(central nervous system)CNS Pharmacology new (1).pdf

Teaching material for pharmacy students

1. Drug Acting On Central
Nervous System
8/13/2025
1

2. 8/13/2025
2

3. Parts of the Brain

8/13/2025
3
 Cerebral cortex – the thinking part
 Diencephalon – Thalamus & Hypothalamus
 Brain stem – mid brain, pons & Medulla
 Cerebellum – mainly coordinates balance
 Limbic system
 Hypocampus
 Amigdaloid complex
 Basal ganglia
 Reticular activating system

4. What is the Central Nervous System?

8/13/2025
4
Brain and spinal cord
 Controls body functions
 Processes information
 Coordinates activity

5. Cont…
8/13/2025
5
Brain
Brain is sensitive structure & protected by Blood
Brain Barrier (BBB)
Creates a more stable, nearly pathogen-free
environment
 Oxygen, glucose & other small non-polar
molecules can cross the barrier
 BBB is the major challenge for drug delivery to
brain

6. Cont…
8/13/2025
6
BBB composed of
 Tight endothelial junction
 Astrocytes
 Highly polar compounds do not enter CNS

7. Cont…
8/13/2025
7
Spinal cord
is essential for communication between brain and
body
 Coordinates reflexes,
 Motor Control
 Sensory Information Transmission

8. Functions of CNS
8/13/2025
8
Thinking, memory, emotions
 Movement control
 Sensory data processing
 Maintaining homeostasis

9. Receptors in the CNS

8/13/2025
9
 Kinase linked receptors :
Eg. cytokine, insulin Rs
 Nuclear receptors
Eg. Steroid R
 Channels
Voltage gated channels (metabotropic) -
GPCRs
Eg. Muscarnic Ach R
 Ligand gated channels (ionotropic)
Eg. Nicotinic Ach, GABAA Rs

10. CNS pathways

8/13/2025
10
A . Excitatory Pathways
1.Opening of Na channels (influx of Na+ )
2. Depressed Cl- influx or K+ efflux or both
3.Changes in internal metabolism of the
postsynaptic neuron to excite cell activity by
by increasing excitatory membrane receptors or
 decrease inhibitory membrane receptors

11. CNS pathways…
8/13/2025
11
B . Inhibitory Pathways
1. Opening of Cl- channels (Influx of Cl- ion )
2. Increase conductance of K+ ions (efflux of
K+)
3. Activation of enzymes which inhibit cellular
metabolic functions & increase inhibitory
synaptic receptors or decrease excitatory
receptors

12. CNS pathways…
8/13/2025
12

13. CNS pathways…
8/13/2025
13
Excitatory neurons – EPSP-increases the
probability of generating an action potential.
 Inhibitory neurons – IPSP-decrease the
probability of generating an action potential.
 There is always interaction b/n these neurons
 The level of electrical activities determine the
state of the patient - seizure, anxiety, …..…..etc

14. CNS pathways…
8/13/2025
14
The basic processes of synaptic transmission
in the CNS are essentially similar to those
operating in the periphery.
 The release of neurotransmitters (NTs) &
receptor binding
 Recognition of the NT by membrane receptors
triggers IC changes
 NT release regulation (presynaptic receptors);

15. CNS pathways…
8/13/2025
15
But major differences are;
 More than 10 NT in the CNS
There are inhibitory and excitatory NT in the CNS
CNS is much more complex than PNS

16. NTs in the CNS

8/13/2025
16
 Can be inhibitory or excitatory
Inhibitory: GABA, Glycine
Excitatory: Glutamate, Aspartate, Ach, NE, DA, 5-
HT
Others
 Neuro-peptides (e.g. sub-P, enkephalins)
 Purine nucleotides (adenosine, ATP)

17. Common CNS disorders

8/13/2025
17
 Sleep disorder (Insomnia, narcolepsy, apnea,…..)
 Anxiety
 Psychosis
 Depression
 Manic depressive disorder
 Eating disorder
 Neurodegenerative diseases
 Eplepsy
 Substance abuse disorders
 Pain (migraine, )

18. Classification of drugs acting on
CNS

8/13/2025
18
 Sedative - hypnotics
 Anti Epileptics
 Anti PD
 Antipsychotics /Neuroleptics
 Anesthetics (local & General)
 Antidepressants
 Analgesics

19. Sedative-Hypnotics
8/13/2025
19

20. Sedative-Hypnotics…
8/13/2025
20
 A sedative( anxiolytic) drug decreases
activity, moderates excitement, and calms the
recipient, whereas
 A hypnotic drug produces drowsiness and
facilitates the onset and maintenance of a
state of sleep that resembles natural sleep and
from which the recipient can be aroused
easily.

21. Sedative-Hypnotics…
8/13/2025
21
A. Effective sedative
 Reduces anxiety without inducing sleep
 Slight decrease on motor activity
 CNS depression should be minimal
 Quicker onset, shorter duration, steeper dose
response curve

22. Sedative-Hypnotics…
8/13/2025
22
B. Effective Hypnotic
 produce drowsiness
 encourage the onset and maintenance of a state
of sleep pronounced depression of CNS
 Graded dose-dependent depression of CNS
function is a characteristic of most sedative-
hypnotics

23. Sedative-Hypnotics…
8/13/2025
23
Hypnotics
at lower dose may act as sedative
and
at higher dose can produce general
anesthesia

24. Sedative-Hypnotics…
8/13/2025
24

25. Classification of sedative-hypnotics

8/13/2025
25
1. Barbiturates (ultra, short and long
action)
2. Benzodiazepines (short, intermediate
& long)
3. New sedative/hypnotics
4. Other drugs

26. Barbiturates

8/13/2025
26
 Potentiate GABA action on chloride entry into
the neuron by prolonging the duration of
the chloride channel openings
 Classified by duration of action
 Ultra short-acting (Thiopental Na) =<20 min
duration
 Short-acting (Secobarbital, pentobarbital) - 3 - 4
hrs

27. Barbiturates…
8/13/2025
27
Intermediate-acting (Amobarbital, aprobarbital &
butabarbital) - 6- 8 hrs
 Long-acting (Phenobarbital, mephobarbital) - 10
- 16 hrs

28. Barbiturates…

8/13/2025
28
Large doses result in death b/c of respiratory
&CVS depression
 They are no longer or rarely used as
sedative hypnotics
Due to their narrower margin of safety (risk of
misuse for suicide) & their potential to produce
physical dependence
 May be used in anesthesia & treatment of
epilepsy

29. Barbiturates action
8/13/2025
29
MoA
 Facilitate the actions of GABA
 At high concentrations, the barbiturates may
also be GABA-mimetic and inhibit excitatory
neurotransmission
Benzodiazepines ↑ frequency and
barbiturates↑ duration of GABA mediated Cl-
channel oppening

30. Therapeutic uses

8/13/2025
30
 Anesthesia: Thiopental are used IV
 Anticonvulsant: Phenobarbital
 Tonic-clonic seizures, status epilepticus, and
eclampsia
 DOC for treatment of young children with
recurrent febrile seizures
 Can depress cognitive performance in children -
cautiously

31. Adverse effects
Drowsiness,
impaired
concentration, mental
and physical
sluggishness
Drug hangover,
nausea,
dizziness
 Physical dependence:
Abrupt withdrawal cause
tremors,
anxiety,
weakness,
restlessness,
nausea and vomiting,
seizures,
delirium,
cardiac arrest

