants as are
barbiturates.
• have similar pharmacologic profiles, but the drugs differ
in selectivity.
• safer in overdose especially compared with
barbiturates.
• produce fewer drug interactions because they do not
induce hepatic microsomal enzymes

9. SAR of benzodiazepines
• Saturation of the 4, 5 double bond or shift to 3, 4-position
decreases activity
• Position 6, 8 and 9 should not be substituted
• The 2-carbonyl function is optimal for activity as is the
nitrogen atom at position 1.
The N substitution should be small
• A phenyl group at the C5 promotes activity
• Ortho or di-ortho substitution with electron attracting
substituents increases activity.
• Para Substituents decrease activity

10. iii. Other sedative hypnotics (miscellaneous)
A. ALCOHOLS
• Acts at the GABAA receptor to potentiate the action of
GABA.
• Also inhibits NMDA (N-Methyl-D-Asparate) glutamate
receptors.
• These actions result in an array of actions including CNS
depression.
• Ethanol has played a sedative –hypnotic role for centuries

11. SAR for hypnotic activity of alcohols
• Activity increases as the chain length increase with
maximum at C8
• Branching the chain increases activity
Tertiary  Secondary  Primary
• Replacing hydrogen with a halogen increases activity
Chlorobutanol
• A tertiary, lipophilic alcohol

12. B. Carbamates
Ethinamate
• Carbamate analogue of acetylenic alcohol
• It is a short-acting hypnotic to which tolerance rapidly
develops; it is indicated only for periods of 7 days or less.

13. 2. Anticonvulsants (anti- epileptics)
• CNS disorder characterized by recurrent abnormal
discharge of CNS neurons
• Characterized by abnormal and excessive EEG
(electroencephalography) and discharge
• May be limited to a focus or encompass wide area
• Causes disturbance of consciousness and hyperactivity of
autonomic nerves

14. Anticonvulsants…
Major types
• Grand mal (generalized tonic clonic seizure):-
• complete loss of consciousness, followed by transient
muscular rigidity (tonic phase)
• Petit mal, non convulsive seizure:- usually momentary
loss of consciousness prevails.

15. Classification of Anticonvulsants
Cyclic ureides and imides
Urea derivatives
Miscellaneous
a) Cyclic ureides and imides
• If both are lower alkyl, the tendency is to be active
against petit mal
• If one is an aryl group, activity tends to be directed to
grand mal epilepsy
• The strength of activity depends on the substituents

16. Class X
Barbiturate
Hydantions
Oxazolidindiones
Succinimides

17. Hydantoins
• Phenytoin and the other hydantoins are “ring
contracted” analogues of the barbiturates
(one carbonyl removed).

18. Oxazolidinediones
Succinimides
• Active against absence seizure

19. b) Ureas
c) Miscellaneous

20. Benzodiazepines (BZDs)

21. 3. Tranquilizers
• Give strong sedation without producing sleep
and produce a state of insignificance and
disinterest.
• Effective in reducing excitation,
agitation/disturbance, aggressiveness and
impulsiveness (major tranquilizers)
• They may be classified into
• Major tranquilizers (neuroleptics):
• used mainly for treatment of psychosis (schizophrenia and
mania)
• Minor tranquilizers (anxiolytics):
• used to reduce pathological anxiety, agitation and tension

22. • Schizophrenia results from increased dopaminergic
neurotransmission
• Hence the strategy is to block these dopaminergic
receptors
• Schizophrenia is a long-term mental disorder of a type
involving a breakdown in the relation between thought,
emotion, and behaviour, leading to
• faulty perception,
• inappropriate actions and feelings, and
• withdrawal from reality into imaginary and delusion
• Mania is a mental illness marked by periods of
excitement, delusions, and over activity.

23. 3.1 Major neuroleptics/Antipsychotics
• Are used in the treatment of schizophrenia/mania
• A disorder involving disruption and disintegration of behavior
• Typical Antipsychotic Drugs:
• Phenothiazines
• Thioxanthenes
• Butyrophenones

24. Phenothiazine SAR
1.Propyl Side Chain
• Propyl is best, butyl is nearly inactive, ethyl has low
activity.
• Compounds with ethyl chains often have antihistaminic
activity.
• Any substituent at the first position of the side chain
decreases activity.
• Large aliphatic substituents are not tolerated.
• A larger range of substitutions are tolerated at position 3.
• The nitrogen is often included as part of a ring.

25. 3.2 Minor tranquilizers (anxiolytics)
Antianxiety drugs
• Anxiety: is sense of apprehensive expectation
•Part of our daily life
• Excessive consider as pathological
• The anxious state is a sense of unpleasant anticipation
and excessive mental tension.

26. • Anxiolytics are drugs used to control moderate or
severe anxiety & tension
• Is situations producing usual Stress & Anxiety disorders
• The most commonly used antianxiety drugs are
benzodiazepines
• The name refers to the portion of the structure of
benzene fused to the seven member diazepine ring.

