Katzung Summary

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DRUGS THAT ACT IN THE CENTRAL

NERVOUS SYSTEM
ANTIDEPRESSANTS
Antidepressants
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Applications Toxicities,
Interactions
Selective serotonin reuptake inhibitors (SSRIs)

Fluoxetine
Citalopram
Escitalopram
Paroxetine
Sertraline
Highly selective
blockade of
serotonin
transporter
(SERT) little
effect on
norepinephrine
transporter
(NET)
Acute increase
of serotonergic
synaptic
activity slower
changes in
several
signaling
pathways and
neurotrophic
activity
Major depression,
anxiety disorders
panic disorder
obsessivecompulsive
disorder posttraumatic stress
disorder
perimenopausal
vasomotor
symptoms eating
disorder (bulimia)
Half-lives from 1575 h

oral activity Toxicity: Well
tolerated but cause sexual
dysfunction Interactions:
Some CYP inhibition
(fluoxetine 2D6, 3A4;
fluvoxamine 1A2;
paroxetine 2D6)
Fluvoxamine: Similar to above but approved only for obsessive-compulsive behavior

Serotonin-norepinephrine reuptake inhibitors (SNRIs)
Duloxetine
Venlafaxine
Moderately
selective
blockade of NET
and SERT
Acute increase
in serotonergic
and adrenergic
synaptic
activity
Major depression,
chronic pain
disorders
fibromyalgia,
perimenopausal
Toxicity: Anticholinergic,
sedation, hypertension
(venlafaxine) Interactions:
Some CYP2D6 inhibition
(duloxetine,
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
otherwise like
symptoms
desvenlafaxine)
SSRIs
Desvenlafaxine: Desmethyl metabolite of venlafaxine, metabolism is by phase II rather than CYP
phase I
Tricyclic antidepressants (TCAs)
Imipramine
Many others
5-HT2 Antagonists
Nefazodone
Trazodone
Tetracyclics, unicyclic
Bupropion
Amoxapine
Maprotiline
Mirtazapine
Monoamine oxidase inhibitors (MAOIs)
Phenelzine
Tranylcypromine
Selegiline
DRUGS USED FOR MOVEMENT DISORDERS

Drugs Used for Movement Disorders
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Levodopa and combinations

Levodopa
Transported into
the central
nervous system
(CNS) and
converted to
dopamine (which
does not enter
the CNS); also
converted to
dopamine in the
periphery
Ameliorates all
symptoms of
Parkinson's
disease and
causes
significant
peripheral
dopaminergic
effects (see
text)
Parkinson's
disease: Most
efficacious therapy
but not always
used as the first
drug due to
development of
disabling response
fluctuations over
time
Oral ~ 68 h effect
Toxicity: Gastrointestinal
upset, arrhythmias,
dyskinesias, on-off and
wearing-off phenomena,
behavioral disturbances
Interactions: Use with
carbidopa greatly diminishes
required dosage use with
COMT or MAO-B inhibitors
prolongs duration of effect.
Levodopa + carbidopa (Sinemet): Carbidopa inhibits peripheral metabolism of levodopa to

dopamine and reduces required dosage and toxicity. Carbidopa does not enter CNS.
Levodopa + carbidopa + entacapone (Stalevo): Entacapone is a catechol-O-methyltransferase
(COMT) inhibitor (see below)
Dopamine agonists
Pramipexole
Direct agonist at Reduces

D3 receptors,
symptoms of
nonergot
parkinsonism
smooths out
fluctuations in
levodopa
response
Parkinson's
disease: Can be
used as initial
therapy also
effective in on-off
phenomenon
Oral ~ 8 h effect
Toxicity: Nausea and
vomiting, postural
hypotension, dyskinesias
Ropinirole: Similar to pramipexole; nonergot; relatively pure D 2 agonist
Bromocriptine: Ergot derivative; potent agonist at D 2 receptors; more toxic than pramipexole or
ropinirole
Apomorphine: Nonergot; subcutaneous route useful for rescue treatment in levodopa-induced

dyskinesia; high incidence of nausea and vomiting
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Monoamine oxidase (MAO) inhibitors

Rasagiline
Inhibits MAO-B
selectively,
higher doses also
inhibit MAO-A
Increases
dopamine
stores in
neurons; may
have
neuroprotective
effects
Parkinson's
disease;
adjunctive to
levodopa; smooths
levodopa response
Oral Toxicity &

interactions: may cause
serotonin syndrome with
meperidine, and
theoretically also with
selective serotonin reuptake
inhibitors, tricyclic
antidepressants
Selegiline: Like rasagiline, adjunctive use with levodopa; may be less potent than rasagiline in
MPTP-induced parkinsonism
COMT inhibitors
Entacapone
Inhibits COMT in
periphery does
not enter CNS
Reduces
metabolism of
levodopa and
prolongs its
action
Parkinson's
disease
Oral Toxicity: Increased

levodopa toxicity nausea,
dyskinesias, confusion
Tolcapone: Like entacapone but enters CNS. Some evidence of hepatotoxicity, elevation of liver
enzymes.
Antimuscarinic agents
Benztropine
Antagonist at M
receptors in
basal ganglia
Reduces tremor Parkinson's

and rigidity
disease
little effect on
bradykinesia
Oral Toxicity: Typical

antimuscarinic effects:
sedation, mydriasis, urinary
retention, dry mouth
Biperiden, orphenadrine, procyclidine, trihexyphenidyl: Similar antimuscarinic agents with CNS

effects
Drugs used in Huntington's disease
Tetrabenazine, Deplete amine
reserpine
transmitters,
especially
dopamine, from
nerve endings
Reduce chorea
severity
Huntington's
disease other
applications, see
Chapter 11
Oral Toxicity: Hypotension,

sedation, depression,
diarrhea tetrabenazine
somewhat less toxic
Tourette's
Oral Toxicity: Parkinsonism,
Haloperidol, other neuroleptics: Sometimes helpful

Drugs used in Tourette's syndrome
Haloperidol
Blocks central D2 Reduces vocal
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
receptors
syndrome other
applications, see
Chapter 29
and motor tic

frequency,
severity
other dyskinesias sedation
Clonidine: Effective in ~ 50% of patients; see Chapter 11 for basic pharmacology

