Download Neurological Agents Chart

LOCAL ANESTHETICS:
Drug
General LA
Potency
Variable
Onset (pKa)
Between 7.8-9.0
-Closer the pKa is to
physiological pH, the faster
the onset (more nonionized
form)
-Can give bicarbonate to
increase speed of onset
Duration (Hydrophobicity)
Variable
-All LAs are hydrophobic
due to presence of
aromatic ring
-Degree of hydrophobicity
determines duration of
action and potency
-Use of EPI (vasoconstrict)
to prolong effects
Toxicity
CNS:
-Stimulation
-Restlessness
-Dizziness
-Tremors
-Confusion
-Respiratory depression
Formulations
Many
Uses
Many
CV:
-Myocardial depression
-Vasodilation (except
cocaine)
Smooth Muscle:
-Depress GI contractions
-Relax vascular and
bronchial smooth muscle
Hypersensitivity: esp.
esters (PABA derivatives)
-Allergic dermatitis
-Asthma
ESTERS
Cocaine
Low
Medium (8.7)
Medium (moderate
hydrophobicity)
Procaine
Low
Slow (8.9)
2-5 minutes
Short (low hydrophobicity)
Benzocaine
Low
Rapid (no amine group and
therefore not protonated)
Short (15-20 minutes)
-Unique mechanism (small
enough to fit in pore to
stabilized CLOSED state)
Tetracaine
High*
Faster (8.2)
Long (high hydrophobicity
due to butyl group)
CNS: toxicity due to local
anesthetic properties
and blockade of
catecholamine reuptake
Topical: anesthesia of
mucous membranes
-Nose
-Mouth/throat
-Ear
Adrenergic Effects:
-HTN
-Increased HR
-Arrhythmia
Hydrolyzed to PABA:
-Hypersensitivity
-Interaction with sulfa
drugs
Parenteral: infiltration
and dental procedures;
also spinal
Cream
Aerosol
Ointment
May be more
pronounced: due to
slower metabolism
Topical:
-Dermal
-Oral (mucus
membranes)
-Insertion of medical
devices
Topical: larynx, trachea,
esophagus anesthesia
Parenteral: spinal
Drug
AMIDES
Lidocaine
Bupivacaine
Ropivacaine
Potency
Onset (pKa)
Duration (Hydrophobicity)
Intermediate
Rapid (7.8- lowest pKa of all)
High
Fast (8.1)
Medium-long (moderate
hydrophobicity)
-Metabolites from
metabolism in the liver also
retain some anesthetic
activity
Very long (highly
hydrophobic due to butyl
piperidine group)
High
GENERAL ANESTHETICS (INTRAVENOUS):
Drug Class
Drugs in Class
Barbiturates
Sodium Thiopental
Thiamylal
Methohexital
Benzodiazepines
Diazepam
Lorazepam
Midazolam
Opioids
Morphine
Fentanyl
Phenols
Propofol
Imidazole
Etomidate
Dissociative
Ketamine (PCP Analog)
Fast (8.1)
Not as long (not as
hydrophobic)
-Is itself a vasoconstrictor
(do not need to add EPI)
Toxicity
Formulations
Ointment
Jelly
Patch
Aerosol
Solution
*Most widely used*
Topical: dermal,
laryngeal, oral
Parenteral: epidural,
infiltration, nerve block,
spinal
Parenteral:
-Epidural*
-Inflitration
-Nerve block
-Spinal
Cardiotoxic properties
Epidural for Labor: give
dilute solution (will
preferentially block
sensory function, not
motor)
*Very similar to
Bupivacaine*
Parenteral:
-Epidural
-Infiltration
-Nerve block
Lower cardiotoxicity
Use
Ultra-short acting barbiturates capable of producing anesthesia within
seconds
Anxiolytic and anterograde amnesic properties (administered 15-60 minutes
before induction to calm patient/erase memory of induction)
Also used for intraoperative sedation
Analgesia (poor amnesics)
*Most popular IV anesthetic*- induction and maintenance
Good choice for ambulatory surgery
Good choice for prolonged sedation in critical care setting
Primarily used in patients at risk for hypotension (no significant cardiac or
respiratory depression)
Induction and maintenance in combo with sedative
Dissociative anesthesia (catatonia, amnesia, analgesia with no LOC)
Use
Other
Duration of Action: 30-60 minutes after single bolus
Fast onset: half-time to blood-brain equilibration 1-3 minutes
Fast recovery: can ambulate earlier after general anesthesia
Metabolism: rapidly in the liver
Issues: high incidence of pain on injection and postoperative N/V
Metabolism: extensive hepatic metabolism + in the plasma
Rapid onset: with profound analgesia
MOA: non-competitive antagonist of NMDA receptor
Issues: only IV anesthetic to produce dose-related
cardiostimulation; may cause hallucinations/irrational behavior
Metabolism: liver
GENERAL ANESTHETICS (INHALATION):
Drug
Onset/Recovery
General Inhalation
Determined by Blood:Gas partition
Anesthetic
coefficient/solubility
-High B:G=High solubility=Slower equilibration
-Low B:G=Low solubility=More rapid equilibration
Other Factors ↑Speed of Onset:
-High blood flow to tissue
-Increased pulmonary ventilation
-Decreased pulmonary blood flow
Factors Affecting Speed of Recovery:
-Faster in agents with low B:G solubility
-Proportional to duration of anesthesia (longer
duration= in muscle and adipose; %body fat can
play a role)
-Rate of recovery accelerated by increased
ventilation
INHALATION AGENTS
Nitrous Oxide
