• Depot preparations are available in intramuscular route.

Haloperidol and Fluphenazine as

decanoates.
• Haloperidol is also available in intravenous form (I.V) but care needs to be exercised as it is
twice as potent as the oral haloperidol and it bypasses first pass metabolism. They are slowly
hydrolysed and released and serve as long lasting preparations that can be given monthly.
This is Useful for poorly adherent patient.
• Adverse effects :—
(i) When there is antagonism of the D2 receptors by the typical antipsychotics, there can be
disinhibition of the indirect pathway to induce parkinsonian symptoms.
(ii) Acute dystonias: involuntary movements- restlessness, torticollis, protruding tongue,
neck muscle spasm occur acutely. Reversible, concomitant muscarinic receptor and 5HT2a
blockade will mitigate this effect.
(iii) Tardive dyskinesia: This is a neurological disorder characterized by involuntary
uncontrollable movements especially of the mouth, tongue, trunk, and limbs and occurring
especially as a side effect of prolonged use of antipsychotic drugs. This occurs with chronic
use after months or years (hence tardive) 20-40%,
Although atypicals like Risperidone, Olanzepine can also cause this ADR.
(iv) Neuroleptic malignant syndrome: a life threatening syndrome characterised by catatonia,
stupor, fever, autonomic instability, myoglobinemia and death in about 10% of cases. It is
commonly associated with typical antipsychotics with high affinity for D2 receptors like
Haloperidol or those who discontinue dopaminergic medications abruptly.
Symptoms are due to the effect of antipsychotics on the dopaminergic systems in the
hypothalamus.
(v) Inhibition of dopamine at the pituitary gland encourage prolactin secretion causing
amenorrhea, galactorrhea, false positive pregnancy test, gynaecomastia.
(vi) Non specific blockade of the muscarinic receptors and adrenergic receptors will cause
dry mouth. Difficult urinating, loss of accommodation,
(vii) Alpha adrenergic antagonism blockade leads to orthostatic hypotension, failure to
ejaculate.
(viii) Central alpha adrenergic pathways blockade causes sedation.
• Idiosyncratic reactions :-
– Jaundice with chlorpromazines
– Leucopenia and agranulocytosis
– Urticarial skin reactions
– Antipsychotic malignant syndrome rapid rise in body temperature and muscle rigidity
• Drug Interactions :-
(i) Antiparkinsonian drugs: they inhibit the action of both dopamine agonists or dopamine
synaptic concentration and worsen parkinsonian symptoms.
(ii) They potentiate sedative effects of benzodiazepine and centrally active antihistamines.
CHLORPROMAZINE
• Active metabolites- 7-hydroxychlorpromazine, chlorpromazine N-oxide
• Mechanism of action:
— Blocks D2 receptors but are not completely selective.
• Works more in positive symptoms of schizophrenia.
• Bioavailability- 32%,
• Less than 1% urinary excretion
• Plasma binding: 95-98%
• Clearance(ml/min/kg): 8.6(2.9)
• Half-life(hours): 30 (+/-7)
• Peak time(h): 1-4
• Peak Concentration(- 25-150ng/ml

1
(2) ATYPICAL ANTIPSYCHOTIC [PROZAC]
Clozapine+,
Olanzapine,
Quetiapine
Zotepine,
Aripiprazole+,
Risperidone+
Paliperidone
Amisulpride,
Sertindole,
• They are atypical in their mode of action and lack of extrapyramidal motor symptoms and adverse
effects profile.
• They have a lower affinity for D2 receptors but their affinity for D2 receptors does not correlate
with their clinically effective dose.
• Mechanism of Action :-
– They block D2 and serotonin 5-HT 2A receptors, and most of the drugs are also
dopamine D4 receptor antagonists.
– A subset of the atypical antipsychotics (Aripiprazole, lurasidone, and asenapine) have
potent activity in blocking 5-HT7 serotonergic receptors and 2A and 2C adrenergic
receptors.
• They occur D2 receptors transiently and dissociate quickly allowing for relatively normal
dopamine neurotransmission. This lowers the risk of extrapyramidal adverse effect (motor
functions), decrease negative symptoms and improve cognition (compared with the typicals).
• These drugs have clinically significant effects on symptoms on mood and anxiety and are used
more often to treat depression and bipolar disorder.
• NOTE:— More effective than typical in treating Negative symptoms.
• Produce Significantly milder extrapyramidal symptoms But produce higher effects such as
metabolic dysfunction, weight gain, sedation.
• Adverse effects :—
– The drug-receptor binding profile determines to a large extent the ADR profile-
(i) Serotonin 2C- Olanzepine and Clozapine may cause metabolic side effect— dysglycemia,
dyslipidemia.
(ii) Histamine- Clozapine, Olanzepine, Quitapine— Weight gain, sedation
(iii) Alpha 1 adrenergic receptors- Risperidone, Clozapine— Orthostatic Hypotension
– Risperidone has the highest affinity for D2 receptors
– Clozapine can cause agranulocytosis.
• Indications :-
- Treatment of schizophrenia
- Psychoses associated with depression and mania
- As an adjunct to benzodiazepines in an acutely disturbed patient.
- May be useful for treatment of resistant anxiety disorders
- Some antipsychotics have antidepressant effects
- Tourette’s syndrome
- Recurrent self-harming behavior
- Dementia #anxiety and mood disorders

2
 ANTIDEPRESSANTS
• An affective disorder characterised by loss of interest or pleasure in almost all a person's usual
activities. An affective disorder characterised mostly by mood changes rather than by thought
disturbances.
SYMPTOMS ASSOCIATED WITH DEPRESSION
• Sadness, Despair, Guilt, Pessimism
• Decrease in energy
• Insomnia and fatigue, decrease in libido
•Thoughts of death and suicide
•Mental slowing, lack of concentration
• Low self-esteem
• Loss of appetite.
• loss of pleasure in usual activities (anhedonia)
• loss of memory, concentration, or decision-making capability.
TYPES OF DEPRESSION
(1) Reactive Depression
(2) Endogenous
(3) Drug induced
(4) Major depression
(5) Chronic depression (Dysthymia)
(6) Atypical depression
(7) Bipolar disorder/Manic depression
(8) Seasonal depression (SAD)
CLINICAL FEATURES OF MAJOR DEPRESSIVE DISORDER(MDD)— DSM -5 criteria for
diagnosis
• The patient would have five or more the following for a 2 week period
(1) There must be depressed mood: sad feelings, hopelessness, tears up without any real
reason
(2) Diminished interest or pleasure in all activities- subjectively or observation
(3) Weight loss when not dieting
(4) Insomnia or hypersomnia
(5) Psychomotor retardation or agitation
(6) Fatigue or feelings of worthlessness
(7) Reduced ability to think or concentrate or indecisiveness
(8) Recurrent thoughts of death or suicidal ideation
(9) Symptoms have negative impact on social and other aspects of life
• No physical or physiological effects or substance abuse
• No explainable schizoaffective disorder or schizophreniform disorder
• No mania or hypomanic episode.
PHARMACOTHERAPY OF DEPRESSION
• The purpose of antidepressants is to increase the levels of circulating neurotransmitters in
the synapse.
• The Neurotransmitters implicated here are;
(1) Norepinephrine (NE) and
(2) Serotonin (5-HT)
CLASSIFICATION OF ANTIDEPRESSANTS
1. INHIBITORS OF MONOAMINE UPTAKE
(i) Tricyclic Antidepressants (TCAs) eg.
[TCAs Definitely Does More Important Action]
Clomipramine
Imipramine
Trimipramine
Desipramine
Amitriptyline
Nortriptyline

3
 Protriptyline
Amoxepine
Doxepin
Maprotiline
• MOA :— TCAs prevent uptake of amines at nerve terminals by competitively binding to
the transporters. They mostly affect Norepinephrine and Serotonin uptake. Thus Increase
the concentration of Serotonin and NA at synapse and potentiate the action.
• Effects seen :—
– In depressed patents: Mood elevation, improved mental alertness, physical activity,
reduction of morbid thoughts
– In non-depressed patients-confusion, motor-incoordination, sedation, tiredness,
light-headedness, difficulty in thinking & concentration, gait disturbances, anxiety....
NOTE:- Imipramine & Amitriptyline are Tertiary amines and work on Serotonin system.
They are more powerful.
Desipramine & Nortriptyline are Secondary amines and work on Nor-epinephrine
system.
Secondary—> PND
Tertiary —> Acid TB
• Side Effects :— Tremor, cardio toxicity & Anticholinergic effect, Somnolence.
• TCAs also block serotonergic, α-adrenergic, histaminic, and muscarinic
receptors. Actions at these receptors are probably responsible for many of the unwanted
effects o f the TCAs.
• Adverse Drug Reactions :—
(1) Antimuscarinic Side effects: dry mouth, constipation, urinary retention, blurred
vision, and confusion ,
(2) cardio toxicity/cardiovascular effects: Life-threatening arrhythmias: The TCAs
are class 2A Aantiarrhythmic agents.
(3) Sedation (H1 antagonism)
(4) Weight gain
(5) Sexual dysfunction
(6) At therapeutic doses, the TCA drugs lower the seizure threshold and at toxic
doses can cause life-threatening seizures (especially Maprotiline)
(7) Amoxepine is a dopamine receptor antagonist and can induce EPS, gynecomastia,
lactation, and neuroleptic malignant syndrome.
NOTE:- In severe depression TCAs appear to be more efficacious.
(ii) Selective serotonin reuptake inhibitors (SSRIs).
Fluoxetine (SSRI with the longest half life)
Fluvoxamine,
Paroxetine,
Citalopram,
Escitalopram
Sertraline,
• MOA:- SSRIs act by selectively preventing serotonin reuptake by blocking the cell
surface serotonin transport. SSRIs allosterically inhibit the serotonin, transporter (SERT) by
binding the receptor at site other than active binding site for serotonin. They specifically
inhibit serotonin reuptake. They are useful in treatment of premature ejaculation.
• As a class, these medications have little or no affinity for cholinergic, β-adrenergic or
histamine receptors and do not interfere with cardiac conduction.
• Pharmacokinetics:-
– Food has little effect on absorption EXCEPT with Sertraline, food increases its
absorption.
– t1/2 = 16-36'hours.
– Fluoxetine t1/2 = 50 hours. t1/2 of its active metabolite is 10 days. It is available as
a sustalned-release preparation allowing once-weekly dosing.
• Metabolism by CYP450 enzymes and glucuronide or sulfate conjugation.
• Dosages should be reduced in patients with hepatic impairment.

