CNS Pharmacology

Abebe Ejigu
Departmenet of Pharmacology

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 CNS
 CNS- brain and the spinal cord
 Semi-liquid structure at body temperature
 Excitable tissues and glial cells
 Brain is sensitive structure and protected by Blood Brain Barrier
(BBB)
 Oxygen, glucose, and other small non-polar are molecules that cross the barrier
 BBB is the major challenge for drug delivery to brain
Receptors in the CNS
 Kinase linked receptors :
Eg. cytokine, insulin Rs
 Nuclear receptors
Eg. Steroid R
 Channels
 Voltage gated channels (metabotropic) -GPCRs
Eg. Muscarnic Ach R
 Ligand gated channels (ionotropic)
Eg. Nicotinic Ach, GABAA Rs
 Types of post synaptic receptors / neurons
A. Excitatory neurons
1. Opening of Na channels (influx of Na+ )
2. Depressed Cl- influx or K+ efflux or both
• Influx of Na+ ion, inhibition of K+ ion conductance and Cl-
ion channel opening causes increased positively inside
postsynaptic neuron
3. Changes in internal metabolism of the postsynaptic neuron to
excite cell activity or by increasing excitatory membrane
receptors / decrease inhibitory membrane receptors
B. Inhibitory neurons
1. Opening of Cl- channels (Influx of Cl- ion )
2. Increase conductance of K+ ions (efflux of K+)
• Influx of Cl- ion and efflux of K+ ion causes
increased negativity inside postsynaptic neuron
3. Activation of enzymes which inhibit cellular metabolic
functions and increase inhibitory synaptic receptors
or decrease excitatory receptors
 The basic processes of synaptic transmission in the
CNS are essentially similar to those operating in the
periphery
 The release of neurotransmitters (NTs) and
receptor binding
 Recognition of the NT by membrane receptors
triggers intracellular changes
 NT release regulation (presynaptic receptors)
 Removal of NT from the synaptic cleft
NTs in the CNS / inhibitory or excitatory
 Inhibitory : GABA, Glycine
 Excitatory : Glutamate, Aspartate
 Others
 Monoamines: DA, NE and 5-HT
 Ach
 Neuropeptides (e.g. sub-P,enkephalins)
 Purine nucleotides (adenosine, ATP)
GABA
 Major inhibitory AA in the mammalian CNS
 Reduced function/amount of GABA will cause
excessive stimulation
 seizure
 Synthesized from glutamate by the action of glutamic
acid decarboxylase
 Linked to chloride channel opening
Hyperpolarization
Types of GABA receptors
GABAA

• Ion channel receptor

• Increase Cl- conductance (postsynaptic)
• Blocked by bicuculine and facilitated by BZDs
GABAB

• G protein coupled receptor

• Increase K+conductance (postsynaptic)
• Decrease Ca 2+ influx (Presynaptic)
• Baclofen (agonist )
 Drugs that interact with
 BZD tranquilizers…facilitate the action of GABA
 Barabiturates…CNS depressant
 Neurosteroids
 Picrotoxin….convulsant (block anion channel)
 GABA deficiency/defect causes excessive stimulation
 Seizure
 In delicate balance with excitatory transmitters
 Agonist / antagonist for GABA receptors
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Glycine
 Inhibitory AA
 Linked to Cl- ion channels
 Mainly limited to the spinal chord & blockade of Glycine
receptors cause seizure
Glutamate
 Excitatory NT with different receptors (NMDA, AMPA,
Kainate, Metabotropic Glu receptors)
 Excessive stimulation may lead to Seizure
 NMDA receptors – role in learning and memory and
pathological disturbances (as in epilepsy, chronic pain or drug
dependance)
 Pathways for the synthesis of EAA and IAA
 Disturbance of any one step will affect both excitatory and
inhibitory mediators
Dopamine (DA)
 NT and a precursor for NA
 Common brain function disorders related with DA
 Parkinson's disease
 psychosis/ schizophrenia
 drug dependence
 attention deficit disorder
 certain endocrine disorders
 depression ?????
 Drugs used clinically to treat these conditions work by
influencing dopamine transmission
Dopaminergic pathways (4)
1. Mesolibic-mesocortical pathway
 Related to emotion and behavior
 Excess DA – causes psychosis
2. Nigrostriatal pathway
 Involved in coordination of voluntary movement
 Deficient DA – causes Parkinsonism
3. Tuberoinfundibular pathway (tuberohypophseal)
 Regulate prolactin secretion
 DA inhibits prolactin secretion
4. Medial periventricular pathway- feeding
 DA receptors located in the CTZ, GI, heart and
splanchnic vessels
 DA acts in CTZ to induce nausea and vomiting
Dopamine (DA)
 Two types of receptors
 D1 family (D1 & D5) activates adenylate cyclase
 D2 family (D2,D3 & D4) inhibits adenylate cyclase
mediates most of DA functions
Bromocriptine (D2 agonist)- to treat parkinsonism
 levodopa (dopamine precursor)- to treat parkinsonism
 Chlorpromazine (D2 antagonists in CTZ)- antipsychotic &
antiemetics
 Metoclopramide and domperidone (D2 antagonists in CTZ)-
antiemetics
Norepinephrin
 β hydroxylation of dopamine
 Mainly inhibitory (β AR) but some are excitatory (α/β AR)
 Important to remain awake
 Increased stimulation during awake phase
 Also play role in
 Attention , control of mood and feeding
 Its reduction will contribute to occurrence of depression
 Imipramine and amitriptyline (NE reuptake inhibitors)- TCA
 Clonidine and methydopa (presynaptic α2 agonists)-centrally acting
antihypertensives
Serotonine ( 5-HT)
 Can exert inhibitory or excitatory effects on individual neuron
acting either pre or postsynapticaly
 Main receptor subtypes in CNS: 5-HT1A, 5-HT1B, 5-HT1D ,5-HT2
and 5-HT3
 Involved
in feeding behavior, behavioural responses, control of
mood and emotion, sensory pathways, body T0 and vomiting
Sumatriptan(5-HT1D agonist) - for migraine treatment
Fluoxetine (SSRI)- antidepressant
Busprone(5-HT1A agonist)- to treat anxiety
Ondasartan(5-HT3 antagonist)- antiemetic
Acetylcholine (Ach)
 Widely distributed in CNS
 Pathways:Interpedencular nucleus, striatum, Septum and basal
nuclei of Meyernet
 Involved in different activities including in arousal, learning,
short-term memory and movement coordination
 Parkinsonism- relatively excessive Ach function
Benzatropine (Muscarnic Ach antagonist)
 Alzheimer - profound cholinergic neuron loss
Revastigmine(cholinesterase inhibitor)
Sites of drug action which can alter synaptic
transmission

 AP in presynaptic fiber
 Alteringsynthesis,
storage,metabolism,release,
reuptake,degradation and
binding site of NT
 Receptor-induced increase
or decrease in ionic
conductance
 Drugs that acts on CNS can :-
 Selectively relieve pain
 Suppress disordered movement
 Induce sleep or arousal
 Antiemetic effect
 Treat anxiety, depression, schizophrenia,
Parkinson’s disease, Alzheimer’s disease, epilepsy,
migraine, etc.
General Anesthetics (GA)

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Comparing features of general & local anesthesia
GA LA
Site of action CNS PNS
Area of body involved Whole body Restricted area
Consciousness lost Maintained
Care for vital functions Essential Not needed

For poor health patient Risky Safer

Surgery For major surgery For minor surgery

Use in non cooperative Possible Difficult

patients
MoA Enhance inhibitory & ↓Na+ entry
inhibit excitatory NTs
actions

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 Triad of general anaesthesia (GA)

Hypnosis

Analgesia Muscle relaxation

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 Death

Coma

Hypnosis
sedation
Amnesia
Awake

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General anesthetics (GA)
Depress CNS to the extent that permit performance of
surgery & other noxious/unpleasant procedures
 Physiologic state induced by GA
 Analgesia
 Amnesia
 Loss of consciousness
 Inhibition of sensory & autonomic reflexes
 Skeletal muscle relaxation

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 The extent of effects depends on
 The drug
 The dosage
 Clinical situation

 Phases of GA
 Induction
 Maintenance
 Recovery

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Property of an Ideal anesthetic
1. For patient
Pleasant, non-irritant, not cause nausea, vomiting &
with wide margin of safety
 Fast induction & recovery without after effect
2. For the surgeon
 Adequate analgesia, immobility and muscle relaxation
3. For the anesthetist
 Easy administration, controllable and versatile

 No single anesthetic has all these

Balanced anesthesia, pre and post operative medications are required

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Stages of anesthesia (’’Guedel's signs’’ )
1. Analgesia
 Initially analgesia, finally both analgesia & amnesia
2. Excitement/delirium
 delirious and excited
3. Surgical anesthesia
 change in ocular movements, eye reflexes, & pupil size
4. Medullary depression/paralysis
 cessation of spontaneous breathing
 severe depression of the vasomotor center in the

medulla

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Mechanism of action of GA
 Mechanism of action is not precisely known
• Unreactive compounds produce narcotic effects(eg.
xenon)
• lipid theory : potency correlated with lipid solubility
(Overton-Meyer correlation)- unitary theory
• Effect on ion channels: recent theory
 Interaction with ligand-gated membrane ion
channels

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 Most anaesthetics enhance activity of inhibitory
GABAA receptors, and inhibit activation of excitatory
receptors such as glutamate and nAch receptors
 However individual anaesthetics differ in their
actions and affect cellular function in several
different ways
 Therefore, unitary theory is n’t sufficient

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 Halogenated hydrocarbons
 Activation of K+channel
 Enhance GABA effect
 Nitrous oxide and Ketamine
 Don’t affect GABA or glycine gated Cl- channel
 Selectively inhibit excitatory NMDA type of
glutamate receptor
 NMDA mainly gates Ca 2+ selective cation channel in
neurons

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1. Inhaled anesthetics (gases or volatile liquids)

 Desflurane Enflurane
 Sevoflurane Halothane
 Isoflurane Ethoxyflurane
(Most commonly used) Nitrous oxide
Diethyl ether
Xenon

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Pharmacokinetics of inhalational anaesthetics

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Main factors that determine the speed of induction and
recovery of inhalational anesthetic
 Properties of the anaesthetic
 solubility in blood (blood:gas partition coefficient)
 Partial pressure of anesthetics
 lipid solubility (oil:gas partition coefficient)
 Physiological factors
 Alveolar ventilation rate
 Cardiac output (CO)

Increased CO greater induction time

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 Pharmacokinetics of inhalational anaesthetics

Low solubility in blood - high parial pressure = fast induction and recovery
Numbers indicate blood:gas partition coefficient 

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 Rapid induction and recovery allowing flexible
control over the depth of anaesthesia
 Speed of induction and recovery determined by
 Solubility in blood
 Solubility in fat (lipid solubility)
 Low solubility in blood produce rapid induction and
recovery (e.g. nitrous oxide, desflurane)
 High solubility in blood - slow induction and
recovery (e.g.halothane)
 High lipid solubility (e.g. halothane) accumulate
gradually in body

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 General actions of inhaled anesthetics

 Respiration
 Depressed respiration and response to CO2
 Kidney
 Depression of renal blood flow and urine output
 Muscle
 High concentrations will relax skeletal muscle

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 CVS
 Generalized reduction in arterial pressure and
peripheral vascular resistance
 CNS
 Increased cerebral blood flow and decreased cerebral
metabolism
 Liver
 Conc-dependent decrease in hepatic blood flow
 permanent changes in liver enzyme function are rare

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 Toxicity
 Hepatotoxicity ( associated with halothane)
 Nephrotoxicity
 Malignant hyperthermia
 Mutagenicity
 Carcinogenicity
 Hematotoxicity

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Individual inhalation anaesthetics
 Halothane (widely used)
 Potent, non-explosive and non-irritant,
hypotensive
 ‘Hangover' likely, due to high lipid solubility
 Risk of liver damage if used repeatedly

