Separation accomplished by tight junctions between:

INTRO TO CNS
Dr. Reyes (Manual, lecture, and **recordings) *I tried*

ORGANIZATION OF THE CNS

CEREBRAL
CORTEX

LIMBIC SYSTEM

Thought, memory, consciousness

Supervisory integration of the ANS
Integrate somatic and vegetative
functions (CVS, GIT)

Emotion and motivation

Regulate extrapyramidal motor system
(voluntary)
Formation of recent memory

DIENCEPHALON

MIDBRAIN AND
BRAIN STEM

CEREBELLUM

SPINAL CORD

Regulatory
control
over
visceral
functions
Integrating region for the entire ANS
Regulate body temp, water balance,
intermediary metabolism, BP, sexual
and circadian cycles
Secretion of adenohypophysis. Sleep,
and emotion
Composed of major mono-amine
containing regions
Central integration for coordination of
essential reflexive acts (swallowing,
vomiting)
Primary receptive region for most
visceral afferent sensory information
Regulation of sleep, wakefulness, level
of arousal, and eye movement
coordination
Vestibular function maintain proper
tone of antigravity musculature and
provide continuous feedback during
volitional movements
Regulate visceral function (HR)
Learning and memory
Conduit for sensory information
Elicit autonomic reflexes (changes in
skin vasculature w/ alteration of temp)

MI CRO AN ATOMY OF THE BR AI N

1.

2.

Neurons functions in an interneuron way

a.

Sensory

b.

Motor

c.

interneuron

Neuroglia
a.

b.

c.

3.

Astrocyte provide metabolic nutrients to neurons,

maintain extracellular ion concentrations, regulate
neurotransmission by removing and recycling
neurotransmitters after release
Oligodendrocytes the myelin sheath insulates the
axons and the speed of signal propagation.
Damage leads to multiple sclerosis
Microglia specialized bone marrow-derived
macrophages are the major immune defense system
in the brain. Actively involved in neuro-inflammatory
processes such as in neurodegenerative diseases.

Blood brain barrier

Capillary endothelial cells

Surrounding layer of astrocytes end-feet

Function in the CNS compartment:

M ACROFUNCTI ONS OF TH E BR AI N FUNCTI ONS

Controls delivery of nutrients

Clears metabolites of transmitters into the CSF by

excretion via acid transport system of the choroid
plexus.

Protects abrupt changes in blood biochemistry that

occur after meals, physical exercises, or in
pathological conditions.

Transport of substances across the BBB:

Passive diffusion partition of solute across the

vasculature

Active membrane transport facilitate entry into the

brain (L-dopa), efflux transporter (P-GP, OATP for
antibacterial and anti-cancer).
**very lipophilic substances pass through very easily.
**major uptake of NE: reuptake
o

Transport family found on the endothelial cells of the BBB:

ATP-binding
cassette
transporter superfamily

MDR-associated
proteins

Solute carrier family

Organic
transporting
polypeptides
(OATP/SLCO)

anion

Organic
cation
transporters
(OCT/SLC22A1-3)

Organic
transporters
(OAT/SLC22A)

anion

Breast
resistance
(BCRP)

Renal
specific
transporter (RST)

cancer
protein

DETERMINANTS FOR THE UPTAKE OF DRUGS BY THE BRAIN

1.

Molecular weight not really significant. When lipophilic,

whether HMW or LMW, it will pass through

2.

Lipophilicity

3.

Charge non-polar, un-ionic, unchanged

FACTORS TH AT M AY INC RE ASE ACCESS OF SUBS TANCES INTO THE

BRAIN
1.

Cerebral ischemia

2.

Inflammation (Penicillin can cross through when there is

Meningitis)

NEUROTRANSMITTER REC EPTORS

1.

Inotropic

2.

Metabotropic uses G-protein coupled receptors

IO N CH A N N E L S
VOLTAGE-GATED CHANNEL respond through membrane potential

TOXINS ACTING ON VGC

VOLTAGE-GATED
CHANNELS

MODE TO TOXIN ACTION

SOURCE

SODIUM CHANNEL
BLOOD BRAIN BARRIER

Protective functional separation of the circulating blood from

the extracellular fluid of the CNS that limits the penetration of
substances, including drugs.

KARA LIBED

TETRADOTOXIN (TTX)

Blocks channel from

outside

Puffer fish

BATRACHOTOXIN (BTX)

Slows inactivation, shifts

activation

Columbian
frog

S E L E C T IV I T Y O F CN S D R U G A C TI O N

POTASSIUM CHANNEL
APAMIN

Blocks small Caactivated K channel

Honeybee

CHARYBDOTOXIN

Blocks big Ca-activated

K channel

Scorpion

CALCIUM CHANNEL

NEUROTRANSMITTERS ARE RELEASED BY DIFFERENT GROUPS OF NEURONS

Often segregated into neuronal systems that sub serve broadly

different CNS functions. **Dopamine

MULTIPLICITY OF RECEPTORS FOR EACH NEUROTRANSMITTER

OMEGA CONOTOXIN

Blocks N-type channel

Pacific cone
snail

AGATOXIN

Blocks P-type channel

Funnel web
spider

LIGAND-GATED CHANNEL

14 different Serotonin receptors are encoded by different gene

w/ differential cellular distributions throughout the CNS

CE L L U L A R O R G A N IZ A T IO N O F T H E B R A I N
HIERARCHICAL SYSTEM

Directly involved in sensory perception and motor control

TOXINS ACTING ON LGC

LIGAND-GATED
CHANNEL

MODE TO TOXIN
ACTION

Relay or projection neurons

SOURCE

NICOTINIC Ach RECEPTOR

ALPHABUNGAROTOXIN

Irreversible
antagonist

Marine snake

Blocks channel

South pacific plant

GLYCINE RECEPTOR
Competitive
antagonist

STRICHNINE

Synaptic influences are very short-lived

(Ionotropic receptors)

