Pharmacology 1_MOD 6

INTRODUCTION TO THE PHARMACOLOGY OF CNS

ORGANIZATION OF THE CENTRAL NERVOUS SYSTEM

★​ Good permeability
○​ Can pass the BBB
○​ Antihistamines - first generation
■​ cause sedation because they readily cross the
BBB

BOOK BASED

CENTRAL NERVOUS SYSTEMS

●​ consists of the BRAIN AND SPINAL CORD.
●​ responsible for integrating sensory information and generating motor
output and other behaviors.

The human brain contains about 100 billion interconnected neurons. These neurons
are surrounded by supporting glial cells.

NEURONS
●​ Electrically excitable cells that process and transmit information via an
electrochemical process.
●​ CLASSIFIED Based on function, location, and neurotransmitter released.
●​ grouped into clusters called NUCLEI or arranged in layered structures
○​ Connections among neurons exist within and between
clusters. These connections form the circuitry that
regulates information flow throughout the CNS.
○​ Eg. of layered structures are the cerebellum and
Hippocampus.

STRUCTURE OF NEURONS
1.​ Cell body (soma): Contains the nucleus and integrates signals.
2.​ Dendrites: Highly branched structures that receive and integrate input
★​ When axons branch out, they will transmit signals to dendrites from other neurons.
★​ Dendrites will receive signals from other neurons via neurotransmitters, 3.​ Axon: Transmits the output signal from the cell body, often over long
initiating a signal that can lead to action potential distances.
★​ Action potential travels to the axon which will trigger the release of 4.​ Axon terminal: Forms synapses, where neurotransmitters are released
neurotransmitters into the synapse to communicate with other neurons.
5.​ Myelin sheath: Formed by oligodendrocytes in the CNS, increasing
signal transmission speed.

ION CHANNELS AND NEUROTRANSMITTERS RECEPTORS

●​ Volted gated channels
●​ Ligand gated channels
●​ Metabotropic Receptors
●​ Membrane delimited regulation of ion channels by metabotropic
receptors
●​ Diffusible second messenger mediated regulation of ion channels by
metabotropic receptors

BOOK BASED

VOLTED GATED CHANNELS

●​ Respond to changes in membrane potential.
●​ Eg.:l Voltage-gated sodium channels initiate and propagate the
action potential along the axon.
●​ Calcium and potassium channels on the cell body, dendrites, and
axon regulate neuronal excitability and firing rate.
●​ Some potassium channels act as a brake, slowing further
produce myelin surrounding the axons
depolarization.
enhancing signal conduction.
OLIGODENDROCYTES
LIGAND GATED CHANNELS
●​ A.K.A IONOTROPIC RECEPTORS, allowing rapid signaling in response to
●​ produce primary action, which
neurotransmitter release.
is for metabolic processes
ASTROCYTES
●​ Most abundant glial cells
Tetrodotoxin (TTX) blocks voltage-gated sodium channels, preventing nerve signal
transmission.
●​ fight infection / primary
infection
●​ Overactivity is linked to VOLTED GATED CHANNELS
MICROGLIA schizophrenia and Alzheimer’s
disease. Example: sodium-potassium channels (PISO)
1. RESTING MEMBRANE POTENTIAL
SCHWANN CELLS also coat axons like oligodendrocytes but in ●​ the resting state does not excite or inhibit
PNS the neuron.
●​ At rest, neurons maintain a negative
charge inside the membrane.
BLOOD BRAIN BARRIER (BBB) ●​ Leaking potassium channels allow K⁺ to
leave, making the inside more negative.
●​ FUNCTION: Protects the CNS by limiting the entry of substances from the ○​ Chlorine for example, inside
blood. the cell there are many
●​ STRUCTURE: negative ions because there
○​ Tight junctions between capillary endothelial cells prevent are leaking channels
FREE DIFFUSION ●​ resting state does not excite or inhibit the neuron.
○​ Astrocyte end-feet surround blood vessels to maintain the
2. DEPOLARIZATION (Excitation)
barrier.
●​ Transport Mechanisms ●​ When an action potential arrives, it triggers the opening of voltage-gated
○​ Only highly hydrophobic molecules or substances with channels
specific transporters can cross. ●​ Na⁺ rushes into the cell, making the inside less negative (more positive).
○​ Eg.: L-DOPA (for Parkinson’s disease) enters the brain using ●​ A cell at resting membrane potential, an influx of sodium ions (Na+) into
an amino acid transporter, while dopamine cannot cross. the cell, causing the inside to become more positive, and ultimately
leading to depolarization
Exceptions: Certain brain regions (circumventricular organs) lack a BBB, allowing
them to detect blood composition and release neurohormones. 3. REPOLARIZATION & RECOVERY
●​ After the sodium channels open and sodium influx causes depolarization,
the action potential reaches its peak, and sodium channels close.
●​ Potassium channels then open, allowing potassium to flow out, leading to
repolarization and the membrane potential returning to a negative state