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 Nitrous oxide
 Odorless and colorless
 Low potency, therefore must be combined with other
agents
 Rapid induction and recovery
 Good analgesic properties
 Risk of bone marrow depression with prolonged
administration

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 Enflurane
 Halogenated anaesthetic similar to halothane
 Less metabolism than halothane , therefore less risk of
toxicity
 Faster induction and recovery than halothane (less
accumulation in fat)
 Some risk of epilepsy-like seizures
 Isoflurane
 Similar to enflurane but lacks epileptogenic property
 May precipitate myocardial ischemia in patients with
coronary disease
 Irritant to respiratory tract
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 Desflurane
 Similar to isoflurane but with faster onset and
recovery
 Respiratory irritant, so liable to cause coughing and
laryngospasm
 Sevoflurane
 Similar to desflurane with lack of respiratory
irritation

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 Ether
 Obsolete except where modern facilities are not
available
 Easy to administer and control
 Slow onset and recovery, with postoperative nausea
and vomiting
 Analgesic and muscle relaxant properties
 Highly explosive
 Irritant to respiratory tract

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2. Intravenous anesthetics
 Barbiturates (eg, thiopental, methohexital)
 Propofol
 Ketamine
 Etomidate
 Dexmedetomidine

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 I.V.
anaesthetics have faster onset of action than the
most rapid inhaled agents (eg. desflurane and
sevoflurane)
 Used for induction of general anesthesia
 Rapid
recovery (but not propofol) and used for short
ambulatory (outpatient) surgical procedures

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Thiopental
(barbiturate)
 High lipid solubility
 Rapid action due to rapid
transfer across BBB
 Short duration due to
redistribution

Redistribution of thiopental
after an intravenous bolus administration
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Thiopental
 Slowly metabolised and liable to accumulate in body fat
 Single
dose produces only a brief period of
unconsciousness (rapid removal from brain)
 No analgesic effect
Adverse effects
 Narrow margin between anaesthetic dose and dose
causing cardiovascular depression
 Risk of severe vasospasm if accidentally injected into
artery

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Etomidate
 Similar to thiopental but more quickly metabolised
 Causes minimal cardiovascular and respiratory
depression(compared to other i.v.anesthetics)
 Used for induction of anesthesia in patients with
limited cardiovascular reserve
 Minimal hypotension even in elderly patients with
poor cardiovascular reserve

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Adverse effects
 Pain on injection
 Postoperative nausea and vomiting
Prolonged use may cause suppresses of adrenal
steroids production
(not to be used for patients with adrenal insufficiency)
Prolonged infusion to critically ill patients may result
in
 Hypotension and electrolyte imbalance
 Oliguria b/c of its adrenal suppressive effects

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Propofol
 Rapidly metabolized / rapid recovery with out hangover
 Patients
are able to ambulate earlier after general
anesthesia
 less postoperative nausea and vomiting
 useful for day case surgery
 For induction and maintenance of anesthesia as part of
total intravenous or balanced anesthesia
 Effective to induce prolonged sedation for patients in
critical care settings (prolonged infusion )

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ketamine
 MoA:
may involve blockage of glutamate on
NMDA receptor subtype
 The only i.v anesthetic with analgesic & dose-
related cardiovascular stimulation effects
 Cardiovascular effects via
 Stimulating central sympathetic nervous system
 To some extent by inhibiting the reuptake of NE
 Slow onset of action (2-5 minutes)

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 Increases cerebral blood flow, oxygen consumption, &
intracranial pressure
 Causes dissociative anesthesia (patient may remain
conscious)

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3. Balanced anesthesia
Combination of i.v and inhaled anesthetics
 i.v.( induction of anesthesia)
 inhaled (maintenance of anesthesia)
Muscle relaxants used to facilitate tracheal intubation
and optimize surgical conditions
Local anesthetics provide perioperative analgesia
Potent opioid analgesics and cardiovascular drugs
(eg, β-blockers, α2 agonists, Ca 2+ channel blockers)

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 Preanesthetic
Anesthetic adjuncts medications
 Benzodiazepines – Anticholinergics
 Analgesics – Anxiolytics
 Neuromuscular – Antiemetics

blocking agents – Antacids

 Post anesthetic medications
– Analgesics

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Local anaesthetics (LAs)

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Coca leaves used to be chewed for numbing effect
they produced on mouth and tongue
The leaves contains cocaine
Cocaine was the 1st local anaesthetic proposed for

surgical procedures
Sigmund Freud studied cocaine's physiological actions
Carl Koller introduced cocaine as ophthalmic

anesthetic
Chronic use of cocaine is associated with

psychological dependence (addiction)

Synthetic substitutes, procaine & many other useful

local anesthetics were developed

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Chemistry of LAs

 Most local anesthetic agents consist of

 hydrophobic /lipophilic group
 Amine substituents /ionizable group
 separated by an intermediate ester or amide
linkage
 Benzocaine does not have basic / ionizable group

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64
 nk Lipophilic Ester Amine
r li group bond substituents
st e
E
 Cocaine

Procaine

Tetracaine

 Benzocaine

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 k
lin
id
Am

Lidocaine

Ropivacaine
Mepivacaine

Bupivicaine

Prilocaine

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  Ester links prone to hydrolysis in plasma or
tissue by non-specific esterases & have short
duration of action
 Amide links are more stable & have longer
plasma half lives
 LAs are weak bases with pKa values mainly
in the range 8-9
Ionized at physiological pH (but not
completely)

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  Relative proportion of the ionized and
unionized forms determined by pKa of the LA
and pH of the body fluid
 Cationic form is the most active at receptor
site
 The receptor for LAs is not readily
accessible from the external side of the cell
membrane
 Therefore , Unionized form is important for
rapid penetration of axonal membranes
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 As the LA needs to penetrate the nerve sheath and the
axon membrane to reach the inner end of the sodium
channel, activity
 Increased at alkaline pH /↑unionized form/
 Reduced at acid pH /↑cationic form /

 Inflamed/infected tissues are often acidic and thus

somewhat resistant to local anaesthetics

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 Pharmacokinetics (ADME)
 Absorption of LA determined by
– Dosage
– Site of injection
– Drug-tissue binding
– Local blood flow
– Presence of vasoconstrictors
– Physicochemical property of the drug

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 Epinephrineinhibit release of substance P & reduce
sensory neuron firing by acting on ά2 AR
 Therefore,
it enhances and prolongs local anesthetic
induced spinal anesthesia
 Vasoconstrictors are less effective in prolonging
anesthetic action of the more lipid-soluble, long-acting
drugs (eg, bupivacaine and ropivacaine)
 May be due to highly tissue-bound
 Cocaine has unique intrinsic sympathomimetic
activity

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 Distribution
 Amides well distributed
 Initial distribution to highly perfused organs (Brain ,
heart, kidney, liver)

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 Metabolism

Amide type (in liver) or ester type(in plasma) converted

to more water-soluble metabolites
Ester-type LAs hydrolyzed very rapidly in the blood to
inactive metabolites
 Enzyme: plasma butyrylcholinesterase
(pseudocholinesterase)
 Amides metabolised in liver
 Enzyme: microsomal cytochrome P450

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 Amide metabolism depends on
• Liver disease & hepatic blood flow
• Competition for the same enzyme
Toxicity from amide type LAs is more likely to occur
in patients with hepatic disease
Reduced hepatic blood flow decreased hepatic
elimination of LAs
 volatile anesthetics reduce liver blood flow

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 Excretion
• Acidification of urine promotes ionization of the
tertiary amine base to the more water-soluble charged
form
• more readily excreted
• Unionized form diffuse readily through lipid
membranes, little/no urinary excretion of the neutral
form occurs

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 Mechanism of action
 LAs block voltage-gated Na+ channel
• Na+ channel function alteration
– Batrachotoxin, veratridine and scorpion venoms
• Prevent inactivation
– Tetradotoxin and saxitoxin
• Block Na channel near the extracellular region
– Local anesthetics
• Bind the intracellular component of the channel

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LAs block the initiation & propagation of action
potentials by preventing the voltage-dependent
increase in Na+ conductance
 Use dependent effect
 Cationic form of LA is able to interact with the
receptor only when the channel is open
 No significant affinity for resting channels
LAs prolong inactive state of the channel & it will
take longer time for recovery
 Refractory period of the fibre increased

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 Higher Ca2+ concentration reduce inactivation of Na+
channel & lowers LA effects
 K+ increases the activity of LA

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 Mechanism of action

Resting Activated Inactivated

-90mV -90 to +35mV +35 to -90mV
BH+ B

Axonal
membrane

LA receptor Axoplasm

B BH+

Activation ( ‘m’) gate near to extra cellular part; inactivation( ‘h’ ) gate at intracellular part
B, unionized LA; BH+ , ionized LA
LAs act on activated or inactivated state of the channel
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Use and techniques of LAs
1. Topical /surface anaesthesia
 Applied to mucus membrane & abraded skin
 Only superficial layer is anaesthetized
 Onset & duration of action depends on the site, the drug,
conc.,& form
 Typically are used LAs; tetracaine (2%), lidocaine (2% to
10%) & cocaine (1% to 4%)
 Dosage form could be
Drops, ointment, cream, spray, suspension,
suppository
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2. Infiltration anesthesia
 Dilute solution of LA is infiltrated under the skin in
the area of operation - block sensory nerve endings
 Duration of action can be approximately doubled by
adding epinephrine to the injection solution
 Epinephrine-containing solutions should not be
injected into tissues supplied by end arteries (Eg. ears,
nose, penis, fingers & toes)
 vasoconstriction may cause gangrene
 Commonly used; lidocaine (0.5% to 1%), procaine
(0.5% to 1%) & bupivacaine (0.125% to 0.25

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3. Conduction block
3.1.Field block anaesthesia
 Injecting LA subcutaneously so that all nerves
coming to a particular field are blocked
 Used in case of appendicectomy,dental procedure,
scalp stitching, operation of forearms & legs, etc

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3. Conduction block
3.2.Nerve block anaesthesia
 Injecting LA into or about individual peripheral nerves
or nerve plexuses
 Blockade of mixed peripheral nerves & nerve plexuses
anesthetizes somatic motor nerves
 producing skeletal muscle relaxation & is essential for
some surgical procedures
 Produces greater areas of anesthesia than the topical &
infltiration anaesthesia do

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4. Spinal Anesthesia
 Injection of LA into the cerebrospinal fluid (CSF) in

the lumbar space

 Safe & effective technique, especially during surgery

involving the lower abdomen, the lower extremities

& the perineum
5. Epidural anesthesia
 Injecting into the epidural space

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CNS effects
 All LAs produce sequence of stimulation followed by
depression
 Initial stimulation is due to inhibition of inhibitory
NTs & at high dose all neurons are inhibited
 Cociane is powerful full CNS stimulant causing the
following effects in sequence
 Euphoria/excitement--mental confusion--convulsion--
unconsciousness--respiratory depression--death
 Effect is concentration dependent

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 Procaine & other synthetic LAs
 Produce little CNS effects at safe clinical dose
 Higher dose produce CNS stimulation followed by
depression
 Lidocaine
 Initially causes drowsiness & lethargy
 At higher dose it produces excitation followed by
depression

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Toxicity
Two major forms of LAs toxicity
1. Systemic effects
• CNS
• CVS
• Hematological
• Allergic reactions from p-aminobenzoic acid derivatives
(ester link LAs metabolite)
2. Direct neurotoxicity from the local effects
• At high concentration
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Sedative Hypnotics
Anxiety
 Anxiety is unpleasant state of tension, apprehension, uneasiness
 Normal fear to response threating stimuli Includes several
components
 Defensive behaviors
 Autonomic reflexes
 Arousal and alertness
 Corticosteroid secretion and negative emotions
 The distinction b/n pathological and normal state of
anxiety……...????
 The anxiety disorder could be
 Generalized anxiety disorder / with out clear reason/
 Panic disorder / fear occurs in association with
somatic symptoms (tachycardia, sweating palpitation,
etc )
 Obsessive-Compulsive disorder (OCD)
Eg. Fear for exposure to germs (obsession) and repetitive action
such as hand washing many times (compulsions)
 Phobia /strong fear for specific things/
 Post–traumatic stress disorder /recalling past stressful
experiences/
 Treatment should involve psychological rather than
or in addition to drug treatment
 Drugs
 Sedative / hypnotics
 Some times
 Antipsychotic and antidepressant drugs
A. Effective sedative
 Reduces anxiety with out inducing sleep
 Some decrease motor activity
 CNS depression should be minimal
 Quicker onset, shorter duration, steeper dose response
curve
B. Effective Hypnotic
 More CNS depression , induce & maintain sleep
 The sleep should resemble natural one
 Slow acting drugs with flatter dose response curve
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 Sedation hypnosis general anesthesia
(increased grades of CNS depression)
 Hypnotics
 At lower dose may act as sedative and
 At higher dose can produce general anesthesia
but BZDs do not
 Sedative Hypnotics
A= Barbiturates
B= BZD
Clinical Uses of Sedative-Hypnotics

