PRINCIPLES OF CNS PHARMACOLOGY

EDUVIERE A.T. (Ph.D.)

DEPARTMENT OF PHARMACOLOGY & THERAPEUTICS,
FACULTY OF BASIC MEDICAL SCIENCES,
DELTA STATE UNIVERSITY, ABRAKA .
 THE BBB: HISTORICAL PERSPECTIVE
• The concept of Blood-Brain Barrier (BBB)
– Based upon experiments of Paul Ehrlich (1885) & Edwin
Goldman (1909)

• Injection of water-soluble dyes into peripheral circulation → brain NOT stained;

CSF NOT colored, but heavy staining of the choroid plexus
• Injection of water-soluble dyes into subarachnoid space → brain stained;
peripheral tissues NOT stained; CSF colored
• Conversely, injection of lipid-soluble dyes into peripheral circulation → brain
stained; CSF colored

• Two barrier systems in the brain (postulated by Broman, 1941):

– the Blood-Brain Barrier at the cerebral microvasculature
– the Blood-CSF barrier at the choroid plexus
The Two Barrier Systems of the Brain
(Blood-Brain Barrier & Blood-CSF Barrier)
Endothelial cells of Brain Capillary

Epithelial cells of Choroid plexus

makes

secretes
 COMPARISONS OF BRAIN & PERIPHERAL
CAPILLARY BED ECS
Brain capillary bed ECs Peripheral capillary bed
ECs
1. Tight junctions of high Fenestrated ECs that
electrical resistance as permits trans-cellular
physical barrier against movement of molecules
molecules

2. Contact with astrocytic Intracellular pinocytotic

foot processes that vesicles (facilitates transca-
separates capillaries & pillary fluid & solute
neurons transport

3. Abundant mitochondria Fewer mitochondria

(active transport of
H2O-soluble nutrients
into brain)
1. Tight junctions – between ECs of brain capillaries;
limit diffusion across BBB
SCHEMATIC DIAGRAM
2. Basement membrane – structural support for
OF BRAIN CAPILLARY
capillaries

3. Astrocytic foot – encircle & support capillaries;

may influence EC function

4. Transport carriers – for glucose & for amino

acids; facilitate entry of solutes into brain

5. 2O Transport system – cause efflux of small,

nonessential amino acids from brain to blood

6. Na+ Transporters (Luminal membrane) & Na+/K+-

ATPase (Adluminal membrane) – together move
Na+ from blood to brain; osmotic driving force for
secretion of interstitial fluid by brain capillaries

7. Enzymatic BBB – (e.g., large neutral amino acid

carriers) for uptake of neurotransmitter
precursors into ECs & subsequent metabolism;
break-down of neurotransmitters in interstitial
fluid by brain capillaries http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi
 FUNCTIONS OF THE BBB
 Physical barrier – via the tight junctions between ECs

 Metabolic (enzymes) barrier – BBB is a system of

cellular transport mechanisms; constitutes the energy-
driven, rate-limiting factor for entry of drugs &
macromolecules into the CNS

 Homeostasis – allows entry of essential nutrients;

entry of potentially harmful chemicals restricted
 HOMEOSTATIC FUNCTIONS OF THE BBB
• Higher Oil/H2O partition coefficient of a molecule = Easier CNS penetration
from systemic circulation
• Small, lipid-soluble molecules & uncharged particles enter readily; polar molecules & charged particles DO
NOT

• Hydrophilic nutrients (glucose & amino acids) enter brain via facilitated
diffusion (Transporters: Hexose transporter (glucose); Amino Acid (AA)
transporters (amino acids)
• L-DOPA gets to the brain via AA transporters; high protein diet competes for entry

• Metabolic BBB – cerebral capillary ECs have enzymes that metabolize

compounds transported through them
– DOPA decarboxylase (L-DOPA → dopamine or DP); DP DOES NOT ENTER CNS

• Multiple drug resistance (MDR) transporters – proteins that limit entry of toxic
lipophilic compounds to the brain
TRANSPORT MECHANISMS @ THE BBB
• Simple diffusion
– Transcellular occurs; high lipophicity = high diffusion
– Paracellular (i.e., between cells) – not common in BBB
– Simple diffusion through an aqueous channel

• Facilitated diffusion - hexose transporter (glucose);

Amino Acid (AA) transporters

• Active transport via protein carriers

 FACTORS GOVERNING PASSAGE OF
MOLECULES THROUGH THE BBB
• Molecular size & Lipophilicity
• Charge – uncharged particles enter readily; charged do
not
• Affinity for carrier mechanisms
• Affinity for efflux mechanisms (i.e., P-glycoprotein)
• Amino acid composition – protein binding ↓CNS entry
• Flexibility & conformation of molecules
• Existing pathological conditions
• Cellular enzymatic stability
PATHOPHYSIOLOGIES INVOLVING THE BBB
• Meningitis – inflammation of the meninges caused by bacterial
infection → ↑Penetration of toxin or antibiotics into the brain

• Epilepsy – failure of BBB is one of the features that trigger chronic

or acute seizures

• Multiple sclerosis – (1) Autoimmune & neurodegenerative disease; (2)

Immune cells (T lymphocytes) attack myelin sheath of central & peripheral
neurons, (3) Presence of T lymphocytes in the brain suggests impaired BBB

• Alzheimer’s disease – impaired BBB allows plasma rich in amyloid

β to enter the brain & adhere preferentially to astrocyte surface
 CNS NEUROTRANSMITTERS
&
BASIS OF DRUG ACTION IN THE CNS
NEUROTRANSMITTERS IN THE CNS

1. Choline ester 3. Amino acids

e.g., Acetylcholine e.g., Glutamate, Aspartate,
GABA, and Glycine

2. Biogenic amines
(are decarboxylated Amino acids)
e.g., Norepinephrine, Dopamine,
Serotonin
CONSEQUENCES OF NEUROCHEMICAL
IMBALANCE IN THE BRAIN – A SIMPLIFIED VIEW
Neurotransmitter Excess Low or Total Lack
Acetylcholine Delirium/confusion Alzheimer’s disease

Dopamine Psychosis Parkinson’s disease; Depression

γ-Aminobutyric CNS depression; Seizures; Movement disorders

acid (GABA) Respiratory depression;
Sedation
Glutamate Schizophrenia
Seizures; Neuronal
degeneration
Norepinephrine Depression
Anxiety; Panic; Anorexia;
Excitability; Insomnia
Serotonin Depression; Pain sensitivity;
Sleep; Hallucinations; Obsessive compulsive disorder
↓Appetite; Anxiety
LIFE CYCLE OF
NEUROTRANSMITTERS
Choline + Acetylcoenzyme A (acetyl CoA) via LIFE CYCLE OF
choline acetyltransferase → Acetylcholine ACETYLCHOLINE

Sources of Choline & Acetyl CoA to the CNS:

(1)Acetycholinesterase degradation of ACh
(30-50%);

(2) Free choline from metabolism of plasma

lipid phosphotidylcholine,

(3) as phosphorylcholine (stored form).

Acetyl CoA is derived from glycolysis by the
enzyme pyruvate dehydrogenase

Rate-limiting step – choline transport into

neuron

Na+-dependent, high-affinity transport;

target for anti-cholinergic drugs, e.g., ACh is stored in vesicles via ACh-H+ antiporter
hemicholinium-3 (against ACh conc. gradient; down H+ conc gradient)
Vesamicol inhibits ACh-H+ antiporter
 L-TYROSINE DERIVED NEUROTRANSMITTERS
Endogenous catecholamines:
Dopamine, Norepinephrine (NE), and
Epinephrine (EPI )
 Derived from L-Tyrosine
 Have Catechol nucleus

Rate-limiting step of entire cascade -

conversion of L-Tyrosine to DOPA
(catalyzed by tyrosine hydroxylase)

 Enzymatic targets for therapeutic purposes

 Tyrosine hydroxylase
 L-Aromatic amino acid decarboxylase

Neurons with Dopamine-β-hydroxylase

 Synthesize NE plus Dopamine

Neurons with Phenoethanolamine N-

Methyl-transferase
 Synthesize EPI (+ Dopamine and NE)
L-TYROSINE Adrenergic
DERIVED NEUROTRANSMITTERS
neuron
L-TYROSINE DERIVED NEUROTRANSMITTERS
Dopaminergic neuron
L-TYROSINE → TYRAMINE (A TRACE AMINES)
1. Decarboxylation of L-Tyrosine in
liver & GIT → Tyramine (a
vasoactive amine)
2. Tyramine is also found in food: red
wine, aged cheese, fermented
sausage, etc
3. Rapid metabolism of tyramine by
MAO (monoamine oxidase)
prevents significant presence of
the amine in blood or tissues
4. Once present in significant
amounts in the blood, tyramine
can be taken up into adrenergic
neuron; stored in vesicles & can
be released as false transmitter
5. Dopamine-β-hydroxylase (DBH) in Clinical significance of Trace amines:
storage vesicles can hydroxylate
tyramine → Octopamine (a Food Drug interactions. MAO
vasoactive trace amine) inhibitors interact with tyramine in food
including wine or cheese → potential
for hypertensive crisis
1. Precursor – Amino acid L-Tryptophan;
important enzymes: Tryptophan hydroxylase,
BIOSYNTHESIS OF 5-HT
and Aromatic L-Amino Acid decarboxylase
2. Rate-Limiting step - The conversion of L-
Tryptophan to 5-Hydroxytryptophan by
Tryptophan hydroxylase.
3. Storage in pre-synaptic vesicles using
vesicular monoamine transporter (VMAT) as
with catecholamines; Reserpine can deplete
serotonin from storage vesicles
4. Regulation of release - Pre-synaptic 5-HT1D
autoreceptors
5. Reuptake – via Serotonin transporter (SERT);
can also be up-taken via Dopamine and
Norepinephrine transporters
6. Metabolism – by Monoamine oxidase (MAO);
isoform A (i.e., MAO-A), which oxidizes NE &
Dopamine also.
7. Targets of Significance
(1) Selective serotonin Reuptake inhibition
(2) Serotonin-Norepinephrine Reuptake inhibition
(3) Monoamine oxidase A (MAO-A) inhibition
(4) 5-HT postsynaptic receptors
(5) 5-HT1D autoreceptors
α-Ketoglutarate (from the Krebs SYNTHESIS & METABOLISM OF GABA
cycle) → Glutamate by GABA
transaminase (GABA-T)
Glutamate → GABA in GABAergic
nerve terminals by GAD (glutamic acid
decarboxylase)
 GAD requires vitamin B6 as a cofactor;
functional GAD correlates with GABA in
brain tissue

 GABA is stored in Presynaptic vesicles

by a transporter (VGAT) – the same as
neurons that release glycine
Targets for Modulation
(1) GABA transporters (GATs) – facilitates
GABA reuptake into neurons & glia cells.
Competitively inhibited by Tiagabine
(2) GABA metabolism by GABA-T -
Vigabatrin - a suicide inhibitor
(3) GABA (and glycine) Release – Tetanus
toxin
(4) GABAA receptor modulators –
Benzodiazepines & barbiturates
(5) GABAB receptor agonist – Baclofen
(muscle relaxant)
Transamination of α-Ketoglutarate
(from the Krebs cycle) → Glutamate SYNTHESIS & METABOLISM
by GABA transaminase (GABA-T) OF GLUTAMATE
Glutamine produced & secreted by
glial cells is transported to nerve
terminals, and converted to
Glutamate by glutaminase

Release via Ca2+-dependent

exocytosis; Reuptake via Na+-
dependent, high affinity transporters
on membranes of pre-synaptic
neurons and glial cells
NB: In Glial cells, glutamine
synthetase converts glutamate to
glutamine; then, recycled in neurons
to glutamate
Functional significance of Glutamate
Glutamate binding to its receptors →
(1) ↑Pain sensation (hyper-algesia)

(2) Cerebral neurotoxicity, e.g.,

associated with stroke
(3) Memory formation & loss
 POSTSYNAPTIC TARGETS OF CNS TRANSMITTERS ACTION

Ionotropic receptors: Activation of these

receptors results in direct opening of ion chan
nels resulting in rapid excitatory or inhibitory
postsynaptic potentials (EPSPs or IPSPs)
– Examples: glutamate NMDA , AMPA
& Kainate (excitatory); GABAA recepto
rs (inhibitory)

Metabotropic or G-protein coupled Rec

eptors: Activation of these receptors activate
s the Intracellular 2nd messenger cascade
– Examples: α-/β-Adrenoceptors; Hista
mine H1/H2; Muscarinic M1/M3; Seroto
nergic (except 5-HT3) receptors, etc.