Most are inhibitory (GABA or Glycine)

Types of pathways:

Recurrent feedback

Feedforward

Indian plant
NON-SPECIFIC OR DIFFUSE NEURONAL SYSTEM

AMPA RECEPTOR
PHILANTHOTOXIN

Excitatory (Glutamate)

Local circuit neurons

GABA A RECEPTOR
PICROTOXIN

Blocks channel

Wasp

Modulate function of the hierarchical pathways

o

SI TE OF DRUG ACTI ON

Dopamine, NE, Serotonin, and Ach

CENTRAL NEUROTRANSMI TTERS

CRI TERI A ESTABLISHED FOR NEUROTRANSMITTER IDENTIFIC ATI ON
LOCALIZATION

A suspected transmitter must reside in the presynaptic terminal

of the pathway of interest.

RELEASE

A suspected transmitter must be released from a neuron in a

response to neuronal activity and in a Ca dependent manner.
(Ca)

SYNAPTIC MIMICRY

Application of the candidate substance should produce a

response that mimics the action of the transmitter released by
nerve stimulation, and application of a selective antagonist
should block the response.

N E U R O TR A N S MI T T E R S
NEUROHORMONES

PRESYNAPTIC CATEGORY
1.

Action potential in
presynaptic fiber

2.

Synthesis of
transmitter

3.

Storage

4.

Metabolism

5.

Release

KARA LIBED

POST SYNAPTIC CATEGORY primary

target: receptors
6.

Reuptake into the nerve

ending or uptake into a
glial cell

7.

Degradation

8.

Receptor for the

transmitter

9.

Receptor-induced or in
ionic conductance

10.

Retrograde signaling

Transmitter released in a hormone-like fashion from peptidesecreting cells of the hypothalamic-hypophyseal circuits
receiving synaptic information from the other central neurons in
a hormone-like fashion.
o

Oxytocin, Arginine-Vasopressin

NEUROMODULATORS

Released by neurons and by astrocytes, they produce slower

pre- or post-synaptic responses.
o

CO2, adenosine, purines, eicosanoids, NO

NEUROMEDIATORS

TYPES OF MEDI ATORS I N THE CNS

Substances that participate in eliciting a post-synaptic response

to a transmitter. (2nd messengers, metabotropic receptors)

NEUROTROPHIC FACTORS
Releases mainly by non-neuronal cells and act on tyrosine
kinase-linked receptors that regulate gene expression and
control neuronal growth and phenotypic characteristics.

MEDIATOR
TYPE

EXAMPLES

Conventional
smallmolecule
mediators

Glutamate,
GABA, Ach,
Dopamine, 5-HT

Neuropeptide

cAMP, cGMP, IP

Classic neurotrophins
Nerve growth factor)

(BDNF,

Neuropoietic factors (Leukemia

inhibitory
factor,
ciliary
neurotrophic factor)

GF peptides (epidermal GF,

TGF-
and
,
glial
cell
neurotrophic factor, activin A)

Fibroblast GF

Insulin-like GF

Plateletderived GF

Axon
guidance
molecules

**Deficiency in BDNF can give rise to depression

TARGETS

MAIN FUNCTION /
ROLE

- Ligandgated ion
channels

-Fast & slow

synaptic
neurotransmission

-G-protein
couple
receptors

neuromodulation

Substance P,
Neuropeptide
Y, Endorphins,
CRF

G-protein
coupled
receptors

Neuromodulation

Lipid
mediators

PG,
endocannabin
oids

G-protein
coupled
receptors

Neuromodulation

Nitric oxide

---------

Guanylyl
cyclase

Neuromodulation

Neurotrophins,
Cytokines

Nerve GF,
BDNF, IL-1

Kinaselinked
receptor

Neuronal growth,
survival and
functional
plasticity

Steroids

Androgens,
Estrogen

Nuclear and
membrane
receptors

Functional
plasticity

AM I NO ACI D TR ANSMI TT ERS

TRANSMITTER
GLUTAMATE

ANATOMY
Relay neurons at all levels and some
interneuron

RECEPTOR SUBTYPE AND

PREFERRED AGONIST

RECEPTOR ANTAGONIST

MOA

NMDA:NDMA

2-amino 5phosphonovalerate,
Dizoclipine

Excitatory: Ca conductance

AMPA:AMPA

NBQX

Excitatory: Ca conductance

KAINATE: Kainic acid,

Domoic acid

ACET

Excitatory: Ca conductance

Metabotropic: ACPD,
Quisquinate

MCPG

Inhibitory: (presynaptic)
conductance, cAMP

Ca

Excitatory: k conductance, IP3

and DAG
GABA

Supraspinal and spinal interneuron involved

in pre- and post-synaptic inhibition

GABA A: Muscimol

Bicuculline, Pricrotoxin

Inhibitory: Cl conductance

GABA B: Baclofen

2-OH, Saclofen

Inhibitory: (presynaptic) Ca
conductance
(post-synaptic) K conductance

GLYCINE

Spinal and some brainstem interneurons

Taurine, B-alanine

Strychnine

Inhibitory: Cl conductance

PR O P ER TI ES O F IO N O TR O P I C G L UT A M A TE R E C E P T O R S
NMDA

AMPA

KAINATE

EFFECTOR
MECHANISM

Ligand-gated cation channels (slow kinetics, Ca

permeability)