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 ●​ Potassium channels take longer to close compared to sodium channels
●​ Must be calcium-dependent, as seen in typical synaptic
transmission
3.​ Synaptic Mimicry
●​ Applying the candidate neurotransmitter should produce
the same effect as nerve stimulation.
●​ A selective antagonist should block this response,
confirming its function

MEMBRANE DELIMITED
●​ CALCIUM CHANNELS
★​ When an action potential reaches the presynaptic terminal,
it triggers the opening of calcium channels, allowing
calcium ions to flow into the axon terminal, which then leads
to the release of neurotransmitters
●​ POTASSIUM CHANNELS

LIGAND GATED CHANNELS

●​ LIGAND + NEUROTRANSMITTER =
opening of channel ★​ Can bind to G coupled protein receptors and then these receptors will
●​ Responsible for fast synaptic bind to the ion channels
transmission typical of hierarchical
pathways in the CNS
DIFFUSIBLE SECOND MESSENGER
●​ Brief opening of the channels

GLYCINE
★​ major inhibitory neurotransmitter,
which suppresses action
potentials, and its inhibitory action
is blocked by strychnine, a
competitive antagonist that binds
to the glycine receptor
○​ Excitatory action
○​ Causes convulsions

★​ Cyclic AMP (cAMP) which is a diffusible second messenger, can bind to

METABOTROPIC RECEPTORS and modulate the function of a family of cyclic-nucleotide-gated ion
●​ Seven-transmembrane G protein-coupled receptors (GPCRs) channels, specifically those permeable to calcium, sodium, and
○​ Do not directly potassium
open ion channels
SYNAPSE AND SYNAPTIC POTENTIALS
but activate
intracellular
signaling pathways.

Gq increase inositol trisphosphate leading to an increase Calcium

Gs stimulates adenylyl cyclase leading to an increase cAMP

★​ Read the picture

GI inhibit the adenylyl cyclase leading to a decrease in cAMP ★​ Acetylcholine is the primary neurotransmitter in cholinergic which acts
on the receptors muscarinic and nicotinic
★​ In the adrenergic system, the neurotransmitters are dopamine,
epinephrine (adrenaline), and norepinephrine (noradrenaline), which act
on alpha and beta adrenergic receptors.

BOOK BASED RESTING MEMBRANE POTENTIAL

Hierarchical Systems
●​ include pathways for sensory perception and motor control.
●​ These pathways use large myelinated fibers, allowing fast conduction
(>50 m/s)
●​ Information is transmitted in bursts of action potentials (phasic signals).
○​ Information is processed sequentially, passing through
relay nuclei before reaching the cortex. Lesions at any
point disrupt the entire system.

Nonspecific or Diffuse Neuronal Systems

●​ involve monoamines (e.g., norepinephrine, dopamine, serotonin) and
acetylcholine.
●​ These neurotransmitters are produced by small, localized nuclei, often
in the brainstem.
●​ Example: Noradrenergic neurons originate from the locus coeruleus,
with only about 12,000 neurons per side of the brain.

Criteria for Neurotransmitter Identification

1.​ Localization
●​ The suspected transmitter must be present in the
presynaptic terminal of the pathway.
2.​ Release ●​ The electrical charge difference across the cell membrane of a neuron
●​ The substance must be released in response to neuronal (or other cells) when the cell is at rest and not transmitting a signal
activity. ★​ No action potential in the cells

