1. INTRODUCTION TO CNS PHARMACOLOGY

2. An overview of the CNS with a focus on Most drugs that affect the central nervous system (CNS) act by altering some step in the neurotransmitters mediating the physiological and pathological responses is essential for understanding neuropharmacology.

3. Nature of Centrally acting Drugs
Drug first needs to cross the blood-brain barrier, so it needs to be lipophilic and unionized,
or it could be actively transported across the barrier.
This ability to cross the blood-brain barrier is essential of the drug because without this,the drug will not be effective.

4. Ion channels & NT receptors
Voltage-gated channels
Respond to AP
Fast action potentials
Include the sodium channels responsible for action potential propagation
Ligand-gated channels (Inotropic)
Chemically-gated
Respond to chemical neurotransmitters
(NTAs) that bind to receptor subunits of
the channel

5. G-protein coupled receptors (Metabotropic)
NTAs also bind to G protein-coupled
receptors
Direct opening voltage-channel through SM

7. CNS PHARMACOLOGY ROLE OF THE ION CURRENT CARRIED BY THE CHANNEL
SYNAPSE- communication
EXCITATORY POSTSYNAPTIC POTENTIALS
2. INHIBITORY POSTSYNAPTIC POTENTIALS

8. CNS PHARMACOLOGY EXCITATORY POSTSYNAPTIC POTENTIALS (EPSPs)
Depolarizing potential change
Generated by
Opening of sodium or calcium channels
Closing of potassium channels

9. CNS PHARMACOLOGY EXCITATORY POSTSYNAPTIC POTENTIALS (EPSPs)
Na+, K+, Ca+2
-70 mV

11. CNS PHARMACOLOGY INHIBITORY POSTSYNAPTIC POTENTIALS (IPSPs)
Hyperpolarizing potential change
Generated by
Opening of potassium or chloride channels

13. CNS PHARMACOLOGY INHIBITORY POSTSYNAPTIC POTENTIALS (IPSPs)
K+ , Cl- at the postsynaptic , Ca+2 at the presynaptic
-70 mV

15. CNS PHARMACOLOGY SITES AND MECHANISMS OF DRUG ACTION
Some drugs exert their effect through direct interactions with molecular components of ion channels on axons
Carbamazepine
Phenytoin
Local anesthetics and some drugs used for general anesthesia

16. CNS PHARMACOLOGY SITES AND MECHANISMS OF DRUG ACTION
Most drugs exert their effect mainly at the synapses

17. CNS PHARMACOLOGY SITES AND MECHANISMS OF DRUG ACTION
May alter Neurotransmitter
Synthesis
Storage
Release
Reuptake
Metabolism

18. CNS PHARMACOLOGY SITES AND MECHANISMS OF DRUG ACTION Activate or block
Pre- and postsynaptic receptors for specific transmitters

19. CNS PHARMACOLOGY CNS ORGANIZATION Major excitatory transmitters
Aspartate
Glutamate

20. CNS PHARMACOLOGY CNS ORGANIZATION 2 TYPES OF NEURONAL SYSTEM
Major inhibitory transmitters:
Gamma amino butyric acid (GABA)
Glycine

21. CNS DRUGS CLASSIFICATION
Chemical structure
Benzodiazepines, Butyrophenones
Pharmacological
MAO inhibitors, SSRI,
Clinical use
Antidepressants, Antipsychotic agents

22. Classification sedatives –hypnotics drugs
“Drugs that reduce anxiety and cause sleep”
Examples
Barbiturates, benzodiazepines

23. Classification 2. Antipsychotic drugs (neuroleptics,
anti-schizophrenia
“Drugs that are effective in relieving symptoms of schizophrenic illness”
Examples
Clozapine, Haloperidol

24. Classification 3. Antidepressant drugs
“ Drugs that alleviate the symptoms of depressive illness”
Examples
TCA, MAOI, SSRI

25. Classification 4. Psychomotor stimulants (Psychostimulants)
“Drugs that can cause wakefulness and euphoria”
Examples
Amphetamines, Cocaine, and caffeine

26. 5. Anticonvulsants: Drugs that prevent or suppress convulsions.
6.Analgesics: Drugs that relieve pain without causing loss of consciousness.
7. General anesthetics: Drugs that produce reversible depression of the CNS leading to loss of consciousness and loss of sensations surgical operations.

27. Definitions…. Tolerance
A decreasing response to repetitive drug doses. Higher doses are needed to produce the same effect.
Cross tolerance:means that individuals tolerant to one drug will be tolerant to other drugs in the same class or other classes

28. Dependence
a state of relying on or chronic need, as for a drug
A physiologic or psychological need for a drug

29. physical dependence (physiological dependence)  in which the drug is used to prevent withdrawal symptoms
psychological dependence in which the drug is used to obtain relief from tension or emotional discomfort; called also emotional dependence.

30. Anxiolytic and Hypnotic Drugs

31. Sedative – Hypnotics Anxiety disorders
Is unpleasant state of tension, apprehension or uneasiness . “ A fear that seems to arise from a sometimes unknown source” .

32. Anxiety is a universal human characteristic which serves as adaptive mechanism to warn about an external threat by activating the sympathetic NS.
Anxiety is in many cases secondary to organic disease (e.g MI, angina, peptic ulcers) which themselves require specific therapy.
Or due to Drug-Induced. or Drug Withdrawal

33. Manifestations of anxiety:
Verbal complaints. The patient says he/she is anxious, nervous.
Somatic and autonomic effects. The patient is restless and agitated, has tachycardia, increased sweating, breathlessness, tremor, fatigue, disturbed sleep. .
Social effects. Interference with normal productive activities.