4
• Advantages of SSRIs over other antidepressants :—
(1) Fewer anticholinergic adverse effects. The SSRIs are generally free of
antimuscarinic side effects (dry mouth, urinary retention, confusion).
(2) Lower cardio toxicity. The SSRIs have no major cardiovascular side effects.
NOTE:- SSRIs are 1st line for treatment of Depression. They have better Adverse effect
profile and are safer in overdose.
• Uses of SSRIs :—
(1) Major Depression: the primary indication Obsessive-compulsive disorder (OCD)
(fluvoxamine, clomipramine)
(2) Generalised anxiety disordes.
(3) Social anxiety disorder (SAD): Fluvoxamine, Venlafaxine
(4) Premenstrual dysphoric disorder (Fluoxetine, Sertraline)
(5) Bulimia nervosa (only Fluoxetine)
• SSRIs Adverse Effects:—
(i) Sexual dysfunction
(ii) GI distress :- Sertraline: Diarrhoea & Paroxetine: constipation.
(iii) Serotonin syndrome (when SSRIs are taken with MAOIs). SSRIs have to be
discontinued 4 to 6 weeks before an MAOI can be administered to mitigate the risk of
serotonin syndrome.
Serotonin syndrome, a serious triad of abnormalities consisting of cognitive,
autonomic, and somatic effects due to excess serotonin.
Symptoms of the serotonin syndrome include hyperthermia, muscle rigidity, myoclonus,
tremors, autonomic instability, confusion, irritability, and agitation; this can progress
toward coma and death.
(iv) CNS: Sleep disturbances, insomnia and somnolence (Fluoxetine is usually
administered in the morning after breakfast). Paroxetine and Fluvoxamine are more
sedating.
(v) SSRIs have also been associated with extrapyramidal side effects, especially
those with Parkinson's disease. Anxiety, reports of aggression
(vi) Overdose can cause seizures
(vii) Weight changes.
(viii) Discontinuation syndrome: All SSRIs have the potential to cause a
discontinuation syndrome after abrupt withdrawal. This withdrawal syndrome appears
most intense for Paroxetine and Venlafaxine due to their relatively short half-lives and,
in the case of Paroxetine, lack of active metabolites. Conversely, the active
metabolite of Fluoxetine, Norfluoxetine, has such a long t1/2 (1–2 weeks) that few
patients experience any withdrawal symptoms with discontinuation of fluoxetine ie.
Fluoxetine has the lowest risk of causing an SSRI discontinuation syndrome.
— Signs and symptoms of SSRI discontinuation syndrome include:
headache, malaise, flu-like symptoms, agitation and irritability, nervousness,
and changes in sleep pattern (insomnia), dizziness and nausea.
• Fluoxetine is the Longest acting.
• Fluvoxamine is Short acting. It is Commonly used in indoor patients.
• Sertraline has less chances of drug interactions.
• Paroxetine is Short acting. It shows More GI side effects.
• Citalopram is Similar to sertraline but should be avoided in patients attempting suicide.
• Fluoxetine and Escitalopram are approved for childhood depression.
• Fluoxetine, Sertraline, and Fluvoxamine are approved for OCD in children.
TCAs VERSUS SSRIs
TCAs SSRIs
• Anticholinergic effects • NO Anticholinergic effect.
• Cardio toxicity • Less chances of arrhythmia
• Alpha blocking action • NO alpha blocking action
• Sedation, seizures • NO sedation, NO seizure ppt
ppt.

5
 • Weight gain • Less incidents of weight gain.
• Low safety margin • Now 1st choice for OCD, Panic disorders, Social Phobia,
Eating. disorders, Premenstrual syndrome, Post traumatic
stress
(iii) Serotonin and noradrenaline/norepinephrine reuptake inhibitors (SNRIs)
eg. [Vex, Don’t Do Mediocre] / DVD
Venlafaxine,
Duloxetine
Desvenlafaxine,
Milnacipran.
• MOA:- They block the 5HT reuptake transporters and NE reuptake transporter in a
concentration dependent manner.
NOTE:-. At low doses they behave like SSRI but at higher doses they increase
extracellular NE levels.
• Side effects :- They act on a HANDful receptors.
• May be effective in treating depression in patients where SSRI are ineffective.
• Adverse effects: Nausea, headache, sedation, dizziness, insomnia, sexual dysfunction,
constipation, suicide.
• SNRI precipitate a discontinuation syndrome if treatment is abruptly stopped.
• NOTE:— Both SNRIs and TCAs, with their dual actions of inhibiting both serotonin and
norepinephrine reuptake, are sometimes effective in relieving physical symptoms of
neuropathic pain such as diabetic peripheral neuropathy
• Effective against chronic painful symptoms, such as backache and muscle aches, against
which SSRIs are relatively ineffective; (pain is modulated by serotonin and norepinephrine
pathways in the CNS).
• Duloxetine ureteral tone. Used in urinary incontinenc (over active bladder).
(iv) Noradrenaline/norepinephrine reuptake inhibitors (NEIs) eg.
Reboxetine.
(v) Norepinephrine-Dopamine Reuptake Inhibitors (NDRIS) eg.
Bupropion
• Adverse effects:- Lowers seizure threshold, suicide.
2. MONOAMINE OXIDASE INHIBITORS (MAOIs):
• They are classified into 2, according to the reversibility of their binding—MAOI-A & MAOI-B.
• MAOA preferentially metabolises 5-HT and NE and can metabolise DA; MAOB is effective
against DA and also 5-HT(?).
• NOTE:— Selective MAO-A inhibitors are more effective in treating major depression than
type B inhibitors
BM-SPIT (MAOA-MAOB mnemonics)
— MAOI-A binds reversibly—
Moclobemide,
Befoxatone,
Brofaromine.
— MAOI-B / n0n selective binds irreversibly—
Selegiline
Phenelzine,
Isoniazid,
Tranylcypramine
Isocarboxazid,
Iproniazid.
NOTE:- Despite their eficacy in treating depression, MAOIs are prone to drug-drug and drug-
food interactions, and are considered to be last-line agents for treatment of depression. Reserved
for treatment of depressions that are resistant to other antidepressants.
• Mechanism of Action:-
– The MAOIs inactivate the enzyme monoamine oxidase (MAO), causing neurotransmitter
molecules to escape metabolism with consequent accumulation within the presynaptic
neuron and leakage into the synaptic space.
• Adverse Effects :—

6
 (1) Orthostatic hypotension,
(2) weight gain,
(3) oedema,
(4) sexual dysfunction
(5) Hepatotoxicity is likely to occur with Isocarboxazid or Phenelzine.
(6) Serotonin syndrome :- MOAIs Must never be combined with SSRIs this causes
Serotonin syndrome. Therefore allow a washout period before switching to another class
of Antidepressants
(7) The most toxic adverse effect of MAO inhibitors use is Systemic Tyramine toxicity.
These agents inhibit both MAOA and MAOB , thereby inhibiting the body’s capacity to
metabolise not only endogenous monoamines such an NE and 5HT but also exogenous
biogenic amines such as Tyramine. Global inhibition of MAOs increases the bioavailability
of dietary Tyramine; Tyramine-induced NE release can cause marked in blood pressure
(Hypertensive crisis).
Some MAOIs are reversible competitive inhibitors of MAOA . These agents such as
Moclobemide and Eprobemide, permit Tyramine to compete for MAOA and thus exhibit
reduced capacity to potentiate the effects of dietary Tyramine.
3) MONOAMINE RECEPTOR ANTAGONISTS:
Mirtazapine,
Trazodone,
Mianserin
4) MELATONIN RECEPTOR AGONIST:
Agomelatine
5) Miscellaneous:
ketamine.
Bupropion (causes seizures in eating disorders)

— First-generation Antidepressants :
• Tricyclics antidepressants (TCAS)
• Monoamine oxidase inhibitors (MAOls)
— Second-generation Antidepressants :
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin-norepinephrine reuptake inhibitors (SNRIs)

Antidepressants are classified as Typical and Atypical based on other

uses.
— Atypical Antidepressants:
• Prominent α blocking and weak 5-HT antagonists.
Nefazodone,
Trazodone
• Serotonin and Noradrenaline reuptake inhibitor (SNRIs)
Venlafaxine,
Duloxetine
• Noradrenegic and specific Serotonergic antidepressants (NaSSA).
Mirtazapin
• Inhibitor of Dopamine and Noradrenaline
Bupropion
• Blockade of pre-synaptic αa receptors
Mianserin
• Increases rather than inhibiting 5-HT uptake
Tianeptine,
Amineptine
• Agomelatine
• Ketamine