Potency
Determined by Oil:Gas partition
coefficient (lipid solubility)/MAC
value
-High lipid solubility=High O:G= Low
MAC= High potency
-Low lipid solubility=Low O:G= High
MAC= Low potency
Low potency
(Low O:G, High MAC)
More potent than N2O
(Higher O:G; Lower MAC)
Higher potency
(High O:G, Low MAC)
Halothane
Medium induction/recovery
(Higher B:G)
Higher potency
(High O:G, Low MAC)
Desflurane
Rapid induction/recovery
(Low B:G)
More potent than N2O
(Higher O:G, Lower MAC)
Isoflurane
Systemic Effects
CV: ↓BP
Respiratory: ↓ ventilatory drive and
airway patency
-Exception: N2O
Brain: ↑ cerebral BF= ↑ ICP
MAC: alveolar concentration required
to eliminate the response to
standardized painful stimuli in 50% of
patients
Rapid induction/recovery
(Low B:G)
Rapid induction/recovery
(Low B:G)
Medium induction/recovery
(Higher B:G)
Sevoflurane
Use
Kidney: ↓ GFR and RBF; ↑ filtration
fraction
Liver: ↓ hepatic blood flow
Not used alone: exception is
dental procedures
-Outpatient use
-Use in children (sweet odor)
*Most commonly used*
-Induction/maintenance
-Pungent odor
-Induction in children (nonpungent)
-Not used in adults (risk of
hepatotoxicity- only one
extensively metabolized in the
liver)
-Most widely used for
outpatient surgery
*Only agent that produces
analgesia*
-Risk of nephrotoxicity (metabolism
to fluoride ions)
-Rare risk of malignant hyperthermia
-Respiratory tract irritation
MORPHINE EFFECTS/USES (PROTOTYPE OPIOID):
EFFECT
USE
Analgesia
*Pain relief WITHOUT general sensory loss or LOC*
-Pain still present but not longer bothers the patient
-Better against dull continuous pain than sharp intermittent pain
-Multiple sites of action (in brain and spinal cord)
Mood/Cognitive Effects
Miosis
Cough Inhibition
SIDE EFFECT
Significant tolerance to this effect
Paradoxical hyperalgesia: MOA unclear (possibly increased glutamate transmission
in dorsal horn)
Clinical Use: surgical anesthesia (in combination with other agents)
Euphoria and tranquility
-Site of action unclear (locus ceruleus, mesolimbic DA, nucleus accumbens?)
-Prompt administration reduces risk for PTSD in combat injured soldiers
--
Respiratory Depression
MOA: depression of cough reflex mediated by medullary cough center (easily
separated from respiratory depression)
--
Increased ICP
--
Nausea/Emesis
--
CV Effects
Use of IV morphine to relieve dyspnea in left ventricular heart failure due to
pulmonary edema: decreases anxiety, venous tone and peripheral resistance
GI Effects
--
Other Effects
OPIOD DRUGS:
Drug
Morphine
MOA
Mu receptor agonist
Pharmacokinetics
Absorption: well absorbed by
multiple routes
Metabolism: extensive first
pass metabolism (35%
bioavailability- limits oral use)
Excretion:
-Polar metabolites excreted in
the urine (active/toxic)
-Some in the bile
Use
See above
Not pleasant in pain free individuals: dysphoria (depression/discontent), difficulty
thinking, drowsiness, nausea
Confusion/sedation possible: especially in the elderly
MOA: excitation of PS innervation to the pupil (sign of intoxication/OD)
Little/no tolerance to this effect with chronic us
-MOA: dose-related depression mediated by brainstem centers (decreased response
to CO2); especially concerning in those with COPD
Synergistic with other CNS depressants
MOA: decreased responsiveness to CO2 leads to increased pCO2 and
cerebrovascular vasodilation; needs to be considered in patients with head trauma
MOA: mediated by area postrema CTZ (more common in ambulatory patients,
suggesting possible vestibular involvement)
Tolerance to this effect develops rapidly
Peripheral vasodilation and inhibition of baroreceptor reflex: orthostatic
hypotension and fainting upon standing (not evident in supine patient)
MOA: may be due to histamine release
Decreased propulsive contractions  ↑H2O reabsorption  Constipation
Little tolerance to this effect: issue with chronic use
Ureters: increased sphincter tone (decreased urinary output); esp. elderly
Uterus: prolongs labor and has effects on fetus
Itching: due to effects on CNS and peripheral nerves (probably due to substance P
or histamine release)
Toxicity/SEs
Renal Insufficiency:
-Build-up of active metabolite
(morphine-6-glucuronide) can lead to
confusion/agitation
-Build-up of proconvulsant metabolite
(morphine-3-glucuronide) can lead to
seizures
Formulations
Long-acting SR beads: do not
chew
Morphine + Naltrexone: prevent
abuse
DepoDur: single injection for
post-surgical use (lasts 48 hours)
Continual epidural or intrathecal
infusion
Heroin
Oxycodone
(Morphine
backbone)
Converted to morphine in
vivo (deacetylation)
Mu receptor agonist
Fast acting and very potent
Drug of abuse
Absorption: more orally active
than morphine
Short-term relief of moderate
