CNS Pharmacology (Medlive by DR Priyanka)

CNS PHARMACOLOGY
Dr. PRIYANKA SACHDEV , MD
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CNS

ALCOHOLS

SAQ
1. Explain how disulfiram produces aversion for ethyl alcohol.

2. Pharmacological basis of Ethanol in methanol poisoning
3. Describe Pharmacological basis for the use of 4-methyl
pyrazole in the treatment of methyl alcohol poisoning.
4.Pharmacological basis of: Disulfiram in chronic alcoholism.
5. Treatment of methanol poisoning.
6. Compare uses & actions and contrast: Ether and Halothane.
7. Disulfiram
8. Alcohol dependence.

Alcohols
•Ethyl Alcohol
•Methyl Alcohol

ETHYL ALCOHOL (Ethanol)

HEADINGS
• Introduction
• Preparation
• ALCOHOLIC BEVERAGES types
• PHARMACOLOGICAL ACTIONS
• Pharmacokinetics
• Interactions
• Contraindications
• Toxicity
ETHYL ALCOHOL (Ethanol)
•By alcohol we mean ethyl alcohol
(CH3CH2OH)
•Hydroxyl and ethyl moiety confer both

hydrophilic and lipophilic properties, thus
it's an amphipathic molecule.
Preparation
•Starchy cereals, e.g. barley, when
soaked produce maltose which can then
be fermented by yeast to produce
alcohol.

•It is prepared from sugar oxidation by
yeast (fermentation)

Distillation
•Distillation is the process to purify by
vaporization and then condensing with
cold.

ALCOHOLIC BEVERAGES
•A. Malted liquors
•B. Wines
•C. Spirits

Malted liquors
•Obtained by fermentation of germinating
cereals
•Undistilled
•Alcohol content is low (3–6%)

•e.g. Beers, Stout.
Wines
•Produced by fermentation of natural sugars
as present in grapes and other fruits.
•These are also undistilled.
•alcohol 16–22%
Spirits
•These are distilled after fermentation
•Though the alcohol content of these can vary

from 40–55%, in India (and almost
internationally) for all licenced brands it is
standardized to 42.8% v/v or 37% w/w.
•e.g. Rum, Gin, Whiskey, Brandy, Vodka, etc.

PHARMACOLOGICAL ACTIONS

• 1. Local effects
• 2. CNS
• 3. CVS
• 4. Blood
• 5. Body temperature
• 6. Respiration
• 7. Liver
• 8. Kidney
• 9. Sexual function
• 10. Teratogenicity

1.Local effects
• On application to skin, it cools by evaporation. Hence alcohol
sponging used for fever.
• Rubbing on skin produces redness and burning sensation, so

used as counterirritant and rubefacient
• Precipitation and dehydration of proteins i.e. astringent effect.
• Hardening and cleaning of the skin → prevention of sweating

so used in ridden patient to prevent bedsores decubitus ulcer.

•Precipitation of bacterial protein and
dissolution of membrane lipids →
Bactericidal, to nearly all the pathogenic
organisms but not the spores, fungus
and viruses
•70% alcohol is effective to kill 90%
bacteria within 2 minutes. Dr. PRIYANKA SACHDEV
•70% concentration is preferred over 100%
since in higher concentration it gets early
evaporation not allowing the sufficient time for
contact.
•On raw surface it is irritating and forms a

coagulum (a hard covering), under which
bacteria may survive, thus it is not used for an
open lesion.
2.CNS:
•The basic effect of alcohol is to depress various
functions of CNS.
•The apparent stimulation is due to depression

of inhibitory mechanism.
•The cortex and the reticular activating system

are most sensitive to alcohol
•The cortex is released from its integrated
control
• There is loss of inhibition and person enjoys social company.
• He is overconfident, freely speaking and enjoying.
• AIcohol could be considered as a 'great mimicker’.

• The mood may swing to extreme happiness or extreme sadness.

•The effect on CNS is directly
proportional to the concentration in
blood.
•The depression progresses as the blood

concentration increases.
•Hangover (headache, dry mouth, laziness,
disturbed mood, impaired performance)
may occur the next morning.
•InitiaIIy alcohol exerts anticonvulsant

action, but this is followed by lowering of
threshold → seizures may be precipitated
in epileptics.
3. CVS
• The effects are dependent on dose.
• Small doses:
• Produce only cutaneous (especially on the face) and gastric
vasodilatation.
• Skin is warm and flushed
• BP is not affected
Moderate doses:
• Cause tachycardia
• Mild rise in BP due to increased muscular activity and sympathetic
stimulation.
Large doses:
•cause direct myocardial as well as vasomotor
centre depression
•There is fall in BP.
•Excessive alcohol or withdrawal may lead to

atrial fibrillation, which is referred as 'Holiday
Heart'.
4. Blood
• Regular intake of small to moderate amounts of alcohol (1–2
drinks) has been found to raise HDL-cholesterol levels and
decrease LDL oxidation.
• This may be responsible for the 15–35% lower incidence of

coronary artery disease in such individuals.
• Protection is lost if > 3 drinks are consumed daily.
• But it is considered inapproptiate to advise nondrinkers to start

drinking on this account, since other adverse consequences
may more than nullify this benefit.
5. Body temperature
•Alcohol is reputed to combat cold.
•It does produce a sense of warmth due to
cutaneous vasodilatation
•But heat loss is actually increased in cold

surroundings.
•High doses depress temperature regulating
centre.
6. Respiration
• Brandy or whiskey are reputed as respiratory stimulants
in collapse.
➢They irritate buccal and pharyngeal mucosa which may

transiently stimulate respiration reflexly.
➢But the direct action of alcohol on respiratory centre is

only a depressant one.

7. Liver:
• Accumulation of fat and proteins in cells lead to cirrhosis
• Cirrhosis is also contributed by malnutrition and vitamins

deficiencies.
• Acetaldehyde produced during metabolism of alcohol appears

to damage the hepatocytes and induce inflammation,

8. Kidney
•Diuresis is often noticed after alcohol intake.
•This is due to water ingested along with drinks

as well as alcohol induced inhibition of ADH
secretion.
•It does not impair renal function.

9. Sexual functions:
•Alcohol is considered as an aphrodisiac (the
substance that stimulates sex drive) due to loss
of inhibition.
•It provokes the desire but takes away the

performance.
• With chronic use there is impotence, testicular

atrophy, gynecomastia and sterility.
10. Teratogenecity:
• Fetal alcohol syndrome characterized by
✓mental retardation,
✓slow growth,
✓microencephaly,
✓facial abnormality,
✓malformations
✓increase risk of infections.
• 1. Local effects
• 2. CNS
• 3. CVS
• 4. Blood
• 5. Body temperature
• 6. Respiration
• 7. Liver
• 8. Kidney
• 9. Sexual function
• 10. Teratogenicity

PHARMACOKINETICS
•Alcohol absorption from the stomach is
slow.
•Absorption from intestines is very fast.
•Peak levels are attained after ~30 min.

•Metabolism of alcohol follows zero order
kinetics, i.e. a constant amount (8–12 ml of
absolute alcohol/ hour) is degraded in unit
time, irrespective of blood concentration.
•Thus, rate of consuming drinks governs

whether a person will get drunk
INTERACTIONS

•1. Alcohol synergises with anxiolytics,
antidepressants, antihistaminics, hypnotics,
opioids
•Marked CNS depression with motor

impairment can occur
•Chances of accidents increase.

