Central Nervous System Drugs
Typical Antipsychotics
Phenothiazines and Butyrophenones
Direct interact D2-type rec. Extrapyramidal Syndrome (EPS)
Combines:
dystonia (spasms)
Inverse agonist - bind to site akathisia (motor restlessness)
produce opposite effect
parkinsonian effect - (mild tremors)
Antagonist - bind but no effect tardive dyskinesia (irregular jerking movement)
CNS Depressants
Anxiolytics
Benzodiazepine (BZD)
Treatment for Overdose
Flumazenil
- competitive molecule
for BZR
BZDs bind to BZR allosteric site to modulate Clconduction.
BZD increases binding rate of GABA to GABAA
receptors
Cl- hyperpolarizes the membrane decreasing
membrane firing
Diazepam
- N-dealkylation
prototype Class A drug, anxiolytic and anesthetic
long-acting
Lorazepam
presence of C3-OH
short-acting
Fluphenazine
-OH side chain moiety piperazine phenothiazine,
- Ester hydrolysis, pro drug lipophilic ester with longer DOA
Alprazolam
prototype Class B drug
contains a triazole ring
Thiothixene
C10-11 double bond piperazine phenothiazine
Midazolam
Haloperidol
prototype butyrophenone
Mania, Tourette syndrome - involuntary jerking
can induce dyskinesia (SE)
prototype Class B drug, also anesthetic
contains a imidazole ring
Non-BZD GABA Agonist
Partial Agonist - tone down,
not full management
Dopamine
trans α-rotamer
Chlorpromazine
prototype phenothiazine aliphatic aminopropyl
side chain
Thioridazine
methylthio (R1) piperidine phenothiazine
Risperidone
has benzisoxazole ring
treats positive & negative symptoms of
Schizophrenia
Hybrid: butyrophenone - antipsychotic, trazodone
- antidepressants
Droperidol
Also anesthetic
has benzimidazoline ring used as preanesthetic
neuroleptic - support impact of anesthesia
Short acting, sedating, antiemetic
Pimozide
- targeted by CYP 3A4
has 4-fluorophenyl ring - increase potency
used as preanesthetic neuroleptic
Atypical Antipsychotics
“RIch QUeens ARe CLumsy OLd ZIllionaires”
(RIsperidone, QUetiapine, ARipiprazole, CLozapine, OLanzapine, ZIprasidone)
Diarylazepine Derivatives
direct D2-type antagonism First line of treatment for schizophrenia except
plus partial D2-type
olanzapine and clozapine
agonism
Side effects: weight gain, insulin resistance,
dyslipidemia, when taken first episodes and
5-HT2 receptor antagonism might aggregate the psychotic mindset of patient,
(reduced EPS - less ADR) trigger psychosis
- serotonergic
Aripiprazole - also a anti-depressant
Clozapine
dibenzodiazepine derivative used to decrease
hallucinations and helps in preventing suicide
attempts
Olanzapine
clozapine analog with more potent D2
antagonism
used also for bipolar disorder and depression
Quetiapine
clozapine analog, used for bipolar disorders
has mood-improving effects
Benzisoxazole/ Benzisothiazoles
Use for Insomnia
highly selective for 𝛂1-GABAA receptor subtype
Zolpidem
prototype non-BZD
with imidazopyridazine ring
R1,R2,R3 substitution - decrease activity
Eszopiclone
with cyclopyrrolone ring
binds at allosteric site of GABAA receptors
Zaleplon
- first pass effect
with pyrazolopyrimidine ring
-CN group provides receptor selectivity
Sedative/ Hypnotics
Barbiturates, derived from barbituric acid
agents of choice until
they developed
tolerance, dependence
and/or toxicity.
Short - 3-4 hours
intermediate- 6-8 hours
long-acting 10-16 hours
- binds to GABAA receptor increasing GABA
binding
- increased GABA binding increases Cl- ion
transport = reversible inhibition
of excitatory neurons
Secobarbital
Unsaturation, sec-pentyl ?