8/13/2025
31

32. Benzodiazepines

8/13/2025
32
 Potentiate effect of GABA by ↑ the
frequency of Cl channel opening
 Classifications
 Short acting agents - Triazolam
 Intermediate acting agents - Alprazolam,
Lorazepam,Oxazepam,Temazepam,Chlordiazepoxi
de
 Long acting agents - Diazepam, Flurazepam

33. Benzodiazepines action

8/13/2025
33
MoA BZDs
 Act selectively on GABAA receptor
 Bind to regulatory site of the receptor
Enhance the response to GABA and
facilitate the opening of GABA activated
chloride channel

34. Benzodiazepines action…
8/13/2025
34
Anticonvulsant: Several of the
benzodiazepines
 Some are used to treat status epilepticus and
other seizure disorders
 Muscle relaxant: At high doses

35. Benzodiazepines action…
8/13/2025
35
Benzodiazepines
 Gained popularity over barbiturates because
BZPs have a high therapeutic index
Hypnotic doses do not affect respiration & CVS
functions
 slight effect on rapid eye movement phase of
sleep, hence there is no hangover

36. Benzodiazepines action…
8/13/2025
36
Produce less physical dependence
 do not alter the disposition of other drugs by
microsomal enzyme induction
Presence of BZD antagonist (flumazenil) as
antidote

37. Therapeutic uses

8/13/2025
37
 Anxiety disorders
 Muscular disorders: Muscle spasms -
Diazepam
 Amnesia – Short acting ones
 Seizures – Clonazepam, diazepam and
lorazepam
 Sleep disorders – Flurazepam, temazepam,
triazolam

38. Adverse effects

8/13/2025
38
Drowsiness,
confusion,
ataxia,
cognitive impairment,
tolerance,
dependence (Psychological and physical
dependence) and
withdrawal symptoms

39. Precautions

8/13/2025
39
 Avoid in pregnancy
 Liver disease, acute narrow-angle glaucoma.
 Alcohol and other CNS depressants
 Less dangerous than older anxiolytic and
hypnotic drugs

40. BZD antagonist / flumazenil

8/13/2025
40
 Anxiogenic and proconvulsant
Use
In case of BZD over dosage (if only respiration
severely depressed)
 also blocks effect of zolpidem, zeleplon (hypnotic
acts similarly to BZDs) but more dose is required
(5mg)
 To reverse BZD anaesthesia and allows early
discharge of patients and easy for post anesthetic
management

41. BZD antagonist / flumazenil…
8/13/2025
41
Flumazenil has fast on set (secs) and short
duration of action (1-2 hrs)
 BZDs have longer duration of action
 Therefore, repeated administration of
flumazenil is needed

42. Newer sedative hypnotics

8/13/2025
42
 Non BZD sedatives: agonist for a subtype of
BZD receptor
 Zopicolone, eszopiclone, Zolpidem & Zaleplon,
 Ramelteon, a melatonin receptor agonist
 Buspirone

43. Newer sedative hypnotics…
8/13/2025
43
Benzodiazepine – like drugs
 zolpidem, zaleplon, and eszopiclone
 not benzodiazepines but appear to exert their
CNS effects via interaction with certain
benzodiazepine receptors,
 In contrast to BZPs, these drugs bind more
selectively, interacting only with GABAA receptor
 Their CNS depressant effects can be antagonized
by flumazenil.

44. Other drugs that induce sedation

8/13/2025
44
 Antihistaminics(promethazine diphenhydramaine)
Neuroleptics/antidepressant(chlorpromazine,amitrylin)
 Opoids (morphine, pethidine)
They have significant sedation effect but not reliable for
treatment of insominia

45. Other drugs that induce sedation…
8/13/2025
45
β-adrenoceptor antagonists (e.g. propranolol)
to treat some forms of anxiety (for physical
symptoms such as sweating, tremor and
tachycardia)
 block of peripheral sympathetic responses
 actors and musicians to reduce the symptoms of
stage fright’
 Propranolol produces insomnia as a side effect

46. 8/13/2025
46



ANTIPARKINSONIAN DRUGS

47. Common neurodegenerative
conditions

8/13/2025
47
Parkinson’s disease (PD)
 Alzheimer's disease (AD)
 Huntington's disease (HD)
 Ischaemic brain damage (stroke)
The disorders are characterized by progressive &
irreversible loss of neurons from specific regions of
the brain

48. Etiology
8/13/2025
48
Factors that may contribute for the
pathogenesis of neurodegenerative disorders
Genetics factors
Environmental Triggers
Infectious agents & environmental toxins
Excitotoxicity
Neural injury that results from the presence of excess
glutamate in the brain
Aging
Oxidative stress

49. Parkinson’s disease (PD)

8/13/2025
49
is disorder of mov’t that occurs mainly in the
elderly
 Occurs for a variety of possible reasons
 Exposure to certain toxins (manganese dust,)
 Drug induced parkinsonism : reserpine,
chlorpromazine, haloperidol & other
antipsychotics that block D2
 Post encephalitic parkinsonism : after viral
infection
 Idiopathic parkinsonism : unknown cause

50. Pathophysiology of PD
8/13/2025
50
The basal ganglia are responsible for controlling
automatic movements of the body by the action
of dopamine (DA)
 Degeneration of basal ganglia in the deeper grey
matter of the brain (substantia nigra) causes
PD.
 DA level in the brain’s substantia nigra normally
fall with ageing
 The level has to fall to one-fifth of normal values
for signs of PD to emerge
 In PD, there is extensive destruction of
dopaminergic neurons of SN (DA deficiency)

51. Pathophysiology of PD…
8/13/2025
51

52. Strategy of Treatment

8/13/2025
52
 Symptoms of Parkinson's reflect
 imbalance b/n the excitatory cholinergic neuron
& the greatly diminished number of inhibitory
dopaminergicneurons.
 Therapy is aimed
 to restore the dopamine in the basal ganglia &
antagonizing the excitatory effects of cholinergic
neurons.
 Thus re-establishing the correct dopamine and -
Ach balance.

53. Cardinal Features

8/13/2025
53
Brady kinesis(slowness in initiating & carrying out
voluntary mov’t)
Muscular rigidity
Resting tremor
Impaired postural balance

54. 8/13/2025
54

55. Overview of Drug Therapy

8/13/2025
55
Therapeutic Goal
To improve ability for activities of daily life (only
symptom relief)
Treatment Strategy
Restore balance between DA and ACh by
activating DA receptors or blocking ACh receptors
Overview of Drugs Employe
Two major categories (dopaminergic &
anticholinergic drugs).