• 2. Disulfiram
• It inhibits the enzyme aldehyde dehydrogenase
• When alcohol is ingested after taking disulfiram, the

concentration of acetaldehyde in tissues and blood
rises and a number of highly distressing symptoms
(aldehyde syndrome) are produced

• Flushing
• burning sensation
• throbbing
• Headache
• Perspiration
• Uneasiness
• tightness in chest
• Dizziness
• Vomiting
• visual disturbances
• mental confusion
• postural fainting
• circulatory collapse Dr. PRIYANKA SACHDEV
HEADINGS
• Introduction
• Preparation
• ALCOHOLIC BEVERAGES types
• PHARMACOLOGICAL ACTIONS
• Pharmacokinetics
• Interactions
• Contraindications
• Toxicity
CONTRAINDICATIONS
• 1. Peptic ulcer, hyperacidity and gastroesophageal
reflux patients (alcohol increases gastric secretion
and relaxes LES).
• 2. Epileptics: seizures may be precipitated.
• 3. Severe liver disease
• 4. Unstable personalities: they are likely to abuse it

and become excessive drinkers.
•5. Pregnant women: Even moderate
drinking during pregnancy can produce
foetal alcohol syndrome resulting in
intrauterine and postnatal growth
retardation, low IQ, microcephaly, cranio-
facial and other abnormalities, and
immunological impairmen

Guidelines for safe drinking

•On an average 1–2 drinks per day is usually
safe.
•Not more than 3 drinks on any one occasion.
•Consumption of >3 drinks per day is associated

with documented adverse health effect
TOXICITY
•Acute alcoholic intoxication
•Chronic alcoholism

Acute alcoholic intoxication
• Unawareness
• unresponsiveness
• stupor
• Hypotension
• Gastritis
• Hypoglycaemia
• Respiratory depression
• Collapse
• coma and death Dr. PRIYANKA SACHDEV
Treatment:
•The first priority is to maintain patent
airway → Tracheal intubation and
positive pressure respiration may be
needed if it is markedly depressed.
•Induction of vomiting.
•Gastric lavage with sodium bicarbonate.
•I/v sodium bicarbonate to correct acidosis
•Maintenance of fluid and electrolyte balance
•Correction of hypoglycaemia by glucose
infusion
•Thiamine (100 mg in 500 ml glucose solution
infused i.v.) should be added.
•Recovery can be hastened by haemodialysis
TOXICITY
•Acute alcoholic intoxication
•Chronic alcoholism

Chronic alcoholism
•Tolerance
•Dependence
•Withdrawal syndrome

Tolerance
•On chronic intake, tolerance develops to

subjective and behavioral effects of
alcohol, but is generally of a low degree.

Dependence
•Psychic dependence occurs only on

heavy and round-the-clock drinking (if
alcohol is present in the body
continuously).

Withdrawal syndrome
•When a physically dependent subject stops
drinking, withdrawal syndrome appears
within a day.
•Its severity depends on the duration and
quantity of alcohol consumed by the subject.
•It consists of anxiety, sweating, techycardia,
tremor, impairment of sleep, confusion,
hallucinations, delirium tremens,
convulsions and collapse.
Treatment

Social and motivational
therapy

Substitution therapy
•Alcohol is abruptly withdrawal and substituted
with a long acting agent such as diazepam (BZDs
are DOC)
•The mean total dose of diazepam needed for

loading is 80-120 mg (4-5 doses over 8-10 hours).
•A dose below 180 mg is suffiecient in more than

90% of patients. Dr. PRIYANKA SACHDEV
Naltrexone:
• Several studies have demonstrated involvement of
opioid system in the pleasurable reinforcing effects of
alcohol through dopamine mediated reward function
• Reinforcement is weakened.
• It helps prevent relapse of alcoholism.
• It reduced alcohol craving, number of drinking days and

chances of resumed heavy drinking.
Acamprosate
•It is a weak NMDA-receptor antagonist with
modest GABAA receptor agonistic activity
•It is being used in USA, UK and Europe for

maintenance therapy of alcohol abstinence.

Disulfiram aversion therapy
(Antabuse )
•It inhibits the enzyme aldehyde
dehydrogenase

•When alcohol is ingested after taking
disulfiram, the concentration of
acetaldehyde in tissues and blood rises
and a number of highly distressing
symptoms (aldehyde syndrome) are
produced
• Flushing
• burning sensation
• throbbing
• Headache
• Perspiration
• Uneasiness
• tightness in chest
• Dizziness
• Vomiting
• visual disturbances
• mental confusion
• postural fainting
• circulatory collapse Dr. PRIYANKA SACHDEV
• Disulfiram aversion therapy is indicated in abstinent
subjects who sincerely desire to leave the habit.
• After making sure that the subject has not taken

alcohol in the past 12 hours, disufiram is given at a
dose of 500 mg/day for one week followed by 250 mg
daily.
• The subject’s resolve not to drink is reinforced by the

distressing symptoms that occur if he drinks a little
bit.
METHYL ALCOHOL
(Methanol, Wood alcohol)
•Methyl alcohol is added to industrial rectified
spirit to render it unfit for drinking.
•It is only of toxicological importance.
•Mixing of methylated spirit with alcoholic

beverages by bootlegers or its inadvertent
ingestion results in methanol poisoning.
PHARMACOKINETICS
•Methanol is metabolized to formaldehyde
and formic acid by alcohol and aldehyde
dehydrogenases respectively, but the rate
is 1/7th that of ethanol.

•Like ethanol, metabolism of methanol
also follows zero order kinetics
•Methanol also is a CNS depressant, but

less inebriating than ethanol.

Methanol toxicity
•Toxic effects of methanol are largely due to
formic acid, since its further metabolism is slow
and folate dependent.
•A blood level of >50 mg/dl methanol is

associated with severe poisoning.
•Even 15 ml of methanol has caused blindness
•30 ml has caused death
•Fatal dose is regarded to be 75–100 ml.
Manifestations
• Vomiting,
• Headache,
• Epigastric pain,
• Uneasiness,drunkenness, disorientation,
• Tachypnoea, dyspnoea, bradycardia and hypotension.
• Delirium and seizures may occur
• The patient may suddenly pass into coma.
• Acidosis is prominent and entirely due to production of formic acid.
• The specific toxicity of formic acid is retinal damage.
• Blurring of vision, congestion of optic disc followed by blindness
always precede death which is due to respiratory failure

Treatment
1. Keep the patient in a quiet, dark room
2. Protect the eyes from light.
3. Supportive measures to maintain

ventilation and BP should be
instituted
•4. Gastric lavage with sod. bicarbonate if the
patient is brought within 2 hours of ingesting
methanol.
•5. Combat acidosis by i.v. Sod. bicarbonate

infusion. This is the most important measure,
prevents retinal damage and other symptoms
•6. Pot. chloride infusion is needed only when

hypokalemia occurs due to alkali therapy.
• 7. Ethanol is preferentially metabolized by alcohol
dehydrogenase over methanol.
• At a concentration of 100 mg/dl in blood it saturates alcohol
dehydrogenase and retards methanol metabolism.
• This helps by reducing the rate of generation of formaldehyde
and formic acid.
• Ethanol (10% in water) is administered through a nasogastric

tube
• loading dose of 0.7 ml/kg is followed by 0.15 ml/kg/hour.

• 8. Fomepizole (4-methylpyrazole) is a specific inhibitor
of alcohol dehydrogenase and the drug of choice for
methanol poisoning by retarding its metabolism.
• A loading dose of 15 mg/kg i.v. followed by 10 mg/kg

every 12 hours till serum methanol falls below 20
mg/dl, has been found effective and safe.
• It has several advantages over ethanol, viz. longer t½

and lack of inebriating action, but is not available
commercially in India.