Phenothiazines, benzodiazepines, carbamazepine: Sometimes of value
SEDATIVE-HYPNOTICS
Sedative-Hypnotics
Subclass
and
Examples
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Benzodiazepines
Alprazolam
Bind to specific
GABAA receptor
Chlordiazepoxide subunits at
central nervous
Clorazepate
system (CNS)
neuronal
Clonazepam
synapses
facilitating
Diazepam
GABA-mediated
chloride ion
Estazolam
channel opening
enhance
Flurazepam
membrane
hyperpolarization
Lorazepam
Midazolam
Oxazepam
Quazepam
Temazepam
Triazolam
Dose-dependent
depressant
effects on the
CNS including
sedation and
relief of anxiety,
amnesia,
hypnosis,
anesthesia,
coma and
respiratory
depression
Acute anxiety
states panic
attacks
generalized
anxiety disorder
insomnia and
other sleep
disorders
relaxation of
skeletal muscle
anesthesia
(adjunctive)
seizure disorders
Half-lives from 240 h

oral activity Hepatic
metabolismsome active
metabolites Toxicity:
Extensions of CNS
depressant effects
dependence liability
Interactions: Additive CNS
depression with ethanol
and many other drugs
Subclass
and
Examples
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Benzodiazepine antagonist
Flumazenil
Antagonist at
benzodiazepine
binding sites on
the GABAA
receptor
Blocks actions
Management of
of
benzodiazepine
benzodiazepines overdose
and zolpidem
but not other
sedativehypnotic drugs
IV, short half-life Toxicity:

Agitation, confusion
possible withdrawal
symptoms in
benzodiazepine
dependence
Barbiturates
Amobarbital
Bind to specific
GABAA receptor
Butabarbital
subunits at CNS
neuronal
Mephobarbital
synapses
facilitating
Pentobarbital
GABA-mediated
chloride ion
Phenobarbital
channel opening
enhance
Secobarbital
membrane
Newer hypnotics hyperpolarization
Eszopiclone
Zaleplon
Dose-dependent
depressant
effects on the
CNS including
sedation and
relief of anxiety
amnesia
hypnosis
anesthesia
coma and
respiratory
depression
steeper doseBind selectively response
Rapid onset of
to a subgroup of relationship
hypnosis with
GABAA receptors, than
few amnestic
benzodiazepines
acting like
effects or day-
benzodiazepines
to enhance
Melatonin receptor
agonist
membrane
hyperpolarization
Ramelteon
Activates MT1
and MT2
receptors in
Zolpidem
suprachiasmatic
nuclei in the CNS
after
psychomotor
depression or
somnolence
Rapid onset of
sleep with
minimal
rebound
insomnia or
withdrawal
symptoms
Anesthesia
(thiopental)
insomnia
(secobarbital)
seizure disorders
(phenobarbital)
Half-lives from 460 h oral

activity hepatic metabolism
phenobarbital 20% renal
elimination Toxicity:
Extensions of CNS
depressant effects
dependence liability >
benzodiazepines
induction of hepatic drugmetabolizing enzymes
Sleep disorders,
especially those
characterized by
difficulty in falling
asleep
Oral activity short halflives CYP substrates

Toxicity: Extensions of
CNS depressant effects
dependence liability
Sleep disorders,
Oral activity forms active
especially those
metabolite via CYP1A2
characterized by Toxicity: Dizziness fatigue
difficulty in falling endocrine changes
asleep not a
Interactions: Fluvoxamine
controlled
inhibits metabolism
substance
5-HT-receptor agonist
Buspirone
Mechanism
uncertain: Partial
agonist at 5-HT
receptors but
Slow onset (12 Generalized

weeks) of
anxiety states
anxiolytic
effects minimal
Oral activity forms active

metabolite short half-life
Toxicity: Tachycardia
paresthesias
Subclass
and
Examples
Mechanism Effects
of Action
affinity for D2
receptors also
possible
Clinical
Pharmacokinetics,
Interactions
psychomotor
impairmentno
additive CNS
depression with
sedativehypnotic drugs
gastrointestinal distress
Interactions: CYP3A4
inducers and inhibitors
ANTIPSYCHOTIC DRUGS & LITHIUM

Antipsychotic Drugs & Lithium
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Phenothiazines
Chlorpromazine Blockade of D2
receptors >>
Fluphenazine
5HT2A receptors
Thioridazine
Thioxanthene
Thiothixene
Butyrophenone
-Receptor
blockade
(fluphenazine
least)
muscarinic (M)receptor
blockade
(especially
chlorpromazine
and thioridazine)
H1-receptor
blockade
(chlorpromazine,
thiothixene)
central nervous
system (CNS)
depression
(sedation)
decreased
seizure threshold
QT prolongation
(thioridazine)
Psychiatric:
schizophrenia
(alleviate positive
symptoms),
bipolar disorder
(manic phase)
nonpsychiatric:
antiemesis,
preoperative
sedation
(promethazine)
pruritus
Oral and parenteral forms,

long half-lives with
metabolism-dependent
Extensions of effects on and M- receptors blockade
of dopamine receptors may
result in akathisia,
dystonia, parkinsonian
symptoms,
tardivedyskinesia, and
hyperprolactinemia
Subclass
Haloperidol
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Blockade of D2
receptors >>
5HT2A receptors
Some blockade,
but minimal M
receptor
blockade and
much less
sedation than
the
phenothiazines
Schizophrenia
(alleviates positive
symptoms),
bipolar disorder
(manic phase),
Huntington's
chorea, Tourette's
syndrome
Oral and parenteral forms

with metabolism-dependent
Extrapyramidal dysfunction
is major adverse effect
No significant
antagonistic
actions on
autonomic
nervous system
receptors or
specific CNS
receptors no
sedative effects
Bipolar affective
disorder
prophylactic use
can prevent mood
swings between
mania and
depression
Oral absorption, renal

elimination half-life 20 h
narrow therapeutic window
(monitor blood levels)
Toxicity: Tremor, edema,
hypothyroidism, renal
dysfunction, dysrhythmias
pregnancy category D
Interactions: Clearance
decreased by thiazides and
some NSAIDs
Atypical antipsychotics
Aripiprazole
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Lithium
Mechanism of
action uncertain
suppresses
inositol signaling
and inhibits
glycogen
synthase kinase3 (GSK-3), a
multifunctional
protein kinase
Newer agents for bipolar disorder

Carbamazepine
Lamotrigine
Valproic acid
DRUGS USED SKELETAL MUSCLE RELAXANTS

Drugs Used
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Depolarizing neuromuscular blocking agent

Succinylcholine
Agonist at
nicotinic
acetylcholine
(ACh) receptors,
especially at
neuromuscular
junctions
depolarizes may
stimulate
ganglionic
nicotinic ACh and
cardiac
muscarinic ACh
receptors
Initial
depolarization
causes
transient
contractions,
followed by
prolonged
flaccid
paralysis
depolarization
is then
followed by
repolarization
that is also
accompanied
by paralysis
Placement of
tracheal tube at
start of anesthetic
procedure rarely,
control of muscle
contractions in
status epilepticus
Rapid metabolism by
plasma cholinesterase
normal duration, ~5 min
Toxicities: Arrhythmias
hyperkalemia transient
increased intra-abdominal,
intraocular pressure
postoperative muscle pain
Nondepolarizing neuromuscular blocking agents

d-Tubocurarine
Competitive
antagonist at
nACh receptors,
especially at
neuromuscular
junctions
Prevents
depolarization
by ACh, causes
flaccid
paralysis can
cause
histamine
release with
hypotension
weak block of
cardiac
muscarinic ACh
receptors
Prolonged
relaxation for
surgical
procedures
superseded by
newer
nondepolarizing
agents
Renal excretion duration,