 To relief anxiety
 For insomnia
 For sedation and amnesia before & during medical and
surgical procedures
 Treatment of epilepsy and seizure states
 As a component of balanced anesthesia
 To control ethanol/other sedative-hypnotic
withdrawal states
 For muscle relaxation in specific neuromuscular
disorders
 As diagnostic aids or for treatment in psychiatry
Insomnia is difficulty in falling asleep or maintaining sleep,
premature awakening and/or lacking refreshment from sleep
 Non-pharmacologic therapies for sleep problems
 Proper diet and exercise
 Avoiding stimulants before bed time
 Ensuring a comfortable sleeping environment
 Retiring at a regular time each night
 Drug treatment of insomnia – hypnotics
Classification of sedative-hypnotics
1. Barbiturates
2. Benzodiazepines
3. Older sedative/hypnotics
4. New sedative/hypnotics
5. Other drugs
 1. Barbiturates
 Long acting: Phenobarbitone
 Short acting: butobarbitone and pentobarbitone
 Ultrashort: Thiopentone, methohexitone
All have CNS depressant activity
 Produce dose dependent effects

Sedation hypnosis general anesthesia comma

 Large doses result in death b/c of respiratory & CVS
depression
 Their use as sedative hypnotics has declined
 Mainly used in anesthesia & treatment of epilepsy
MoA
 Facilitate the actions of GABA

 At high concentrations, the barbiturates may also be

GABA-mimetic and inhibit excitatory
neurotransmission

 benzodiazepines ↑ frequency and barbiturates

↑ duration of GABA mediated Cl- channel oppening
 Less selective in their actions than benzodiazepines
 Multiplicity of sites of action of barbiturates
 To induce full surgical anesthesia
 To have more pronounced central depressant effects
(low margin of safety) compared with benzodiazepines
and the other hypnotics
2.Benzodiazepines(BZDs)
 Hypnotics
Diazepam,Flurazepam,Nitrazepam,
Alprazolam,Temazepam,Triazolam
 Antianxiety
Diazepam,Chlordiazepoxide, Oxazepm, Lorazepam, Alprazolam
 Anticonvulsant
Diazepam,Lorazepam,Clonazepam,Clobzam
MoA BZDs
 Act selectively on GABAA receptor
 Bind to regulatory site of the receptor (allosteric
binding site)
 Enhance the response to GABA and facilitate the
opening of GABA activated chloride channel
Pharmacological use

 Reduction of anxiety and aggression

 Sedation and induction of sleep
Decrease time to get sleep & increase total duration
of sleep
 Reduction of muscle tone and coordination
 Increased muscle tone (common future of anxiety) may
cause aches and pain
 Anticonvulsant effect
 BZD are selective anticonvulsant against GABAA
mediated convulsion
 Strychnine induces convulsion via glycine receptor
 Therefore, BZDs are not effective against strychnine
induced convulsions
 Anterograde amnesia
BZD erase memory of event while under their
influence…for minor surgical
Why BZDs are preferable to barbiturates ?
1. BZDs have high therapeutic index
2. Hypnotic doses do not affect respiration or CVS
3. Cause less distortion on sleep architecture
4. Do not affect disposition of other drugs
5. Have relatively low abuse liability
6. Presence of BZD antagonist (flumazenil) as antidote
BZD antagonist / flumazenil
 Anxiogenic and proconvulsant
 Use
 In case of BZD over dosage
(if only respiration severely depressed)
 Also blocks effect of zolpidem (hypnotic acts
similarly to BZDs) but more dose is required (5mg)
 To reverse BZD anaesthesia and allows early discharge
of patients and easy for post anesthetic management
 Flumazenil has fast on set (secs) and short duration of
action (1-2 hrs)
 BZDs have longer duration of action
 Therefore, repeated administration of flumazenil is
needed
Side effects of BZDs

 Drowsiness, confusion, amnesia and impaired

coordination
 BZDs enhance depressant effect of other drugs ( eg
alcohol) synergistically
 Long lasting hangover effects
 Withdrawal syndromes
 Development of dependence
☼ Sedative / hypnotics should not be used for longer duration
Many BZDs have active metabolites
 Duration of action of BDZs varies as a function of
the metabolites they produce
 Not produce metabolite (eg lorazepam)
Intermediate t½ (10-20hrs)- can be used for elderly
 Longer acting BZDs (eg. Flurazepam,and
Diazepam) produce active metabolites with t½ 20-
120hrs- avoid in elderly patients
3.Older sedative hypnotics
Alcohol,Chloral hydrates, Mebrobamate, Glutethimide
and Methyprylon
4. Newer sedative hypnotics
 Non BZD sedatives: agonist for a subtype of BZD
receptor
Zopicolone Zolpidem & Zalepon
 Buspirone ( potent agonist for 5-HTA receptor)
 Buspirone

 Also binds to brain dopamine receptor (D2 )

Less effective in panic disorders /acute anxiety states
b/c of slow on set of action (effects take days or weeks
to develop)
Relief anxiety without causing marked sedative,
hypnotic, or euphoric effects
Minimal abuse liability & no anticonvulsant or muscle
relaxant properties (unlike BZDs)
No rebound anxiety/withdrawal signs on abrupt
discontinuance
 Buspirone

Side effects
 dizziness, nausea, headache, but not sedation or loss

of coordination
 less troublesome than with benzodiazepines
5. Other drugs that induce sedation
 Antihistaminics (promethazine / diphenhydramaine)
 Neuroleptics / antidepressant (chlorpromazine,amitryline)
 Opoids (morphine, pethidine)
 They have significant sedation effect but not reliable for treatment of
insominia
 β-adrenoceptor antagonists (e.g. propranolol ) to treat some
forms of anxiety (for physical symptoms such as sweating,
tremor and tachycardia)
 block of peripheral sympathetic responses
 ‘ ….actors and musicians to reduce the symptoms of stage fright’
 Propranolol produces insominia as a side effect
Analgesics
Pain (algesia)
 Unpleasant sensory & emotional experience
 Associated with actual or potential tissue

damage
 Evoked by an external or internal noxious

stimuli
 Mediated by different NTs & peptides such
as glutamate & substance P
 It is a warning, primarily protective in nature
The pain can be
Superficial
- Stimulation of skin & mucous membranes
- Fast response
Deep
- Arises from muscles, joints, tendons, heart, e.t.c
- Slow response
 Classification

Physiological Clinical
– Nociceptive
– Acute
– Neuropathic
– Chronic
– Psychological
– Malignant
‘Nociceptive’
 Normal physiology (mechanisms known)
 Treated with conventional analgesics (NSAIDs,
acetaminophen, opioids)
‘Neuropathic’
 Aberrant physiology (mechanisms unknown)
 Associated with neural damage
 Difficult to treat
Pathopysiology of pain

Involves four physiological processes

- Transduction
- Transmission
- Modulation
- Perception
 Pathophysiology of pain
Noxious stimulus

NSAIDs Release of inflammatory substances

(PG, His, 5-HT, Sub.P etc)

Transduction (generation & electrical impulses)

Transmission (conduction by nerve fibers)

Modulation (Modification with spinal cored)

Opioids

Perception
Analgesics
 Drugs that selectively relieve pain with out
significant change on patient consciousness
 Act on CNS or periphery pain mechanism
 Analgesic classification
1. Narcotics /opioids/
Morphine & morphine like drugs
2. Non-narcotics
NSAID
3. Adjuvant analgesic /coanalgesics
TCAs, Antiepileptics, Steroids
Management of pain

1. Mild pain
NSAID + adjuvant
2. Moderate pain
Weak narcotic + NSAID + adjuvant
3. Severe pain
Strong narcotic + NSAID + adjuvant
Opioids analgesics
 Opium: a mixture of alkaloids from seed capsule
of opium poppy
 Most opioid analgesics are related to morphine
 morphine has 5 rings, 3- & 6-OH groups (phenolic &
alcoholic), piperidine ring with N-methyl group
 Codeine is morphine O-methylated at position 3
 Heroin is morphine O-acetylated at positions 3 & 6
 Replacing the N-methyl with something larger
(allyl, cyclopropyl, cyclobutyl) produces opioid
with antagonist properties
 Meperidine (pethidine) is a synthetic opioid with
only fragments of the morphine structure
 Opiates  Opioid receptor
subtypes
• Pure agonists • μ (mu)
• Partial agonists • Κ (kapa)
• Mixed agonist- • δ (delta)
antagonists • σ (sigma)( ?)
All belong to the family of
GPCRs

132
μ (mu) receptor
 Supraspinal analgesia
 Euphoria
 Respiratory depression, constipation, urinary
retention, nausea, vomiting, physical depende
nce, miosis
 Most opioid analgesics are relatively selective μ o
pioid agonists
δ (delta) receptor
 Spinal analgesia
 Nausea & vomiting
К (kapa) receptor
 Spinal analgesia
 Sedation
 Miosis
Opiate receptor interactions
Drugs Receptor
mu kappa delta sigma
Full agonists
Morphine +++ ++ +
Fentanyl ++++ +
Alfentanil +++ ?
Sufentanil +++++ +
Hydromorphone +++ ++
Methadone +++ ++
Meperidine ++ ++
Codeine +
Levorphanol +++ ++?
Opiate receptor interactions
Receptor
mu kappa delta sigma*
Mixed agonist-antagonists
Nalbuphine --- +++
Pentazocine - +++ ++
Nalorphine - +++
Antagonists
Naloxone --- - - -
Naltrexone --- - - -
Endogenous opioid peptides
 Enkephalins
 Relatively selective δ ligands
 Endorphins
 Bind preferentially to μ receptors
 Dynorphins
 Highly selective agonist at κ receptors
Mechanism of action of opiates
 Opioids produce analgesia by binding to specific
GPCRs located in brain & spinal cord regions
involved in the transmission & modulation of pain
 Inhibit adenylyl cyclase → ↓ cAMP