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 AMPA RECEPTORS ●​ Present on all neurons
EXCITATORY POSTSYNAPTIC POTENTIAL ●​ GluA2 (permeable to Na+ and K+, but not to
●​ Excitatory pathway is stimulated Ca2+)
●​ Depolarization
●​ Less negative inside the cell
★​ Produce more positive ions toward the cell KAINATE ●​ hippocampus, cerebellum, and spinal cord.
RECEPTORS ●​ permeable to Na+ and K+ and in some
subunit combinations can also be
INHIBITORY POSTSYNAPTIC POTENTIAL permeable to Ca2+.
●​ Inhibitory pathway is stimulated ●​ DOMOIC ACID
●​ Hyperpolarization (opening of chloride channels) ○​ Potent agonist at kainate and
★​ Occurs because of leaking channels AMPA receptors
★​ Chloride channels are found outside the cell
★​ The opening of chloride channels leading to the increase
inflow of chloride is the mechanism of action of GABA and NMDA RECEPTORS ●​ GluN1 subunit and a GluN2 subunit
Glycine ●​ high permeability to Ca2+, Na+, K+ and are
○​ Ex. Benzodiazepines blocked by Mg2+ in a voltage-dependent
●​ More negative inside the cell manner.
★​ Ex. Glycine which activates the inhibitory pathway and also the GABA ●​ Glutamine + Glycine + depolarization
★​ If they are ligand gated, they need to bind
the receptor to the ligand for it to open
★​ When glutamate and glycine are added to
the receptor, it will not open because there is
Mg that blocks them, hence it is needed to
increase the depolarization of receptors
○​ more action potential = more
depolarization

★​ Group I
○​ Post synaptic receptors
○​ Activates phospholipase
C → increases
SITE OF DRUG ACTION intracellular calcium
1.​ Action potential in presynaptic fiber ★​ Group II and II
2.​ Synthesis of transmitter ○​ Pre synaptic receptors
3.​ Storage - Reserpine ○​ G inhibitory
4.​ Metabolism - Acetylcholinesterase inh. ○​ Reduces the
5.​ Release - Amphetamine, Tetanus toxoid neurotransmitter release,
6.​ Reuptake into the nerve ending or uptake into a glial cell - Cocaine inhibiting
7.​ Degradation neurotransmitter
8.​ Receptor for the transmitter - Opioid channels
9.​ Receptor-induced increase or decrease in ionic conductance ○​ Occurs when glutamate
10.​ Retrograde signaling - Endocannabinoid levels are too high and
this considered as the
negative feedback
★​ From the synthesis to the neurotransmitter until the degradation of
enzymes, these steps can be a site for drug action
★​ Ex. Cocaine inhibits the reuptake of synaptic dopamine and serotonin
and Tetanus toxoid which inhibits the release of inhibitory
neurotransmitters

CENTRAL NEUROTRANSMITTERS AMINO ACIDS - GABA

●​ GAMMA-AMINOBUTYRIC ACID
●​ MAIN INHIBITORY NEUROTRANSMITTER in the CNS
●​ GABA A
★​ most important subtypes of GABA receptors
★​ ionotropic ligand gated
★​ When GABA is binded to GABA A will open the channels
especially the chloride channels allowing inflow of chloride
ions
○​ Negative cells leading to hyperpolarization
●​ GABA B

GABA A
●​ Most important subtype of GABA
●​ Ionotropic, ligand gated, Cl-
channels ions
●​ Pentamers of subunits that each
contain four transmembrane
domains and assemble around a
central anion-specific pore
●​ Fast component
●​ PICROTOXIN and BICUCULLINE
★​ Parkinson’s disease - ↓ dopamine and ↓ serotonin
(Blockers)

AMINO ACIDS - GLUTAMATE

●​ EXCITATORY NEUROTRANSMITTER
○​ MOST ABUNDANT
○​ FAST EXCITATORY

GABA B
●​ Ligand- gated ion channels ●​ Slow component
(ionotropic) or metabotropic ●​ Metabotropic GPCRs
GPCRs ○​ Interact with Gi and Gq
★​ Group I (mGluR1 ●​ Presynaptic GABA B
and mGluR5) ○​ Autoreceptors that inhibits GABA release (inhibiting Ca2+
★​ Group II (mGluR2 channels)
and mGluR3) ●​ Postsynaptic
★​ Group III (mGluR4, ○​ Selective increase in K conductance
mGluR6, mGluR7, ●​ Activated by BACLOFEN
and mGluR8)
●​ 4 subunits (Glu1-4)
●​ Ionotropic Glutamate receptors AMINO ACIDS - GLYCINE
○​ NMDA receptors ●​ INHIBITORY NEUROTRANSMITTER
○​ AMPA receptors ●​ Brainstem and Spinal Cord
○​ KA receptors ●​ Glycine receptors are pentameric
structures that are selectively
permeable to Cl–
●​ Co-Agonist at NMDA receptors
★​ Glutamate and
glycine is needed to
open the NMDA
receptors
●​ STRYCHNINE
○​ Blocks glycine receptor inhibitor
★​ Can block the inflow of chloride

