PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS

LYLAH D. REYES, MD (JAN 10, 2018)

ORGANIZATION OF THE CENTRAL NERVOUS SYSTEM MICROANATOMY OF THE BRAIN

MACROFUNCTIONS OF THE REGIONS OF THE BRAIN

Neurons
v
" Classified according to function:
§ Sensory
§ Motor
§ Interneurons – facilitate transmission of impulses
v Neuroglia
o Astrocyte
" Most abundant glial cells in the brain
v Cerebral Cortex " Plays homeostatic support roles, including providing
" Thought, memory, consciousness metabolic nutrients to neurons and maintaining
" Supervisory integration of the ANS extracellular ion concentrations (since the end-feet are
" Integrate somatic and vegetative functions (CVS, GIT) connected with the vasculature of the brain and the
v Limbic System other with the neuron)
" Responsible for emotion and motivation and regulate " Also involved in the removal and recycling of
extrapyramidal motor system (voluntary) neurotransmitters after release and play increasingly
" Governed by Dopamine appreciated roles in regulating neurotransmission
" Damage of the nigrostriatal area leads to Parkinson’s disease o Oligodendrocytes
v Diencephalon " Cells that wrap around the axons of projection neurons
" Regulatory control over visceral functions in the CNS forming the myelin sheath, which insulates
" Integrating region for the entire ANS the axons and increases the speed of signal propagation
" Regulate body temperature, water balance, intermediary " Damage occurs in multiple sclerosis and thus is a target
metabolism, BP, sexual and circadian cycles of drug discovery efforts.
" Secretion of adenohypophysis, sleep and emotion • Multiple sclerosis is characterized by slow
v Midbrain and Brainstem transmission of impulses
" Composed of major monoamine-containing neurons (eg. o Microglia
Dopamine, NEP, Serotonin) " Specialized macrophages derived from the bone
" Central integration for coordination of essential reflexive marrow that are found in the CNS
acts (swallowing, vomiting) " Major immune defense system in the brain that are
" Primary receptive region for most visceral afferent sensory actively involved in neuroinflammatory processes in
information many pathological states including neurodegenerative
" Regulation of sleep, wakefulness, level of arousal, and eye diseases (eg. Parkinson’s disease, Huntington’s disease)
movement coordination
v Cerebellum BLOOD-BRAIN BARRIER
" Vestibular (position-stabilizing) function " Serves as a protective functional separator of the circulating blood
F Maintain proper tone of antigravity musculature from the extracellular fluid of the CNS that limits the penetration
and provide continuous feedback during volitional of substances, including drugs.
movements of the trunk and extremities • Separation is accomplished by the presence of tight junctions
" Regulate visceral function (HR) between the capillary endothelial cells and surrounding layer
" Learning and memory; Writing reflexes are controlled of astrocyte end-feet
v Spinal cord " Functions:
" Conduit for sensory information µ Controls delivery of nutrients (Not all substances can pass
" Elicit autonomic reflexes (eg. Changes in skin vasculature through the BBB)
with alteration of temperature) µ Clears metabolites into the CSF by excretion through the
choroid plexus
µ Protects abrupt changes in blood biochemistry that occur
after meals, physical exercises or in pathological conditions

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REFERENCES: Bianca Cala Trans + 2016 trans + Katzung 13 ed + Goodman and Gilmans, 12 ed By: LUBY
 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)

TRANSPORT OF SUBSTANCES ACROSS THE BBB

v Passive Diffusion
" Dependent on the partition of solute across the membrane
(concentration gradient of the solute)
" Can easily pass through membranes and does not require
energy (eg. O2, electrolytes, gases)
v Active Membrane Transport
" Energy-dependent
" Aids substances that cannot transport alone through the BBB
• Example: L-DOPA
F Dopamine alone cannot cross the BBB.
F In cases of Parkinson’s disease, L-DOPA is combined
with a decarboxylase inhibitor, Carbidopa, to
prevent decarboxylation of L-DOPA to Dopamine
" Efflux transporters
• Facilitate movement of substances to the brain
F ATP-binding cassette (ABC) transporters
F Organic anion transporting polypeptide (OATP)
ð Antibacterial, anticancer
F Organic cation transporters (OCT/OCT, SLC22A1-3)
ð One of the minor pathways involved in the
elimination of NEP from the synaptic cleft
ð Reuptake through NET eliminates 90% of NEP v Ligand-gated channels
F P-glycoprotein " A ligand/agent has to bind to the binding site to open the
F Solute carrier family (SLC family) channel
F MDR-associated proteins(MRPs) " Example: AMPA receptor for Glutamate
F Breast cancer resistance protein (BCRP) • Once Glutamate binds to its ligand-binding site on the
F Renal specific transporter (RST) AMPA receptor, the Na channels will open
• Problems encountered: Genetic polymorphisms may " Activation of these channels typically results in a brief (a few
affect function of transporters milliseconds to tens of milliseconds) opening of the channel
" Responsible for fast synaptic transmission, typical of
DETERMINANTS FOR THE ENTRY OF DRUGS BY THE BRAIN hierarchical pathways in the CNS
µ Molecular Weight
" More relevant on hydrophilic substances
" Greater molecular weight cause less ease in transport
µ Lipophilicity
µ Charge
µ Polarity
µ Small, Unionized, Uncharged, Non-polar substances can easily
cross the BBB

FACTORS THAT MAY INCREASE ACCESS OF SUBSTANCES

µ Cerebral ischemia
µ Inflammation
" Can cause vasodilatation (gaps between the endothelial cells
are wider)
" Penicillin does not cross the BBB but it can cross the
membrane due to the presence of inflammation (eg.
Meningitis) or if given in high doses

ION CHANNELS & NEUROTRANSMITTER RECEPTORS

ION CHANNELS
v Voltage-gated channels
" Respond to changes in membrane potential causing activation
or inactivation of the channel
" Example: Calcium channels
• If the presynaptic fiber is depolarized (positively
charged), the voltage gated Ca channels will open à
Ca will enter à NEP will be released

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 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
• Drugs used for Alzheimer’s disease, a
NEUROTRANSMITTER RECEPTORS neurodegenerative disorder that causes
v Ionotropic impairment in cognition and memory
" Behaves like a ligand-gated channel • Tertiary in nature/lipophilic that’s why they can
" Receptors consist of multiple subunits and insensitive or only easily transfer to the membrane
weakly sensitive to membrane potential • Ach degradation is inhibited à Ach acts on M1
v Metabotropic/G-protein coupled receptors à M1 promotes attention, learning and memory
" Binding to the receptor engages a G protein, which results 8. Transmitter Receptor
in the production of second messengers that mediate " Primary site of drug action
intracellular signaling cascades 9. Receptor induced increase or decrease in ionic
conductance
SITE OF DRUG ACTION 10. Retrograde signaling

SELECTIVITY OF CNS DRUG ACTION

Based on 2 Primary Factors:
µ Different neurotransmitters are released by different groups of
neurons
" Often segregated into neuronal systems that subserve
broadly different CNS functions
" There is a particular area in the CNS that secretes these
NTAs
" Example:
F Serotonin is usually situated in the median raphe
nuclei
F Dopamine is secreted by neurons in the limbic area
µ Multiplicity of receptors for each neurotransmitter
" For example, at least 14 different serotonin receptors are
encoded by different genes with differential cellular
distributions throughout the CNS, allowing for the
development of drugs that selectively target particular
receptors and CNS functions.
" Some NTAs exhibit the lock-and-key phenomenon, in
which one drug is indicated for a specific receptor. Not all
v Pre-synaptic Category drugs can act on all receptor subtypes.
" Involves drugs acting on the:
1. Action potential generation CELLULAR ORGANIZATIONS OF THE BRAIN
2. Synthesis
" Example: 5-HT2A blockers (eg. Clozapine) v Hierarchical Systems
• 5-HT2A is found on the presynaptic fiber of the " Include all the pathways directly involved in sensory
dopamine neurons perception and motor control
• If Serotonin occupies 5-HT2A, Dopamine " Generally clearly delineated, composed of large myelinated
release is inhibited. Once 5-HT2A is blocked, fibers
Dopamine will be released. " Information is typically phasic and occurs in bursts of action
3. Storage potentials
" Example: Reserpine " In sensory systems, the information is processed
• Reserpine depletes monoamine synapses of sequentially by successive integrations at each relay
transmitters by preventing transfer of nucleus on its way to the cortex.
Dopamine into the VMAT TYPES:
4. Metabolism § Relay/Projection Neurons
5. Release of NTAs " Form the interconnecting pathways that transmit
v Post-synaptic Category signals over long distances
" Drugs may affect: " Cell bodies are relatively large
6. Reuptake " Axons can project long distances but also emit small
" Example: Anti-depressants collaterals that synapse onto local interneurons
• Depression is said to be due to reduced " Neurons are excitatory which involve ionotropic
monoamines. Most drugs for depression receptors and short-lived synaptic influences
inhibit reuptake to accumulate the " Release glutamate
monoamines within the synaptic cleft. " Pharmacologic manipulations in this area produce
7. Degradation profound effects on the overall excitability of the CNS
" Examples: Acetylcholinesterase inhibitors (Tacrine,
Donepezil, Rivastigmine)