short-acting agent
Butabarbital
Ethyl, butyl
intermediate-acting agent
Phenobarbital
Ethyl, Phenyl
long-acting agent
Thiopental
Thiobarbiturates
ultra short-acting agent, anesthetic only
Melatonin Receptor Agonist
CYP 1A2, 2C19, 3A4
(even the metabolites
are still active in
inducing sleep)
binds to MT1R decreasing SCN firing promoting
sleep
binds to MT2R affecting circadian rhythm (CNS
clock)
Ramelteon
SAR
• Aromatic ring system: indole (melatonin) or
indane - ramelteon
- essential for receptor binding
- essential to be separate 3-amide and
5-methoxy side chains = for binding and
functional activity
Benzisoxazole: Y = O
Benzisothiazole: Y = S
similar with diarylazepines but with higher affinity
and antagonism at 5-HT2 receptors
Ziprasidone
- CYP 3A4
Benzisothiazole - ethyl
(Y = S, X = N, Z = H)
Tiospirone
Benzisothiazole, butyl
(Y = S, X = N, Z = H)
8-10x affinity to MTR
than melatonin
Lurasidone
- N- dealkylation
Benzisothiazole,
(Y = S, X = N, Z = H)
Histamine (H1) Receptor Agonists)
Iloperodione
- CYP 2D6 and CYP 3A4
- keto reduction
Benzisoxazole
(Y = O, X = CH, Z = F)
Risperidone
CYP 2D6 and CYP 3A4
Benzisoxazole
(Y = O, X = CH, Z = F, W = H)
Paliperidone
Benzisoxazole
(Y = O, X = CH, Z = F, W = OH)
Arylpiperazine Quinoline
Aripiprazole
ONLY drug in this group
has high oral bioavailability
highly protein bound,
longer DOA
high affinity for D2-type receptors (partial
agonist) & serotonin (5-HT) GPCRs
partial agonist for 5-HT2A & 5-HT2C receptors
Agonist at D2 receptors
CYP 2D6 and 3A4
Tasimelteon
Indane, under study
first generation ethanol amine ether agents that can cross BBB and
produce sedative effects.
Diphenhydramine
Methyl -ether
Doxylamine
Ethyl - ether
MOA: blocks the histamine release in the TMN
inhibiting cerebral cortex arousal (wakefulness).
It has marginal usefulness and develops
tolerance and side effects (e.g. drowsiness)
Anti-Manic
Lithium Salts
(Carbonate or Citrate)
MOA: Unknown, but have several hypothesized
actions:
plays a role in brain structure changes
neurotransmission modulation
intracellular changes.
Anesthesia
S1: Analgesia (onset to loss of eyelash reflex) S1 and S2 - induction period
S2: Delirium (agitation and delirium)
S3: Surgical Anesthesia (absence of somatic reflex with painful stimuli)
S4: Respiratory Paralysis (onset of apnea, respiratory and circulatory failure
Up to S3 only, S4 - toxic overdosing
Volatile General Anesthetics, simple lipophilic gas vapors in large doses
Drugs: Halogenated
hydrocarbons and ethers
Meyer-Overton Theory: high lipophilicity = low
MAC = high potency - Minimum Alveolar Conc.
Ion-Channel/Protein Receptor Theory:
CYP 2E1 in the liver (may anesthetic agent potentiates inhibitory GABAA
produce toxic metabolite)
receptors and inhibits/modulates excitatory
No SAR, depend on dosing nAChR nicotinic Acetylcholine Receptor
Anti-Seizures - For Epilepsy
Simple - affects an entire
hemisphere or a lobe within a
hemisphere of
the brain.
Frontal - motor, wave-like
Temporal - sensory, deja vu
Occipital - hallucinations
Complex temporal/psychomotor
seizures, mistaken for
psychotic behavior.
Absence (petit mal) - brief loss of awareness (blank
stare), postseizure amnesia but with no loss of motor
activity.
Myoclonic seizures - no loss of consciousness and
involves short siezure duration.