Ligand-gated cation channels (Fast

kinetics: GluR2A subunits show Ca
permeability)

Ligand-gated cation channel

(Fast kinetics, Ca permeability)

LOCATION

Post-synaptic, Wide distribution

Post-synaptic (also glial)

Pre- and post-synaptic

FUNCTION

Slow EPSP

Fast EPSP

Fast EPSP

Synaptic plasticity (long-term potentiation, longterm depression

Wide distribution

Presynaptic inhibition
Limited distribution

Excitotoxicity

KARA LIBED

ENDOGENOUS
AGONIST

RECEPTOR SITE:
Glutamate, Aspartate

MODULATORY SITE:
Glycine, D-serine

Glutamate

Glutamate

OTHER AGONIST

NMDA

Cycloserine

AMPA, Quisquinate

Kainate, Domoate

ANTAGONIST

AP-5, CPP

7-Chlorokynurenic acid,
HA-466

NBQX

NBQX. ACET

Cyclothiazide, Piracetam, CX-516

----------

------------

-----------

OTHER
MODULATORS

Polyamines (Spermine, Spermidine)

CHANNEL
BLOCKERS

Dizoclipine, Phencyclidine, Ketamine,

Remacemide, Memantine, Mg

Mg, Zn

PR O P ER TI ES O F IN HI B I TO R Y R E CE P TO R S ( G A B A )
GABA A

GABA B

GLYCINE

EFFECTOR
MECHANISM

Ligand-gated Cl channel

G-protein coupled receptor; inhibition of

AC, inhibition of Ca channels, activation
of K channels

Ligand-gated Cl
channel

LOCATION

Widespread; GABAergic interneurons

Pre- and post-synaptic

Post-synaptic
(brainstem and
spinal cord)

Widespread
FUNCTION

Post-synaptic inhibition (fast IPSP and tonic inhibition)

Presynaptic inhibition (Ca entry)

Post-synaptic inhibition (K permeability)

RECEPTOR SITE

MODULATORY SITE
(BZD)

MODULATORY SITE
(Allosteric)

ENDOGENOUS
AGONIST

GABA

Unknown

Neurosteroids
(Progesterone
metabolites)

OTHER AGONIST

Muscimol,
Gboxadol

Anxiolytic
(Benzodiazepines)

Barbiturates, Steroids,
Anesthetic
(Alphaxolone)

ANTAGONIST

Bicuculline,
Gabazine

Flumazenil (inverse
agonist)

CHANNEL
BLOCKERS

Post-synaptic
inhibition (fast IPSP)

GABA

Glycine, B-alanine,
Taurine

Baclofen

---------

2-hydroxylsaclofen, CGP 35348, and

others

Strychnine

Picrotoxin

M ONO AMI NE TRANSMI TTE RS

NORADRENALINE IN THE CNS

Arousal system, controlling wakefulness and alertness

BP regulation

Control of
depression)

mood

(functional

deficiency

contributing

to

RECEPTOR

LOCATION

ACTION

DRUG

ALPHA 1

Cell bodies in
pons and
brainstem project
to all levels

Excitatory: K
conductance; IP3
and DAG

Blocked by
Prazosin

Inhibitory
(presynaptic): Ca
conductance

Activated by
Clonidine

ALPHA 2

Inhibitory (postsynaptic): K
conductance

PATHWAYS:
1.

median forebrain bundle

2.

descending spinal tracts

3.

terminate diffusely in the cortex, hippocampus, hypothalamus,

cerebellum, and spinal cord

KARA LIBED

BETA 1

Excitatory: K
conductance;
cAMP

BETA 2

Inhibitory: Na
pump

Blocked by
Propanolol

D O P A M IN E I N T HE CN S
D1 type

D2 type

D1
SIGNAL TRANSDUCTION

D5

D2

Gs-coupled: activate adenylyl cyclase

EFFECT

D3

D4

Gi/G0 coupled:

Mainly post-synaptic inhibition

inhibit adenylyl cyclase

activates K channels and inhibits Ca channels (No dopamine: inhibitory)

may also activate Phospholipase C

Pre- and post-synaptic inhibition

stimulation/inhibition of hormone release

**D2 suppress synthesis of Dopamine by inhibiting the enzyme, the phosphorylation of the rate-limiting enzyme, tyrosine hydroxylase.
**Dopamine - post-synaptic inhibition

DOPAMINE PATHWAY

FUNCTIONAL ROLE

D1 TYPE

D2 TYPE

D1

D5

D2

D3

D4

NIGOSTRIATAL

Motor control

+++

++

MESOLIMBIC

Behavioral affects: emotion, stereotypic behavior

+++

++

MESOCORTICAL

Arousal, mood

+++

++

TUBEROHYPOPHYSEAL or TUBEROINFINDIBULAR

Endocrine control

++

DOPAMINE AGONIST

D1 type
D1

DOPAMINE

DOPAMINE ANTAGONIST

D2 type
D5

+ (low potency)

