3. Introduction
• The CNS is composed of the brain and spinal cord
• It is responsible for integrating sensory information and generating
motor output
• The human brain contains about 100 billion interconnected neurons
surrounded by various supporting glial cells.
• BBB is a protective functional separation of the circulating blood
from the ECF of the CNS that limits the penetration of substances,
including drugs, accomplished by the presence of tight junctions
• As such, to enter the CNS, drugs must either be highly hydrophobic
or engage specific transport mechanisms (e.g. glucose & aa)
3
4. CNS pathways
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
4
5. CNS pathways
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
5
6. 7
• Excitatory neurons –increases the probability of generating
an action potential.
• Inhibitory neurons –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
7. 8
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);
But major differences are;
More than 20 NT in the CNS
There are inhibitory and excitatory NT in the CNS
CNS is much more complex than PNS
9. 10
NTs in the CNS
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)
10. • Noradrenaline (Norepinephrine):
• Noradrenergic transmission is important in
»control of mood (functional deficiency
resulting depression)
»wakefulness, and
»alertness.
11
11. • Dopamine:
• Dopamine is important in
• Motor control,
• Has behavioral effects (excessive dopamine
activity is implicated in schizophrenia)
• Important in hormone release (prolactin, GH)
• Chemoreceptor trigger zone causes nausea and
vomiting.
12
12. • Serotonin (5-HT):
Physiological functions associated with 5-HT
pathways include;
Feeding behavior
Behavioral response (hallucinatory behavior)
Control of mood and emotion,
Control of body temperature
Vomiting
13
13. • Acetylcholine(Ach): has effects
On arousal
Movement
On learning, and short-term memory
Dementia and parkinsonism are associated with
abnormalities in cholinergic pathways.
14
16. SEDATIVE HYPNOTICS
• 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.
18
17. Sedative / hypnotics ….
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
19
18. 20
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
Sedative Hypnotics
19. 21
• Hypnotics
at lower dose may act as sedative and
at higher dose can produce general
anesthesia
Sedative Hypnotics
Sedation hypnosis general anesthesia comma
22. Barbiturates
• 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
– Intermediate-acting (Amobarbital, aprobarbital &
butabarbital) - 6- 8 hrs
– Long-acting (Phenobarbital, mephobarbital) - 10 - 16 hrs
23. Barbiturates action
• Depression of CNS
– At low doses - Produce sedation (calming effect, reducing
excitement)
– At higher doses - Hypnosis, followed by anesthesia (loss
of feeling or sensation), and finally, coma and death
– No analgesic properties - May even exacerbate pain
– Chronic use leads to tolerance
• Respiratory depression
– Suppress hypoxic and chemoreceptor response to CO2
• Enzyme inducers - ↓ Action of other drugs
24. Barbiturates cont…
Therapeutic uses
• 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
• Anxiety - Mild sedatives for anxiety, nervous tension and
insomnia
– As hypnotics, they suppress REM sleep
25. Barbiturates cont…
Adverse effects
• Drowsiness, impaired concentration, mental and physical
sluggishness (depressant effects synergize with ethanol)
• Drug hangover, nausea, dizziness
• Physical dependence: Abrupt withdrawal cause tremors,
anxiety, weakness, restlessness, nausea and vomiting,
seizures, delirium, and cardiac arrest
– Withdrawal is much more severe than that associated with
opiates and can result in death
• Drug Interactions- other depressants, oral contraceptives, etc
26. Benzodiazepines
• Potentiate effect of GABA by ↑ the frequency of Cl channel
opening
• Classifications
– Short acting agents - Triazolam
– Intermediate acting agents - Alprazolam, Lorazepam,
Oxazepam, Temazepam, Chlordiazepoxide
– Long acting agents - Diazepam, Flurazepam
27. Benzodiazepines action:
• Reduction of anxiety - At low doses
• Sedative and hypnotic actions: All have some sedative
properties and some produce hypnosis at higher doses
• Anterograde amnesia - Temporary impairment of memory
– Impairs a person's ability to learn and form new memories
• Anticonvulsant: Several of the benzodiazepines
– Some are used to treat status epilepticus and other
seizure disorders
• Muscle relaxant: At high doses
28. 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
Produce less physical dependence
do not alter the disposition of other drugs by
microsomal enzyme induction
Presence of BZD antagonist (flumazenil) as antidote
30
30. Benzodiazepines …
• Adverse effects
– Drowsiness, confusion, ataxia, cognitive impairment,
tolerance, dependence (Psychological and physical
dependence) and withdrawal symptoms
• Precautions
– Avoid in pregnancy
– Liver disease, acute narrow-angle glaucoma.