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 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
§ Local circuit neurons "Substances that participate in eliciting postsynaptic
" Smaller than relay response from the transmitter as a biochemical effector
neurons (True among metabotropic receptors)
" Axons arborize in " Examples: cAMP, cGMP, IP
the immediate v Neurotrophic Factors
vicinity of the cell " Link receptors to regulate gene expression and control
body neuronal growth and phenotypic characteristics
" Most are inhibitory " 7 Categories:
" Release either GABA § Classic neurotrophins (Brain-derived neurotrophic
or Glycine factor/BDNF, nerve growth factor)
" Modulate the " BDNF promotes trophic stimulation of neuronal
excitatory effects of cells responsive to monoamines
the relay neurons " BDNF deficiency can lead to depression because it
" Pathways: takes a while for BDNF to recover
• Recurrent • Depression takes 2-3 weeks to be alleviated by
feedback anti-depressants
• Feed-forward • It is said that Omega-3 and DHA are good
supplements. Increased DHA can be protective
against Alzheimer’s disease by reducing PSEN
gene activity and increasing BDNF
• DHA can also reduce post-partum depression
among pregnant women
§ Neuropoietic factors (leukemia inhibitory factor, ciliary
v Nonspecific/Diffuse neurotrophic factors)
neurons § Growth factor peptides (epidermal growth factor, TGF-
" Produced by only a limited number of neurons whose cell alpha and beta, glial cell neurotrophic factor, activin A)
bodies are located in small discrete nuclei, often in the § Fibroblast growth factors
brainstem § Platelet-derived growth factors
" Projects widely (has multiple receptors) producing diverse § Axon guidance molecules
effects. Each receptor type will have a different effect.
" Modulate the function of the hierarchical pathways TYPES OF MEDIATORS OF THE CNS
" Examples: Monoamines (Dopamine, NEP, Serotonin); Ach
MEDIATOR EXAMPLES TARGETS MAIN FUNCTION
CENTRAL NEUROTRANSMITTERS TYPE ROLE
CRITERIA FOR TRANSMITTER IDENTIFICATION Conventional Glutamate Ligand- Fast and slow
v Localization small-molecule GABA gated ion synaptic
" Must reside in the presynaptic terminal of the pathway of Ach channels neurotransmission
interest and stored in a vesicle Dopamine GPCR Neuromodulation
v Release 5-HT
" Must be released from a neuron in response to neuronal Neuropeptides Substance P GPCR Neuromodulation
activity and in a calcium-dependent manner Neuropeptide Y
v Synaptic mimicry Endorphins
" Application of the candidate substance should produce a CRF
response that mimics the action of the transmitter released Lipid mediators PG GPCR Neuromodulation
by nerve stimulation, and application of a selective Endocannabinoids
antagonist should block the response. Nitric oxide --- Guanylyl Neuromodulation
cyclase
CLASSIFICATIONS
Neurotrophins Nerve GF Kinase- Neuronal growth
v Neurohormones Cytokines BDNF linked Survival
" Released in a hormone-like fashion from peptide-secreting IL-1 receptors Functional plasticity
cells of the hypothalamic-hypophyseal circuits Steroids Androgens Nuclear and Functional plasticity
" Examples: Oxytocin, Arginine-Vasopressin Estrogens Membrane
v Neuromodulators receptors
" Released by neurons and astrocytes
" Produce slower pre or postsynaptic responses Functional plasticity is important for continued cognition and
" Tend to regulate action of other transmitters sustained capacity of the brain for learning and memory
" Examples: CO2, Adenosine, Purines, Eicosanoids, NO § Patients who are menopausal/andropausal may experience
v Neuromediators forgetfulness due to decreased estrogen and androgen
" Do not directly activate voltage-gated ion channels or respectively
receptors § It’s important to keep the brain working always! Accept that
we have to be perpetual students for life hahahahuhuhu

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 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
" Heterotetramers assembled from four subunits
AMINO ACID TRANSMITTERS (GluA1–GluA4)
" Majority contain the GluA2 subunit and are
GLUTAMATE 2+
permeable to Na+ and K+, but not to Ca
NTA ANATOMY RECEPTOR RECEPTOR MECHANISMS • Open quickly; Will provide fast excitatory
SUBTYPES & ANTAGONISTS postsynaptic potential
AGONISTS
" Some AMPA receptors, typically present on
Glutamate Relay N-Methyl-D- 2-Amino-5- Excitatory: ↑ inhibitory interneurons, lack the GluA2 subunit and
neurons at aspartate phosphonovalerate, cation
are also permeable to Ca2+.
all levels and (NMDA): dizocilpine conductance,
some NMDA particularly o Kainic acid (KA)
interneurons
2+
Ca " Not as uniformly distributed as AMPA receptors,
being expressed at high levels in the hippocampus,
AMPA: AMPA NBQX Excitatory: ↑ cerebellum, and spinal cord
cation " Formed from a number of subunit combinations
conductance (GluK1–GluK5)
o N-methyl-d-aspartate (NMDA)
Kainate: ACET Excitatory: ↑
" Ubiquitous as AMPA receptors, being present on
Kainic acid, cation
Domoic acid conductance
essentially all neurons in the CNS
Metabotropic: MCPG Inhibitory " All require the presence of the subunit GluN1.
ACPD, (presynaptic): " The channel also contains one or two GluN2 subunits
quisqualate ↓ Ca
2+
(GluN2A–GluN2D).
2+
conductance, " All NMDA receptors are highly permeable to Ca as
↓ cAMP; well as to Na+ and K+.
Excitatory: • Open slowly; Will provide slow excitatory
↓ K+
postsynaptic potential
conductance,
↑ IP3, DAG

MECHANISM OF GLUTAMATE BINDING TO NMDA & AMPA

RECEPTORS:
1. Glutamate is released from the presynaptic fiber once
2+
intracellular Ca increases. Fusion proteins from the storage
vesicle will fuse with the membrane of the presynaptic fiber
" Glutamate can be synthesized to glutamine and vice versa by glycine
2. Once it is released, glutamate will bind to its ligand binding site
synthetase. Glutamine can also be converted to Glutamate by
on the AMPA and NMDA receptors
glutamate synthase. +
3. AMPA will now mediate opening of Na channels. However, with
ð Substrates from the citric acid cycle, with the enzyme 2+ 2+
NMDA, Mg blocks the entry of Ca
glutamate synthase, can be converted to Glutamate +
ð For Mg2+ to be driven out, Na entry should sufficiently
ð Glutamate can be converted to GABA via glutamate 2+
depolarize the cell à Facilitate entry of Ca
decarboxylase 2+
4. Ca entry will produce a second messenger that promotes
ð GABA may be taken up by the astrocyte à Converted to
insertion of more AMPA receptors à Functional plasticity
Glutamine à Brought back to the neuron à Converted
ð The more AMPA inserted in the postsynaptic membrane
back to glutamate
will result to more excitation
" Excitatory because it increases cationic conductance, which 2+
5. Ca entry will also produce a second messenger to increase NO
involves activation of both:
production
• Ionotropic Receptors
ð Once NO goes to the presynaptic membrane, it further
o α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
stimulate Glutamate release
(AMPA)