D2

D3

APOMORPHINE

PA (low potency)

+ (high potency)

BROMOCRIPTINE

PA (low potency)

+ (high potency)

QUINIPIROLE

inactive

Active

**In dopamine antagonist, D2 type (D2), examples are antipsychotics.

5 - HY D R O X Y TR Y TA M IN E IN T H E CN S

neurons concentrated in the midline raphae nuclei in the

brainstem projecting to the cortex, limbic system, hypothalamus,
and spinal cord

5-HT can exert inhibitory of excitatory effects in individual

neurons: pre-synaptic and post-synaptic

Histaminergic neurons originate un the hypothalamus: H1-H4

receptors

Functions associated w/ 5-HT pathways:

o

Behavioral responses (hallucinatory, behavior, wetdog shakes)

Feeding behavior

Control or mood and emotion

Control of sleep/wakefulness

Control of sensory pathways (nociception)

Control of body temp

Vomiting

D2 type

D5

D2

D3

CHLORPROMAZINE

+++

++

HALOPERIDOL

+++

++

++

SPIPERONE

+?

+++

+++

+++

D4

+ (high potency)

D1 type
D1

D4

SULPRIDE

++

++

CLOZAPINE

++

ARIPRIPRAZOLE

+++ (PA)

++

RACLOPRIDE

+++

++

RECEPTOR

ACTION

DRUG

5-HT1A

Inhibitory: K
conductance

Buspirone partial agonist

5-HT2A

Excitatory: K
conductance; IP3 and
DAG

Blocked by Clozapine,
Risperidone, and
Olanzapine

5-HT3

Excitatory: cation
conductance

Blocked by Ondansetron

5-HT4

Excitatory: K
conductance; cAMP

5-HT FUNCTION

DRUGS

ACTION

Behavioral responses: antipsychotics

Clozapine

5-HT2A
antagonist

Control of emotions: anti-depression

SSRIs

5-HT reuptake
inhibitor

Control of sleep/wakefulness:
anxiolytic

Buspirone

5-HT1A agonist

Control of sensory pathways

(nociception): anti-migrane

Sumatripan

5-HT1D
antagonist

Pizotifen

5-HT2
antagonist

KARA LIBED

Vomiting: anti-emetic

Ondasetron

5-HT3
antagonist

ACEY TLCHOLI NE I N THE CNS

Involved in the following pathways:

o

Basal forebrain (magnocellular) nuclei, including

cortex

Septohippocampal projection

Short interneurons in the striatum and nucleus

accumbens

FUNCTION

Reproduction

Social behaviors

Appetite

Arousal

Pain

Reward

Learning and memory

OTHER SUBST AN CES

Abnormalities

neurodegenerative
diseases (dementia, Parkinsons disease)
PURINES

Receptors:

MOA

Implicated in several CNS functions:

Nicotinic central effects (Presynaptic: main, postsynaptic:few)

Muscarinic (M1) behavioral

learning, and memory)

effects

M4

Gq/11 PLC IP3 + DAG

Ca + PKC

Gi/0 inhibit AC
inhibit cAMP
promote K channel
opening

-in the temporal lobe

promote
memory
and
cognition

ATP acts on:

(arousal,

M1

-Increase
activity
of
the
cholinergic projections from
pedunuculopontine nucleus,
the lateral tegmental nucleus,
and nucleus basalis of Meynert
promote attention

-inhibition of
nociceptive
transmission from the
rostral ventral medulla
to the dorsal horn
-suppression of AP
firing from the
secondary sensory
neurons

Ionotropic P2X receptors excitatory

Metabotropic receptors (P2Y) neuromodulator

Excessive release neurotoxic

Converted to ADP, AMP, Adenosine

A D E N O S IN E

Released by carrier mechanisms or generated from ATP under

pathological conditions.

Mainly inhibitory effects through A1 and A2 receptors

o

EFFECTS: sedative, anticonvulsant, neuroprotective

ME T HY L X A N TI N E

Antagonist at 2-receptors

EFFECT: wakefulness

CLINICAL USE:

N I TR I C O XI D E

Muscarinic agonist (M1)

Alzheimers
Disease

Galantamine, Rivastagmine

Tacrine,

Donezepil,

Production is by mechanisms that raise intracellular Ca

ACTION:

Muscarinic antagonist
o

Amnesia Hyoscine

Parkinsons disease Benztropine

cGMP inhibitory and excitatory

Forms Peroxynitrite (large amounts) neurotoxicity

ME L A T O N IN
NICOTINE

MOA: opening of Na/K channels

MAJOR ACTION:
o

Stimulation

Somplex arousal, attention, analgesia

Low doses: weak analgesia

High doses: tremors convulsions

Synthesized from 5-HT, mainly in the pineal gland

Secretion controlled by light intensity (diurnal; promote sleep)

o

Mechanism of controlling the Pineal gland:

o

Low by day, high by night

Fibers from the retina suprachiasmatic nucleus

sympathetic innervation control pineal gland

MT1 and MT2 receptors effect: sedation

o

AGONIST: induce sleep, anti-depressant

NEUROPEPTI DES

Opioid peptides (enkephalins, endorphins)

Neurotensin

Substance P

Neuropeptide Y

Thyrotropin-releasing hormone

KARA LIBED

ACTIONS OF DRUGS IN THE CNS

SPECIFIC
When the drug affect and identifiable molecular mechanism
unique to target cells that bear receptors for that drug.