9. Haemodialysis: clears methanol as
well as formate and hastens recovery.

Ethylene glycol poisoning
•Same as methanol

SAQ
1. Explain how disulfiram produces aversion for ethyl alcohol.

2. Pharmacological basis of Ethanol in methanol poisoning
3. Describe Pharmacological basis for the use of 4-methyl
pyrazole in the treatment of methyl alcohol poisoning.
• 4.Pharmacological basis of: Disulfiram in chronic alcoholism.
• 5. Treatment of methanol poisoning.
• 6. Compare uses & actions and contrast: Ether and Halothane.
• 7. Disulfiram
• 8. Alcohol dependence.

Sedatives and Hypnotics

SAQ
• 1. Pharmacological basis of Diazepam preferred over phenobarbitone
as a sedative agent.
• 2. Pharmacological basis of: Forced alkaline diuresis in the treatment
of Barbiturate Poisoning.
• 3. Compare uses & actions and contrast: Diazepam &
Phenobarbitone.
• 4. Why Diazepam is preferred over Phenobarbitone as hypnotic
• 5. Why benzodiazepines preferred over barbiturates as sedative and
hypnotic agents ?
• 6. Compare and contrast: Benzodiazepines and Barbiturates.
• 7. Why benzodiazepines are preferred over barbiturates as
hypnosedatives ? Write four uses of benzodiazepines.
•9. Chlordiazepoxide.
•10. Phenobarbitone mechanism of action
•11. Pharmacological basis of:Mannitol in
barbiturate poisoning.
•12. Diazepam mechanism of action
•13. Therapeutic uses of barbiturates.
•14. Therapeutic uses of benzodiazepines.
LAQ
• 1. Discuss mechanism of action of benzodiazepines. Describe therapeutic
uses and adverse effects of diazepam.
• 2. Classify antianxiety drugs. Write in short mechanism of action, uses and
contrairidications of Diazepam.
• 3. Classify sedative and hypnotic drugs. State advantages of
benzodiazepines over barbiturates. Describe mechanism of action and
therapeutic uses of benzodiazepines.
• 3. Describe the pharmacology & therapeutic uses of barbiturates. Add a
note on treatment of its poisoning.
• 4. Classify hypnotics. Give the desirabie properties in an ideal hypnotic.
• Describe the various uses of barbiturates.
Sedatives and Hypnotics
•Hypnotic is the agent 'that produces sleep
(Hypnos (in Greek) = Sleep).
•Drugs are used to treat insomnia
•Sedative is an agent that quietens the patient

and makes him drowsy without inducing sleep.
•Calms the patient, i.e. it reduces tension and
anxiety.
Sleep
•The duration and pattern of sleep varies
considerably among individuals.
•Age has an important effect on quantity
and depth of sleep.
•Sleep is an architectured cyclic process

BARBITURATES

HEADINGS
•Introduction
•Classification
•MOA
•Pharmacological actions
•Interactions
•Barbiturates are inferior to BZP
•Uses
•Adverse effects
•Barbiturate Poisoning
BARBITURATES
•Barbiturates are substituted derivatives
of barbituric acid (malonyl urea).
•Barbituric acid as such is not a hypnotic

but compounds with alkyl or aryl
substitution on C5 are
Classification

Mechanism of Action
•GABA is an inhibitory neurotransmitter
•Glutamate is an exitatory neurotransmitter

NormaIIy

GABA (gamma amino butyric acid)
• GABA (gamma amino butyric acid) is an inhibitory
neurotransmitter in CNS
• GABA is synthesized from glutamate by GAEL (glutamic

acid decarboxylase).
• GABA is removed mainly by neuronal uptake and partly

by deamination catalyzed by GABA transaminase.
• It acts on two different types of receptors namely GABAa

and GABAb
GABAa receptor
•GABAa receptor is an ionotropic receptor,

directly coupled to chloride channels
•Ionotropic GABAa receptor has a

pentameric structure consisting of 2α, 2β
and 1γ subunits.
GABA
GABAA-receptor activation
It increases flow of chloride ions into the cell,
Hyperpolarizes the neurons
Inhibition

MOA of BARBITURATES
•3 Mechanisms

GABA facilitatory action

BARBITURATE
Binds to an accessory site on GABAa receptor (located either on α or β subunit)
Increases affinity of GABA receptor to GABA
Increasing the lifetime of Cl' channel opening caused by GABA (GABA facilitatory
action)
Inhibition
GABA mimetic action

At high concentrations
barbiturates directly activates GABAa receptors
Increase Cl conductance (GABA mimetic action)
Inhibition
BARBITURATE
Inhibit glutamate-induced depolarization

through AMPA receptors

Action on CNS
• Barbiturates depress all areas of CNS, but the reticular
activating system is most sensitive.
• Barbiturates produce dose-dependent effects:

sedation → sleep → anaesthesia → coma.
1. Sleep latency (time taken to fall asleep) is shortened

2. Sleep duration is increased.
3. Sleep architecture is disturbed (REM, stage 3,4 sleep
are decreased).
•The sleep is arousable, but the subject may
feel confused and unsteady if waken early.
•Night awakenings are reduced.
•Hangover (dizziness, distortions of mood,

irritability and lethargy) may occur in the
morning after a nightly dose.
•Barbiturates can impair learning, shortterm
memory and judgement
•They have no analgesic action , may even

cause hyperalgesia (Diazepam has analgesic
action).
• Barbiturates have anticonvulsant property

Interactions
1. Barbiturates induce several hepatic
microsomal enzymes and increase the rate of
their own metabolism as well as that of
many other drugs -→
•warfarin, steroids (including
contraceptives), tolbutamide, griseofulvin,
chloramphenicol, theophylline
•2. Additive action with other CNS depressants
—alcohol, antihistamines, opioids, etc.
•3. Sodium valproate increases plasma

concentration of phenobarbitone.
•4. Phenobarbitone decreases absorption of

griseofulvin from the g.i.t
USES
1. Phenobarbitone in epilepsy
2. Thiopentone in anaesthesia
•No other barbiturate is used now.

•As hypnotic and anxiolytic they have been
superseded by BZDs.
Adverse Effects
• Drowsiness/hangover (residual depression of CNS and
feeling tiredness).
• Sleep disturbances on withdrawal.
• Paradoxical excitement especially in debilitated or aged

patients.
• Respiratory depression, cough, sneezing, laryngospasm,

hiccough, etc.

• Drug automatism: Owing to amnesia, patient gets confused and he takes
repeated doses without remembering that earlier dose has been taken.
• Hypersensitivity reactions.
• Tolerance/drug dependence.
• Rapid i / v injection carries the risk of CVS collapse.
• Increased vitamin D metabolism can lead to osteomalacia.
• Increased vitamin K metabolism can lead to bleeding.

Barbiturate Poisoning
Excess amount of a barbiturate leads to →
➢Unconsciousness
➢ Respiratory depression
➢circulatory collapse
➢shock
•There may be renal failure, GI bleeding,

pulmonary edema and/or cardiac irregularity.
Management
1.Gastric lavage/emesis/activated
charcoal/saline cathartic.
2.Airway/oxygen.
3.I/v fluid and dopamine to raise BP.
4.If renal and cardiac functions are satisfactory
and patient is hydrated, forced alkaline
diuresis for rapid renal excretion.
5.Hemodialysis if there's renal failure.
REMEMBER
•There is no specific antidote for barbiturates.