pain (ie. cancer patients)
Drug of Abuse: possibly lethal
Efficacy: roughly equivalent to
maximal efficacy of oral
morphine
Perodan: combo with aspirin
Percocet: combo with
acetaminophen
Combunox: combo with
ibuprofen
Acurox: combo w/ niacin and
ingredients that convert to gel
upon extraction (abuse
deterrent)
Meperidine
Codeine
Fentanyl
Propoxyphene
Nalbuphine
Butaphanol
Pentazocine
Tramadol
Primarily a kappa receptor
agonist
Weak mu receptor agonist
(deacetylation to morphine)
Note: 10% of population
lacks enzyme to do this
Mu receptor agonist
Mu partial agonist
Kappa agonists with mu
mixed agonist/antagonist
effects
Synthetic codeine derivative
-Active metabolite is a weak
mu agonist
-Also blocks 5HT and NE
uptake
-GABA action?
Onset/Duration: rapid onset
with short duration of action
Absorption: good oral
absorption
Metabolism: not much first
pass metabolism (high
oral:parenteral potency ratio)
Potency: 100x more potent
than morphine
Duration of action: short (no
active metabolites)
Efficacy: very low
Pain killer used in acute pain
management only (ie. postsurgical)
IM injection: irritating to tissue
Toxicity: seizures, twitching, delirium,
psychiatric changes
-Due to accumulation of toxic
metabolite
-Painkiller (often given in
combo formulation)
-Antitussive effects
(questionable)
-IV use for surgical anesthesia
(w/droperidol)
-Acute post-op pain (PCA)
Being pulled from the
market due to toxicity
Less analgesia
Less respiratory depression
Less tolerance
Limited to chronic
neuropathic pain: needs to
be titrated
Tylenol 3
Sustained release formulation
Very potent: potentially dangerous
Transdermal patch:
-Be careful of heat exposure
-Careful with CYP3A4 inh.
Safety: very low TI
Unique delivery routes:
-Transdermal patch (change
every 2-3 days)
-Buccal tablet, film or lozenge
(breakthrough pain)
Combo with aspirin/caffeine
Combo with acetaminophen
Toxicity: due to buildup of toxic
metabolite
-Cardiotoxic
-Convulsions
-OD
Less naloxone reversibility: for
example, in OD
More adverse behavioral symptoms:
psychomimetic, Salvinorin-A like
effects
Increased frequency of seizures: esp.
in those with seizure history OR on
antidepressants
DDIs: may lead to serotonin syndrome
Extended release
Combo with acetaminophen
Tapentadol
Methadone
Tramadol-like compound
-Weak mu agonist
-NE reuptake inhibitor, but
NOT 5HT
Mu agonist
Duration: long half-life (needs
careful initial titration)
Metabolism: hepatic (no
active metabolites, so safe in
renal failure)
Potency: more potent than full
agonist methadone
Duration: long duration of
action
-Slow dissociation from R
-Resistance to naloxone
reversal
Buprenorphine
Partial agonist at mu
Naloxone
Opiate receptor antagonist
(mu>kappa and delta)
Naltrexone
Opiate receptor antagonist
(mu>kappa and delta)
Methylnaltrexone
Opiate receptor antagonist
Does NOT cross BBB: does not
affect analgesia
Diphenoxylate
Loperamide
Dextromethophan
Mu receptor agonist
Mu receptor agonist
D isomer of methylated
levorphanol
-NMDA receptor antagonist
-Sigma receptor agonist
Poor gut absorption
Poor gut absorption
Nalfurafine
Kappa opioid receptor
agonist
Chronic pain: esp. in patients
with renal failure
Addict detoxification or
maintenance: carefully
dispensed
Sublingual
Combo with naloxone: prevent
abuse
Sustained release: once a month
formulation being tested
Opioid overdose
-Blocks analgesic,
antidiarrheal and antitussive
effects
Prevention of relapse to
heavy drinking
Opioid induced constipation
in terminal patients under
palliative care
Exclusive use in diarrhea
Exclusive use in diarrhea
Antitussive: MOA unclear
Relief of itching
ER form: for use in opioid OD
Oral Form: hepatotoxic in overdose
Oral form: poor compliance
Injectable ER form: once a month
depot recently approved
Naltrexone + Buprenorphine:
obesity treatment
Injectable
Diphenoxylate+Atropine=Lomotil
Potential for abuse
Contraindications:
-Young children
-Combination products (ie. with
antihistamines)
Use of kappa agonist along should be
unpleasant: psychomimetic effects
Combination products
discouraged
SEDATIVE HYPNOTICS:
Drug Class
Drug
General
Benzodiazepines
MOA
Bind BZ receptor (part
of GABA-A R) and
prolong the effects of
GABA
-Increase FREQUENCY
of GABA-mediated Cl
channel opening
Pharmacokinetics
Highly Lipid Soluble:
-Cross BBB rapidly
-Cross placenta
-Detected in breast milk
Pharmacodynamics
CNS effects highly dose
dependent: depressant
effects additive with
other sedative hypnotics
Metabolism:
Phase I: most undergo
hepatic oxidation by P450
(CYP3A4/2C19)
Phase II: all conjugated to
form glucuronides
Safer than benzos: flatter
dose-response curve
Long Acting Agents: have
active metabolites (can
accumulate)
Antagonist/Antidote:
Flumazenil
-Administer repeatedly
(short half-life)
-Be careful in patients
with seizure history
Use
Anxiety: intermediate
or long acting agents
(short-term mgt.)
-Panic/phobic disorders
-GAD
Insomnia: and other
sleep disorders
Anesthesia: anxiolytic
Skeletal muscle
relaxation: low doses
Spasticity: diazepam
Excretion: glucuronides
excreted by kidney
Seizures: clonazepam
Withdrawal from EtOH
or other S-H: long
acting agents
Adverse Effects
DDIs: be careful of CYP3A4
interactions
Adverse Events:
-Impaired psychomotor
functions
-Behavioral disinhibition
-Decreased REM sleep
-Rebound increased REM
sleep (discontinution)
-Anterograde amnesia
-Tolerance (chronic/high
dose)
-Dependence (physical,
psychological)
Withdrawal: more common
with shorter acting drugs
-Longer acting drugs selftaper
OD: respiratory arrest,
hypotension, CV collapse
-Less common with benzos
Oxazepam
Lorazepam
Short-acting:
-Does not accumulate (no
active metabolites)
-Do not undergo hepatic
microsomal oxidation
(conjugated directly)
Short-acting: same as above
Alprazolam
Triazolam
Intermediate-acting
Intermediate-acting
Diazepam
Long-Acting:
-Active metabolites
accumulate with continuous
dosing
High dose IV: used in
treatment of status
epilepticus
Panic/Phobic disorders
Primary insomnia and
sleep disorders
Highly lipophilic: makes
use by IM injection
unreliable
High dose IV: used in
treatment of status
epilepticus
Spasticity: effective at
sedative doses
Anxiety
Anesthesia: anxiolytic
Withdrawal effects common:
one of the examples listed
Daytime anxiety and
amnesia: shorter acting
Psychomotor dysfunction:
more common with long
acting benzos (long-lived
metabolites)
Prazepam
Clorazepate
Chlordiazepoxide
Long-Acting
Long-Acting
Long-Acting
Flurazepam
Highly lipophilic: makes
use by IM injection
unreliable
Long-Acting:
-Active metabolites
accumulate with continuous
dosing
Primary insomnia and
sleep disorders
Midazolam
Clonazepam
General
Barbiturates
Interact with other sites
on GABA-A receptor (do
not compete with BZ or
GABA)
-Prolong inhibitory
effects of GABA
-Increase DURATION of
GABA mediated Cl
channel opening
Highly Lipid Soluble:
-Cross BBB rapidly
-Cross placenta
-Detected in breast milk
Management of
withdrawal
CNS effects highly dose
dependent: depressant
effects additive when 2
or more given together
More dangerous than
benzos: steeper doseresponse curve
Production of
anesthesia
Low Dose: non-sedating
dose used for treatment
of seizures (selectivity)
Panic/phobic disorders
Anesthesia: induction
by most barbiturates
Seizures: phenobarbital
Skeletal muscle
relaxation: low doses
Cannot use flumazenil as
antagonist: in OD
Psychomotor dysfunction:
more common with long
acting benzos
SEs:
-Impaired psychomotor
functions
-Behavioral disinhibition
-Tolerance (chronic, high
doses)
-Dependence (physical,
psychological)
-Induction of formation of
liver microsomal enzymes
-Precipitation of acute
intermittent porphyria
Withdrawal: more common
with shorter acting drugs
OD: respiratory arrest,
hypotension and CV collapse
-More likely with barbiturates
Thiopental
Thiamylal
Pentobarbital
Methohexital
Phenobarbital
Ultra-short acting
Most lipophilic agent:
-Enters CNS rapidly
Ultra-short acting
Induction of
anesthesia: due to high
lipophilicity
Anesthesia: induction
Withdrawal: short acting
agent given as example
Ulltra-short acting
Long-acting
Duration of Action: over 30
hours
Anesthesia: induction
Low Dose: non-sedating
dose used for treatment
of seizures (selectivity)
High dose IV: used in
treatment of status
epilepticus
Carbamate
Meprobromate
Highly Lipid Soluble:
-Cross BBB rapidly
-Cross placenta
-Detected in breast milk
Muscle relaxant: shows
selectivity for this effect
OD: respiratory and CV
depression more likely than
with benzos
Additive CNS depression
Induction of the formation of
liver microsomal enzymes:
increase drug metabolism
(same as barbiturates)
Displacement of coumarins
from plasma protein binding
sites (increase anticoagulant
effects)
No use of flumazenil
Alcohol
Chloral Hydrate
Highly Lipid Soluble:
-Cross BBB rapidly
-Cross placenta
-Detected in breast milk
Additive CNS depression
No use of flumazenil
Short duration of action:
only a few hours
Buspirone
Partial 5HT1a agonist
and agonist/antagonist
at D2 receptor
OD: respiratory and CV
depression more likely than
with benzos
Additive CNS depression
uncommon: no sedation
or cognitive impairment
No cross-tolerance:
therefore, will not
prevent benzo
withdrawal
BZ R Agonists
Zolpidem
Zaleplone
Eszopiclone
Modulate GABA-A R via
interaction with BZ
binding site
Melatonin Agonist
Ramelteon
Melatonin R agonist
Short duration of action:
only a few hours
Non-Prescription Hypnotics:

Antihistamines:
Diphenydyramine
Doxylamine

Serotonin Precursor: L-tryptophan

Serotonin Biosynthetic Pathway Product: melatonin (secreted by pineal gland in circadian rhythm)
Only anxiolytic effects:
no hypnotic, euphoric,
muscle relaxant or
anticonvulsant effects
Flumazenil can be used
as antidote: b/c of MOA
No risk of abuse: not a
controlled substance
Anxiety: esp. in patients
with a past hx of
substance abuse
-Exact MOA unknown
-Effects take ~week to
develop (start on benzo
and taper off)
Sleep disorders and
primary insomnia:
-Less daytime sedation
-Minimal effects on
sleep patterns (no
rebound increase in
REM when stopped)
Sleep onset: not sleep
maintenance
Dependence: less of an issue
with these than others
↑ serum prolactin
↓ serum testosterone
ANTIPSYCHOTICS:
Drug
General APD
MOA
MOA(s) not well understood
Commonality of all APDs is D2 DA R
blockade
Pharmacokinetics
Administration: oral and
parenteral forms (compliance)
Absorption: most readily but
incompletely absorbed
Metabolism: significant first pass
metabolism by P450
Excretion: conjugated for urinary
excretion
Use
Schizophrenia: primary indication
Schizoaffective disorder: APD plus
-Antidepressant
-Lithium
-Valproate
Neuroleptoanesthesia: droperidol +
fentanyl
Pre-Surgical Use: older APDs with H1
block (anti-emetic effects, sedation and
relief of itching)
Other Uses:
-Depression/BPD
-Agitation in AD/Dementia (black box
warning)
-Autism (aggression/self-injurious
behavior)
-BPD in children over 10
FIRST GENERATION
Chlorpromazine
Haloperidol
Other First Generation:
-Perphenazine
-Thioridazine
-Mesoridazine
-Trifluoroperazine
-Fluphenazine
Receptor Affinities:
Alpha1>D2=H1>M
Generic and inexpensive: may be a
good choice for some patients
Receptor Affinities:
D2>Alpha1>>H1>>M
Generic and inexpensive
Depot preparation: compliance
Side Effects
Relatively Safe: high TI
Muscarininc:
-Dry mouth
-Urinary retention
-Constipation
Alpha Adrenergic Block:
-Orthostatic hypotension
-Impotence
CV Effects: varies based on agent;
overall result is 2x increased risk of
sudden cardiac death (dosedependent; both typical and
atypicals)
Endocrine: decreased action of DA
-Amenorrhea
-Galactorrhea
-Infertility
-Impotence
Metabolic Effects: atypicals (H1/5HT
block)
-Weight gain
-Diabetes
Early EPS:
-Acute dystonic reaction
-Parkinsonism
-Akathisia
-Neuroleptic malignant syndrome
Late EPS:
-Tardive dyskinesia** (can be hard to
reverse)
Adverse autonomic effects: alpha1
and muscarinic block
Risk of EPS/TD: action at D2
CV Effects: ↑HR, abnormal ECG
Less autonomic effects: less block at
alpha1 and M
Higher risk for EPS/TD: stronger D2
block
CV Effects: ↑HR, abnormal ECG (all
phenothiazines)
SECOND GENERATION
Clozapine
Receptor Affinities:
5HT2A>Alpha1=M>D2
Clearly most effective for refractory
cases: but toxicity limits use
Expensive: no generic
Olanzapine
Receptor Affinities:
5HT2A=M>D2>Alpha1
BPD: acute mania and mixed episodes
-All atypicals approved for these
More tolerable than other APDs
May be somewhat more effective
Expensive: no generic
Risperidone
Receptor Affinities:
5HT2A>D2=Alpha1>>M
BPD: acute mania and mixed episodes
Refractory Depression: combined with
fluoxetine (mixed results)
Autism: aggression/self-injurious
behavior in kids over 5
May be more tolerable than other APDs
Generic and inexpensive
Depot preparation: compliance
Seizures: 1-4% of patients
Agranulocytosis: potentially fatal
(requires weekly blood counts)
Less risk for EPS/TD: less D2 block
Weight gain/diabetes: more action
at 5HT2A
Less Risk of EPS/TD: less D2 block
Metabolic Effects: more action at
5HT2A (most prominent)
-Weight gain
-Diabetes
Borderline typical/atypical:
-Less 5HT-related weight gain
-More DA-related SEs (↑PRL, EPS)
Risperidone + Li: approved for
refractory BPD
Quetiapine
Arpiprazole
Ziprasidone
BPD: acute mania and mixed episodes
BPD: acute mania and mixed episodes
BPD in Children: over the age of 10
BPD: acute mania and mixed episodes
BPD in Children: over the age of 10
BPD: acute mania and mixed episodes
CV Effects: risk of QT prolongation
(possible with several atypical APDs,
but most prominent with
ziprasidone)
ANTISEIZURE DRUGS:
Drug
Phenytoin
(First Generation)
Carbamazepine
(First Generation)
Valproic Acid
(First Generation)
MOA
Blockade of Na channels (prolong
inactivation) is primary effect, but
not only effect
Pharmacokinetics
Absorption: depends on formulation
-Fosphenytoin: soluble prodrug that
can be given IM or IV
Blockade of Na channels (prolong
inactivation) is the primary effect
Elimination: via the liver
-Dose-dependent elimination, so
need to titrate slowly at first
Metabolism: significant microsomal
induction of P450s (induces its own
metabolism)
-May need to adjust dose of this
and/or other drugs
Broad spectrum of action probably
due to multiple MOAs
-Blockade of Na channels
-GABA effects
-Histone deacetylation inhibition to
increase gene expression
-Effects on Ca++ channels (works for
absence seizures)
Phenobarbital
(First Generation)
Potentiate GABA effects
(barbiturate)
Lamotrigine
(Second Generation)
Blockade of Na channels (may have
addition MAOs due to broad
spectrum of activity)
Levetiracetam
(Second Generation)
Binds SV2A to interfere with release
of NT
Different Formulations:
-Divalproex Na ER (complex partial
seizures, absence seizures, migraine)
Use
Partial seizures (simple/complex)
Generalized tonic-clonic seizures
Although considered 2nd line by
some, still one of the most widely
used drugs in the world
Fosphenytoin: status epilepticus
Partial seizures (simple/complex)
Generalized tonic-clonic seizures
Other Uses:
-BPD
-Trigeminal neuralgia
-Possibly for drug abuse
Partial seizures (simple/complex)
Generalized tonic-clonic seizures
Absence seizures
Myotonic seizures
Atonic seizures
Combination seizures
Other Uses:
-BPD
-Migraine (Divalproex sodium ER)
Alternative for:
Partial seizures (simple/complex)
Generalized tonic-clonic seizures
Status epilepticus (IV)
Factors that can make it a DOC:
rapid effects, safety profile (prevents
seizures in low dose), and cost
Alternative for:
Partial seizures (simple/complex)
Generalized tonic-clonic seizures
Shown to be as effective as DOCs:
may now be considered one
Alternative for:
Partial seizures (simple/complex)
Generalized tonic-clonic seizures
Good for refractory seizures: in
adults and kids; possible DOC
Adverse Effects
Early: nystagmus
Dose-Limiting: diplopia and ataxia
Chronic Use: gingival hyperplasia
and hirsutism
Teratogenicity: fetal hydantaoin
syndrome (possibly)
Exacerbation of myoclonic and
absence seizures: do not use!
Dose-Related: diplopia and ataxia
Elderly: idiosyncratic blood dyscrasia
Rare: SJS (serious skin reaction)
-Genetically determined (HLA test)
-More common in Asians
ER Formulation: may decrease SEs
Serious effects are rare: but may not
be first line because of them
-Risk of severe idiosyncratic
hepatotoxicity
-Need to monitor liver function
Teratogenicity: risk of spina bifida
and IQ effects
Sedative effects: can be limiting
Rare Event: life threatening
dermatitis in infants
Well tolerated
Gabapentin and Pregabalin
(Second Generation)
Binds voltage gated Ca channel
subunit (NOT related to GABA)
Topiramate
(Second Generation)
Broad spectrum, probably with
multiple MOAs
Ethosuximide
Blocks T-type Ca++ channel
Clonazepam
Benzodiazepine (increases frequency
of GABA channel opening)
Diazepam/Lorazepam
Benzodiazepines
Alternative for:
Partial seizures (simple/complex)
Generalized tonic-clonic seizures
Other Uses:
-Neuropathic pain
-Migraine
-Anxiety
-Surgical analgesia
Alternative for:
Partial seizures (simple/complex)
Generalized tonic-clonic seizures
Absorption: good
Metabolism: complete
ONLY for use in absence seizures
Absence seizures: less effective than
VA or ethosuximide
Myoclonic seizures
Atonic seizures
Infantile spasms
IV treatment of status epilepticus
(followed by IV treatment with
Phenobarbital or fosphenytoin)
NON-PHARMACOLOGICAL INTERVENTIONS:

Ketogenic Diet: low calories and high fat (simulates fasting)
MOA: unclear
Use: refractory seizures in children (ie. Lennox-Gastaut Syndrome)

Surgery:
Anterior temporal lobectomy: effective for refractory and harmful cases of most common partial seizures of adults
Corpus callostomy: Lennox-Gastaut Syndrome
Hemispherectomy: Ramussen Syndrome (autoimmune) and Sturge-Weber Syndrome

Vagal Nerve Stimulation:
Use: poor surgical candidates with refractory complex partial and generalized seizures
MOA: unclear but effective
Well tolerated:
-Dose-related gastric distress
-Rare cases of rashes/psychosis
Typical benzo SEs: limit use
-Sedation
-Development of tolerance
-Withdrawal syndrome
ANTIPARKINSON’S DRUGS:
Drug
Levodopa (L-dopa)
MOA
Precursor to DA (replenish DA)
Use
Early Use: very effective (more for
bradykinesia than tremor)
Over time: decreased efficacy (wearing
off after 2-5 years)
Side Effects
Major Issues:
-On/Off phenomenon
-Dyskinesias (up to 80% of patients; dopa-PD
interaction)
Other Effects:
-Early: anorexia, nausea, hypotension
-Chronic use: hallucinations, delusions,
agitations, insomnia, gambling and
hypersexuality
Formulations
Sinemet/Atamet: levodopa +
carbidopa (3-6 times/day)
-Carbidopa: amino acid
decarboxylase inhibitor; allows
more levodopa to reach the brain
-SR formulation now available
Parcopa: immediate release
levodopa/carbidopa taken w/o
water (management of acute
events)
Lodosyn: carbidopa alone (if
needed to be added to regimen)
Bromocriptine (Ergot)
DA receptor agonist
Pergolide (Ergot)
DA receptor agonist
Pramipexole (Non-Ergot)
DA receptor agonist (D3>D2)
Not typically used for PD anymore
Current Use: neuroleptic malignant
syndrome (due to APDs)
Not typically used for PD anymore
Current Use: low doses for
hyperprolactinemia
First line monotherapy in PD: probably
not as effective as L-dopa (originally
just an adjunt), but better SE profile
Other Use: Restless Leg Syndrome
Ropinirole (Non-Ergot)
Apomorphine
DA receptor agonist (D2)
DA receptor agonist (some D2
preference)
Same as pramipexole
PD: treatment of off episodes
(injectable formulation for rescue)
Rotigone
Selegiline
DA receptor agonist
MAO-B inhibitor (inhibition of DA
metabolism)
-Increased DA
-Metabolism to amphetamine
-Antidepressant effects
Similar to pramipexole
PD: in combination with dopa or as
initial monotherapy (modest benefits)
Use limited due to side effects
Use limited due to side effects: incidence of
cardiac valve regurgitation
SEs:
-Nausea
-Edema
-Hypotension
-Pathologic gambling/other compulsions
-Somnolence (drowsiness)
Treatment of SEs:
-Daytime sleep attacks (modafinil)
-Peripheral DA effects (trimethobenzamide,
domperidone)
Same as pramipexole
Same as pramipexole, PLUS
-Yawning
-Hypersexuality
Treatment of SEs:
-Emesis/nausea (trimethobenzamide)
Contraindications: ondansetron is
contraindicated for treatment of nausea due
to risk of severe hypotension
Similar to pramipexole
MAO-B specific: less peripheral MAO
inhibition (less cheese effect)
Transdermal Patch: convenience
Rasagiline
MAO-B inhibitor (inhibitor of DA
metabolism)
-Increased DA
-Metabolism to amphetamine
-Antidepressant effects
-Neuroprotective (?)
COMT inhibitor (given with L-dopa
to increase its levels by blunting
metabolism in periphery and brain)
PD: clearly effective in treatment of
early PD (monotherapy) or as adjunct
in advanced PD
Amantadine (Antiviral)
Relevant MOA may be NMDA
antagonism
Antimuscarinics:
Benztropine
Trihexyphenidyl
Procyclidine
Biperiden
Decreases action of ACh to offset
neurochemical imbalance in
striatum created by loss of DA
PD: modest and transient benefits
(may only last a few weeks); better for
TREMOR
PD: only useful for the following (NOT
bradykinesia)
-Early onset tremor
-Rigidity
-Drooling
Entacapone
PD: adjunt to Sinemet to reduce
fluctuations and off time
TREATMENT OF COMORBIDITIES:

Depression: SSRIs

Psychosis: clozapine or other atypicals

Dementia: cholinesterase inhibitors
SURGICAL INTERVENTIONS:

DA cell replacement

Ablations: not done anymore (irreversible)

Deep Brain Stimulation: effective (esp. subthalamic nucleus)
Use:
o
Patients refractory to medication
o
Patients with significant dyskinesia
o
Patients with significant clinical fluctuation
o
Patients with intact cognition

Neurorestoration: local injections of trans-genes currently in trials
ESSENTIAL TREMOR:

Description: action/kinetic tremor (similar to cerebellar intention tremor) with uncertain pathology

Treatment:
Beta blockers
Anti-Seizure drugs: primadone, topiramate
DBS: refractory patients
MAO-B specific: less peripheral MAO
inhibition (less cheese effect)
Other Effects:
-Nausea
-Orthostatic hypotension
May increase risk of dyskinesia (increases
action of L-dopa)
No hepatotoxicity (unlike early COMT
inhibitor tolcapone)
Livedo reticularis: lace-like purple
discoloration of skin
Psyhosis: rare
Prominent side effects: may limit use
-CNS: impaired memory, drowsiness,
confusion and delusions
-PNS: dry mouth, blurred vision, urinary
retention, tachycardia
ALZHEIMER’S DRUGS
Drug
Donepezil
MOA
Reversible ChE inhibitor
Pharmacokinetics
Long Half-Life: once-daily dosing (convenient)
Metabolism: hepatic (CYP2D6/3A4)- DDIs
Use
AD: mild, moderate, severe
Mild cognitive impairment
PD with dementia
Lewy body dementia
Vascular dementia
Rivastigmine
Reversible, non-competitive ChE
inhibitor
Galantamine
Reversible, competitive ChE
inhibitor
-Also binds allosterically to nACh R
AD: mild to moderate
PD with dementia
Lewy body dementia
AD: mild to moderate
Vascular dementia
Memantine
Uncompetitive NMDA receptor
antagonist
-Binds R once it has bound Glu
-Blockade of the most active NMDA
R that pass Ca++, possibly leading to
excitotoxicity
Shorter Half-Life: BID dosing
Metabolism: ChE hydrolysis (no DDIs)
Transdermal patch available: good absorption
Shorter Half-Life: BID dosing
-Now an ER formulation as well
Metabolism: hepatic (CYP2D6/3A4)- DDIs
Excretion: some also secreted unchanged
Shorter Half-Life: BID dosing
Excretion: unchanged in the urine
AD: moderate to severe
Vascular dementia
Aggression/agitation: try before use
of APDs (black box warning)
Side Effects
Occur esp. during dose escalation;
decrease over time:
-N/V/D
-Muscle cramps
-Bradycardia
-Urinary incontinence
Same as donepezil
Same as donepezil
Well tolerated:
-Headaches
-Dizziness
-Confusion
Efficacy: similar to ChE inhibitors
NEW THERAPIES:

Anti-Amyloid Therapy: has decrease plaque formation but so far, no effect on disease process
Increasing Aβ Clearance: active or passive immunization
Decreasing Aβ Generation:
o
Inhibition of BACE1
o
Inhibition of γ-Secretase

Semagegecestat (did not slow disease progression; increased risk of skin cancer)

Targeting GSAP (new hope for therapeutics directed toward this target)
Disruption of Amyloid Aggregation:
o
Arenflurbril and Tramiprosate
o
PTB2 (modulator of copper and zinc)