7
 MOOD STABILISERS
(1) Lithium Carbonate :-
1949 by John FJ Cade
• Has a narrow therapeutic index; that is the therapeutic concentrations and the toxic
concentrations are close.
• High plasma concentrations are avoided by using sustained release formulations that
deliver peak plasma lithium concentration in 5 hours.
• Distributed throughout the total body water, but a higher concentration in the brain, thyroid
gland and bones.
• steady state in 5-6 days.
• Slow onset of the therapeutic effects up to 2-3 weeks so Lithium is used in conjunction
with benzodiazepines or antipsychotics.
• therapeutic range (0.4-1mmol/L).
• Signs of intoxication> 1.5mmol/L.
• severe overdose>2mmol.
• Kidneys eliminate lithium and the intake of sodium and water are the primary determinant
of its eliminations.
• NOTE:- Use of a diuretic cam reduce the clearance of lithium and precipitate toxicity.
• They are not every effective for Bipolar affective disorder (BAD).
• There can be a rebound effect if Lithium is discontinued within 2 years.
• thyroid function (especially in women) and renal function (plasma creatinine and
electrolytes) should be measured before initiation and every 3–6 months during therapy.
• Adverse reactions :-
— With therapeutic range (0.4-1mmol/L): polyuria, polydipsia, weight gain, edema,
hypothyroidism, acne, rash, cardiac arrhythmia, mild cognitive impairment.
— Signs of intoxication >1.5mmol/L: Gastrointestinal disorders: (diarrhoea, anorexia,
vomiting), Neurological (blurred vision, muscle weakness, drowsiness, sluggishness and
coarse tremor, leading on to giddiness, ataxia and dysarthria).
— Frank toxicity: severe overdose>2mmol.l: medical emergency
(2) Sodium Valproate :-
• Inhibition of voltage-sensitive Na+ channels (VSSC). Diminish excitatory glutamate
neurotransmission.
• Enhancing actions of GABA - promote inhibitory neurotransmission.
• Regulating downstream signal transduction cascades promote neuroprotection and long
term plasticity.
(3) Carbamazepine :-
Mechanism of action.
• Blocks voltage sensitive Na+ channels (VSSC)
• Reduces glutamate release.
• Decreases turnover of norepinephrine and dopamine.
• Facilitates 5HT neurotransmission.

SEDATIVE-HYPNOTIC DRUGS
• Sedatives are drugs that tend to calm, moderate, or tranquilize nervousness or excitement
• Hypnotics are drugs that tend to produce sleep.
• They include the following drug classes :
(1) Benzodiazepines & Non-benzodiazepines.
(2) Barbiturates & Non-barbiturates.
(3) GABA receptor agonists.
(4) 5HT Receptor agonists.
(5) Melatonin Receptor agonists.

BENZODIAZEPINES

8
 Diazepam (Oral, IM, IV, rectal)
Lorazepam (Oral, IM, IV)
Clonazepam (Oral)
Midazolam (Oral, IM, IV)
Alprazolam (Oral)
Temazepam (Oral)
• Mechanism of Action :-
– Benzodiazepines bind to regulatory sites on GABAA receptors and cause an increase
in the stimulation of the receptors causing chloride influx and hyper-polarisation and
increase in binding of GABAA receptors which is an inhibitory receptor. This conclusively
cause inhibition and in totality sedation.
– Benzodiazepines are allosteric modulators of GABAA receptor function. They the
affinity of the GABAA receptor for GABA and thereby enhance GABA-induced Cl– currents.
Thus, in terms of channel kinetics, benzodiazepines the frequency of opening of the
GABAA receptor Cl– channel in the presence of GABA.
• Pharmacokinetics:-
– Benzodiazepines are well absorbed after oral administration.
– diazepam has a half-life >24 hours.
– They have a high volume of distribution and are highly lipid soluble and bind to plasma
proteins (>99 % for diazepam).
– They can cross into the placenta and can be secreted in breast milk.
– They are metabolised by CYPs enzymes (CYP3A4 & CYP2C19). The metabolism of
benzodiazepines occurs in three steps including N-dealkylation, hydroxylation and
conjugation.
• Side effects :-
(i) Lethargy,
(ii) impairment of motor function,
(iii) confusion,
(iv) amnesia,
(v) increased reaction times.
(vi) Psychological effects such as hallucination, anxiety, irritability, and nightmares.
NOTE:- Flumazenil is an antagonist at GABAA receptors that can be used to manage
Benzodiazepine overdose and toxicity. It is usually given intravenously for this purpose.
• NON-BENZODIAZEPINES
Zopiclone,
Zolpidem.
– These hypnotics act on the benzodiazepine site present on GABA channels. They are
sedatives that bind to benzodiazepine sites on the GABA receptor but lack a benzodiazepine
structure.
– Zopiclone :- Zopiclone has agonistic properties at GABAA receptor. It is short acting (<6 hrs.),
well absorbed after oral administration and has a large volume of distribution. It metabolised to
inactive N-oxides and excreted in the urine. Zopiclone causes a bitter metallic after taste.
BARBITURATES
Phenobarbital
Thiopental
Pentobarbital
• Barbiturates are pyrimidine derivatives that have been largely replaced by benzodiazepines.
• Mechanisms of action :-
– They potentiate GABAminergic transmission at GABAA receptors.
– Barbiturates bind to a distinct allosteric site on the GABAA receptor; binding leads to an
increase in the mean open time of the GABA-activated Cl– channel, with no effect on
frequency. At higher concentrations, barbiturates directly activate channel opening, even in
the absence of GABA.
– Therefore Barbiturates unlike Benzodiazepines don’t only potentiates GABA receptors,
they also act directly on the chloride channels themselves to its action.
– Barbiturates also reportedly inhibit glutamate release via an effect on voltage-activated
Ca2+ channels.

9
 – These multiple actions, especially the direct gating effect on the GABAA channel, may
explain the potent CNS depressant effects of barbiturates as compared to benzodiazepines.
– Both benzodiazepines and barbiturates bind to allosteric sites on the GABAA receptor.
– Pentobarbital chloride conductance and the action of voltage gated calcium
channels.
• Pharmacokinetics :-
– They are rapidly absorbed after oral administration and the presence of food can interfere
with their absorption.
– Barbiturates are highly lipid soluble, widely distributed and they cross the placental
barrier.
– They undergo oxidation to less toxic metabolites which are conjugated and excreted in
the urine.
– Phenobarbital undergoes N-glycosylation.
– They can modulate the activity of the microsomal enzymes system and interact with
the metabolism of steroids and vitamin K.
• Side effects :-
(i) Drowsiness,
(ii) acute porphyria,
(iii) adverse effects on respiratory and cardiovascular function.
NOTE :— In severe Barbiturates intoxication, the patient is comatose; respiration is affected
early. Breathing may be either slow or rapid and shallow. Eventually, blood pressure falls
because the effect of the drug and of hypoxia on medullary vasomotor centers; depression of
cardiac contractility and sympathetic ganglia also contributes. Pulmonary complications (e.g.,
atelectasis, edema, and bronchopneumonia) and renal failure are likely to be the fatal
complications of severe barbiturate poisoning. The treatment of acute barbiturate intoxication is
based on general supportive measures, which are applicable in most respects to poisoning by
any CNS depressant. The use of CNS stimulants is contraindicated (not advised as a course
of treatment or procedure). If renal and cardiac functions are satisfactory and the patient is
hydrated, forced diuresis and alkalinization of the urine will hasten the excretion of Phenobarbital.
• NON-BARBITURATES :-
Etomidate,
Meprobamate,
Propofol etc.
• These are drugs that have anxiolytic effects but do not belong to the barbiturate group of
drugs.
• Propofol is a general anesthetic agent that is proposed to have GABAergic activity.
• Etomidate is used for the induction of anaesthetic.
GABA RECEPTORS AGONISTS
Gabapentin
Pregabalin
Baclofen
Gabapentin :-
• Gabapentin promotes the release of GABA and modulates the activity of voltage-gated
calcium channels.
• Pharmacokinetics:- It is well absorbed on oral administration, not protein bound and
excreted unchanged in the urine.
• Side effects :- Dizziness, dry mouth.
• Gabapentin has been used to manage anxiety disorders.
Pregabalin :-
• Pregabalin is a GABA analogue that increases total GABA content of the brain.
• It is similar to gabapentin and has been shown to be effective against generalised anxiety
disorders (GAD) in clinical trials.
Baclofen :-
• Baclofen is a GABAB agonist.
• It is used in managing the spasticity associated with multiple sclerosis and cerebral
palsy.