BENZODIAZEPINES

HEADINGS
•Classification
•MOA
•Pharmacological actions
•Pharmacokinetics
•BZP are superior to
Barbiturates Uses
•Adverse effects
MNEMONIC

Mechanism of action of
benzodiazepines (BZDs)
GABA facilitatory effect onIy

BENZODIAZEPINE
Binds to an accessory site on GABAa receptor (on the interface of α and γ

subunits)
More frequent opening of chloride channels (increases frequency not duration)

(GABA facilitatory effect)
Cl enters in the cells
Hyperpolarization
Inhibition
REMEMBER
•BZDs do not themselves increase Cl"
conductance, i.e. they have only GABA
facilitatory but no GABA mimetic action.
•Barbiturates have both GABA facilitatory

and GABA mimetic actions
•BZDs require GABA to activate the
receptor hence safe since effect depends
on release of GABA.
•Barbiturates do not require GABA to

activate the receptor hence not safe

REMEMBER
• The GABAA antagonist bicuculline antagonizes BZD action in a
noncompetitive manner.
• The competitive BZD-antagonist flumazenil blocks the sedative

action of BZDs
• BZD-inverse agonists like dimethoxyethyl-carbomethoxy-β-

carboline (DMCM) inhibit GABA action and are convulsants.
• Picrotoxin : Blocks Cl¯ channel noncompetitively; acts on

picrotoxin sensitive site
Action on CNS
•Sedation.
•Hypnosis (less REM suppression).
•Anticonvulsants but not preferred for

routine management of epilepsy owing
to development of tolerance.
• Anterograde amnesia: They impair recent memory. Amnesia occurs
for the events occurring after the administration of drug that
creates an illusion of anesthesia. True general anesthesia is not
caused since awareness usually persists.
• Muscle relaxation—clonazepam and diazepam relieve muscles

spasticity. However tolerance may develop.
• Analgesia: There's transient analgesia after i/v administration, but

no hyperalgesia.
• Antidepressant—alprazolam shows additional antidepressant

effect.
Advantages of BZDs
• 1. BZDs have a high therapeutic index. Ingestion of even 20
hypnotic doses does not usually endager life →
Benzodiazepines have flat dose response curves.
• 2. Hypnotic doses do not affect respiration or cardiovascular

function.
• 3. BZDs have practically no action on other body system.
• 4. BZDs cause less distortion of sleep architecture —> rebound

phenomena on discontinuation of regular use are less marked.
•5. BZDs do not alter disposition of other drugs
by microsomal enzyme induction
•6. They have lower abuse liability -»tolerance

is mild, psychological and physical dependence
and withdrawl syndrome are less marked
•7. A specific BZD antagonist ‘flumazenil” is

available which can be used in case of
poisoning.
USES
•Anxiety: Alprazolam, chlordiazepoxide, diazepam,
lorazepam.
•Insomnia: Triazolam, temazepam, oxazepam,

flurazepam.
•Epilepsy:
1.Absence seizures - Clonazepam
2.Convulsive emergencies-Diazepam, lorazepam
• Pre-anesthetic medication : Midazolam, diazepam, and
lorazepam.
• For procedures like endoscopy, ECT, cardioversion and minor

surgical or dental procedures to relieve anxiety, tension and
to produce amnesia (to decrease patient's recall):
Midazolam.
• Muscle spasm and spasticity: In muscular strain, spasticity in

degenerative disorders such as multiple sclerosis, cerebral
palsy, athetosis, and Stiffman syndrome: Diazepam,
clonazepam.
• Tetanus -to control spasm and convulsions: Diazepam.
• Acute alcohol withdrawal - for relief of acute agitation,

tremor, hallucination and delirium tremens: Diazepam,
chlordiazepoxide, and oxazepam.
• Alcohol addict as substitution therapy: Diazepam.
• Psychosomatic disorders like hypertension, peptic ulcer and

angina to relieve anxiety.

Adverse Effects:
•There may be tiredness, somnolence,
ataxia, headache, vertigo, dizziness and
impaired judgment.
•Prolonged effects and hangover.
•Tolerance.
•Dependence.
•Use for more than two weeks need gradual
tapering.
NEWER DRUGS/
NON-BENZODIAZEPINE AGONISTS

Zalpelon, Zolpidem, Zopiclone
•Chemically they are different but act in
a similar manner on the
benzodiazepine receptors with
selectivity to bind to isoforms
containing α1 subunits

Major differences are→
1.Lack of muscle relaxant and anticonvulsant
effect.
2.Lack of memory impairment.
3.Short duration of action.
4.Effectiveness in sleep onset insomnia.
5.Less suppression of REM.
6.Less drug withdrawal and rebound effect.
Zolpidem
•Zolpidem is a non-benzodiazepine
hypnotic.
•It acts on α1 subunit of BZD receptors.
•It has minimal suppressive effect on REM
sleep → sleep architecture is not
disturbed. Sleep latency is shortened and
sleep duration is prolonged.
• Hangover or withdrawl phenomena on
discontinuation is less than BZDs → less
day time residual sedation
•Flumazenil blocks the depressant action of
BZDs, zolpidem, zoleplon
•Zolpidem is used for short term treatment of

insomnia - Currently it is one of the most
commonly prescribed hypnotic.
•It has no muscle relaxant or anticonvulsant

property
Zopiclone
• Mechanism of action is similar to zolpidem.
•It has no effect on REM sleep and tends to

prolong stage 3 and 4 (BZDs tends to shorten
REM sleep, stage 3 and 4).
•It does not produce hangover or withdrawl

phenomena on discontinuation.
•It is used for short term insomnia and to
wean off insomniacs taking regular BZD
medication.
•Side effects are metallic or bitter after taste,

impaired judgement and alertness,
psychological disturbances, dry mouth.
Zopeplon
• This is the shortest acting of newer non-BZD
hypnotic.
•It does not plolong sleep time, but sleep

latency is shortened -» useful in persons having
difficulty to fall asleep (sleep onset insomnia).
•As with all non-BZD hypnotic, sleep architecture

is less disturbed than BZDs
REMEMBER

SAQ
• 1. Pharmacological basis of Diazepam preferred over phenobarbitone
as a sedative agent.
• 2. Pharmacological basis of: Forced alkaline diuresis in the treatment
of Barbiturate Poisoning.
• 3. Compare uses & actions and contrast: Diazepam &
Phenobarbitone.
• 4. Why Diazepam is preferred over Phenobarbitone as hypnotic
• 5. Why benzodiazepines preferred over barbiturates as sedative and
hypnotic agents ?
• 6. Compare and contrast: Benzodiazepines and Barbiturates.
• 7. Why benzodiazepines are preferred over barbiturates as
hypnosedatives ? Write four uses of benzodiazepines.
•9. Chlordiazepoxide.
•10. Phenobarbitone mechanism of action
•11. Pharmacological basis of:Mannitol in
barbiturate poisoning.
•12. Diazepam mechanism of action
•13. Therapeutic uses of barbiturates.
•14. Therapeutic uses of benzodiazepines.
LAQ
• 1. Discuss mechanism of action of benzodiazepines. Describe therapeutic
uses and adverse effects of diazepam.
• 2. Classify antianxiety drugs. Write in short mechanism of action, uses and
contrairidications of Diazepam.
• 3. Classify sedative and hypnotic drugs. State advantages of
benzodiazepines over barbiturates. Describe mechanism of action and
therapeutic uses of benzodiazepines.
• 3. Describe the pharmacology & therapeutic uses of barbiturates. Add a
note on treatment of its poisoning.
• 4. Classify hypnotics. Give the desirabie properties in an ideal hypnotic.
• Describe the various uses of barbiturates.
Antiparkinsonian Drugs

SAQ
• 1. A patient of Parkinsonism stabilised on L-DOPA takes a
multivitamins preparation on his own. What are the possible
consequences ?
• Explain why they occur ?
• 2. Explain why l-dopa is not useful is drug induced Parkinsonism.
• 3. Levodopa & Carbidopa in parkinsonism.
• 4. Levodopa.
• 5. Amantidine.
• 6. Pharmacological basis for: Levodopa parkinsonism.
• 7. Amantidine in Parkinsonism.
• 8. Why Levodopa not effective in drug induced parkinsonism.
LAQ
• 1. Explain pharmacoogica basis of Levodopa in Parkinsonism

and explain its advantages and disadvantages ?
• 2. Drugs used for Parkinsonism. Describe action and adverse
effects of Levodopa.
• 3. Classify Antiparkinsonian drugs. What is the rationale of use
of Levodopa with carbidopa ?