Autoreceptors – on pre-synaptic nerve te

rminals, and K+ channels – on glial cells
 CENTRALLY-ACTING DRUGS ACT VIA FOUR
BROAD MECHANISMS
• Neuron-specific actions – such drugs interact with the transporters
and ion channels maintaining neuronal electrical properties.
E.g. Sedatives-hypnotics, antiparkinsonian drugs.

• Transmitter-specific actions- drugs that interfere with the life cycle

of specific transmitter molecules. E.g. antidepressants and anti-
psychotic drugs acts this way

• Signal-specific actions - drugs mimic or interfere with specific signal

transduction systems shared by different receptors
e.g. anticholinesterases (treatment of Alzheimer’s disease)

• “General” actions on molecules expressed by all cell types, e.g.,

DNA, lipids, & structural proteins
 CNS effects via Neuron-Specific Actions
A. Inhibitory neurotransmitters, e.g., Glycine, GA
BA (γ-Amino butyric acid) opens Cl- channels ,
resulting in post-synaptic target hyper-
polarization

 GABA can also open K+ channels resulting in pre-

or post-synaptic target Hyperpolarization

B. Excitatory neurotransmitters, e.g., Glutamate,

Aspartate, Acetylcholine opens Na+ or Ca2+
channels, resulting in depolarization of post-
synaptic targets (increase inward currents)

 Glutamate can also cause depolarization via

closing K+ channels (decrease outward currents)
 INHIBITORY POSTSYNAPTIC
POTENTIALS (IPSPs)
K+, Cl- at the postsynaptic ,
Ca2+ at the presynaptic

-70 mV
EXCITATORY POSTSYNAPTIC
POTENTIALS (EPSPs)
Na+, K+, Ca2+

-70 mV
 CNS effects via Transmitter-Specific Actions
(i.e., Processes Numbered 1-7) on this Slide
A. These processes are the same for all
neurons – Adrenergic; Cholinergic;
Dopaminergic, Serotonergic; GABAnergic,
or Glutaminergic neurons

B. Enzymatic Synthesis (1); Storage (2) in

synaptic vesicles; Pre-synaptic APs → Release
(3); Transmitter Binds to Receptors (4) on post-
synaptic membrane → EPSPs or IPSPs;
inactivation (5) Reuptake; pre-junctional
autoreceptors activation (6), or Enzymatic
degradation (7).

EPSPs = Excitatory post-synaptic potentials; IPSPs = Inhibitory post-synaptic potentials

EXAMPLE: TARGETING ADRENERGIC NEURONAL PROCESSES
Process Neuromodulators Target modulated Clinical significance
Synthesis Tyrosine hydroxylase Tyrosine hydroxylase Hypertension
Inhibition enzyme

Storage Reserpine Vesicular monoamine Psychosis;

transporter (VMAT) Hypertension

Release Guanethidine Dopamine or Hypertension

Norepinephrine
transporter

Action(s) Norepinephrine or Membrane receptors Hypertension;

Epinephrine Hyperthyroidism

Termination Cocaine or Monoamine Depression or

(neuronal uptake or Seligelline transporter or Parkinson’s Disease
enzymatic Monoamine oxidase
metabolism) inhibition
SIGNAL-SPECIFIC ACTION
(E.G USE OF LITHIUM IN TREATMENT OF BIPOLAR DISORDER)

• Mechanisms of action:

Lithium ↓ dephosphorylation of inositol

monophosphate → ↓Regeneration of
IP3.
CNS NEUROTRANSMITTER RECEPTORS & MESSENGERS
Neurotransmitters Receptor subtypes Receptor class Signaling mechanisms
GABA (10 Inhibitory GABAA Ionotropic ↑Cl- Conductance
transmitter) GABAB Metabotropic ↓Ca2+/↑K+ Conductance
AMPA Ionotropic ↑Na+ & K+ Conductance
Glutamate (10 Excitatory Kainate Ionotropic ↑Na+ & K+ Conductance
transmitter) NMDA Ionotropic ↑Na+, K+, & Ca2+ Conductance
mGlu(1-7) Metabotropic ↓cAMP; ↑IP3/DAG/Ca2+
Dopamine D1, D5 Metabotropic ↑cAMP
D2, D3, & D4 Metabotropic ↓cAMP; ↑K+, ↓Ca2+ Conductance

Alpha (α1) Metabotropic ↑IP3/DAG/Ca2+

Norepinephrine Alpha (α2) Metabotropic ↓cAMP; ↑K+, ↓Ca2+ Conductance
Beta (β)1, β2, β3 Metabotropic ↑cAMP

5-HT1 Metabotropic ↓cAMP; ↑K+ Conductance

5-HT2 Metabotropic ↑IP3/DAG/Ca2+
Serotonin 5-HT3 Ionotropic ↑Na+ & K+ Conductance
5-HT4-7 Metabotropic ↑cAMP

Nicotinic Ionotropic ↑Na+, K+, & Ca2+ Conductance

Acetylcholine Muscarinic Metabotropic ↑IP3/DAG/Ca2+
PSYCHOPHARMACOLOGY
INTRODUCTION TO PSYCHOPHARMACOLOGY
 The treatment of psychiatric disorder's in past constituted mere
institutionalization then called the asylums. At that time use of medicines
were considered as ridiculous.
 Psychopharmacology originated in the early 19th century with the recreational
and experimental human use of organic drugs and medicines

 Plant-derivatives such as tea and opium were freely accessible in the oriental
region; tobacco and coffee in America and alcohol prevalent worldwide.
 As time progressed, scientists became progressively curious as to the effects
of drugs on animal behaviour.
 As animal testing evolved, the efficacy of certain drugs and substances
became increasingly evident.
 During the latter part of the 19th century, newly synthesised alkaloids such
as morphine and chloral hydrate were growing in prevalence among asylums
and university hospitals.
INTRODUCTION TO PSYCHOPHARMACOLOGY
 The term psychopharmacology was first used in the early 20th century
and the modern history of psychopharmacology starts with the
synthesis of chlorpromazine.
 Introduction of chlorpromazine in 1952 revolutionized the treatment of
psychiatric disorders

 The term psychopharmacology as it is known today refers to the effect

of certain medications on an individuals’ mind and behaviour

 Psychotropic or psychoactive drugs can be defined as chemicals that

affects the brain and nervous system, alter feelings and emotions.

 These drugs also affect the consciousness in various ways. A broad

range of these drugs is used in emotional and mental illnesses.
PHARMACOLOGY OF CNS STIMULANTS
CNS STIMULANTS
 Central nervous system (CNS) stimulants fall into three broad categories:

1. Convulsants and respiratory stimulants

2. Psychomotor stimulants

3. Psychomimetic drugs (Hallucinogens)

CONVULSANTS AND RESPIRATORY STIMULANTS

 These drugs have little clinical use. They have relatively little
effect on mental function.

 They act mainly on the brain stem and spinal cord.

 They produce exerggerated reflex excitability, an increase in

activity of the respiratory and vasomotor centres. They cause
convulsions with higher dosage.

 Examples include: Certain short acting respiratory stimulants

like doxapram and amiphenazole, used in respiratory failure.
Strychnine, picrotoxin and leptazole used as chemical tools in
experimental pharmacology in various animal models.
STRYCHNINE

 It is an alkaloid from the seeds of Strychnosnux-vomica,

 It is a potent convulsant. The convulsions are reflex, tonic-clonic and

symmetrical.

 Mechanism of action: Strychnine acts by blocking post-synaptic inhibition

produced by the inhibitory transmitter glycine. Due to loss of synaptic
inhibition, any nerve impulse becomes generalized, resulting in apparent
excitation and convulsions.

 There are no valid uses of strychnine now. Accidental poisonings,

especially in children, do occur.
PICROTOXIN
 Picrotoxin is obtained from Anamirta
cocculus (fish berry), a climbing plant
found in southeast Asia and India.
 It is a potent convulsant—convulsions are
clonic, spontaneous and asymmetrical
which are accompanied by vomiting,
respiratory and vasomotor stimulation.
 Mechanism of action: It acts as a non-
competitive antagonist or inhibitor of
GABAA receptor, blocking presynaptic
inhibition mediated through GABA. i.e. it
does not act on GABA receptor itself, but
on a distinct site and prevents Cl¯ channel
opening.
 Picrotoxin has no therapeutic indication.
BICUCULLINE
 Bicuculline is a synthetic convulsant with picrotoxin-like actions.
 It is a competitive GABAA receptor (intrinsic Cl¯ channel receptor)
antagonist, while GABAB receptor (G-protein coupled receptor) is
insensitive to it.
 It is only used as a research tool.

Pentylenetetrazol (PTZ)
• It is a powerful CNS stimulant, believed to be acting by direct
depolarization of central neurons. However, a generally accepted
mechanism of PTZ is noncompetitive antagonism of GABAA receptor.
• Low doses cause excitation, large doses produce convulsions which are
similar in pattern to those caused by picrotoxin.
• Antagonism of PTZ induced convulsions is an established method of
testing anticonvulsant drugs in laboratory animals .
PSYCHOMOTOR STIMULANTS
 These drugs affect mental function and behaviour. They
produce excitement and euphoria, reduce the sensation of
fatigue and increase motor activity.

 Some enhance cognitive function.

 Examples include: Amphetamine and related compound

(dexamphetamine, methamphetamine), Cocaine,
Methylxanthines (caffeine, theophylline), Modafinil,
Methylphenidate, Mephedrone
 Amphetamines
 The amphetamines (DL-amphetamine, dextroamphetamine and methamphetamine) act by
releasing monoamines, primarily dopamine and noradrenaline, from nerve terminals in
the brain.
 They do this via:
1. Acting as competitive inhibitors of dopamine and norepinephrine uptake. They
are substrates for dopamine transporter (DAT) and norepinephrine transporter
(NET), thus reducing the reuptake of dopamine and noradrenaline.
2. They are also taken up by vesicular monoamine transporter 2 (VMAT-2) and
displace dopamine and noradrenaline from the storage vesicles into the
cytoplasm.
3. Amphetamines are weak MAO-B inhibitors and so at high concentrations, can
inhibit MAO-B, an enzyme which breaks down cytoplasmic monoamines resulting
in accumulation of monoamines.

 All of the above will combine to increase the concentration of extracellular dopamine and
noradrenaline in the vicinity of the synapse, resulting in monoamine nerve terminal
degeneration and eventually cell death
PHARMACOLOGICAL EFFECTS OF AMPHETAMINES

CNS effects
 The main central effects of amphetamine-like drugs are:

1. Locomotor stimulation due to release of dopamine

2. Euphoria and excitement
3. Insomnia
4. Increased stamina
5. Anorexia
6. Long-term psychological effects: psychotic symptoms, anxiety, depression
and cognitive impairment.

Peripheral effects
1. Hypertension and occasionally cardiac arrythmias
2. Inhibition of gastrointestinal motility

 Amphetamine-induced stereotype behaviour in rodents (mice or rats)

PHARMACOKINETICS

 Amphetamines are readily absorbed from the gastrointestinal tract, but to

increase the intensity of the hit, the drugs can be snorted or injected.