56. Classification of drugs

8/13/2025
56
1. Drugs affecting brain dopaminergic system
a. Dopamine precursors: levodopa
b. Peripheral decarboxylase inhibitors: carbidopa &
benserazide
c. Dopaminergic agonists: bromocriptine, lisuride,
pergolide, ropinirole, cabergoline & pramipexole
d. MAO-B inhibitors : Selegiline
e. COMT inhibitors: Entacapone, tolcapone
f. Dopamine facilitator : Amantidine

57. Classification of drugs…
8/13/2025
57
2. Drugs affecting brain cholinergic system
a. Anticholinergcs: Benzatropine, Trihexyphenidyl
(benzhexol), Procyclidine, biperiden
b. Antihistaminics: promethazine
3. Neural transplantation (on experimental
phase)

58. Levodopa (L-DOPA)

8/13/2025
58
first-line treatment for PD
 is the immediate metabolic precursor of
dopamine
 Prodrug for DA
Levodopa can cross BBB while DA does not

59. Levodopa (L-DOPA)…

8/13/2025
59
Pharmacokinetics
 Levodopa is rapidly absorbed from the small
intestine
 Food delays absorption of the drug
 should be taken 30–60 minutes before meals
 More than 95% of oral dose is decarbxylated in
periphery tissue mainly in gut & liver
 DA in periphery thus acts on peripheral organs & may
cause unwanted effects. It also acts on CTZ
 Therefore, peripheral dopa decarboxylase
inhibitor (carbidopa or benserazide) reduce
Levodopa metabolism in periphery

60. Levodopa (L-DOPA)…
8/13/2025
60

61. Levodopa (L-DOPA)…
8/13/2025
61
Pharmacodynamics
The benefits of levodopa treatment begin to
diminish after about 3 or 4 years of therapy
regardless of the initial therapeutic response.
 Initial effective doses may fail to produce
therapeutic benefit & responsiveness to levodopa
may be lost completely. Possibly due to
 The disappearance of dopaminergic nigrostriatal
nerve (disease progresses beyond ability of L-dopa to
control it.)
 Some pathologic process directly involving the striatal
dopamine receptors like tolerance.

62. Levodopa (L-DOPA)…
8/13/2025
62
Early initiation lowers mortality rate but does
not stop the progression
 Long term therapy associated with number of
adverse effects
 The most appropriate time to introduce
levodopa therapy must be determined
individually

63. Levodopa (L-DOPA)…
8/13/2025
63
Two main adverse effects after prolonged
therapy
 Dyskinesia (involuntary writhing movements)
 Happened to 80% of patients receiving levodopa
therapy for long periods
 The margin between the beneficial & the dyskinetic
effect becomes progressively narrow
 On / off phenomenon
 Fluctuations in clinical response with increasing
frequency as treatment continues
 Patient's motor state may fluctuate dramatically with
each dose of levodopa

64. Levodopa (L-DOPA)…
8/13/2025
64
Strategies to manage On / off phenomenon
Infusion, sustained release, or multiple short
interval doses of L-Dopa
Add selegiline to prevent metabolism by MAOB.
Use receptor agonists

65. Levodopa (L-DOPA)…
8/13/2025
65
Other adverse effects
 Nausea & anorexia
 Occurs at initial therapy & tolerance gradually develops
(dose can be progressively increased )
 Antiemetics : domperidone (DA antagonist on CTZ )
 Postural hypotension, cardiac arrthymias &
excerbation of angina
 Due to β adrenergic action of peripherally formed DA
 More sever for patients with pre existing heart diseases
 Psychological effects: schizophrenia-like syndrome
 C/I to psychotic patients

66. Levodopa (L-DOPA)…
8/13/2025
66
Drug Interactions
 Pharmacologic doses of vit B6 enhance extracerebral
metabolism of levodopa as pyridoxine (vit B6) is
cofactor for DOPA decarboxylase
 Phenothiazines, butyrophenones & metoclopramide
block DA receptors
 Nonselective MAO inhibitors prevent degradation of
peripherally synthesized DA & NA --- hypertensive
crisis can occur
 Levodopa should not be given to patients taking
MAO- A inhibitors or within 2 weeks of their
discontinuance

67. Dopamine receptor agonists

8/13/2025
67
Unlike levodopa, DA receptor agonists
 Lower incidence of on /off phenomenon &
dyskinesias
 Do not require enzymatic conversion to active
metabolite
 No DA toxic metabolites
 Do not have oxidative stress induced
dopaminergic neural damage
 Selectively affect certain DA receptors

68. Dopamine receptor agonists…
8/13/2025
68
Used for patients who have largely lost the
capacity to synthesis, store & release
dopamine from levodopa
 Have longer duration of action than that of
levodopa
Act directly on postsynaptic DA receptor types
(primarily D2)
Effective as monotherapy or as adjuncts to
carbidopa /levodopa therapy

69. Dopamine receptor agonists…
8/13/2025
69
DA receptor agonists available for
treatment of PD
 Bromocriptine (Ergot derivative)
 Potent D2 agonist & partial D1 agonist
 High dose is needed if used alone
 Used only in late case as supplement to levodopa
 Also used for treatment of hyperprolactinemia
(reduce prolactine release) in lower doses than
for PD
 gynecomastia

70. Dopamine receptor agonists…
8/13/2025
70
Pergolide
 Ergot derivative
 Agonist of both classes (D1 & D2)
 More effective than bromocriptine in relieving the
symptoms & signs of PD
 Increase "on-time" among response fluctuators
 Allow the levodopa dose to be reduced

71. Dopamine receptor agonists…
8/13/2025
71
Pramipexole
 Nonergoline derivative
 Selective activity at D2 class (D2 & D3 receptors)
 little or no activity at D1
 Effective when used as monotherapy for mild
parkinsonism
 Also helpful in patients with advanced disease
 permitting dose of levodopa to be reduced &
smoothing out response fluctuations
 Scavenge hydrogen peroxide /neuroprotective
effect/

72. Dopamine receptor agonists…
8/13/2025
72
Ropinirole
 Nonergoline derivative
 Relatively pure D2 receptor agonist
 Effective as monotherapy in patients with mild
PD
 Used as a means to smoothen the response to
levodopa in patients with more advanced disease
& response fluctuations
 Metabolized by CYP1A2
 drugs metabolized by CYP1A2 may significantly
reduce clearance of ropinirole

73. Adverse effects of DA agonists

8/13/2025
73
GIT effects
 Anorexia , nausea & vomiting : can be minimized
by taking the medication with meals
 Constipation, dyspepsia, & symptoms of reflux
esophagitis may also occur
CVS effects
 Postural hypotension at the initiation of therapy
 Cardiac arrhythmias an indication for
discontinuing treatment
 Cardiac valvulopathy may occur with pergolide

74. Adverse effects of DA agonists…
8/13/2025
74
Dyskinesias
 Abnormal movements similar to those produced by
levodopa
 Can be reversed by reducing the total dose of the
drug
Mental disturbances
 Confusion, hallucinations, delusions & other
psychiatric reactions
 More common & severe with DA receptor agonists
than with levodopa
 They clear on withdrawal of the medication

75. C/I

8/13/2025
75
 DA agonists are C/I in patients with
 History of psychotic illness
 Recent myocardial infarction
 Active peptic ulceration
 Patients with peripheral vascular disease
should avoid taking ergot-derived agonists

76. MAO-B inhibitors

8/13/2025
76
MAO-B : The predominant form of MAO in the
striatum & responsible for most of oxidative
metabolism of DA in the brain
Selegiline (deprenyl)
 At low to moderate doses ( < 10mg/day), it is
selective & irreversible MAO-B inhibitor
 It does not metabolize peripheral catecholamine
 At dose > 10mg/day , MAO-A can be inhibited
 Used as adjunctive therapy for patients with
declining or fluctuating response to levodopa

77. MAO-B inhibitors…
8/13/2025
77
Selegiline
 In advanced PD, it may aggravate the adverse
motor & cognitive effects of levodopa therapy
 Metabolites of selegiline (amphetamine &
methamphetamine) may cause anxiety &
insomnia
Rasagiline (MAO–B inhibitor )
 More potent than selegiline in preventing MPTP
induced PD