– Alcohol and other CNS depressants
– Less dangerous than older anxiolytic and hypnotic drugs
31. 33
BZD antagonist / flumazenil
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
32. 34
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
BZD antagonist / flumazenil
33. 3. Newer sedative hypnotics
Non BZD sedatives: agonist for a subtype of BZD receptor
Zopicolone, eszopiclone, Zolpidem & Zaleplon,
Ramelteon and Tasimelteon, a melatonin receptor agonist
Buspirone – serotonin receptor antagonist
Suvorexant- orexin antagonist
35
34. 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.
36
35. Benzodiazepine – like drugs
• efficacies similar to those of the hypnotic
benzodiazepines
• Favorable clinical features, rapid onset of activity and
modest day-after psychomotor depression with few
amnestic effects
• Zaleplon acts rapidly and short DOA-management of
patients who awaken early in the sleep cycle
• bind more selectively because these drugs interact only
with GABAA-receptor isoforms that contain α1 subunits.
37
36. 40
Buspirone
Partial agonist at serotonin receptor (5-HT 1A receptor)
Also binds to brain dopamine receptor (D2 )
Less Psychomotor impairment than benzodiazepines
Selective with minimal depressant effects on the CNS
Less effective in panic disorders /acute anxiety states b/c of slow
onset of action (effects take days or weeks to develop)
Relief anxiety without causing marked sedative, hypnotic, or euphoric
effects
Minimal abuse liability & no anticonvulsant or muscle relaxant
properties (unlike BZDs)
No rebound anxiety/withdrawal signs on abrupt discontinuance
38. 44
Parkinson’s disease (PD)
• is disorder of mov’t that occurs mainly in the elderly
• Occurs for a variety of possible reasons
– Exposure to certain toxins (manganese dust, CS2)
– Drug induced parkinsonism : reserpine, chlorpromazine,
haloperidol & other antipsychotics that block D2
– Post encephalitic parkinsonism : after viral infection
– Idiopathic parkinsonism : unknown cause
39. 45
• 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) mainly due to accumulation of alpha-
synuclein (due to lack or defective parkin & ubiquitin)
Pathophysiology of PD
41. Strategy of Treatment
• Symptoms of Parkinson's reflect
– imbalance b/n the excitatory cholinergic neuron & the
greatly diminished number of inhibitory dopaminergic
neurons.
• 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.
47
45. Overview of Drug Therapy
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).
51
46. 52
Classification of drugs
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
47. 53
2. Drugs affecting brain cholinergic system
a. Anticholinergcs: Benzatropine, Trihexyphenidyl
(benzhexol), Procyclidine, biperiden
b. Antihistaminics: promethazine
3. Neural transplantation (on experimental phase)
48. 54
Levodopa (L-DOPA)
• first-line treatment for PD
• is the immediate metabolic precursor of dopamine
– Prodrug for DA
– Levodopa can cross BBB while DA does not
49. 55
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 (vomiting)
• Therefore, peripheral dopa decarboxylase inhibitor (carbidopa
or benserazide) reduce Levodopa metabolism in periphery
Levodopa
52. 59
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.
Levodopa
53. 60
• 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
Levodopa
54. 61
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
Levodopa
55. 62
• On / off phenomenon
–Each dose of levodopa
• Effectively improves mobility for few hours with marked
dyskinesia (on - period)
• Marked rigidity & akinesia return rapidly at the end of the
dosing interval (off - period) - wearing off
–Most common on late stage of PD
–'on-off' effect is not seen in untreated PD patients or with other
anti-PD drugs
–Apomorphine may provide temporary benefit for patients with
severe off-periods who are unresponsive to other measures
56. 63
The possible reason for on/off effect
As the disease advances
The ability of neurons to store dopamine is lost
The therapeutic benefit of levodopa depends on the
continuous formation of extraneuronal dopamine
Continuous supply of levodoapa is required otherwise the
on/off phenomenon will occur
Strategies to manage:
Infusion, sustained release, or multiple short interval doses
of L-Dopa
Add selegiline to prevent metabolism by MAO-B.