 In crystal form, the free base of methamphetamine can be ignited and

smoked in a manner similar to crack cocaine.

 Amphetamines freely penetrate the blood–brain barrier. They do this more

readily than other indirectly acting sympathomimetic amines such as
ephedrine or tyramine, which probably explains why they produce more
marked central effects than those drugs.

 Amphetamines are mainly excreted unchanged in the urine, and the rate of
excretion is increased when the urine is made more acidic.

 The plasma half-life of amphetamines varies from 5 - 30 hours, depending

on urine flow and urinary pH.
 CLINICAL USE OF AMPHETAMINES

1. In attention deficit-hyperactive disorder (ADHD): The main use of amphetamines is in

the treatment of ADHD, particularly in children. ADHD is a common condition in
children whose nonstop over-activity and very limited attention span disrupt their
education and social development. Disorders of noradrenaline and dopamine
pathways in the frontal cortex and basal ganglia are thought to underlie ADHD
symptomatology, but the mechanism of action of amphetamine is still unclear.

2. Narcolepsy: This is a rare, disabling condition in which the patient suddenly and
unpredictably falls asleep at frequent intervals during the day, while suffering
insomnia at night. It is often accompanied by cataplexy (abrupt onset of paralysis of
variable extent often triggered by a strong emotion, sometimes with ‘frozen’ posture).
Amphetamine is helpful but not completely effective.

3. Appetite suppression in humans: Amphetamines and similar drugs such as

dexphenfluramine reduce appetite, but are no longer used for this purpose. They are
ineffective in producing maintained weight loss, and have harmful CNS and
cardiovascular side effects, in particular pulmonary hypertension, which can be so
severe as to necessitate heart–lung transplantation.
TOXICITY AND ADVERSE EFFECTS OF AMPHETAMINES
1. Acute intoxication with amphetamine is associated with tremor, confusion,
irritability, hallucinations and paranoid behavior
2. Hypertension and occasionally cardiac arrhythmias
3. Sweating
4. Insomnia
5. Anorexia
6. Tremor
7. Risk of strong psychological dependence and tolerance to stimulant effect
8. Development of ‘amphetamine induced psychosis’ which closely resembles acute
schizophrenic attack after prolonged use
9. Development of repetitive stereotyped behavior
10. Stimulant effect lasts for a few hours and is followed by depression and anxiety.
11. There is evidence that high, chronic doses of the amphetamines can cause
degeneration of dopaminergic neurons, possibly because of the formation of an
endogenous neurotoxin 6-hydroxydopamine
12. Convulsions and death may occur
COCAINE
 Cocaine is a major alkaloid component from the Andean bush
Erythroxylon coca, a south American plant growing on the foothills of the
Andes. The leaves of this plant are chewed by Andean Indians to
decrease the feeling of hunger and fatigue.
 Cocaine acts by binding to and inhibiting the transporters DAT, NET, and
serotonin transporter (SERT), thereby producing a marked psychomotor
stimulant effect, and enhancing the peripheral effects of sympathetic
nerve activity.

 The reinforcing (i.e. dependence-producing) effects of cocaine are

thought to result from its ability to inhibit the reuptake of dopamine and
thereby to increase dopaminergic activity, particularly in the ventral
tegmental area and the nucleus accumbens, so enhancing the activity of
the dopaminergic system in the mesolimbic areas of the brain.
 Pharmacological effects of cocaine
 In humans, cocaine produces euphoria, increased motor activity and a
magnification of pleasure. Users feel alert, energetic and physically
strong and believe they have enhanced mental capabilities. Its effects
resemble those of amphetamines, although it has less tendency to
produce stereotyped behavior, delusions, hallucinations and paranoia.
 When consumed in excess, cocaine triggers tremors and convulsions,
followed by respiratory and vasomotor depression.

 In the periphery, cocaine causes tachycardia, vasoconstriction and an

increase in blood pressure. Body temperature may increase, owing to
the increased motor activity coupled with reduced heat loss.

 Cocaine is still occasionally used topically as a local anesthetic, mainly

in ophthalmology and minor nose and throat surgery, where its local
vasoconstrictor action is an advantage, but has no other clinical uses.
PHARMACOKINETICS

 Cocaine is readily absorbed by many routes.

 When given intravenously, cocaine produces an intense and immediate

euphoria, whereas nasal inhalation produces a less dramatic sensation
and also tends to cause atrophy and necrosis of the nasal mucosa and
septum.

 The duration of its stimulant effect is about 30 min

 It is rapidly metabolized in the liver.

 A cocaine metabolite (benzoylegonine) is deposited in hair, and analysis

of its content along the hair shaft allows the pattern of cocaine
consumption to be monitored. Cocaine exposure in utero can be
estimated from analysis of the hair of neonates.
TOXICITY AND ADVERSE EFFECTS OF COCAINE
1. The most serious toxic effects of cocaine involve changes in the cardiovascular
system. These include cardiac arrhythmias, myocardial ischemia and infarction,
and cerebrovascular spasm, all of which can be largely explained by the facilitation
of the action of catecholamines on the cardiovascular system and the direct
vasoconstrictive properties of its major metabolite, norcocaine.

2. Seizures, probably due to the local anesthetic effects of the drug at toxic doses
can occur, particularly in those predisposed to epilepsy.

3. Anxiety and panic attacks may be associated with high doses of cocaine. These
effects may be associated with paranoid ideation, visual and tactile hallucinations
and visual pseudohallucinations (seeing snow lights)

 There is a poor correlation between the euphoric effects of cocaine and its
cardiotoxicity, so that someone who uses the euphoric effect of the drug to regulate
the dose may be unaware of the cardiovascular toxicity. Thus one of the main
reasons why a cocaine user may die suddenly is the differential psychological and
cardiovascular tolerance
METHYLXANTHINES

 Through non-competitive inhibition of the phosphodiesterase enzyme,

methylxanthines cause an intracellular increase in levels of cAMP and cGMP. This
signals results in bronchial smooth muscle relaxation, vasodilatation, CNS
stimulation and cardiac stimulation .

 Adenosine receptors in the basal forebrain are essential in signaling mental fatigue
to the brain. As adenosine accumulates and increasingly binds its receptors, the
longer one stays awake. Methylxanthines also bind these receptors with nearly
identical affinity to adenosine, and this antagonism is the drug’s primary means of
CNS stimulation.

 Caffeine increases energy metabolism throughout the brain but decreases at the
same time cerebral blood flow, inducing a relative brain hypoperfusion.

 Caffeine also activates noradrenaline neurons and seems to affect the local release
of dopamine.
PHARMACOLOGICAL ACTION OF METHYLXANTHINES
CNS stimulation
1. Caffeine and theophylline are CNS stimulants, primarily affecting the higher centers.
They both have very similar stimulant effects on the CNS. Caffeine 150–250 mg
produces a sense of wellbeing, alertness, beats boredom, relieves fatigue, improves
mental performance without euphoria. It tends to increase motor activity. Caffeine is
more active than theophylline in producing these effects.
2. Higher doses cause nervousness, restlessness, panic attack, insomnia and
excitement.
3. Still higher doses produce tremors, delirium and convulsions.
4. By comparison with amphetamines, methylxanthines produce less locomotor
stimulation and do not induce euphoria, stereotyped behavior patterns or a
psychotic state, but their effects on fatigue and mental function are similar

Peripheral effects
1. Diuresis
2. Stimulation of cardiac muscle
3. Relaxation of smooth muscle, especially bronchial muscle
CLINICAL USES AND ADVERSE EFFECTS OF
METHYLXANTHINES
 Caffeine can be included with aspirin in some preparations for treating headaches
and other aches and pains, and with ergotamine in some antimigraine preparations,
the objective being to produce a mildly agreeable sense of alertness.

 Several methylxanthine derivatives are used for the treatment of reversible airway
obstruction diseases such as chronic bronchitis, emphysema and asthma.

 It is worth noting that that the new GOLD criteria for the treatment of COPD (released
in 2018) relegated methylxanthines from its treatment algorithm due to an
imbalance between benefits and side effects.

 In vitro tests show that theophylline has mutagenic activity, and large doses are
teratogenic in animals. This findings have not been shown in humans.

 Methylxanthines have a narrow therapeutic range, and therefore, a high incidence of

adverse effects

 High doses can cause vomiting, arrhythmias, irregular heartbeat, cardiac arrest,
allergic skin reactions, or seizures.
METHYLPHENIDATE
 Like the amphetamines, methylphenidate inhibits the NET and DAT transporters on
the neuronal plasma membrane (and, with much lower potency, inhibits the 5-HT
transporter, SERT).
 But unlike the amphetamines, methylphenidate is not a substrate for these
transporters and thus does not enter the nerve terminals to facilitate noradrenaline
(NA) and dopamine (DA) release.
 It produces a profound and sustained elevation of extracellular NA and DA.
 It is used in the treatment of ADHD
 Methylphenidate is orally active and is being absorbed from the intestine and colon,
but it undergoes presystemic metabolism such that only ~20% enters the systemic
circulation.
 Absorption is slow following oral administration (it reaches peak level after approx. 2
hours),which may limit the intensity of any euphoric response to the drug.
 It is metabolized by carboxylesterase and has a half life of approx. 2–4 h.
MODAFINIL

 Modafinil is the first FDA-designated "wakefulness-promoting agent." It is

approved by the FDA for the treatment of excessive sleepiness associated
with narcolepsy, shift work sleep disorder, or obstructive sleep apnea.

 It acts by inhibiting dopamine reuptake by binding to DAT and causes a

smaller release of dopamine compared with other stimulants.

 It is claimed to enhance cognitive performance, and is gaining popularity as a

‘lifestyle drug’ for this reason.
 Modafinil is well absorbed from the gut, metabolized in the liver and has a
half-life of 10–14 h.
 The drug appears to be well tolerated, with the most frequent side effects
being headache and nausea.
 Side effects have been found to increase with increasing doses, and very high
doses (800 mg) have been found to be associated with higher rates of
tachycardia and hypertension
 COGNITION ENHANCERS

 Cognition enhancers (cerebroactive drugs) are drugs that are used in the
treatment of psychiatric conditions associated with cognitive impairment, such
as Alzheimer’s disease, schizophrenia, depression and drug addiction, or
(controversially) to make normal people more ‘intelligent’.

 These drugs have the characteristics of:

1. Reducing fatigue (stimulants), thus permitting the user to function for longer
(i.e. perform complex tasks, study for examinations, overcome jet lag)
2. Increasing motivation and concentration
3. Altering memory processing (i.e. enhance memory).

 Cerebroactive drugs may be grouped into:

a. Cholinergic activators: Tacrine, Rivastigmine, Donepezil, Galantamine
b. Glutamate (NMDA) antagonist: Memantine
c. Miscellaneous cerebroactive drugs: Piracetam, Pyritinol (Pyrithioxine),
Dihydroergotoxine (Codergocrine), Citicoline, Piribedil.
PSYCHOTOMIMETIC DRUGS
(HALLUCINOGENS)
 Introduction to Psychotomimetic drugs (Hallucinogens)
 The term hallucinogen is often used to describe a drug that produces a
change in sensory perception, usually either visual or auditory.