34. Anxiety become pathological when:
1.Fear is greatly out-of-proportion to risk/ severity of threat.
2.Response continues beyond existence of threat.
3.Social or occupational functioning is impaired.

35. insomnia is "difficulty initiating or maintaining sleep, or both" or the perception of poor quality sleep.

36. BASIC PHARMACOLOGY OF SEDATIVE-HYPNOTICS
An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect with little or no effect on motor or mental functions.
A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state.

37. General anesthetic: the drug which causes reversible and controllable loss of consciousness associated with absence of response to pain.
Sedation Hypnosis  Anesthesia  Coma and death. After progressive dose increments.

38. BASIC PHARMACOLOGY OF SEDATIVE-HYPNOTICS
Hypnotic effects involve more pronounced depression of the central nervous system than sedation, and this can be achieved with most sedative drugs simply by increasing the dose.
Graded dose-dependent depression of central nervous system function is a characteristic of sedative-hypnotics.

39. Classification of anxiolytic and hypnotic drugs
1. Benzodiazepines “most important class”
2. Hydroxyzine – H1 blocker.
3. β – receptor antagonist “propranolol”.
Use to treat some forms of anxiety, particularly when physical (autonomic) symptoms (sweating, tremor, tachycardia) are severe.
4. barbiturates

40. SEDATIVE/HYPNOTICS ANXYOLITICS
GABAergic SYSTEM

41. Ⅰ.Benzodiazepines

42. Ⅰ.Benzodiazepines Classification Short acting  e.g. Midazolam
Intermediate acting  e.g. Alprazolam
Long acting  e.g. Diazepam
The BNZ for most part, end in “pam” or “lam’

43. MOA of Benzodiazepines (BDZ)

44. Mechanism of action of the benzodiazepines

45. Benzodiazepines MOA

46. The main effects of benzodiazepines are:
1. Reduction of anxiety at low doses.
2. Sedation and hypnosis at higher doses.
3. Anterograde amnesia: temporary impairement of memory ,decreased person’s ability to learn and form new memories.
4. Anticonvulsant.
5. Muscle relaxant .

47. Therapeutic Uses of BDZs
1. Anxiety disorders: for continued sever anxiety and NOT to alleviate the normal stress of every day of life.
Only for short period. Addiction potential.
Benzodiazepines with intermediate or long durations of action are favored
Alprazolam for Phobic and panic attacks

48. Therapeutic Uses of(BDZ)
2. Sleep disorders:
latency of sleep onset is decreased.
total duration of sleep is increased.
Both effects decline after prolonged use.
Nursing points
Dependence can occur with long –term use of all hypnotics. use the minimum dose for the minimum time…
Depression can cause insomnia

49. Therapeutic Uses of(BDZ)
3. Anticonvulsant: clonazepam diazepam and lorazepam.
4. Preanesthetic medication: to produce amnesia in anxiety provoking and unpleasant procedures as endoscopy and dental procedures.

50. 5.Muscular disorders: in skeletal muscle spasm , spasticity of multiple sclerosis and cerebral palsy.
6. Control of ethanol and other hypnotic withdrawal.

51. Day time drowsiness
Cognitive impairment
Blurred vision & confusion
Tolerence and dependence (physical and psycological). Specially in high dose for long period. Withdrawal manifestation are more with BDZ of short duration.

52. BZs antagonists
Flumazenil reverse the effects of BZs
This drug is available by I.V. administration only
Has rapid onset and short duration of action

53. Ⅱ.BARBITURATES
They were formerly used to sedate the patient; today they have been replaced by BZ because:
BZ are safer (wide therapeutic index)
BZ have ↓ risk of physical dependence
BZ have ↓ drug-drug interaction (less induction of liver enzymes)
BZs have less withdrawal symptoms

54. Ⅱ.BARBITURATES Classification
Ultra-short-acting barbiturates: act within seconds, and their duration of action is 30min. Therapeutic use of Thiopental is used I.V. to induce anesthesia

55. (2) Long-acting barbiturates: have a duration of action greater than 6h. Such as Phenobarbital. Therapeutic uses: hypnotics and sedative, and antiepileptic agents for long term management of Tonic-Clonic seizure & status epilepticus

56. MECHANISM OF ACTION
Barbiturates share with benzodiazepines the ability to enhance the action of GABA, but they bind a different site on the GABA-receptor/chloride channel,

57. Barbiturates will:
Produce sedation,hypnosis,coma and death.
Suppress respiration(overdose can lead to death).
Induce the liver P-450 system.

58. Benzodiazepines vs. Barbiturates
Criteria BZ
Barb.
Relative Safety
High
Low
Maximal CNS depression
Respiratory Depression
Suicide Potential
Abuse Potential
Antagonist Available?
Yes No

59. Other anxiolytic agent:
Hydroxyzine: an antihistamine that is useful for patients with anxiety disorders who have history of drug abuse.
often used for sedation prior dental procedure or surgery.
Drowsiness is possible adverse effects

60. -Adrenoreceptor Antagonists (eg. Propranolol)
Use to treat some forms of anxiety, particularly when physical (autonomic) symptoms (sweating, tremor, tachycardia) are severe.
Adverse effects of propranolol may include: lethargy, vivid dreams, hallucinations.

61. Question
Benzodiazepines are thought to cause sedative and/or anxiolytic effects by
A. increasing functional activity at GABAB receptors
B. enhancing the actions of dopamine
C. blocking the NMDA glutamate receptor subtype
D. acting as a partial agonist at 5HT receptors
E. facilitating GABA-mediated increases in chloride ion conductance