Use receptor agonists
57. 64
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
58. 66
Dopamine receptor agonists
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
• 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
59. 67
Act directly on postsynaptic DA receptor types (primarily
D2)
Effective as monotherapy or as adjuncts to carbidopa
/levodopa therapy
Dopamine receptor agonists
60. 68
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
prolactin release) in lower doses than for PD
• Gynecomastia
61. 69
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
DA receptor agonists
62. 70
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/
DA receptor agonists
63. 72
• Initial t/t with bromocriptine or pergolide (non selective
agonists)
– may cause hypotension
– induce nausea & fatigue
• Symptoms are transient & require slow upward
adjustment of the dose over a period of weeks to months
• Selective agonists (pramipexole & ropinirol) are well
tolerated
– Can be initiated more quickly
– Therapeutic doses can be achieved in a week or less than
DA receptor agonists
64. 73
Adverse effects of DA agonists
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
65. 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
Adverse effects of DA agonists
66. 75
C/I
• 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
DA receptor agonists
67. 76
MAO-B inhibitors
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 ( < 10 mg/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
68. 77
↓ free radical generation
from DA metabolites
↓oxidative stress
Neuroprotective effect ( ?)
MAO-B Inhibitor
Reduce DA metabolism ↑DA concentration
in striatum
-Allow levodopa dose reduction
-May reduce on / off phenomena
Enhance action of
levodopa
71. 80
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
COMT Inhibitors
72. 81
Amantadine
• 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
73. 82
Muscarinic receptor antagonists
• 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
74. 83
• Benzatropine (muscarinic receptor antagonist) used for
parkinsonism caused by antipsychotic drugs
• Other antimuscarnic agents: trihexyphenidyl, biperiden,
orphenadrine, procyclidine,
• Side effect profile is similar to atropine
– Dryness of mouth, constipation, palpitation, cardiac
arthymias, confusion, agitation, restlessness, mydriasis,
increased intraocular pressure, defective accommodation
Muscarinic receptor antagonists
76. Seizure
• refers to a transient alteration of behavior due to the
disordered, synchronous, and rhythmic firing of populations
of brain neurons
Epilepsy
refers to a disorder of brain function characterized by the
periodic and unpredictable occurrence of seizures
Seizures can be "non-epileptic" when evoked in a normal
brain by treatments such as electroshock or chemical
convulsants or
It is "epileptic" when occurring without evident provocation
86
78. • Partial seizures
begins focally in a cortical site
Simple-partial seizure
No loss of consciousness
May have muscle twitching or sensory hallucinations
Complex-partial seizure
Impaired consciousness
With confusion and post seizure amnesia
88
79. Generalized Seizures
• Involves both hemispheres of the brain, not one specific
location
• Types:
Tonic
– body becomes rigid, lasts a minute or less
Clonic
Initiated with muscle jerks, and may be accompanied by
shallow breathing, loss of bladder control, and excess
salivation
89
80. Myoclonic
– Occurs with sudden, massive, brief muscle jerks or non-
massive, quick jerks
– Consciousness is not lost
– Can occur during sleep
Atonic
– Begins with sudden loss of muscle tone and
consciousness
– Muscles relax, limbs go limp (weak)
– Lasts a few seconds to a minute, then patient can resume
standing and walking 90
81. Absence
– It causes interruption of activities by:
Blank stare (absence of fixed looking)
Rotating eyes
Uncontrolled facial movements
Rapid eye blinking, and/or jerking of an arm or leg
– No generalized convulsions
– Usually lasts 30 seconds or less
– Many times it progresses to tonic-clonic as the patient
gets older
91
82. Status epileptics
– Continuous tonic-clonic seizures with or without return to
to consciousness
– High fever and lack of oxygen severe enough to cause
brain damage or death
92
83. Pathophysiology of Seizures
Increased EAA
• Increased EAA Transmission
• Increased sensitivity to EAA
• Progressive increase in
glutamate release
• Increased glutamate and
aspartate at start of seizure
• Up regulation of NMDA
receptors
Decreased GABA
• Decreased binding of
GABA and
benzodiazepines
• Decreased Cl- currents in
response to GABA
• Decreased glutamate
decarboxylase activity
• Interfere with GABA
93
84. • Strategies in treatment of epilepsy
– 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 94
85. Antiseizure /antiepileptic drugs
• 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 enhancer
• Vigabatrin, tiagabine, gabapentine
95
86. Phenytoin
• 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
