DRUGS ACTING ON THE CENTRAL NERVOUS

SYSTEM

Abel D. (BPharm, MSc)

Parts of the Brain

• Cerebral cortex – the thinking and abstract

• Diencephalon – Thalamus & Hypothalamus

• Brain stem – mid brain, pons & Medulla

• Cerebellum – mainly coordinates balance

• Limbic system

– Hippocampus

– Amigdaloid complex

– Basal ganglia

• Reticular activating system

Central Nervous System

• CNS includes brain and the spinal cord

– Semi-liquid structure at body temperature

– Excitable tissues and glial cells

– Glial cells are important

Cellular Organization of the Brain

• The CNS is made up of several types of specialized

cells

– Neuronal cells

– Support cells
Neurons

• Neurons are the highly polarized signaling cells of the

brain and are classified into types based on function
• sensory

• motor

• interneuron

• Neurons are electrically active cells that express a variety of ion

channels and ion transport proteins

• The sites of interneuronal communication in the CNS are

termed synapses functionally analogous to “junctions” ANS.
Support Cells

• A diverse cast of support cells outnumbers neurons in

the CNS.
• Neuroglia (glia)
– are the most abundant support cells.
– maintain important brain functions, such as
• holding neurons in place
• supplying oxygen and nutrients to neurons
• insulating signaling between neurons
• destroying potential pathogens.
• Neuroglia are classified as either micro- or macroglia

• The macroglia consist of

– Astrocytes

– Oligodendroglia

– Ependymal cells

– Radial glia
• Astrocytes
– are the most abundant of the glial cells

– Have metabolic support roles, including furnishing energy

intermediates,

– Anchoring neurons to their blood supply

– regulating the external environment of the neuron by

active removal of neurotransmitters and excess ions
following release.
• Oligodendroglia

– produce myelin, the multilayer, compacted membranes that

electrically insulate segments of axons and permit

nondecremental propagation of action potentials.

• Ependymal cells: line the spinal cord and ventricular

system and are involved in the creation of CSF.

• Radial cells: act as neuroprogenitors and scaffolds.

• Microglia
• consist of specialized immune cells found within the CNS.

• act as macrophages to protect the neurons and are

therefore mediators of immune response in the CNS.

• Microglia respond to neuronal damage and inflammation,

and many diseases are associated with deficient microglia.
Blood-Brain Barrier
• The BBB is an important boundary separating the periphery
(capillaries carrying blood) from the CNS.

• BBB composed of
– Tight endothelial junction

– Astrocytes

• Highly polar compounds

do not enter CNS

Neuronal Excitability and Ion Channels
• The primary signaling cells of the brain, release neurotransmitters in
response to a rapid rise and fall in membrane potential known as an
action potential.
• Major cations
– Na+ EC (~140 mM)  IC (~14 mM)
– K+ IC (~120 mM)  EC (~4 mM)
– Ca2+ IC (100 nM to 1 μM)
• Anion
– Cl– EC (~116 mM)  IC(20 mM)

• are regulated via their flow through highly discriminative ion channels
• The basal conditions, cellular homeostatic
mechanisms is maintained via
– Na+,K+-ATPase

– Na+,Ca2+ exchanger

– Ca2+-ATPases

– the sequestration of releasable Ca2+ in storage

vesicles maintain the concentrations of these ions.
Cell Signaling and Synaptic Transmission

• Neurotransmitter synthesis

• Neurotransmitter Storage

• Neurotransmitter release

• Neurotransmitter recognition

• Termination of action
Fast Neurotransmission

• It is also called directly gated transmission.

• Ligand-gated ion channels also called ionotropic receptors.

• NTs bind directly to ligand-gated ion channels on the

postsynaptic membrane to rapidly open the channel and
change the permeability of the postsynaptic site, leading to
depolarization or hyperpolarization.

E.g. GABA, glycine, glutamate, aspartate; 5HT3, nicotinic ACh

Slow Neurotransmission
• Slower transmission

– although still relatively fast, often on a time scale of seconds

• is mediated by neurotransmitters that do not bind to ion channels

but to receptors with a very different architecture called

metabotropic receptors.