78. COMT inhibitors

8/13/2025
78
Tolcapone & entacapone
 Inhibition of DDC associated with activation of
other levodopa metabolism pathways by COMT
 Addition of COMT inhibitors to carbidopa /
levodopa combination delays ’’wear off’’
phenomenon

79. COMT inhibitors…
8/13/2025
79
Tolcapone
 Has long duration of action
 Inhibit both central & peripheral COMT
 Associated with hepatotoxicity
 Should be used with appropriate monitoring for
hepatic injury only when other therapies are not
effective
Entacapone
 Has short duration of action
 Act peripherally

80. Amantadine
8/13/2025
80
 Antiviral agent with several pharmacological
effects
 MoA for its anti PD activity is not clear,
possibly by
 Facilitating synthesis, release or reuptake of DA
in the striatum
Its anticholinergic properties
 Blocking NMDA glutamate receptors

81. Muscarinic receptor antagonists

8/13/2025
81
 Drugs with higher central to peripheral
anticholinergic ratio than atropine but they
have similar pharmacological profile
 Reduce the unbalanced cholinergic activity in
striatum
 The only drugs effective in drug
(phenothiazine) induced parkinsonism
 Treatment has to start from small dose &
gradually increased until benefit occurs or side
effects limit further increment

82. Muscarinic receptor antagonists…
8/13/2025
82
Benzatropine (muscarinic receptor
antagonist) used for parkinsonism caused by
antipsychotic drugs
 Other antimuscarnic agents: Biperiden,
orphenadrine, procyclidine, trihexyphenidyl
Side effect profile is similar to atropine
 Dryness of mouth, nausea, constipation,
palpitation, cardiac arthymias, confusion,
agitation, restlessness, mydriasis, increased
intraocular pressure, defective accommodation

83. 8/13/2025
83


DRUG TREATMENT OF PSYCHIATRIC
DISORDERS

84. Nature of Psychosis & Schizophrenia

8/13/2025
84
 The term "psychosis" denotes a variety of
mental disorders:
 delusions (false beliefs), hallucinations(false
perception) and disorganized thinking.
 Schizophrenia is a chronic psychotic illness
characterized by
 Disordered thinking and
 Reduced ability to comprehend reality.

85. Schizophrenia
8/13/2025
85
Etiology & Pathogenesis
 Although there is strong evidence that
schizophrenia has a biologic basis, the exact
etiology is unknown.
1.Genetic & Environmental factors
 Number of susceptibility genes are identified w/c
show strong but incomplete hereditary tendency
 Some environmental factors have been identified
as possible predisposing factors (E.g. maternal
virus infections)

86. Etiology & Pathogenesis…

8/13/2025
86
2.Neurochemical theories
 A change in amine NTs especially DA has been
proposed as a cause of psychosis.
 The main neurochemical theories centre on DA &
glutamate
 However, 5-HT & other NTs might also involve

87. Etiology & Pathogenesis…
8/13/2025
87
3. Anatomic damage
 In psychotics brain, there are certain areas
w/c gets atrophied
 Computed Tomography (CT) scan and MRI
studies reveal
Enlarged ventricles
Suggest deterioration or atrophy of brain tissue
 Positron emission tomography (PET) scans
Suggest atrophy in the prefrontal areas

88. Main clinical features

8/13/2025
88
Positive symptoms : delusions,
hallucinations & thought disorder
 Commonly occur in acute phase of the illness
 Usually respond to antipsychotic drug therapy
 Negative symptoms: apathy, social
withdrawal & lack of drive
 Occur in the chronic phase of illness
Tend to be resistant to drug therapy

89. Main clinical features…
8/13/2025
89
Cognitive dysfunction
impaired attention, working memory, and
executive function.
Mood Symptoms
depression, agitation…….suicidal.

90. Classification of Antipsychotic Drugs

8/13/2025
90
Based on generation
Antipsychotic drugs /neuroleptics broadly
classified in to
 Conventional / 1st generation /typical
antipsychotics
 2nd generation/ atypical antipsychotic

91. Classification of Antipsychotic Drugs…
8/13/2025
91
Based on potency(1
st
generation)
Low potency
chlopromazine, thioridazine
Low EPS
Higher anticholinergic effect
High potency
haloperidol, thiothixene, fluphenazine
Higher EPS
Lower anticholinergic effect

92. Atypical vs. Conventional
Antipsychotics
8/13/2025
92
Typical antipsychotics:
Tend to produce Extrapyramidal side effects:
Parkinsonism – tremors, rigidity, slowness of
movement, temporary paralysis
Dystonia – involuntary muscle contractions
Akathisia – inability to resist urge to move
Tardive dyskinesia – involuntary movements of
the mouth, lips, and tongue ,Chewing, grimacing,
etc.

93. Atypical vs. Conventional
Antipsychotics…
8/13/2025
93
Atypical antipsychotics :
 do not induce EPSE
 Block D2 receptors and 5-HT receptors
 As opposed to typicals, these are more
loosely bound to D2 receptors
Easier dissociation
 the higher occupation of D2 receptors by
drug, the higher incidence of EPSE

94. Cont…
8/13/2025
94
Typical antipsychotic drugs associated
with
anticholinergic,
sedation, &
cardiovascular side effects
EPS
Atypical antipsychotic drugs may cause
metabolic syndrome but
do not cause EPS

95. Mechanism of Action

8/13/2025
95
 All effective antipsychotic drugs block D2
receptors
 The degree of blockade on different receptors
considerably varies
 Chlorpromazine: α1 > 5-HT2A > D2 > D1
 Haloperidole: D2 > α1 > D4 > 5-HT2A> D1>H1
 Clozapine: D4 = α1 > 5-HT2A> D1=D2
 Aripiprazole: D2= 5-HT2A >D4 > α1 = H1 >>D1
 Olanzapine: 5-HT2A >H1>D4>D2> α1 =
H1>>D1

96. Pharmacological Action

8/13/2025
96
1. ANS
 Varying degree of α adrenergic blocking activity
 More potent drugs have lesser α blocking activity
 Anticholinergic property is generally weak
2. Local anesthetic
 CPZ is potent LA as procaine however it causes
irritation

97. Pharmacological Action…
8/13/2025
97
3.CVS
 Antipsychotics produce postural hypotension by
central & peripheral action on sympathomimetic
tone
4. Endocrine effects
 Increase prolactine secretion by blocking the
inhibitory effect of DA
 Galactorrhoea, gynaecomastia
 increased libido (women), decreased libido (men)

98. Use of Antipsychotics

8/13/2025
98
1.Schizophrenia
2.Anxiety
Should not be used for simple anxiety b/c of
autonomic & EPS
BZDS are preferable; however, those not responding
or having psychiatric base for anxiety may be treated
with neuroleptics.
3. As antiemetics
Control wide range of drug & disease induced
vomiting at dose much lower than those needed for
psychosis but ineffective in motion sickness

99. Use of Antipsychotics…
8/13/2025
99
4. Other uses
Potentiate hypnotics, analgesics, & anasthetics
Intractable hiccough may respond to parentral
CPZ
In tetanus, CPZ is used achieve skeletal muscle
relaxation

100. Adverse Effects

8/13/2025
100
I. Dose related toxicity
1.CNS : Drowsiness, lethargy, mental confusion,
Increased appetite & weight gain (not
with haloperidol)
2. CVS: Postural hypotension, Palpitation
3. Anticholinergic: Dry mouth, blurred vision
4. Endocrine: Hyperprolactinemia
Atypical antipsychotics don’t raise prolactin level

101. Adverse Effects…
8/13/2025
101
5. Extrapyramidal disturbances (EPS)
Pseudo parkinsonism
Rigidity, tremor, hypokinesia, mask like face
Appears within 1- 4 weeks of therapy & persist
unless dose is reduced
Anti PD drugs can be given together with
antipsychotics????