 Reduce neuronal excitability

 b/c of the ↑ K+ conductance causes

hyperpolarisation of the membrane
 Reduce transmitter release
 Due to inhibition of Ca 2+ entry
Se
c on
da
ry
aff
ere
nt
ne
ur o
n
Clinical use of opiates
1. Analgesic effect
 Selective relief of pain at doses which do not produce
hypnosis or impair sensation
 Some types of pain more responsive to opioids than
others
 More effect in prolonged, burning pain than
sharp, intermittent pain
 Neuropathic pain can be resistant
 Therefore, opioids are mainly used for severe &
constant pain
 Chronic pains such as in cancer patients may need
continuous use of potent opioid analgesics
 Potent opioid analgesics associated with tolerance
& dependence
 But this should not be barrier to provide the
best possible care for the patients
 Slow release dosage forms may give longer & more
stable level of analgesia
 Fentanyl transdermal system (fentanyl patch) can be
used over long periods if disturbances of GIT
prevents the use of oral sustained-release morphine
 Buccal transmucosal fentanyl
 Opioid analgesics are used during obstetric labor
 As opioids cross the placental barrier, care
must be taken to minimize neonatal depression
 If it occurs, immediate injection of the
antagonist naloxone will reverse the depression
 Opioids like meperidine produce less
depression (particularly respiratory depression)
in newborn infants than does morphine
2. Cough Suppression / antitussives
 Depression of cough centers in the medulla
(possibly in the periphery too)
 Different molecular mechanism than analgesia or
respiratory depression
 Cough suppressed by dextro-isomers of opioids
(e.g. dextromethorphan), compounds which have
no analgesic activity
3. Diarrhea
 Opioids cause constipation beneficial for treatment
of diarrhea
 Diarrhea from almost any cause can be controlled
with the opioid analgesics
 But if diarrhea is associated with infection
,appropriate chemotherapy should be used
 Synthetic drugs (diphenoxylate & loperamide) with
selective effect on GIT
 poorly-absorbed & have little/no central effects
4. Shivering
 All opioid agonists have some propensity to
reduce shivering
 Meperidine is reported to have the most
pronounced anti-shivering properties
 Single doses of meperidine is effective in the
treatment of postanesthetic shivering
 Via the action on subtypes of the α 2
adrenoceptor.
5. Applications in anesthesia
 Used in cardiovascular surgery b/c of low cardiac
depressant effects
 Opioids can be used
 Preoperatively b/c of their sedative, anxiolytic
& analgesic properties
 Intraoperatively as adjuncts to other
anesthetic agents & as a primary component
of the anesthetic regimen
 Postoperatively as analgesics
Side effects
 Most opioid side effects associated with mu
receptors
 Respiratory depression (reduces sensitivity of
respiratory centres in brain stem to CO2)
 Euphoria
 Sedation
 Hypothermia
 Constipations
 Tolerance & dependence
 Bronchoconstriction (histamine release
stimulated)
Non Steroidal Anti inflammatory Drugs
(NSAIDs)

Antipyretic

Analgesic

Anti-inflammatory agents
Mechanism of action
 Inhibits cycloxygenase (COX) enzyme &
hence prostaglandin synthesis
 COX-1 is a primarily constitutive in most
normal cells & tissues
 COX-2 is induced isoform but is also
constitutively expressed in certain areas of
kidney & brain
 NSAIDs do not inhibit the lipoxygenase
pathways & hence do not suppress leukotriene
formation
 All NSAIDs except aspirin are competitive
inhibitors of COX
 Aspirin irreversibly acetylates the enzyme
Mechanism of action
Clinical use of NSAIDs

 All NSAIDs have

• Antiinflammatory
• Antipyretic
• Analgesic effects
However acetaminophen (paracetamol) is devoid of
antiinflammatory activity
 Analgesic effect
• Effective only in pain of low-to-moderate intensity
• Have less maximal efficacy than opiates but devoid
of the unwanted adverse effects of opiates
 Antipyretic
• Reduce fever in most situations
 However not for the circadian variation in
temperature or the rise in response to exercise or
increased ambient temperature
 Anti-inflammatory effect
• Generally provide only symptomatic relief
from pain & inflammation associated with the
disease
• Do not arrest the progression of pathological
injury
• In the treatment of rheumatoid arthritis &
osteoarthritis
• For the treatment of ankylosing spondylitis &
gout
Adverse effects
GIT
 Anorexia, nausea, dyspepsia, abdominal pain, &
diarrhea
• Induce gastric /intestinal ulcers
 Proposed mechanisms for the GI ulceration
1. Inhibition of COX-1 in gastric epithelial
cells depresses synthesis of PGI2 & PGE2
2. Direct local irritation of gastric mucosa
 Cardiovascular
• Aspirin is associated with cardioprotection
• They depress PGI2 formation by endothelial
cells without concomitant inhibition of
platelet thromboxane
 Renal & renovascular adverse effects
• Loss of PG-induced inhibition of reabsorption
of Cl- & the action of ADH
 Retention of salt & water
• COX-2 inhibition in kidney attributed for ed
production of vasodilator PGs (PGE2 & PGI2)
 Raise the likelihood of hypertensive
complications
 Drug interactions
 Reduce effectiveness of ACE inhibitors as
production of prostaglandins is inhibited
 May increase GI ulceration when combined with
corticosteroids
 Augment risk of bleeding in patients on warfarin
Classification
1. Salicylates eg Aspirin
2. Para-aminophenol derivatives E.g.
Acetaminophen
3. Acetic acid derivatives E.g. indomethacine
Sulindac
4. The Fenamates (N-phenylanthranilic acid
derivatives) E.g. mefenamic, meclofenamic, and
flufenamic acids
5. Phenylacetic acid derivative (declofenac)
6. Propionic acid derivatives E.g. ibuprofen,
naproxen, fenoprofen
7. Pyrazolon derivatives E.g. phenylbutazone,
antipyrine, dipyrone
8. Miscellaneous
Eg. Apazone (Azapropazone), Nimesulide
Classification according to selectivity
A.Non selective COX inhibitors
•Aspirin, ibuprofen, mephenamic acid,

declofenac, indomethacin, phenylbutazole

B.Preferentially COX- 2 inhibitors
•Nemesulide, meloxicam, nabumetone

C.Selective COX -2 inhibitors

•Celecoxib, etoricoxib, parecoxib
1. Salicylates

 Salicylic acid is irritating (for externally use)

 Derivatives of salicylic acid synthesized for
systemic use
• Esters of salicylic acid (SA)
• Salicylate esters of organic acids
• Salts of salicylic acid
 Pharmacological Properties

 Analgesia & antipyresis

 Respiration

• Increase O2 consumption & CO2 production

 In turn increases respiration
 Cardiovascular effects
• Low doses of aspirin (<100 mg daily) used

widely for their cardioprotective effects

• Aspirin inhibits irreversibly platelet COX-1-

derived TXA synthesis by chronic dosing with

low doses
• At high therapeutic doses (>3 g daily) salt &

water retention can lead to plasma volume

expansion
 increased cardiac output & work
 CHF & pulmonary edema in patients with

compromised cardiac function

 GIT effects
• Nausea & vomiting
• Epigastric distress
• Gastric ulceration, exacerbation of peptic
ulcer symptoms & erosive gastritis
• Gastrointestinal haemorrhage
 Effects on the blood
• Prolongs the bleeding time
• Due to risk of haemorrhage, patients with
hypoprothrombinemia, severe hepatic
damage, vitamin K deficiency &
hemophilia should avoid aspirin
 Salicylates & Pregnancy
• No evidence of teratogenicity for moderate
therapeutic doses of salicylates
• Avoid administration during the 3 rd trimester
as they may cause
 Prolonged gestation & complicated
deliveries
 Premature closure of the ductus arteriosus
 Local irritant effects
• SA is irritating to skin & mucosa
 destroys epithelial cells
• Its keratolytic action employed for the
treatment of fungal infections & certain types
of eczematous dermatitis
Therapeutic uses
 Systemic uses
• Antipyresis
• Analgesia
• Rheumatoid arthritis
 Local use
• Inflammatory bowel syndrome
Adverse Effects
 GI disturbance (most common)
• Peptic ulceration & rarely severe GI
hemorrhage
 In toxic doses: tinnitus, hearing impairment,
blurred vision & light-headedness
 Salicylates are C/I in children with febrile viral
illnesses
• because of a possible increased risk of Reye’s
syndrome
2. Para-aminophenol derivative
 Acetaminophen (paracetamol) ; N-acetyl-p-
aminophenol
 It is an effective alternative to aspirin as an
analgesic-antipyretic agent
 However, its antiinflammatory effects are much
weaker
 Acetaminophen is well tolerated & has low
incidence of GI side effects
Pharmacological Properties
 It has analgesic & antipyretic effects similar
to aspirin…..central analgesic action
 Weak antiinflammatory effects due to a
generally poor ability to inhibit COX
 Single or repeated therapeutic doses of
paracetamol have no effect on CV &
respiratory systems
Therapeutic Uses

 Suitable substitute of aspirin for analgesic or

antipyretic uses
• Especially when aspirin is contraindicated
(peptic ulcer, aspirin hypersensitivity, children
with a febrile illness)
Toxicity & common adverse effects

 Well tolerated at therapeutic doses

 Rash & other allergic reactions occur occasionally
 Neutropenia, thrombocytopenia
 Overdosage causes a potentially fatal hepatic
necrosis
3. Acetic acid derivatives
Indomethacin
 Antiinflammatory, analgesic & antipyretic
 More potent COX inhibitor than is aspirin

Therapeutic uses
 For treatment of acute gouty arthritis,

rheumatoid arthritis, ankylosing spondylitis

& osteoarthritis
 Not recommended for use as a simple

analgesic or antipyretic
Adverse effects
 GIT: diarrhea
C/I in peptic ulcer disease (PUD )
 Acute pancreatitis, hepatitis
 CNS effect (frontal headache, dizziness,
vertigo, light-headedness, seizures, confusion,
severe depression, psychosis, hallucinations &
suicide
 Hematopoietic (neutropenia, thrombocytopenia
& aplastic anemia)
4. The Fenamates

 They are derivatives of N-phenylanthranilic acid

 Mefenamic, meclofenamic & flufenamic acids
 They have no clear advantages over other
NSAIDs & frequently cause GI side effects
 Used mostly in the short-term treatment of pain in
soft-tissue injuries, dysmenorrhea, rheumatoid &
osteoarthritis
 Not recommended in children or pregnant women
5. Diclofenac
 Diclofenac is the most commonly used NSAID in

Europe
 Its potency against COX-2 is greater than that of

several NSAIDs
Therapeutic Uses
 Long-term symptomatic treatment of rheumatoid

arthritis, osteoarthritis & ankylosing spondylitis

 Short-term treatment of acute musculoskeletal

pain, postoperative pain & dysmenorrhea

 Treatment of postoperative inflammation

following cataract extraction

 Common adverse effects
 GI (20%)
 Reversible elevation of hepatic transaminases
(Bromfenac withdrawn due its severe, irreversible
liver injury)
 CNS effects, rashes, allergic reactions, fluid
retention & edema
 Rarely impairment of renal function
 Not recommended for children, nursing mothers, or
pregnant women
 6.Propionic acid derivatives
 Used as an analgesic and antipyretic as well as in
symptomatic treatment of rheumatoid arthritis,
osteoarthritis, ankylosing spondylitis & acute gouty
arthritis
 Include ibuprofen, naproxen, fenoprofen,
ketoprofen, flurbiprofen
 All are nonselective COX inhibitors with effects &
side effects common to other NSAIDs
Drug Interactions
 May interfere with the action of
antihypertensive & diuretic agents
 Increase the risk of bleeding with warfarin
 Increase the risk of bone marrow suppression
with methotrexate
 7.Pyrazolon derivatives
 Include phenylbutazone, antipyrine, dipyrone,
oxyphenbutazone & aminopyrine
 Are not commonly in use b/c of their propensity to
cause blood dyscrasias
 Only antipyrine, used in as otic drops is available in
the US today
 Phenylbutazone is used in Canada, and dipyrone is
used in some European countries.
Selective COX-2 inhibitors
 Do not affect the house keeping activity of COX-1

 Inhibits COX-2 which is believed to be dominant

in inflammatory sites & cancers
 Hence, drugs cause inhibition of PG synthesis in
inflammatory sites while the gastric cytoprotective
function of PG is left intact
 Several older drugs such as nimesulide, diclofenac
& meloxicam exhibit relative selectivity for COX-
2 inhibition
 Coxibs such as celecoxib, parecoxib & etoricoxib
are selective COX-2 inhibitors
 Which one is better?
Selective or non selective cox inhibitor

 Use of non-selective COX inhibitors cause frequent

GI side effects due to significant inhibition of
cytoprotective effect of PGs synthesized by the
COX-1 enzyme
 Use of COX-2-Selective inhibitors associated with
↑ed cardiovascular hazards
 PGI2 inhibit platelet aggregation whereas TXA2
is potent platelet aggregator & vasoconstrictor
 The platelet actions of TXA2 are restrained in
vivo by PGI2
 Selective COX-2 inhibitors reduce PGI2
formation without concomitant inhibition of
platelet TXA2
 Therefore, selective COX-2 inhibitors inhibit
PGI2 synthesis with out affecting COX-1 induced
TXA production & hence associated with
cardiovascular risk
Epilepsy and Antiepileptic
drugs