 These drugs also affect thought, perception and mood without causing
marked psychomotor stimulation or depression. For this reason they are
sometimes called psychedelic or psychotomimetic drugs.
 The individual under the influence of these drugs is incapable of normal
decision making, because the drug interferes with rational thought.
 Psychomimetic drugs include:

1. Drugs that act on 5-hydroxytryptamine (5-HT) receptors and transporters:

LSD-like (LSD, psilocybin and mescaline) and MDMA (ecstasy)
2. NMDA receptor antagonists: Phencyclidine and ketamine
3. Δ9-Tetrahydrocannabinol (THC) the active ingredient in cannabis which
produces a mixture of psychotomimetic and depressant effects similar to,
but less pronounced than, those of LSD.
LYSERGIC ACID DIETHYLAMIDE (LSD)
 LSD is an ergot alkaloid. It is very potent and produces both CNS and
peripheral effects.
 Lysergic acid diethylamide (LSD) activates the serotonin 5-HT2A receptors on
glutaminergic neurons in the prefrontal cortex, enhancing glutamatergic
transmission, thus making the neurons more excitable.
 Activation of the sympathetic nervous system occurs, which causes pupillary
dilation, increased BP, piloerection (goose bumps), and increased body
temperature.
 The effects of LSD may be observed for 8 hours. During this time, subjects
have impaired ability to make rational judgments and understand common
dangers, which puts them at risk for accidents and personal injury.
 The specific acute effects of LSD include euphoria, depersonalization,
enhanced awareness of sensory input, alterations in the perception of time
or space or body image, and to some extent, minor stimulant effects.
 Sometimes the dreamlike quality of the experience produces relaxation,
good humor, and a sense of wonder or euphoria.
MDMA (ECSTASY)
 Methylenedioxymethamphetamine (MDMA) or ecstasy is an amphetamine-
related compound
 It is a stimulant drug that also has mild hallucinogenic effects.
 It is the prototypic ‘designer drug’ distributed in parties and taken orally.
 MDMA was originally used in some forms of psychotherapy, because its main
effect appears to be to foster feelings of intimacy and empathy without
impairing intellectual capacities.
 It act as a substrate of the monoamine transporters; SERT, NET, DAT,
especially SERT, thereby acting as competitive antagonist of monoamines,
inhibiting their reuptake. It also displaces monoamines from their synaptic
vesicles into the cytosol, and into the synaptic cleft. The net effect being a
large increase in free 5-HT in certain brain regions, followed by depletion.
 The effects on 5-HT function determine the psychotomimetic effects, while
dopamine and noradrenaline changes account for the initial euphoria and
later rebound dysphoria.
 ADVERSE EFFECTS OF MDMA
Although not addictive, MDMA carries serious risks, both acute and long
term.
Short-term
1. Dehydration
2. Cases of life-threatening hyponatremia
have developed in MDMA users
attempting to prevent dehydration by
consuming excessive amounts of water
without replenishing electrolytes
Long-term
1. Neurodegeneration in striatal,
hippocampal, prefrontal and
occipital serotonergic axon
terminals
2. Depression even after cessation

3. Hyperthermia which can be fatal of use

4. Increased heart rate and blood pressure 3. Immunosuppressive effects in the

5. Insomnia peripheral nervous system

6. Increased perspiration and sweating 4. Proinflammatory effects in the

7. Increased psychomotor activity CNS

8. Memory impairment 5. Cardio- and neurotoxic to fetus

9. Anxiety, depression, irritability 6. Withdrawal syndrome

10. Anhedonia, etc
PHENCYCLIDINE AND RELATED COMPOUNDS
 Phencyclidine (PCP or ‘angel dust’) and ketamine produce a feeling of
separation of mind and body (which is why they are called dissociative
anesthetics) .

 The principal mechanism of action is a use-dependent inhibition of NMDA

glutamate receptors. Both PCP and ketamine bind with high affinity to a site
on the NMDA receptor, preventing the movement of calcium ions into the
cell.

 The pronounced effect of PCP on locomotor activity and the psychomimetic

effects may be as a consequence of its facilitatory effects on dopaminergic
transmission, particularly in the mesolimbic regions of the brain.

 They possesses CNS stimulatory actions, and induce a wide variety of

psychotomimetic and hallucinatory effects during emergence from
anesthesia.
ADVERSE EFFECTS
 At low doses, individuals believe they are thinking and acting rapidly and
efficiently. The general mood is happiness

 At higher doses the stimulatory effects are more pronounced and the
likelihood of tremendous mood swings more likely

 At near anesthetic doses, it produces more typical depressant effects,

including motor incoordination, catalepsy, vacant stare, or even amnesia.
Coma is produced subsequent to respiratory depression.

 Tolerance to the effects of phencyclidine develops in both animals and

man.

 Repeated use is associated with serious and persistent toxic effects,

including abdominal pain, ulcerative cystitis (with associated severe
bladder pain), liver damage and cognitive impairment
Δ9-TETRAHYDROCANNABINOL (THC)
 THC is the major psychoactive alkaloid constituent in marijuana. It is an
exogenous cannabinoid.

 THC, like the endogenous cannabinoids anandamide and 2-arachidonyl

glycerol (2-AG), act as neurotransmitters at the presynaptic CB1 receptors.

 These very lipid-soluble compounds are released at the postsynaptic

membrane, and diffuse through the extracellular space to bind at
presynaptic CB1 receptors, where they inhibit the release of either
glutamate or GABA.

 Because of such backward signaling, endocannabinoids are called

retrograde messengers.
PHARMACOLOGICAL EFFECTS
 Smoking a cigarette comprising of 2% THC causes temporal disintegration (i.e.
impairment of the ability to undertake memory-dependent, goal-directed
behaviour). This process is correlated with a tendency to confuse the past,
present and future, and to feel depersonalized.
 There is an enhanced sense of well-being and euphoria, accompanied by a
feeling of relaxation and sleepiness.
 Higher doses are associated with hallucinations, delusions and paranoid ideas;
the sense of depersonalization also becomes more intense.
 Chronic cannabis users frequently exhibit the amotivational syndrome,
characterized by apathy, impaired judgment, memory defects, and loss of
interest in normal social pursuits.
 On the cardiovascular system, THC causes tachycardia, and increased systolic
BP.
 Reddening of the conjunctivae
 Impaired pulmonary function
 In utero exposure causes behavioural abnormalities in childhood
THERAPEUTIC USES OF THC
 Feeling of well-being
 Increased sociability
 Muscle relaxant
 Analgesic effect
 Appetite stimulation
 Antiemetic effect
 Anticonvulsant effect
 Treatment of glaucoma (lowers intraocular pressure)
 Research in mice showed that treatment with purified extract of THC when
used with radiation, increased the cancer-killing effects of the radiation
DRUG DEPENDENCE, ADDICTION
AND SUBSTANCE ABUSE
 DRUG DEPENDENCE
 It is defined as a syndrome in which someone continues to take the drug because
of the reinforcing effect which is derived from it. These drugs produce effects that
are so desirable that the user is motivated to continue taking the drug for his/her
well-being. This leads to a change in the behavior of the dependent person, which
varies from a mild desire to obtain the drug to a craving or compulsion.

 Three factors are generally involved in drug dependence: tolerance, physical

dependence, and psychological dependence.

1. Tolerance: This is a phenomenon whereby an increasing amount of the drug

must be administered to obtain the required pharmacological effect. Tolerance
may occur as a result of the drug being more rapidly metabolized (called
metabolic tolerance) or through a drug-induced insensitivity of the receptors or
target sites upon which it acts within the brain (tissue tolerance).

 Psychological tolerance is the term used to describe the reduction in the desired
psychological effects of the drug.
2. Physical dependence: This describes the phenomenon in which
abnormal behavioral and autonomic symptoms occur when the
drug is abruptly withdrawn or its effects are terminated by the
administration of a specific antagonist.

3. Psychological dependence: It is the subjective feeling that the user

needs the drug to maintain a feeling of well-being.

 Cross-dependence: Cross dependence arises when a drug can

suppress the symptoms of withdrawal due to another drug. For
example, the effects of alcohol withdrawal can be suppressed by the
administration of benzodiazepine. As both drugs enhance
GABAergic neurotransmission, though by different mechanisms, a
benzodiazepine can prevent the withdrawal symptoms that arise
following the abrupt cessation of alcohol.
DRUG ADDICTION
 Addiction can be defined as recurrent substance abuse by individuals who
realize it is harmful to their health but cannot fulfill their desire to stop.
CHARACTERISTICS OF DRUG ADDICTION
DRUG ABUSE
 The term ‘drug abuse’ refers to the use of any drug in a manner which is
at variance with the approved use. This term may also be applied when
a legally obtainable medication is used excessively and for unintended
purposes or is diverted to someone else’s use.

 Non-medical drug use: This term includes the occasional recreational

use of licit and illicit drugs for their pleasurable effects (e.g. the use of
cannabis or amphetamine) and outside their approved medical
indications.
THE MAIN DRUGS OF ABUSE
Type of drug Examples Dependence liability
Narcotic analgesics Morphine Very strong
Diamorphine Very strong
General CNS depressants Ethanol Strong
Barbiturates Strong
Anaesthetics Moderate
Anxiolytics Benzodiazepines Moderate
Psychomotor stimulants Cocaine Very strong
Amphetamine Strong
Nicotine Very strong
Caffeine Weak
Psychotomimetic agents LSD Weak or absent
Mescaline Weak or absent
Phencyclidine Moderate
Cannabis Weak or absent
DRUG USE TERMS AND DESCRIPTIONS
 Street drugs: Drugs that are taken for non-medicinal reasons (usually for
mind-altering effects). E.g. Alcohol, heroin, methamphetamine, cocaine and
marijuana (Cannabis).
 Hard drugs: Drug that are generally considered to be more dangerous, with a
higher risk of dependence. Use of these drugs leads to severe addiction E.g.:
Heroin, cocaine, methamphetamine.
 Soft drugs: While they do not cause physical dependence, some of them may
still lead to psychological dependence. E.g.: LSD, Cannabis
 Illicit drug: An illegal drug which cannot be prescribed. E.g.: Cocaine, heroin,
LSD, marijuana.
 Designer drug: A synthetic drug illicitly produced with the intent of developing
substances that differ slightly in chemical makeup to existing controlled
substances while retaining their pharmacological effects. E.g. MDMA
 Recreational drugs: Recreational drugs are those used for non
medicinal purposes, in particular, for fun or leisure. They are usually
started to provide pleasure, or to improve life in some way. However,
they can lead to addiction, health and social problems and crime.
Most of them are illegal. E.g.: methamphetamine, LSD, MDMA,
cannabis, alcohol, tobacco, etc.
ETHYL ALCOHOL (ETHANOL)
 Ethanol is a clear colorless hydroxylated hydrocarbon that is the product of
fermentation of fruits, grains, or vegetables.
 It is the most important drug of dependence in all industrialized countries.
 Alcohol abuse is defined as a condition whereby social life is impaired for
at least one month as a result of alcohol.

 It is thought that ethanol exerts its desired and toxic effects through
several mechanisms:
1. Enhancing the effects of the inhibitory neurotransmitter GABA via
increase chloride flux through the GABAA receptor and suppression of
glutamate activity via reduction of calcium flux through the NMDA
receptor

2. Inducing the release of endogenous opioids

3. Increases levels of serotonin and dopamine

PHARMACOKINETICS
 Alcohol is readily absorbed from an
empty stomach; the rate of absorption is
impeded by food
 It is widely distributed throughout the
body according to the water content of
the tissue, easily penetrating both the
BBB and placental barriers.
 Normally 90 – 98% of alcohol is
metabolized by alcohol dehydrogenase
to acetaldehyde and then by aldehyde
dehydrogenase to acetate in the liver,
which can be further metabolized to
CO2 and water, or used to form acetyl-
CoA. The remaining 2 – 10% is excreted
unchanged in the urine and expired air.
 Ethanol can also be oxidized to
acetaldehyde by Microsomal Ethanol-
Oxidizing System (MEOS) or the
microsomal mixed function oxidase
system
PHARMACOKINETICS

 The microsomal mixed function oxidase system consists primarily of CYP 2E1,
1A2, and 3A4.

 During chronic alcohol consumption, MEOS activity is induced. As a result,

chronic alcohol consumption results in significant increases not only in
ethanol metabolism but also in the clearance of other drugs eliminated by the
cytochrome P450s that constitute the MEOS system, and in the generation of
the toxic by-products of cytochrome P450 reactions (toxins, free radicals,
H2O2).