102. Extrapyramidal disturbances (EPS)…
8/13/2025
102
Akathisia
Restlessness, feeling discomfort, agitation as a
complete desire to move about with out anxiety
Occurs with in 1-8 weeks of therapy & misleads as
‘exacerbation of psychosis’
No specific antidote available
 Central anticholinergic may reduce the intensity but
propranolol is more effective
Addition of diazepam may also be used
 However, most cases of akathisia require dose
reduction or alternative antipsychotic

103. Extrapyramidal disturbances (EPS)…
8/13/2025
103
Malignant neuroleptic syndrome
 It has been reported with the SGAs, including
clozapine, but is less frequent than with the FGAs.
Rarely occurs with potent antipsychotics
 Patient develops marked rigidity, immobility, tremor,
fever, semi consciousness, fluctuating BP & HR
 Lasts 5 – 10 days after withdrawal & may be fatal
 treatment should begin with antipsychotic
discontinuation and supportive care

104. Extrapyramidal disturbances (EPS)…
8/13/2025
104
Tardive dyskinesia
 Manifests as purposeless involuntary facial & limb
movements like constant chewing, puffing of
cheeks & lip licking
 More common in elderly women
 May subside months or yrs after withdrawal of
the t/t or may be life long
 Dosage reduction or discontinuation

105. Adverse Effects…
8/13/2025
105
II. Hypersensitivity
1. Cholestatic jaundice
2. Skin rash, urticaria, contact dermatitis ,
photosensitivity ( more common with CPZ)
3. Agranulocytosis, rarely, ( more common with
clozapine)
4. Myocarditis

106. Drug Interaction

8/13/2025
106
1. Neuroleptics potentaite all CNS depresant:-
Hypnotics, anxiolytics, alcohol, opioids,
antihistamines & analgesics
2. Neuroleptics block the action of levodopa &
DA agonists in parkinsonism
3. Antihypertensive effect of clonidine &
methyldopa is reduced
4. They are poor enzyme inducers

107. Drugs of Choice

8/13/2025
107
 Base for antipsychotic selection on
the need to avoid certain side effects,
concurrent medical or psychiatric disorders, and
patient or family history of response.

108. 8/13/2025
108



Antiepileptic Drugs

109. 8/13/2025
109

110. Seizure & Epilepsy
8/13/2025
110
Seizure: result of sudden, usually brief,
excessive electrical discharges in a
group of brain cells (neurons)
Epilepsy: Disorder characterized by recurrent,
unprovoked seizures
Convulsion: violent muscle spasm– part of
body,all of body
involuntary contraction(s) of the voluntary
muscles

111. Epileptic seizure classification

8/13/2025
111

112. Epileptic seizure classification…
8/13/2025
112
Status epileptics
 Continuous tonic-clonic seizures with or
without return to consciousness
 High fever and lack of oxygen severe enough
to cause brain damage or death
More than 30 minutes of continuous seizure
activity

113. Pathophysiology of Seizures
Increased EAA
Increased sensitivity to
EAA
Progressive increase in
glutamate release
Increased glutamate
and aspartate at start
of seizure
Decreased binding of
GABA and
benzodiazepines
 Decreased Cl-
currents in response
to GABA
 Decreased glutamate
decarboxylase activity
 Interfere with GABA
8/13/2025
113
Increased EAA Decreased GABA

114. SYMPTOMS OR WARNINGS
8/13/2025
114
EARLY WARNING SIGNS:
Smells, sounds, tastes, vision lost, fear, panic,
pleasant feelings, dizziness, lightheaded, nausea,
and numbness.
SEIZURE SYMPTOMS:
Blackout (faint),confusion, deafness, loss of
consciousness, convulsions, stiffening, difficulty
breathing, incontinence, inability to move.

115. Cont…
8/13/2025
115
AFTER SEIZURE SYMPTOMS:
Memory loss, confusion, frustration, headache,
nausea, pain, exhaustion, fear, thirst, and
difficulty speaking.

116. Epilepsy Differential Diagnosis
8/13/2025
116
The following should be considered in the diff. dg.
of epilepsy:
Syncope attacks (when pt. is standing; results from
global reduction of cerebral blood flow; prodromal
pallor, nausea, sweating; jerks!)
Cardiac arrythmias . Prolonged arrest of cardiac
rate will progressively lead to loss of consciousness –
jerks!
Complicated migraine may lead to loss of
consciousness!
Hypoglycemia – seizures or intermittent behavioral
disturbances may occur….etc

117. Strategies in treatment of epilepsy

8/13/2025
117
 Stabilize membrane and prevent
depolarization by action on ion channels
 Increase GABAergic transmission
 Decrease EAA transmission
Types of Treatment
 Medication
 Surgery
 Nonpharmacologic treatment
 Ketogenic diet
 Vagus nerve stimulation

118. Classification of Anticonvulsants
8/13/2025
118

119. Cont…
8/13/2025
119
NEWER AGENTS DIFFER FROM OLDER
DRUGS BY………..
Relatively lack of drug-drug interaction
simple pharmacokinetic profile
Improved tolerability
HOWEVER THEY ARE…………
Costly with limited clinical experience

120. General Facts About AEDs
8/13/2025
120
Good oral absorption and bioavailability
Most metabolized in liver but some excreted
unchanged in kidneys
Classic AEDs generally have more severe CNS
sedation than newer drugs (except
ethosuximide)
Because of overlapping mechanisms of
action, best drug can be chosen based on
minimizing side effects in addition to efficacy

121. Cont…
8/13/2025
121
Drug therapy may not be indicated in patients
who have had only one seizure or those whose
seizures have minimal impact on their lives.
Patients who have had two or more seizures
should generally be started on AEDs.
Factors favoring successful withdrawal of AEDs
include
a seizure-free period of 2 to 4 years,
complete seizure control within 1 year of onset,
an onset of seizures after age 2 years and before age
35 years, and a normal EEG.