190
Epilepsy

 Seizure associated with the episodic high-frequency

discharge of impulses by a group of neurons in the
brain
 Starts as a local abnormal discharge may then spread to
other areas of the brain
 Site of the primary discharge and extent of its spread
determine symptoms that are produced
 The particular symptoms produced depend on the
function of the region of the brain that is affected
 Involvement of
 motor cortex- convulsions
 hypothalamus-peripheral autonomic discharge
 reticular formation in the upper brain stem - loss of
consciousnes
Types of epilepsy

A. Generalized seizures 
 Generalized tonic-clonic (grand mal) seizures
 Absence (petit mal) seizures
 Atonic seizures 
 Clonic and myoclonic seizures 
 Infantile spasm (hypsarrhythmia)
B.  Partial seizures
 Simple partial seizures
 Complex partial seizures
  Partial seizures secondarily generalized
A. Generalized seizures(GS)
 Involves the whole brain
 Abnormal electrical activity throughout both hemispheres
 Immediate loss of consciousness
1.Generalized tonic-clonic seizures(grand mal, major
epilepsy) - GTCS
 Tonic phase (< 1 min)
 Sudden loss of consciousness
 Patient become rigid and falls to ground , respiration arrested
 Clonic phase (2mins) -Jerking of the body musculature
 Clonic phase followed by prolonged sleep and depression of
all CNS functions
 defecation, micturition and salivation often occur
Immediately after the seizure the patient may
 recover consciousness
 drift in to sleep
 have further convulsion (status epilepticus or serial
seizure)
Convulsion with out recovery of consciousness
(status epilepticus)- May lead to brain damage and
death
Further convulsion, after recovering consciousness
(serial seizure)
2. Absence (petit mal) seizures– minor epilepsy
 Prevalent in child and cease at the age of 20
 Momentary loss of consciousness, patient freezes and
stares in one direction
 Onset and termination of attacks are abrupt
 Patient abruptly ceases whatever he/she was doing
 Impairment of external awareness is so brief that patient
is unaware of it
 Many seizures each day may occur as compared to GTCS
3. Atonic seizures  (astatic epilepsy)
 Unconsciousness with relaxation of all muscles due to
excessive inhibitory discharges
4.Clonic and myoclonic seizures
 Shock like momentary movement, contraction of muscles
of a limb or whole body
5.Infantile spasm ( hypsarrythmia)
 Intermittent muscle spasm and progressive mental
deterioration
 Epileptic syndrome rather than a specific seizure type
B. Partial seizure
 The discharge begins locally and often remains localized
 Symptoms depend on the brain region/regions involved
 involuntary muscle contractions
 abnormal sensory experiences
 autonomic discharge
 effects on mood and behaviour (psychomotor epilepsy)
1. Simple partial seizures (cortical focal epilepsy)
 Lasts 0.5 – 1 min
 Convolutions are confined to a group of muscles or
localized sensory disturbance depends on the area of
cortex involved
E.g. If motor cortex supplying to left thumb is affected then
jerking of left thumb occurs
 With out loss of consciousness
2. Complex partial seizures (temporal lobe epilepsy,
psychomotor)
 Confused behaviors, purposeless movements,
emotional changes
 Seizure focus is located in temporal lobe
3. Simple or complex  partial seizures secondarily
generalized
 Partial seizures occurs followed by GTCS with loss
of consciousness
 Possible causes of seizures
 primary (idiopathic) – most of the cases
 secondary to trauma/ surgery on head, intracranial
tumor, tuberculoma,cerebral ischemia, etc
Mechanism of action of antiepileptic drugs

1. Enhancement of GABA action

 Barbiturates & BZDs
 Vigabartrin and valproat (GABA transaminase
inhibitor)-increase synaptic GABA conc.
Gabapentin (increase GABA release from presynaptic
neuron)
 Tiagabine (inhibit GABA reuptake to
presynapticneuron)
All these facilitate GABA mediated Cl- channel opening
and end up with inhibitory effect
2. Inhibition of Na+ channel function
 Drugs: Phenytoin, Carbamazepine, Valproic acid,
Lamotrigine, Topiramate, Zonisamid
prolong Na+channel inactivation state
3. Inhibition of Ca 2+ channel function
 Drugs: Ethosuximide, Trimethadione, Valproate
Inhibit T-type Ca2+ current
 Postsynaptic neuron

GAT-1 - Tiag.
GABA-T GABA
Gabp
-
Extra cellular

SSA
Viga. &
Valp.
A
GAB
Na + Ca 2+
Barb BZD

Cell
membrane

- Cl- -
+
Intra cellular

Prolongation
Facilitation of GABA
Inhibition of
of Na+ Ca 2+
mediated
Channel
Cl- channel Channel
inactivation state
opening function
 Individual drugs
Phenytoin (diphenylhydantoin)
Oldest nonsedative antiseizure drug
Used against partial seizures and generalized tonic-
clonic seizures
Mechanism of action
Prolonging inactive state of voltage sensitive Na+
channel------ use-dependent effect
Inhibitionof high frequency discharge with little effect
on low frequency discharges
At high/ toxic conc:reduce ca 2+ influx, inhibition of
glutamate,and facilitate GABA responses
Adverse effects
At therapeutic concentration

 Gum hypertrophy/ gingival hyperplasia (20%)

 Hirsutism, coarsening of facial feature, acne
 Megaloblastic anemia(decrease absorption and
increased excretion of folate)
 Abnoramal Vit D, Vit K and Ca+ metabolism
(Osteomalecia, Hemorrhage)
 Hyperglycemia / inhibit insulin release
 Fetal hydantoin syndrome (hypoplastic phalanges, cleft
palate, microcephally )
 At high plasma level
 Dose related toxicity
-Ataxia, vertigo,diplopia, nystagmus
-drowsiness, behavioral alterations ,mental confusion ,
hallucination
-Epigastria pain, nausea and vomiting
Drug interaction
 Drug interactions related to plasma protein binding or drug
metabolism
 90% plasma proteins binding
 Hypoalbuminemia and drugs which displace phenytoin from
plasma proteins alter total plasma conc. of the drug
 Phenytoin induce microsomal enzymes
 Enhance metabolism of drugs which get metabolized by
microsomal enzyme
 Fosphenytion
 Water soluble prodrug of phenytoin
 Introduced to over come difficulties in i.v.
administration of phenytoin in status epilepticus
 Phenobarbitone
 Effective against GTC,SP and CP seizures
 Can be used for status epilepticus but with slow onset of
action
 Ineffective in absence seizure
 less commonly used than phenytoin, carbamazepam,or
valproate
 Similar clinical use as phenytoin
 Phenytoin is preferred because of the absence of
sedation
Mechanism of action
 Exact mechanism of action is unknown
 Probably through enhancement of inhibitory processes
and diminution of excitatory transmission
 Binds to allosteric regulatory site of GABAA receptor
( inhibitory effect)
 Enhances the GABA receptor-mediated current by
prolonging the openings of the Cl- channels
 Inhibiting excitatory responses by glutamate
Adverse effects
 Sedation
 Tolerance and dependence with prolonged use
 Hypersensitivity
 Nystagmus and ataxia occur at excessive dosage
 Agitation and confusion in the elderly
 Irritability and hyperactivity in children
Drug interaction
 Additive effect with CNS depressants
Induce metabolism of many drugs (warferin,oral
contraceptives,chloramphinicol,theophyline,griseoful
vin)
Phenobarbitone competitively inhibits as well as
induces phenytoin and impramine metabolism
It decrease GIT absorption of griseofulvin
Plasma conc increased by sodium valproat
Carbamazepine
 Is tricyclic compound and closely related to TCA
 Pharmacological actions resemble phenytoin
 Exert lithium like therapeutic effect in mania and
bipolar mood disorder
 Antidiuretic effect / enhance ADH action
 Effective in most forms of epilepsy (except absence
seizures)
 Particularly effective in psychomotor epilepsy (CPS)
 Also useful in trigeminal neuralgia
Adverse effects
 Sedation,dizzines,vertigo,diplopia,and ataxia
 Vomiting,diarrhoea
 Worsening of seizure with higher dose
 Water retention and hyponatremia
 Foetal malformation reported
 Teratogenesity doubled if combined with valproate
Drug interaction
 Enzyme inducer
 Its metabolism induced by phenobarbitone,
phenytoin, valproate and vice vesa
 Erythromycine, fluoxetine and isoniazid inhibit
carmamazepine metabolism
Oxacarbazepine
carbamazepine Oxacarbazepine
 Closely related to carbamazepine
 Active metabolite is glucoronide conjugated
 Toxic effect due to epoxide metabolite is avoided
 Useful in the same seizure types but less potent
 Weak enzyme inducer (drug interaction and auto
induction of own metabolism are less)
 Risk of hepatotoxicity is less
 Hyponatraemia is more
Valproic acid (sodium valproate)
 Fund by serendipity when used as solvent in the
search for other drugs effective against seizures
 Effective against GTCS, partial seizures as well as
absence seizures
 Ethosuximide is the drug of choice when absence
seizures alone occur
 Valproate is better in mixed absence seizures and
GTCS
 Mixed absence seizures and GTCS is more common
than pure absence seizures
Mechanism of action
 Phenytoin like frequency dependent prolongation of Na+
channel inactivation
 weak reduction of Ca 2+ ‘T’ current ( ethosuximide like )
 Effect on GABA metabolism (degradation & uptake
inhibition, increase synthesis from glutamic acid)
 Adverse effects (low toxicity)
 Anorexia,vomiting, hear burn, drowsiness, ataxia, tremor
 Spinal bifid and other neural tube defects in the
offspring( during pregnancy)
Drug interaction
 Inhibit phenobarbitone metabolism
 Displaces phenytoin plasma protein binding and
decrease metabolism (phenytoin toxicity)
 Valproate and carbamazepine induce each other’s
metabolism
 Fetal abnormality if valproate and carbamazepine
given together
Ethosuximide
 Introduced as a "pure petit mal" drug
 Drug used to treat absence seizures and may
exacerbate other forms
 Both ethosuximide and valproate are equally effective
for absence seizure
 However, valpraote is more commonly used
Mechanism of actions : blocking T-type calcium
channels
 Relatively few unwanted effects mainly nausea and
anorexia
 Phensuxamde and methsuxamide are conegeners
 Methsux. is more toxic and phensux. is less effective
Other drugs
 Topiramate & lamotrigine
 Felbamate, zonisamide & levatiracetum
 Vigabatrine,Gabapentine & Tiagabine
 Oxazolidinediones ( trimethadione, dimethadione &
paramethadione)
 BZDs (diazepam & clonazepam)
Drug of choice for……….
1.GTCS/ SP with or with out generalization
1st choice: carbamazepine, phenytoin
2nd choice : valproate, phenobarbitone
2. Complex partial with or with out generalization
1st choice : carbamazepine,valproate, phenytoin
2nd choice: gabapentin,lamotrigine
3. Absence seizure
1st choice: valproate ,
2nd choice: ethosuximide,lamotrigine
4. Status epilepticus
1st choice: diazepam(i.v.), lorazepam(i.v.)
2nd choice: fosphenytoin, phenobarbitone
Alternative/add on drugs : general anesthetics
Anti psychotic drugs
 Anti psychotics
 Anti psychotics are drugs that primarily affect psyche
(mental process) & useful in psychiatric disorders
 Also called
 Psychopharmacological agents
 Psychotropic drugs

 Neuroleptics

 Major tranquillizers
 Schizophrenia
 Geek words: Skhizo( to split) & Phern (mind) w/c means
the split b/n the emotions & the intellect
 It is one particular kind of psychosis

Main clinical features

Positive symptoms : delusions, hallucinations & thought
disorder
Commonly occur in acute phase of the illness
Usually respond to antipsychotic drug therapy
Negative symptoms : apathy, social withdrawal & lack of
drive
Occur in the chronic pahse of illness
Tend to be resistant to dug therapy
 Etiology & Pathogenesis