Antiparkinsonian Drugs
•These are drugs that have a therapeutic
effect in parkinsonism.

Parkinsonism
• It is an extrapyramidal motor disorder
characterized by
1. Tremor
2. Rigidity
3. Hypokinesia
• Secondary manifestations like defective posture

and gait, mask-like face and sialorrhoea;
dementia may accompany
Pathogenesis
•Major pathology is the degeneration of
dopamenergic neurone in substantia nigra and
nigrostriatal tract of basal ganglia.
•An imbalance occurs between

❑Dopaminergic (inhibitory)
❑Cholinergic (facilitatory) system
•Producing motor defect (parkinsonism).

Basal ganglia are rich in iron
In the presence of ferrous iron →Oxidation of DA by MAO-B and

aldehyde dehydrogenase generates hydroxyl free radicals (•OH)
Normally these free radicals are quenched by glutathione
Age-related defect in protective mechanism allows the free radicals to

damage lipid membranes and DNA
Neuronal degeneration of dopamenergic neurone

•Neuronal degeneration of dopamenergic
neurone
•An imbalance occurs between dopaminergic

(inhibitory) and cholinergic (facilitatory)
system
•Producing motor defect (parkinsonism).

Thus for treatment of parkinsonism
•1. Increase brain dopaminergic activity
or
•2. Decrease brain cholinergic activity (though

the cholinergic is not primarily affected, its
suppression tends to restore balance between
cholinergic and dopaminergic system)
LEVODOPA

Introduction
• Dopamine itself cannot cross blood brain barrier (BBB) but
its precursor levo-dopa can cross BBB.
• So Levodopa is inactive by itself, but is the immediate

precursor of the transmitter DA
• Levo-dopa is metabolized by dopa decarboxylase (contains

pyridoxine as co-factor) to dopamine.
• This conversion occurs both in periphery as well as in the

brain
Peripheral conversion
• More than 95% of an oral dose is decarboxylated in
peripheral tissues (mainly in gut and liver)
• Dopamine thus formed acts on heart, blood vessels

and on CTZ.
• About 1-2% of administered levodopa crosses the

BBB is decarboxylated to dopamine which has
therapeutic effect for parkinsonism.

Disadvantages of Peripheral conversion
• 1. Dopamine can not cross BBB (so only 1-2% of
administred levodopa which crosses BBB is effective).
• 2. Dopamine produces peripheral adverse effects.
Peripherally formed dopamine can lead

a) Postural hypotension
b) Arrhythmias.
c) Nausea and vomiting occurs commonly due to CTZ
stimulation by dopamine
•Therefore levo-dopa is always given in
combination with peripheral dopa
decarboxylase inhibitors like carbidopa
or benserazide.

Addition of carbidopa to I-dopa
therapy
1. Increase entry of L-dopa in brain.
2. Decrease adverse effects due to

peripherally formed dopamine

MOA

Levodopa + carbidopa
Peripheral conversion of levodopa by DDC is

prevented by carbidopa
Maximum Levodopa crosses BBB
In brain→ Levodopa is taken up by the surviving

dopaminergic neurones,

In brain→ Levodopa is taken up by the surviving
dopaminergic neurones
Converted to DA by DDC
DA is stored and released as a transmitter.
Balance between dopaminergic (inhibitory) and cholinergic

(facilitatory) system
smoothening movements and reducing muscle tone

ADVERSE EFFECTS
•At the initiation of therapy
•After prolonged therapy

At the initiation of therapy

1. Nausea and vomiting →
•Due to CTZ stimulation by peripherally

formed DA .
•It occurs in almost every patient.
•Tolerance gradually develops and then the
dose can be progressively increased.
•This is reduced by carbidopa

2. Postural hypotension →
•Due to Stimulation of vascular
dopaminergic receptor by peripherally
formed DA
•It is more common in patients receiving
antihypertensives.
•Tolerance develops with continued
treatment and BP normalizes.

3. Cardiac arrhythmias and
Exacerbation of angina→
•Due to β adrenergic action of
peripherally formed DA

4. Alteration in taste
sensation

After prolonged therapy

1. Abnormal movements (dyskinesias)
• Facial tics, grimacing, tongue thrusting, choreoathetoid
movements of limbs
• Their intensity corresponds with levodopa levels.

• No tolerance develops to this adverse effect, but dose
reduction decreases severity.
• Abnormal movements may become as disabling as the original

disease itself, and are the most important dose-limiting side
effects.
• This is not reduced by carbidopa
2. Behavioural effects
•Excessive DA action in the limbic system is
probably responsible (antidopaminergic drugs
are antipsychotic).
•Range from mild anxiety, nightmares, etc. to

severe depression, mania, hallucinations,
mental confusion or frank psychosis.
•Levodopa is contraindicated in patients with
psychotic illness.
•This is not reduced by carbidopa
3. Fluctuation in motor performance
•After 2–5 years of therapy, the level of

control of parkinsonian symptomatology
starts showing fluctuation.
•on-off’ effect.
•With time ‘all or none’ response develops
• On means patient is having no symptoms of Parkinsonism (but
abnormal movements are present)
• Off means patient has full blown symptoms of Parkinsonism

(like no treatment is given).
• This effect is due to short half life (1-2hrs) of l-dopa
• This is reduced by carbidopa

•Levo-dopa should be given carefully in patients
with
1. Active peptic ulcer (increased risk of bleeding)
2. Malignant melanoma (levo-dopa is a precursor

of melanin)
3. Glaucoma Dr. PRIYANKA SACHDEV

REMEMBER
•Considering that oxidative metabolism of DA
generates free radicals which may rather
hasten degeneration of nigrostriatal
neurones, it has been argued that levodopa
therapy might accelerate progression of PD.
•There is no proof yet for such a happening,

•Thus, it may be prudent to delay use of
levodopa and begin with
anticholinergics/ amantadine/selegiline
or newer direct DA agonists in
early/mild/ younger patients.



