Antimanic & CNS Stimulant

B.
Rammohan
 Also known as Manic depressive disorder
 Episodes of mood swings are unrelated to life

events
 Preponderance of catecholamines activity may be

the reason
 There is a strong familial component

Lithium
Valproate
Carbamazepine
Lamotrigine
Olanzapine
÷ It is a monovalent cation
÷ Discovered in 1949
÷ Lithium carbonate is referred to as anti-manic drug
÷ It is used as a mood stabilizer in manic disorder

PHARMACOKINETICS
Absorption
÷ Completely absorbed within 6-8 hrs

÷ Peak plasma levels in 30 min-2hrs
Distribution
÷ In total body water

÷ Slow entry in intracelluar compartment
÷ Some sequestration in bone
÷ No protein binding
PHARMACODYNAMICS
MOA
Still unclear
Following points are under investigation:
÷ Effect on electrolytes and ion transport
÷ Effects on neurotransmittor release
÷ Effects on second messengers

Effects on Electrolytes and Ion Transport
Lithium is closely related to sodium in its

properties
It can substitute Na (sodium) in generating action

potentials and Na-Na exchange across
membranes
At therapeutic levels (around 1mmol/L),it

doesn’t effect Na/Ca exchange or Na /K ATPase
sodium pump
Effects on Neurotransmittors
÷ Serotonin
Appears to enhance some actions of serotonin
÷ Norepinephrine and dopamine

It may decrease the turnover of these
neurotransmittors
It may also augment the synthesis of Ach.
Effects on Second Messenger
 Current working hypothesis for lithium's
therapeutic mechanism of action is that its
effects on phosphoinositol turnover, leading to
reduction of myoinositol in human brain
 Lithium inhibits norepinephrine-sensitive

adenylyl cyclase (antidepressant and its
antimanic effects)
 Bipolar Disorder
Lithium carbonate was the preferred treatment
for bipolar disorder (esp. in the manic phase)
With the approval of valproate, olanzapine, a
smaller percentage of bipolar patients now
receive lithium
 Depressive phase of manic-depressive disorder

requires concurrent use of an antidepressant
drug
 Recurrent endogenous depression:
with a cyclic pattern is controlled by lithium
or imipramine
 Schizophrenia: Lithium in combinaion with

antipsychotic is used
 Before therapy following should be obtained
÷ Complete blood picture

÷ Urinalysis
÷ ECG in elderly and cardiac patients
÷ Patients age, body weight and renal
functions should be assessed
Initial dosing
Initial volume would be the same as body water

0.5-0.6 L/Kg-----Females
0.55-0.7 L/Kg---Males
Dosage is to be adjusted in renal impairment and

elderly patients
Initially Lithium is given in daily divided
doses to avoid gastric irritation
Drug is to be taken with or after meals
Slow release dosage forms are also available
Later on single dosaging may be possible

÷ Serum concentration of lithium is assessed
÷ These are taken 10-12 hrs after last dose
÷ Initial measurement is to be taken after 5

days of start of therapy
A. Neurologic and Psychiatric Effects
1.Tremors(Relieved by propranolol)
2.Choreoathetosis
3.Motor hyperactivity
4.Ataxia
5.Dysarhtria
6.Aphasia
7.Mental confusion
B. Effects on Thyroid function
1.Hypothyroidism
2.Thyroid enlargement
C. Renal Effects
1.Polydipsia, Polyuria(nephrogenic
diabetes insipidus)
2. Chronic interstitial nephritis

3. Minimal change glomerulonephritis
D. Edema
It is a frequent effect of Lithium therapy
E. Cardiac Effects
“Sick sinus syndrome” is a definite
contraindication
F. Misc.
Transient acneiform eruptions
Leucocytosis
Disturbed sexual function in men
Therapeutic overdoses can occur due to change
in patients status:
Use of diuretics
Fluctuating renal function
Pregnancy
Treatment
Dialysis( peritoneal dialysis, haemodialysis)
Alternative to lithium when the latter is less
than optimally efficacious
Used to treat acute mania and also for

prophylactic therapy
 An antiepileptic drug
 Efficacy equivalent to that of lithium during

the early weeks of treatment
 Becoming a first-line treatment for manic

phase
 Lamotrigine
 Olanzapine
Cocaine Ephedrine
Methamphetamine Methylphenidate
I. Cocaine, Crack (free base or hydrochloride).
II. Amphetamines:
D-Amphetamine, Methamphetamine, methylphenidate
(use to treat attention deficit disorders in children),
phenmetrazine (Preludin) - used to treat obesity,
hallucinogens = MDA, MDMA, DOM;
III. Khat: Cathinone, methcathinone.
IV. Methylxanthines: caffeine (coffee), theophyline (tea),
theobromide (chocolate).
 Alkaloid from Erythroxylon coca
 Indigenous to western South America
 Coca leaves used for religious, mystical,
social, stimulant, and medicinal purposes
 Main stimulant uses: endurance, feeling of
well-being, alleviate hunger
 Medical uses: local anesthetic,
vasoconstrictor
 Coca paste extracted from soaked and mashed leaves (60-
80% cocaine)
• Cocaine powder made by mixing paste with hydrochloric acid (cocaine HCl)
• Freebase/crack extracted from powder with baking soda