1. Genetic & environmental factors

 Number of susceptibility genes are identified w/c
show strong but incomplete hereditary tendency
 Some environmental factors have been identified
as possible predisposing factors (Eg. maternal
virus infections)
2. Neurochemical theories
 A change in amine NTs especially DA has been
proposed as a cause of psychosis
 The main neurochemical theories centre on DA &
glutamate
 However, 5-HT & other NTs also might also
involve
2.1. Dopamine theory
The theory suggests that schizophrenia is caused by
abnormality of DA receptors in particular D2
Evidences to proof the theory
 Drugs like
 Levodopa (DA precursor)
 Amphitamine (DA release)
 Apomorphine & bromochriptine (DA agonists)
either aggravate or produce psychosis de novo in
some patients
• Most antipsychotic drug act by blocking D2 on
mesolimbic system
• There is an ↑ in DA receptor density in treated &
untreated schizophrenics when compared with
normal control
• DA receptor density has been found to be ↑ ed in
the brains of schizophrenics who have not been
treated with antipsychotic drugs (postmortem)
 After successful treatment with antipsychotics,
there is change in the amount of homovanillic
acid in the CSF, plasma & urine
Evidences against DA theory
 Drugs w/c block DA should bring complete cure

……practically not true

 Phencyclin (NMDA receptor antagonist) produce

much more schizophrenia like symptom

 Atypical antipsychotics has less affinity for D2
2.2 . Glutamate theory
 NMDA receptor antagonists (phencyclidine,
ketamine & dizocilpine) produce psychotic
symptoms
 Reduced glutamate concentrations & glutamate
receptor densities have been reported in
postmortem schizophrenic brains
2.3. Other theories
 Many effective antipsychotic drugs, in addition to
blocking DA receptors also act as 5-HT2A receptor
antagonists
 5-HT modulates dopamine pathways
 Whether 5-HT2A receptor blockade accounts
directly for their antipsychotic effects, or merely
reduces undesirable side effects associated with D2-
receptor antagonists remains controversial.
3. Anatomic damage
In psychotics brain, there are certain areas w/c gets
atrophied
However recent studies do n’t support this theory
Classification of antipsychotic drugs
(based on chemical structure)
1.Phenothiazine derivatives
1.1. With an alipahtic side chain
Chlorpromazine (CPZ), triflupromaizne
1.2. With a piperidine ring side chain
Thioridazine, mesoridazine, piperacetazine
1.3. With a piperazine ring side chain
Fluphenazine, trifluoperazine
2. Butyrophenones
Haloperidole, trifluperidole, penfluperidole
3. Thioxanthenes Chlorprothixene, flupenthixol
4. Atypical neuroleptics Clozapine,
risperidone, olanzapine, ziprasidone,
aripiprazole
5. Miscellaneous
Reserpine
 Broad category of antipschotic drugs
1st generation ('typical') & 2nd generation ('atypical')
No clear distinction b/n them ; however, grouping is based
on
 Receptor profile
 Incidence of extrapyramidal side effects (less in atypical
group)
 Efficacy in 'treatment-resistant' patients
 Efficacy against negative symptoms
(2nd generation ) Newer generation causes metabolic
syndrome
Eg. Clozapine (atypical group)
 Has broad spectrum of activity than traditional
antipsychotics but less affinity for D 2
 Has some efficacy for treatment resistant
schizophrenia & negative symptoms
 ’’atypical’’ is used to describe antipsychotic drugs
w/c do n’t cause EPS
 While ‘typical’ antipsychotic drugs associated with
anticholinergic, sedation, & cardiovascular side
effects in addition to EPS
Depot antipsychotics
 Estrefication of the antipsychotic with long chain
fatty acid
 The drug will be released at constant rate for long
time
 Reduce compliance problem

 However reduced flexibility of dosage, pain at site

of administration, high incidence of EPS & weight
gain
Some antipsychotic available as Depot
Haloperidol, Flupenthixol, Zulcopenthioxol,
Fluphenazine, pipothiazine
Mechanism of action

 All effective antipsychotic drugs block D2

receptors
 The degree of blockade to other actions on
different receptors considerably varies
Chlorpromazine: α1 > 5-HT2A > D2 > D1
Haloperidole: D2 > α1 > D4 > 5-HT2A> D1>H1
Clozapine: D4 = α1 > 5-HT2A> D1=D2
Aripiprazole: D2= 5-HT2A >D4 > α1 = H1 >>D1
Olanzapine: 5-HT2A >H1>D4>D2> α1 = H1>>D1
 Antipsychotic action has shown good correlation
with the capacity to bind to D2 receptor
 There no clear correlation with antipsychotic activity
& the capacity to bind with D1, D3, & D4
 Activities on other NT receptors may determine side
effect profile
Pharmacological action
1. ANS
 Varying degree of α adrenergic blocking activity
 More potent drugs have lesser α blocking activity
 Anticholinergic property is generally weak
2. Local anesthetic
CPZ is potent LA as procaine however it has irritation
3.CVS
Antipsychotics produce postural hypotension by centeral &
peripheral action on sympathomimetic tone
4. Endocrine effects
Increase prolactine secretion by blocking the
inhibitory effect of DA
 Galactorrhoea, gynaecomastia
 increased libido (women), decreased libido

(men)
 Use of antipsychotics
1.Schizophrenia

2.Anxiety

Should not be used for simple anxiety b/c of

•

autonomic & EPS

•BZDS are preferable; however, those not
responding or having psychiatric base for the
anxiety may be treated with neuroleptics
3. As antiemetics
Control wide range of drug & disease induced
vomiting at dose much lower than those needed for
psychosis but ineffective in motion sickness
4. Other uses
 Potentiate hypnotics, analgesics, & anasthetics
 Intractable hiccough may respond to parentral CPZ
Intetanus , CPZ is secondary drug to achieve
skeletal muscle relaxation
Adverse effects
I. Dose related toxicity
1.CNS

Drowsiness, lethargy, mental confusion

•

Increased appetite & weight gain (not with haloperidol)

•

• Aggravation of seizures in epileptics

Non epileptics may develop seizure at high dose of
some antipsychotics such as clozapine &
olanzapine
Potent phenothiazines such as ziprasidone have little
effect on seizure threshold
2. CVS
 Postural hypotension
 Palpitation

3. Anticholinergic
• Dry mouth, blurred vision
4. Endocrine
• Hyperprolactinemia
• Atypical antipsychotics do n’t raise
prolactin level
5. Extrapyramidal disturbances
a. Pseudo parkinsonism
Rigidity, tremor, hypokinesia, mask like face
•

Appears b/n 1- 4 weeks of therapy & persist unless

•

dose is reduced
 Anticholinergic anti PD drugs can be given
together with antipsychotics
b. Acute muscular dystonias
Muscle spasm mostly in linguo-facial muscles
•

Grimacing , tongue thrusting, torticollis, locked

•

jaw
 • More common in children bellow 10 & girls
• Occurs with in a few hrs of single dose or at 1 st
week of therapy
• i.m injection of central anicholinergic
(promethazine or hydrxyzine) can clear the
reaction with in 10 – 15 minutes
c. Akathisia
• Restlessness, feeling discomfort, agitation as
complete desire to move about with out anxiety
• Occurs with in 1-8 weeks of therapy &
misleads as ‘exacerbation of psychosis’
• No specific antidote available
 Central anticholinergic may reduce the

intensity but propranolol is more effective

 Addition of diazepam may also be used

 However, most cases of akathisia require

dose reduction or alternative antipsychotic

d. Malignant neuroleptic syndrome
• Rarely occurs with potent antipsychotics
• Patient develops marked rigidity, immobility,
tremor, fever, semi consciousness, fluctuating
BP & HR
• Lasts 5 – 10 days after withdrawal & may be
fatal
• Anticholonergics are of no help rather large
dose of bromocriptine may be use full
e. Tardive dyskinesia
Manifests as purposeless involuntary facial
•

& limb movements like constant chewing,

pouting, puffing of cheeks & lip licking
• More common in elderly women
•May subside months or yrs after withdrawal
of the treatment or may be life long
• No satisfactory solution found
II. Hypersensitivity
1. Cholestatic jaundice
Skin rash, urticaria, contact dermatitis ,
2.
photosensitivity ( more common with CPZ)
Agranulocytosis rarely ( more common
3.

with clozapine)
4. Myocarditis
Drug interaction
1. Neuroleptics potentaite all CNS depresant
 Hypnotics, anxiolytics, alcohol, opioids,
antihistamines & analgesics
2. Neuroleptics block the action of levodopa & DA
agonists in parkinsonism
3. Antihypertensive effect of clonidine &
methyldopa is reduced
4. They are poor enzyme inducers
Drug of choice ……..
 Individual patients differ in their response to
different antipsychotics
 There is no way to predict w/c patient will respond
better to w/c drug
 However drug selection should consider state of the
patient & side effect profile of the drug
Eg. If the patient is aggressive, sedating drugs such as
CPZ would be drug of choice
Haloperidol is drug of choice if postural hypotension
is a problem
If there is difficulty in frequent administering of the
drug go for depot antipsychotic drugs
Antidepressant drugs
 Depression
 At any given moment about 3–5% of the population
is depressed & an estimated 10% of people may
become depressed during their lives
’’depression’’ is a misleading term
 Every one in the normal course of daily life will
experience mood alteration
 In this context depression does not represent a
disorder or illness
 Lowered mood as normal response to the ups &
downs of living is more correctly termed as sadness
& happiness
 Depression is defined as disorders of mood rather
than disturbances of thought or cognition
 Major depression & dysthymia (minor) are pure
depressive syndromes whereas bipolar disorder &
cyclothymic disorder signify depression in
association with mania
The symptoms of depression
 Emotional symptoms

 Misery, apathy & pessimism

 Low self-esteem: feelings of guilt,

inadequacy & ugliness

 Indecisiveness, loss of motivation.

 Biological symptoms
 Retardation of thought & action
 Loss of libido

 Sleep disturbance & loss of appetite

 Etiology & pathogenesis
 Genetic causes
 Environmental factors
 Biochemical factors
 Deficiency of NT amines in certain part of
the brain (NA, 5-HT & DA)
 Endocrine factors
 ↑ plasma cortisol level in depressed patients
 Dexamethasone suppression test
 Monoamine theory
 The theory states that depression is caused by a
functional deficit of monoamine transmitters
(NA &/or 5-HT) at certain sites in the brain,
while mania results from a functional excess
 Pharmacological evidence for monoamine hypothesis
Effect in depressed
Drug(s) Principal action Patients
TCAs Inhibit NA & 5-HT reuptake Mood ↑

MAOIs Increase stores of NA & 5-HT Mood ↑

Reserpine Inhibits NA & 5-HT Mood ↓

storage
Mood ↓(calming of manic
α-Methyl tyrosine Inhibits NA synthesis patients)

Mood ↓
Methydopa Inhibits NA synthesis

Electro convulsive Mood ↑

therapy ↑ CNS responses to NA &
5-HT
 Recent evidence suggests that depression may be
associated with neurodegeneration & reduced
neurogenesis in the hippocampus
 Prodepressive pathways involve the hypothalamic-pituitary-
adrenal axis
 The antidepressive pathways involve the monoamines & the
BDNF
Classification of antidepressants

1. Tricyclic antidepressants (TCAs)

2. Selective serotonin reuptake inhibitors (SSRIs)
3. Monoamine oxidase inhibitors (MAOIs)
4. Miscellaneous ('atypical') antidepressants
Mechanism of action of antidepressants
Mechanism of action of antidepressants
I. Tricyclic antidepressants (TCAs)