87. Phenytoin cont…
• 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)
88. Carbamazepine
• 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 as enzymes of other drugs
• SEs:
– Drowsiness, headache, dizziness & incoordination
– Allergic reactions, rare but sever aplastic anemia
– Most SEs occur at first therapy & tolerance develops
– Toxicity is low as compared to phenytoin
89. Ethosuximide
• 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)
90. GABA transmission enhancers
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
91. GABA transmission enhancers cont…
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
92. GABA transmission enhancers cont…
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
93. GABA transmission enhancers cont…
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
94. Clinical Uses of Antiepileptic Drugs
• 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
104
95. Antidepressants
Depression
• Life-time prevalence is about 15 % although in women it is as high
as 25%
• Typical symptoms
Depressed mood (feels sad or empty, tearful)
Loss of interest or pleasure
Decreased energy or increased fatigability
Loss of confidence or self-esteem
Unreasonable feelings of guilt
Recurrent thoughts of death or suicide
Agitation or retardation
105
96. Depression
• 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
106
97. Tricyclic Antidepressants
• block norepinephrine and serotonin reuptake into the neuron
• TCAs also block serotonergic, α-adrenergic, histaminic, and
muscarinic receptors
Therapeutic uses:
• Treating moderate to severe depression
• Bed-wetting in children (imipramine)
• To treat migraine headache and chronic pain syndromes
(neuropathic pain) (amitriptyline)
• Insominia
107
99. Tricyclic Antidepressants
• Adverse effects:
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 H1 receptors: sedation, weight gain
Erectile dysfunction in men and anorgasmia in women
109
100. Monoamine Oxidase Inhibitors
• Monoamine oxidase (MAO) is a mitochondrial enzyme which
functions as a “safety valve” to oxidatively deaminate and
inactivate any excess neurotransmitter molecules
(norepinephrine, dopamine, and serotonin).
Therapeutic uses
• Depressed patients who are unresponsive or allergic to TCAs
• MAOIs are considered to be last-line agents
110
102. Monoamine Oxidase Inhibitors
Adverse effects
• 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 tyramine-
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103. Selective Serotonin Reuptake Inhibitors (SSRI)
• Specifically inhibit serotonin reuptake
• Have little blocking activity at muscarinic, α-adrenergic, and
histaminic H1 receptors
Common side effects associated with TCAs, such as
orthostatic hypotension, sedation, dry mouth, and blurred
vision, are not commonly seen with the SSRIs
• The drugs of choice in treating depression
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106. SSRIs
• Adverse effects
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
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108. Psychosis
Psychosis: a group of severe mental disturbance with loss of
contact with reality
The term "psychosis" denotes a variety of mental disorders:
- Delusions (false beliefs), hallucinations, and disorganized
thinking
Neurosis- mental disturbance with intact contact with reality
E.g Anxiety, phobia, compulsive disorder
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109. Psychosis..
Psychosis may be part of mood disorder
- Schizophrenia (severe thought disorder)
- Mania (elevated mood)
- Depression
- Toxic psychosis (drug induced)
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110. Schizophrenia
Schizophrenia (severe thought disorder)
- characterized by delusions, hallucinations, disorganized
thinking and speech, abnormal motor behavior, and
negative symptoms
- as common as DM (1%)
- starts on adult age
- increased ventricular size and decreased gray matter, have
been reported
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111. Schizophrenia...
Etiology & Pathogenesis
• Although there is strong evidence that schizophrenia has a
biologic basis, the exact etiology is unknown.
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 viral infections)
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112. Neuro-chemical theories
Dopamine hypothesis of schizophrenia suggests that
schizophrenia results from excess activity at dopamine
synapses in certain areas of the brain.
Glutamate hypothesis of schizophrenia suggests the problem
relates partially to deficient activity at glutamate receptors.
• Especially in the prefrontal cortex
Serotonin hypothesis of schizophrenia suggests that results
from excess activity of 5-HT.
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Schizophrenia….
113. Symptoms of schizophrenia
Positive symptoms
Added to personality
- Delusions &
hallucinations
- Disorganized speech
(association disturbance)
- Behavior disturbance
(disorganized or
catatonic), and illusions.