~4060 min Toxicities:
Histamine release
hypotension prolonged
apnea
Cisatracurium
Similar to
tubocurarine
Like
tubocurarine
but lacks
histamine
Prolonged
relaxation of
surgical
Not dependent on renal or

hepatic function duration,
~2545 min Toxicities:
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
release and
procedures
Prolonged apnea but less
antimuscarinic relaxation of
toxic than atracurium
effects
respiratory
muscles to
facilitate
mechanical
ventilation in
intensive care unit
Rocuronium
Similar to
cisatracurium
Like
Like cisatracurium
cisatracurium
useful in patients
but slight
with renal
antimuscarinic impairment
effect
Hepatic metabolism
duration, ~2035 min
Toxicities: Like
cisatracurium
Mivacurium: Rapid onset, short duration (1020 min); metabolized by plasma cholinesterase
Vecuronium: Intermediate duration; metabolized in liver
Centrally acting spasmolytic drugs
Baclofen
GABAB agonist,
facilitates spinal
inhibition of
motor neurons
Cyclobenzaprine Poorly
understood
inhibition of
muscle stretch
reflex in spinal
cord
Pre- and
postsynaptic
inhibition of
motor output
Severe spasticity
due to cerebral
palsy, mulitple
sclerosis, stroke
Reduction in
Acute spasm due
hyperactive
to muscle injury
muscle
inflammation
reflexes
antimuscarinic
effects
Oral, intrathecal Toxicities:

Sedation, weakness
Hepatic metabolism
duration, ~46 h
Toxicities: Strong
antimuscarinic effects
Chlorphenesin, methocarbamol, orphenadrine, others: Like cyclobenzaprine with varying degrees of

antimuscarinic effect
Diazepam
Tizanidine
Facilitates
GABAergic
transmission in
central nervous
system (see
Chapter 22)
-Adrenoceptor
Increases
interneuron
inhibition of
primary motor
afferents in
spinal cord
central
sedation
Chronic spasm
due to cerebral
palsy, stroke,
spinal cord injury
acute spasm due
to muscle injury
Hepatic metabolism
duration, ~1224 h
Toxicities: See Chapter 22
Presynaptic
Spasm due to
Renal and hepatic
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
agonist in the
spinal cord
and
postsynaptic
inhibition of
reflex motor
output
multiple sclerosis,
stroke,
amyotrophic
lateral sclerosis
elimination duration, 36 h
Toxicities: Weakness,
sedation hypotension
Reduces actinmyosin
interaction
weakens
skeletal muscle
contraction
IV: Malignant
hyperthermia
Oral: Spasm due
to cerebral palsy,
spinal cord injury,
multiple sclerosis
IV, oral duration, 46 h

Toxicities: Muscle
weakness
Direct-acting muscle relaxants

Dantrolene
Blocks RyR1
Ca2+-release
channels in the
sarcoplasmic
reticulum of
skeletal muscle
ANTISEIZURE DRUGS
Antiseizure Drugs
Subclass
Mechanis Pharmacokineti Clinical

Toxicities,
m of
cs
Application Interactions
Action
s
Cyclic ureides
Phenytoin,
fosphenytoin
Blocks highfrequency
firing of
neurons
through action
on voltagegated (VG)
Na+ channels
decreases
synaptic
release of
glutamate
Absorption is
formulation dependent
highly bound to plasma
proteins no active
metabolites dosedependent elimination,
t1/2 1236 h
fosphenytoin is for IV,
IM routes
Generalized
tonic-clonic
seizures, partial
seizures
Toxicity: Diplopia,
ataxia, gingival
hyperplasia, hirsutism,
neuropathy
Interactions: Phenobarbi
tal, carbamazepine,
isoniazid, felbamate,
oxcarbazepine,
topiramate, fluoxetine,
fluconazole, digoxin,
quinidine, cyclosporine,
steroids, oral
contraceptives, others
Primidone
Similar to
phenytoin but
converted to
Well absorbed orally

not highly bound to
Generalized
tonic-clonic
seizures, partial
Toxicity: Sedation,
cognitive issues, ataxia,
Subclass

Toxicities,
m of
cs
Action
s
phenobarbital
plasma proteins peak

seizures
concentrations in 26 h
t1/2 1025 h two active
metabolites
(phenobarbital and
phenylethylmalonamide)
hyperactivity
Interactions: Similar to
phenobarbital
Phenobarbital Enhances
phasic GABAA
receptor
responses
reduces
excitatory
synaptic
responses
Nearly complete
absorption not
significantly bound to
plasma proteins peak
concentrations in to 4
h no active metabolites
t1/2 varies from 75 to
125 h
Generalized
tonic-clonic
seizures, partial
seizures,
myoclonic
seizures,
generalized
seizures,
neonatal
seizures, status
epilepticus
Toxicity: Sedation,
cognitive issues, ataxia,
hyperactivity
Interactions: Valproate,
carbamazepine,
felbamate, phenytoin,
cyclosporine, felodipine,
lamotrigine, nifedipine,
nimodipine, steroids,
theophylline, verapamil,
others
Ethosuximide Reduces low

threshold Ca2+
currents (Ttype)
Well absorbed orally,

with peak levels in 37
h not protein-bound
completely metabolized
to inactive compounds
t1/2 typically 40 h
Absence seizures Toxicity: Nausea,

headache, dizziness,
hyperactivity
phenobarbital,
phenytoin,
carbamazepine,
rifampicin
Well absorbed orally,

with peak levels in 68
h no significant protein
binding metabolized in
part to active 10-11epoxide t1/2 of parent
ranges from 812 h in
treated patients to 36 h
in normal subjects
Generalized
tonic-clonic
seizures, partial
seizures
Tricyclics
Carbamazepi
ne
firing of
neurons
through action
on VG Na+
channels
decreases
synaptic
release of
glutamate
Toxicity: Nausea,
diplopia, ataxia,
hyponatremia, headache
Interactions: Phenytoin,
carbamazepine,
valproate, fluoxetine,
verapamil, macrolide
antibiotics, isoniazid,
propoxyphene, danazol,
phenobarbital,
primidone, many others
Oxcarbazepine: Similar to carbamazepine; shorter half-life but active metabolite with longer
duration and fewer interactions reported
Subclass

Toxicities,
m of
cs
Action
s
Benzodiazepines
Diazepam
Potentiates
GABAA
responses

Status
rectal administration
epilepticus,
gives peak
seizure clusters
concentration in ~1 h
with 90% bioavailability
IV for status epilepticus
highly protein-bound
extensively metabolized
to several active
metabolites t1/2 ~2 d
Toxicity: Sedation
Interactions: Minimal
Clonazepam
As for
diazepam
>80% bioavailability
extensively metabolized
but no active
metabolites t1/2 2050
h
Toxicity: Similar to
diazepam Interactions:
Minimal
Absence
seizures,
myoclonic
seizures,
infantile spasms
Lorazepam: Similar to diazepam

