Central nervous system, Drugs acting on CNS- General anaesthetics, sedatives, and hypnotics, antimanic, antidepression, antiepileptic,

2. DRUGS ACTING
ON
CENTRAL NERVOUS
SYSTEM
Vaheeda rahman, (PhD),
Dept of pharmacology,

3.  Central nervous system :
• Brain
• Brain stem
• Spinal cord

5. GENERAL
ANAESTHETICS

6. INTRODUCTION
DEFINITION:
 General anaesthetics: These are drugs which produce
reversible loss of all sensations
and consciousness.
Anaesthesia means:
an- without
aesthesis- sensation

7. HISTORY
Alcohol, opium
Nitrous oxide
Ether
Chloroform
Cyclopropane
Thiopentone
Halothane
1844
1846
1847
1929
1956
1935
19th
century

8. MECHANISM
 LIPID THEORY:

9.  EFFECTS ON ION CHANNELS:

10. STAGES OF ANAESTHESI
 stage of analgesia
 stage of delirium/excitement
 stage of surgical anaesthesia
 stage of medullary paralysis

11. PROPERTIES OF AN IDEAL ANA

12. TECHNIQUES OF INHALATION O
 Open drop method
 Through anaesthetic machines
a.Open system
b.Closed system
c.Semi closed system

13. CLASSIFICATION
General
anaesthetics
Inhalation
Gases
Volatile
Liquid
Intra venous
Inducing
agents
Slower
acting drugs
Balanced anaesthesia (both inhalational and i.v )

14.  GASES: Nitrous oxide
 VOLATILE LIQUIDS: Ether
Halothane
Enflurane
Isoflurane
Desflurane
Sevoflurane
 INDUCING AGENTS: Thiopentone sodium
Methohexitone sodium
Propofol
Etomidate
 SLOWER ACTING DRUGS:
 BENZODIAZEPINES: Diazepam
Lorazepam
Midazolam
 DISSOCIATIVE ANAESTHESIA: Ketamine
 OPIOID ANALGESIA: Fentanyl

15. INHALATIONAL GENERAL ANA
GASEOUS:
NITROUS OXIDE:
Pharmacokinetics:
• Onset of action ------- quick and smooth
•Metabolism ------ does not occur
• Excretion ------ quickly removed by lungs
• MAC ------ 105%
•Recovery ------- rapid
• Second gas effect and diffusion hypoxia occurs
• Dose ------- 70% Nitrous oxide, 25-30% of oxygen,
0.2-2% another potent drug
Advantages:
•Cheap and very commonly used
• Non toxic to lever, kidney, brain
Uses:
• Nitrous oxide(50%) along with oxygen
can be used for obstetric and dental

16. VOLATILE LIQUIDS:
ETHER: (DIETHYL ETHER)
Pharmacokinetics:
• Induction is prolonged and unpleasant with struggling
• Recovery ------ slow
Mechanism:
• Reduces Ach output from motor nerve endings
Advantages:
•Potent drug, produce good analgesia
•Still using in developing countries because it is cheap
• Can be given by open drop method
Adverse effects:
• Post anaesthetic vomit and nausea
•Breath holding, salivation and marked respiratory secretions
•Premedication atropine given

17. HALOTHANE(FLUOTHANE) :
Pharmacokinetics:
•Induction ------ reasonably quite and pleasant
•Metabolism: 20% by liver, remaining exhaled out
• Elimination: 24-48 hrs after prolonged administration
• Recovery: smooth and reasonably quick
• Dose :------ for induction --- 2-4%
for maintenance --- 0.5-1%
•causes direct depression of myocardial contractility by reducing
intracellular calcium concentration and sympathetic activity fails to increase
Adverse effects:
•Malignant hyperthermia
• Metabolite of halothane causes chemical and immunological injury
• Repeated use causes hepatitis(1 in 10,000)
• Cardiac output is reduced with deep anaesthesia
• BP falls
• Vascular bed dilates
• Heart rate reduces, tachyarrhythmia occurs
• Greater depression of respiration, breathing shallow