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 ACETYLCHOLINE
●​ First neurotransmitter to be discovered H2 ★​ Mostly acts on Gi that increases gastric acid secretion
●​ Ionotropic ligand gated channels (Nicotinic receptors) ★​ Ex. Cimetidine, Famotidine, Nizatidine, and Ranitidine
●​ Metabotropic GPCR (Muscarinic)
●​ ALZHEIMER’S
H3 mostly on CNS
○​ Degradation of cholinergic pathway
○​ Low levels of acetylcholine
○​ Longest duration - Rivastigmine? H4 inflammatory conditions

MONOAMINE NEUROTRANSMITTERS

NEUROPEPTIDE
DOPAMINE ●​ Predominant catecholamine in CNS ★​ Neuropeptides are small protein molecules produced and released by
●​ Substantia nigra neurons through the regulated secretory pathway
●​ Motivation and Reward ★​ Modulators of neurotransmitters
●​ Metabotropic receptors
○​ D1-like (D1and D5) - SUBSTANCE P ●​ Pain transmission, inflammation, and
stimulates adenylyl the regulation of mood.
cyclase leading to
increase cAMP
○​ D2-like (D2, D3, D4) - ENDORPHINS, ●​ Act as the body’s natural pain relievers
inhibit adenylyl ENKEPHALINS, and are integral to the brain’s reward
decrease cAMP BETA-ENDORPHIN system
●​ Exerts a slow inhibitory action on
CNS neurons
OXYTOCIN ●​ childbirth, lactation

NOREPINEPHRINE ●​ locus coeruleus or the lateral

VASOPRESSIN ●​ regulating water balance in the
tegmental area of the reticular
kidneys and maintaining blood
formation.
pressure
●​ Metabotropic
●​ Hyperpolarization of neurons
NEUROPEPTIDE Y (NPY) ●​ Influences appetite control, as well as
responses to anxiety and stress
5-HYDROXY TRYPTAMINE ●​ 5-HT, serotonin
●​ midline raphe nuclei of the pons
and upper brain stem. CORTICOTROPIN-RELEASI ●​ Vital for managing stress and
●​ Metabotropic NG FACTOR (CRF) modulating the HYPOTHALAMIC
○​ Except 5HT3 receptor PITUITARY ADRENAL (HPA) axis
●​ Perception, mood, anxiety, pain,
sleep, appetite, temperature,
neuroendocrine control, and OREXINS
aggression ●​ Produced in lateral and posterior hypothalamus
★​ Important for inducing vomiting ●​ Hypocretins
★​ Ex. ondansetron, etc ●​ Metabotropic (Ox1, OX2)
●​ Promotes wakefulness and project to and activate monoamine and
★​ 5HT3 receptor - usually given for
acetylcholine neurons involved in sleep-wake cycles
cancer patients
○​ narcolepsy and disrupted sleep-wake patterns
★​ Low dopamine = Parkinson’s disease ●​ Energy homeostasis, feeding behaviors, autonomic function, and reward
★​ High dopamine = Schizophrenia

ENDOCANNABINOIDS
●​ Δ9-tetrahydrocannabinol
●​ The two receptor subtypes (CB1 and CB2)
●​ Loaded in the presynaptic terminal
●​ retrograde synaptic messengers

NITRIC OXIDE AND PURINES

●​ NITRIC OXIDE
○​ High levels of Nitric Oxide synthase (NOS)
★​ Activates calcium, calmodulin, NMDA receptors
leading to increase intracellular calcium
○​ Long-term depression of synaptic transmission in the
cerebellum
★​ More calcium = increase nitric oxide production
●​ PURINE
○​ adenosine, ATP, UTP, and UDP
●​ HISTAMINE ○​ memory and learning, locomotor behavior, and feeding
○​ tuberomammillary nucleus (TMN) in the posterior ★​ Important for DNA synthesis
hypothalamus. ★​ Adenosine can bind to presynaptic calcium receptors and
○​ arousal, attention, feeding behavior, and memory inhibit calcium release, hence it will not allow the release of
○​ Metabotropic (H1 - H4) neurotransmitter
○​ Centrally acting antihistamines are used for sedative