" Present on all neurons

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REFERENCES: Bianca Cala Trans + 2016 trans + Katzung 13 ed + Goodman and Gilmans, 12 ed By: LUBY
 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)

PROPERTIES OF IONOTROPIC GLUTAMATE RECEPTORS GABA & GLYCINE

PROPERTY NMDA AMPA Kainate
Effector Ligand-gated cation channel Ligand-gated Ligand-gated NTA ANATOMY RECEPTOR RECEPTOR MECHANISMS
mechanism (Slow kinetics, High Ca cation channel cation SUBTYPES & ANTAGONISTS
permeability) (Fast kinetics; channel (Fast AGONISTS
Channels kinetics, Low GABA Supraspinal GABAA: Bicuculline, Inhibitory: ↑ Cl–
possessing Ca and spinal muscimol (for picrotoxin conductance
GluR2A permeability) interneurons seizures)
subunits show involved in
low Ca pre- and GABAB: 2-OH saclofen Inhibitory
permeability) postsynaptic baclofen (presynaptic): ↓
Location Postsynaptic (Some Post synaptic Pre- and inhibition (muscle Ca2+
presynaptic, also glial) (also glial) postsynaptic relaxant) conductance;
Wide distribution Wide Limited Inhibitory
distribution distribution (postsynaptic): ↑ K+
Function Slow EPS Fast EPSP Fast EPSP conductance
Synaptic plasticity Presynaptic
(Long-term potentiation, Long- inhibition Glycine Spinal Taurine, β- Strychnine Inhibitory: ↑ Cl–
term depression) interneurons alanine conductance
Excitotoxicity and some
Endogenous Receptor Modulatory Glutamate Glutamate brainstem
agonist site: Site (Gly): interneurons
Glutamate Glycine
Aspartate D-serine
Other NMDA Cycloserine AMPA Kainate PROPERTIES OF INHIBITORY AMINO ACID RECEPTORS (GABA)
agonist Quisqualate Domoate PROPERTY GABA A GABA B Glycine
Effector Ligand-gated Cl channel GPCR Ligand-
Antagonist AP-5 7-Chloro- NBQX NBQX mechanism inhibition of gated Cl
CPP kynurenic ACET adenylyl channel
acid cyclase,
HA-466 (-) of Ca
Other Polyamines (Spermine, Cyclothiazide --- channels, (+)
modulators Spermidine) Piracetam K channels
Location Widespread, mainly GABAergic Pre- and Postsynaptic(
Mg, Zn CX-516
interneurons postsynaptic mainly in
Channel Dizoclipine, Phecyclidine, --- --- brainstem
Blockers Ketamine (for general Widespread
and SC)
anesthesia), Remacemide, Function Postsynaptic inhibition (Fast IPSP and Presynaptic Postsynaptic
Memantine, Mg tonic inhibition) inhibition (↓ inhibition
Ca (Fast IPSP)
entry)
• Certain anti-seizure agents may affect these receptors because
seizure is brought about by the depolarization of the cell. Postsynaptic
Inhibition
Propagation and synchronization of seizure impulses are
(↑K
brought by Dec GABA, Inc Glutamate. Further propagation of permeability)
impulses is brought about by Na and Ca ions
• Anti-seizure agents either Dec GABA, Inc Glutamate or close Na Receptor Modulatory Modulatory
and Ca channels Site Site Site
(BZD) (Others)
Various
Endogenous GABA Unknown GABA Glycine
• Metabotropic Receptors/GPCR agonist neurosteroids B-alanine
" AMPA act indirectly on ion channels via G proteins. (eg.
Taurine
Progesterone
" Metabotropic receptors (mGluR1–mGluR8) have been
metabolites)
divided into three groups: Other Muscimol Anxiolytic Barbiturates Baclofen ---
§ Group 1: Located postsynaptically and agonist Gaboxadol BZD steroid
activate phospholipase C, leading to inositol Anesthetic
trisphosphate mediated intracellular Ca2+ (eg.
release. Alphaxolone)
§ Groups II and III: Located on presynaptic Antagonist Bicuculline Flumaxenil --- 2-OH saclofen Styrchnine
Gabazine (inverse CGP35348
nerve terminals and act as inhibitory
agonist) Others
autoreceptors
Channel Picrotoxin --- ---

Blockers


Benzodiazepines and Barbiturates are modulatory because when they bind to
GABA modulatory/allosteric site, they amplify the activity of binding site to
increase GABA activity.

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REFERENCES: Bianca Cala Trans + 2016 trans + Katzung 13 ed + Goodman and Gilmans, 12 ed By: LUBY
 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
" Both NTAs are inhibitory due to increased anionic conductance • If NEP is not released, no NEP will act on a1 & b2 receptors on
" Released from local interneurons: the blood vessels à M3 & M5 (Parasympa) will predominate
• Glycine is restricted to the spinal cord and brainstem à Vasodilatation à Dec PVR à LOW BP
• GABA is present throughout the CNS • If NEP is not released, no NEP will act on b1 receptors on the
" Glycine receptors are pentameric structures that are selectively heart à Dec HR à Dec CO à LOW BP
−
permeable to Cl • At the same time, no NEP will act on b1 receptors on the
" GABA Receptors are divided into two main types: kidneys à Dec RAAS Activity à BVs will dilate, Dec H2O
• GABAA (Fast component) Retention & Aldosterone activity à Dec CO à Dec TPR à
ð Ionotropic, pentameric structures that are also LOW BP
−
selectively permeable to to Cl
ð When Cl- enters the cell, it becomes more negative à
DOPAMINE
Hyperpolarized state à Not amenable to any form of
stimulus NTA ANATOMY RECEPTOR RECEPTOR MECHANISMS
• GABAB (Slow component) SUBTYPES & ANTAGONISTS
ð Metabotropic, presynaptic, decreases Ca conductance AGONISTS
ð When Ca conductance is decreased in the presynaptic Dopamine Cell bodies at D1: Phenothiazines Inhibitory (?):
all levels; dihydrexidine ↑ cAMP
areas, NTA release is inhibited
short,
ð There is also the outward flow of K. When K medium, and D2: Phenothiazines Inhibitory
conductance is increased in the postsynaptic area, it long bromocriptine Butyrophenones (presynaptic):
becomes less positive until it becomes negative à connections ↓ Ca2+;
Hyperpolarized state Inhibitory
" GABA is indicated for seizures (Anti-convulsants) to outweigh the (postsynaptic):
imbalance of Glutamate and GABA by: ↑ in K+
• Inhibiting reuptake of GABA conductance,
↓ cAMP
ð GABA will be accumulated in the synaptic cleft

• Preventing metabolism of GABA
" The major pathways containing Dopamine are the projection
MONOAMINE TRANSMITTERS linking the substantia nigra to the neostriatum and the projection
linking the ventral tegmental region to limbic structures,
NORADRENALINE IN THE CNS particularly the limbic cortex
NTA ANATOMY RECEPTOR RECEPTOR MECHANISMS
" Has metabotropic receptors that fall into two categories: D1-like
SUBTYPES & ANTAGONISTS (D1 and D5) and D2-like (D2, D3, D4)
AGONISTS • Gs activates adenylyl cyclase which leads to ↑ cAMP. As
NEP Cell bodies in a1:Phenylephrine Prazosin Excitatory: ↓ K+ cAMP increases, Ca is sucked through the ER à Dec
conductance, cytosolic Ca à Effect is INHIBITION
pons and
↑ IP3, DAG
brainstem Inhibitory
• Gi inhibits adenylyl cyclase but the effect is mainly on
a2: Clonidine Yohimbine
project to all (presynaptic): ↓ activating K channels à K goes out à Hyperpolarized

levels Ca2+ " Generally exerts a slow inhibitory action on CNS neurons, which
conductance; are best characterized on dopamine-containing substantia nigra