18. INTRAVENOUS GENERAL
ANAESTHETICSINDUCING AGENTS
THIOPENTONE SODIUM:
• Derivative of thiobarbiturate (ultra short acting)
Pharmacokinetics:
• Highly soluble in water
•Distribution: depends on organ blood flow (brain gets large amount)
•Metabolism: hepatic
• Elimination t1/2 is 7-12 hrs
•Dose: injected I.V (3-5mg/kg) as 2.5%solution
• Must prepare freshly before injection
Pharmacology:
•Produce unconsciousness in 15-20 seconds
•Consciousness is regained in 6-10 min
• t1/2 of distribution phase is 3min
Adverse effects:
•laryngospasm is a main adverse effect
• Recovery with shivering and delirium
• Other uses: control of convulsions

19. PROPOFOL:
Pharmacokinetics:
• I.V given for both induction and maintenance
• Distribution t1/2 2-4 minutes(rapidly)
• Elimination t1/2 (100 min) shorter than thiopentone due to rapid metabolism
• Unconsciousness occurs 15-45 seconds and lasts 5-10 min
• Suitable for outpatient surgery
Advantages:
• Post operative nausea and vomiting –low
• Patient acceptability is very good
Adverse effects:
• Excitatory effects and involuntary movements noted for some patients
• Fall in BP- due to vasodilation
• Bradicardia is frequent
• Dose dependent respiratory depression
• Pain during injection is also frequent- can be
minimized by combining with lidocaine
• Dose: 2mg/kg i.v bolus --- for induction
9mg/kg/hr -----------for maintenance

20. SLOWER ACTING DRUGS
BENZODIAZEPINES:
Pharmacokinetics:
• Distribution: t1/2 of diazepam is 15 min
•This is a premedication product
• Now frequently using for inducing, maintenance, and
supplement anaesthesia as well as conscious sedation
• Dose: 0.2-0.3mg/kg or equivalent diazepam
•Unconsciousness in 5-10 min
• Amnesia persists------ 2-3 hrs
• Sedation persists------ 6hrs or more
•Post operative nausea and vomiting is absence
Adverse effects:
• Injected i.v produce sedation and amnesia
• If large doses given recovery delays
• BZD’s are poor analgesics
• An opioid or nitrous oxide is added if produced pain
• Involuntary movements are not stimulated
• Requires neuromuscular blockers
• Uses: now preferred for endoscopies, angiographies, fracture setting etc

21. COMPLICATIONS OF
GENERAL ANAESTHESIA
• Respiratory depression
• Cardiac arrhythmias, asystole, fall in BP
• Aspiration of gastric contents
• Laryngospasm and asphyxia
• Fire and explosion (rare)
• Delirium, convulsions, excitatory effects
• Recall of events during surgery
During
anaesthesia
• Nausea and vomiting
• Persisting sedation
• Pneumonia, atelectasis
• Organ toxicities
• Nerve palsies
• Emergency delirium
• Cognitive defects
After
anaesthesia

22. DRUG
INTERACTIO
NS
• Antihypertensive's-general anaesthetics: BP fall
• Corticosteroid-anaesthetics: cardiovascular collapse
Treatment: give 100mg of hydrocortisone
• Insulin need of a diabetic is increased
during general anaesthetics
• Neuroleptics, opioids, clonidine and
monoamine oxidase inhibitors potentiate
anaesthetic effect
• Halothane sensitizes heart to Adr

23. PREANAESTHETIC
MEDICATION Preanaesthesia: agents which show synergic effect on the
anaesthetic drugs
 Advantages of preanaesthetics:
 Decrease acidity and volume of gastric juice: less damages if aspirated
 Anti emetic effect extending to the postoperative period
 Decrease secretions and vagal stimulation
 Supplement analgesic action of anaesthetics and potentiate them: less
anaesthetic is needed
 Amnesia for pre and postoperative events
 Relief of anxiety and apprehension preoperatively
and to facilitate smooth induction