A. NA + 5-HT reuptake inhibitors

Imipramine Amitriptline
Trimipramine Dothiepin
Doxepin Clomipramine
B. Predominantly NA reuptake inhibitors
Amoxapine Desipramine
Nortriptylin Reboxetine
 Mechanism of TCAs
 Block reuptake of NA &/or 5-HT
 ↑NTs concentration on synaptic cleft
 On the 1st few weeks of treatment the increased NTs
activate presynaptic autoreceptors (α2, 5-HT1A & 5-
HT1D)
 Presynaptic autoreceptors
 Mediated negative-feedback mechanisms
 Respond to increased synaptic transmitter by
down-regulating NTs synthesis & release
• Uptake blockage occurs quickly but
antidepressant action develops after weeks
• Mianserin (atypical) has no uptake blockage
action rather it block presynaptic receptors
• Trimipramine is weak NA/5-HT reuptake
blocker but an equally effective antidepressant
Therefore antidepressant action of TCAs is
beyond reuptake inhibition
 After long term adminstration of TCAs (2-3 wks)
 The drug desensitize presynaptic auto receptors
(α2, 5-HT1A & 5-HT1D)
 ↑concentration of NTs in synaptic cleft
 Increased sensitivity of postsynaptic receptors
 Hence, the net effect after long term therapy is
enhanced noradrenergic & serotogenic
transmission
 The receptor change might be more related to the antidepressant
action than the reuptake inhibition mechanism
Pharmacological action
1.CNS
In normal individuals
 Clumsy feeling, tiredness, lightheadedness,
sleepiness, difficulty in concentration & thinking
In depressed patients
 After 2 -3 weeks of continuous treatment
mood gradually elevated & start taking interest
in self & surrounding
 Drugs are not euphorients rather antidepressant
 Lower seizure threshold & produce convulsion
2.ANS
Most TCAs are potent anticholinergics
3.CVS
 Tachycardia (due to anticholinergic & NA
potentiation action)
 Postural hypotension (due to
cardiovascular reflex & α1 blockade)
 ECG change & cardiac arrhythmias (T
wave suppression or inversion)
Major limitations of conventional TCAs
 Anticholinegics, cardiovascular & neurological side
effects
 Relatively low safety margin, dangerous in over dose
 Lag time 2-4 weeks before antidepressant action
manifests
 Incomplete response by significant number of
patients & some do not respond
II. Selective serotonin reuptake inhibitors
(SSRIs)

Fluoxetine Maprotiline
Fluvoxamine Trazodone
Paroxetine Nefazodone
Citalopram
Sertraline
SSRIs
 1st line drugs
 Due to their relatively safe & acceptability
 Produce little or no sedation
 Not produce anticholineric side effects
 Devoid of α AR blocking action (no postural
hypotension)- suitable for elderly patients
 No seizure precipitating propensity & not inhibit
cardiac conduction
 No weight gain
 For TCAs & SSRIs as onset of action is slow
Treatment should be for at least 4-6 weeks
before concluding that the drug is ineffective
 If there is a partial response, treatment should
be continued for several more weeks before
increasing the dose
Treatment should continue for at least 4 months
following remission
III. Monoamine oxidase inhibitors
(MAOIs)
 MAO-A is primarily responsible for NE, 5-HT &
tyramine metabolism
 MAO-B is more selective for DA
 Non-selective MAOIs or selective MAO-A inhibitors
have antidepressant effect
 Older non selective MAOIs :Tranylcypromine,
phenelzine & isocarboazid
 Irreversible, long-acting & non-selective
 Moclobemide (MAO-A inhibitor)
 Reversible, short acting & selective
IV. Miscellaneous ('atypical') antidepressants
Trazodone
 Selective but less efficiently block 5-HT uptake
 Prominent α blocking & 5-HT2 antagonistic effect
Mianserin
 Not inhibit either NA or 5-HT uptake
 Block presynaptic α2
Tianeptine
 ↑5-HT uptake , it is not sedative & stimulant
 Effective for anxiodpressive state
Amineptine
 Like tianeptine but has antidepressant action
Venlafaxine & duloxetine
‘serotonin & NA reuptake inhibitor ’ = SNRI
 In contrast to older TCAs,
 They do not interact with cholinergic, adrenergic,
or histaminergic receptors
 No sedative effect
Mirtazapine
 Block α2 autoreceptor ( on NA neuron) & hetro
receptors( on 5-HT neurons )
Bupropion
 Inhibit DA & NA uptake
 Has excitant rather than sedative effect
Clinical indications of antidepressants
 Major depression
 Anxiety disorders
 panic, generalized anxiety, social phobia &
obsessive-compulsive disorders
 Enuresis
 Chronic pain
 Migraine
 Amitryptiline has prophylactic use
 Pruritus
 Some TCAs have antipruritic action
Eg. Topical doxepine
 Other indications
 Bulimia (fluoxetine)
 Premenstrual dysphoric disorder (fluoxetine)
 Aattention deficit hyperkinetic disorder
(imipramine, desipramine)
Adverse effects
 TCAs
 Sedation, tremor & insomnia
 Blurred vision, constipation, urinary
hesitancy, confusion 
 Orthostatic hypotension, conduction defects,
arrhythmias  
 Aggravation of psychosis 
 Seizures  
 Weight gain, sexual disturbances
 MAOIs
 Headache
 Drowsiness
 Dry mouth
 Weight gain
 Postural hypotension
 Sexual disturbances
 SSRIs
 Anxiety
 Insomnia
 Gastrointestinal symptoms
 Decreased libido, sexual dysfunction
 Teratogenic potential with paroxetine
Drug interactions
TCAs
1. Potentiate directly acting sympathomimetics
2. Abolish antihypertensive effect of clonidine
3.Potenciate CNS depressants
4. Phenytoin, phenylbutazole, ASA & CPZ can displace
TCAs from PPB
5. PhB induce as well as competitively inhibit impramine
metabolism
6.SSRIs inhibit metabolism of several drugs
including TCAs
7. TCAs delay absorption of their own & other drugs
MAO- A inhibitors
Tyramine containing food
‘Cheese’ like reaction
Drug treatment of mania & manic
depressive disorder
Drugs used
 Neuroleptics
 TCAs

 Lithium

 Carbamazepine

 Valproate

 BZDs
A. Neuroleptics
 Commonly used drugs: haloperidol or
chlorpromazine or zuclopenthixol (acuphase)
 Haloperidol is drug of choice
 As it is less sedating & free from many of
cardiovascular problems of CPZ
 Control sever behavior disturbance with
additional sedatives such as lorazepam
injection
 Atypical antipsychotics (olazapine, resperidone)
& other newer antipsychotics with or with out a
BZD are now 1st line drugs for control of acute
mania
B. Lithium carbonate
 Lithium used as carbonate salt b/c it is less
hygroscopic & less gastric irritant than LiCl &
other salts
 Lithium carbonate is referred to as an "antimanic"
drug
 However, it is considered a "mood-stabilizing“
agent
 B/c of its primary action of preventing mood
swings in patients with manic-depressive disorder
 Mechanism of action
 Antimanic/mood stabilizing action remains unclear
 It has been suggested that
1. Li+ partly replace body Na+ & nearly equally
distributed inside & out side cells & hence it interferes
ionic fluxes
2. It
↓ NA & DA release in treated animals with out
affecting 5-HT release
3. Effects
on secondary messengers : one of the best-
defined effects of Li+ (action on inositol phosphates)
Effects on secondary messengers
 IP3 & DAG : important second messengers for
adrenergic & muscarinic transmission
 Blocking the pathway leads to depletion of PIP2
(precursor of IP3 & DAG)
 Hyperactive neurons involved in manic state may
be preferentially affected
i.e. Li+ could cause a selective depression of the
overactive neurons
 Li+ has no acute effect on normal individuals
 Mechanism of action

PIP2 : phosphatidylinositol-4,5-bisphosphate
PLC: phospholipase-C
G: coupling protein
EFFECTS: activation of protein kinase C, mobilization of intracellular Ca 2+, etc.
Pharmacokinetics

 Slowly & well absorbed (orally)

 No plasma binding & metabolism
 Gradually well distributed in total body water
 Excreted from kidney in the same way as Na+
Clinical use of Li+
For acute mania
Duringacute phase, Li+ response is low & control of
plasma level is difficult
 Neuroleptics (i.m. route) with or with out
potent BZDs (clozapam or lorazepam) is
preferable in acute phase
 Li+ treatment can be started after the epsoid
is under control & maintenance therapy is
generally for 6 – 12 months
 Clinical use of Li+
 As prophylaxis in bipolar disorder
 For recurrent unipolar depression
 Initially combination of TCAs with Li+ &
then Li+ alone in maintenance phase
 For recurrent neuropsychiatric illness, cluster
headach, & adjuvant to TCAs in resistant major
depression
 Adverse effects
1. Nausea, vomiting & mild diarrhea
2. Thirst & polyuria
3. CNS toxicities: coarse tremors, ataxia, motor
incoordination, mental confusion, etc
• No specific antidote for Li+ toxicity
• Osmotic diuretics & sodium bicarbonate
infusion promote Li+ excretion
 Adverse effects

4. On long term therapy

•Some patients develop renal diabetes
inspidus
•Goiter is also reported in few patients b/c

Li+ interfere with tyrosine iodination

5. C/I during pregnancy
•Foetal goiter & congenital abnormalities
may occur
 Drug Interaction
1. Diuretics ( thiazides, frusemide) promotes proximal
reabsorbtion of Na+ as well as Li+ (↑ plasma Li+ )
2. TTC, NSAIDs, & ACE inhibitors can also cause Li +
retention
3. Li+ enhances insulin/sulfonylurea hypoglycemia
C. TCAs
 The depressive phase of manic-depressive
disorder often requires concurrent use of an
antidepressant drug
 TCAs linked to precipitation of mania
 with more rapid cycling of mood swings
but most patients do not show this effect
 SSRIs are less likely to induce mania but may
have limited efficacy
 D. Carbamazepine
 The mode of action of carbamazepine is unclear, and
oxcarbazepine is not effective
 Carbamazepine may be used to treat acute mania &
also for prophylactic therapy
 May be used alone or, in refractory patients, in
combination with lithium or, rarely, valproate
 The use of carbamazepine as a mood stabilizer is
similar to its use as an anticonvulsant
 E.Valproate
 Valproic acid is becoming recognized as an appropriate
first-line treatment for mania
 It is not clear that it will be as effective as Li+ as a
maintenance treatment in all subsets of patients
 Mechanism of action of is unclear
 It shows efficacy equivalent to that of Li+ during the early
weeks of treatment
 It has been effective in some patients who have failed to
respond to lithium
F. BZDs
• Used as adjuvant with other antimanic drugs
OVERVIEW OF PARKINSON'S
DISEASE
 Parkinsonism: - is a progressive neurologic disorder
of muscles movement characterized by
 tremors(hand ankles)
 muscular rigidity
 postural abnormalities
 Brady kinesis(slowness in initiating & carrying out
voluntary movements)
 Ethiology
 Cause is unknown for most patients.

 It is correlated with destruction of dopaminergic

neurons in the substantia nigra
 Consequently, reduction of dopamine actions in the
corpus striatum parts of the brain's basal ganglia system
that are involved in motor control.
1. Substantia nigra
 Is the source of dopaminergic neurons that terminate in the
striatum.
 Each DAnergic neuron synapse with neostriatum
 Modulates activity of large no. of cells.
 fire tonically, rather than in response to specific muscular
movements or sensory inputs.
2. Neostriatum
 Connected to Substentia nigra by neurons that secret
inhibitory NT GABA at their terni in in substentia nigra
 In turn, cells of substentia nigra send neurons back to
neostriatum, secreting the inhibitory transmitor Dopamin at
their termini.
Strategy of Treatment
 Symptoms of Parkinson's reflect
 imbalance b/n the excitatory cholinergic neuron & the
greatly diminished number of inhibitory dopaminergic
neurons.