Inhibitory: ↑ K+
conductance, ↓ neurons, where D2-receptor activation opens potassium channels
cAMP via the Gi coupling protein.
b1: Atenolol, Excitatory: ↓ K+ • Once the D2 receptors are activated, they suppressed the
Practolol conductance,
Isoproterenol,
↑ cAMP
synthesis of dopamine by inhibiting the phosphorylation of
Dobutamine the enzyme tyrosine hydroxylase à no tyrosine à no
dopamine synthesis
b2: Albuterol Butoxamine Inhibitory: may
involve ↑ in • In the postsynaptic area, D2 receptors may be excitatory

electrogenic as it may liberate Ca from the ER by increasing IP3
sodium pump; ↑ formation
cAMP
• D3 activates K channels and inhibits Ca channels à Ca K
moves out à Ca does not move in à no release of
" Metabotropic receptors
dopamine
" Functions:
• Arousal system, controlling wakefulness and alertness MONOAMINE TRANSMITTERS: DOPAMINE IN THE CNS
• BP regulation D1 type D2 Type
• Control of mood (functional deficiency contributing to D1 D5 D2 D3 D4
depression) Signal Gs coupled G1/G0 coupled – inhibit adenylyl
" Receptors are present on the cell bodies in the pons and brainstem transduction (+) Adenylyl cyclase
cyclase Activates K channels
" Example: Clonidine & Methlydopa (a2-agonists)
Inhibits Ca channels
• Used for hypotension (Central sympatholytics; act on a2 in the May also activate phospholipase C
presynaptic fiber) à Dec Ca conductance à NTA release is Effect Mainly Pre- and postsynaptic inhibition
inhibited postsynaptic Stimulation/inhibition of hormone
inhibition release

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REFERENCES: Bianca Cala Trans + 2016 trans + Katzung 13 ed + Goodman and Gilmans, 12 ed By: LUBY
 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
" Functions associated with 5-HT pathways:
DOPAMINERGIC PATHWAYS • Behavioral responses (ex: hallucinatory, behavior, “wet
PATHWAY FUNCTIONAL ROLE D1 Type D2 Type dog shakes”)
D1 D5 D2 D3 D4 • Feeding behavior
Nigrostriatal Motor control +++ + ++ + +
• Control of mood and emotion
Mesolimbic Behavioral effects +++ + ++ +
• Control of sleep/wakefulness
Emotion
Stereotypic behavior • Control of sensory pathways, including nociception
Mesocortical Behavioral effects +++ - ++ - + • Control of body temperature
Arousal, mood • Vomiting
Tuberohypophyseal or Endocrine control - - ++ + -
Tuberoinfundibular
5-HT RECEPTORS

RECEPTOR ACTION DRUG
" When Dopamine is DECREASED in the nigrostriatal area, it can lead
5-HT1A Inhibitory: ↑ K+ conductance, Buspirone – partial
to Parkinsonian signs and symptoms
↓ cAMP agonist
" INCREASED Dopamine in the mesolimbic area causes hallucinations,

seen as positive symptoms of schizophrenia
5-HT2A Excitatory: ↓ K+ conductance, Blocked by
" DECREASED Dopamine in the mesocortical area may lead to
↑ IP3, DAG Clozapine,
negative symptoms of schizophrenia such as avolition, non-
↑ Ca Risperidone and
motivated/non-goal oriented movements, loss of fluency of speech
Olanzapine
" Dopamine inhibits the release of prolactin. DECREASED levels in the

tuberohypophyseal area leads to enhancement of prolactin
production 5-HT3 Excitatory: ↑ cation Blocked by
conductance Ondansetron
DOPAMINE AGONISTS
AGONIST D1 Type D2 Type 5-HT4 Excitatory: ↓ K+ conductance
D1 D5 D2 D3 D4
Nigrostriatal + (Low potency) + (High potency)
Mesolimbic PA (Low potency) + (High potency) 5-HT FUNCTIONS
Mesocortical PA (Low potency) + (High potency) FUNCTION DRUG ACTION
Tuberohypophyseal or Inactive Active Behavioral responses: Clozapine 5-HT2A antagonist
Tuberoinfundibular anti-psychotics
" D2-Type of receptors have high potency. This is the reason why Control of emotions: SSRI 5-HT reuptake
these are targeted by drugs used for the management of anti-depressant inhibitor
schizophrenia (anti-psychotics). Control of Buspirone 5-HT-1A receptor
• REMEMBER: D2 inhibits Dopamine synthesis. If D2 receptors sleep/wakefulness: agonist
are blocked presynaptically, this leads to Inc DOPAMINE anxiolytic
• In the mesolimbic area, there is a physiological Control of sensory Sumatriptan 5-HT-1D receptor
depolarization inactivation. Thereby, the effect becomes pathways, including Pizotifen antagonist
inhibitory nociception and anti- 5-HT-2 receptor
DOPAMINE ANTAGONISTS migraine antagonist
ANTAGONIST D1 Type D2 Type Vomiting: anti-emetic Ondansetron 5-HT3 receptor
D1 D5 D2 D3 D4 antagonist
Chlorpromazine + + +++ ++ +
Haloperidol + + +++ ++ ++
Spiperone +? - +++ +++ +++ NOTE:
Sulpride - - ++ ++ + • 5-HT-1D Receptor is a vasodilator. Migraine is characterized by
Clozapine + + + + ++ dilatation of cerebral blood vessels. Once an antagonist is given, it
Aripiprazole - - +++ (PA) ++ - will cause vasoconstriction.
Raclopride - ? +++ ++ - • 5-HT3 receptor antagonist is indicated for vomiting.
o In chemotherapy or in patients with renal failure developing
5-HYDROXYTRYPTAMINE/SEROTONIN azotemia and uremia à 5-HT will be released à Act on 5-HT3
receptors on the chemoreceptor trigger zone à Vomiting
" Part of Nonspecific/Diffuse Neurons
o Note: Drugs for vomiting are dependent on the cause:
" They are concentrated in several parts of the brain such as, the o
§ 2 to chemo and renal failure – 5-HT3 antagonist
midline raphe nuclei in the brainstem projecting to the cortex,
limbic system, hypothalamus, and spinal cord § Motion sickness – Anti-muscarinic
" 5-HT can exert inhibitory or excitatory effects on individual • 5-HT2A inhibits the release of dopamine. Anti-schizophrenics and
neurons: Presynaptic & Postsynaptic anti-psychotics can cause drug interactions.
" Histaminergic neurons originate in the hypothalamus: H1 to H4
receptors
o Each receptor type will produce a different action

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 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)

ACETYLCHOLINE NICOTINE
" Involved in the following pathways: " Was used as a pesticide
• Basal forebrain (magnocellular) nuclei including cortex " Mechanism: opening of Na/K channels
• Septohippocampal projection " Major action:
• Short interneurons in the striatum and nucleus accumbens • Stimulation
" Abnormalities à neurodegenerative diseases (dementia, • Complex arousal, attention analgesia
Parkinson’s disease) • Low doses: weak analgesia
" Receptors: • High doses: tremors à convulsions
• Nicotinic
F Central effects NEUROPEPTIDES
F Location: presynaptic (main), postsynaptic (few) " Examples:
• Muscarinic (predominantly M1) • Opioid peptides (eg. Enkephalins, Endorphins)
F Behavioral effects (arousal) • Neurotensin
F Learning • Substance P
F Short-term memory • Neuropeptide Y
" Clinical use: • Thyrotropin-releasing hormone
• Muscarinic agonist " Implicated in several CNS functions:
F Alzheimer’s disease – Tacrine, Donezepil, • Reproduction
Galantamine, Rivastigmine • Social behavior
• Muscarinic antagonist • Appetite
F Amnesia – Hyoscine • Arousal
F Parkinson’s disease (Benztropine) • Pain
• Reward
RECEPTORS
• Learning and Memory
v M1
" Excitatory OTHER SUBSTANCES
" Mechanism: Gq/11 à PLC à IP3 + DAG à Ca + PKC
v PURINES
" Function:
" ATP acts on:
• Increase activity of the cholinergic projections from
" Ionotropic P2X receptors – excitatory
pedunculopontine nucleus, the lateral tegmental
" Metabotropic receptors P2Y – neuromodulator
nucleus, nucleus basalis of Meynert à promote " Excessive release à neurotoxic
attention " Converted to ADP, AMP, adenosine
• In the temporal lobe à promote memory and
cognition v ADENOSINE
v M4 " Released by carrier mechanisms or generated from released
" Inhibitory ATP under pathological conditions
" Mechanism: Gi/0 à inhibit AC à inhibit cAMP production " Mainly inhibitory effects through A1 and A2 receptors
à promote K channel opening " Effects:
" Function:
• Sedative
• Inhibition of nociceptive transmission from the rostral • Anticonvulsant
ventral medulla to the dorsal horn
• Neuroprotective
• Suppression of action potential firing from the