24.  Examples:
 Sedatives-anti anxiety drugs
 Opioids
 Anticholinergics
 Neuroleptics
 H2 blockers
 Antiemetics

25. SEDATIVES
AND
HYPNOTICS

26. INTRODUCTION
DEFINITION:
 SEDATIVE: drug that subdues excitement and calms
the subject without inducing sleep
 HYPNOTIC: drug that induces and/or maintains sleep,
similar to normal arousable sleep
Sedative
Hypnotic
General
anaesthesia

27. STAGES OF SLEEP
 Stage 0 (awake)
 Stage 1 (dozing)
 Stage 2 (unequivocal sleep)
 Stage 3 (deep sleep transition)
 Stage 4 (cerebral sleep)
 REM sleep (paradoxical sleep)

28. CLASSIFICATION

29.  Barbiturates:
• Long acting: phenobarbitone
• Short acting: Butobarbitone,
Pentobarbitone
• Ultra short acting: Thiopentone,
Methohexitone
 Benzodiazepines:
• Hypnotic: Diazepam
Flurazepam
Nitrazepam
Alprazolam
Temazepam
Triazolam
• Antianxiety: Diazepam
Chlordiazepoxide
Oxazepam
Lorazepam
Alprazolam
• Anticonvulsant: Diazepam
Lorazepam
Clonazepam
Clobazam

30. BARBITURATES:
 PHARMACOKINETICS:
 Well absorbed from g.i. tract
 Widely distributed in body
 Rate of entry into CNS is dependent on lipid solubility
 High lipid soluble has instantaneous entry
 Less lipid soluble takes longer and enters very slowly
 REDISTRIBUTION: its imp in case of highly lipid soluble
 After i.v injection consciousness is regained in 6-10 min due to redistribution
 Ultimate disposal occurs by metabolism
 t1/2 of elimination phase is 9 hours
 METABOLISM: intermediate lipid solubility
 primarily metabolized in liver by oxidation,
dealkylation, and conjugation
 plasma t1/2 12-40 hrs
 EXCRETION: low lipid solubility
 excreted unchanged in urine
 t1/2 of phenobarbitone is 80-120 hrs

31.  PHARMACOLOGY:
 CNS:
 Barbiturates produce dose dependent effects
 Sedation Sleep Anaesthesia Coma
 HYPNOTIC DOSE: (100-200mg of short acting barbiturates)
 Shorten time taken to fall sleep & increase sleep duration
 Sleep arousable, but subject may feel confused & unsteady if waken early
 Night awakening are reduced
 REM and 3,4 sleep decreased
 REM –NREM sleep cycle disrupted
 Effect of sleep progressively reduces if taken every night
 When drug is discontinued rebound increase in REM sleep and night mares
 Takes several days for normal pattern restore
 After a night dose hang over may occur
 SEDATIVE: (smaller dose of long acting barbiturates)
 Given at day time can produce drowsiness, reduction in anxiety & excitement
 They have no analgesic action
 Smaller dose may even cause hyperalgesia
 Barbiturates have anticonvulsant activity
 Barbiturates depress all areas of CNS

32.  OTHER SYSTEMS:
 RESPIRATION: depressed by relatively higher doses
 Neurogenic, respiratory centers depressed
 Barbiturates donot have selective antitussive actions
 CVS: decrease in BP & heart rate
 Toxic doses produce marked fall in BP due to ganglionic blockade,
vasomotor centre depression and direct decrease in cardiac contractility
 Reflex tachycardia can occur,
 Dose producing cardiac arrest is about 3 times larger than that causing
respiratory failure
 SKELETAL MUSCLE: Anaesthetic doses reduce muscle contraction
 SMOOTH MUSCLES: Hypnotic dose- tone and motility of bowel reduced
 Action on bronchial, and uterine muscles is not significant
 KIDNEY: Reduce urine flow by decrease BP
and increase ADH release