122. Antiseizure /antiepileptic drugs

8/13/2025
122
 Class of drugs for epilepsy
Type I antiepileptics - Inhibit Na+ channels
 Phenytoin, Carbamazepine, lamotrigine, felbamate,
oxycarbazepine
Type II antiepileptics – Multiple action
Inhibit Ca++ or Na+ channels or promote GABA
activity Valporic acid, benzodiazepines, primidone,
Phenobarbital
Type III antiepileptics - Ca++ channel inhibitors
 Ethosuximide, trimethadione
Type IV - GABA promoters
 Vigabatrin, tiagabine, gabapentine

123. Phenytoin

8/13/2025
123
 is one of the Na+ channel inhibitor antiepileptic
drugs
 Limited water solubility, slow, incomplete and
variable absorption
 Equal efficacy as phenobarbital but with lesser
CNS depressant effect
 It is highly plasma protein bound

124. Phenytoin…
8/13/2025
124
Adverse effects
 Acute toxicity - Results of over dosage
 Nystagmus, ataxia, vertigo, diplopia
 Chronic toxicity - Related to long term use
 Behavioral changes
 Gingival Hyperplasia (overgrowth of the gums)
 Enlargement of lips & nose
 Coarsening of facial features
 Hirsutism (excessive hairiness)

125. Carbamazepine

8/13/2025
125
Is highly efficacious & well tolerated, Na+
channel blocker
 Has fewer long term side effects than other anti-
epileptics
 Metabolized in the liver by the CYP450 enzymes
 Enzyme inducer & can induce its own metabolizing
enzyme as well asenzymes of other drugs

126. Carbamazepine…
8/13/2025
126
SEs:
 Drowsiness, headache, dizziness & incordination
 Allergic reactions, rare but sever aplastic anemia
Most SEs occur at first therapy & tolerance
develops
 Toxicity is low as compared to phenytoin

127. Ethosuximide

8/13/2025
127
Drug of choice for Absence seizure
 Not effective in other seizure types
 Blocks Ca++ currents (T-currents) in the
thalamus
SEs
 GI complaints - Most common
 CNS effects - Drowsiness & lethargy
 Potentially fatal bone marrow toxicity and skin
reactions (both rare)

128. GABA transmission enhancers

8/13/2025
128
1. Phenobarbital
 Is the only barbiturate with selective
anticonvulsant effect
 Bind at allosteric site on GABA receptor & ↑
duration of opening of Cl channel
 Inducer of microsomal enzymes → Drug
interactions
 Toxic effects
Sedation (tolerance develops), nystagmus, ataxia at
higher dose, osteomalacia, folate and vitamin K
deficiency

129. GABA transmission enhancers…
8/13/2025
129
2. Benzodiazepines
 Clonazepam, lorazepam & clorazepate
 Bind to another site on GABA receptor & increase
frequency of opening of the Cl- channel
 Are well absorbed from the GIT
 Metabolized by CYP450 enzymes to active
metabolites
Toxicities
 Lethargy, drowsiness, CNS sedation

130. GABA transmission enhancers…
8/13/2025
130
3. Gabapentin - Developed as GABA analogue
 ↑ release of GABA from gabanergic neurons by
unknown mechanism
4. Vigabatrin
 Irreversible inhibitor of GABA transaminase
enzyme which metabolizes GABA
5. Tiagabine
 ↓ GABA uptake by neuronal and extraneuronal
tissues so as to increase GABA at the synapse

131. GABA transmission enhancers…
8/13/2025
131
6. Valporic Acid
 Effective in the treatment of multiple seizure types
 Works by multiple mechanisms
Blocks both Na+ & Ca++ channels and ↑ GABA activity
Drug interactions: Inhibits metabolism of
phenobarbital, Carbamazepine & phenytoin
Side effects
 Fatal hepatic failure (most serious SE), reversible hair
loss, ↑ in body weight, transient GI disturbances

132. Clinical Uses of Antiepileptic Drugs

8/13/2025
132
 Tonic-clonic (grand mal) seizures:
 Carbamazepine preferred because of low
incidence of side-effects, phenytoin, valproate,
Phenobarbital
 Use of single drug is preferred when possible,
because of risk of pharmacokinetic interactions
 Partial (focal) seizures:
 carbamazepine, valproate; clonazepam or
phenytoin are alternatives

133. Clinical Uses of Antiepileptic Drugs…
8/13/2025
133

134. Clinical Uses of Antiepileptic Drugs…
8/13/2025
134

135. 8/13/2025
135



Antidepressant Drugs

136. Depression
8/13/2025
136
At any given moment about 3–5% of the
population is depressed & an estimated 10% of
people may become depressed during their lives.
 Every one in normal course of daily life
experiences mood alteration (sadness, not clinical
depression)
 Major depression is characterized by feelings of
intense sadness and despair, loss of
concentration, pessimistic worry, lack of pleasure
and/or self-deprecation.

137. Symptoms of depression

8/13/2025
137
Emotional symptoms
 Misery, apathy & pessimism
 Low self-esteem: feelings of guilt, inadequacy &
ugliness
 Indecisiveness, loss of motivation.
Biological symptoms
 Retardation of thought & action
 Loss of libido
 Sleep disturbance & loss of appetite

138. Etiology & Pathogenesis

8/13/2025
138
 Genetic causes
 Environmental factors
 Biochemical factors
Deficiency of NT amines in certain part of the
brain (NA, 5-HT & DA)
 Endocrine factors
 ↑ plasma cortisol level in depressed patients
 Dexamethasone suppression test

139. …
8/13/2025
139
Monoamine Hypothesis:
Depression is due to a deficiency of
monoamine NTs, notably nor-epinephrine (NE)
and serotonin (5-hydroxytryptamine [5HT])
Certain drugs that depleted these NTs could
induce depression, the tricyclic
antidepressants and the MAO inhibitors with
pharmacological actions that boosted these
neurotransmitters are antidepressants

140. Classification of Antidepressants

8/13/2025
140
1. Tricyclic antidepressants (TCAs)
2. Selective serotonin reuptake inhibitors (SSRIs)
3. Monoamine oxidase inhibitors (MAOIs)
4. Miscellaneous ('atypical') antidepressants

141. Tricyclic antidepressants (TCAs)

8/13/2025
141
block norepinephrine and serotonin reuptake into
the neuron
 TCAs also block serotonergic, α-adrenergic,
histaminic, and muscarinic receptors
A. NA & 5-HT reuptake inhibitors
Imipramine Amitriptline
Trimipramine Dothiepin
Doxepin Clomipramine
B. Predominantly NA reuptake inhibitors
Amoxapine Desipramine
Nortriptylin Reboxetine

142. Therapeutic uses

8/13/2025
142
 Treating moderate to severe depression
 Bed-wetting in children (imipramine)
 To treat migraine headache and chronic pain
syndromes (neuropathic pain) (amitriptyline)
 Insomnia

143. Adverse effects

8/13/2025
143
 Antimuscarnic: blurred vision, xerostomia (dry
mouth), urinary retention, sinus tachycardia,
constipation, and aggravation of narrow-angle
glaucoma
 Block α-adrenergic receptors: orthostatic
hypotension, dizziness, and reflex tachycardia
 Block histamine H1receptors: sedation,
weight gain
 Erectile dysfunction in men and anorgasmia in
women

144. Selective Serotonin Reuptake
Inhibitors (SSRI)

8/13/2025
144
1st line drugs
Due to their relative safety & acceptability
 Produce little or no sedation
Not produce anticholineric side effects
Devoid of α AR blocking action (no postural
hypotension)- suitable for elderly patients
No seizure precipitating propensity & donot
inhibit cardiac conduction
No weight gain

145. Selective Serotonin Reuptake
Inhibitors (SSRI)…
8/13/2025
145
Selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine
Fluvoxamine
Paroxetine
Citalopram
Sertraline
Maprotiline
Trazodone
Nefazodone

146. Adverse effects

8/13/2025
146
SSRIs are considered to have fewer and less
severe adverse effects
Headache, sweating, anxiety and agitation,
gastrointestinal (GI) effects (nausea, vomiting,
diarrhea), weakness and fatigue, sexual
dysfunction, changes in weight, sleep
disturbances