secondary sensory neurons
v METHYLXANTHINE
" Example: Coffee
NOTE: " Antagonist at A2 receptors
• Drugs used for Alzheimer’s disease are acetylcholinesterase " Effect: increase wakefulness
inhibitors. Agonists to the muscarinic receptors do not cause much
to the CNS due to the quaternary structure v NITRIC OXIDE (nNOS)
o Ache is inhibited à Inc availability of Ach to work on M1 " Production increased by mechanisms that raise intracellular
receptors calcium (Neuromodulator)
• In Parkinson’s disease, Dopamine inhibits acetylcholine release. Dec " In the CNS, it promotes Glutamate release à Excitatory
Dopamine = Inc Ach à Movement disorders • However, its prolonged effect is that it will promote too
o DOC: L-DOPA + Decarboxylase inhibitor or Dopamine agonist much release of glutamate and deplete storage à
o Anticholinergic agents are only given if these are not Becomes inhibitory
working/do not give optimum response " Action:
• • Increased cGMP à effect: inhibitory and excitatory
• Forms peroxynitrite (in large amounts) à neurotoxicity

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 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
v MELATONIN
" Synthesized from 5-HT GENERAL CLASSIFICATION OF DRUGS ACTING ON THE CNS
" Mainly in the pineal gland DRUG CLASS CLINICAL USE DRUGS
" Secretion controlled by light intensity Isoflurane
General anesthetics Surgical anesthesia
• Low by day Propofol
• High by night (Secreted when it is dark) Analgesics Pain control Opiates
" Mechanism of controlling pineal gland: Fibers from retina à Carbamazepine
suprachiasmatic nucleus à sympathetic innervation à Gabapentin
control pineal gland Anxiolytics and sedatives Relieve anxiety and Benzodiazepines
" MT1 and MT2 receptors à Effect: sedation Hypnotics, sedatives, minor insomnia Benzodiazepine
tranquilizers receptor ligand
" Agonist:
Barbiturates
• Induce sleep Buspirone
• Antidepressant Antiepileptic/anticonvulsants Reduce seizures Carbamazepine
Phenytoin
ACTIONS OF DRUGS IN THE CNS Valproate
v Specific Lamotrigine
Antipsychotic Relieve symptoms Typical – Haloperidol
" Happens when the drug affects an identifiable molecular
Atypical – Clozapeine,
mechanism unique to target cells that bear receptors for drugs/neuroleptics of schizophrenia Risperidone
that drug Antidepressants Alleviate depressive SSRI, SNRI, TCA,
v Nonspecific disorders MAO
" When a drug produces effects on many different target cells Psychomotor stimulants Promote Amphetamine
and acts by diverse molecular mechanisms Psychostimulants wakefulness and Cocaine
" Example: Several sites of serotonin are activated = produce euphoria Methylphenidate
diverse molecular mechanisms Caffeine
Psychotomimetics Relieve perception Lysergic acid
EXCEPTIONS: Hallucinogens (hallucinations) and diethylamide
• Highly specific drug at low concentration may exhibit non- Psychodysleptics behavioral Mescaline
specific action at higher doses and vice versa Phencyclidine
disturbances
• Drugs with specific actions may produce non-specific effects if Cognition enhancers Improve memory Acetylcholinesterase
the dose and route of administration produce high tissue Nootropics and cognition inhibitors
concentration performance Donepezil
• Example: Hypnotic-sedatives Galantamine
o If given at low concentrations = Specific effects Rivastigmine
NMDA receptor
(hypnosis & sedation)
antagonists:
o If given at high dosage/a route that will foster increase memantine
concentration = Nonspecific CNS depressant Others: piracetam

ACTION DRUGS
OPIOID AGONISTS AND ANTAGONISTS
General (non-specific) CNS Anesthetic gases and vapors
depressant Alipathic alcohols TYPES OF PAIN/NOCICEPTION
Hypnotic-sedative v Acute Pain
General (non-specific) CNS Pentylenetetrazole " Mechanism: Small high-threshold fibers sensory afferent
stimulants Methylxanthines fibers are activated
• Blockade of inhibition " Examples of such stimuli include a hot coffee cup, a needle
• Direct neuronal stick, or an incision.
excitation v Chronic Pain
Selective modifier of CNS Anticonvulsants " 2 Mechanisms:
function Anti-parkinson’s drugs • Tissue Injury
• Depression or excitation Opioid and non-opioid analgesics - May be an injury to tissues or local
Appetite suppressants inflammation
Anti-emetics - Example: Arthritis (injury to the nerves)
Analgesics-antipyretics • Nerve Injury
Neuroleptics - Example: Diabetic Neuropathy
Antidepressants
Sedative-hypnotics NERVE FIBER BUNDLES
Treatment for Alzheimer’s disease " Send impulses entering to the dorsal horn to activate the
ascending system of the spinothalamic tract
v Aδ Fibers
" Nociceptive Transmission: Rapid or fast, myelinated
fibers
" Etiology: Sharp, painful stimuli

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 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
v C Fibers v Nerve Injury
" Nociceptive Transmission: Slow, non-myelinated " May not depend on the activation of small afferents, but may
fibers be initiated by low-threshold sensory afferents (e.g., Aβ
" Etiology: Dull, aching pain fibers).
" Such nerve injuries result in the development of ectopic
STATES/PHASES OF PAIN
activity arising from the neuromas formed by the nerve injury
1. Acute Nociception and the injured axons of the dorsal root ganglia
" Caused by a transient noxious stimulus that will result to the " The neuromas will discharge pain impulses from time-to-time
irritation of the specific area " The injury to the peripheral nerve will yield an anatomical
" Examples: stimuli caused by a hot coffee cup, a needle stick and biochemical changes in the nerve and spinal cord that
or an incision induce spontaneous dysesthesias (shooting, burning pain)
2. Nociceptive Pain State and allodynia (light touch hurts)
" A noxious stimulus causes an ongoing or prolonged pain state
that may cause a tissue injury or a local inflammation
" Examples: burns, post-incision, abrasion of the skin, joint
inflammation, musculoskeletal injury
3. Neuropathic Pain State
" A noxious stimulus causes an injury or damage to the
peripheral nerves/neural tissues
" Examples: nerve trauma or compression (carpal tunnel
syndrome), chemotherapy, diabetes, shingles

MECHANISMS UNDERLYING PAIN STATES

v Acute Nociception
" An acute activation of small high-threshold sensory afferents
(Aδ & C fibers) generates transient input into the spinal cord
" The input will activate neurons that project contralaterally to
the thalamus going to the somatosensory cortex PAIN ASSESSMENT
" At the same time, another spinofugal projection/excitation
goes to the medial thalamus going to the anterior cingulate
cortex (which is a part of the limbic system)
" The all-in-all or total output by acutely activating the
ascending system is sufficient to evoke pain.

v Tissue Injury
" When a noxious stimulus
results to an ongoing
pain state (following
tissue injury or local
inflammation) -> active
factors such as
prostaglandins,
+
bradykinin, cytokines, H
ions are released to the
injury site. Ø Importance: The severity of pain will tell what kind of
" The released factors have analgesic should be used.
the ability to activate the Ø Examples:
terminal of small high- • Visual Analog Pain Scale
threshold afferents (Aδ & • “Faces” Pain Rating Scale
C fibers)
" However, WHO ANALGESIC LADDER
prolonged/ongoing activation of the sensory afferents may
cause “peripheral sensitization”
" The ongoing afferent traffic initiated by the injury leads to
the activation of spinal facilitatory cascades which will lead to
a greater output to the brain
" The greater output will now cause too much pain
(hyperalgesic state)
" Such tissue injury-evoked pain is often referred as
“nociceptive” pain