Clobazam: Indications include absence seizures, myoclonic seizures, infantile spasms
GABA derivatives
Gabapentin
Decreases
excitatory
transmission
by acting on
VG Ca2+
channels
presynaptically
( 2 subunit)
Bioavailability 50%,
decreasing with
increasing doses not
bound to plasma
proteins not
metabolized t1/2 68 h
Generalized
tonic-clonic
seizures, partial
seizures,
generalized
seizures
Toxicity: Somnolence,
dizziness, ataxia
Pregabalin
As for
gabapentin

not bound to plasma
proteins not
Partial seizures
dizziness, ataxia
Vigabatrin
Irreversibly
70% bioavailable not
inhibits GABA- bound to plasma
transaminase proteins not
metabolized, t1/2 57 h
Partial seizures,
infantile spasms
Toxicity: Drowsiness,
dizziness, psychosis,
visual field loss
Subclass

Toxicities,
m of
cs
Action
s
(not relevant because of
mechanism of action)
Miscellaneous
Valproate
firing of
neurons
modifies
amino acid
metabolism
Well absorbed from

several formulations
highly bound to plasma
proteins extensively
Generalized
tonic-clonic
seizures, partial
seizures,
generalized
seizures,
absence
seizures,
myoclonic
seizures
Toxicity: Nausea, tremor,

weight gain, hair loss,
teratogenic, hepatotoxic
Interactions:
Phenobarbital,
phenytoin,
carbamazepine,
lamotrigine, felbamate,
rifampin, ethosuximide,
primidone
Lamotrigine
Prolongs
inactivation of
VG-Na+
channels acts
presynaptically
on VG-Ca2+
channels,
decreasing
glutamate
release
Well absorbed orally no

significant protein
binding extensively
metabolized, but no
active metabolites t1/2
2535 h
Generalized
tonic-clonic
seizures,
generalized
seizures, partial
seizures,
generalized
seizures,
absence seizures
Toxicity: Dizziness,
headache, diplopia, rash
carbamazepine,
oxcarbazepine,
phenytoin,
phenobarbital,
primidone, succinimides,
sertraline, topiramate
Levetiraceta
m
Action on
synaptic
protein SV2A

not bound to plasma
proteins metabolized to
3 inactive metabolites
t1/2 611 h
Generalized
tonic-clonic
seizures, partial
seizures,
generalized
seizures
Toxicity: Nervousness,
dizziness, depression,
seizures Interactions:
Phenobarbital,
phenytoin,
carbamazepine,
primidone
Tiagabine
Blocks GABA
reuptake in
forebrain by
selective
blockade of
GAT-1
Well absorbed highly

bound to plasma
metabolized, but no
active metabolites t1/2
48 h
Partial seizures
Toxicity: Nervousness,
dizziness, depression,
seizures Interactions:
Phenobarbital,
phenytoin,
carbamazepine,
primidone
Topiramate
Multiple
actions on
Well absorbed not
Generalized
tonic-clonic
cognitive slowing,
Subclass

Toxicities,
m of
cs
Action
s
synaptic
function,
probably via
actions on
phosphorylatio
n
bound to plasma
metabolized, but 40%
excreted unchanged in
the urine no active
metabolites t1/2 20 h,
but decreases with
concomitant drugs
seizures, partial
seizures,
generalized
seizures,
absence
seizures,
migraine
confusion, paresthesias
Interactions: Phenytoin,
carbamazepine, oral
contraceptives,
lamotrigine, lithium?
Zonisamide
firing via
action on VG
Na+ channels
Approximately 70%
bioavailable orally
minimally bound to
plasma proteins >50%
metabolized t1/2 5070
h
Generalized
tonic-clonic
seizures, partial
seizures,
myoclonic
seizures
Toxicity: Drowsiness,
cognitive impairment,
confusion, poor
concentration
Lacosamide
Enhances slow
inactivation of
Na+ channels
blocks effect of
neurotrophins
(via CRMP-2)
Well absorbed minimal

protein binding one
major nonactive
metabolite t1/2 1214 h
Generalized
tonic-clonic
seizures, partial
seizures
Toxicity: Dizziness,
headache, nausea small
increase in PR interval
DRUGS USED FOR LOCAL ANESTHESIA

Drugs Used for Local Anesthesia
Subclass Mechanism
of Action
Effects
Clinical
Applications
Pharmacokinetics,
Toxicities
Slows, then
blocks action
potential
propagation
Short-duration
procedures
epidural, spinal
anesthesia
Parenteral duration 3060 min

26 h with epinephrine
Toxicity: CNS excitation
Same as
lidocaine
Longer-duration
procedures
Parenteral duration 24 h
Toxicity: CNS excitation
cardiovascular collapse
Amides
Lidocaine
Blockade of
sodium channels
Bupivacaine Same as lidocaine
Subclass Mechanism
of Action
Effects
Clinical
Applications
Pharmacokinetics,
Toxicities
Prilocaine, ropivacaine, mepivacaine, levobupivacaine: Like bupivacaine

Esters
Procaine
Like lidocaine
Like lidocaine Very short

procedures
Parenteral duration 1530 min

3090 min with epinephrine
Toxicity: Like lidocaine
Cocaine
Same as above
also has
sympathomimetic
effects
Same as
above
Topical or parenteral duration

12 h Toxicity: CNS
excitation, convulsions, cardiac
arrhythmias, hypertension,
stroke
Procedures
requiring high
surface activity and
vasoconstriction
Tetracaine: Used for spinal, epidural anesthesia; duration 23 h
OPIOIDS, OPIOID SUBSTITUTES, AND OPIOID ANTAGONISTS

Opioids, Opioid Substitutes, and Opioid Antagonists
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Applications Toxicities
Strong opioid agonists

Morphine
Methadone
Fentanyl
Strong receptor
agonists
variable affinity
for and
receptors
Analgesia
relief of
anxiety
sedation
slowed
gastrointestinal
transit
Severe pain
adjunct in
anesthesia
(fentanyl,
morphine)
pulmonary edema
(morphine only)
maintenance in
rehabilitation
programs
(methadone only)
First-pass effect duration

14 h except methadone,
46 h Toxicity:
Respiratory depression
severe constipation
addiction liability
convulsions
Hydromorphone, oxymorphone: Like morphine in efficacy, but higher potency

Meperidine: Strong agonist with anticholinergic effects
Sufentanil, alfentanil, remifentanil: Like fentanyl but shorter durations of action
Partial agonists
Subclass
Codeine
Hydrocodone
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Less efficacious
than morphine
can antagonize
strong agonists
Like strong
agonists
weaker effects
Mild-moderate
pain cough
(codeine)
Like strong agonists,

toxicity dependent on
genetic variation of
metabolism
Like strong
agonists but
can antagonize
their effects
also reduces
craving for
alcohol
Moderate pain
some
maintenance
rehabilitation
programs
Long duration of action 4