H1 ★​ Promotes excitatory action

★​ Targets allergy and sleep
★​ Second generation antihistamine are less sedative than
the first generation
★​ H1 blockers are very common in OTC drugs especially in
Neozep
★​ Ex. Chlorphenamine, Diphenhydramine

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 SEDATIVE HYPNOTICS CHEMICAL CLASSIFICATION
●​ SEDATIVE (ANXIOLYTICS)
○​ Reduce anxiety and exert calming effects
BENZODIAZEPINES Widely used sedative hypnotics
●​ HYPNOTICS
○​ Maintenance of a state of sleep and drowsiness
NOVEL BENZODIAZEPINES RECEPTOR ●​ Zaleplon
AGONISTS ●​ Zolpidem
●​ Eszopiclone
★​ Also used in insomnia
★​ Z kase related sa sleep zZZ
MELATONIN CONGENERS ●​ Ramelteon
●​ Tasimelteon

BARBITURATES older , less commonly used sedative hypnotics

MISCELLANEOUS ETHANOL AND CHLORAL HYDRATE

NEW AND EMERGING AGENTS

●​ ANXIETY
○​ ↓ GABA
○​ ↓ Serotonin
★​ Limbic system regulates mood and interacts with
sympathetic nervous system
★​ MUST KNOW THE DRUG CLASS
★​ GABA and serotonin maintains the homeostasis of limbic
system
★​ Low GABA and Low Serotonin levels = will not block the
sympathetic action of limbic system LEADING TO BOOK BASED
TACHYCARDIA AND TREMORS
Benzodiazepines, barbiturates, and newer hypnotics undergo hepatic metabolism,
primarily through phase I oxidation via cytochrome P450 enzymes (especially
●​ INSOMNIA CYP3A4) and phase II conjugation, leading to urinary excretion.
○​ ↓ Malatonin
○​ ↓ GABA BENZODIAZEPINES
○​ ↑ Orexin ●​ most contain a carboxamide group in the seven-membered
○​ ↑ Histamine heterocyclic ring structure
●​ produce active metabolites with long half-lives, contributing to
prolonged effects. In contrast, some, like lorazepam and oxazepam,
★​ PINEAL GLAND produces MELATONIN which will bind to the receptors (M1
undergo direct conjugation, reducing accumulation risks.
and M2)
○​ These receptors are found in the SUPRACHIASMATIC
Clorazepate
NUCLEUS (SCN).
●​ Prodrug, is converted to its active form, desmethyldiazepam
■​ When melatonin binds to the SCN, it inhibits its
(nordiazepam), by acid hydrolysis in the stomach
activity.

Barbiturates, except phenobarbital, are extensively metabolized, with prolonged

Role of the Suprachiasmatic Nucleus (SCN) half-lives leading to cumulative effects. Newer hypnotics, including zolpidem and
zaleplon, are rapidly metabolized, with metabolism affected by CYP3A4 inhibitors
●​ During wakefulness, the (SCN) is active and inhibits the VENTROLATERAL
and inducers
PREOPTIC NUCLEUS (VLPO), which is crucial for promoting sleep.
●​ When SCNis inhibited, it will not inhibit VLPO thus VLPO will be activated,
promoting sleep

DRUG CLASSIFICATION
GABA
BENZODIAZEPINES
★​ The primary inhibitory neurotransmitter, promotes sleep by inhibiting brain ●​ Promotes binding of GABA to GABA A Receptor
activity, particularly in the reticular formation, which is involved in ●​ bind at α/γ interfaces
wakefulness, thus produces sleep ●​ Allosteric modulators of GABA A receptors
Orexins (hypocretins) ○​ Increase affinity of GABA A receptor to GABA
○​ Enhance GABA induced Cl- currents
★​ neuropeptides produced in the hypothalamus, promote wakefulness by
●​ Increase FREQUENCY of opening of GABA A receptors
binding to orexin receptors (OX1R and OX2R) and exciting other
★​ If there is no GABA present, it will not activate the receptors because
arousal-promoting neurons, including histaminergic neurons
they are only allosteric modulators
Pineal gland, reticular formation, and posterior hypothalamus are the ones who
regulates the sleep wake-cycles
●​ Triazolam, Oxazepam, Midazolam,
SHORT-ACTING Brotizolam, Etizolam
●​ Lorazepam, Alprazolam, Estazolam,
INTERMEDIATE ACTING Clonazepam, Lormetazepam, Nitrazepam,
Temazepam
●​ Diazepam,Chlordiazepoxide, Clorazepate,
LONG ACTING Flurazepam, Quazepam, Flunitrazepam