• Upon activation, these receptors generate second messengers.

• E.g. GPCRs
Termination of Neurotransmitter Action
• There are two primary mechanisms for terminating the signaling of
released transmitters.

• conversion of the transmitter into an inactive compound via an

enzymatic reaction. E.g. AchE

• clearance of the neurotransmitter by transport proteins present on

presynaptic neurons E.g. NET, SERT and DAT

 slow diffusion of the transmitter away from the synapse and

subsequent degradation
CNS Neurotransmitters

• Neurotransmitters can be classified by chemical

structure into various categories, including
– Amino acids
– Acetylcholine
– Monoamines
– Neuropeptides
– Purines
– Lipids
– Gases
CNS Neurotransmitters…
• Neurotransmitters in the CNS are either inhibitory or Excitatory
• Inhibitory
– GABA
– Glycine
– Monoamines including Dopamine

• Excitatory
– Glutamate
– Aspartate
– Acetylcholine
CNS Neurotransmitters…
GABA
• Is ubiquitous inhibitory transmitter

• Substantia nigra, globus pallidus, hypothalamus, the

gray matter and hippocampus.

• Synthesis by GAD requires pyridoxine

• Linked to chloride channels

CNS Neurotransmitters…

GABA

• Stimulation causes opening of chloride channels

– Hyperpolarization

• Types of GABA receptors

– GABAA Linked to Chloride channels

– GABAB linked to G proteins

• Eventually affects Potassium and Calcium channels
CNS Neurotransmitters…

GABA

• It has a number of ligands occurring together with

it

– BZD, Barabiturates, Neurosteroids …

• Its deficiency causes excessive stimulation

– Seizure
Glycine
• Glycine act as an inhibitory neurotransmitter, particularly in the

spinal cord and brainstem.

– terminated by reuptake through specific transporters (GLYT1 and GLYT2).

– linked to Cl– channels and are prominent in the brainstem and spinal

cord.

– Taurine and β-alanine are agonists of glycine receptors; strychnine, a

potent convulsant, is a selective antagonist.

– Blockade of Glycine receptors cause seizure

Glycine…
Glutamate
• Glutamate is the principal fast excitatory NT and its activity is
terminated by Uptake

• Majorly found in hippocampus, amygdala and basal ganglia.

• Glutamate acts though receptors that are classified as either ligand

gated ion channels (ionotropic) or metabotropic GPCRs.

• Ionotropic glutamate receptors are ligand-gated ion channels that

were historically divided into three classes
– NMDA receptors

– AMPA receptors

– Kainate receptors
Pharmacologic binding sites on the NMDA receptor

Binding of both glutamate and glycine is necessary for activation

Acetylcholine
• Excitatory transmitter
• Active during awakeness and REM sleep
• Cholinergic pathways is a hallmark of Alzheimer disease.
• Cholinergic blockers and memory
• Cholinergic receptors
– Nicotinic
– Muscarinic
• M1, 3, 5- linked to Gq
• M2, 4- linked to Gi
Dopamine
• Is an inhibitory catecholamine transmitter
• Synthesized from tyrosine
• There are many pathways that uses dopamine
– Mesolibic-mesocortical pathway- Behavior
– Nigrostriatal pathway- Movement
– Tuberoinfundibular pathway- Prolactin
– Medial periventricular pathway- feeding
(Histaminergic and serotonin neurons also involved in
feeding)
Dopamine…
• Two types of receptors
– D1-like (D1, D5) activates Adenylate Cyclase
– D2-like (D2, D3, D4) Inhibits Adenylate Cyclase

• Disorders related to it
– Schizophrenia
– Parkinsonism
– Depression ?
Norepinephrine

• Beta hydroxylation of Dopamine

• Inhibitory but causes arousal

• Locus ceruleus and Lateral tegmental area

• Important to remain awake

– Increased stimulation during awake phase

• Depression, Feeding
HISTAMINE
• Histaminergic neurons are located in the ventral posterior hypothalamus

• It is thought to affect arousal, body temperature, and vascular dynamics.