10
 • It poorly penetrates the CNS and hence is usually prescribed at high dose which
increases its tendency to elicit side effects such as drowsiness, confusion, and muscle
weakness.
SEROTONIN (5HT) RECEPTOR AGONISTS
Buspirone
The Triptans (Sumatriptan)
Buspirone :-
• Buspirone is a 5HT1A receptor agonist that lacks sedative properties.
• It is used the management of generalised anxiety disorders.
• Buspirone selectively suppresses the action of serotonin.
• It also has weak dopamine D2 receptor affinity.
• Buspirone exerts delayed effects (takes weeks for full clinical manifestation).
• It undergoes first pass metabolism and is metabolised by CYP3A4 system.
• Its metabolite, buspirone piperazine acts as an α2-adrenergic antagonist.
• It could cause nausea, dizziness.
The triptans :-
• These agents bind to 5HT1B/D receptors and are used to treat acute migraine attack.
• On binding to these receptors, the cause vasoconstriction of the cranial blood vessels.
• They also act on autoreceptors, modulating neurotransmitter release.
• Triptans could also block the secretion of neuroinflammatory peptides and reduce the risk
of extravasation.
• Sumatriptan has a fast onset of action with about >95 % bioavailability.
• It is metabolized by monoamine oxidase inhibitor (MAO-B).
• Side effects include coronary artery vasospasms, arrythmias and myocardial infarction.
MELATONIN RECEPTOR AGONISTS
Ramelteon
Agomelatine
• Melatonin is a hormone secreted from the pineal gland and regulates the sleep-wake cycle and
memory.
• Melatonin has been shown to demonstrate anxiolytic activity.
• melatonin exerts its action by binding to its MT1 and MT2 receptors.
• Melatonin receptor agonists are used as hypnotics for the treatment of insomnia.
• Ramelteon :-
– is a non-selective MT1/MT2 agonist used for treatment of insomnia.
– It is metabolised by CYP3A4.
• Agomelatine :-
– is also a non-selective MT1/MT2 agonist with anxiolytic and anti-depressant activity.
– it also binds to 5HT2c receptors.
• Melatonin controlled release tablets which contain melatonin.

ANTI-EPILEPTIC DRUGS
NEUROTRANSMITTERS IN NERVOUS SYSTEM
— Neurotransmitters in the Peripheral Nervous system (PNS) :
• Acetylcholine.
• Norepinephrine.
— Neurotransmitters in the Central Nervous system (CNS) :
• GABA.
– Major Inhibitory neurotransmitter in the CNS.
– GABA receptors include: GABAA & GABAB.
• Glutamate.
– Major Excitatory neurotransmitter in the CNS.
– Glutamate receptors include: NMDA, AMPA, Kainate & mGIu (1-7).
• Acetylcholine.
• Norepinephrine.
• Serotonin.

11
 • Dopamine.
• Histamine.
• Adenosine.
• Aspartate.
• Glycine.
• Nitric oxide.
– A SEIZURE:- A Paroxysmal derangement of cerebral function caused by excessive and
generally synchronised activity of groups of neurones in the brain. It is a transient epileptic event.
– EPILEPSY:- Refers to the clinical syndrome of recurrent unprovoked seizures and implies a
pathological state that predisposes to further future seizures. Two or more unprovoked seizures that
can’t be explained by a medical condition.
NOTE:- EPILEPSY is abnormal, excessive and hyper synchronous activity in the brain.
Neuronal activity is normally Asynchronous in the brain.
Any distortion in the balance of the excitatory and inhibitory neurotransmitter in the brain causes
an event.
Abnormal synchronous activity often arises from an area in the brain referred to as seizure
focus.
À decrease in the overall level of inhibitory transmission in the brain can precipitate a seizure.
Such decreases can occur after the administratn of GABA antagonists, or during withdrawal from
repeated exposure to GABA agonists such as alcohol or benzodiazepines.
CELLULAR & NETWORK LEVELS ARE THE FACTORS THAT PROTECT AGAINST
REPETITIVE & SYNCHRONOUS FIRING CHARACTERISTICS OF SEIZURES
CELLULAR LEVEL:
— This is due to Refractory period due to Na+ channel inactivation and K+ and Cl- channels
induced hyperpolarisation.
– Glutamate receptors open up inward Na+ and Ca+ channels and cause Depolarisation.
GABAB receptors open Outward K+ channels causing Repolarisation. Finally GABAA receptors
open up inward Cl- channels causing Hyperpolarisation.
• Neuropeptide Y is co-released with GABA and
potentiates the inhibition.
NOTE:- An epileptic seizure probably arises from a localised imbalance between excitatory
neurotransmission, principally mediated by
glutamate, and inhibilory neurotransmission
mediated by GABA, which leads to a focus of
neuronal instability.
NOTE:- Most anti-epileptic drugs produce their main anti-epileptic effects either by blockade of
depolarising ion channels (Na+ & Ca2+) ie. Blockade of Glutamate receptors, or by enhancing the
inhibitory actions of GABA.
NOTE:- Antibiotic —Quinolone can lower seizure firing threshold.
NETWORK LEVEL:
— Surround inhibition :- This occurs in single neuron with >1000 synaptic connections. The
presence of inhibitory interneurons
that release GABA Limits AP.
— Essential in normal functioning
— Focal seizures are thought to happen as a consequence of loss of surround inhibition.
— Surround inhibition is a process that normally inhibit the firing of neurones around a seizure
focus.
— Drugs that surround inhibition and prevent the spread of synchronous activity are effective
in the treatment of focal seizures.
NOTE:— Glutamate causes the Threshold AP.
GABAA causes Repolarisation.
GABAB causes hyperpolarisation
CAUSES OF SEIZURES
– Nevborns: Neonatalbypoxia; intracranial hemorrhage; maternal druguse
– In infants and children: Fevers; infections
– In adults and the elderly: Traumatic brain injury; stroke; metabolic disturbances (hypoglycemia,
hypocalcemia, hypomagasemia, hyponatremia, lactic acidosis, uremia);

12
– drugs, alcohol, and toxins includingwithdrawal from barbiturates and other central nervous
system depressants.
(1) Primary (idiopathic): Genetic abnormalities.
(2) Secondary: Toxins, autoantibodies, acquired lesions.
(3) Unclassified eg. Neonatal seizures, Infantile spasms.
CLASSIFICATION OF SEIZURES
— There are three (3) main types of seizures : Partial, Generalised, and Unclassified.
NOTE:- The clinical manifestations depend on the site of the discharge:
(1) Partial (focal) seizures: localised to a hemisphere. In partial or focal seizures the discharge
starts in a localised area of the brain and may remain localised or may secondarily spread to
affect the whole brain.
• Simple partial seizures: Most common. Also called ‘Jacksonian March’. There may be
Motor, psychic or somatosensory symptoms. Consciousness NOT impaired and
manifestations are focal.
• Complex partial seizures: Temporal lobe, psychomotor; Consciousness is impaired
• Secondary generalised seizures:These begin as partial seizures then it spreads to
become generalised, usually of tonic-clonic variety. It occurs in partial seizures especially
those with a focus in the frontal lobe. Treated with Na+ channel blockers.
(2) Generalised seizures:- In generalised seizures the abnormal discharge affects the whole of
the brain, bilateral. Generalised seizures involve both hemispheres and thalamic synchronising
mechanisms. Many generalised seizures are associated with developmental disorders.
• Tonic-clonic seizures :The most common generalised seizures. Also called grand mal
seizures. Initial rigid extensor spasm, respiration stops, defecation, micturition and
salivation occur (tonic phase, =1 min). Violent synchronous jerks (clonic phase, 2-4 min).
Treated with Na+ channel blockers.
• Tonic seizures
• Clonic seizures
• Myoclonic seizures : Seizures of a muscle or group of muscles
• Absence seizures : Also called petit mal seizures. Abrupt loss of awareness of
surroundings , little motor disturbance (occur in children)
• Atonic seizures: Loss of muscle tone and strength.
TREATMENT OF SEIZURES
The goal of treatment:
1. Prevent further seizures,
2. Avoid adverse effects
3. Enable patients to lead active lives
— The ideal Anti-Epileptic Drug must prevent the excessive, synchronised discharges that occur
during a seizure without impeding the normal neuronal firing of the brain or causing any
unwanted adverse effects. Must be tolerableto the patient.
General consideration of AEDs
• May have more than one class effect: Pleiotropism: Na, K, and GABA-mediated.
• They are interchangeable.
• Additive with other CNS depressants (antihistamine, alcohol).
• Abrupt withdrawal may precipitate seizures. Withdrawal over a period of 6 months
NOTE:- efficacy of OCPs (Oral Contraceptive pills).
• Choice, mainly determined by seizure type and tolerability.
• Absorption by food in stomach.
NOTE:- Absorption: Complete, having high bioavailability of ≈ 100% (except for Gabapentin)
MCQ!!
• Not initiated following a single seizure event.
• Commenced initially as mono-therapy.
• AEDs with narrow therapeutic index: (PCP).
Phenytoin,
Carbamazepine and
Phenobarbital

13
• Focal onset seizures must be distinguished from generalised onset seizures because some
drugs effective for focal seizures do not prevent and may exacerbate some generalised seizure
types.
• Agents used for the treatment of epilepsy depress aberrant neuronal firing primarily by
- altering ion channel activity
- enhancing GABA-mediated inhibitory NT
- dampening glutamate-mediated excitatory NT.
• Anti-seizure drugs used in the chronic therapy of epilepsy must be orally bioavailable.
CLASSIFICATION OF ANTI-EPILEPTIC DRUGS
7 classes!
(1) Drugs that block Na+ channel
(2) Drugs that enhance K+ channel conductance [Retigabine].
(3) Drugs that inhibit Ca2+ channel [Every Valid Goal Pursues Zion].
(4) Drugs that enhance GABA-mediated inhibition.
(5) Drugs that block Glutamate receptors [FeLa].
(6) Carbonic anhydrase Inhibitors [ToZo].
The ONLY AEDs that cause weight loss.
(7) Levetiracetam

(1) DRUGS THAT BLOCK Na-CHANNELS:

— [PLOC LVT] PLOC act on only Na+ channels.
Phenytoin** (Non-sedating)
Carbamazepine **
Oxcarbazepine **
Lacosamide** (Non-sedating)
Lamotrigine
Valproic acid
Topiramate
Felbamate
NOTE:— Asterisks on the first 4 drugs indicate that they act PREDOMINANTLY or
ONLY as sodium channel blockers.
NOTE:— Na Valproic acid reduce metabolism of Carbamazepine & Lamotrigine.
NOTE:— Carbamazepine is the drug of choice for Partial seizures.
NOTE:— Lamotrigine is the favoured 1st line agent in tonic-clonic seizures.
NOTE:— Na Valproate Can inhibit seizure initiation and propagation.
– Na-channel inactivation protects against rapid, repetitive firing.
– These channels exist in three states: Resting, Activated, Inactivated
– NOTE:- AEDs that act exclusively on Na+ channels show strong specificity for treatment of
Partial/Focal seizures (with or without secondary generalised seizures)— EXCEPT Lamotrigine,
and Generalised onset Tonic-clonic seizures— Phenytoin and Oxcarbazepine. [MCQ!!!]
– Targets high frequency, repetitive firing neurones (seizure focus).
NOTE:- These drugs may exacerbate certain types of generalised onset seizures, including
absence and myoclonic seizures.
NOTE:— Phenytoin & Oxcarbazepine are also used in generalised seizures.
NOTE:— Exclusive Na+ channel blockers only stop focal seizure propagations NOT initiation.
Phenytoin (hydatoin derivative)
Developed in 1937
– Oldest non-sedating AED
– Acts exclusively on axonal Na+ channels,
– Slows rate of recovery (Inactivated state to the
Resting state)
– NOTE:- Prevents seizure propagation (Not initiation)
– Treatment of: Focal seizures and Tonic-clonic seizures.
— Pcokinétics:
• 95% protein bound
• NOTE:- Non-linear. Relationship between dose and plasma concentration.
Small increase in doses above a certain level leads to large and unpredictable

14
 increase in plasma drug conc. ie. Narrow therapeutic window. The dose at which
this transition occurs varies from patient to patient but is usually between 400–
600mg/day. Risk in adverse effects
• NOTE:- No longer 1st line agent
• t1/2: 24 hrs
• 95% metabolised by liver
• Zero-order kinetics. Enzymes of elimination become saturated. Rate of
elimination is independent on conc
• Metabolised by P450 enzymes. Affected by other inducers and inhibitors.
• Induces metabolism of OCPs, warfarin methadone
— Adverse effects:
(1) Concentration dependent
• Cerebellar symptoms:- Dysarthria (inability to speak properly), Ataxia (inability to
coordinate voluntary muscular movements), Nystagmus (involuntary usually rapid
movement of the eyeballs), Intention tremor.
• GIT: Anorexia, Nausea & vomiting
• Others: Chorea (movement disorder marked by involuntary spasmodic
movements especially of the limbs and facial muscles), peripheral neuropathy,
seizures.
(2) Long term.:-
Cosmetic side effects: Acne, coarse Facies, hirsutism (excessive growth of hair of
normal or abnormal distribution), gingival hyperplasia (over growth of gums of the
teeth—a common side effect of Phenytoin).
(3) Other adverse effects.
• NOTE:-Drug-induced SLE
• Osteomalacia (Vit D malabsorption)
• Megaloblastic anemia (Folate deficiency)
• Dupuytrens contracture
• Fetal hydantoin syndrome (growth retard, microcephaly, craniofacial
abnormalities)
• Aplastic anaemia
— Parenteral formulation of Phenytoin
NOTE!!!:- 1st line therapy in status epilepticus. Must only be administered
intravenously.
NOTE:- Phenytoin is ONLY given Intravenously (IV) because, it is Strongly
alkaline: if given otherwise route is causes:
• irritation of tissues (if extravasated)
• swelling and discoloration of hands (purple glove syndrome)
• Precipitates as salt (dihydatoin Na) in acidic solutions (5% Dextrose solutions) ie.
Phenytoin precipitates in 5% D/W. Therefore must be given in normal saline. Given
slowly not as push because of its CNS effects.
• Avoid rapid intravenous administration. This causes Depression of CVS
(hypotension and heart block) and CNS (respiratory arrest). NOTE:— Rate
should not exceed 50mg/min. There is need for resuscitation facilities, and cardiac
monitor (cardiac rhythm, and BP) during infusion.
• Caution: Measure serum conc. after 2 weeks (Therapeutic drug monitoring)
• Other uses: Antiarrhythmic, Trigerminal neuralgia
— Contraindication: (Phenytoin is Not given to these patients)
(1) Porphyria, and heart block (2nd and 3rd degree),
(2) absence seizures (Phenytoin worsens absence seizures).
(3) Not given to patient on Oral Contraceptives (OCPs).
NOTE:- Fosphenytoin
 Prodrug of Phenytoin.
 Can be admimistered more rapidly
 Administered only IV and IM
 Close monitoring still needed.
 Major drawback: Very expensive

15
 Carbamazepine (Carboxamide derivative)
– Developed 1974
– MOA similar to that of phenytoin.
– NOTE:— It has less protein binding capacity hence less drug-drug interaction.
– Prevents seizure propagation
– NOTE:— Drug of choice for partial seizures
— Pharmacokinetics:-
• t1/2, initially about 1.5 days, but reduces after 2-3wks due to induction of P450
enzymes (auto-induction ie. Induces enzymes that metabolises itself). Potent
Inducer of P450; Auto-induction.
• nearly completely metabolised by CYP3A4.
• Dose adjustment (from 200mg daily to 200mg B.D)
• Induces metabolism of other drugs; OCPs and Warfarin.
NOTE:- Na valproate and Levetiracetam can inhibit its metabolism. (MCQ!!!)
— Other uses: Trigeminal neuralgias, Prophylaxis for mood swings in manic- depressive
episodes, Diabetes insipidus.
— Contraindications :- Carbamazepine is Contraindicated (Not given to these patients)
in :
(1) Myoclonic and Absence seizures,
(2) Porphyria,
(3) Cardiac conduction defects,
(4) Bone marrow suppression,
(5) Patients on MAOIs.
— Adverse effects;
(1) Rash (5-15%, most notable among AEDs, can cause Steven Johnson Syndrome
[SJS] & TEN).
(2) Depression of CNS (cerebellar and brain stem dysfnctn) and CVS (conduction
defects). NOTE:- All Anti-epileptic drugs are CNS and CVS depressants.
(3) Osteomalacia
(4) Leucopenia
(5) Aplastic anaemia
(6) It cause syndrome of inappropriate secretion of Antidiuretic hormone (SIADH)
which can cause Dilutional Hyponatraemia, cerebral oedema and eventually
seizures.
(7) Teratogenicity: Cleft lip and palate, Spinal bifida (low risk)
HOW WILL CARBEMAZEPINE CAUSE SEIZURES???
Answer:- by causing SIADH: syndrome of inappropriate secretion of ADH—>Dilutional
hyponatraemia —>cerebral oedema —> seizures.
Contraindications in absence and myoclonic seizures.
Oxcarbazepine (Carboxamide derivative)
– Another carboxamide derivative
– Developed 2000
– Acts predominantly on Na+ channels
– Has similar indication with carbamazepine
– NOTE:- A pro-drug (active metab; Eslicarbazine)
– t1/2: 1-2hrs
– NOTE:- Less potent inducer of P450 enzymes
– Less risk of rash (SJS)
– Drawback: Higher risk of dilutional hyponatraemia due to SIADH.
Lacosamide
– Developed 2008
– Binds predominantly to Na channels (high frequency
– t1/2: 13hrs
– Metabolised by liver
– Non-sedating (NOTE)
– No drug-drug interaction (NOTE)
– Reserved for Refractory partial seizures (NOTE)

16
 — Adverse effects: Prolongation of PR interval, dizziness, nausea and headache.
Lamotrigine (PhenyItriazine)
– Developed 1995
— MOA:
~ Inhibit Na+ channel
~ Inhibits T-type Ca2+ channels
~ Glutamate receptor blocker and Inhibits Glutamate release
— Uses:
(1) Focal and Generalised (tonic-clonic) seizures,
(2) Absence seizures
(3) Bipolar disorders
– t1/2: 24hrs ( by other P450 inducers)
– Induces CYP450
– Metabolism inhibited by Na valproate
– NOTE:- Good adverse effect profile
– Major side effect is skin rash (10%) reduces with low dose.
– NOTE:- Favoured 1st line agent in tonic-clonic seizures.
– Also used as a mood stabiliser in manic- depressive disorder taken once daily in the
morning (associated with insomnia)
(2) ENHANCERS OF K-CHANNEL CONDUCTANCE
Retigabine
– 1st drug to be developed (2011)
– NOTE:— Retigabine is used as an ‘adjunctive’ therapy for partial seizures with or
without secondary generalisation.
– t1/2: 6-10hrs
– Adverse effects:- Urinary retention, blue skin discolouration and retina abnormalities.
– NOTE:— Baseline vision testing required
(3) DRUGS THAT INHIBIT Ca2+ CHANNELS
— [Every Valid Goal Pursues Zion]
Ethosuximide**
Valproic acid (T-type)
Gabapentin (N-type)
Pregabalin
Zonisamide
NOTE:— Ethosuximide only is purely a Ca channel blocker. It is a T-type Ca channel
blocker and is used in absence seizures. 1st line for absence seizures.
— Two types of Ca2+ ions:
(i) T-type (low voltage)——>(Absence seizures).
(ii) N-type (High-voltage)—>(Partial/Focal seizures).
T-type (low voltage)
• Control Ca2+ entry into the Post-synaptic terminal.
• Opened by the activated glutamate receptors
• provide for rhythnic firing of thalamic neurones
• thought to be involved in generating spike-wave discharges in absence seizures.
• NOTE:- T-type Ca2+ blockers are used in treatment of Absence seizures.
High-voltage-activated (HVA)
• Control Ca2+ entry into the Presynaptic terminal.
• Control release of NTs.
• NOTE:- N-type Ca2+ channel blockers are used in treating focal seizures (‡ secondary
generalisation), Primary generalised seizures.
~ Not used in absence seizures. Do not use the ones that block N-type in absence seizures!!
(NOTE)
Ethosuximide
– Succinimide-derivative
– Developed 1960
– Blocks low-threshold- Ca2+ channels (T-type) in the thalamus
– NOTE:- Activated in absence, and myoclonic seizures