Normal Parkinson’s disease

 Therapy is aimed
 to restore the dopamine in the basal ganglia & antagonizing
the excitatory effects of cholinergic neurons.
 Thus re-establishing the correct dopamine and -Ach
balance.
DRUGS USED IN PARKINSON, S
DISEASE
 Currently available drugs after temporary relief
from the symptoms of the disorder,
 but do not arrest or reverse the neuronal degeneration
caused by the disease.
A. Levodopa (L-Dopa)

 MOA
 Levodopa inters the brain via an active transport
system that carries it across the BBB.
 Converted by decarboxylase to DA which helps
restore a proper balance between DA and Ach.
A. Levodopa (L-Dopa)
 Pharmacokinetics
 Administered orally and absorbed rapidly, foods, delay
absorption (by slowing gastric emptying).
 Metabolized in the periphery, primarily by
decarboxylase enzymes to DA, and to a lesser extent,
by COMT
 Less than 2% of each dose enters the brain
 A. Levodopa (L-Dopa)
 Adverse effect
 Are dose dependent
 Nausea and vomiting – by stimulating the CTZ
 dyskinesias – head bobbing, tics grimacing
 Cardiovascular effects
 Postural hypotension early in the treatment
 Arrhythmias in patients with cardiac disease
 Psychosis; clozapine can reduce psychotic symptoms with out
intensifying symptoms of PD.
 Other adverse effects.
 May darken sweat and urine; patients should be forewarned of this
harmless effect.
 Levodopa plus carbidopa
 More effective than levodopa alone
 Carbidopa enhances effects of levodopa by inhibiting
decraboxylases in periphery so levodopa available for
CNS increases
 Advantages of carbidopa - Combination
superior in 3 ways
 Increases fraction of levodopa available for CNS
 Levodopa dose can be reduced by 75%
 Decreases cardiovascular response.
B. Dopamine Agonists

 Unlike levodopa
 They donot requier enzymatic conversion to an acitve
metabolite
 Have no potentially toxic metabolites
 Do not compete with other substances for active
transport in to blood and BBB.
 Some how selective to dopamine agonists
 May have limited Adverse Effect than L-dopa
B. Dopamine Agonists
 Four dopamine agonists are available
 ergot derivatives
 Bromocriptine
 Pergolide
 nonergot derivatives
 Pramipexole,
 Ropirinole
 Cause fewer side effects than the ergot derivatives
 B. Dopamine Agonists
 BROMOCRIPTINE
 D2 agonist, now rarely used as an antiparkinsonian
 Absorbed to a variable extent from GIT, Peak= 1-2 h
 Excreted in the bile and feces
 Usual daily dose 7.5 – 30 mg ( built up slowly 2-3 M)
 PERGOLIDE
 Ergot derivative
 Stimulates both D1 & D2
 More effective than Bromocriptine
 No longer avialable (Associated with valvular heart disease)
B. Dopamine Agonists
 PRAMIPEXOLE
 Not an erogt derivative, prefers D3 receptor
 Effective as a monotherapy for mild parkinsonism
 Permits the dose of L-dopa to be reduced and soothing
out response flactuations.
 Started at low dose and slowly increased
 ROPINIROLE
 Nonergoline derivative
 Relatively pure D2 receptor agonist, effective as
monotherapy
C. COMT inhibitors
 Two COMT inhibitors are available Entacapone
and Tolcapone.
 Benefits of both derive from inhibiting metabolism
of levodopa in the periphery
 these drugs have no direct therapeutic effects of
their own.
D. Monoamine Oxidase Inhibitors
SELEGILINE, RASAGILINE
 Actions and uses

 A selective inhibitor of type B monoamine oxidase, which

is the enzyme that inactivates dopamine in striatum
 does not present risk of hypertensive crisis;
 used with levodopa and may delay progression of disease.
 Pharmacokinetics –
 Rapidly absorbed,
 penetrates blood- brain barrier
 D. Selegiline
 Adverse effects – insomnia
 Drug interactions
 Levodopa combined produces intensified adverse
responses
 dangerous interaction with meperidine;
 should not be combined with fluoxetine, as this could be
fatal.
E. Centrally acting
Anticholinergics
 Play an adjuvant role in parkinsonism therapy

 Adverse effects: - similar to anti muscarinic agents

xerostomia (dryness of mouth) interfere with GIT
peristalsis sandy eye (dry eye).
F. Amantadine
 Is antiviral drug effective in the treatment of influenza A.
 has anti-parkinsonism action.
 Its mode of action in parkinsonism is unclear, but it may
potentiate dopaminergic function by influencing the
synthesis, release, or reuptake of dopamine.
 It is given together with levo-dopa.
 Peak plasma concentration 1-4 h after PO, t1/2 =2-4 h
 Less efficacious than L-dopa
 Adverse effects
 restlessness, depression, irritability, insominia, hallucination
and confusion.
CNS Stimulants
Molecular basis of CNS stimulation
 Balance b/n inhibitory and excitatory neurons
 Potentiation or enhancement of excitatory
neurotransmission
e.g. Amphetamine
 Depression or antagonism of inhibitory
transmission
e.g. Strychnine
Classification of CNS Stimulants

I. Analeptics
 Respiratory stimulants
 Convulsants

II. Psychomotor stimulants

 Sympathomimetics /adrenergic CNS
stimulants
 Methylxanthines

III. Psychotomimetics / hallucinogens

 I. Analeptics
Diverse chemical classes
Majority can be absorbed orally
Effect terminated through metabolism
 Short t1/2
Common mechanism of Action
 Alteration of Cl- conductance
 Convulsions is the primary effect
Used as experimental tools but have limited clinical
uses
 Analeptic

Respiratory stimulant
Doxapram
Convulsants
Pentylenetetrazole (PTZ)
Picrotoxin
Bicuculline
Strychnine
 Respiratory stimulant

Doxapram
Has a bigger margin of safety b/n respiratory stimulation
& convulsions
At low dose more selective for respiratory center than
other analeptics
 Occasionally used as an i.v. infusion in patients with
acute respiratory failure
May be used to abolish episodes of apnoea for premature
infants who don't respond for thoephyline
 Counteract post-operative respiratory depression
Associated with nausea, coughing & restlessness w/c
limit its usefulness
 Convulsants

Pentylenetetrazole (PTZ)
Precise mechanism is not known
Antiepilepticdrugs w/c inhibit PTZ-induced
convulsions imply their effectiveness against absence
seizures
Used to test potential anticonvulsant dugs in
laboratory animals ……has no clinical use
Used for screening of latent epileptics as it can
precipitate the typical EEG pattern of absence
seizures in susceptible patients …..????
 Convulsants

Picrotoxin
 Blocks the action of GABAA on Cl- channels but
not competitively
 Obtained from the fishberry
 The plant's name reflects the native practice of
incapacitating fish
 Like bicuculline, it causes convulsions & has no
clinical uses
 Diazepam facilitate GABAergic transmission
 Antidote for picrotoxin poisoning
 Convulsants

Bicuculline
 Resembles strychnine in its effects with different
mechanism of action i.e. Strychnine block glycine
receptor while bicuculline block GABA receptor
 It is competitive GABAA antagonist (block the
receptor) but not affect GABAB receptor
 The main effects are on the brain rather than the
spinal cord
 Useful experimental tool for studying GABA-
mediated transmission….. has no clinical uses
 Convulsants

Strychnine
 Potent convulsant
 Tonics containing strychnine …. ‘’banned’’
 Acts particularly throughout spinal cord, causing
violent extensor spasms that are triggered by minor
sensory stimuli, the head being thrown back & the
face fixed
 Mechanism of action : blocking glycine receptors
 Treatment of strychnine poisoning is similar to status
epilepticus
Convulsion
 Convulsants

 The action superficially resembles that of tetanus

toxin produced by the C.tetani w/c blocks release of
glycine from inhibitory interneurons
 This is very similar to the action of botulinum toxin
w/c is produced by C. genus & causes paralysis by
blocking Ach release
 In small doses, strychnine causes a measurable
improvement in visual & auditory acuity
 II. Psychomotor stimulants

1. Amphetamine & related compounds

(Eg. dexamphetamine, methylamphetamine,
methylphenidate, fenfluramine)
2. Methylxantines
(Caffeine, theophyline)
 Psychomotor stimulants

1. Amphetamine & related compounds

 Are indirect sympathomimetic agents
 Displace stored catecholamines from the
presynaptic adrenergic nerve ending
 Inhibit reuptake of catecholamines
 Additionally
 Direct agonist of DA & 5-HT receptors
 May inhibit MAO
 Amphetamine (A)

A  release

A Inhibit
reuptake

A inhibits
MAO
 Pharmacological Actions
Wakefulness/alertness, mood elevation, ↓fatigue, ↑ed
ability to concentrate, ↑ motor & speech activity
 locomotor stimulation, stereotyped behaviour,
euphoria & excitement
Stimulate the respiratory center especially when it
has been depressed by drugs
Anorexia / lose of appetite by inhibiting
hypothalamic feeding center
 with continued use this effect wears off in a few
days & food intake may return to normal
Amphetamine & related compounds

Therapeutic uses
 For attention deficit-hyperactivity disorder (ADHD):

Hyperkinesias
 Drug used : methylphenidate
 at doses lower than those causing euphoria &

other side effects

 For narcolepsy - amphetamine / methylphenidate
 As appetite suppressants for obesity: Fenfluramine
 Now a days it is abandoned
Amphetamine & related compounds

Adverse Effects
 Euphoria, tremor, irritability, insomnia, convulsion
(at higher doses), hyperthermia & coma
 Cardiac stimulation leads to headache, palpitations,
cardiac arrhythmias, anginal pain
 Hypertension
 weight loss, Psychotic reaction
 Psychic dependence, tolerance & physical
dependence
Amphetamine & related compounds

 MDMA (methylenedioxymethamphethamine)
caused sudden deaths even after a single/moderate
dose
 Condition resembling heatstroke, associated with
muscle damage & renal failure
 Inappropriate secretion of ADH, leading to thirst,
over-hydration & hyponatraemia ('water
intoxication')
 Cerebral haemorrhage after amphetamine use,
possibly the result of acutely raised blood pressure
Amphetamine & related compounds

Drug interactions
 Tricyclic antidepressant
 Antihypertensive agents
 Foods with high tyramine content
Amphetamine & related compounds
Misuse of amphetamines
 By soldiers, military pilots & others to increase
performance & to remain alert under extremely
fatiguing conditions
 By students vaguely as a means of helping to
concentrate before & during exam
 As the improvement caused by reduction of
fatigue can be offset by the mistakes of
overconfidence
 By athletes to ↑ performance w/c end up with
deterioration
Drugs used by athletes as CNS stimulant & officially
prohibited
 Ephedrine & methylephedrine
 Amphetamines & its derivatives

 Cocaine

 Nikethamide, amiphenazole, strychnine,

caffeine
 Other CNS stimulants

’’Dope test’’ for athletics

 Psychomotor stimulants
2. Methylxantines

 Caffeine in coffee, tea, cocoa

 Theophylline in tea & cocoa
 Theobromine in cocoa
 Mechanisms of Action
 Increase cyclic nucleotide concentration
 Blocks adenosine receptors
 Alters intracellular Ca 2+ distribution
Pharmacological activity/adverse Effects
 Low doses: 50-250mg/caffeine
 ↑ed mental alertness & ↓ed drowsiness
 Lessen fatigue
 Larger doses: 250-600mg/Caffeine
 Irritability, restlessness, tremor, insomnia,
headache, palpitations & GI upset
 Very large doses: > 1000 mg
 Overt excitement, delirium, clonic seizures
 Cardiovascular System
Chronotropic & inotropic (low doses)
Arrhythmias at higher doses
Peripheral vasodilation, hypotension & cardiac
arrest (rapid i.v. theophyline)
Relaxes vascular smooth muscle (Theophylline >>
Caffeine)
Diuresis (Theophylline > Caffeine)
Xanthines shorten clotting time by increasing tissue
prothrombin & factor V
Therapeutic uses

 Migraine headaches
 OTC preparations
 Theophylline: Prophylaxis for chronic asthma

 Bronchodilator for relief of asthmatic

symptoms
 Respiratory Stimulant
Adverse effects

 Stimulate gastric secretions

 Dehydration-vomiting & diuresis (theophyline)
 Allergic reaction (aminophylline)
 Psychic dependence (Caffeine)
 III. Psychotomimetics / hallucinogens

The main types

 LSD (lysergic acid diethylamide), psilocybin &
mescaline
 Actions related to 5-HT & catecholamine
 MDMA (methylenedioxymethamphetamine)
'ecstasy'
 Phencyclidine