NON-SPECIFIC
When a drug produces effects on many different target cells
and acts by diverse molecular mechanisms.

EXCEPTIONS:

Highly specific drug at low concentrations may exhibit nonspecific action at high doses.

Drugs w/ specific actions may produce non-specific effects if the

dose and route of administration produce high tissue
concentration.

ACTION
GENERAL CNS
DEPRESSANT (NONSPECIFIC)

DRUGS
Anesthetic gases and vapors, aliphatic
alcohols; Hypnotic-sedative

GENERAL CNS
STIMULANT (NONSPECIFIC)
-

Blockade of
inhibition

Pentylenetetrazole

Methylxanthines

Direct
neuronal
excitation

SELECTIVE MODIFIER OF
CNS FUNCTION

Depression
or excitation

KARA LIBED

GENERAL CLASSIFICATI ON OF DRUGS ACTING O N

CNS
DRUG CLASS

CLINICAL USE

EXAMPLES

General
anesthetics

Surgical anesthesia

Isoflurane, Propofol

Analgesics

Pain control

Opiates,
Carbamazepine,
Gabapentin

Anxiolytics and
sedatives

Relieve anxiety and

insomia

Benzodiazepine,
Barbiturates, Buspirone

Anti-epileptic /
anticonvulsants

Reduce seizures

Carbamazepine,
Phenytoin, Valproate,
Lamotrigine

Antipsychotics /
neuroleptics

Relive symptoms of
Schizophrenia

Antidepressants

Alleviate depressive
disorders

SSRI, SNRI, TCA, MAOI

Psychomotor
stimulants

Promote
wakefulness and
euphoria

Amphetamine,
Cocaine,
Methylpenidate,
Caffeine

Psychomimetics

Relieve perception
and behavioral
disturbances

Lysergic acid
diethylamide,
Mescaline,
Phencyclidine

Hallucinogens
Psychodysleptics
Condition
enhancers

Anticonvulsants,
Anti-parkinson;s
drugs,
opioid and non-opioid analgesics, appetite
suppressants,
anti-emetics,
analgesicsantipyretics, neuroleptics, antidepressants,
sedative-hypnotics, and treatment of
Alzheimers Disease

Nootropics

Improve memory
and cognition
performance

TYPICAL Haloperidol
ATYPICAL Clozapine,
Risperidone

AchE inhibitors:
Donezepil,
Galantamine,
Rivastigmine
NMDA antagonist:
Memantine
Others: Piracetam

OPIOID AGONISTS AND ANTAGONISTS

CHRONI C NOCI CEPTI VE P AI N

PHASES OF PAIN
1.

Transient noxious stimulus, corresponding to acute painful

sensation.

2.

The consequences of a prolonged noxious stimulation comprise

the substrate of the chronic nociceptive pain states.

3.

The consequences of damage or injury to the neural tissue itself,

this correlates w/ the various neuropathic pain states.

TR ANSI ENT ACUTE P AI N

Nerve injury-evoked nociception

Carpal tunnel syndrome, chemotherapy, diabetes, postherpetic state

Tissue injury

peripheral nerve
degeneration neuroma
spontaneous
afferent activity

Information is propagated predominantly by the A fibers.

The underlying synaptic events are mediated predominantly by

glutamate acting at the AMPA/Kainate receptors.

spinal sensitization

A afferent fibers

spontaneous dysenthesia

allodynia

(shooting, burning pain)

(light touch hurts)

Only to a minimal degree by neurokinins (substance P) acting at

NK1 receptors.

NEUROP ATHI C P AI N

PA IN / N O C IC E P TIO N : TY P ES
TYPE

ETIOLOGY

MECHANISM

ACUTE

Supeficial: wounds, chemical

irritants, thermal stimuli

Activate small highthreshold sensory

afferents

Spontaneous pain w/ burning quality or intermittent, sharp,

stabbing, or lancinating pain.

Thermal hyperalgesia, to both cold and hot stimuli.

Mechanical allodynia, elicited by ouch or brushing.

Deep somatic: injection of

chemical irritants, ischemia

(A and C fibers)

Visceral: inflammation
CHRONIC

Unknown: cancer, arthritis

This is a very common neuropathic manifestation,

considered hallmark of the neuropathic pain.

Opioids, NSAIDs

Neuropathic: diabetic
neuropathies, shingles, ischemia
following stroke, phantom limb
pain

PHARMACOKINETICS
OPIOIDS compounds that work at opioid receptors
OPIATE naturally occurring alkaloids: Morphine, Codeine, Thebaine, and
Papaverine.