Tonic-Clonic (grand mal) -bilateral muscular jerking,
loss of consciousness, tonic-clonic spasms. Absence - Ethosuximide,Methosuximide, trimethadione T
Myoclonic - topiramate
Grand Mal - CBZ, Carbamazepine
Seizure - not neuropathic pain but it can cause seizure
MOA: Anti-seizure drugs alter ion channel or receptor function to
promote synaptic inhibition or modulate synaptic excitation- X over firing
Methoxyflurane
most potent, lowest MAC, renal toxicity,-kidney
Old Agents
Halothane
most hepatotoxic, not big issue of healthy liver
Isoflurane
forms CO degradation product
Ureides, class of drugs
hydantoins, barbiturates, oxazolidinediones and
w/ similar pharmacophore succinimides
Enflurane
forms CO degradation product
Hydantoins
Sevoflurane
most nephrotoxic, kidney
Desflurane
forms CO degradation product
MET: CYP 2C9 catalyzed aromatic hydroxylation followed by PSII
glucuronidation, sulfation bulky C5 is optimal for activity (at least 1)
Nitrous Oxide
least potent, laughing gas, dental procedure
↑ lipophilicity = ↑ potency
↑ MAC = ↓ potency
Halogenation = ↑ potency, stability, ↓ flammability
↑ halogen atomic mass = ↑ potency
Injectable IV General Anesthetics
(IV/IM) are used to induce
rapid, short-acting
anesthesia which is
maintained by volatile
anesthesia. - “primer”
No SAR, no similar PC
Propofol, R-Etomidate, Thiopental: enhances GABA transmission
glucuronidation (propofol,
ketamine), CYP 3A4 and 2B6
(ketamine), hepatic esterase
(etomidate), CYP oxidation
(thiopental)
Ultra-short acting barbiturates: thiopental
Cylcohexylamines: ketamine
Benzodiazepines: diazepam, midazolam
Butyrophenones: droperidol
Opioid Analgesic: morphine, fentanyl
Propofol
glucuronidation
has 2,5-diisopropylphenol
Onset of 30-60 seconds, DOA: 5-10 mins
Enhance Gaba transmission, for prime
Ketamine, CYP 3A4, 2B6
Glucoronidation,
well-known as a “dissociative anesthetic”
don’t remember , DOA: 10-25 mins
R-Etomidate
hepatic esterase
short DOA (<3 mins), Enhance Gaba transmission
Ketamine: prevents ion flow (deactivation of
neurons); (indirect) antagonist with the cationic
channel of NMDA receptor complex; and
interacts with opioid, 5-HT, muscarinic
receptors. N-methyl-D-aspartate receptor glutamate receptor, excitatory
ThiopentalCYP oxidation anesthetic barbiturate ultra-short DOA 30-40 sec
Enhance Gaba transmission
Local Anesthetics
applied topically to
produce anesthetic effect
on a specific area without
loss of consciousness or
cardiorespiratory
impairment.
MOA: reversibly binds to VGSC voltage-gated
Na+ channel = blocking Na+ transport =
decreasing nerve conduction and sensory.
M: benzoic acid-type is extensively hydrolyzed
by pseudocholinesterase;
anilide-type is acted by CYP 1A2
Benzoic Acid Derivative
Cocaine analogs
Anilide Derivative
Isogramine analogs CYP 1A2
Cocaine
first topical anesthesia ,used for nasal surgery
Procaine
solve irritability and instability with cocaine
Tetracaine
solve low potency and short DOA with procaine
Benzocaine
only member without 3°amine
ESTER TYPE : ONE “I” IN THEIR NAMES
ESTER-TYPE WITH 2 “I”: PRIMACAINE, PIPEROCAINE, DIMETHOCAINE
ESTER-TYPE WITHOUT “-CAINE”: BUTAMBEN, BUTETHAMINE, NAEPAINE
Lidocaine
first amide type
can be toxic: CNS & Heart
Prilocaine
a regional IV anesthesia
Rapid metabolism, low CNS toxicity
Mepivacaine
used for infiltration anesthesia and dental
procedure
Bupivacaine
↑ lipophilicity ↑ potency & DOA
can be toxic: CNS and Heart
AMIDE TYPE : TWO “I” IN THEIR NAMES
AMIDE-TYPE WITH 1 “I”: OXETACAINE, TOLYCAINE, PYRROCAINE, RODOCAINE
AMIDE-TYPE WITHOUT “-CAINE”: DIPERODON
Phenytoin
can induce CYP 3A4 levels increasing the risk
of drug-drug interaction - consider in formulation
- metabolize faster
has a 5,5-diphenyl giving it maximal activity.
Fosphenytoin
disodium phosphate ester of phenytoin =
water soluble, better stability for parenteral
administration.
used for generalized seizures, partial seizures, status epilepticus
Oxazolidinedione
Trimethadione
- not used due to toxicity
has no bulky C5 groups eliminates activity for
grand mal, but increases activity for petit mal
(absence seizure)
high toxicity limits therapeutic applications
Succinimide
Ethosuximide
- ~20% excreted
unchanged, CYP 3A4
and 2E1
drug of choice for absence seizure (petit mal)
has no C5 bulky group
Replaced the -O- (in oxazolidinedione) with
-CH2 = safer with retained activty
Valproic acid
promotes GABA
transmission by inhibiting
GABA metabolism.
blocks VGSC, decreasing
excessive neuronal firing.