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 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
STEP 1: Mild to Moderate Pain OPIOID ANALGESICS: PHARMACODYNAMICS
" Superficial, no need for a centrally-acting pain reliever
RECEPTORS & ENDOGENOUS OPIOID PEPTIDES
" NSAIDs or acetaminophen may be used
STEP 2: Moderate to Severe Pain
" Short-acting or mild opioids as required with or without a non-
opioid round the clock with or without an adjuvant
" Mild Opioids: codeine, hydromorphone, oxycodone
" Non-opioids: NSAIDs or acetaminophen
STEP 3: Severe Pain
" Long-acting or strong opioids with or without non-opioids
" Strong opioids: a sustained-release dosage form of oxycodone,
morphine or oxymorphone or a transdermal form of fentanyl

OPIOID ANALGESICS: PHARMACOKINETICS

ABSORPTION
" Most opioid analgesics are well-absorbed when given by
subcutaneous, intramuscular and oral routes
" In oral doses of opioids, it will undergo the first-pass mechanism in
the liver which may slow down the onset and need a higher dose to
elicit a therapeutic effect
RECEPTOR DISTRIBUTION
DISTRIBUTION
Drug Receptor Effects
" Since most opioids are lipophilic, these drugs are widely distributed μ (mu) δ (delta) Κ (kappa)
to the body tissues such as the brain, lungs, liver, kidneys and Morphine +++ +
spleen. Hydromorphone +++
" Opioids can cross the placental barrier therefore; it is Oxymorphone +++
contraindicated to pregnant women. Methadone +++
METABOLISM Meperidine +++
Fentanyl +++
" Opioids are converted to inactive, polar glucoronide metabolites by
Sulfentanil +++ + +
hepatic microsomal enzyme degradation
Alfentanil +++
" Approximately 10% of Morphine is metabolized to Morphine-6-
Remifentanil +++
glucoronide (M6G), which has the same activity with Morphine.
" Opioids are mostly prodrugs (drugs that give rise to active Levorphanol +++
metabolites) Codeine ± +
" Hepatic P450 metabolism Hydrocodone ±
• Genetic polymorphism (demethylation) of CYP2D6 causes Oxycodone ++
loss of function in metabolizing codeine, oxycodone and Pentazocine ± +
hydrocodone into morphine Nalbuphine -- ++
• Therefore, the analgesic property of the agents may lessen Buprenorphine ± -- --
" Plasma esterase metabolism Butorphanol ± +++
• Ester-containing drugs (such as Remifentanil and Heroin) are +++,++,+ means a strong or full agonist on a specific receptor; ± means
rapidly hydrolyzed by common plasma and tissue esterases a partial agonist; -- means an antagonist
• Heroin (Diacetylmorphine) is hydrolyzed to
monoacetylmorphine and finally to morphine, which is then " Example: Morphine is a full mu agonist whereas Buprenorphine is
conjugated with glucoronic acid a partial mu agonist and a kappa antagonist which makes it a
• Rapidly hydrolyzed agents lose their analgesic properties. mixed agonist-antagonist
" Partial agonists are agents that activate the receptor but not to
EXCRETION its full extent. Remember, in pharmacodynamics, partial agonists
" In patients with renal impairment, the effects of active, polar are also considered as antagonists.
metabolites should be considered before the administration of " Mixed agonist-antagonists are types that activate a specific
potent opioids such as Meperidine. receptor and inhibit another specific receptor as well
" Once Meperidine is metabolized to Normeperidine in patients with " The general effects of opioids may be divided based on what type
renal impairment, the accumulation of the metabolite will lead to of receptor subtype is agonized.
exaggerated response and may even cause seizures at high plasma " The general effects of μ (mu) agonism include:
levels • Analgesia
• Euphoria
• Respiratory depression
• Muscle relaxation -> hyperthermia by vasodilation
• Physical dependence (addiction)

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 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
" Κ (kappa) agonism is said to have less respiratory depressive and " Opioid agents produce analgesia by binding to specific G protein-
addictive properties, and induces hypothermia instead. Agents coupled receptors (metabotropic type) that are located in the
that act on this receptor (Nalbuphine, Butorphanol) can cause brain and spinal cord regions involved in the transmission a nd
psychomimetic effects like hallucinations, nightmares and modulation
anxiety. " Once the G protein-receptors or MOR (mu-opioid receptors) are
activated:
SPECIFIC OPIOID AGENTS • Adenylyl cyclase activity will be inhibited
• Increase K conductance which makes the cell less positive
v FULL AGONISTS (hyperpolarized)
§ Strong mu agonists • The receptor also reduces the opening of voltage-gated
• Phenanthrenes: Morphine, Hydromorphone, Ca channels
Oxymorphone • Expected effect of the agents will be INHIBITORY
• Phenylheptylamines: Methadone
• Phenylpiperidines: Fentanyl, Sulfentanyl, Alfentanil, MECHANISMS OF OPIOID-INDUCED ANALGESIA
Remifentanil
• Morphinans: Levorphanol
§ Mild to moderate agonists
• Phenanthrenes: Codeine, Dihydrocodeine,
Hydrocodone, Oxycodone
• Phenylheptylamines: Propoxyphene
• Phenylpiperidines: Diphenoxylate, Loperamide
v MIXED AGONISTS-ANTAGONISTS
• Phenanthrenes: Buprenorphine, Nalbuphine
• Morphinans: Butorphanol
• Benzomorphans: Pentazocine
• Remember: All mixed agonist-antagonists can
activate the kappa receptor except for
BUPRENORPHINE
v ANTAGONISTS
• Naloxone
• Naltrexone

• Nalmefene

NOTE: v Spinal Action
You may try these mnemonics: " Direct G protein-coupled actions on the pre-synaptic and
ü All morphinans end in “-ol” post-synaptic neurons
ü Phenanthrenes are the “-phone”, “-phine”, “-codone”, • Pre-synaptic nerve terminals
morphine and codeine - Opiates prevent the opening of voltage-
ü Phenylpiperidines are the “fentanyls” gated Ca+ channels which will result to lesser
neurotransmitter release (acetylcholine,
MECHANISM OF ACTION norepinephrine, serotonin, glutamate and
other endogenous opioid peptides)
• Post-synaptic neurons
- Increasing K conductance which will
hyperpolarize the cell (non-amenable to any
form of stimulation)
- Postsynaptic inhibitory effect
v Supraspinal Action
" The opiates block the release of GABA from tonically active
mesencephalic periaqueductal gray (PAG) matter. The
tonically active GABA regulates the activity in projections
(excitations) to the medulla. It simply modulates the
bulbospinal release of serotonin and norepinephrine.
" When the release of GABA is inhibited, the release of
serotonin and norepinephrine from the bulbospinal tract
will be ENHANCED.
" However, norepinephrine acts on alpha-2 receptors at the
spinal level (spinal action). Since alpha-2 receptors are
inhibitory regulative G-protein receptors, activating these
receptors results to INHIBITION of neurotransmitter
release by reducing the influx of Ca+

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 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
" Therefore, the end-action would INHIBIT spinal pain input OPIOID-MEDIATED EFFECTS
that will reduce the transmission of pain from the
CENTRAL NERVOUS SYSTEM EFFECTS
bulbospinal area going back to the dorsal horn.
v Peripheral Action § Analgesia
" Injecting opiates into the peripheral sites (small sensory § Euphoria
afferents) have demonstrated that under conditions of - inhibition of the GABAnergic activity from the nucleus
inflammation, when there is hyperalgesia, the local action of accumbens will increase the output from the ventral
opiates can exert a normalizing effect on the exaggerated pallidum
thresholds. § Sedation
" Naloxone, which is an opioid antagonist, does not reverse - inhibition of the ascending excitatory drive from the
the peripheral effects of opioids mesencephalic reticular activating systems at the
brainstem
MOOD ALTERATIONS & REWARDING PROPERTIES § Respiratory Depression
" Behavioral and pharmacologic data point to a pivotal role of the - there’s a decrease in the ventilator response to CO2 that
mesocorticolimbic dopamine system that projects to the nucleus will increase the threshold for CO2
accumbens (NAc) in drug induced reward and motivation - CO2 is the most potent stimulus for the activation of the
respiratory center; as it accumulates, apnea prolongs
- count the RR in one full minute
- usually given post-op in an intra-thecal administration for
patients who have undergone extensive surgery to
control pain
§ Cough Suppression
- a direct inhibitory effect of opioids at the cough center
§ Miosis
- in the periaqueductal grey area and nucleus accumbens,
GABA is inhibited.
- when GABA is inhibited, the release of acetylcholine will
increase which leads to parasympathomimetic effects
" In the Ventral Tegmental Area (VTA), this is where the mesolimbic § Truncal Rigidty
dopamine system originates. The dopamine inhibits the release of § Nausea & Vomiting
GABA from the NAc.
- activates the chemoreceptor trigger zone and may be due
" When the GABA in NAc is working, it will regulate glutamate activity
to gastric stasis caused by constipation
down to the Ventral Pallidum (VP)
§ Temperature
" When the opiates activate MOR (mu-opioid receptors), it reduces
- the activation of mu-opioid receptor agonists
excitability and transmitter release at the sites indicated by
administered to the anterior hypothalamus produces
inhibiting Ca+ influx and enhancing K+ current.
hyperthermia