27. • Benzodiazepines have replaced the
barbiturates because they have
• a lower abuse potential,
• relatively lower adverse reactions
• (chiefly, death is a relatively common result in
barbiturate overdoses) and
• Lower drug interactions.
• less tendency to tolerance and dependency

28. 4. Central skeletal muscle relaxants
• are used to decrease muscle contraction or spasticity that
occurs in certain neurologic and musculoskeletal
disorders.
• Muscle spasm or cramp is a sudden involuntary painful
muscle contraction that occurs with trauma or an irritant.
• It occurs with neurologic disorders such as spinal cord
injury and multiple sclerosis
2 type:
• Centrally acting muscle relaxants,
• Which appears to act on the central nervous system
• Peripherally acting muscle relaxants
• at the level of the nerve muscle connection

29. • The first drug recognized to exhibit spasmolytic activity
was antodyne or 3- phenoxy- 1,2- propanediol
3- phenoxy- 1,2- propanediol

30. • SAR studies of a series of simple glyceryl ethers
related to antodyne, lead to development &
introduction of mephenesin
• Is a prototype of intraneuronal blocking type of muscular
relaxant because of its safety and selective action on
the spinal cord

31. B. CNS Stimulant drugs
1. Analeptics
• Have a specific stimulant action on the central nervous
system.
• These are primarily employed to combat the drug-induced
respiratory depression.
• Agent that cause nonselective CNS stimulation and
causes muscle contraction
• Particularly a term used to describe compounds that
cause contraction and rigidity of the muscles of respiration

32. 2. Antidepressant
• Depression is due to low level of monoamines (NE,
serotonin & dopamine) in the synapse

33. It is characterized by the following symptoms
• Sadness
• Helplessness
• Inferiority
• hopelessness,
• Worthlessness
• Crying
• Suicidal tendencies
• fatigue or decreased energy
• restlessness, irritability
• sleep disturbances

34. • Monoamine reuptake inhibitors and monoamine
oxidase inhibitors: Act as antidepressant
• History of antidepressants
• Most antidepressant drugs were discovered by
serendipity
• Imipramine, the first TCA, develop during the search of
drugs for schizophrenia
• Monoamine hypothesis suggests that small
amount of neurotransmitter causes depression
• Drugs act by normalizing this deficit.

35. Classification of Antidepressant
A. Selective serotonin reuptake inhibitors (SSRIs)
• SSRIs represent a relatively new class of antidepressant
dugs.
• 5-HT (serotonin) is a major player in depressive illness,
and serotonergic pathways are closely related to mood
disorders, especially depression.
• Thus drugs affecting the 5-HT levels in the neural
synapse and serotonergic pathways may lead to effective
therapy of depression

36. B. Selective norepinephrine reuptake inhibitors
(SNRIs)

37. C. Norepinephrine and serotonin reuptake
inhibitors (NSRIs)/TCA

38. D. Norepinephrine and dopamine reuptake
inhibitors (NDRIs)

39. 3. CNS Adrenergics
Amphetamine SAR

40. 4. Xanthine derivatives
• have a wide spectrum of therapeutic applications
ranging:
• stimulation of cardiac muscle,
• enhanced diuresis,
• stimulation of CNS
• soothing relaxation of bronchi and the coronary arteries.
• A few typical examples of the members of this
category are :
• caffeine, theophylline, theobromine, aminophylline,
etofylline and proxyphylline.

41. • Caffeine is a potent central stimulant.
• It also acts on the cardiac muscle and on the
kidneys.
• It stimulates the higher centers of the CNS
• Caffeine helps in the stimulation of respiratory
centers.
Its diuretic action is due to:
• enhanced glomerular filtration rate,
• increased renal blood flow and
• above all the reduction of the normal tubular
reabsorption.

42. Narcotic Analgesics & Antagonists
• Narcotic is an addictive drug, especially an illegal one,
affecting mood or behaviour.
• The development of narcotic analgesics is a good
example of the traditional approach in drug discovery.
Morphine
• is still one of the most effective painkillers available to medicine.
• It is especially good for treating dull, constant pain rather than
sharp, periodic pain.

43. SAR of morphine
• The molecule contains five rings labelled A-E
• It is basic because of the tertiary amino group,
• but it also contains a phenolic group, an alcohol group,
an aromatic ring, an ether bridge, and a double bond.
• The phenolic OH
• By methylating the phenolic OH, the analgesic activity
drops drastically
• This drop in activity is observed in other analogues
containing a masked phenolic group.
• Clearly, a free phenolic group is crucial for analgesic
activity.

44. The aromatic ring
• The aromatic ring is essential.
• Compounds lacking it show no analgesic activity [ring A]
The ether bridge
• The ether bridge is not required for analgesic activity.
• To sum up, the important functional groups for analgesic
activity in morphine are shown below

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