17
– Drug of choice in absence seizures, also useful in myoclonic-seizures
– t1/2: 60 hrs (adults): 30 hrs (children)
– Adverse effects: Ataxia, lethargy, psychoses, allergic rxns, Gl irritation, drug-induced
SLE.
NOTE:- Ethosuximide is Activated in absence, and myoclonic seizures BUT
Carbamazepine is NOT.
NOTE:- Phenytoin, Carbamazepine & Ethosuximide induce SLE.
Valproic acid (Sodium Valproate)
– Fatty acid derivalive
– Developed 1978
– NOTE:- Administered as Na+ valproate absorbed as valproic acid (small intestine).
– NOTE:- It has widest spectrum of activity same with Zonisamide, Topiramate &
Lamotrigine.
— MOA:
• Inhibits Na+ channels
• Inhibits T-type Ca2+ channels
• Enhances GABA mediated inhibition by; glutamic acid decarboxylase activity
to GABA and Inhibiting GABA transaminases
– NOTE:- Na Valproate Can inhibit seizure initiation and propagation.
– NOTE:- Inhibits P450 enzymes; auto-inhibition (inhibits self) and metabolism of other
AEDs.
– t1/2: 13 hrs
— Uses: widest range of use!!
(1) NOTE:- Used in All forms of epilepsy.
(2) Drug of choice for Myoclonic epilepsy
(3) Diverse, idiopathic generalised seizure types & Focal seizures.
(4) Absence seizures (2nd line)
(4) Bipolar disorders
(5) Migraine prophylaxis
— Adverse effects:
(1) NOTE:— Highest risk of congenital malformation when compared with other
AEDs.
(2) Elevation of liver enzymes and blood ammonia levels is common. Fatal hepatitis
may occur, but overall the risk is small (approximately 1 in 40,000).
(3) Disliked by women: Weight gain, POS, hair loss ff re-growth of curly hair.
(4) Impaired glucose tolerance.
Gabapentin
– Developed 1992
– Structural analogue of GABA. Was Designed to enhance GABA-mediated inhibition but
do NOT bind to GABA receptors or affect GABA metabolism or reuptake.
— Mechanism of Action:-
• Primarily inhibits HVA-Ca2+ channels (N-type Ca2+ channels)
• Enhance GABA activity
– Not bound to plasma protein. Thus Has low drug-drug interaction.
– t1/2: 5-7hrs
– Does not induce or inhibit metabolism of other anticonvulsants.
– NOTE!!! Incomplete absorption from gut. Lowest Bioavailability.
– Not metabolised. Excreted unchanged by kidneys
– Absorbed in the proximal intestine by L-amino acid transport system.
– Bioavailability is dose limited because of transporter saturation (<60%).
– Gabapentin blood levels linearly with dose, up to about 1.8 g per day
— Uses:
(1) NOTE:- It’s an 'add-on' AED not a first line drug for Partial seizures (with or
without secondary generalisation).
(2) Neuropathic pain.
(3) Anxiety.
— Adverse effects:- Dizziness, somnolence , Wt. gain

18
 Pregabalin
– Developed 2005
– Similar to Gabapentin
– Has addition effect on substance P, and calcitonin (neuropathic pain).
— Uses:
(1) NOTE More potent than Gabapentin as an 'add-on' AED.
(2) Neuropathic pain
(3) Anxiety
– Unlike Gabapentine it is absorbed throughout the small intestine and by the
ascending colon.
– It is not subject to saturation unlike Gabapentin.
– used in generalised anxiety disorders
– t1/2:- 6.5hrs
– Absorbed more rapidly and Has a higher bioavailability than Gabapentin (>90%).
– Metabolised in kidneys
– Devoid of pharmacokinetic interactions with other agents.
— Adverse Effects :- Dizziness, somnolence, ataxia, Wt gain.
(4) DRUGS THAT ENHANCE GABA MEDIATED INHIBITION
Benzodiazepines
Barbiturates
Vigabatrin
Tiagabin
Benzodiazepines
— Examples include: Diazepam (1963),
Lorazepam,
Clonazepam,
Clobazam
– Positive allosteric modulators (PAMs) of GABAA receptors.
— MOA:
• Increase affinity of GABA for GABAA receptors.
• Enhance GABA channel opening in the presence of GABA which increase CI-
influx.
— Dual effects
(i) Increase threshold of membrane AP inhibits seizures initiation.
(ii) Strengthening surround inhibition.
— Adverse effects- has limited its use to aborting seizures acutely (Drowsiness,
Dizziness and Ataxia, forgetfulness and confusion).
– Major drawbacks include: Addiction and Tolerance.
Thus, they have been limited to aborting seizures ONLY. —> Diazepam &
Lorazepam
– 1st line in Status epilepticus (Diazepam, Lorazepam).
– I.V Diazepam- is formulated as an emulsion to reduce the incidence of thrombophlebitis
ie. inflammation of a vein with formation of a thrombus.
– Partial or complete tolerance to the antiepileptic action of benzodiazepines often
occurs after about 4-6 months of continuous treatment
– Also associated with Addiction (draw back)
— Clonazepam:
• Prevents the GABA-mediated paroxysmal hyperpolarization that activates the T-
type Ca2+ channels ie. Inhibits the T-type Ca2+ channels (seen in absence
seizures).
• Reserved as the 4th drug for Absence seizures.
Ethosuximide—>Na valproate—> Lamotrigine —› Clonazepam
– Benzodiazepines Also useful in myoclonic, seizures.
— Clobazam:
• Reserved as an adjunctive treatment for Lennox-Gastaut syndrome (A severe
paediatrics epileptic syndrome. Onset between 3-5 yrs. It is characterised by
developmental disabilities, refractory tonic, atonic and atypical absence seizures.)

19
 – Contraindication for long use Benzodiazepines (Clonazepam & Clobazam) :— Narrow
angle glaucoma.
Barbiturates
Examples are Phenobarbital, Primidone
(1) Phenobarbital:
– A weak acid that is absorbed with a bioavailability of >90%.
– rapidly distributed to all tissues.
– Metabolised by hepatic CYP (CYP2C9) and by N-glucosidation.
– Phenobarbital is a major inducer of CYP.
– Also undergoes autoinduction.
— MOA:
• duration of GABA-activated Cl- channel opening
• Agonist effect at GABAA receptors.
• Also has, the dual effect of Benzodiazepines.
– Useful in partial and tonic-clonic seizures.
– t1/2: 100 hrs
– Elimination is by hepatic metabolism and renal excretion
– Phenobarbital has profound sedating effect (limitation) & Tolerance to both unwanted
and therapeutic effects occurs during long term treatment. Dependence with a physical
withdrawal reaction is also seen after long term treatment.
NOTE:- Phenobarbital is never drawn using a plastic syringe because it precipitates in it.
A glass strings is used instead.
(2) Primidone:
– is the prodrug of phenobarbital
– Both are used in status epilepticus
– CYP450 inducer
Vigabatrin
– Developed 2009
– Structural analogue of GABA
—MOA:
• Irreversibly inhibits GABA transaminase thereby increasing GABA levels.
– NOTE:—It has a long duration of action longer than it’s stated half life this is because,
Duration of action is determined by the time required for GABA-T synthesis, rather than the
half life of elimination of the drug.
– Its efficacy is therefore unrelated to the plasma drug concentration.
– Hence blood concentration monitoring is of no value.
– NOTE:- Vigabatrin is Restricted to infantile spasms and refractory focal seizures.
– Vigabatrin is rapidly absorbed from the gut and is excreted unchanged by the kidney.
Gabapentin and Vigabatrin are excreted unchanged in the Kidneys.
– Causes severe irreversible peripheral visual field defects, and Psychiatric disorders
(drawback).
Tiagabine
– a potent inhibitor of GABA transporter 1(GAT-1), a transporter that removes released
GABA from the synaptic space and returns it to the nerve terminal for recycling or
catabolism. Thus, increasing GABA Conc. in the synaptic space.
– Tiagabine is oxidised primarily by CYP3A4 to inactive metabolites excreted in both the
urine and feces.
– Has a half-life of 5-8 h
– "add-on" for treatment of partial seizures.
(5) DRUGS THAT BLOCK GLUTAMATE RECEPTORS
Felbamate (NMDA Glutamate receptor blockers)
Lamotrigine (AMPA Glutamate receptor blockers)
Felbamate
– NMDA receptor blocker
— Also has the following actions:
• blocks Na+ channels,
• blocks Ca2+ channels,

20
 • potentiates GABA actions
– Potent inhibitor of seizure generation
— Draw back: Aplastic anaemia., Liver failure
– Reserved for refractory epilepsy (especially Lennox Gastaut syndrome). Same as
Clobazam.