• Histamine signals through four GPCR subtypes (H1–H4) that regulate either
adenylyl cyclase or PLC

– H1 receptors are widely distributed in the brain

– H2 receptors activate adenylyl cyclase and are primarily involved in

gastric acid secretion and smooth muscle relaxation

– H3 receptors are also present in the CNS and can act as autoreceptors on
histaminergic neurons

– H4 receptors are expressed on cells of hematopoietic origin

5-HT

• Serotonin signaling that play a role in modulating

mood, depression, anxiety, phobia, and GI effects.

• All but one of the serotonin receptors are GPCRs and

are targets for both therapeutic and recreational
drugs.

• These effects are mediated by 13 distinct GPCRs and

1 ligand-gated ion channel
Purines
• Adenosine, ATP, UDP, and UTP have roles as
extracellular signaling molecules.
• ATP is also a component of many neurotransmitter
storage vesicles and is released along with
transmitters.
• Extracellular nucleotides and adenosine can act on a
family of diverse purinergic receptors,
– involved in memory and learning, locomotor behavior, and
feeding.
Cannabinoids
• THC was identified as a psychoactive substance in
marijuana.
• Two cannabinoid receptors and the identification of
endogenous compounds that modulate them.
• The two receptor subtypes
– CB1-brain
– CB2-immune cells

• are GPCRs that couple to Gi/Go to inhibit adenylyl

cyclase
General Anesthetics
Introduction

• General anesthetics depress the CNS to a sufficient degree

to permit the performance of surgery and unpleasant

procedures.

• General anesthetics have low therapeutic indices and thus

require great care in administration.

General Principles of Surgical Anesthesia

• The administration of general anesthesia is driven by three general

objectives:

1. Minimizing the potentially deleterious direct and indirect effects

of anesthetic agents and techniques.

2. Sustaining physiologic homeostasis during surgical procedures.

3. Improving postoperative outcomes that may lead to short- or

long-term sequelae.
The Anesthetic State

• The components of the anesthetic state include

STAGES OF GENERAL ANAESTHESIA
STAGES OF GENERAL…
• The potency of general anesthetic agents is measured by

determining the concentration of general anesthetic that prevents

movement in

response to surgical stimulation.

• For inhalational anesthetics, anesthetic potency is measured in

MAC units.

• 1 MAC defined as the minimum alveolar concentration that

prevents movement in response to surgical stimulation in 50% of

• Generally, the potency of intravenous agents

– is defined as the free plasma concentration (at equilibrium)

that produces loss of response to surgical incision (or other

end points) in 50% of subjects.

Molecular Mechanisms of General Anesthetics
• Most intravenous general anesthetics act predominantly through

• GABAA receptors
– chloride channels gated by the inhibitory GABAA receptors are sensitive to a
wide variety of anesthetics.

• Modulating GABA receptor

• Glycine receptor
• Glycine-gated Cl- channels may play a role in mediating inhibition by
anesthetics

• NMDA receptors
– glutamate-gated cation channels that are somewhat selective for Ca2+

• Also has effect on neuronal nicotinic receptors and 5-HT3 receptors

INHALATIONAL ANAESTHETICS
• Inhalational anaesthesia refers to the delivery of gases or
vapours to the respiratory system to produce anaesthesia

• It is explosive

• Irritant to respiratory tract

• High incidence of nausea and vomiting during induction

and post-surgical emergence
• Colourless, odourless gas at room temperature.
• Very insoluble in blood and other tissues (quick recovery)
• Rapid induction of anaesthesia and rapid emergence
following discontinuation of administration.
• Completely eliminated by the lungs.
• It is weak anaesthetic and powerful analgesic.
• The mac value is 105%.
• Causes megaloblastic anaemia.
• Used as adjunct to supplement other inhalationals.
• Volatile liquid at room temperature.
• Light sensitive
• High fat solubility => slow induction & recovery
• Eliminated unchanged via lungs
• Commonly used in children
• It is marketed in amber bottles with thymol added as a
preservative
• Metabolized in liver by Cyt-P450
• Side effects of halothane :
– CVS : Cardiac arrhythmia, depression of myocardial contraction.
– Respiratory system : Depression of respiration
– Muscles : Malignant hyperthermia
– Kidney : Decrease renal blood flow and GFR
– Liver and GIT: Cause halothane induced hepatitis & nausea and vomiting