 The rate of metabolism depends on the degree of tolerance of the individual.

The non-tolerant person metabolizes approximately 10-15 ml of absolute
alcohol per hour.

 The alcohol metabolizing system is thus easily saturated, and its elimination
is governed by ‘zero-order’ kinetics.
PHARMACOLOGICAL ACTIONS
 CNS effects: Alcohol is primarily a CNS depressant, and the degree of
depression is directly proportional to the quantity of ethanol consumed.
 Behavioral effects: These include slurred speech, motor incoordination,
increased self-confidence and euphoria. The effect on mood varies among
individuals. At higher levels of intoxication, the mood tends to become
highly labile, with euphoria and melancholy, aggression and submission,
often occurring successively.
 Peripheral vasodilation: A moderate amount of ethanol causes peripheral
vasodilation especially of cutaneous vessels.
 Ethanol is a diuretic. This effect may be caused by its ability to inhibit
secretion of antidiuretic hormone from the posterior pituitary, which leads
to a reduction in renal tubular water reabsorption. The large amount of fluid
normally consumed with ethanol also contributes to increased urine
production.
ADVERSE EFFECTS
1. Acute ethanol intoxication: One of the consequences of ethanol intoxication is
the hangover, a condition characterized by headache, nausea, sweating, and
tremor.
2. Hypothermia frequently results, with body temperature falling toward that of the
ambient environment.
3. Immunosuppression
4. Causes irreversible neurological damage
5. Liver cirrhosis
6. Excessive consumption in pregnancy causes impaired fetal development,
associated with small size, abnormal facial development and other physical
abnormalities, and mental retardation. It can also cause spontaneous abortion.
7. Causes psychological dependence, physical dependence and tolerance
8. Sexual dysfunction in male
9. Sudden cessation of ethanol ingestion in a heavy drinker can precipitate
withdrawal symptoms manifested by tachycardia, sweating, tremor, anxiety,
agitation, hallucinations, and convulsions
ALCOHOLISM AND ITS TREATMENT
 Alcoholism is defined as the occurrence of tolerance and dependence that results
from prolonged alcohol abuse. It decreases life expectancy by 10 to 15 years
 Treatment for alcoholism include:
1. Aversion therapy using drugs such as disulfiram. Disulfiram blocks the oxidation of
acetaldehyde to acetate by inhibiting aldehyde dehydrogenase. Thus, acetaldehyde
accumulates in the blood, causing flushing, tachycardia, hyperventilation, and
nausea. This induces the patient to abstain from alcohol to prevent the unpleasant
effects of acetaldehyde accumulation.

 Several other drugs (e.g., metronidazole, cefotetan, trimethoprim) inhibit aldehyde

dehydrogenase and can cause a disulfiram-like reaction if combined with ethanol.

2. Use of Naltrexone, an opioid antagonist. Although the exact mechanism is not

entirely understood, the brain interacts with alcohol in a very similar manner to how
it reacts with opioids, and naltrexone also suppresses the euphoria and
pleasurable sensations of alcohol. Naltrexone can help uncouple alcohol and
pleasure. It is not sufficient when taken alone and so must be taken in concert with
other forms of treatment.
3. Acamprosate: It eases withdrawal symptoms such as insomnia, anxiety,
restlesness, and feeling of sadness/depression that can last for months
after alcohol cessation. Acamprosate works by interacting with and
balancing GABA and glutamate abnormalities in the brain, thus providing
stability.

4. The antiseizure drugs, gabapentin and topiramate also interact with GABA
and glutamate systems. Studies show that they may help peple avoid
drinking, drink less, and have fewer cravings.
ALCOHOL POISONING
 Alcohol poisoning is a serious and sometimes deadly consequence of
consuming large amounts of alcohol, usually over a short period. This result
to a very high blood alcohol level which is considered toxic.
 Symptoms include vomiting, extreme confusion, hypothermia,
unresponsiveness, and shallow breathing
 In serious cases, seizures may occur, heart attack may occur, breathing
might stop completely, severe dehydration, hypothermia, hypoglycaemia
and the person may choke on their own vomit, the vomit might be inhaled
into the lungs causing a serious infection.
 Pharmacological antidotes of alcohol poisoning include:
1. Fomepizole: competitively antagonizes ethanol, has greater affinity for
alcohol dehydrogenase than ethanol and has a considerably better safety
profile than ethanol.
2. B vitamins (thiamine, pyridoxine): they favor the formation of less toxic
metabolites.
NICOTINE
 Exposure to nicotine occurs mainly through smoking, chewing and snuffing of
tobacco. It is one of the most addictive drugs.
 Nicotine is a selective agonist of the nicotinic acetylcholine receptor (nAChR) that
is normally activated by acetylcholine.

 nAChRs are found in limbic system (e.g. striatum, hippocampus, accumbens),

midbrain (e.g. VTA, substantia nigra), various cortical areas (frontal lobe)
 One of the most prominent effect of nicotine is stimulated release of dopamine,
accounting for its rewarding effect.

 nAChRs are expressed on dopamine neurons in the VTA, when nicotine excites
projection neurons, dopamine is released particularly in the nucleus accumbens,
which is a major component of the reward system.
 Nicotine also stimulates the release of endogenous opioids and glucocorticoids.
PHARMACOKINETICS
 Nicotine is readily absorbed from all over the body, including Lungs
(smoked), Mucosa (cigar, chewing tobacco, gum, nasal spray), Skin (patch)
and Gastrointestinal tract (uncommon)
 Nicotine is majorly absorbed into the bloodstream through inhalation.
Nicotine taken in by cigarette or cigar smoking takes only 10-15 seconds to
reach the brain but has a direct effect on the body for only approximately
30 minutes
 A typical cigarette contains 20 mg of nicotine and approximately 2.5 mg of
it is absorbed
 Half-life is about 2 hours
 About 80-90% metabolized in the liver by CYP2A6
 Nicotine is also metabolized in the lungs to cotinine and nicotine-N-oxide.
Cotinine and the remaining nicotine is filtered from the blood by the kidneys
and excreted in the urine
 Studies have shown that something in cigarette smoke seems to slow the
metabolism of dopamine by affecting MAO levels
PHARMACOLOGICAL EFFECTS OF NICOTINE

Acute effects
 Classic stimulant effects of arousal (e.g. increased heart rate and blood
pressure, alertness, appetite suppression)
 Carbon monoxide (in smoked form) reduces oxygen transport to heart and
other organs
 Vasoconstriction
 Can have calming (anxiolytic) effects in some individuals
 Mild euphoria
 Cognitive enhancements
 Antidepressant effects
Positive effects
1. In Alzheimer's disease, patients showed increased
capacity for learning verbal material when exposed to
nicotine. This is due to the fact that nicotine activates
receptors for the neurotransmitter acetylcholine.
Nicotine has also been shown to enhance connections
between sets of neurons in the prefrontal cortex.

2. Nicotine has been shown to reduce symptoms in

teenagers and adults with ADHD and Tourette's
Syndrome.
CHRONIC EFFECTS

1. Chronic obstructive pulmonary disease (COPD)

2. Tobacco smoking increases the risk of cancer, particularly of the lung and upper
respiratory tract. It can also cause cancer of the esophagus, pancreas and bladder.
The tar produced from the smoke is responsible for the cancer.
3. Coronary heart disease and other forms of peripheral vascular diseases (e.g.
stroke). It is estimated that nearly one-fifth of deaths from heart disease are
attributable to smoking

4. In pregnancy: Smoking, particularly during the latter half of pregnancy, significantly

reduces birth weight and increases perinatal mortality. Other effects on pregnancy
include spontaneous abortion, premature delivery and placenta previa.

 There is also evidence that children born to smoking mothers remain behind, in both
physical and mental development, for at least 7 years. By 11 years of age, the
difference is no longer significant.
5. On the new born: Nicotine is excreted in breast milk in sufficient amounts to cause
tachycardia in the infant.
SECONDARY (PASSIVE) SMOKE

 Passive smoke also increases the risk for many diseases

 Secondhand smoke is estimated to cause approximately 3,000 lung

cancer deaths per year among nonsmokers and contributes to as
many as 40,000 deaths related to cardiovascular disease
 Exposure to tobacco smoke in the home increases the severity of
asthma for children and is a risk factor for new cases of childhood
asthma
 Environmental tobacco smoke exposure has been linked also with
sudden infant death syndrome
DEATH BY CIGARETTE 2005-2009
NICOTINE ADDICTION AND TREATMENT
1. Nicotine replacement therapy (NRT):
a. Nicotine transdermal patch systems
b. Nicotine nasal spray
c. Nicotine delivery through the oral mucosa

 This is the most common medication used in the treatment of nicotine

addiction. Its main mechanism of action is to partially replace the nicotine
formerly obtained from tobacco smoking. This aids smoking cessation by
reducing the severity of withdrawal symptoms and cravings and also
reduces the reinforcing effects of nicotine delivered via tobacco while
providing an alternative source.

 Common adverse events common to NRT products include dizziness,

nausea and headache
 Non-nicotine therapies

I. Bupropion is an antidepressant that exert its effect mainly by inhibiting

dopamine reuptake in the nucleus accumbens via inhibition of DAT.

 This, reduces dopamine deficiency experienced in nicotine withdrawal and

explains the attenuating effect bupropion has on nicotine withdrawal
symptoms.

 It is most effective when combined with behavioral therapies.

 Bupropion has also been shown to possess weak nicotinic antagonistic

activity, which may contribute to its effect.

 The most common adverse effects with bupropion are insomnia and dry
mouth.
II. Varenicline is the first new prescription drug for smoking
cessation.

 It is a partial agonist selective for α4β2 subunit of nAChRs on

dopamine neurons in the VTA of the brain. It partially stimulates the
receptors without creating the full effect of nicotine and blocks the
receptors, thus preventing nicotine from binding.

 These effects provide relief from the cravings and withdrawal

symptoms experienced by smokers during an attempt to stop
smoking.

 Varenicline is generally well tolerated, with the most commonly

reported adverse effects being nausea, insomnia, GI upsets and
headache.
III. Nortriptyline: it’s a 2nd generation antidepressant used in the
treatment of major depression.

 It has been administered as a second-line agent in smoking

cessation studies.

 Its therapeutic effect on tobacco dependence is due to its

antidepressant action, its nicotine receptor antagonist activity
and its ability to replace nicotine on noradrenergic receptors,
although no studies have been carried out to validate these
claims.

 Potential adverse effects of nortriptyline include sedation,

dizziness, insomnia, blurred vision, constipation and nausea.
IV. Clonidine: It is an antihypertensive drug also shown to be
effective in reducing symptoms of nicotine withdrawal, and
for this reason is listed as second-line tobacco cessation
drug.

 It is believed that clonidine’s efficacy for smoking cessation

is based on its ability to counteract CNS features of nicotine
withdrawal, including craving and anxiety.

 Adverse effects of clonidine include dose-dependent

sedation, hypotension, dry mouth and constipation
Final word on drug addiction......
DEVELOPMENTAL
PSYCHOPHARMACOLOGY
NEURODEVELOPMENTAL DISORDERS
 Neurodevelopmental disorders (NDDs), according to the Diagnostic
and Statistical Manual of Mental Disorders 5th edition (DSM-5), are
defined as a group of conditions with onset in the developmental
period, inducing deficits that produce impairments of functioning.

 They are characterized by early-onset deficits of variable severity in

personal, social, academic, or occupational functioning.

 In other words, they are a group of disorders that perturbs the

development of the CNS, leading to disabilities associated primarily
with the functioning of the neurological system and brain.

 These disabilities can manifest as neuropsychiatric problems or

impaired motor function, learning, language or non-verbal
communication.
 While the symptoms and behaviors of neurodevelopmental disabilities
often change or evolve during growth, some disabilities are
permanent.