CNS AND PNS EFFECT OF BENZODIAZEPINE

●​ CNS
○​ Sedation
○​ Hypnosis
○​ Decreased anxiety
○​ Muscle relaxation
○​ Anterograde amnesia
○​ Anticonvulsant
●​ PNS
○​ Coronary vasodilation (IV use)
○​ Neuromuscular block (High doses)
GABA A RECEPTORS
●​ Site of action of Sedative Hypnotics
drugs SYSTEMIC EFFECTS OF BENZODIAZEPINE
●​ Major inhibitory receptor in the CNS ●​ RESPIRATION
●​ FIVE SUBUNITS ○​ Hypnotic doses: No effect on respiration
○​ GABA binds at the ○​ HIGHER DOSES: Depresses alveolar ventilation, respiratory
interfaces of α and β acidosis
classes of subunit ●​ CARDIOVASCULAR
○​ Decrease blood pressure and increase heart rate
○​ Midazolam: Decreases peripheral vascular resistance
○​ Diazepam: Decrease cardiac output
●​ GI TRACT
○​ improve a variety of “anxiety-related” GI disorders.

GABA + GABA A RECEPTORS

DRUG INTERACTIONS
●​ Ethanol
○​ increases both the rate of absorption of benzodiazepines
and the associated CNS depression.
●​ Valproate and benzodiazepines
○​ used in combination may cause PSYCHOTIC EPISODES.

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 THERAPEUTIC USES ULTRA SHORT ACTING ●​ Methohexital
●​ TREAT ALCOHOL WITHDRAWAL ●​ Thiopental
○​ Diazepam
●​ ANTICONVULSANTS ●​ Amobarbital
○​ Clonazepam, Nitrazepam, Lorazepam, Diazepam ●​ Butabarbital
●​ ANESTHESIA SHORT-ACTING ●​ Mephobarbital, Pentobarbital
○​ Diazepam, Lorazepam, Midazolam ●​ Secobarbital
LONG ACTING ●​ Phenobarbital

ADVERSE EFFECTS
●​ Drowsiness
●​ Excessive sedation
●​ Impaired motor coordination
●​ Confusion
●​ Memory loss
●​ FLURAZEPAM, TRIAZOLAM, TEMAZEPAM
○​ allergic, hepatotoxic, and hematologic reactions
●​ FLURAZEPAM
○​ Increase incidence of nightmares
●​ Chronic use may cause dependence and abuse

I.​ NOVEL BENZODIAZEPINES RECEPTOR AGONISTS

NOVEL BENZODIAZEPINE AGONISTS
1.​ Zolpidem (pyrazolopyrimidine)
2.​ Zaleplon (imidazopyridine)
3.​ Zopiclone
4.​ Eszopiclone
●​ (+) enantiomer of zopiclone
●​ Agonist effects at the benzodiazepine site of the GABA receptor
○​ Interact with GABA A receptor with alpha 1 subunit
●​ Less anticonvulsants or muscle relaxants, less dependence and abuse
than benzodiazepines ORGAN EFFECTS OF BARBITURATES
●​ Treatment for insomnia
●​ All degrees of depression of the CNS
●​ Antagonized by Flumazenil
●​ Anticonvulsant activity
○​ 5-phenyl substituent
III. FLUMAZENIL: ○​ Phenobarbital and Mephobarbital
BENZODIAZEPINE RECEPTOR ANTAGONIST ○​ Sleep: decrease sleep latency, the number of
awakenings, and the durations of REM and slow-wave
FLUMAZENIL
sleep.
●​ IMIDAZOBENZODIAZEPINE ●​ Anesthetic: (Tiopental, methohexital)
●​ Competitive antagonist ●​ TOLERANCE, ABUSE, AND DEPENDENCE
○​ Antagonizes action of ●​ Depress transmission in autonomic ganglia and reduce nicotinic
benzodiazepine excitation by choline esters
zolpidem, zaleplon, ●​ Respiratory depression
and eszopiclone ●​ Decrease the tone of the GI musculature
●​ but does not antagonize the CNS ●​ CYP enzyme inducer
effects of other ●​ Severe oliguria and anuria
sedative-hypnotics, ethanol, ●​ SE: Respiratory depression, hypersensitivity, enhance porphyrin
opioids, or general anesthetics. synthesis, severe depression of CNS
★​ Flumazenil is the antidote for
benzodiazepine toxicity