8 h may precipitate
abstinence syndrome
Mixed opioid agonist-antagonists

Buprenorphine
Nalbuphine
Partial agonist
antagonist
Agonist
antagonist
Similar to
Moderate pain
buprenorphine
Like buprenorphine
Antitussives
Dextromethorphan Poorly
Reduces cough Acute debilitating 3060 min duration
understood but reflex
cough
Toxicity: Minimal when
strong and
taken as directed
partial agonists
are also
effective
Codeine, levopropoxyphene: Similar to dextromethorphan
Opioid antagonists
Naloxone
Antagonist at , Rapidly
Opioid overdose
, and
antagonizes all
receptors
opioid effects
Duration 12 h (may have

to be repeated when
treating overdose)
Toxicity: Precipitates
abstinence syndrome in
dependent users
Naltrexone, nalmefene: Like naloxone but longer durations of action (10+ h); naltrexone is used in
maintenance programs and can block heroin effects for up to 48 h
Alvimopan, methylnaltrexone bromide: Potent antagonists with poor entry into the central nervous
system; can be used to treat severe opioid-induced constipation without precipitating an abstinence
syndrome
Other analgesics used in moderate pain
Tramadol
Mixed effects:
weak agonist,
Analgesia
Moderate pain
Duration 46 h Toxicity:
adjunct to opioids
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
moderate SERT
inhibitor, weak
NET inhibitor
in chronic pain
syndromes
Seizures
NET, norepinephrine reuptake transporter; SERT, serotonin reuptake transporter.
DRUGS USED TO TREAT DEPENDENCE AND ADDICTION

Drugs Used to Treat Dependence and Addiction
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Application Toxicities,
Interactions
Opioid receptor antagonist

Naloxone
Nonselective
antagonist of
opioid receptors
Reverses the
Opioid overdose
acute effects of
opioids; can
precipitate severe
abstinence
syndrome
Effect much shorter than

morphine (12 h), therefore
several injections required
Naltrexone
Antagonist of
opioid receptors
Blocks effects of
illicit opioids
Treatment of
alcoholism
Half-life ~ 4 h
Acute effects
similar to
morphine (see
text)
Substitution
High oral bioavailability
therapy for opioid half-life highly variable
addicts
among individuals (range 4
130 h) Toxicity:
Respiratory depression,
constipation, miosis,
tolerance, dependence, and
withdrawal symptoms
Synthetic opioid
Methadone
Slow-acting
agonist of opioid receptor
Partial -opioid receptor agonist

Buprenorphine Partial agonist at Attenuates acute
-opioid
effects of
receptors
morphine
Nicotinic receptor partial agonist
Oral substitution
therapy for
opioid-addicts
Long half-life (40 h)

formulated together with
naloxone to avoid illicit IV
injections
Subclass
Varenicline
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Partial agonist of
nicotinic
actylecholine
receptor of the
4 2-type
Smoking
cessation
Occludes
"rewarding"
effects of
smoking
heightened
awareness of
colors
Toxicity: Nausea and

vomiting, convulsions,
psychiatric changes
Cytisine: Natural analog (extracted from laburnum flowers) of varenicline

Benzodiazepines
Oxazepam,
others
Positive
modulators of
the GABAA
receptors,
increase
frequency of
channel opening
Enhances
GABAergic
synaptic
transmission;
attenuates
withdrawal
symptoms
(tremor,
hallucinations,
anxiety) in
alcoholics
prevents
withdrawal
seizures
Delirium tremens Half-life 415 h

pharmacokinetics not
affected by decreased liver
function
Lorazepam: Alternate to oxazepam with similar properties

N-methyl-D-aspartate (NMDA)
Acamprosate
Antagonist of
May interfere
NMDA glutamate with forms of
receptors
synaptic plasticity
that depend on
NMDA receptors
Treatment of
alcoholism
effective only in
combination with
counseling
Allergic reactions,
arrhythmia, and low or high
blood pressure, headaches,
insomnia, and impotence
hallucinations, particularly
in elderly patients
Approved in USA
and Europe to
treat obesity
Smoking
cessation is an
Major depression, including

increased risk of suicide
Cannabinoid receptor agonist

Rimonabant
CB1 receptor
agonist
Decreases
neurotransmitter
release at
GABAergic and
glutamatergic
Subclass
Mechanism Effects
of Action
synapses
Clinical
Pharmacokinetics,
Interactions
off-label
indication
AUTONOMIC DRUGS
DRUGS USED FOR CHOLINOMIMETIC EFFECTS
Drugs Used for Cholinomimetic Effects
Subclass
Mechanism
of Action
Effects
Clinical
Pharmacokinetics
Application , Toxicities,
s
Interactions
Activates M1
through M3
receptors in all
peripheral tissues
causes
increased
secretion,
smooth muscle
contraction
(except vascular
smooth muscle
relaxes), and
changes in heart
rate
Postoperative and
neurogenic ileus
and urinary
retention
Direct-acting choline esters

Bethanechol
Muscarinic agonist
negligible effect at
nicotinic receptors
Oral and parenteral,

duration ~ 30 min does
not enter central nervous
system (CNS) Toxicity:
Excessive
parasympathomimetic
effects, especially
bronchospasm in
asthmatics Interactions:
Additive with other
parasympathomimetics
Carbachol: Nonselective muscarinic and nicotinic agonist; otherwise similar to bethanechol; used
topically almost exclusively for glaucoma
Direct-acting muscarinic alkaloids or synthetics
Pilocarpine
Like bethanechol,
partial agonist
Like bethanechol Glaucoma;

Sjgren's
syndrome
Cevimeline: Synthetic M3-selective; similar to pilocarpine
Oral lozenge and topical

Toxicity & interactions:
Like bethanechol
Subclass
Mechanism
of Action
Effects
Clinical
Pharmacokinetics
s
Interactions
Activates
autonomic
postganglionic
neurons (both
sympathetic and
parasympathetic)
and skeletal
muscle
neuromuscular
end plates
enters CNS and
activates NN
receptors
Medical use in
Oral gum, patch for
smoking
smoking cessation
cessation
Toxicity: Increased
nonmedical use in gastrointestinal (GI)
smoking and in
activity, nausea, vomiting,
insecticides
diarrhea acutely
increased blood pressure
high doses cause seizures
long-term GI and
cardiovascular risk factor
Interactions: Additive with
CNS stimulants
Direct-acting nicotinic agonists

Nicotine
Agonist at both NN
and NM receptors
Varenicline: Selective partial agonist at

cessation
4 2 nicotinic receptors; used exclusively for smoking
Short-acting cholinesterase inhibitor