PA IN : E TI O L O G Y , N O C I C E P TIV E TR A N S M IS SI O N & N O CI CE P T I V E
F IB ER B UN D L ES
FIBER
BUNDLE

NOCICEPTIVE TRANSMISSION

ETIOLOGY

Rapid

Sharp,
painful stimuli

Myelinated fibers that enter the dorsal

horn activate ascending systems of
spinothalamic tract
C

Slow

Dull, aching

Non-myelinated fibers enter the dorsal

horn, synapse on spinothalamic tract
neurons

Causes pain characterized by burning, throbbing, or aching

pain

tissue injury

ongoing pain /
hyperalgesia

local release of
active factors (PG,
BK, K)

exaggerated outpt
for given stimulus
input

ABSORPTION

Well absorbed when taken orally

Undergo
extensive
first-pass
metabolism
(Morphine,
Hydrocodone, and Oxymorphine) **Reduced BA, but give rise
to active compounds

Parenteral preparation w/ sustained-release: Morphine and

Oxycodone

DISTRIBUTION

LOCAL I NFL AMM ATI ON

NARCOTIC originally used to describe sleep-inducing medications

persistent activation
/ sensitization of
A/C

Widely distributed to body tissues

Can cross the placenta

METABOLISM

Hepatic enzymatic degradation into inactive glucuronide

conjugates

Metabolites:
morphine-6-glucoronide

morphine-3glucoronide (primary metabolite) neuroexcitation

Codeine, Oxycodone, and Hydrocodone are metabolized by

CYP2D6
o

activity in ascending
pathways + spinal
facilitation

Burn, post-incision,
musculoskeletal injury

KARA LIBED

abrasion,

joint

inflammation,

If w/ isozyme genotypic variability demethylation of

CYP2D6 Morphine variability in analgesic
response

Remifentanil (congener of Fentanyl) metabolized by plasma

and tissue esterases

and

Meperidine metabolized to Normeperidine seizures at high

plasma level

EXCRETION
Kidneys

OPI OI D RECEPTOR SUBT YPES

Mu

FUNCTION

ENDOGENOUS OPIOID
AFFINITY

Supraspinal and spinal

analgesia

Endorphins > enkephalins

> dynorphins

O P IA TE CO U PL IN G A N D E F F E C T I N G - PR O T E I N CO U PL E D
R E C E P TO R S

Inhibition of adenylyl cyclase activity

Reduced opening of voltage-gated Ca channels

Stimulation of K current through several channels (G-protein

coupled inwardly rectifying K channel)

Activation of PKC and PLC-

M ECHANI SM OF OPI OD -I NDUCED AN ALGESI A

SUPRASPINAL

Sedation
Inhibition of respiration
Slowed GI transit
Modulation of hormone and
neurotransmitter release
Delta

Supraspinal and spinal

analgesia

Enkephalins > endorphins

and dynorphins

Modulation of hormone and

neurotransmitter release
Kappa

Supraspinal and spinal

analgesia

Dynorphins >> endorphins

and enkephalins

Psychomimetic effects
Slowed GI transit
SPINAL DIRECT G -PROTEIN COUPLED ACTI ONS ON NEURONS
O P IO ID R E C PT O R SU B T Y PE S

1.

Closure of voltage-gated Ca channels on presynaptic nerve

terminals reduce transmitter release (Ach, NE, 5-HT,
Glutamate, and Substance P)

2.

Opening of K channels hyperpolarize inhibit post-synaptic

neurons

EFFECTS
Mu1

Mediate analgesic and euphoric effects and

physical dependence

Mu2

Mediate bradycardia and respiratory depression

Delta (2
subtypes)

Mediate spinal analgesia; modulate tolerance to

Mu-opioids

Action mediated by opiate receptors on peripheral terminal of

small primary afferents

Kappa (3
subtypes)

Mediate spinal analgesia, miosis, sedation, and

diuresis

Mechanism: unclear

Direct application

PERIPHERAL

R EC E P TO R D I S TR IB U TI O N
DRUG

RECEPTOR EFFECTS

Local anesthetic-like action at high concentrations

In areas of inflammation, normalize effect upon

exaggerated thresholds or pain response

**need inflammation to have effect

MORPHINE

+++

HYDROMORPHONE

+++

OXYMORPHONE

+++

METHADONE

+++

MEPERIDINE

+++

FENTANYL

+++

SUFENTANIL

+++

ALFENTANIL

+++

Phenantrenes: Morphine, Hydromorphone,

Oxymorphone

REMIFENTANIL

+++

Phenylheptylamine: Methadone

LEVORPHANOL

+++

CODEINE

Phenypiperidine: Fentanyl, Sufentanil, Alfentanil,

Remifentanil

HYDROCODONE

OXYCODONE

++

KARA LIBED

OPIOID DRUGS
DRUG
SUBCLASS
FULL AGONIST
+

DRUG
STRONG Mu RECEPTOR AGONIST:

Morphinans: Levorphanol

MILD-MODERATE Mu RECEPTOR AGONIST:

DEGREE OF TOLERANCE
HIGH

Phenantrenes: Codeine, Dihydrocodeine,

Hydrocodone, Oxycodone
Phenylheptylamine: Propoxyphene
Phenypiperidine: Diphenoxylate, Loperamide

ANTAGONIST
MIXED
AGONIST-

Analgesia, euphoria, dysphoria,

mental clouding, sedation,
respiratory depression, N&V, antidiuresis, cough suppression

Bradycardia

MINIMAL OR
NONE
Miosis,
constipation,
convulsion

Naloxone, Naltrexone, Nalmefene

Phenantrenes: Buprenorphine, Nalbuphine

D E PE N D E N C E W I T H O P IO ID S

Morphinans: Butorhanol

ANTAGONIST

MODERATE

Benzomorphans: Pentazocine

** concentrations in the brain, lungs, liver, kidney, and spleen.

Degree of dependence generally reflected by the severity of

withdrawal signs.