PERIPHERAL DECARBOXYLASE
INHIBITORS

Drugs
•Carbidopa and benserazide are
extracerebral dopa decarboxylase
inhibitors;

MOA
•They does not cross BBB so there is
inhibition of only peripheral enzyme
•So increases the entry of levodopa in CNS.
•It is combined with levodopa

Benefits of the combination
•1. The plasma t½ of levodopa is
prolonged and its dose is reduced to
approximately 1/4th.
•2. Systemic concentration of DA is

reduced, nausea and vomiting are not
prominent— therapeutic doses of
levodopa can be attained quickly.
•3. Cardiac complications are minimized.
•4. Pyridoxine reversal of levodopa effect

does not occur.
•5. ‘On-off’ effect is minimized since

cerebral DA levels are more sustained.
DOPAMINERGIC AGONISTS
•The DA agonists can act on striatal DA
receptors even in advanced patients
who have largely lost the capacity to
synthesize, store and release DA from
levodopa

MAO-B INHIBITOR

Selegeline (deprenyl) MOA
•Selegeline (deprenyl) inhibitis MAO-B
•So intracerebral degradation of DA is

retarded → therapeutic effect in
parkinsonism.
Advantages
• Administered with levodopa, it prolongs levodopa action→
attenuates motor fluctuations and decreases ‘wearing off’
effect.
• Based on the hypothesis that oxidation of DA and/or

environmental toxins (MPTP-like) in the striatum by MAO to
free radicals was causative in parkinsonism, it was proposed
that early therapy with selegiline might delay progression
of the disorder.
• As an adjuvant to levodopa, it is beneficial in 50–70%

patients and permits 20–30% reduction in levodopa dose
Adverse effects
1. Postural hypotension,
2. nausea,
3. confusion,
4. Accentuation of levodopa induced involuntary
movements and psychosis
5. Selegiline is partly metabolized by liver into
amphetamine which sometimes causes
insomnia and agitation. Selegiline is
contraindicated in patients with convulsive
disorders.
COMT INHIBITORS

MOA
•2 MOA

Peripheral

When peripheral decarboxylation of levodopa is blocked by
carbidopa/ benserazide
It is mainly metabolized by COMT to 3-O-methyldopa
Blockade of this pathway by entacapone/tolcapone
Prolongs the t½ of levodopa
Allows a larger fraction of administered dose to cross to brain.

Central
•Since COMT plays a role in the
degradation of DA in brain as well,
COMT inhibitors could preserve DA
formed in the striatum and supplement
the peripheral effect

Use
•Both entacapone and tolcapone
enhance and prolong the therapeutic
effect of levodopa- carbidopa in
advanced and fluctuating PD.
•They are not indicated in early PD cases

Adverse effects
1. Worsening of levodopa adverse effects
such as nausea, vomiting, dyskinesia,
postural hypotension, hallucinations, etc.
2. Diarrhoea in 10– 18% patients (less with

entacapone) and
3. Yellow orange discolouration of urine
GLUTAMATE (NMDA receptor)
ANTAGONIST (Dopamine facilitator)

MOA
1. Antagonistic action on NMDA type of
glutamate receptors, through which the striatal
dopaminergic system exerts its influence
2. Promotes presynaptic synthesis and release of

DA in the brain
3. Has anticholinergic property.

Adverse effects
•Insomnia, restlessness, confusion,
nightmares, anticholinergic effects and
rarely hallucinations.
•A characteristic side effect due to local

release of CAs resulting in postcapillary
vasoconstriction is livedo reticularis (bluish
discolouration) and edema of ankles.
CENTRAL ANTICHOLINERGICS

MOA
•They act by reducing the unbalanced
cholinergic activity in the striatum of
parkinsonian patients.

•Central cholinergic drugs are the only
effective drugs in drug induced
parkinsonism

Adverse effects
•The side effect profile is similar to
atropine

SAQ
• 1. A patient of Parkinsonism stabilised on L-DOPA takes a
multivitamins preparation on his own. What are the possible
consequences ?
• Explain why they occur ?
• 2. Explain why l-dopa is not useful is drug induced Parkinsonism.
• 3. Levodopa & Carbidopa in parkinsonism.
• 4. Levodopa.
• 5. Amantidine.
• 6. Pharmacological basis for: Levodopa parkinsonism.
• 7. Amantidine in Parkinsonism.
• 8. Why Levodopa not effective in drug induced parkinsonism.
LAQ
• 1. Explain pharmacoogica basis of Levodopa in Parkinsonism

and explain its advantages and disadvantages ?
• 2. Drugs used for Parkinsonism. Describe action and adverse
effects of Levodopa.
• 3. Classify Antiparkinsonian drugs. What is the rationale of use
of Levodopa with carbidopa ?

Antiepileptic Drugs
Dr. PRIYANKA SACHDEV ,MD
Epilepsy
•Epilepsy is a disorder of brain function
characterized by the periodic and
unpredictable occurrence of seizures.
•These are a group of disorders of the

CNS characterized by paroxysmal
cerebral dysrhythmia
•Seizures are transient disturbance of cerebral
functions due to an abnormal, excessive and
temporary neuronal discharge leading to
disturbance of sensation, movement,
behavior, perception and/or consciousness.
•These episodes are unpredictable and their

frequency is highly variable.

•Epilepsy has a focal origin in the brain,
manifestations depend on the site of the
focus, regions into which the discharges
spread and postictal depression of these
regions.

TYPES
•I. Generalised seizures
•II. Partial seizures

I. Generalised seizures
•1. Generalised tonic-clonic seizures

•2. Absence seizures
•3. Atonic seizures
•4. Myoclonic seizures
•5. Infantile spasms (Hypsarrhythmia)
II. Partial seizures
•1. Simple partial seizures
•2. Complex partial seizures
•3. Simple partial or complex partial
seizures secondarily generalized

Mechanism of action
•4 MOA

4 MOA
•1. Prolongation of Na+ channel inactivation
•2. Facilitation of GABA mediated Cl- channel

opening
•3.Decrease in excitatory neurotransmission
•4. Inhibition of T type Ca2+ Channels

1. Prolongation of Na+
channel inactivation

• Normally Na+ channel has following phases.
Resting
Activated (open)
Inactivated (open)
Resting
Normally
Opening of sodium channels in neurons
Generate action potential
Then channels close leading to inactivation.
This inactivation makes them refractory to a

stimulus.
During seizure
During seizure
Neurons depolarize
Opening of sodium channels in neurons
Fire action potential at high frequencies
Seizures
MOA of antiepileptic drugs

Anticonvulsant drugs bind to Na+ channel in inactivated but still open state
Prolongation of inactive state
Na+ channel is not able to come in resting stage
This inactivation makes them refractory to a stimulus

Further activation is not possible.
Thus the rate of recovery of sodium channels is reduced
There is limitation in the neuronal activities to fire at high frequency
Siezures are controlled

Drugs acting by this
mechanism
•Phenytoin
•Carbamazepine
•Valproate
•Lamotrigine
•Topiramate
•Zonisamide
4 MOA

opening

2. Facilitation of GABA
mediated Cl- channel opening

We know that

•Glutamate is an exitatory
neurotransmitter

So we can say that
•Seizures are due to
1. Reduction in inhibitory synaptic

activities (GABA)
2. Enhancement of excitatory activities

(glutamate).
NormaIIy

GABA (gamma amino butyric acid)
• GABA (gamma amino butyric acid) is an inhibitory neurotransmitter
in CNS
• GABA is synthesized from glutamate by GAEL (glutamic acid

decarboxylase).
• GABA is removed mainly by neuronal uptake and partly by

deamination catalyzed by GABA transaminase.
• It acts on two different types of receptors namely GABAa and

GABAb
GABAa receptor
•GABAa receptor is an ionotropic receptor,

directly coupled to chloride channels
•Ionotropic GABAa receptor has a

pentameric structure consisting of 2α, 2β
and 1γ subunits.
GABA
GABAA-receptor activation
Inhibition

During seizures

GABA is reduced
GABAA-receptor activation is reduced
Decrease flow of chloride ions into the cell
Depolarizes the neurons
Excitation
Seizures Dr. PRIYANKA SACHDEV


mechanism

•Barbiturates and benzodiazepines both
increase activity of GABA through
GABAA receptor.