• DRUG INTERACTION : Halothane + adrenaline, theophylline =>

arrhythmia may be precipitated.
• CONTRAINDICATION : Hepatic dysfunction and/or jaundice
• Pleasant smell , non irritant and bronchodilation makes it agent of choice for
paediatric anaesthesia.
• 2nd agent of choice for
• Neuro anaesthesia.
• Cardiac anaesthesia .
• Asthmatics.
• Agents that should not be given with soda lime.
• Sevoflurane.
• Desflurane
• Two important characteristics of Inhalational anaesthetics which
govern the anaesthesia are :
• Oil-gas partition coefficients :

– It indicates the amount of gas that is soluble in oil phase

– It is a measure of lipid solubility of anaesthetic

– It a measure of anaesthetic potency

– Higher the solubility of general anaesthetics in oil greater is the anaesthetics action

• Blood-gas partition coefficients :

– The ratio of the concentration in blood to the concentration in the gas phase

– Lower the blood : gas coefficient faster the induction and the faster the recovery
INTRAVENOUS ANAESTHETICS
• Ultra-short acting barbiturate
• High lipid solubility rapid entry into the brain
• Rapid onset (20 sec) , short duration
• Risk of severe vasospasm if accidently injected into artery
• Depress cerebral blood flow
• Decrease intracranial pressure
• Tissue necrosis—gangrene, hypotension, apnea
• Build-up in adipose tissue = very long emergence from
anaesthesia
• Rapid onset and have a short duration of action

• Highly protein bound in vivo and is metabolized by

conjugation in the liver

• Very good anesthetic for induction and maintenance

of anesthesia with no accumulation effect

• Side-effects are pain on injection, hypotension and transient apnea

following induction

• Used for the induction, maintenance of GA and sedation

• Useful for day-case surgery

• Dissociative anaesthetic

• NMDA Receptor Antagonist

• Cardiovascular stimulant

• Catatonia, analgesia, and amnesia without loss of

consciousness

• Useful for anesthetizing patients at risk for hypotension and

bronchospasm and for certain paediatric procedures
• Rapid induction

• Minimal change in cardiac function and respiratory rate

• Not analgesic

• Cause pain on injection and nausea postoperatively

• Prolonged administration may cause adrenal suppression

LOCAL ANAESTHETICS
FEATURES OF LOCAL ANAESTHETICS

• Should have quick onset of action

• Should not be irritating to skin & mucous membranes

• Duration of action must be long enough to allow desired surgery to

be completed

• Should be effective on both injection & local application

• Should have low Systemic toxicity

• Should not cause any permanent damage on any tissue.

• Should be relatively free from producing allergic reaction.

• Should be stable in solution and readily undergo

biotransformation.
Based on linkage they can be classified as
Esters:

• cocaine, procaine, tetracaine, and chloroprocaine.

• hydrolyzed in plasma by pseudo-cholinesterase.

Amides:
• lidocaine, mepivicaine, prilocaine, bupivacaine, and etidocaine.

• metabolized in the liver to inactive agents.

• True allergic reactions are rare (especially with lidocaine)

ADVANTAGE OF AMIDE LAs OVER ESTER LAs

• Produce more intense and longer lasting anaesthesia

• Bind to α1acid glycoprotein in plasma.

• Not hydrolysed by plasma esterases.

• Rarely causes hypersensitivity reaction.