 NDDs include:

1. Attention deficit hyperactive disorder (ADHD)

2. Autism spectrum disorder (ASD)
3. Fetal Alcohol Spectrum disorder (FASD)
4. Intellectual disability (ID)
5. Learning disorders
6. Conduct disorders
7. Communication disorders
8. Neurodevelopmental motor disorders (Tic disorders)

 Diagnosis and treatment of these disorders can be difficult; treatment

often involves a combination of professional therapy, pharmaceuticals,
and home- and school-based programs.
CAUSES OF NDDS
1. Genetics: NDDs arising from rare genetic mutations in a complex of proteins
(e.g. SWI/SNF complex, which is involved in DNA regulation), can cause
atypical cognitive function, intellectual disability, and developmental delays

2. Fetal exposure to smoking, alcohol, illicit drugs, or medications during

pregnancy.

3. Exposure to environmental contaminants such as lead, methylmercury,

polychlorinated biphenyls (PCBs), organophosphate pesticides, polycyclic
aromatic hydrocarbons, arsenic, etc.

4. Low socioeconomic status

5. Preterm birth and low birth weight

 However, most NDDs have complex and multiple contributors rather than any
one clear cause. These disorders likely result from a combination of genetic,
biological, psychosocial and environmental risk factors.
ATTENTION-DEFICIT HYPERACTIVITY DISORDER
 Attention-deficit/hyperactivity disorder (ADHD) is a disruptive behavioral
disorder characterized by symptoms of inattention and/or hyperactivity-
impulsivity, occurring in several settings and more frequently and
severely than is typical for other individuals in the same stage of
development.

 Three major types of ADHD include the following:

 ADHD, combined type. This, the most common type of ADHD, is
characterized by impulsive and hyperactive behaviors as well as
inattention and distractibility.
 ADHD, impulsive/hyperactive type. This, the least common type of
ADHD, is characterized by impulsive and hyperactive behaviors without
inattention and distractibility.
 ADHD, inattentive and distractible type. This type of ADHD is
characterized predominately by inattention and distractibility without
hyperactivity.
CHARACTERISTICS OF ADHD
In children
1. impairments in several areas of executive functioning such as
working memory, planning, response inhibition and cognitive
flexibility.

2. Inattention:
 Short attention span for age (difficulty sustaining attention)

 Difficulty listening to others

 Difficulty attending to details

 Easily distracted

 Forgetfulness

 Poor organizational skills for age

 Poor study skills for age

3. Impulsivity:
 Often interrupts others

 Has difficulty waiting for his or her turn in school and/or social
games
 Tends to blurt out answers instead of waiting to be called upon

 Takes frequent risks, and often without thinking before acting

4. Hyperactivity:
 Seems to be in constant motion; runs or climbs, at times with no
apparent goal except motion
 Has difficulty remaining in his/her seat even when it is expected

 Fidgets with hands or squirms when in his or her seat; fidgeting

excessively
 Talks excessively and has difficulty engaging in quiet activities

 Loses or forgets things repeatedly and often

 Inability to stay on task; shifts from one task to another without

bringing any to completion
In adults
1. Impulsiveness
2. Disorganization and problems prioritizing
3. Poor time management skills
4. Problems focusing on a task
5. Trouble multitasking
6. Excessive activity or restlessness
7. Poor planning
8. Low frustration tolerance
9. Frequent mood swings
10. Problems following through and completing tasks
11. Hot temper
12. Trouble coping with stress
CAUSES OF ADHD
1. Genetics
2. Maternal mental health and drug use (smoking, alcohol use)
3. Stress
4. Preterm birth and low birth weight
5. Psychosocial adversity (such as low socioeconomic status and in-home
conflict) in childhood.
6. Environmental contaminants (lead, PCBs)
7. Brain function and structure: Studies involving brain scans have suggested
that certain areas of the brain may be smaller in people with ADHD,
whereas other areas may be larger. Also, studies have suggested that
people with ADHD may have an imbalance in the level of neurotransmitters
in the brain, or that these neurotransmitters may not be functioning
properly.
 While uncertainties remain, findings to date indicate that ADHD is caused by
combinations of genetic and environmental factors.
 PHARMACOLOGICAL THERAPIES FOR ADHD
1. CNS stimulants: They are used for their ability to balance chemicals in the
brain that prohibit the child from maintaining attention and controlling
impulses. They help "stimulate" or help the brain to focus and may be used
to reduce the major characteristics of ADHD.
Medications that are commonly used to treat ADHD include the following:

i. Methylphenidate: of the variety of CNS stimulants available, methylphenidate is the

most effective. Its effects are also immediate
ii. Dextroamphetamine
iii. Pemoline: it is long-lasting and has more stable plasma levels than methylphenidate
and dextroamphetamine
iv. Atomoxetine: it’s a non-stimulant selective serotonin norepinephrine reuptake
inhibitor medication with benefits for related mood symptoms.
v. Lisdexamfetamine: it’s a substituted amphetamine and a prodrug of
dextroamphetamine

2. Tricyclic antidepressants (TCAs) such as imipramine and desipramine.

 Side effects of TCAs include: dry mouth, tachycardia and increases in blood
pressure.
SIDE EFFECTS OF CNS STIMULANTS IN ADHD THERAPY
i. Initial functional symptoms such as sleeplessness, appetite suppression,
headaches, and abdominal pain. These symptoms usually settle down
fairly quickly, and at worse often respond to dose adjustments

ii. Growth retardation

iii. Occasionally, tics and stereotyped movement disorders have been

associated with long-term stimulant medication

iv. Risk of epilepsy (dextroamphetamine is preferred because it is less

epileptogenic).

v. Perseverative thinking

vi. Decreased cognitive flexibility

vii. Dysphoria (particularly in brain-damaged subjects)

viii. Changes in heart rate and blood pressure

 AUTISM SPECTRUM DISORDERS
 Autism spectrum disorders (ASDs) are a group of developmental disabilities
defined by significant social, communication, and behavioral impairments.

 The term “spectrum disorders” refers to the fact that although people with
ASDs share some common symptoms, ASDs affect different people in
different ways, with some experiencing very mild symptoms and others
experiencing severe symptoms.

 Children with ASDs may lack interest in other people, have trouble showing
or talking about feelings, and avoid or resist physical contact.

Symptoms of ASD
The symptoms of ASD generally appear between the ages of 2 to 3 years.
1. A range of communication problems are seen in children with ASDs: some
speak very well, while many children with an ASD do not speak at all.

2. Demonstration of restrictive or repetitive interests or behaviors, such as

lining up toys, flapping hands, rocking his or her body, or spinning in circles
 CAUSES OF ASD
 To date, no single risk factor sufficient to cause ASD has been identified; rather each
case is likely to be caused by the combination of multiple genetic and environmental risk
factors
1. Environmental contaminants such as pesticides, mercury and mercury-containing
substances (e.g., thimerosal, a mercury-containing preservative that is used in some
vaccines to prevent contamination and growth of harmful bacteria in vaccine vials),
traffic air pollutants, polyvinyl chloride (PVC) flooring
2. de novo mutations, meaning that the genetic defect is not present in either of the
parents’ genes, yet can be found in the genes of the child when a new genetic mutation
forms in a parent’s germ cells (egg or sperm), potentially from exposure to
contaminants
3. Many studies have linked increasing paternal and maternal age with increased risk of
ASDs. The role of parental age in increased autism risk might be explained by evidence
that shows advanced parental age can contribute significantly to the frequency of de
novo mutations in a parent’s germ cells. Advanced parental age signifies a longer
period of time when environmental exposures may act on germ cells and cause DNA
damage and de novo mutations.
4. A recent study concluded that the role of genetic factors in ASDs has been
overestimated, and that environmental factors play a greater role than genetic factors
in contributing to autism
PHARMACOLOGICAL THERAPIES FOR ASD
 Behavioural therapy is usually the first-line treatment.

 Pharmacological approach to is usually based on treatment of the

symptoms.
A. Treatment of irritability and aggression
1. Risperidone: a second generation antipsychotic, was the first drug
approved by the Food and Drug Administration (FDA) to treat autism-related
irritability
2. Aripiprazole
3. Clozapine
4. Haloperidol
5. Sertraline

B. Treatment of aberrant social behaviour

1. Risperidone and haloperidol
2. Oxytocin
3. Secretin
 FETAL ALCOHOL SPECTRUM (FASD)
 These are a group of conditions associated with physical, behavioural and
learning problems which may range from mild to severe.
 There are 3 types of FASDs:
 Fetal alcohol syndrome (FAS),
 Alcohol-related neurodevelopmental disorder (ARND)
 Alcohol-related birth defect (ARBD)

 The only way to prevent FASD is for a woman not to take alcohol during
pregnancy.
 However, there is no cure for FASD, but researches show that early
intervention/treatment services can improve a child’s development.

 Signs and symptoms of FASDs:

 A small head, a smooth ridge between the upper lip and nose, small and wide
set of eyes, a very thin upper lip as well as other irregular facial features.
 Other features includes:
 Hyperactivity , under weight and below average height, lack of focus and
poor coordination.

 FASD is also considered as a brain related disorder. To date there is no

proven research that the damage done by alcohol can be reserved.

 Pharmacological management of FASD symptoms:

 Stimulants
 Antidepressants
 Neuroleptics (antipsychotics)
 Anxiolytics

 It is worthy of note that these medications can affect each child differently,
one medication might work well for one child but not for another.
C. Treatment of hyperactivity and inattention
1. Methylphenidate
2. Venlafacine

D. Treatment of repetitive behaviors

1. Fluoxetine
2. Citalopram
3. Bumetanide

E. Treatment of cognitive disorders

1. Memantine
2. Rivastigmine

F. Treatment of insomnia
1. Melantonin
2. Mirtazapine
CONDUCT DISORDERS
 Conduct disorders typically present with various mixtures of symptoms such as
defiance, disobedience, tantrums, fighting, destructiveness, stealing and lying.

 While the symptoms may be situationally specific (to either home or school), in
pervasive form they predict potentially serious outcomes, as reflected in
increases in later psychiatric disorders, poor marital adjustment, poor job
histories, deficient parenting skills, and higher rates of premature death.

 Causes of conduct disorders include genetic, environmental factors and drug

and alcohol abuse.

 Drugs used for treatment of conduct disorders are mainly for the control of
difficult aggressive behaviour. They are:

1. Neuroleptics: such as chlorpromazine, thioridazine and haloperidol

2. Anti-epileptic drugs such as carbamezapine due to its sedative property
3. Propranolol
4. Lithium
 INTELLECTUAL DISABILITY (MENTAL RETARDATION)
 Intellectual disability (also called mental retardation) is a descriptive term for sub-
average intelligence usually defined as an IQ less than 70 and impairments in life
skills such as communication, self-care, home living, and social or interpersonal
skills.
 People with intellectual disabilities can learn new skills, but they learn them more
slowly.
 Some causes of intellectual disability include
1. Genetic disorders
2. Traumatic injuries
3. Prenatal events such as maternal infection or exposure to alcohol
4. Exposure to environmental contaminants such as lead, mercury, PCBs and
organophosphate pesticides
 The causes are more frequently identified for cases of severe retardation (IQ less
than 50), whereas the cause of mild retardation (IQ between 50 and 70) is
unknown in more than 75% of cases.
 Antipsychotics, e.g. risperidone are the most prescribed drugs for intellectual
disability
LEARNING DISABILITY
 Learning disability (or learning disorder) is a general term for a neurological
disorder that affects the way in which a child’s brain can receive, process,
retain, and respond to information.
 A child with a learning disability may have trouble learning and using certain
skills, including reading, writing, listening, speaking, reasoning, and doing math,
although learning disabilities vary from child to child.
Causes
1. As with many other neurodevelopmental disorders, the causes of learning
disabilities are not well understood. Often learning disabilities run in the family,
suggesting that heredity may play a role in their development.
2. Drug or alcohol use during pregnancy, low birth weight, lack of oxygen, or
premature or prolonged labor
3. Environmental contaminants such as lead, childhood exposure to
environmental tobacco smoke, prenatal mercury and PCB exposure
 The most common treatment for learning disorder is special education.
 Children with specific learning disorder sometimes have other conditions such
as ADHD or anxiety disorders, and so should be treated accordingly.
 SEDATIVE-HYPNOTIC
DRUGS
Drugs that reduce anxiety and cause sleep
Sedative: A drug that subdues excitement and calms the subject without
inducing sleep, though drowsiness may be produced.
Sedation refers to decreased responsiveness to any level of stimulation. It is
associated with some decrease in motor activity and ideation.
For a drug to be classified as an effective sedative, it should reduce anxiety
(anxiolytic) and exert a calming effect. The degree of central nervous system
(CNS) depression caused by a sedative should be the minimum consistent
with therapeutic efficacy.