Negative symptoms
Removed from personality
- Alogia (poverty of speech)
- Avolition (lack of willpower)
- Flat affect
- Anhedonia
- Social isolation
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Cognitive symptoms: impaired attention, working memory, and
executive function
+ve symptoms: Due to excess meso-limbic dopamine release
-ve & cognitive symptoms: Due to less meso-corical DA functioning
114. Antipsychotic (Neuroleptic) Agents
Antipsychotic drugs are able to reduce psychotic symptoms in a
wide variety of conditions, including:
- Schizophrenia
- Bipolar disorder
- Drug-induced psychosis
They also improve mood , reduce anxiety and sleep disturbances
But they are not the Rx of choice when these symptoms
are the primary disturbance in non-psychotic patients.
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115. Anti psychotic drugs…..
1st generation (conventional, typical, or traditional)
- D2 antagonists
- Strongly bind with D2 with longer duration
- Manage positive symptoms
- Block mesolimbic & other dopaminergic pathways (nigro straital
path ways……)
- Hence, Extra Pyramidal Side Effects (less dopamine, higher
(unbalanced) Ach)
Affect motor & movement
- Neuroleptic refers to the tendency of these drugs to cause
neurologic side effects, particularly EPS
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117. Anti psychotic drugs….
Atypical (2nd generation, modern drugs)
Strong 5H2A antagonists; weak & transient D2 antagonists
Characteristics features of atypical antipsychotics
- Less (none) EPS and tardive dyskinesia
- Lack of effect on serum prolactin
- Greater efficacy for refractory schizophrenia
- Greater activity against negative symptoms
• Clozapine is actually the only atypical agent which fulfills all of
the criteria stated above.
- Atypicals associated with a higher risk of metabolic side effects,
such as Diabetes, hypercholesterolemia, and weight gain
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119. Dopamine Vs Serotonin
Serotonin is known to exert a regulatory effect on
dopaminergic receptors or dopamine release.
Serotonin tonically inhibits dopamine release
Therefore, 5-HT2A antagonism should enhance dopaminergic
transmission.
It has been proposed that the atypical properties of
antipsychotics (efficacy against negative symptoms and low
propensity to produce EPS) are due in part to augmentation of
dopaminergic function via 5-HT2A blockade in the mesocortical
and nigrostriatal pathways and limbic specificity.
121. Actions ….
Antiemetic effects
- With the exception of aripiprazole, most have antiemetic
effects that are mediated by blocking D2 receptors of the CTZ
Olanzapin has multiple actions
- Also used for Anxiety, depression , mania & OCD
Aripiprazole
- Has partial agonist activity at D2 and 5-HT1A receptors and
antagonist activity at serotonin 5-HT2A receptors.
- Is a functional antagonist at D2 receptors under
hyperdopaminergic conditions but exhibits functional agonist
properties under hypodopaminergic conditions. 133
122. Pharmacokinetics
- Show variable absorption that is unaffected by food (except for
ziprasidone and paliperidone, the absorption of which is
increased with food).
- Non polar and have a large VD
- Metaolized by CYP450 (most with CYP2D6) system in the liver
- Some metabolites are active (quetiapine, risperidone,
haloperidol, chlorpromazine, aripiprazole, clozapine )
- Polymorphism in CYP1A2 can cause decreased metabolism of
clozapine.
- Eating or drinking within 10 minutes of asenapine sublingual
administration reduces bioavailability.
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123. Pharmacokinetics…
- Most antipsychotics have half-lives of elimination in the range of 20
to 40 hours.
- After dosage stabilization, most antipsychotics (except quetiapine
and ziprasidone) can be dosed once daily
- long-acting injectable (LAI) formulations are available
• With partial or poor adherence, a long-acting injectable
antipsychotic should be considered (eg, risperidone
microspheres, paliperidone palmitate, extended-release
olanzapine, haloperidol decanoate, or fluphenazine
decanoate).