33.  USES:
 Enzyme inducing property of phenobarbitone can be utilized to
clearance of congenital nonhaemolytic jaundice
 adjuvant in psychosomatic disorders
 ADVERSE EFFECTS:
 SIDE EFFECTS: hang over, mental confusion, traffic accidents
 IDIOSYNCRASY: excitement
 HYPERSENSITIVITY: Rashes, Swelling of eyelids, lips
 TOLERENCE AND DEPENDENCE: Tolerance due to repeated use
Withdrawal symptoms are – excitement , hallucinations, delirium
convulsions, and death
 ACUTE BARBITURATE POISONING: patient will be flabby,
comatose with shallow and failing respiration
fall in BP and cardiovascular collapse
renal shut down, pulmonary complications
Lethal dose depends on lipid solubility
it is 2-3g for more lipid soluble agents
5-10g for less lipid soluble agents
TREATMENT: gastric lavage, alkaline diuresis, haemodialysis etc

34.  DRUG INTERACTIONS:
 Barbiturates - warfarin, tolbutamide, griseofulvin etc: induce metabolism
and
reduce their effectiveness
 Sodium valproate – phenobarbitone: increase plasma concentration
 Phenobarbitone – phenytoin and imipramine: competitively inhibits and
induces metabolism
 Phenobarbitone – griseofulvin: decreases absorption from g.i.t

35. ANTI-
EPILEPTIC
DRUGS

36. INTRODUCTION
DEFINITION:
 EPILEPSY: group of disorders of CNS characterized by
paroxysmal cerebral dysrhythmia, manifesting as brief
episodes(seizures) of loss or disturbances of consciousness
with/without characterized body movements(convulsions)
sensory or psychiatric phenomena
 ANTIEPILEPTICS: drugs which reduces
epilepsy (mainly seizures) in
human body

37. TYPES OF SEIZURES
GTCS
Absence
seizures
Atonic
seizures
Myoclonic
seizures
Infantile
spasms
Generalized
seizures SPS
CPS
SPS/CPS
Partial
seizures

38. CLASSIFICATION
• Barbiturates
• Deoxybarbiturates
• Hydantoin
• Iminostilbene
• Succinamides
• Aliphatic carboxylic
acid
• Benzodiazepines
• Phenyltriazine
• Cyclic GABA analogue
• Newer drugs
• Prolongation of sod
channel inactivation
• Facilitation of GABA
mediated chlorine
channel opening
• Inhibition of T type
calcium current
Based
on
chemical
structure
Based
on
mechanism
of action

39. • Barbiturates: phenobarbitone
• Deoxybarbiturates: primidone
• Hydantoin: phenytoin, fosphenytoin
• Iminostilbene: carbamazepine, oxcarbazepine
• Succinamides: ethosuximide
• Aliphatic carboxylic acid: valproic acid, divalproex
• Benzodiazepines: clonazepam, diazepam, lorazepam
• Phenyl triazine: lomatrigine
• Cyclic GABA analogue: gabapentin
• Newer drugs: vigabatrin, topiramate,
tiagabine, zonisamide,
BASED ON CHEMICAL NATURE:

40. BASED ON MECHANISM OF ACTION:
 Prolongation of sod channel inactivation:
• Phenytoin
• Carbamazepine
• Valproate
• Lomatrigine
• Topiramate
• Zonisamide
 Facilitation of GABA mediated chlorine channel opening:
• Barbiturate
• Benzodiazepine
• Vigabatrin
• Valproate
• Gabapentine
• Tiagabine
 Inhibition of T type calcium current:
• Ethosuximide
• Trimethadione
• Valproate

41. PHENYTOIN
 PHARMACOKINETICS:
 Absorption:
• oral route
• 80-90% bound to plasma protein
 Metabolism:
• Hepatic
• t1/2 is 12-24 hrs
 Excretion:
• 5% unchanged in urine