Lamotrigine
– Blocks AMPA glutamate receptor
(6) CARBONIC ANHYDRASE INHIBITORS
Topiramate
Zonisamide
Topiramate
Developed 1997
— MOA:
• Carbonic anhydrase inhibilor
• Na+ channel inhibitor
• Glutamate receptor blocker
• Enhances GABAA activity
— Uses:
(1) Used alone or as an add on treatment for drug resistant partial or generalised
seizures
(2) Migraine prophylaxis
— Adverse effects: weight loss, IOP, cognitive Impairment, renal stones due to
metabolic acidosis.
Zonisamide
– Developed 2000
– Sulphonamide analogue
— MOA
• Carbonic anhydrase inhibitor
• Na+ channel blocker
• T-type Ca2+ channel blocker
— Uses: Same as Topiramate
— Adverse effect:
(1) same (weight loss)
(2) Binds extensively to erythrocytes approximately 8 fold higher Conc. in RBCs
than plasma. Therefore has a longer half-life.
(7) LEVITIRACETAM
–developed in 1999
– a member of a family of cyclic derivatives of GABA (eg, piracetam).
– a racemically pure S-enantiomer. R-enantiomer has no anticonvulsant property.
—MOA:-
Unknown but a postulate is given:
• It inhibits Synaptic Vesicle Protein 2A (SVA2A), a ubiquitous synaptic vesicle membrane
glycoprotein involved in exocytosis synaptic vesicle recycling
• Thus preventing the recycling of the vesicles and consequently the inhibition of excitatory
neurotransmitters such as glutamate release from end terminal.
• Also produces blockage of N-type Ca2+ channels.
– Oral Bioavailability = almost 100%.
– Vd is as TBW (0.5-0.7 L/kg)
– T1/2 is 7 hours
– Nearly completely absorbed and not bound to plasma proteins.
– Levetiracetam readily crosses the BBB.
– has high therapeutic index.
– NOTE:- It has very low drug-drug interaction.
— Uses: it’s used as a 1st line in Partial (focal) & generalised seizures EXCEPT Absence
seizures.
– Has a high Therapeutic Index

21
— Adverse effect: can cause sedation and behavioral adverse effects, including irritability.
Psychotic-like reactions can occur, especially in individuals with a previous psychiatric illness. \
— Drugs used in absence seizures
[Eno Na Lean Chick]
Ethosuximide,
Sodium valproate,
Lamotrigine
Clonazepam.
— Drugs used in Status Epilepticus
Diazepam,
Lorazepam,
Phenytoin,
Phenobarbital,
Primidone
— Drugs used in Lennox Gastaut syndrome
Felbamate
Vigabatrin (restricted to infantile spasms and refractory focal seizures).
Clobazam (adjunctive treatment )
— Primary Generalised Tonic-clonic Seizures First-line agents:
Lamotrigine
Valproic acid
Topiramate
Levetiracetam
— Partial Seizures First-line agents:
Carbamazepine
Valproic Acid
Levetiracetam
Oxcarbazepine
— AEDs that induce SLE
Phenytoin,
Carbamazepine
Ethosuximide
— myoclonic seizures first line agents
Na valproate,
Ethosuximide
— AEDs that show auto-induction
Carbamazepine
Na valproate
Phenobarbital
— AEDs that are excreted unchanged in urine.
Gabapentin,
Pregabalin,
Vigabatrin
Levetiracetam
They have low propensity for drug-drug interactions.
— Broadest spectrum amongst anti seizure drugs.
Na Valproate
Topiramate
Zonisamide
Lamotrigine
They are used in focal seizures and diverse generalised seizure types.
— Refractory partial seizures
Lacosamide
Vigabatrin
ADVERSE DRUG REACTIONS FOR ANTI-EPILETIC DRUGS
AEDs and PREGNANCY
NOTE:- Most teratogenic AEDs are;

22
 • Na valproate
• Phenobarbital
• Topiramate
• Phenytoin
— Na Valproate is associated with Neural tube defects due to folate deficiency. Thus administer
5g folic acid before pregnancy.
It is Also associated with limb defects, orofacial/ craniofacial defects
— Topiramate is associated with Cleft lips
— Phenobarbital associated with congenital malformations— cardiac.
NOTE :— The most safest anti-epileptics are: Lamotrigine and Levetiracetam.
NOTE:- Magnesium Sulphate (MgSO4) is the drug of choice for Eclampsia (an attack of
convulsions during pregnancy or childbirth).
NOTE :— Enzymes inducing antiepileptics cause serum levels of Vit. K and this leads to
post partum haemorrhage. Hence, Administer Vit. K to pregnant women during last 2 weeks of
pregnancy (36 weeks).
Children may also develop Vit. K deficiency. Hence administer intra muscular Vit. K to neonate
shortly after birth.
AEDs and OCPs
AEDs induce steroid metabolising enzymes and this metabolise OCPs thus reducing serum
levels and causing contraceptive failure.
This there is need to dose of OCPs or use of non-Oestrogenic forms of contraception.
AEDs and Breastfeeding
— Phenobarbital, Primidone, Ethosuximide are Secreted by breast milk and this pose a Risk of
sedation and poor suck.
STATUS EPILEPTICUS
– This is the state of continous seizure activity or 2 or more sequential seizures without full
recovery of consciousness between seizures.
– Prolonged tonic clonic seizure lasting for 10 mins or more. Focal seizures— 5 minutes.
TREATMENT
• 1st line — I.V. Benzodiazepines (Diazepam, Lorazepam).
• 2nd line — I.V. Phenytoin or Fosphenytoin, Phenobarbital (in that order).
Drawbacks :—
Causes persistent sedation and may have serious cardiopulmonary adverse effect including
respiratory depression and hypotension.
REFRACTORY STATUS EPILEPTICUS
– It occurs when seizures continue to happen at least 30 minutes following treatment with 1st line
and second line treatment.
— Treated with anaesthetic agents
• Propofol
• Midazolam
SUPER REFRACTORY STATUS EPILEPTICUS

23
 NEURODEGENERATIVE DISORDERS
– Characterised by progressive and irreversible loss of Specific neurones in the CNS.
– Damage/death to CNS neurones in adult is usually irreversible.
– In neurodegenerative diseases there can only be management underlying cause not cure.
– In neurodegenerative diseases there is relative Specific/selective Vulnerability of neurones in
certain brain areas/arrears.
• In Parkinson’s disease (PD) there is destruction of dopaminergic neurones of
substantia nigra but not cortex or other
brain regions
• In Alzheimer’s disease (AD) it is in the hippocampus.
• HD-mutant gene found in other organs
TYPES OF NEURODEGENERATIVE DISEASES
• Parkinson's Disease (PD)
• Huntington's Disease (HD)
• Alzheimer's Disease (AD)
• Amyotrophic Lateral Disease (ALS)
• Wilson's Disease (WD)
• Multiple Sclerosis
• CVA-Ischaemic Brain Disease (Ishaemic Stroke) & Haemorrhagic stroke
• Prion Diseases viz:
- Creutzfeldt-JaKob Disease (C]K)
- variant Creutzfeldt-JaKob Disease (vCJK)
- Gerstmann-Sträussler-Scheinker syndrome (GSS),
- Femilial Insomnia (FFI)
MECHANISM OF PATHOGENESIS OF SOME NEURODEGENERATIVE DISEASES
• PD & HD —> Loss of neurones from basal ganglia: resulting in movement abnormalities &
movement control
• AD —> loss of hippocampal and cortical neurones; memory impairment and cognitive ability
• ALS —> Degeneration of spinal, bulbar and cortical in neurones; muscular weakness
• WD —> Abnormalities ni Cu metabolism, excess Cu.: in the CNS.
NEUROTRANSMITTERS IMPLICATED IN ND
– The major neurotransmitters implicated are :
• Dopamine (DA)
• Acetylcholine (Ach)
– In Parkinson’s disease (PD) there is insufficient DA.
– In Alzheimer’s there is inadequate Ach
– In Huntington's Disease there is excess DA
This is Relevant for Pharmacotherapy.
PARKINSONISM
— A disease of basal ganglia of brain, characterised by:
 tremor,
 rigidity and
 akinesia or Bradykinesia.
which includes:
• Post-encephalitic- Parkinsonism
• Wilson's disease
• Multiple small strokes
• Poisoning by Mn, CO, or cyanide
• Long-term use of typical antipsychotic drugs.
• Traumatic brain injury