BENZODIAZEPINES VS BARBITURATES
●​ Allosteric agonist at GABA A receptors
IV. MELATONIN CONGENERS ●​ Higher concentrations of Barbiturates
MELATONIN ○​ Directly activate GABA A receptors
○​ Greater organ effect (CNS depression)
●​ Sleep hormone
●​ MT1 and MT2 receptors (Suprachiasmatic nucleus) ○​ More toxic than Benzodiazepines
○​ M1: Promotes onset of sleep
○​ M2: Shift the timing of circadian rhythm
VI. MISCELLANEOUS SEDATIVE HYPNOTICS

RAMELTEON
1.​ CHLORAL HYDRATE
●​ tricyclic analogue of melatonin ●​ treat patients with paradoxical reactions to benzodiazepines.
●​ MELATONIN AGONIST
●​ reduced rapidly to the active compound TRICHLOROETHANOL
○​ Binds MT1 and MT2 receptors in suprachiasmatic nucleus
○​ Exerts barbiturate effects on GABA A
○​ SE: Dizziness, fatigue, endocrine changes (Decreased
testosterone and increased prolactin) ●​ literary poison, the “knockout drops” added to a strong alcoholic
●​ beverage to produce a “Mickey Finn” or “Mickey,”

TASIMELTEON
2.​ BUSPIRONE
●​ Selective agonist for m1 and M2 receptor
●​ treatment of non–24-h sleep-wake syndrome in totally BLIND PATIENTS ●​ Partial agonist at 5-HT receptors and possibly D2 receptors
experiencing CIRCADIAN RHYTHM DISORDER ●​ Generalized anxiety
●​ NO any convulsant or muscle relaxant

V. BARBITURATES
●​ Binds to GABA A receptors 3.​ MEPROBAMATE
●​ Increase duration of the chloride ●​ Can cause CNS depression, it cannot produce anesthesia.
opening channel
●​ SE: Ataxia and drowsiness
●​ Block glutamate
●​ WITHDRAWAL SYNDROME
neurotransmission
●​ CARISOPRODOL
○​ Voltage activated
Calcium ○​ Skeletal muscle relaxant (Meprobamate, active metabolite)
●​ HIGHER DOSES: Binds to GABA A
receptors even without GABA
4.​ OTHER AGENTS
●​ melatonin receptor agonist and a 5HT2C
receptor antagonist
●​ prescribed for the treatment of DEPRESSION
AGOMELATINE and may aid in INSOMNIA

sedative, muscle relaxant, and anticonvulsant

CLOMETHIAZOLE properties
barbituric acid (2,4,6-trioxo
hexahydropyri midine) DIPHENHYDRAMINE & ●​ OTC prescription sleeping ids
●​ Thiobarbiturates vs Oxy DOXYLAMINE ●​ Antihistamine
Barbiturates
●​ INCREASE LIPID SOLUBILITY ●​ TRICYCLIC ANTIDEPRESSANT
○​ decrease duration of action ●​ Treats insomnia
○​ decrease latency to onset of activity DOXEPIN ●​ antagonism of H1 receptor function when
○​ accelerate metabolic degradatio administered in LOW DOSES
○​ increase hypnotic potency
●​ Orally ●​ IV anesthetic
●​ Na+ salts absorbed more rapidly ●​ lacks pulmonary and vascular depressant

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ETOMIDATE activity, negative inotropic effect of heart

●​ ANXIOLYTIC AGENT that binds to Ca2+

channel α2δ subunits,
PREGABALIN ●​ Treats insomnia
●​ In,I patient suffering from Generalized
Anxiety Disorder

●​ rapidly acting and highly lipophilic

diisopropylphenol
●​ used in the INDUCTION and maintenance of
PROPOFOL general anesthesia
★​ Michael Jackson was overdosed from this
drug

●​ 5HT2A/2C receptor antagonist

●​ promote SLOW-WAVE SLEEP IN PATIENTS with
chronic primary
RITANSERIN ●​ insomnia or generalized anxiety disorder

●​ inhibitor of orexin 1 and 2 receptors

SUVOREXANT ●​ Treatment for insomnia

QUIZON-LARROZA-FELICIANO| PHARM 2B | PAGE 7