Drugs w/ long half-life produce gradual and prolonged

withdrawal. (Methadone heroine detoxification)

Characteristic of opioids useful in the treatment of addiction:

O P IO ID M ED I A T ED EF F E C TS
CNS
Analgesia
Euphoria inh of GABA in
nucleus accumbens
Sedation
Respiratory depression -
ventilator response to CO2,
threshold
Cough suppression repress
reflux, direct inh effect in
cough center

PERIPHERAL
CVS Morphine causes Histamine
release, BP
GIT closes all sphincters, acid
secretion, urinary retention
(Morphine)

Longer duration of action (To wean out dependent

patients, need long half-life )

Lower BA

WI T HD R A W A L O R A B S T IN E N CE S Y N D R O M E W/ O P IO D S

Occurs when a drug is stopped or an antagonist is administered.

ONSET: 6-10 hours after last dose

Renal

PEAK: 36-48 hours

Uterus - contractility

SIGNS AND SYMPTOMS: end 72 hours to 5 days after last dose:

Neuroendocrine

Inhibition of adrenal
function

Truncal rigidity - doses,

muscle tone

Release ADH, oxytocin,

and PRL

Inhibit LH and FSH release

Temperature - hyperthermia

Slower onset

Biliary tract close sphincter of Odi

(Biliary colic)

Miosis - parasyma effect if

GABA is inh

Nausea and vomiting

actvates CTZ, constipation due
to gastric stasis

Miscellaneous Flushing and Pruritus

(facial area only)

CHRONIC

Respiratory depression,
N&V, pruritus, urticarial,
urinary retention,
constipation, delirium,
sedation, myoclonus,
seizures, postural
hypotension

Hypogonadism, immunosuppression,
feeding, GH secretion, withdrawal
effects, tolerance/dependence,
abuse/addiction, hyperalgesia,
impairment while driving

MANIFESTATIONS DETECTABLE: 6 months to 1 year after last dose:

o

Restlessness, anxiety, drug craving

D R U G I N T E R A C TI O N S O F O PIO I D S
DRUG

O P IO D - MED IA T ED A D V E R S E EF F EC T S
ACUTE

Mydriasis (most prominent), rhinorrhea, lacrimation,

diarrhea, nausea, chills, fever, sweating, HTN,
piloerection, muscle jerks, yawning

INTERACTION

SEDATIVEHYPNOTICS

CNS depression (respiratory depression)

ANTI-PSYCHOTIC
TRANQUILIZERS

sedation. Variable effects on respiratory

depression. Accentuation of CVS effects
(antimuscarinic and -blocking actions).

MAOI

Relative contraindication to all opioid analgesic

because of the high incidence of hyperpyrexic
coma. HTN has also been reported

MeperIdine, Fentanyl, Pentazocine, and Tramadol + SSRI = SEROTONIN

SYNDROME **SYMPTOMS: confusion, agitation, restlessness, dilated pupils,
headache, HTN, hyperpyrexia.

TO L E R A N C E W IT H O P IO D S
INTRACELLUL AR MECHANISMS OF TOLERANCE

Morphine and its congeners exhibit cross-tolerance on the following

actions:

Analgesic, euphoriant, sedative, respiratory effects

intracellular Ca, K efflux

production of cAMP

Alterations in phosphorylation of intracellular and intranuclear

proteins

CL I N I CA L U S E S O F O P I O ID S

Analgesia

Return to normal levels of released neurotransmitters and

neuromodulators

Acute pulmonary edema **reduce anxiety or perception of apnea

Cough (Dextromethorphan, Codeine, Levopropoxyphene)

Diarrhea (Diphenoxylate or Loperamide)

Shivering (Meperidine) **2 activation

Anesthesia (Fentanyl, Morphine)

Opioid abuse treatment (Methdaone)

Clinically manifest until 2-3 weeks of frequent exposure to ordinary

therapeutic dose.

It is related to the change in receptor number induced by chronic

opioid administration. **opioid receptors decreases

**tolerance is not common w/ drugs w/ high intrinsic activity, Fentanyl, only

occupy few receptors.

KARA LIBED

10

R O U TE O F A D M IN IS TR A T IO N

D IF F E R E N CE O F A G O N IS T -A N T A G O N IS T A N D P A R T I A L A G O N I S T
F R O M MO R P HI N E

ROUTE

DRUG

ORAL

Fentanyl lozenge, Hydromorphone, Levomethadyl

acetate, Levorphanol, Meperidine, Methadone,
Oxycodone

PARENTERAL

Alfentanil, Codeine, Fentanyl, Hydromorphone,

Levorphanol, Meperidine, Methadone, Morphine,
Oxymorphone, Remifentanil, Sufentanil

RECTAL
INTRATHECAL
TRANSDERMAL
PATCH

Induce withdrawal signs that differ from those of Morphine

Produce excitatory effects related to sympathetic discharge of

NE

Morphine > Buprenorphine, Butorphanol, Nalbuphine

Fentanyl

Buprenorphine, Butorphanol, Nalbuphine = Codeine > Pentazocine

**Fentanyl is more potent than Morphine

CL I N I CA L U S E

With impaired pulmonary function **asthma, COPD (effect will be

more marked)

Chronic use during pregnancy **after delivery, baby may suffer

withdrawal symptoms

Use in patients with endocrine diseases (Adrenal insufficiency or

Addisons disease: hypothyroidism or myxedema) **prolonged
depressant effects
Those on weak partial agonist (Pentazocin)
In patients w/ impaired renal and hepatic functions

WHO AN ALGE SI C L ADDER

STEP 1: MILD TO MODERATE PAIN

Analgesia

Supplement to Anesthesia (Pentazocine)