- the activation of kappa agonists induces hypothermia


PERIPHERAL EFFECTS

§ Cardiovascular System

- Morphine promotes histamine release

- histamine will cause vasodilation that will decrease the
total peripheral resistance -> patient may become
hypotensive
§ Gastrointestinal Tract
- it promotes release of acetylcholine from the myenteric
plexus
- the cholinergic activation will make the sphincters
contract (it simply inhibits the relaxation of the lower
esophageal sphincter)
- but in the intestines, there will be an anti-cholinergic
effect and constipation should be expected
§ Biliary Tract
" The opiates inhibit the release of dopamine from the ventral - in the biliary area, the sphincter of Oddi that will cause
tegmental area and GABA from nucleus accumbens pain on the right upper quadrant of the abdomen
" When GABA is inhibited, the activity of glutamate towards the
ventral pallidum will be ENHANCED. § Renal
" The excitation will result to euphoria, tranquility, and other - urinary voiding is also reduced because the urinary
alterations of mood sphincters are contracted
- urinary retention

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 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
§ Uterus
- on supraclinical doses (very, very high doses) CLASSIFICATION OF OPIOIDS RELEVANT TO TOLERANCE
- in experimental trials, increase uterine contractility was v High intrinsic activity drugs
observed more with kappa receptor agonists than the - Example: Fentanyl
mu receptor agonists - it only needs to occupy a few receptors to produce its
§ Neuroendocrine effects
- adrenal function is inhibited because it reduces CRF - therefore, these drugs are not affected by any change in
release from the hypothalamus -> no release of ACTH the number of receptors
from the pituitary gland -> inhibition of the adrenal v Low intrinsic activity drugs
function - Example: Morphine
- at the same time with the inhibition of the CRF release, - for it to produce an effect, it has to occupy several
endorphin release are also inhibited; decreased receptors
endorphins results to depression - therefore, a decrease in the number of receptors will not
- take note: the release of glutamate from the ventral cause any effect from morphine
pallidum neutralizes the effect of depression by inducing
euphoria
- ADH will be released to compensate for histamine-
induced hypotension; as ADH will be released from the
posterior pituitary gland, oxytocin will also be released
- prolactin will be released due to the inhibition of
dopamine release from the ventral tegmental area
- FSH & LH release will be inhibited due to inhibition of
GnRH release
§ Flushing & Pruritus
- flushing and pruritus on the facial area are due to
histamine release caused by opioids
ADVERSE EFFECTS NOTE:
Ø A high degree of tolerance may develop to the analgesic,
ACUTE CHRONIC sedating, and respiratory depressant effects of opioid
• respiratory depression • hypogonadism agonists. It is possible to produce respiratory arrest in a
• nausea and vomiting • immunosuppression nontolerant person with a dose of 60 mg of morphine.
• pruritus • increased feeding Ø However, in a patient who is opioid-dependent or requires
• urticarial • increased growth hormone escalating opioid administration to manage intractable
• urinary retention secretion cancer pain, doses such as 2000 mg of morphine taken over
• constipation • withdrawal effects a 2- or 3-hour period may not produce significant respiratory
• delirium • tolerance dependence depression.
• sedation • abuse/addiction
• myoclonus (secondary to • hyperalgesia DEPENDENCE
increase glutamate activity • impairment while driving
" The development of physical dependence is an invariable
in the ventral pallidum)
accompaniment of tolerance to repeated administration of an
• postural hypotension
opioid of the mu type
• seizures (due to inhibition
" Withdrawing a continuous administration of opioids may result in
of GABA interneurons at
a characteristic abstinence syndrome that reflects an exaggerated
high doses)
rebound from the clinical effects of opioid
TOXICITY & UNDESIRED EFFECTS " the signs and symptoms of withdrawal include rhinorrhea,
TOLERANCE WITH OPIOIDS lacrimation, yawning, chills, gooseflesh (piloerection),
hyperventilation, hyperthermia, mydriasis, muscular aches,

vomiting, diarrhea, anxiety, and hostility
" At same doses with repeated administration, tolerance may
" administration of an opioid at this time suppresses abstinence
occur
signs and symptoms almost immediately (you need to take the
" tolerance develops most readily when large doses are given at
drug again)
short intervals and is minimized by giving small amounts of drug
" In methadone, several days are required to reach the peak of the
with longer intervals between doses
abstinence syndrome, and it may last as long as 2 weeks
" The analgesic effect will be lost and may also cause “rebound
" The abusive potential of methadone will only be observed if given
hyperalgesia” (the effects will be opposite with that of opioids)
7 times above its therapeutic dose; its trough level is not that
" Although development of tolerance begins with the first dose of
high
an opioid, tolerance may not become clinically manifest until
" The slower subsidence of methadone effects is associated with a
after 2-3 weeks of frequent exposure to ordinary therapeutic
less intense immediate syndrome, and this is the basis for its use
doses
in the detoxification of heroin or codeine addicts (to limit the

abstinence syndrome)

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 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
such use must not substitute for appropriate
ADDICTION chemotherapy.
Characteristic of opioids in the treatment of addiction: § Shivering
Ø Slower onset " Although all opioid agonists have some propensity to
Ø Longer duration of action reduce shivering, meperidine is reported to have the most
Ø lower oral bioavailability pronounced anti-shivering properties.
Withdrawal or abstinence syndrome with opioids: " Meperidine apparently blocks shivering mainly through an
" Onset: 6 to 10 hours after the last dose action on subtypes of the α2 adrenoceptor.
" Peak: 36 to 48 hours
" Signs and Symptoms: 72 hours to 5 days after the last dose COMMON OPIOID ANALGESICS
" Manifestations: detectable at 6 months to 1 year after the
last dose because drug craving may still exist (restlessness, Drug Dose (mg) Potency Duration Efficacy
anxiety, drug craving) Ratio
Morphine 10 Low 4-5 High
DRUG INTERACTIONS Hydropmorphone 1.5 Low 4-5 High
Oxymorphone 1.5 Low 3-4 High
DRUG GROUP INTERACTION WITH OPIOIDS Methadone 10 High 4-6 High
Sedative-Hypnotics Additive effect with opioids may cause Meperidine 60-100 Medium 2-4 High
increased CNS depression, particularly Fentanyl 0.1 Low 1-1.5 High
respiratory depression Sulfentanil 0.02 IV only 1-1.5 High
Antipsychotic Agents Antipsychotics can also block alpha-blocking Alfentanil Titrated IV only 0.25- High
and anti-muscarinic effect, which may cause 0.75
several cardiovascular effects. Since opioids Remifentanil Titrated IV only 0.05 High
can cause vasodilation, an interaction with infusion
these drugs will cause beta-1 receptors to 0.025-0.2
predominate (marked vasodilation = mcg/kg/min
hypotension). Increased sedation. Variable Levorphanol 2-3 High 4-5
effects on respiratory depression. Codeine 30-60 High 1-4 Low
Monoamine Oxidase Monoamine oxidase inhibitors can increase Hydrocodone 5-10 Medium 2-6 Moderate
Inhibitors levels of serotonin. And opioids can induce
Oxycodone 4.5 Medium 3-4 Mod-High
serotonin activity in the bulbospinal tract due

to inhibition of GABA. An interaction of these

drugs will cause marked increase in serotonin ROUTES OF ADMINISTRATION

that will result to hypertension. Serotonin ROUTE DRUG
syndrome may also occur. Oral Fentanyl lozenge
Hydromorphone
CLINICAL USE OF OPIOID ANALGESICS Levomethadyl acetate
Levorphanol
§ Analgesia Meperidine
§ Acute Pulmonary Edema Methadone
" Opioids MAY be given because it can promote sedation. Oxycodone
" The relief produced by intravenous morphine in patients Parenteral Alfentanil
with dyspnea from pulmonary edema associated with left Codeine
ventricular heart failure is remarkable. Fentanyl
" Proposed mechanisms include reduced anxiety (perception Hydromorphone
of shortness of breath) and reduced cardiac preload Levorphanol
(reduced venous tone) and afterload (decreased peripheral Meperidine
resistance) Methadone
§ Cough (Dextromethorphan, Levopropoxyphene, Codeine) Morphine
" Suppression of cough can be obtained at doses lower than Oxymorphone
those needed for analgesia. Remifentanil
" Do not give opioids in patients with productive cough Sufentanil
(prescribe expectorants) Rectal Morphine
" Dextromethorphan does not have addicting potential. Oxymorphone
Codeine can remove the pain while coughing but Intrathecal Ziconotide
dextromethorphan cannot.
Transdermal Pouch Fentanyl
§ Diarrhea (Diphenoxylate, Loperamide)