24
 NOTE:— It must Have a known cause or it is not referred to as Parkinsonism but
PARKINSON’S DISEASE.
PARKINSON’S DISEASE
– Parkinson’s disease is an idiopathic (cause unknown), progressive movement disorder/disease
of the basal ganglia characterised by: Tremor, muscle Rigidity, Bradykinesia and postural
imbalance.
Characteristic Symptoms
» T.R.A.P
• T- tremors at rest
• R- muscular rigidity and resistance to movement
• A- abnormalities in movement, hypokinesia and bradykinesia
• P- postural imbalance
– PD is the first disease to be associated with
a specific transmitter abnormality in the brain.
– Parkinson’s disease is caused by loss of dopaminergic (DA) neurons in the substantia nigra and
the presence of Lewy bodies (eosinophilic cytoplasmic inclusions) in surviving DA neurones.
– With deteriorating dopaminergic neurone, the balance between excitatory Cholinergic and
inhibitory Dopaminergic stimulation is lost.
– Therefore, there is over activity of the Cholinergic interneurones in the Striatum.
NOTE:— Frank symptoms of PD appear only when more than 80% of these neurones have
degenerated.
– About one-third of patients with PD eventually develop dementia.
SYNTHESIS OF DOPAMINE:-
Oxidation of Tyrosine to L-dopa is the rate limiting step in the production of all catecholamines
STEP 1: conversion of Phenylalanine to Tyrosine by Phenylalanine hydroxylase
STEP 2: conversion of Tyrosine to L-DOPA by Tyrosine hydroxylase.
STEP 3: decarboxylation of L-DOPA to Dopamine by L-aromatic amino acid decarboxylase
(AADC)
Phenylalanine —> Tyrosine —> L-dopa —> Dopamine
DEGRADATION OF DOPAMINE :-
Dopamine is degraded by Monoamine oxidase (MAO) to DOPAC (3,4-dihydroxyphenylacetic
acid) and HVA (homovanillic acid).
REUPTAKE & INACTIVATION OF DOPAMINE:
Dopamine transporters (DAT) found on dopaminergic neuronal cell membranes are responsible
for reuptake and clearance of dopamine from the synaptic cleft after action.
NOTE:— L-Tyrosine, L-Dopa & Dopamine can be easily converted to Melanin hence, the dark
colour of the Substantia nigra & surrounding areas.
NOTE:— In the synaptic cleft:
– DA can bind to both postsynaptic DA receptors and Pre-synaptic DA autoreceptors
– Most of the DA released into the synaptic cleft is transported back into the pre-synaptic cell by
the dopamine transporter (DAT)
Note that the dopamine transporter is not specific it can bind to Cocaine, Methamphetamine &
Amphetamine. Users are one to developing Parkinsonism.
— In presynaptic cell:
> Recycled into vesicles
> Degraded by monoamine oxidase (MAO) or catcchol-O-methyhtransferase(COMT)

— MAOs exist in two isoforms:

> MAO-A (the brain and periphery)
> MAO-B (the CNS)
NOTE:— Dopamine is mostly degraded by MAO-B
– Catecholamines are degraded by MAO-A (Risk of toxicity when inhibitors are given with
tyramine found in wine and cheeses)
– Dopaminergic Receptors are G-protein coupled:- D1–D5.
– Both D1 and D2 receptors are expressed at high levels in the striatum (caudate and putamen)
– D2 class, serve as autoreceptors.

25
 BASAL GANGLIA
— Receives inputs from cerebral cortex and returns it via the thalamus to the cortex and
brainstem.
— Responsible for organizing and smoothening all movements especially walking and writing.
— Components of Basal Ganglia:
 Caudate nucleus.
 Putamen.
 Globus pallidus ( GP): Internal( Gpi) and External (GPe).
 Sub-thalamic nucleus ( STN).
 Substantia nigra (SN): reticular part (SNr) and the compact part (SNc).
NOTE:—
— Caudate nucleus + Putamen = STRIATUM (Str)
— Putamen + Globus pallidus (Ext and Int) = LENTIFORM NUCLEUS.
That is, The caudate nucleus and the Putamen together make up the Striatum. The
Putamen and the Globus pallidus together make up the Lentiform nucleus.
— DOPA decarboxylase is expressed by dopaminergic neurons in the brain but it also
expressed throughout the body in almost all cell types.
— The basal ganglia do not connect directly to spinal motor neurons and thus do not
directly control the individual movements of muscles. It uses the extra pyramidal system as
the executor.
—Dopamine has a central role in the operation of this system, including signaling when
desired movements are exccuted successfully and driving the Iearning process.
— The basal ganglia use different pathways to initiate and terminate the motor program.
DOPAMINERGIC PATHWAYS
All originating from the Basal ganglia.
(1) Mesolimbic pathway :- Regulate reward and learned behaviours
• Dysfunction associated with Addiction, Psychosis, schizophrenia and learning deficits
(2) Mesocortical pathway :- Regulate emotions and motivation
• Dysfunction associated with Psychosis and Attention-deficit hyperactivity
(3) Nigrostriatal pathway :- Key regulator of purposeful movement. The largest DA tract in the
brain is the nigrostriatal system (80% of brain DA).
• Dysfunction associated with Movement disorders—Parkinson’s disease, tar-dive
dyskinesia.
(4) Tuberoinfundibular pathway :- Regulates prolactin release.
—NOTE:— Dopamine is produced in the mid brain and hypothalamus.
The midbrain, containing the Substantia-nigra and Adjacent-ventral tegmental area (VTA).
The hypothalamus containing the Arcuate nucleus.

26
— Nigrostriatal DA neurones project from the Substantia nigra to the Striatum (caudate nucleus
and putamen) and are involved in the control of posture and movement: These neurones
degenerate in Parkinson disease.
— The ventral tegmental neurons extend to the cortex and limbic system, referred to as the
Mesocortical and Mesolimbic pathways.
— DA is also synthesised by neurons originating in the arcuate and periventricular nuclei of the
hypothalamus extending to the pituitary known as the Tuberoinfundibular pathway. (These neurons
regulate pituitary function and decrease prolactin secretion).

NOTE:— The largest DA tract in the brain is the Nigrostriatal system, which contains about
80% of the brain's DA. It is Involved in the stimulation of purposeful movement. Drugs used for
the treatment of Parkinson’s disease stimulate this Nigrostriatal DA system.
Whereas drug used for the treatment of psychotic disorders, such as schizophrenia block
them.
NOTE:— The Area postrema (floor of the fourth ventricle) has D2 receptors which when
stimulated cause Nausea and Vomiting. Anti emetic drugs block this DA receptors and as a
result could eventually cause Parkinsonism.
NIGROSTRIATAL PATHWAY
— They assist in learning coordinated patterns of movement and by facilitating the execution of
learned motor patterns.
— The basal ganglia do not connect directly to spinal motor neurons and thus do not directly
control the individual movements of muscles.
— This Nigrostriatal pathway(extrapyramidal) help to intiate and terminate the motor program :
Control the muscle tone muscle length, speed and strength of the movement. While the pyramidal
system are the executor.
—The striatum (caudate and putamen) is the primary input nucleus of the system, while the
globus pallidus pars interna and substantia nigra pars reticulata are the output nuclei.
— These are interconnected through twO internuclei, the subthalamic nucleus and the globus
pallidus pars externa.
THE STRIATUM
— Information processing centre
— The cortical inputs to the Striatum are excitatory and use glutamate as a transmitter
— It is also the target of the dopaminergic nigrostriatal pathway
— They release the inhibitory transmitter GABA.
— Send their projections via the: Direct pathway and the Indirect pathway.
— It also contains several small interneurons that release Acetylcholine. They participate
in the intercommunication between the Direct and Indirect pathways.
— The balance of activity between the direct and indirect pathways regulates movement.
— The balance of activity between the direct and indirect pathways of the Nigrostriatal
pathway is maintained by Acetylcholine.
DIRECT PATHWAY
— It’s Excitatory.

27
— The direct pathway contains primarily, dopamine D1 receptors.
— The direct pathway initiates movement
— Pathway: cortex —› striatum —>globus pallidus pars interna —> thalamus —› motor
cortex —>spinal cord /brainstem.
INDIRECT PATHWAY
— It is Inhibitory.
— The indirect pathway, predominantly expresses D2 receptors.
— the indirect pathway stops movement.
— Pathway: cortex —> striatum —> globus pallidus pars externa —> subthalamic nucleus —>
globus pallidus pars interna —> thalamus —> motor cortex —> spinal cord / brainstem
— The neurons in the subthalamic nucleus are excitatory glutamatergic neurons. The final result
of this pathway is a increased muscle tone or inhibition of movement.
— Movement is brought about by the corticospinal tract but coordination of movement by the
striatum.
NOTE:—
 Excess uncontrolled movement is usually due to damage to the indirect pathway.
 D1 receptors are more affected by decrease in dopamine from the Substantia nigra
compacta than the D2 receptors.
 TONE is resistance to passive movement.
 Increased D2 activity / damage to direct pathway would lead to more tone and less
movement (hypertonia & Bradykinesia).
 Increased D1 activity / damage to indirect pathway would lead to more movement
& less tone (hypotonia & tachykinesis).

28
29
Basal ganglia functions
 Start movements.
 Stop movements.
 Modulate movements.
Disorders of the basal ganglia
 Damage to the direct pathway.
 Damage to the indirect pathway.
 Damage to the Nigrostriatal pathway.
CLINICAL IMPLICATIONS OF BASAL GANGLIA DISORDERS
Classified into two categories:
(1) Hypertonic-hypokinetic (Damage to the direct pathway).
(2) Hypotonic-hyperkinetic ( Damage to the indirect pathway).
NOTE:— Hypertonic-hypokinetic:
 Degeneration of the neurones that form the direct pathway. Pathway that serves for the
planning of the movement
 Patients present with either Bradykinesia (slow movement) or Akinesia (inability to move
at all because the individual is unable to plan).
 This is the case in Parkinsonism (Parkinson’s disease).

IN SUMMARY:— Parkinson’s Disease is:

 A Progressive neurodegenerative disorder involving the dopaminergic neurones in the
Substantia Nigra Pars Compacta.
 A state of dopamine defficiency: the direct pathway shows reduced activity, while the indirect
pathway is overactive.

30