Opioid dependence treatment (Buprenorphine, or Buprenorphine +

Naloxone) **no withdrawal symptoms

O T H E R E F F E CT S O F A G O N I S T -A N T A G O N I S T D R U G S

Sedation

Respiratory depression

Tachycardia, HTN **secondary to NE discharge

Constipation: high dose Pentazocine = Morphine

Tolerance, cross-tolerance

Physical dependence (Buprenorphine) **at high doses becomes

antagonist (potentially reversed by Naloxone)

Non-adjuvant w/ o w/o adjuvant agent

o

Acetaminophen or NSAID

STEP 2: MILD TO MODERATE PAIN OR PAIN UNCONTROLLED AFTER STEP 1

Produce a low degree of physical dependence

AN ALGESIC ACTIVI TY

With head injury from a vehicular accident

Ziconotide

Produce excitatory hallucinogenic effects

Morphine, Oxymorphone

CO N TR A I N D I CA T IO N S F O R O PI O ID U SE

Short-acting opioid as required w/ or w/o non-opioid, round the

clock w/ or w/o adjuvant
o

Morphine, Oxycodone, or Hydromorphone +

Acetaminophen or NSAID for maximum flexibility of
opioid dose

Onset: 2-14 days

Duration: 1-2 weeks

ADVERSE EFFECTS
**high doses of Pentazocine, can be reversed by Naloxone

Dizziness, drowsiness, sweating, nausea, anxiety, hallucinations,

nightmares, dysphoric, psychomimetic effects

R O U TE O F A D M IN IS TR A T IO N
STEP 3: MODERATE TO SEVERE PAIN OR PAIN UNCONTROLLED AFTER STEP 2
**pain scale of 8-10

ROUTE
ORAL

Sustained-release or long-acting opioid RTC, or continuous

infusion + short-acting opioid as required w/ or w/o non-opioid
w/ o w/o adjuvant agent
o

Sustained-release
Oxycodone,
Oxymorphone, or transdermal Fentanyl

PARENTERAL
INTRAMUSCULAR

Morphine,

NASAL SPRAY
TRANSDERMAL PATCH

DRUG
Buprenorphine, Pentazocine
Butorphanol, Pentazocine
Buprenorphine
Butorphanol
Buprenorphine

AGONIST- ANTAGONIST DRUGS

DRUG

RECEPTOR EFFECTS

PENTAZOCINE (Partial Agonist)

NALBUPHINE

D R U G I N T E R A C TI O N S

Morphine precipitate abstinence syndrome (Nalbuphine,

Buprenorphine)

Fentanyl reversal of respiratory depression (Buprenorphine)

++

BUPRENORPHINE (Partial Agonist)

BUTORPHANOL

+++

**Buprenorphine has a long duration because it dissociates w/ Mu slowly

KARA LIBED

11

MISCELLANEOUS

TR A MA D O L

PHARMACODYNAMICS
o

IV onset of action: 1-3 minutes

Normalizes the ff. w/ acute depression secondary to

opioid OD:

Weak -receptor agonist

Respiration

MOA

Level of consciousness

Blockade of serotonin reuptake by (+) enantiomer

Pupil size

Weak NE reuptake blocker and stimulates 2receptor by (-) enantiomer

Bowel activity

Awareness of pain

USE relief of mild to moderate pain and labor pain and adjunct
to opioids in chronic pain syndrome

Partially antagonized by Naloxone

PHARMACOKINETICS

CLINICAL USE
o

BA: 68% (oral, 100% (IV)

Peak: 2-3 hours

Duration: 6 hours

METABOLISM:

For dependent subjects: may precipitate abstinence

syndrome

Major application:

Acute opioid OD

Neonatal respiratory depression induced

by maternal opioid administration

Treatment of opioid AE (low-dose Naloxone)

liver by CYP2D6 and CYP3A4

Constipation (Methylnaltrexone)

O-demethylation active metabolite **24x more potent that active compound

Management of abuse syndromes (Naltrexone)

**because of long half-life

T : 6 hours; 7.5 hours active metabolite

Maintenance drug for addicts

EXCRETION: Renal

Decrease
alcoholics

Facilitate abstinence from nicotine

SIDE EFFECTS:
o

N&V, dizziness, dry mouth, sedation, headache,

respiratory depression, constipation, seizures, physical
dependence, abuse, addiction, withdrawal

Relative contraindication: Seizure disorders

Drug interactions: SSRI, MAOI

alcohol

craving

among

TA P E N T A D O L

MOA:
o

Strong NE reuptake inhibitor

Modest -opioid reuptake affinity

Monoamine reuptake inhibitor activity

Activity, efficacy, SE, contraindication, and DI profile is similar to

Tramadol **can also cause Serotonin syndrome

PHARMACOKINETICS
o

Metabolism: conjugation w/ glucuronic acid

Excretion: urine (70%)

OPIOID ANTAGONIST
N A L O XO N E , N A L TR E X O N E , N A L ME F E N E

AFFINITY: mu > kappa, delta

PHARMACOKINETICS
NALOXONE

Duration: 1-2 hours

NALTREXONE

Metabolism: glucuronide conjugation

Well-absorbed orally
Rapid first-pass metabolism
T : 10 hours

NALMEFENE

Derivative of Naltrexone: IV
T : 8-10 hours

KARA LIBED

12