Hypnotic: A drug that induces and/or maintains sleep, similar to normal

arousable sleep. A hypnotic drug should produce drowsiness and encourag
e the onset and maintenance of a state of sleep.
Hypnotic effects involve more pronounced depression of the CNS than
sedation.
 ANXIETY
• Anxiety is a fear response characterized by defensive behaviours, autonomic refle
xes, arousal and alertness, corticosteroid secretion and negative emotions which o
ccur in an anticipatory manner, independent of external events.
• Anxiety disorders recognized clinically include the following:
1. Generalized anxiety disorder: This is an ongoing state of excessive anxiety lackin
g any clear reason or focus.
2. Social anxiety disorder: Fear of being with and interacting with other people)
3. Phobias: Extreme or irrational fears of specific objects or situations, e.g. spiders, f
lying, blood, etc.
4. Panic disorder: Sudden attacks of overwhelming fear that occur in association wit
h marked somatic symptoms, such as sweating, tachycardia, chest pains, tremblin
g and choking.
5. Post-traumatic stress disorder: Anxiety triggered by recall of past stressful or trau
matic experiences such as sexual assault, war, etc.
6. Obsessive–compulsive disorder: An anxiety disorder in which time people have
compulsive ritualistic behaviour (obsessions) that make them feel driven to do so
mething repetitively (compulsions) e.g. frequent hand washing due to fear of cont
amination or dirt, following a strict routine, etc.
DRUGS FOR ANXIETY DISORDERS (ANXIOLYTICS)
 BARBITURATES

• Barbiturates have been popular hypnotics and sedatives of the

last century up to 1960s, but are not used now to promote sleep
or to calm patients due to their adverse effects.

• However, they are described first because they are the

prototype of CNS depressants.

• They are classified as long acting, short acting, ultra-short

acting.

• Long acting: Phenobarbitone

• Short acting: Butobarbitone, Pentobarbitone
• Ultra-short acting: Thiopentone, Methohexitone
 MECHANISM OF ACTION OF BARBITURATES
• Barbiturates binds to GABAA ionotropic
receptors and potentiate GABAergic
inhibition by increasing the lifetime of Cl¯
channel opening induced by GABA.
• They do not bind to the Benzodiazepine
receptor site, but bind to another site on
the same macromolecular complex to exert
their action. They also enhance
Benzodiazepine binding to its receptor.
• At high concentrations, barbiturates
directly increase Cl¯ conductance, inhibit
Ca2+ dependent release of
neurotransmitters and depress voltage
sensitive Na+ and K+ channels as well.

• In addition they depress glutamate

induced neuronal depolarization through
AMPA receptors (a type of excitatory
amino acid receptors).
 PHARMACOLOGICAL ACTIONS OF BARBITURATES
1. CNS effects
i. Barbiturates produce dose-dependent effects: sedation → sleep →
anaesthesia → coma.
ii. They have hypnotic and sedative properties, however, they do not have
selective anti-anxiety action.
iii. Barbiturates have anticonvulsant property
iv. They have no analgesic action
2. Other effects
i. Respiratory effects: Respiration is depressed by relatively higher doses.
ii. Cardiovascular: Hypnotic doses of barbiturates produce a slight decrease in
BP and heart rate. Toxic doses produce marked fall in BP due to vasomotor
center depression, ganglionic blockade and direct decrease in cardiac
contractility
iii. Kidney: Barbiturates tend to reduce urine flow by decreasing BP and
increasing antidiuretic hormone (ADH) release.
iv. Smooth muscles: Bowel smooth muscles tone and motility is decreased
slightly by hypnotic doses
 THERAPEUTIC USES
1. Except for phenobarbitone
in epilepsy and thiopentone
in anaesthesia no other
barbiturate is used now. As
hypnotic and anxiolytic they
have been superseded by
benzodiazepines.
2. They are occasionally
employed as adjuvants in
psychosomatic disorders.
ADVERSE EFFECTS
(i) Abuse liability: They are
potent inducers of hepatic CYP
enzymes, this causes tolerance.
(ii) Overdose causes respiratory
depression
(iii) Idiosyncrasy: In an
occasional patient barbiturates
produce excitement. This is
more common in the elderly.
(iv) Hypersensitivity: Rashes,
swelling of eyelids, lips, etc
 BENZODIAZEPINES (BZD)
Chlordiazepoxide and diazepam were introduced around 1960 as antianxiety d
rugs. Since then this class has replaced barbiturates as hypnotic and sedative a
s well, because:
1.BZDs produce a lower degree of neuronal depression than barbiturates. They
have a high therapeutic index.
2.Hypnotic doses do not affect respiration or cardiovascular functions. Higher
doses produce mild respiratory depression and hypotension which is problem
atic only in patients with respiratory insufficiency or cardiac/haemodynamic a
bnormality.
3.BZDs have practically no action on other body systems. Only on i.v. injection
the BP falls and cardiac contractility decreases.
4.BZDs cause less distortion of sleep architecture; rebound phenomena on disc
ontinuation of regular use are less marked.
5.BZDs do not alter disposition of other drugs by microsomal enzyme inductio
n.
6.They have lower abuse liability
7.A specific BZD antagonist flumazenil is available which can be used in case of
poisoning
 MECHANISM OF ACTION OF BZDS
• BZDs bind to specific BZD receptor
which is an integral part of the GABAA
receptor–Cl¯ channel complex.

• They enhance the response to GABA b

y facilitating the opening of GABA-
activated Cl- channels

• Increase Cl- influx causes hyper-

polarization of post-synaptic cell mem
brane and a decrease in initiation of
action potentials by excitatory stimuli

• The BZDs also enhance GABA binding

to GABAA receptor.
 PHARMACOLOGICAL ACTIONS OF BZDS

• Sedation – calming effect: BZDs decrease excitement and moderates

hyperexcitability. Just like barbiturates, benzodiazepines produce
dose-dependent effects: sedation → hypnosis → anaesthesia → coma.
• Hypnotic (sleep-inducing): BZDs induce drowsiness and the promotion and
maintenance of sleep. They relieve insomnia in two ways: (i) they decrease
sleep latency, and (ii) increase total sleep time
• Anxiolytic (anti-anxiety)
• Anticonvulsant
• Skeletal muscle relaxation – via inhibition of inter-neuronal activity in
the spinal cord; Diazepam inhibits monosynaptic reflex pathways
without inducing sedation; other BZDs do so with CNS depression
• Amnesic: (promotes forgetfulness)
THERAPEUTIC USES Duration of
BZDs Clinical uses
OF BZDS action
Short-acting
Clorazepate AD, Seizures 3-8 hours
• Anxiety disorders (AD) Midazolam Pre-anesthetic 3-8 hours
• (Panic/ Generalized anxiety Triazolam Insomnia 3-8 hours
disorder)
• Agitation Intermediate-acting
Alprazolam Anxiety disorders 11-20 hrs
• Insomnia
Lorazepam AD, Anesthesia 11-20 hrs
• Seizures Temazepam Insomnia 11-20 hrs
• Muscle spasms (MS)
• Alcohol withdrawal (AW) Long-acting
• Pre-anesthetic medication Chlordiazepoxide Alcohol Withdrawal 1-3 days
Clonazepam Seizures 1-3 days
(PM)
Diazepam AD, MS, AW 1-3 days
• Anesthetic medication for Flurazepam Insomnia 1-3 days
induction and maintenance
of anesthesia Antagonist
Flumazenil BZD overdose; Reversal ≈ 1 hr; onset
of sedative effects =1-2 min. peak=
6-10 min.
Given I.V.
 PHARMACOKINETICS
• BZDs are lipophilic, rapid in action and
• completely absorbed
• They are administered via oral, I.M or I.V.
routes
• They are metabolized by hepatic P450
• enzymes (specifically CYP3A4)
• They are excreted in the urine as glucuronides
or oxidized metabolites

Drug interaction potentials:

1. CYP3A4 Inducers (e.g., rifampicin,
omeprazole) decrease BZDs effectiveness
2. CYP3A4 Inhibitors (e.g., macrolide
antibiotics, ketoconazole,) increase BZDs
effectiveness
.. In the elderly /Very Young and patients wit
h impaired liver function , there is an
increase in BZDs effectiveness

 Lorazepam: metabolized in liver and

 kidney; preferred in treating alcohol with
drawal if hepatic dysfunction is an issue.
 ADVERSE EFFECTS OF BZDS
1. General effects
 Sedation, light-headedness, ataxia, lethargy.
 Anterograde amnesia (impaired ability create new memories, leading to
inability to recall recent past memories )
 Paradoxical CNS stimulation : Hyperactivity, irritability & aggressivenes
s
 Hangover: daytime sedation and performance impairment

2. Drug-dependence liability
 Tolerance develops after 2-4 weeks of continuous use
 Physical dependence with autonomic withdrawal symptoms
 Rebound anxiety or insomnia – characterized by increased wakefulness
(may last for 1-2 nights after abrupt stoppage of BZDs with short or inter
mediate half-lives)

3. Drug interactions
 Potentiates CNS depressant effects of alcohol, antihistamines, antipsych
otics, antidepressants and opioids
 Elimination half-life prolonged by CYP3A4 inhibitors
 NON-BENZODIAZEPINE HYPNOTICS
BZD RECEPTOR AGONISTS MELATONIN RECEPTOR AGONISTS,
(Z-HYNOTICS: ZALEPLON, ZOLPIDEM & ESZOPICLONE) E.G., RAMELTEON

• Also called Z-drugs.  Ramelteron activates Melatonin type 1 (M

T1) and Melatonin type 2 (MT2) Receptors.
• They are part of a larger category known
as nonbenzodiazepines (in that they lack
the defining fused benzene and diazepin  Activation of these receptors induces sleep
e rings of benzodiazepines via decreasing the activity of
Suprachiasmatic nucleus (the circadian pace
• Binds to GABAA, causing potentiation of
maker or “master clock”) of hypothalamus
GABA at specific receptor subtypes
• They have sedative; devoid of anticonvu  They are devoid of rebound insomnia, tole
lsant, anxiolytic, or muscle relaxant effe rance, or withdrawal symptoms
cts

Side effects: headache and dizziness (dose- Side effect: headache, lethargy, dizziness, and
related); chest pain and anti-cholinergic e somnolence
ffects (Zaleplon and Eszopiclone)
• Eszopiclone – unpleasant taste

• Relatively devoid of tolerance & withdr

awal symptoms at normal doses
 NON-BENZODIAZEPINE ANXIOLYTICS
BUSPIRONE
(A PARTIAL AGONIST AT 5-HT1A RECEPTORS)
• Alternative to BZDs for long-term ther
apy of generalized anxiety; does not pr
oduce rebound effect after discontinua
tion
• Partial agonist at 5-HT1A receptor; mod
erate affinity for D2 receptors
• No physical or psychological depende
nce
• Delayed onset of action (several weeks
to be seen); not good for acute anxiety
attacks
• Adverse effects: dizziness, drowsiness,
dry mouth, headache muscle spasm, &
lightheadedness
PROPRANOLOL
(A βeta-ADRENERGIC RECEPTOR
ANTAGONIST)
 Useful in “stage fright” or performance a
nxiety
 Act by suppressing somatic and autonom
ic (but not emotional) symptoms of
anxiety
 Decrease central sympathetic drive to
peripheral organs
 Clonidine, an α2-adrenergic autoreceptor
agonist also act centrally to decrease sym
pathetic drive, producing anxiolytic prop
erties
EPILEPSY
INTRODUCTION TO EPILEPSY
 Epilepsy is a chronic disease, in which seizures result from the abnormal
high-frequency discharge of a group of neurons, starting focally and
spreading to a varying extent to affect other parts of the brain.