Edrophonium Alcohol, binds
briefly to active site
of
acetylcholinesteras
e (AChE) and
prevents access of
acetylcholine (ACh)
Amplifies all
Diagnosis and
actions of ACh
acute treatment of
increases
myasthenia gravis
parasympatheti
c activity and
somatic
neuromuscular
transmission
Parenteral quaternary
amine does not enter
CNS Toxicity:
Parasympathomimetic
excess Interactions:
Additive with
parasympathomimetics
Intermediate-acting cholinesterase inhibitors

Neostigmine
Forms covalent
bond with AChE,
but hydrolyzed and
released
Like
edrophonium,
but longeracting
Myasthenia gravis
postoperative and
neurogenic ileus
and urinary
retention
Oral and parenteral;

quaternary amine, does
not enter CNS. Duration
24 h Toxicity and
Interactions: Like
edrophonium
Pyridostigmine: Like neostigmine, but longer-acting (46 h); used in myasthenia

Physostigmine: Like neostigmine, but natural alkaloid tertiary amine; enters CNS
Long-acting cholinesterase inhibitors
Echothiophat
Like neostigmine,
Like
Obsolete was
Topical only Toxicity:
Subclass
Mechanism
of Action
Effects
but released more

slowly
neostigmine,
but longeracting
Clinical
Pharmacokinetics
s
Interactions
used in glaucoma
Brow ache, uveitis, blurred

vision
Malathion: Insecticide, relatively safe for mammals and birds because metabolized by other
enzymes to inactive products; some medical use as ectoparasiticide
Parathion, others: Insecticide, dangerous for all animals; toxicity important because of agricultural
use and exposure of farm workers (see text)
Sarin, others: "Nerve gas," used exclusively in warfare and terrorism
DRUGS WITH ANTICHOLINERGIC ACTIONS

Drugs with Anticholinergic Actions
Subclass Mechanism Effects

of Action
Clinical
Pharmacokinetics,
Interactions
Motion sickness drugs

Scopolamine Unknown
mechanism in
CNS
Reduces
vertigo,
postoperative
nausea
Prevention of
motion sickness
and postoperative
nausea and
vomiting
Transdermal patch used for

motion sickness IM injection
for postoperative use
Toxicity: Tachycardia, blurred
vision, xerostomia, delirium
Interactions: With other
antimuscarinics
Gastrointestinal disorders
Dicyclomine Competitive
Reduces
Irritable bowel
antagonism at M3 smooth muscle syndrome, minor
receptors
and secretory diarrhea
activity of gut
Hyoscyamine: Longer duration of action
Available in oral and

parenteral forms short t1/2 but
action lasts up to 6 hours
Toxicity: Tachycardia,
confusion, urinary retention,
increased intraocular pressure
antimuscarinics

of Action
Clinical
Pharmacokinetics,
Interactions
Glycopyrrolate: Similar to dicyclomine

Ophthalmology
Atropine
Competitive
Causes
antagonism at all mydriasis and
M receptors
cycloplegia
Retinal
examination;
prevention of
synechiae after
surgery
Used as drops long (56

days) action Toxicity:
Increased intraocular pressure
in closed-angle glaucoma
antimuscarinics
Scopolamine: Faster onset of action than atropine

Homatropine: Shorter duration of action (1224 h)
Cyclopentolate: Shorter duration of action (36 h)
Tropicamide: Shortest duration of action (1560 min)
Respiratory (asthma, COPD)
Ipratropium
Competitive,
nonselective
antagonist at M
receptors
Reduces or
prevents
bronchospasm
Prevention and
relief of acute
episodes of
bronchospasm
Aerosol canister, up to qid

Toxicity: Xerostomia, cough
antimuscarinics
Tiotropium: Longer duration of action; used qd

Urinary
Oxybutynin
Nonselective
muscarinic
antagonist
Reduces
Urge incontinence;
detrusor
postoperative
smooth muscle spasms
tone, spasms
Oral, IV, patch formulations

Toxicity: Tachycardia,
constipation, increased
intraocular pressure,
xerostomia Patch: Pruritus
antimuscarinics
Darifenacin, solifenacin, and tolterodine: Tertiary amines with somewhat greater selectivity for M 3
receptors
Trospium: Quaternary amine with less CNS effect
Cholinergic poisoning
Atropine
Nonselective
competitive
antagonist at all
Blocks
muscarinic
excess at
Mandatory
Intravenous infusion until
antidote for severe antimuscarinic signs appear
cholinesterase

of Action
Pralidoxime
Clinical
Pharmacokinetics,
Interactions
muscarinic
receptors in CNS
and periphery
exocrine
inhibitor poisoning continue as long as necessary
glands, heart,
Toxicity: Insignificant as long
smooth muscle
as AChE inhibition continues
Very high affinity

for phosphorus
atom but does
not enter CNS
Regenerates
active AChE;
can relieve
skeletal muscle
end plate block
Usual antidote for Intravenous every 46 h

early-stage (48 h) Toxicity: Can cause muscle
cholinesterase
weakness in overdose
inhibitor poisoning
SYMPATHOMIMETIC DRUGS
Sympathomimetic Drugs
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Agonists
Midodrine
Activates
phospholipase C,
resulting in
increased
intracellular
calcium and
vasoconstriction
Vascular smooth Orthostatic

muscle
hypotension
contraction
increasing blood
pressure (BP)
Oral prodrug converted to

active drug with a 1-h peak
effect Toxicity: Produces
supine hypertension,
piloerection (goose bumps),
and urinary retention
Phenylephrine: Can be used IV for short-term maintenance of BP in acute hypotension and

intranasally to produce local vasoconstriction as a decongestant
2
Agonists
Clonidine
Inhibits adenylyl
cyclase and
interacts with
other intracellular
pathways
Vasoconstriction Hypertension
is masked by
central
sympatholytic
effect, which
lowers BP
Oral transdermal peak

effect 13 h half-life of oral
drug ~12 h produces dry
mouth and sedation
-Methyldopa, guanfacine and guanabenz: Also used as central sympatholytics

Dexmedetomidine: Prominent sedative effects and used in anesthesia
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Tizanidine: Used as a muscle relaxant

Apraclonidine and brimonidine: Used in glaucoma to reduce intraocular pressure
1
Agonists
Dobutamine1
Activates
Positive inotropic Cardiogenic
IV requires dose titration to
adenylyl cyclase, effect
shock, acute heart desired effect
increasing
failure
myocardial
contractility
Agonists
Albuterol
See other
Activates
adenylyl cyclase
Bronchial
smooth muscle
dilation
Asthma
Inhalation duration 46 h
Toxicity: Tremor,
tachycardia
agonists in Chapter 20
Dopamine
D1 Agonists
Fenoldopam
Activates
adenylyl cyclase
Vascular smooth Hypertension

muscle
relaxation
Requires dose titration to

desired effect
Restores
dopamine
actions in the
central nervous
system
Oral Toxicity: Nausea,

headache, orthostatic
hypotension
D2 Agonists
Bromocriptine Inhibits adenylyl
cyclase and
interacts with
other intracellular
pathways
Parkinson's
disease,
prolactinemia
See other D2 agonists in Chapters 28 and 37
Dobutamine has other actions in addition to
-agonist effect. See text for details.
SYMPATHETIC ANTAGONISTS
Sympathetic Antagonists
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics
Applications , Toxicities,
Interactions
Alpha-adrenoceptor antagonists
Phenoxybenzamin Irreversibly
blocks 1 and
indirect
baroreflex
activation
Phentolamine: 1 and
pheochromocytoma
Prazosin
Block
Lowers blood
pressure (BP)
but heart rate
(HR) rises due
to baroreflex
activation
Pheochromocytom
a high
catecholamine
states
Irreversible blocker halflife > 1 day Toxicity:

Orthostatic hypotension
tachycardia myocardial
ischemia
antagonist; half-life about 45 min after IV injection; used to treat
, but not Lower BP
Doxazosin
Hypertension
benign prostatic
hyperplasia
Larger depressor effect

with first dose may cause
orthostatic hypotension
Terazosin
Tamsulosin
1A Blockade
Tamsulosin is
Benign prostatic
slightly selective may relax
hyperplasia
for 1A
prostatic
smooth
muscles more
than vascular
smooth
muscle
Orthostatic hypotension
may be less common with
this subtype
Yohimbine
Blocks 2 elicits Raises BP and Male erectile

increased central HR
dysfunction
sympathetic
hypotension
activity
increased
norepinephrine
release
May cause anxiety excess

pressor effect if
norepinephrine
transporter is blocked
Labetalol (see
carvedilol section
below)
>
block
Beta-adrenoceptor antagonists
Lowers BP
with limited
HR increase
Hypertension
Oral, parenteral Toxicity:

Less tachycardia than
other 1 agents
Subclass
Propranolol
Mechanism Effects
of Action
Block 1 and
receptors
Nadolol
Timolol
Metoprolol
Block
>
Atenolol
Alprenolol
Clinical
Pharmacokinetics
Interactions
Lower HR and Hypertension

BP reduce
angina pectoris
renin
arrhythmias
migraine
hyperthyroidism
Oral, parenteral Toxicity:

Bradycardia worsened
asthma fatigue vivid
dreams cold hands
Lower HR and Angina pectoris

BP reduce
hypertension
renin may be arrhythmias
safer in
asthma
Bradycardia fatigue vivid

dreams cold hands
Increases
peripheral
resistance
Toxicity: Asthma
provocation
Betaxolol
Nebivolol
Butoxamine1
Blocks
Pindolol
1,
2, with
Lowers BP
intrinsic
modestly
sympathomimeti lower HR
c (partial
agonist) effect
Acebutolol
Carteolol
>
No clinical
indication
Hypertension
Oral Toxicity: Fatigue
arrhythmias
vivid dreams cold hands
migraine may
avoid worsening of
bradycardia
Bopindolol1
Oxprenolol1
Celiprolol1
Penbutolol
Carvedilol
>
block
Long half-life
Heart failure
Oral Toxicity: Fatigue
Intravenous
use half-life
Rapid control of BP Parenteral only Toxicity:

and arrhythmias,
Bradycardia hypotension
Medroxalol1
Bucindolol1 (see
labetalol above)
Esmolol
>
Subclass
Mechanism Effects
of Action
~ 10 min
Clinical
Pharmacokinetics
Interactions
thyrotoxicosis and
myocardial
ischemia
intraoperatively
Tyrosine hydroxylase inhibitor

Metyrosine
Blocks tyrosine
hydroxylase
reduces
synthesis of
dopamine,
norepinephrine,
and epinephrine
Lowers BP in Pheochromocytom Extrapyramidal symptoms

central
a
nervous
crystalluria
system may
elicit
extrapyramida
l effects (due
to low
dopamine)
CARDIOVASCULAR-RENAL DRUGS
DRUGS USED IN HYPERTENSION
Drugs Used in Hypertension
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
s
Interactions
Diuretics
Thiazides:
Block Na/Cl
Hydrochlorothiazide transporter in
renal distal
convoluted
tubule
Reduce blood
Hypertension,
volume plus
mild heart failure
poorly
understood
vascular effects
Loop diuretics:
Furosemide
Like thiazides
Severe
greater efficacy hypertension,
heart failure
Block Na/K/2Cl
transporter in
renal loop of
Henle
See Chapter 15
Subclass
Spironolactone
Eplerenone
Mechanism Effects
of Action
Block
aldosterone
receptor in renal
collecting tubule
Clinical
Pharmacokinetics,
s
Interactions
Increase Na
Aldosteronism,
and decrease K heart failure,
excretion
hypertension
poorly
understood
reduction in
heart failure
mortality
Sympathoplegics, centrally acting

Clonidine,
methyldopa
Activate 2
adrenoceptors
Reduce central
sympathetic
outflow reduce
norepinephrine
release from
noradrenergic
nerve endings
Hypertension
clonidine also
used in
withdrawal from
abused drugs
Oral clonidine also patch

Toxicity: sedation
methyldopa hemolytic
anemia
Sympathetic nerve terminal blockers

Reserpine
Blocks vesicular
amine
transporter in
noradrenergic
nerves and
depletes
transmitter
stores
Reduce all
sympathetic
effects,
especially
cardiovascular,
and reduce
blood pressure
Hypertension but
rarely used
Oral long duration (days)

Toxicity: Reserpine:
psychiatric depression,
gastrointestinal
disturbances
Guanethidine
Interferes with
amine release
and replaces
norepinephrine
in vesicles
Same as
reserpine
Same as
reserpine
Guanethidine: Severe
sexual dysfunction
Blockers
Prazosin
Terazosin
Doxazosin
Blockers
Selectively block Prevent

Hypertension
sympathetic
benign prostatic
1
adrenoceptors
vasoconstriction hyperplasia
reduce
prostatic
smooth muscle
tone
Oral Toxicity: Orthostatic

hypotension
Subclass
Mechanism Effects
of Action
Metoprolol, others Block 1

receptors;
Carvedilol
carvedilol also
blocks
receptors
Prevent
sympathetic
cardiac
stimulation
reduce renin
secretion
Clinical
Pharmacokinetics,
s
Interactions
Hypertension
heart failure
See Chapter 10
Propranolol: Nonselective prototype blocker

Atenolol: Very widely used
toxicity
-selective blocker; claimed to have reduced central nervous system
Vasodilators
Verapamil
Diltiazem
Nonselective
block of L-type
calcium
channels
Nifedipine
Block vascular
calcium
Amlodipine, other channels >
dihydropyridines
cardiac calcium
channels
Hydralazine
Causes nitric
oxide release
Minoxidil
Metabolite
opens K
channels in
vascular smooth
muscle
Reduce cardiac Hypertension,

rate and output angina,
reduce
arrhythmias
vascular
resistance
See Chapter 12
Reduce
vascular
resistance
Hypertension
See Chapter 12
Vasodilation
reduce vascular
resistance
arterioles more
sensitive than
veins reflex
tachycardia
Hypertension
Oral Toxicity: Angina,
minoxidil also
tachycardia Hydralazine:
used to treat hair Lupus-like syndrome
loss
Minoxidil: Hypertrichosis
Parenteral agents
Nitroprusside
Releases nitric
oxide
Fenoldopam
Activates D1
receptors
Powerful
vasodilation
Hypertensive
emergencies
Parenteral short duration