42.  PHARMACOLOGY:
 Mechanism:
•Therapeutic level:
• Prolongation of sodium channel inactivation
•At high concentration:
•Reduction in calcium influx
•Inhibition of glutamate and facilitation of GABA responses
Action of phenytoin:
• On Tonic clonic epilepsy

43.  ADVERSE EFFECTS:
 At therapeutic level:
• Hypersensitivity
• Megaloblastic anemia
• Osteomalacia
• Hyperglycemia
• Foetal hydantoin syndrome
• Hirsutism
• Gum hypertrophy
 At high plasma levels:
• Fall in BP, cardiac arrhythmias---when i.v injected
• Nausea, vomiting
• Drowsiness, hallucination, mental confusion

44. Anti-
parkinsonian
drugs

45. INTRODUCTION
DEFINITION:
 Parkinsonism: A group of neurological disorders marked by
hypokinesia, tremor, muscular rigidity
 Antiparkinsonians: Drugs that have a therapeutic effect
in parkinsonism

46. CLASSIFICATION
Drugs effecting brain dopaminergic system
• Dopamine precursor: LEVODOPA
• Peripheral decarboxylase inhibitors: CARBIDOPA
• Dopaminergic: BROMOCRIPTINE
• MAO-B inhibitors: SELEGILINE
• COMT inhibitors: ENTACAPONE
• Dopamine facilitator: AMANTADINE
Drugs effecting brain cholinergic system
• Central anticholinergics: PROCYCLIDINE
• Antihistamines: PROMETHAZINE

47. LEVODOPA
 PHARMACOKINETICS:
 Absorption:
• Small intestine
• Bioavailability: Gastric emptying
Amino acids present in food
 Metabolism:
• First pass metabolism
• Plasma t1/2 of levodopa is 1-2 hrs
 Excretion: through urine

48.  PHARMACOLOGY:
 CNS:
• Hypokinesia and rigidity resolved first later tremor
•D1 like (D1, D5): excitatory
• D2 like (D2, D3, D4): inhibitory
 CVS:
• Tachycardia
 CTZ:
• Nausea and vomiting
 ENDOCRINE:
• Inhibit prolactin release

49.  ADVERSE EFFECTS
 At initiation of therapy:
• Nausea and vomiting
• Postural hypotension
• Cardiac arrhythmias
• Exacerbation of angina
• Alteration in taste sensation
 After prolonged therapy:
• Abnormal movements
• Behavioral effects
• Fluctuation in motor performance

50.  INTERACTIONS:
 antihypertensives – levodopa
 Non selective MAO inhibitors – levodopa
Atropine and anticholinergic – levodopa
 Pyridoxine - levodopa

51. ANTI-
PSYCHOTIC
DRUGS

52. INTRODUCTION
DEFINITION:
 Psychosis: A severe mental disorder in which thought
and emotions are so impaired that contact is
lost with external reality
 Antipsychotics: class of medicines used
to treat psychosis and other
mental and emotional conditions

53. • Aliphatic side chain: CHLORPROMAZINE
• Piperidine side chain: THIORIDAZINE
• Piperazine side chain: TRIFLUOPERAZINE
Phenothiazines
• HALOPERIDOL
• PENFLURIDOLButyrophenones
• FLUPENTHIXOLThioxanthenes
• LOXAPINE
• PIMOZIDE
Other
heterocyclic's
• CLOZAPINE
• OLANZAPINE
• ZIPRASIDONE
Atypical
antipsychotics
CLASSIFICATION

54. neuroleptics
CHLORPROMAZINE
 PHARMACOKINETICS:
 Absorption:
• Oral
• Highly bound to plasma and tissue proteins
 Metabolized:
• Liver metabolism
• By CYP 2D6
 Elimination:
• t1/2 is variable and 18-30 hrs

55.  PHARMACOLOGY:
 CNS
• In normal individuals:
• Psychomotor slowing
• Emotional quietening
• In psychotic patients:
• Anxiety is relieved
• Hyperactivity, hallucinations, and
delusions are suppressed
• Chlorpromazine lowers seizures &
can precipitates
fits in untreated epilepsy