It is a 2-propylpentanoic acid and is used for
both grand and petit mal. 2 rare side effects
that limits its use: hepatotoxicity and
teratogenicity - limited
Oldest agent
New Agents, BCDs,- also benzodiazepine
Iminostilbene, CBZ are derivatives of TCAs Tricyclic Anti-depressant
Carbamazepine
prototype iminostilbene used for grand mal and
partial seizures (adults)
blocks VGSC resulting to 2 phenyl groups essential for activity
inactivation of excessive - keto, hydroxy, acetate ester can be substituted
neuronal firing.
at C10 = less potent but active
GABA Analogs, Gabaminergic
Gabapentin
Pregabalin
Met: minimal, almost
leave the body
unchanged
Both agents are analogs of GABA (inhibitory
neurotransmitter)
modulates Ca+2 influx by regulating VGCC
Voltage-gated Calcium channel resulting
activation of glutamic acid decarboxylase (GAD)
resulting to glutaminergic neurotransmission
inhibition.
Phenyltriazine
Lamogatrine
- Glucuronidation
Useful for both grand mal, petit mal, and
partial seizures for adults
blocks both VGSC and VGCC, stabilizing
presynaptic neuronal membranes, inhibiting
glutamate release producing no excitatory
response.
Dicarbamate
Felbamate
Ester hydrolysis,
oxidation
It is very potent and widely used agent but has
very toxic severe side effects: aplastic anemia
and hepatic failures
- interacts with NMDA decreasing glutamate
transmission resulting to decreased neuronal
excitation.
CNS Stimulants
Selective Serotonin Reuptake Inhibitors (SSRIs)
Methylxanthines
Xanthine derivatives found Competitive inhibition of phosphodiesterase
in plants acts as CNS
and antagonism of adenosine receptors stimulants
boost neural firing
Met: liver CYP, xanthine oxidase (into uric acid)
inhibits SERT with high
affinity and selectivity for
SERT
Electronegative (-X) 4-substitution = essential for
selectivity and affinity for SERT
SSRI stereochemistry significantly affects SERT
selectivity:
Metabolism
highly metabolized in the liver by CYP isozymes
(especially CYP 2D6)
N-demethylation for N-methyl SSRIs
Escitalopram
S-isomer is more active
Citalopram
R-isomer
Fluvoxamine
E-isomer is essential for SERT inhibition
Fluoxetine
R-isomer more potent S-isomer higher affinity
for SERT
Caffeine
1,3,7-Trimethylxanthine
Most CNS, Respiratory, Skeletal Muscle
stimulation
Paroxetine
(-)-3S,4R-isomer is more active for SERT
inhibition
Seritaline
1S,4S-isomer is more active for SERT inhibition
Theophylline
Tea
1,3-Dimethylxanthine
Most Diuresis, Coronary Dilation, Cardiac Stim.
Monoamine Oxidase Inhibitors (MAOIs)
Theobromine Chocolate
3,7-Dimethylxanthine
Antidepressants - serotonin, norepinephrine, dopamine
enzyme responsible for deamination of amines. 5-HT is a substrate for MAO-A, while
Epinephrine, NE, and DA are substrates for MAO-A and MAO-B
result to hypertensive crisis (severe headache, tachycardia, diaphoresis,
hyperpyrexia) when combined with sympathomimetics or tyramine containing food.
Monoamine Hypothesis - lack of NE, Serotonin
Receptor Sensitivity Hypothesis - hypersensitivity,
based on the balanced
relationship between 5-HT, NE prolonged depression, initial dose will jumpstart
Permissive Hypothesis - balance of NE and 5-HT
and DA neurotransmitters.
Hormonal Hypothesis - changes in hormones
inhibits metabolism of
NE, 5-HT and DA =
increasing conc. in the
brain, inhibit MAO
- some has similar structure with amphetamine
Example of Drugs
TCAs (SNRI/NSRI) SSRIs, MAOIs,
5HT2 Antagonist/SRM
Moclobemide
reversible inhibitor of MAO-A antidepressant
w/o hypertensive crisis
MOA Options
Agonize 5HT receptors
Agonize NE receptors
Serotonin - happy hormon
Block 5HT reuptake (go back to the vesicles)
Block NE reuptake
Block metabolism by MAO
Or any combination
Trancyclopromine
resembles amphetamine with 𝛼-methyl
condensing with β-carbon
Depression
- presence of electron-withdrawing groups =
increase potency
Met: Oxidation and N-acetylation
MAOI - Cumulative, stay within a month
Phenelzine
irreversible inhibitor of the enzyme
TCAs (SNRIs/NSRIs), SSRIs, NDRI, and SARI
Selegiline
selective irreversible inhibitor of MAO-B
target a transporter
protein: SERT, NET, and
DAT.