 Synthetic analog of ephedrine,
active ingredient in mahuang
 Mahuang used in China for asthma
 Methamphetamine and
Methylphenidate (Ritalin) are very
similar
 Medical uses: obesity, ADHD,
narcolepsy
 alertness/vigilance, concentration
 mental acuity, sensory awareness London et al., 1999
 euphoria/elevated mood
 brain electrical activity
 self-confidence, grandiosity
 need for sleep (insomnia)
 appetite
 brain blood flow, glucose metabolism
 sexual desire, but cocaine can  performance
 anxiety, suspiciousness, paranoia
 convulsions, tremor, seizure
 psychosis, delirium
 locomotion at low/moderate doses
 repetitiveness, stereotypy at high doses
 reinforcement/addiction
 judgement, complex multi-tasking
Fight/Flight/Fright Syndrome  Blood pressure
(sympathetic nervous system arousal)
 Blood sugar
 Heart rate
Irregular heart beat
Vasoconstriction
 Body temperature
Bronchodialation
& Impaired breathing

 Routes of administration
 Insufflated (snorted)
 IV (mainlined)
 Inhaled (freebased)
 Oral
 Both cocaine and amphetamines penetrate BBB easily
 Half-lives
 Cocaine: 50-90 min
 Amphetamine: 5-10 hours
 Meth: 12 hours
 Metabolites include active and inactive compounds
 Cocaine is unusual in that it “autometabolizes” in the
blood in addition to normal liver metabolism.
 Cocaine ----> norcocaine, ecgonine methyl ester, benzoylecgonine
 Alcohol inhibits metabolism of cocaine
• Cocaethylene
– Similar effects to cocaine
– Greater cardiac toxicity than cocaine
– 3-5x the half-life of cocaine
– associated with seizures, liver
damage, compromised immune
system
 Indirect Agonist for
 DA (high affinity)
 NE (high affinity)
 5-HT (modest affinity)
• Mechanism:
– Blocks monoamine reuptake
 Indirect Agonist for
 DA (high affinity)
 NE (high affinity)
 5-HT (low affinity)
• Mechanisms:
– Blocks monoamine reuptake
– Inhibit vesicular storage
– Inhibit MAO metabolism
– Reverses reuptake
 High abuse potential (Schedule 2)
 Physical and psychological dependence
 Tolerance to euphoria, appetite suppression; sensitization
to psychomotor
 Withdrawal
 Physically mild to moderate (hunger, fatigue, anxiety, irritability,
depression, panic attacks, dysphoric syndrome)
 Route of administration important to addiction risk

Treatment of withdrawal:
 Alpha-blockers
 Chlorpromazine: DA antagonist (also blocks alpha
receptors)
 Haloperidol (antipsychotic – 50x more potent than
chlorpromazine).
 Alprazolam (Xanax - benzodiazepine) for panic attacks.
 Antidepressants (fluoxetine or desipramine).
 Diazepam (Valium) for seizures - binds to benzodiazepene
site of GABAa receptor.

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B.

 Episodes of mood swings are unrelated to life

 Preponderance of catecholamines activity may be

 There is a strong familial component

÷ Lithium carbonate is referred to as anti-manic drug

÷ It is used as a mood stabilizer in manic disorder

÷ Completely absorbed within 6-8 hrs

÷ In total body water

÷ Effect on electrolytes and ion transport

÷ Effects on neurotransmittor release

÷ Effects on second messengers

Lithium is closely related to sodium in its

It can substitute Na (sodium) in generating action

At therapeutic levels (around 1mmol/L),it

÷ Norepinephrine and dopamine

 Lithium inhibits norepinephrine-sensitive

 Depressive phase of manic-depressive disorder

 Schizophrenia: Lithium in combinaion with

÷ Complete blood picture

Initial volume would be the same as body water

Dosage is to be adjusted in renal impairment and

Drug is to be taken with or after meals

Slow release dosage forms are also available

Later on single dosaging may be possible

÷ These are taken 10-12 hrs after last dose

÷ Initial measurement is to be taken after 5

2. Chronic interstitial nephritis

Used to treat acute mania and also for

 Efficacy equivalent to that of lithium during

 Becoming a first-line treatment for manic

• Freebase/crack extracted from powder with baking soda

& Impaired breathing

 Route of administration important to addiction risk

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