 Classification of seizures according to the focus and spread of discharges:

 Partial (focal) – which originate at a specific focus and do not spread to
involve other cortical areas. The effect on the body of focal seizures depends
on the location of the abnormal signal focus: e.g. involvement of the motor
cortex will produce convulsions whereas involvement of the brainstem can
produce unconsciousness. They also present with convulsive or tonic activity
corresponding to the neurons involved, e.g. the left arm.

 Generalized – which usually have a focus (often in the temporal lobe) and
then spread to other areas. It is associated with loss of consciousness, and it
may be convulsive or non-convulsive. It also results from a partial seizure with
cortical activity localized to the temporal lobe. Such seizures are
characterized by features including impaired consciousness or confusion,
amnesia, emotional instability, atypical behaviour and outbursts.
COMMON TYPES OF EPILEPTIC SYNDROME
 Tonic-clonic (grand-mal seizures) – convulsive generalized seizure
characterized by periods of tonic muscle rigidity followed later by jerking of
the body (clonus).

 Absence (petit-mal seizures) – generalized seizures characterized by changes

in consciousness lasting less than 10 seconds. They occur most commonly in
children, where they can be confused with daydreaming.

 Another type of epileptic syndrome is status epilepticus. This is a state in

which fits follow each other without consciousness being regained. Status
epilepticus constitutes a medical emergency because of possible exhaustion
of vital centres.
CAUSES OF EPILEPSY
 The aetiology of epilepsy is unknown in 60–70% of cases, but heredity is an
important factor. Damage to the brain – for example, by tumours, head injury,
infections or cerebrovascular accident – may subsequently cause epilepsy.

 The neurochemical basis of the abnormal discharges involves altered GABA

metabolism.

 Treatment of epilepsy
 Drugs used to treat epilepsy are termed antiepileptics; the term
anticonvulsant is also used.

 The aim of pharmacological treatment of epilepsy is to minimize seizure

activity/frequency, without producing adverse drug effects.
 MECHANISMS OF ACTION OF ANTIEPILEPTICS
1.. Inhibition of ionic channels involved in neuronal excitability
 Drugs such as phenytoin, carbamazepine and valproate inhibit the ‘fast’
sodium current. These drugs bind preferentially to inactivated (closed)
sodium channels, preventing them from opening.
2. Inhibition of excitatory transmission
 Drugs such as Lamotrigine, inhibits the release of glutamate.

3. Enhancement of GABA-mediated inhibition: This can take any of the following

forms:
 Enhancement by direct GABA agonist properties, e.g. by gabapentin (which mimic GABA),

 Potentiation of chloride currents through the GABAA/Cl– channel complex, e.g. by

benzodiazepines and barbiturates. The increased postsynaptic inhibitory chloride current at
GABAA receptors, hyperpolarizes neurons and makes them refractory to excitation.

 Inhibition of GABA degradation in the CNS, e.g. by vigabatrin, which is an irreversible inhibitor of
GABA transaminase (GABAT), the enzyme normally responsible for metabolism of GABA in the
neuron. Inhibition of GABAT, therefore, leads to an increase in synaptic levels of GABA and so
enhances GABA mediated inhibition.
ANTIEPILEPTIC DRUGS (ANTICONVULSANTS)
 Antiepileptic drugs can be classified according to their mechanism of action,
but in clinical practice it is useful to think of the drugs according to their use.
 PHENYTOIN
 Mechanism of action—This involves use-dependent block of voltage-gated sodium
channels. It reduces the spread of a seizure. It does not prevent the ignition of an
epileptic discharge, but it does stop it spreading and causing overt clinical
symptoms.
 Route of administration—Oral, intravenous.
 Indications—Phenytoin is indicated in all forms of epilepsy except absence
seizures; ; neuralgic pain.
 Contraindications—Phenytoin has many contraindications, mainly because it
induces the hepatic cytochrome P450 oxidase system, increasing the metabolism
of oral contraceptives, anticoagulants, dexamethasone and pethidine.

 Adverse effects—The adverse effects of phenytoin may be dosage- or non-dosage-

related. The dosage-related effects of phenytoin affect the cerebellovestibular
system, leading to ataxia, blurred vision and hyperactivity.
 Acute toxicity causes sedation and confusion.
 The non-dosage- related effects include collagen effects such as gum hypertrophy
and coarsening of facial features;
 allergic reactions, e.g. rash, hepatitis and lymphadenopathy;
 haematological effects, e.g. megaloblastic anaemia;
 endocrine effects, e.g. hirsutism(hair growth); and teratogenic effects (it may
cause congenital malformations).
SODIUM VALPROATE
 Mechanism of action—Sodium valproate has two mechanisms of action: like
phenytoin, it causes use dependent block of voltage-gated sodium channels;
it also increases the GABA content of the brain when given over a prolonged
period.

 Route of administration—Oral, intravenous.

 Indications—Sodium valproate is useful in all forms of epilepsy.

 Contraindications—Sodium valproate should not be given to people with acute

liver disease or a history of hepatic dysfunction.

 Adverse effects—Sodium valproate has fewer side effects than other

antiepileptics; the main problems are gastrointestinal upset and, more
importantly, liver failure. Hepatic toxicity appears to be more common when
sodium valproate is used in combination with other antiepileptics.
 CARBAMAZEPINE
 Mechanism of action—Like phenytoin, carbamazepine causes use-dependent
block of voltage-gated sodium channels. Oxcarbazepine, another antiepileptic,
 It is structurally a derivative of carbamazepine. It has an extra oxygen atom on the
dibenzazepine ring, which helps reduce the impact on the liver of metabolizing
the drug, and also prevents the serious forms of anaemia occasionally associated
with carbamazepine.
 It is thought to have the same mechanism of action as carbamazepine.

 Route of administration—Oral, rectal.

 Indications—Carbamazepine can be used in all forms of epilepsy except absence

seizures; ; neuralgic pain.

 Contraindications—Like phenytoin, carbamazepine is a strong enzyme inducer

and so causes similar drug interactions.

 Adverse effects—Ataxia, nystagmus, dysarthria, vertigo, sedation.

ETHOSUXIMIDE
 Mechanism of action—Ethosuximide exerts its effects by inhibition of low-
threshold calcium currents (T-currents).

 Route of administration—Oral.

 Indications—Ethosuximide is the drug of choice in simple absence seizures

and is particularly well tolerated in children.

 Contraindications—Ethosuximide may make tonic-clonic attacks worse.

 Adverse effects—The adverse effects of ethosuximide include gastrointestinal

upset, drowsiness, mood swings and skin rashes. Rarely, it causes serious
bone marrow depression.
VIGABATRIN
 Mechanism of action—Vigabatrin exerts its effects by irreversible inhibition of
GABA transaminase.

 Route of administration—Oral.

 Indications—Vigabatrin is indicated in epilepsy not satisfactorily controlled by

other drugs.

 Contraindications—Vigabatrin should not be used in people with a history of

psychosis because of the side-effect of hallucinations.

 Adverse effects—Drowsiness, dizziness, depression, visual hallucinations.

 Therapeutic notes—Vigabatrin is a new drug, used as an adjunct to other

therapies.
LAMOTRIGINE
 Mechanism of action—Lamotrigine appears to act via an effect on sodium
channels, and inhibiting the release of excitatory amino acids.

 Route of administration—Oral.

 Indications—Monotherapy and adjunctive treatment of partial seizures and

generalized tonic-clonic seizures; neuralgic pain.

 Contraindications—Hepatic impairment.

 Adverse effects—Rashes, fever, malaise, drowsiness and, rarely, hepatic

dysfunction.
GABAPENTIN
 Mechanism of action—Gabapentin is a lipophilic drug that was designed to
act like GABA in the CNS (agonist), though it does not appear to have
GABAmimetic actions.

 Its mechanism of action remains elusive, but its antiepileptic action almost
certainly involves voltage-gated calcium-channel blockade.

 Route of administration—Oral.

 Indications—As an adjunct to therapy in partial epilepsy with or without

secondary generalization.

 Contraindications—Avoid sudden withdrawal, in elderly patients and in those

with renal impairment.

 Adverse effects—Somnolence, dizziness, ataxia, fatigue and, rarely, cerebellar

signs.
 BARBITURATES
 Examples of barbiturates include phenobarbital and primidone (which itself, is
largely converted to phenobarbital).

 Mechanism of action—Barbiturates cause potentiation of chloride currents

through the GABAA/Cl–channel complex.

 Route of administration—Oral, intravenous.

 Indications—Barbiturates are used in all forms of epilepsy, including status

epilepticus.

 Contraindications—Barbiturates should not be used in children, elderly people,

and people with respiratory depression.

 Adverse effects—The main side-effect of barbiturates is sedation, which limits

their use clinically, along with the danger of potentially fatal CNS depression in
overdose. Phenobarbital is a good inducer of cytochrome P450, and so it can be
involved in drug interactions.
BENZODIAZEPINES
 Examples of benzodiazepines include clonazepam and clobazam.

 Mechanism of action—Benzodiazepines cause potentiation of chloride

currents through the GABAA/Cl– channel complex.

 Route of administration—Oral, intravenously.

 Indications—Clonazepam is occasionally used for tonic-clonic and partial

seizures. Lorazepam and diazepam are effective in the management of
status epilepticus.

 Contraindications—Benzodiazepines should not be used in people with

respiratory depression.

 Adverse effects—The most common adverse effect of the benzodiazepines is

sedation. Intravenous lorazepam and diazepam can depress respiration.
STATUS EPILEPTICUS
 Intravenous benzodiazepines (lorazepam or diazepam) are first-line drugs in
status epilepticus.

 If these fail to bring an end to seizure activity,

 intravenous sodium valproate or phenytoin, or carbamazepine via a

nasogastric tube should be attempted, ideally in an intensive care setting.

 Alternatively intravenous fosphenytoin, a prodrug of phenytoin, can be given

more rapidly but requires.

 ECG monitoring. Thiopental can be used as a final option.

 FEBRILE SEIZURES
 Simple febrile seizures
• Under 15 minutes (usually 1-2 minutes)
• Generalised tonic clonic convulsion
• >18 months of age
• <6 years of age
• Clear focus of infection
• 1 event isolated to illness
 Complex febrile convulsion (CFS)
• Prolonged seizure
• Focal, or generalized
• Greater than 15 min duration
• Recurring more than once in 24 h,
• And/or associated with postictal neurologic
abnormalities, (Todd’s palsy)
DRAVET SYNDROME
 Severe myoclonic epilepsy of infancy

 Clinical diagnosis
• seizure history, clinical aspects, neurologic examination

 EEG pattern:
• Normal interictal EEG in the early stages,
• progresses to generalized spike-and-wave discharges (a
variety of interictal EEG findings is common)
 Normal metabolic work up
 Neuroimaging studies (CT and MRI) unremarkable
 DNA analysis: SCN1A gene positive (~80%)
THANKS
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