• ↑DOA (2 to 4 weeks)
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124. Therapeutic uses
Treatment of schizophrenia
Prevention of nausea and vomiting: The older antipsychotics
(most commonly, prochlorperazine) are useful in the treatment
of drug-induced nausea
Chlorpromazine is used to treat intractable hiccups
For treatment of the motor and phonic tics of Tourette disorder-
Pimozide
Risperidone and Aripiprazole are approved for the
management of disruptive behavior and irritability secondary to
autism
Neuroleptic anesthesia-Droperidol
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125. Adverse effects
Anticholinergic Effects
- Most likely to occur with low potency 1st generation
antipsychotics
- include impaired memory, dry mouth, constipation,
tachycardia, blurred vision, inhibition of ejaculation, and
urinary retention
- Elderly patients are especially sensitive to these side effects
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126. Central Nervous System
a) Extrapyramidal effects
- Due to relative excess of cholinergic influence
- More common with highly potent FGA
- Time and Dose dependent
- Drugs that exhibit strong anticholinergic activity, such as
thioridazine, show fewer extrapyramidal disturbances among
typical drugs
- Atypical antipsychotics –less EPSEs
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127. CNS…ADR
a) Extra pyramidal effects (EPSEs):
- Dystonias (prolonged tonic muscle contractions)hrs to days
- Akathisia (motor restlessness) days to weeks
- Pseudo parkinsonism(Akinesia, tremor, rigidity) weeks to
months
- Tardive dyskinesia (involuntary movements, usually of the
tongue, lips, neck, trunk, and limbs) months to years
b)Poikilothermia-Affecting thermoregulation at hypothalamus
(condition in which body temperature varies with the
environment)-Hyperpyrexia & hypothermia
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129. CNS…ADR
c) Neuroleptic malignant syndrome (esp. haloperidol)
- A rare (0.5% to 1% of patients) but potentially lethal adverse
effect
- The cardinal features includes
- Muscular rigidity
- Hyperthermia
- Autonomic dysfunction (unstable BP, tachycardia,
diaphoresis, tachypnea, and urinary or fecal incontinence)
- Altered consciousness
- The risk is more in FGAs than for SGAs
- Dantrolene, Bromocriptine & Amantadine may be helpful
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130. CNS…ADR
d) Sedation and cognition
- Due to CNS depression and antihistaminic effects
- Administration of most or the entire daily dose at bedtime can
decrease daytime sedation and may eliminate the need for
hypnotics.
- Compared to FGAs, the SGAs have shown cognitive benefits
e) Seizures
- All patients treated with antipsychotics have an increased risk of
seizures.
- The highest risk for antipsychotic-induced seizures is with the use
of chlorpromazine or clozapine
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131. Endocrine system ADR
a) Increased prolactin (Block D2 at anterior pituitary)- causing
amenorrhea, galactorrhea, gynecomastia, infertility, and
decreased libido
• These effects may be dose related and are more common (up
to 87%) with the use of FGAs.
b) Significant weight gain (5-HT2C receptors blockade)
- frequent with antipsychotic therapy involving SGAs, but
ziprasidone, aripiprazole, asenapine, and lurasidone cause
minimal weight gain
c) Glucose and lipid profiles increased (high prevalence of
Type 2DM) -Olanzapine and clozapine have the highest risk
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132. Hematologic System
• Antipsychotic can cause transient leukopenia, but it usually
does not progress to clinical significance
• Agranulocytosis reportedly occurs in 0.01% of patients
receiving FGAs, and it may occur more frequently with
chlorpromazine and thioridazine.
• The risk of developing agranulocytosis with clozapine is
approximately 0.8%.
• The risk of severe agranulocytosis necessitates frequent
monitoring of WBC counts otherwise severe infection
develops including myocarditis
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133. Use in pregnancy and lactation
• a slightly increased risk of birth defects with low-potency FGAs
• women taking FGAs have a greater than two-fold increased risk
of preterm birth
• Antipsychotics appear in breast milk (milk:plasma ratios of
0.5:1)
• Use of clozapine (highly concentrated in milk) during breast-
feeding is not recommended
• no relationship between haloperidol use and teratogenicity
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134. Selection of an Antipsychotic
In all pts, the selection of a specific antipsychotic agent
should be individualized.
The choice of a specific medication is usually based on a
number of factors and is frequently more art than science.
Important factors include
- prior experience (efficacy and side effects)
- ease of attaining a therapeutic dose
- available dosage forms
- formulary or cost considerations
135. Selection of an Antipsychotic…
Most antipsychotics except clozapine and ziprasidone can be
safely given once a day.
Treatment is initiated at a subtherapeutic dose and gradually
titrated upward to an effective dose.
This approach is taken to allow the patient to develop
tolerance to adverse events
Once a patient has been stabilized or has become tolerant to
the adverse effects, the goal is to give medication once a
day, usually at bedtime.
136. Selection of an Antipsychotic…
2nd agents are generally used as first-line therapy for
schizophrenia to minimize the risk of debilitating EPS
associated with the first-generation drugs
Refractory patients:
- Clozapine has shown to be an effective
- But, Its clinical use is limited to refractory patients
because of serious adverse effects.
- Good for suicidal attempting patients
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