56.  MECHANISM OF ACTION:

57.  LOCAL ANAESTHETICS:
• Potent as procaine but not used because of irritant action
 CVS:
• Hypotension
 SKELETAL MUSCLE:
• No effect
 ENDOCRINE:
• Increase prolactin results in gynaecomastia & galactorrhoea
• Reduce gonadotropin secretions
• Decreased in ADH release– more urine

58. Anti manic drugs
Antimanic drugs: mood stabilizers
Example: lithium carbonate
hallucinogens
Indole amines
cannabinoids

59. ANTI-
DEPRESSANT
DRUGS

60. INTRODUCTION
DEFINITION:
 Depression: state of low mood and aversion to activity
that can have a negative effect on a person’s thought
behavior, feelings, world view and physical well being
 Antidepressants: drugs which have the
effect on depression/
drugs for the treatment of depression

61. CLASSIFICATION
RIMAs
• Moclobemide
• Clorgyline
TCAs
• NA+5-HT reuptake inhibitors: Imipramine, doxepin
• Predominantly NA reuptake inhibitors: Amoxapine
SSRIs
• paroxetine
• Fluoxetine
Atypical
• Amineptine
• Trazodone

62. Tricyclic antidepressants
 PHARMACOKINETICS:
 Absorption:
• Oral
• Highly bound to plasma and tissue proteins
 Metabolism:
• Liver
 Excretion:
• Through urine over 1-2 weeks

63.  PHARMACOLOGY:
 CNS:
• In normal individuals:
• Peculiar clumsy feeling
• Tiredness, light headache, sleepiness, difficulty in thinking
• In depressed patients:
• Mood is gradually elevated
• Patient become more communicative
• Produce convulsions on over dose

64. MECHANISM OF ACTION:
Inhibition of nerve terminal NE neuronal uptake system
Increase in synaptic concentrations of NE
Desensitization of nerve terminal 2-adrenoceptors
Increase in neuronal NE release
Further increase in synaptic concentrations of NE
Desensitization of postsynaptic -adrenoceptors with no
change in postsynaptic 1-adrenoceptor sensitivity

65. Mechanism of action

66.  ANS:
• Dry mouth, blurring of vision
• Constipation, urinary hesitancy
 CVS:
• Tachycardia
• Postural hypotension
• ECG changes and cardiac arrhythmias

67.  ADVERSE EFFECTS:
• Sweating and fine tremors
•Postural hypotension
• Sedation, mental confusion and weakness
• Increased appetite and weight gain
• Seizures threshold is lowered
• Cardiac arrhythmias especially in ischemic heart disease
• Rashes and jaundice due to hypersensitivity
• Anticholinergic: dry mouth, bad taste epigastric distress
• Acute poisoning

68.  INTERACTIONS:
• Phenytoin, phenylbutazone, aspirin, and CPZ – TCAs
• Phenobarbitone – imipramine
• TCAs – CNS depressants
• MAO inhibitors - TCAs

69. ANTIANXIETY DRUGS
 Anxiety: it is an emotional state, unpleasant, uneasiness,
discomfort, and concern or fear about some defined
or undefined future threats
 Antianxiety: drugs which are aimed to control the symptoms
of anxiety
Classification:
Benzodiazepines: Diazepam
Chlordiazepoxide
Oxazepam
Azapirones: Gepirone
Ispapirone
Sedative antihistaminic: Hydroxyzine
Beta blockers: Propranolol

70. REFERENCES
 Essentials of MEDICAL PHARMACOLOGY: KD Tripathi
 RANG and DALE’S pharmacology
 BASIC AND CLINICAL PHARMACOLOGY –LANGE
 modern pharmacology with clinical applications –
Lippincott
 www.doctors.ac.in
 www.wikipedia.org
 www.surgeryencyclopedia.com