Inhibit them, avoid going
back to vesicle
Serotonin-2 Antagonist/Serotonin Reuptake Modulators
(SARIs/SRMs),
- blocks transporter proteins preventing
inactivation of NTs, allowing NTs to function.
- increased levels of 5-HT, NE, and DA
relieves the signs of NT deficiency —
antidepressant activity.
Phenylpiperazine
derivatives
antagonizes 5-HT2 receptors (sedated) and/or
selectively inhibits SERT
Nefazodone - hepatotoxic
Selective Norepinephrine Reuptake Inhibitor (SNRIs) and
Norepinephrine/Serotonin Reuptake Inhibitors (NSRIs)
Trazodone
with phenylpiperazine ring 5-HT2A antagonist
blocks excitation, hypnotic effects
TCAs “anti-HAM” effect anti-H1 (sedation)
Like phenothiazines EPS anti-𝛼1 (orthostatic hypotension)
anti-M1 (dry mouth, constipation, blurred vision,
Tricyclic Antidepressants
urinary retention)
Vortioxetine
5-HT1A agonist and SERT inhibitor
Vilazodone
partial 5-HT1A agonist
postsynaptic releases of 5-HT
MOA
Aripiprazole
Atypical anti-psychotic
antagonist at 5-HT2A receptor- hypnotic
effects, and partial agonist at 5-HT1A receptor
SNRI - selectively blocks NET
NSRI - blocks NET and SERT (binding is
dependent on NE:5HT potency ratio)
Dibenzazepines TCAs “-Pramine”
Desipramine
SNRI agent, blocks NET
Imipramine
NSRI prototype drug, blocks NET and SERT
Clomipramine
NSRI agent, blocks NET and SERT
CYP 2D6 hydroxylation (SNRI at C10;
Clomipramine at C8)
CYP 2D6 demethylation
Dibenzocycloheptadiene TCAs - “Tryptyline”
Nortriptyline
SNRI Agent, has N5-C12 double bond
Protriptyline
SNRI Agent has C10-11 double bond
Amitriptyline
NSRI Agent
has a propylene moiety in the B-ring
Doxepine
NSRI Agent (E/Z isomers)
E selectively inhibits NET
S selectively inhibits SERT
Non-TCA SNRIs/ NSRIs
Norepinephrine/Dopamine Reuptake Inhibitor (NDRI)
Buproprion
Unique compound acting on monoamine
receptors useful in the management of
depression and smoking cessation
selective inhibition of DAT CYP 2B6 alkyl hydroxylation resulting to
and NET = increasing NE hemiketal forms and reduction resulting to theo
and erythro hydrobupropion isomers and
Induce release DA, NE
hemiketal
Alpha-2-Noradrenergic/ Selective Serotonin Antidepressants (NaSSA)
Mirtazapine
single representative of NaSSA that has a
complex mechanism of action.
CYP3A4:
N-demethylation and
N-oxidation CYP 2D6:
aromatic hydroxylation
blocks presynaptic 𝛂2-adrenergic and 5-HT
receptors (may lead to orthostatic hypotension) =
increasing NE and 5-HT levels.
selectively antagonizes 5-HT2 and 5-HT3 (may lead to
sedation)
Anti-Parkinsonism - extrapyramidal dopaminergic, basal ganglia degrade
Levadopa, Amantadine, Bromocriptine, Anticholinergic, Selegiline, and Entacapone
Dementia more common for Parkinson’s Disease Patients
Levadopa L-DOPA
Lipophilic DA precursor:
Atomoxetine
SNRI Agent, R-enantiomer is more active
Amantadine
DA agonist and Reuptake inhibitor
Duloxetine
NSRI Agent
Aromatic hydroxylation
Bromocriptine,
DA agonist
Pergolide, Pramipexole
Milnacipran
NSRI Agent
Venlafaxine
NSRI Agent
CYP 2D6 demethylation
Benztropine, Biperiden, Anticholinergics, management of tremor,
Trihexypehnidyl
symptomatic relief only
Selegeline, Rasagiline
MAO-B inhibitors (w/o hypertensive crisis)
Entacapone,Tolcapone
COMT Inhibitors, prevent metabolism of DA