MOA of BARBITURATES
•3 Mechanisms

GABA facilitatory action

BARBITURATE
Binds to an accessory site on GABAa receptor (located either on α or β subunit)
Increasing the lifetime of Cl' channel opening caused by GABA (GABA facilitatory
action)
Inhibition
GABA mimetic action

At high concentrations
barbiturates directly activates GABAa receptors
Increase Cl conductance (GABA mimetic action)
Inhibition
Mechanism of action of
benzodiazepines (BZDs)
GABA facilitatory effect onIy

BENZODIAZEPINE
Binds to an accessory site on GABAa receptor (on the interface of α and γ

subunits)
More frequent opening of chloride channels (increases frequency not duration)

(GABA facilitatory effect)
Cl enters in the cells
Hyperpolarization
Inhibition
REMEMBER
•BZDs do not themselves increase Cl"
conductance, i.e. they have only GABA
facilitatory but no GABA mimetic action.
•Barbiturates have both GABA

facilitatory and GABA mimetic actions
mechanism

MOA of Valprote and vigabatrine
Valprote and vigabatrine
Inhibit enzyme GABA transaminase which

degrades GABA
Conc. Of GABA is increased
Inhibition
MOA of Tiagabine
Tiagabine
Inhibits the uptake of GABA into the

neurones by inhibiting GAT-1
Conc. Of GABA is increased
Inhibition
4 MOA
•2. Facilitation of GABA mediated Cl-

channel opening

3.Decrease in excitatory
neurotransmission

We know that

•Glutamate is an exitatory
neurotransmitter

So we can say that
•Seizures are due to
1. Reduction in inhibitory synaptic

activities (GABA)
2. Enhancement of excitatory activities

(glutamate).
Normally
Glutamate and aspartate (major

excitatory neurotransmitters of brain)
Act on NMDA or AMPA receptors.
Excitation
During seizure
Increased Glutamate and aspartate (major
excitatory neurotransmitters of brain)
Act on NMDA or AMPA receptors.
More Excitation
Seizures
Antiepileptic drugs
Acts by inactivating NMDA receptors
Inhibition
Control of seizures
mechanism
•Felbamate

4 MOA

opening

4. Inhibition of T type Ca2+ Channels

During seizures
T (transient) current is low threshold Ca+2 current (due
to inward flow of Ca+2 through T type Ca+ channels).
Excitation
This is important in generation of absence seizure.

Antiepileptic drugs inhibit these low threshold
Ca+2 current
Inhibition
Control of absence seizure.

mechanism

REMEMBER
•Valproate is the only drug which acts by
all above 3 mechanisms

PHENYTOIN

Introduction
•Phenytoin is an antiepileptic with out CNS
depression.
•There's no increase in seizure threshold so

aura is not eliminated.
•Experimentally, it abolishes tonic hind limb
response in MES.
Adverse effects:
•1. Rapid i/v injection may cause

cardiovascular collapse, arrhythmia and
CNS depression.

2. CNS:
•a. Cerebellovestibular effects such as

nystagmus, vertigo, diplopia, ataxia etc.
There may be blurring of vision, mydriasis,
and ophthalmoplegia.
•b. Behavioral effects like hyperactivity,

confusion, dullness, drowsiness and
hallucination.
3. Gingival hyperplasia:
•Gums grow over the teeth.

•There's an altered collagen metabolism so
overgrowth of tissues and hence, there
may also be coarseness of facial features.
It slowly regresses after termination of
therapy and so treatment is not stopped.
Good oral hygiene minimizes the risk.
4. GIT:
•Nausea, vomiting, epigastric pain,

anorexia.

5. Endocrinal effects:
•Decreases insulin release, so

hyperglycemia and glycosuria.
•Also it reduces ADH secretion.

6. Osteomalacia:
•Decreases absorption of calcium and
increases metabolism of vitamin D (due to
enzyme induction).
•Also it decreases concentration of vitamin K

dependant proteins, which are important
for normal calcium metabolism in bones.
•This is why osteomalacia is not always
improved by vitamin D.
7. Hypoprothrombinemia and
hemorrhage in newborns
•Hypoprothrombinemia and hemorrhage in

newborns of mother receiving phenytoin.
•Treatment and prevention is by vitamin K.

•8. Megaloblastic anemia due to altered folate
absorption and metabolism.
•9. Hypersensitivity reactions: rashes, Steven's

Johnson syndrome, SLE etc.
•10. Blood dyscrasias: neutropenia,

leukopenia, thrombocytopenia,
agranulocytosis.
• 11. Hirsutism
• 12. Lymphadenopathy resembling Hodgkin's lymphoma
• 13. Fetal malformations (fetal hydantoin syndrome):

There may be cleft palate, hare lip, CHD, slow growth and
mental deformity due to formation of an r epoxide.
• 14. Reduced libido and impotence owing to 3 increase in

metabolism of sex hormone

MNEMONIC

Therapeutic indications:
•1. Tonic clonic or partial epilepsy
•2. Arrhythmia: ventricular or digitalis^
induced.
•3. Neuralgias.
•4. Paroxysmal nightmares.

CARBAMAZEPINE

Adverse effects
•Mostly similar to phenytoin
•Except gingival hyperplasia and the

reduction in insulin release.
•Additionally there may be cholestatic

jaundice and water retention.
Therapeutic indications
1. All but absence seizures.

2. Neuralgias.
3. Lightning tabetic pain.
4. Bipolar affective disorders.
Valproic Acid (Sodium Valproate)
•Valproic acid is a broad-spectrum

antiepileptic that inhibits MES induced
hind limb extension as well as PTZ
induced seizures.
Mechanism of action:
•Valproate is the only drug which acts by
all above 3 mechanisms

Adverse effects

• GIT—nausea, vomiting, abdominal pain, diarrhea.
• CNS—sedation, ataxia, tremors.
• Hepatic toxicity—occasional but may be fatal.
• Acute pancreatitis; hyperammonemia.
• Thinning and curling of hair, alopecia.
• Increase appetite, weight gain.
• Teratogenecity: Increase risk of neural tube defect. Dr. PRIYANKA SACHDEV

Therapeutic indications:

Ethosuximide:

Mechanism of action
•Already discussed

Adverse effects
•GIT
•CNS, and Parkinson like symptoms,
•Photophobia
•Hypersensitivity reactions
•Hematological effects.
First line drug

• Partial seizure: Carbamazepine, phenytoin or
valproic acid
• Tonic-clonic seizures: Carbamazepine, phenytoin or

valproic acid
• Myoclonic seizure: Valproic acid,clonazepam
• Absence seizure: Valproic acid or ethosuximide

•Infantile spasm: ACTH or corticosteroids;
vigabatrin is also effective
•Lennox- Gastaut syndrome: Lamotrigine
•Seizure of eclampsia: Magnesium sulfate
•Isoniazid induced seizure: Pyridoxine

Antipsychotic drugs
•The psychopharmacological agents or
psychotropic drugs are those having
primary effects on psyche (mental
processes) and are used for treatment
of psychiatric disorders

Types
1. Psychoses
2. Neuroses

Psychiatric disorders
Psychoses Neuroses
Organic Functional Anxiety

Phobia
Delirium Schizophrenia OCD
Dementia Paranoid states Reactive depr
Mood (affective) disorders PTSD
Hysterical

Psychoses
•These are severe psychiatric illness with
serious distortion of thought,
behaviour, capacity to recognise reality
and of perception (delusions and
hallucinations).

• Mania—elation or irritable mood, reduced sleep,
hyperactivity, uncontrollable thought and speech, may be
associated with reckless or violent behaviour
• Depression—sadness, loss of interest and pleasure,

worthlessness, guilt, physical and mental slowing,
melancholia, self-destructive ideation.
• A common form of mood disorder is bipolar disorder with

cyclically alternating manic and depressive phases.