Order of sensory function block

1. Pain

2. Cold

3. warmth

4. Touch

5. deep pressure

6. motor
CLASSIFICATION
1. INJECTABLE ANAESTHETIC:
– LOW POTENCY, SHORT DURATION
• procaine
• chloroprocaine

– INTERMEDIATE POTENCY AND DURATION

• Lidocaine
• prilocaine

– HIGH POTENCY, LONG DURATION

• tetracaine
• bupivacaine
• ropivacaine
• dibucaine
2. SURFACE ANAESTHETIC:

• SOLUBLE INSOLUBLE

cocaine benzocaine

lidocaine butylaminobenzoate

tetracaine oxethazaine

benoxinate
MECHANISM OF ACTION
• LA blocks the nerve conduction by reducing entry of Na+ through

the voltage gated channels

• Due to this, they block the initiation & propagation of nerve

impulse.

• At higher doses it also blocks

1. Voltage gated Ca2+ channels

2. K+ channels
VASOCONSTRICTOR

• Vasoconstrictor used – adrenaline (1:50,000 to 1:200,000).

• prolongs duration of action of LAs by decreasing rate of

removal from local site into circulation

• Enhances intensity of nerve block

• Reduces systemic toxicity of LAs

• Provides more bloodless field for surgery

SYSTEMIC ACTIONS
• CNS: All LAs are capable of producing a sequence of
stimulation followed by depression
• CVS: LAs are cardiac depressants, but no significant effects
are observed at conventional doses. But at high doses they
decrease automaticity, excitability, contractility,
conductivity.
• BLOOD VESSELS: LAs tend to produce fall in BP. This is
primarily due to sympathetic blockade, but higher doses
cause direct relaxation of arteriolar smooth muscle
SYSTEMIC TOXICITIES OF LOCAL ANESTHETICS
• Central Nervous System Toxicities:
– Excitement: Tremors, shivering, and convulsions characterize
the CNS excitement.
– Depression: respiratory depression at higher doses

• CVS derangement— High plasma titers may depress the

cardiovascular system directly.
– Blood pressure may fall because of arteriolar dilation,
myocardial depression, and/or cardiac conduction disruption.
– Treatment includes patient positioning, IV fluids, and
vasopressors.
• Haemotological: large dose of prilocaine > 10mg/Kg
Accumulation of it’s metabolite- o toludine-oxidises
haemoglobin to methaemoglobin
– Patient – cyanosed, decompensate in patients with preexisting
cardiac /res. Disease

• Treatment: I.V methylene blue /ascorbic acid-a reducing

agent – convert methaemoglobin to Hb
• Hypersensitivity: Some patients are hypersensitive
(allergic) to some local anesthetics.

• There are two basic types of local anesthetics (the amide

type and the ester type).

• A patient who is allergic to one type may or may not be

allergic to the other type.
PHARMACOKINETICS

Absorption

• Local anesthetics are absorbed when ingested. Some

local anesthetics may be absorbed in toxic amounts
after topical use.

• Absorption after an injection depends on drug

solubility in lipid and in water, tissue vascularity and
local anesthetic and vasoconstrictor effects on local
circulation.
• Distribution: amides-wide distribution –I.V-lipophilics taken up by highly
perfused organs-then moderately perfused

• Ester type- short plasma half life

Metabolism and excretion

• Esters are hydrolyzed by plasma and liver esterases. Longer-acting esters

are often metabolized more slowly. Patients with altered pseudo-
cholinesterase activity may be highly sensitive to these drugs.

• Amides are metabolized in the liver by cyp450.-N-dealkylation then

hydrolysis except prilocaine hydrolysis first-o toludine-can cause
methhamoglobinemia
PRECAUTIONS AND INTERACTIONS

• Inject the LA slowly & take care not to exceed the

maximum safe dose, especially in children.

• Propranolol may reduce metabolism of lidocaine and

other amide LAs by reducing hepatic blood flow.

• Vasoconstrictor (Adr) containing LA should be

avoided for patients with ischemic heart disease,
cardiac arrhythmia, uncontrolled hypertension those
receiving β-blockers or tricyclic antidepressants