147. Therapeutic uses

8/13/2025
147
The primary indication for SSRIs is depression,
Other indications:
 Obsessive-compulsive disorder
 Panic disorder
 Generalized anxiety disorder
 Posttraumatic stress disorder
 Social anxiety disorder
 Premenstrual dysphoric disorder

148. Cont…
8/13/2025
148
For TCAs & SSRIs as onset of action is slow
Treatment should be for at least 4-6 weeks
before concluding that the drug is ineffective
If there is a partial response, treatment should
be continued for several more weeks before
increasing the dose
Treatment should continue for at least 4
months following remission

149. Monoamine oxidase inhibitors (MAOIs)

8/13/2025
149
 MAO-A is primarily responsible for NE, 5-HT
&tyramine metabolism
 MAO-B is more selective for DA
 Non-selective MAOIs or selective MAO-A
inhibitors have antidepressant effect
 Older non selective MAOIs :Tranylcypromine,
phenelzine & isocarboxazid
Irreversible, long-acting & non-selective
 Moclobemide (MAO-A inhibitor)
 Reversible, short acting & selective

150. Therapeutic uses

8/13/2025
150
 Depressed patients who are
unresponsive or allergic to TCAs
 MAOIs are considered to be last-line
agents

151. Adverse effects

8/13/2025
151
Hypertensive crisis:
Tyramine, which is contained in certain foods,
such as aged cheeses and meats, chicken liver,
preserved fish , and red wines, is normally
inactivated by MAO in the gut.
Individuals receiving a MAOI are unable to
degrade tyramine obtained from the diet.
Tyramine causes the release of large amounts of
stored catecholamines from nerve terminals
Patients must, therefore, be educated to avoid
tyraminecontaining foods.

152. Miscellaneous ('atypical') antidepressants

8/13/2025
152
Trazodone
 Selective but less efficiently block 5-HT uptake
 Prominent α blocking & 5-HT2 antagonistic effect
Mianserin
 Does not inhibit either NA or 5-HT uptake
 Block presynaptic α2
Tianeptine
 ↑5-HT uptake , it is not sedative & stimulant
 Effective for anxiodpressive state
Amineptine
 Like tianeptine but has antidepressant action

153. Miscellaneous ('atypical') antidepressants…
8/13/2025
153
Venlafaxine & Duloxetine
‘serotonin & NA reuptake inhibitor ’ = SNRI
 In contrast to older TCAs,
 They do not interact with cholinergic, adrenergic, or
histaminergic receptors
 No sedative effect
Mirtazapine
 Block α2 autoreceptor ( on NA neuron) & hetroreceptors (
on 5-HT neurons )
Bupropion
 Inhibit DA & NA uptake
 Has excitant rather than sedative effect

154. Clinical Indications of Antidepressants

8/13/2025
154
 Major depression
 Anxiety disorders
 panic, generalized anxiety, social phobia &
obsessivecompulsive disorders
 Enuresis
 Chronic pain
 Migraine
 Amitryptiline has prophylactic use

155. Clinical Indications of Antidepressants…
8/13/2025
155
Pruritus
 Some TCAs have antipruritic action
Eg. Topical doxepine
 Other indications
 Bulimia (fluoxetine)
 Premenstrual dysphoric disorder (fluoxetine)
 Attention deficit hyperkinetic disorder
(imipramine, desipramine)

156. Drug Interactions

8/13/2025
156
TCAs
1. Potentiate directly acting sympathomimetics
2. Abolish antihypertensive effect of clonidine
3.Potentiate CNS depressants
4. Phenytoin, phenylbutazole, ASA & CPZ can
displace TCAs from PPB

157. Drug Interactions…
8/13/2025
157
5. Phenobarbitone induce as well as competitively
inhibit impramine metabolism
6. SSRIs inhibit metabolism of several drugs
including TCAs
7. TCAs delay absorption of their own & other drugs
8. MAO- A inhibitors with tyramine containing food
‘Cheese’ like reaction

158. 8/13/2025
158


ANALGESICS

159. Introduction
8/13/2025
159
Pain (algesia)
 Unpleasant sensory & emotional experience
 Associated with actual or potential tissue damage
 Evoked by an external or internal noxious
stimuli
Mediated by different NTs & peptides such as
glutamate & substance P
 It is a warning, primarily protective in nature

160. Introduction…
8/13/2025
160
The pain can be
Superficial
 Stimulation of skin & mucous membranes
 Fast response
Deep
 Arises from muscles, joints, tendons, heart, e.t.c.
 Slow response

161. Analgesics

8/13/2025
161
 Drugs that selectively relieve pain with out
significant change on patient consciousness
 Act on CNS or periphery pain mechanism
Analgesic classification
 Narcotics/opioids/
 Morphine & morphine like drugs
 Non-narcotics
 NSAID
 Adjuvant analgesic /co-analgesics
 TCAs, Antiepileptics, Steroids

162. Analgesics…
8/13/2025
162
Management of pain
1. Mild pain
NSAID +/-adjuvant
2. Moderate pain
 Weak narcotic +/-NSAID +/-adjuvant
3. Severe pain
 Strong narcotic +/-NSAID +/-adjuvant

163. 8/13/2025
163
OPIOID ANALGESICS AND
ANTAGONISTS

164. Opioid

8/13/2025
164
The term opioid refers broadly to all
compounds related to opium poppy(opiates)
They include the natural products morphine,
codeine, thebaine and many semisynthetic
derivatives also synthetic.

165. Endogenous opioid peptides

8/13/2025
165
They are the naturally occurring ligands for opioid
receptors
Three distinct families of classical opioid peptides
have been identified:
Enkephalins
It is discovered in the brain
Endorphins
Dynorphins
Each family derives from a distinct precursor protein
and has a characteristic anatomical distribution

166. Endogenous opioid peptides…
8/13/2025
166
The endogenous opioids have been implicated
in the modulation of most of the critical
functions of the body, including:
 Hormonal fluctuations
Thermoregulation
Mediation of stress and anxiety
Production of analgesia

167. Endogenous opioid peptides…
8/13/2025
167
Development of opioid tolerance and dependence
Maintain homeostasis
Amplify signals from the periphery to the brain,
and serve as neuromodulators of the body’s
response to external stimuli
As such, the endogenous opioids are critical to
the maintenance of health and a sense of
well-being

168. Opioid receptors
8/13/2025
168
The three opioid receptors µ, δ, and k
Mu (µ) receptor
Located at supraspinal and spinal sites
Supraspinal analgesia
 Euphoria
 Respiratory depression, constipation, urinary
retention,
nausea, vomiting, physical dependence, miosis
 Most opioid analgesics are relatively selective μ
opioid agonist

169. Opioid receptors…
8/13/2025
169
δ –Receptors
It is binding sites for endogenous peptides
It mediates:
Spinal analgesic effects
Dysphoria,
hallucinations
k-opioid receptors
 They are thought to mediate:
Spinal analgesia
Miosis
Sedation
Diuresis

170. Opioid receptors…
8/13/2025
170
Table. Opioid receptor subtypes, their functions, and their
endogenous peptide affinities

171. Opioid analgesics
8/13/2025
171
Mechanism of action
Opioid agonists produce analgesia by binding to specific
GPCRs that are located in brain and spinal cord regions
involved in the transmission and modulation of pain