" Opioids slows down motility causing constipation

" Diarrhea from almost any cause can be controlled with the

opioid analgesics, but if diarrhea is associated with infection

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 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
• Dysphoric
CONTRAINDICATIONS FOR OPIOID USE • Psychotomimetic effects
§ With head injury from a vehicular accident
" When opioids are given, you wouldn’t know what is causing COMPARATIVE ANALGESIC ACTIVITY:
the CNS depression " Morphine has a greater effect than buprenorphine,
§ With impaired pulmonary function (asthma, COPD) butorphanol and nalbuphine
" Effects will be more marked " Buprenorphine, butorphanol and nalbuphine has an equal
analgesic effect with codeine
NOTE: " Codeine has a greater analgesic effect than Pentazocine
• Buprenorphine is a potent long acting agent. It is also been
used for detoxification of heroin addicts. OTHER EFFECTS OF AGONIST-ANTAGONIST DRUGS:
• Duration of action is long because it dissociates with mu • Sedation
receptors slowly that is why its effect is longer. • Respiratory depression
• In higher doses, it becomes an antagonist to the receptors • Tachycardia, hypertension
kaya uncommon ang respiratory depression. • Constipation: high dose pentazocine = morphine
• Only partially reversed by Naloxone. • Tolerance, cross-tolerance
• The preferred route of drugs is sublingual which bypasses • Physical dependence (Buprenorphine)
the first pass effect. " Onset: 2 to 14 days
" Duration: 1 to 2 weeks
§ Chronic use during pregnancy

" Fetus may suffer from withdrawal symptoms because
CLINICAL USES:
opioids can cross the placental barrier
Ø Analgesia
§ Use in patients with endocrine disease (ex: Adrenal insufficiency
Ø Supplement to anesthesia (Pentazocine)
or Addison’s disease, hypothyroidism or myxedema)
Ø Opioid dependence treatment (Buprenorphine or
" Depressant effects will be more marked in patients with
Buprenorphine with Naloxone)
hypothyroidism (bradycardia happens)
Drug Dose Potency Duration Efficacy
§ Those on weak partial agonist such as Pentazocine (mixed
(mg) Ratio
agonist-antagonist)
" Analgesic effect of morphine will be reduced Pentazocine 30-50 Medium 3-4 Moderate
§ In patients with impaired renal and hepatic function Nalbuphine 10 IV only 3-6 High
" Prolonged effects of opioids in patients with hepatic Buprenorphine 0.3 Low 4-8 High
dysfunction Butorphanol 2 IV only 3-4 High

ROUTES OF ADMINISTRATION
AGONIST-ANTAGONIST DRUGS
Route Drug

Oral Buprenorphine
Drug Receptor Effects
Pentazocine
mu delta kappa
Parenteral Pentazocine
Pentazocine ± +
Butorphanol
Nalbuphine - ++
Intramuscular Buprenorphine
Buprenorphine ± - -
Transfermal patch Buprenorphine
Butorphanol ± +++
Nasal spray Butorphanol


§ Butorphanol has the greatest psychomimetic effect
DRUG INTERACTIONS:
§ Buprenorphine should not be associated with any psychomimetic
• Morphine + buprenorphine – precipitate abstinence syndrome
effect
(nalbuphine)

DIFFERENCE OF MIXED AGONIST-ANTAGONIST AND PARTIAL • Fentanyl – reversal of respiratory depression by buprenorphine
AGONISTS FROM MORPHINE: MISCELLANEOUS DRUGS
" Produce excitatory hallucinogenic effects except for
Buprenorphine v TRAMADOL
" Produce a low degree of physical dependence as compared to " Weak μ-receptor agonist
morphine " Mechanism of action:
" Induce withdrawal signs (but less severe) that differ from those of • Blockade of serotonin reuptake by (+) enantiomer
morphine • Weak norepinephrine reuptake blocker and stimulates
" Produce excitatory effects related to sympathetic discharge of NE alpha 2 adrenergic receptors by (-) enantiomer
• Mixed agonist-antagonist may cause positive inotropic • Partially antagonized by naloxone
effects on the heart which will increase the force of " Pharmacokinetics:
contraction • Bioavailability: 68% (oral), 100% (IM)
• Peak: 2 to 3 hours
ADVERSE EFFECTS: • Duration: 6 hours
• Dizziness, drowsiness, sweating, nausea, anxiety • Metabolism:
• Hallucinations, nightmares F Liver by CYP2D6 and CYP3A4

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REFERENCES: Bianca Cala Trans + 2016 trans + Katzung 13 ed + Goodman and Gilmans, 12 ed By: LUBY
 PHARMACOLOGY B: INTRODUCTION TO CNS DRUGS, OPIOIDS
LYLAH D. REYES, MD (JAN 10, 2018)
F O-demethylation -> active metabolite F Neonatal respiratory depression induced by
• Half-life: 6 hours maternal opioid administration
F 7.5 hours active metabolite F Treatment of opioid adverse effects (low-dose
" Side effects: naloxone)
• Nausea, vomiting, dizziness, dry mouth, sedation, F Constipation (methylnaltrexone)
headache F Management of abuse syndrome (naltrexone
• Respiratory depression (less) – has longer half life)
• Constipation ð Maintenance drug for addicts
• Seizure ð Decrease alcohol craving among
• Physical dependence, abuse, addiction, withdrawal alcoholics
" Clinical uses: ð Facilitate abstinence from nicotine
• Relief of mild to moderate pain and labor pain
• An adjunct to opioids in chronic pain syndrome
• Relative contraindication:
• Seizure disorders
" Drug interaction:
• SSRI
• MAOI
• Partially antagonized by Naloxone

v TAPENTADOL
" Action:
• Strong norepinephrine reuptake-inhibiting activity
• Modest μ-opioid receptor affinity
• Monoamine reuptake inhibitor activity
" Activity, efficacy, side effect, contraindication and drug
interaction profile: similar to Tramadol
" Pharmacokinetics:
• Metabolism: Conjugation with glucuronic acid
• Excretion: urine (70%)

OPIOID ANTAGONISTS

v Naloxone, Naltrexone, Nalmefene
" Affinity: mu > kappa, delta
" Pharmacokinetics:
o Naloxone
- Duration: 1 to 2 hours
- Metabolism: glucuronide conjugation
o Naltrexone
- Well-absorbed orally
- Rapid first-pass metabolism
- Half-life: 10 hours
o Nalmefene
- Derivative of naltrexone
- Available: IV
- Half-life: 8 to 10 hours
" Pharmacodynamics:
• IV onset of action: 1 to 3 minutes
• Normalizes the following with acute depression
secondary to opioid overdose:
Ø Respiration
Ø Level of consciousness
Ø Pupil size
Ø Bowel activity
Ø Awareness of pain
• For dependent subjects: precipitate abstinence
syndrome
" Clinical use:
• Major applications:
F Acute opioid overdose

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REFERENCES: Bianca Cala Trans + 2016 trans + Katzung 13 ed + Goodman and Gilmans, 12 ed By: LUBY