Psychoses Neuroses

Phobia
Hysterical

Neuroses
•These are less serious;
•Ability to comprehend reality is not
lost, though the patient may undergo
extreme suffering.

Psychoses Neuroses

Phobia
Hysterical

•(a) Anxiety
•(b) Phobic states
•(c) Obsessive-compulsive disorder
•(d) Reactive depression
•(e) Post-traumatic stress disorder
•(f) Hysterical
(a) Anxiety
•An unpleasant emotional state
associated with uneasiness, worry,
tension and concern for the future

(b) Phobic states
•Fear of the unknown or of some
specific objects, person or situations

(c) Obsessive-compulsive
disorder
•Limited abnormality of thought or behaviour;
•Recurrent intrusive thoughts or ritual like

behaviours which the patient realizes are
abnormal or stupid, but is not able to
overcome even on voluntary effort.
•The obsessions generate considerable anxiety

and distress.
(d) Reactive depression
•Due to physical illness, loss, blow to
self-esteem or bereavement, but is
excessive or disproportionate.

(e) Post-traumatic stress disorder
•Varied symptoms following distressing

experiences like war, riots, earthquakes,
etc

(f) Hysterical
•Dramatic symptoms resembling
serious physical illness, but situational,
and always in the presence of others;
•The patient does not feign but actually

undergoes the symptoms, though the
basis is only psychic and not physical
Pathophysiology
•Dopaminergic overactivity in the limbic
system may be involved in
schizophrenia and mania
•Monoaminergic (NA, 5-HT) deficit may

underlie depression.
CLASSIFICATION
1. Antipsychotic (functional psychosis,
especially schizophrenia)
2. Antimanic (mania)
3. Antidepressants (depression)
4. Antianxiety (anxiety and phobic
states)
5. Psychotomimetic (produce
psychosis-like states / drugs of abuse)
ANTIMANIC DRUGS

•Major depression and mania are two
extremes of affective disorders which
refer to a pathological change in mood
state.

•Mania—elation or irritable mood,
reduced sleep, hyperactivity,
uncontrollable thought and speech, may
be associated with reckless or violent
behaviour

LITHIUM CARBONATE
•Lithium is a small monovalent cation.

MOA
•3 MOA

Li partly replaces body Na+
Li is nearly equally distributed inside and outside the cells

(contrast Na+ and K+ which are unequally distributed)
This may affect ionic fluxes across brain cells
Modify the property of cellular membranes
Effective in mania
Lithium decreases the presynaptic release of NA and
DA in the brain without affecting 5-HT release.
This may correct any imbalance in the turnover of

brain monoamines
Effective in mania

In mania overactive receptors functioning through phosphatidyl inositol hydrolysis
Lithium inhibits hydrolysis of inositol-1-phosphate by inositol monophosphatase
The supply of free inositol for regeneration of membrane phosphatidylinositides,
IP3 and DAG is reduced
hyperactive neurones involved in the manic state may be preferentially affected
Effective in mania

Pharmacokinetics
• Different serum concentrations have different
effect: -
1. Therapeutic level - 0.8-1.2 mEq/L (For tit of

acute mania)
2. Prophylactic level - 0.5-0.8 mEq/L (For relapse

prevention in bipolar disorder)
3. Toxic lithium levels > 2.0 mEq/L

•Lithium has narrow (very low)
therapeutic index6
•Therefore requires therapeutic drug

monitoring (TDM)

MNEMONIC
TDM

Use

1. Acute mania
• Though lithium is effective in controlling acute mania,
response is slow and control of plasma levels is difficult
during the acute phase.
• Most psychiatrists now prefer to use an atypical

antipsychotic orally or by i.m. injection, with or without
a potent BZD like clonazepam/ lorazepam, and start
lithium after the episode is under control.
• Maintenance lithium therapy is generally given for 6–

12 months to prevent recurrences.

2. Prophylaxis in bipolar disorder
•It lengthens the interval between cycles of
mood swings: episodes of mania as well as
depression are attenuated
•Patients have been maintained on lithium

therapy for over a decade
• 3. Lithium is being sporadically used in many other recurrent
neuropsychiatric illness, cluster headache and as adjuvant to
antidepressants in resistant nonbipolar major depression.
• 4. Cancer chemotherapy induced leukopenia and

agranulocytosis: Lithium may hasten the recovery of leukocyte
count.
• 5. Inappropriate ADH secretion syndrome: Lithium tends to

counteract water retention, but is not dependable.

Adverse effects

1) Neurological
•Tremor is the commonest side effect of
lithium.
•Other CNS side effects are giddiness, ataxia,

motor incordination, hyperreflexia, mental
confusion, nystagmus.
•Propranolol is used to treat lithium

induced tremor.
2) Renal
•Nephrogenic diabetes insipidus with
polyuria & polydipsia.
•Amiloride is the DOC for Lithium

induced nephrogenic

3) Cardiovascular
•Effects are similar to hypokalemia
which causes arrhythmia
•Most common ECG change is T wave

depression.

4) Endocrine
•Goitre, hypothyroidism

5) GIT→
•Nausea, vomiting, diarrhoea, metallic
test, abdominal pain.

6) Dermatological
•Acneiform eruptions,
•Papular eruption
•Exacerbation of psoriasis

7) Teratogenicity
•Ebstein’s anomaly in fetus

MNEMONIC

Interactions
•1. Diuretics (thiazide, furosemide) by
causing Na+ loss promote proximal tubular
reabsorption of Na+ as well as Li+ → plasma
levels of lithium rise.
•Potassium sparing diuretics cause milder Li+

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CNS PHARMACOLOGY

Dr. PRIYANKA SACHDEV , MD

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1. Explain how disulfiram produces aversion for ethyl alcohol.

Dr. PRIYANKA SACHDEV

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•Hydroxyl and ethyl moiety confer both

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

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•Alcohol content is low (3–6%)

•These are also undistilled.

•Though the alcohol content of these can vary

•e.g. Rum, Gin, Whiskey, Brandy, Vodka, etc.

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

• Rubbing on skin produces redness and burning sensation, so

• Precipitation and dehydration of proteins i.e. astringent effect.

• Hardening and cleaning of the skin → prevention of sweating

Dr. PRIYANKA SACHDEV

•On raw surface it is irritating and forms a

•The apparent stimulation is due to depression

•The cortex and the reticular activating system

• There is loss of inhibition and person enjoys social company.

• He is overconfident, freely speaking and enjoying.

• AIcohol could be considered as a 'great mimicker’.

Dr. PRIYANKA SACHDEV

•The depression progresses as the blood

•InitiaIIy alcohol exerts anticonvulsant

•Excessive alcohol or withdrawal may lead to

• This may be responsible for the 15–35% lower incidence of

• Protection is lost if > 3 drinks are consumed daily.

• But it is considered inapproptiate to advise nondrinkers to start

•But heat loss is actually increased in cold

➢They irritate buccal and pharyngeal mucosa which may

➢But the direct action of alcohol on respiratory centre is

Dr. PRIYANKA SACHDEV

• Accumulation of fat and proteins in cells lead to cirrhosis

• Cirrhosis is also contributed by malnutrition and vitamins

• Acetaldehyde produced during metabolism of alcohol appears

Dr. PRIYANKA SACHDEV

•This is due to water ingested along with drinks

•It does not impair renal function.

•It provokes the desire but takes away the

• With chronic use there is impotence, testicular

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

•Thus, rate of consuming drinks governs

Dr. PRIYANKA SACHDEV