172. Opioid analgesics…
8/13/2025
172
Strong agonists
Strong agonists are useful in the treatment of
severe pain
They includes
Morphine, hydromorphone, and oxymorphone,
heroin, Methadone, Meperidine, Levorphanol

173. Opioid analgesics…
8/13/2025
173
Fentanyl is one of the most widely used
agents in the family of synthetic opioids
The fentanyl subgroup now includes:
Sufentanil
Alfentanil
Remifentanil
Fentanyl and sufentanil, are very important
drugs in anesthetic practice

174. Opioid analgesics…
8/13/2025
174
Mild to moderate agonists
They includes:
Codeine, dihydrocodeine, hydrocodone, oxycodone,
Propoxyphene
All somewhat less efficacious than morphine and
often have adverse effects that limit the maximum
tolerated dose
Oxycodone is more potent
Combinations of hydrocodone or oxycodone
with acetaminophen are the predominant
formulations of orally used dose for the
treatment of mild to moderate pain

175. Opioid analgesics…
8/13/2025
175
Diphenoxylate
are not used for analgesia
it is used for the treatment of diarrhea
Loperamide
It is used to control diarrhea
It has an action on peripheral μ-opioid receptors
and lack of effect on CNS receptors
It is therefore available without a prescription

176. Opioid analgesics…
8/13/2025
176
Other opioid agonists
Tramadol
It is a synthetic codeine analog that is a weak Mu
opioid receptor agonist
Tramadol is as effective as morphine or meperidine in
the treatment of mild to moderate pain
For the treatment of severe or chronic pain, tramadol
is less effective
Tramadol is as effective as meperidine in the
treatment of labor pain and may cause less neonatal
respiratory depression

177. Organ system effects of opioids
8/13/2025
177
Central nervous system effects
The principal effects of opioid analgesics with
affinity for μ receptors are on the CNS
These effect include analgesia, euphoria,
sedation, and respiratory depression
With repeated use, a high degree of tolerance
occurs to all of these effects

178. Organ system effects of opioids…
8/13/2025
178
Peripheral effects
Cardiovascular system
Most opioids have no significant direct effects
on the heart and, other than bradycardia
Meperidine is an exception to this
generalization because of its antimuscarinic
action can result in tachycardia
Hypotensive effect

179. Organ system effects of opioids…
8/13/2025
179
Gastrointestinal tract
Opioids cause constipation
This effect does not diminish with continued
use of opioids
GIT motility may decrease
Gastric secretion of hydrochloric acid is
decreased

180. Organ system effects of opioids…
8/13/2025
180
Biliary tract
Opioids contract biliary smooth muscle
It can result in biliary colic
reflux of biliary and pancreatic secretions
elevated plasma amylase and lipase levels

181. Organ system effects of opioids…
8/13/2025
181
Renal
Opioids depressed renal function
This is chiefly due to decreased renal plasma
flow
μ opioids have been found to have an
antidiuretic effect in humans
Mechanisms may involve both the CNS and
peripheral sites
Opioids also enhance renal tubular sodium
reabsorption

182. Organ system effects of opioids…
8/13/2025
182
Uterus
The opioid analgesics may prolong labor by reduce
uterine tone
Opioid analgesics stimulate the release of ADH,
prolactin, and somatotropin but inhibit the release of
luteinizing hormone
Pruritus
Opioid analgesics produce flushing and warming of
the skin accompanied sometimes by sweating and
itching
CNS effects and peripheral histamine release may be
responsible for these reactions

183. Clinical use of opioid
analgesics

8/13/2025
183
Analgesia
opioids are mainly used for severe& constant pain
Chronic pains such as in cancer patients may
need continuous use of potent opioid
analgesics
Potent opioid analgesics associated with tolerance
& dependence

184. Clinical use of opioid
analgesics…
8/13/2025
184
Opioid analgesics are used during obstetric
labor
 As opioids cross the placental barrier, care must
be taken to minimize neonatal depression

185. Clinical use of opioid
analgesics…
8/13/2025
185
Acute pulmonary edema
IV morphine relief dyspnea from pulmonary
edema associated with left ventricular heart
failure
Proposed mechanisms include :
Reduced anxiety ( perception of shortness of breath)
Reduced cardiac preload (reduced venous tone)
Reduced afterload (decreased peripheral resistance)
However, if respiratory depression is a problem,
furosemide may be preferred for the treatment
of pulmonary edema

186. Clinical use of opioid
analgesics…
8/13/2025
186
Cough
Suppression of cough can be obtained at doses lower than
those needed for analgesia ,e.g. codaine
Cough suppressed by dextro-isomers of opioids (e.g.
dextromethorphan), compounds which have no
analgesic activity
Diarrhea
Diarrhea from almost any cause can be controlled with the
opioid analgesics
Agents with more selective gastrointestinal effects and
few or no CNS effects are used , eg, diphenoxylate or
loperamide
But if diarrhea is associated with infection ,appropriate
chemotherapy should be used

187. Clinical use of opioid
analgesics…
8/13/2025
187
Shivering
All opioid agonists have some propensity to
reduce shivering
 Meperidine is reported to have the most
pronounced anti-shivering properties
 Single doses of meperidine is effective in the
treatment of postanesthetic shivering

188. Clinical use of opioid
analgesics…
8/13/2025
188
Applications in anesthesia
Used in cardiovascular surgery b/c of low cardiac
depressant effects
 Opioids can be used
Preoperatively b/c of their sedative, anxiolytic &
analgesic properties
 Intraoperativelyas adjuncts to other anesthetic
agents & as a primary component of the anesthetic
regimen
Postoperatively as analgesics

189. Side effects

8/13/2025
189
Most opioid side effects associated with mu
receptors
 Respiratory depression (reduces sensitivity of
respiratory centres in brain stem to CO2)
 Euphoria
 Sedation
Hypothermia
Constipations
Tolerance & dependence
 Bronchoconstriction (histamine release stimulated)

190. Opioid antagonists

8/13/2025
190
It binds competitively to one or more of the
opioid receptors
It robustly antagonize the effects of receptor
agonists
Therapeutically utilized in the treatment of
opioid overdose
Naloxone and naltrexone are interact with
all types of opioid receptors

191. Opioid antagonists…
8/13/2025
191
Naloxone
It has fast onset action (within minutes)
It is administered through IV route for the
reversal of opioid overdose
The half-life of naloxone in plasma is 1 hour
Naloxone given orally has a large first-pass effect,
which reduces its potency significantly
The heart rate and blood pressure of the patient
may rise significantly
 It precipitates of acute withdrawal signs

192. Opioid antagonists…
8/13/2025
192
Naltrexone
It is 3-5 times as potent as naloxone
It has a duration of action of 24 -72 hours
It is used orally in the treatment of opioid
abstinence
Naltrexone exhibits a large first-pass effect in
the liver
It is used to decrease the craving for opioids
in highly motivated recovering addicts

193. Opioid antagonists…
8/13/2025
193
Therapeutic Uses
Treatment of opioid overdosage
Naloxone rapidly reverse respiratory depression
caused by opioid overdose
Management of constipation
Management of abuse syndromes

194. Opioid antagonists…
8/13/2025
194
Side effects
Side effects are more common with
naltrexone than naloxone
These includes:
Headache, difficulty of sleeping, lethargy,
increased blood pressure, nausea,
Sneezing, delayed ejaculation, blurred vision, and
increased appetite

195. 8/13/2025
195



End