Anti-Tau/Tangles Therapy: not targeted as often as amyloid
AL-108 (NAP): derived from neuroprotective protein (reduces tangles and plaques in animal models)
Methylthioninium Chloride (Methylene Blue): disrupts tau-tau binding (tau mediated tangle formation); showed some benefit in cognition in trials
Lithium and Valproic Acid: both inhibit GSK03 (may be involved in tau hyperphosphorylation)
ANTIDEPRESSANTS:
Drug Class
TCAs:
Imipramine (5HT and NE)
Desipramine (NE)
Chlorimipramine (5HT)
SSRIs:
Fluoxetine
Sertraline
Paroxetine
Citalopram
Vilazodone (SSRI + 5HT1A agonist
activity)
SNRIs:
Venlafaxine
Desvenlafaxine
Duloxetine
Milnacipran
MAOIs:
Phenelzine
Tranylcypromine
Selegiline (MAO-B)
Moclobemide (MAO-A)
MOA
Regulated serotonergic and
noadrenergic neurotransmission by
inhibiting re-uptake of these
monoamines
Selective inhibition of 5HT reuptake
Inhibition of both 5HT and NE
reuptake
Inhibition of the enzyme monoamine
oxidase (MAO-A and/or MAO-B)
leading to an increase in monoamine
packaging and release (5HT, NE, DA)
Therapeutic Considerations
Delayed therapeutic effects: 2-4
weeks (although increase in
monoamines is immediate)
-Suggests need to develop secondary
adaptive responses to Tx
-Reflects persistence of memory
Response varies: not everyone will
respond to a given TCA
Pharmacokinetics
Absorption: generally well absorbed orally
Distribution: bind to plasma proteins (DDIs)
and accumulate in tissue (lipophilic)
Metabolism: hepatic (CYPs- DDIs)
-Some production of active metabolites
Most widely used antidepressants
Delayed therapeutic effects: 2-4
weeks (although increase in
monoamines is immediate)
-Suggests need to develop secondary
adaptive responses to Tx
-Reflects persistence of memory
Response varies: not everyone will
respond to a given SSRI
Augment w/ Atypical APD: may
modestly augment efficacy, but also
increases adverse effects
Same as SSRIs
Absorption: generally well absorbed orally
Distribution: variable plasma protein
binding and half-lives (hours-days)
Metabolism: multiple hepatic enzymes
-Some active metabolites (ie. norfluoxetine)
Non-Specific MAOIs: irreversibly
inhibit both MAO-A and MAO-B
MAO-A: found in 5HT, NE and DA neurons
MAO-B: found mostly in 5HT neurons
MAO-B Specific: Selegiline
(irreversible inhibitor for use in PD)
DDIs: potential DDIs with uptake inhibitors
MAO-A Specific: Moclobemide
(reversible inhibitor- not in US)
Other:
Burpropion
Mirtazapine
Nefazodone
Trazodone
Precise MOA as it is related to
depression is unknown
Use: based upon relief of specific
side effects
-Example: Trazodone given to help
with insomnia (sedative properties)
Low Safety: ODs potentially life threatening
due to cardiac toxicity
-Conduction delays
-Arrhythmias
Same as SSRIs
Side Effects
Limit use:
-Antimuscarinic: dry mouth,
constipation, blurred vision
-Anti-alpha1: orthostatic
hypotension
Other:
-Weight gain
-Sedation
-Sexual dysfunction
-Induction of mania in
patients with undiagnosed
BPD
Much less prominent than
with TCAs:
-Jitteriness
-Insomnia
-N/V/D
-Headache
-Dizziness
-Fatigue
-Sexual dysfunction
Use in pregnancy: relatively
low risk
Same as SSRIs
Non-Specific: loss of ability to
metabolize tyramine, possibly
leading to hypertensive crisis
MAO-B Specific: less in the
periphery and therefore
cheese effect less likely
MAO-A: cheese effect less
likely due to reversibility
-Increase in NE results in
outcompeting for MAO-A
(levels never get too high)
MOOD STABILIZERS:
Drug
Lithium
Proposed MOA
Inhibition of phosphoinositol
signaling: prevents recycling of
inositol phospholipids, preventing
formation of PIP2
Inhibition of GSK-3: inhibition of
WNT signaling
Pharmacokinetics
Safety: low TI (monitor plasma
levels)
Absorption: well absorbed orally
Elimination: by the kidney
-[Li] affected by changes in Na
clearance (ie. diuretics)
Use
Acute mania: in combo with
antipsychotic or benzodiazepine
Maintenance: monotherapy is
effective, but often combine with
valproic acid or carbamazepine
*Protective against suicide*
Better choice for use in pregnancy
Anticonvulsants:
Valproic Acid
Carbamazepine
Lamotrigine
(Topiramate, Gabapentin)
Inhibition of inositol signaling: VA
inhibits an enzyme involved in
metabolism of inositol phospholipids
Inhibition of GSK-3: VA inhibits WNT
signaling
VA/Carbamazepine:
-Neither approved for maintenance
treatment, but extensively used
-Not protective against suicide
Side Effects
At Therapeutic Doses:
-N/V/D
-Daytime drowsiness
-Polyuria/polydipsia
-Weight gain
-Fine tremor
-Acne
Toxicity: only Tx is supportive
-N/V/D
-Mental confusion
-Tremor and ataxia
-Convulsions
-Coma
VA/Carbamazepine: use during
pregnancy is discouraged (Li
preferred agent)
Lamotrigine: only approved for
maintenance
Atypical Antipsychotics:
Quetiapine
Olanzapine
Risperidone
Aripiprazole
Ziprasidone
PANIC DISORDER:

SSRIs:
Fluoxetine
Sertraline
Paroxetine
Fluvoxamine

SNRIs: Velafaxine

TCAs/MAOIs: second line

Benzodiazepines: provide rapid relief, but not for long-term management
OCD:

TCA: chlorimipramine (slightly superior to SSRIs)

SSRIs/SNRIs: same as panic disorder

MAOIs

Note: NE uptake inhibitors NOT effective in OCD treatment
Topiramate/Gabapentin: have not
yet been proven effective
Use: effective for management of
acute episodes AND possibly
maintenance
Side effects limit use
DRUGS FOR MIGRAINE:

Non-Severe (no N/V): NSAIDs

Severe (N/V):
Triptans: mainstay of Tx (very effective); best when given early (prevent inflammatory process from starting) and in combo with NSAID
o
Sumatriptan
o
Frovatriptan (longer acting)
Dihydroergotamine: more SEs and less efficacy

Prevention:
Beta blockers
Antiepileptic drugs:
o
Valproate
o
Topiramate
TCAs: amitriptiline
Non-Drug Therapy: behavioral therapy (relaxation, EMG biofeedback, cognitive therapy)

Future:
CGRP Receptor Antagonist: block vasodilation/extravasation