Toxicity: Excessive
hypotension, shock
Subclass
Diazoxide
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
s
Interactions
Opens K
channels
Angiotensin-converting enzyme (ACE) inhibitors

Captopril, many
others
Inhibit
angiotensin
converting
enzyme
Reduce
Hypertension
angiotensin II
heart failure,
levels reduce
diabetes
vasoconstriction
and aldosterone
secretion
increase
bradykinin
Oral Toxicity: Cough,

angioedema teratogenic
Same as ACE
inhibitors but
no increase in
bradykinin
Hypertension
heart failure
Oral Toxicity: Same as

ACE inhibitors but no
cough
Hypertension
Oral
Toxicity: Hyperkalemia,
renal impairment
potential teratogen
Angiotensin receptor blockers

Losartan, many
others
Block AT1
angiotensin
receptors
Renin inhibitor
Aliskiren
Inhibits enzyme Reduces

activity of renin angiotensin I
and II and
aldosterone
DRUGS USED IN ANGINA PECTORIS

Drugs Used in Angina Pectoris
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Releases nitric
oxide in smooth
muscle, which
Angina: Sublingual Very high first-pass effect, so

form for acute
sublingual dose is much
episodes oral and smaller than oral high lipid
Nitrates
Nitroglycerin
Smooth
muscle
relaxation,
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
activates
guanylyl cyclase
and increases
cGMP
transdermal forms
for prophylaxis IV
form for acute
coronary syndrome
especially in
vessels other
smooth
muscle is
relaxed but
not as
markedly
vasodilation
decreases
venous return
and heart size
may increase
coronary flow
in some areas
and in variant
angina
solubility ensures rapid

absorption Toxicity:
Orthostatic hypotension,
tachycardia, headache
Interactions: Synergistic
hypotension with
phosphodiesterase type 5
inhibitors (sildenafil, etc)
Isosorbide dinitrate: Very similar to nitroglycerin, slightly longer duration of action

Isosorbide mononitrate: Active metabolite of the dinitrate; used orally for prophylaxis
Beta blockers
Propranolol
Nonselective
competitive
antagonist at
adrenoceptors
Atenolol, metoprolol, others:
Decreased
heart rate,
cardiac
output, and
blood
pressure
decreases
myocardial
oxygen
demand
Prophylaxis of
angina for other
applications, see
Chapters 10, 11,
and 13
Oral and parenteral, 46 h

duration of action Toxicity:
Asthma, atrioventricular
block, acute heart failure,
sedation Interactions:
Additive with all cardiac
depressants
-Selective blockers, less risk of bronchospasm, but still significant
See Chapters 10 and 11 for other blockers and their applications

Calcium channel blockers
Verapamil,
diltiazem
Nonselective
block of L-type
calcium channels
in vessels and
heart
Reduced
vascular
resistance,
cardiac rate,
and cardiac
force results
in decreased
Prophylaxis of
angina,
hypertension,
others
Oral, IV, duration 48 h

Toxicity: Atrioventricular
block, acute heart failure;
constipation, edema
other cardiac depressants
and hypotensive drugs
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
oxygen
demand
Nifedipine (a
Block of vascular
dihydropyridine) L-type calcium
channels >
cardiac channels
Like
Prophylaxis of
verapamil and angina,
diltiazem; less hypertension
cardiac effect
Oral, duration 46 h
Toxicity: Excessive
hypotension Interactions:
Additive with other
vasodilators
Other dihydropyridines: Like nifedipine but slower onset and longer duration (up to 12 h or longer)
Miscellaneous
Ranolazine
Inhibits late
sodium current
in heart also
may modify fatty
acid oxidation
Reduces
Prophylaxis of
cardiac
angina
oxygen
demand fatty
acid oxidation
modification
may improve
efficiency of
cardiac
oxygen
utilization
Oral, duration 68 h
Toxicity: QT interval
prolongation, nausea,
constipation, dizziness
Interactions: Inhibitors of
CYP3A increase ranolazine
concentration and duration of
action
Ivabradine: Investigational inhibitor of sinoatrial pacemaker; reduction of heart rate reduces

oxygen demand
DRUGS USED IN HEART FAILURE

Drugs Used in Heart Failure
Subclass
Mechanism Effects
of Action
Clinical
Applicatio
ns
Pharmacokinetic
s, Toxicities,
Interactions
Loop diuretic:
Decreases NaCl
and KCl
reabsorption in
thick ascending
Acute and
chronic heart
failure severe
hypertension e
dematous
Oral and IV duration

24 h Toxicity:
Hypovolemia,
hypokalemia, orthostatic
hypotension, ototoxicity,
Diuretics
Furosemide
Increased excretion
of salt and water
reduces cardiac
preload and
afterload reduces
Subclass
Mechanism Effects
of Action
Clinical
Applicatio
ns
Pharmacokinetic
s, Toxicities,
Interactions
limb of the loop

of Henle in the
nephron (see
Chapter 15)
pulmonary and
peripheral edema
conditions
sulfonamide allergy
Same as
furosemide, but
less efficacious
Mild chronic
failure mildmoderate
hypertension
hypercalciuria
Oral only duration 10

12 h Toxicity:
Hyponatremia,
hypokalemia,
hyperglycemia,
hyperuricemia,
hyperlipidemia,
sulfonamide allergy
Hydrochlorothiazi Decreases NaCl

de
reabsorption in
the distal
convoluted
tubule
Three other loop diuretics: Bumetanide and torsemide similar to furosemide; ethacrynic acid not a
sulfonamide
Many other thiazides: All basically similar to hydrochlorothiazide, differing only in pharmacokinetics
Aldosterone antagonists
Spironolactone
Block
cytoplasmic
aldosterone
receptors in
collecting
tubules of
nephron
possible
membrane
effect
Increased salt and

water excretion
reduces remodeling
reduces mortality
Chronic heart
failure
aldosteronism
(cirrhosis,
adrenal tumor)
hypertension
Oral duration 2472 h

(slow onset and offset)
antiandrogen actions
Eplerenone: Similar to spironolactone; more selective antialdosterone effect; no significant

antiandrogen action
Angiotensin antagonists
Angiotensinconverting
enzyme (ACE)
inhibitors:
Captopril
Inhibits ACE
Arteriolar and
reduces AII
venous dilation
formation by
reduces aldosterone
inhibiting
secretion increases
conversion of AI cardiac output
to All
reduces cardiac
remodeling
Chronic heart
failure
hypertension
diabetic renal
disease
Oral half-life 24 h but

given in large doses so
duration 1224 h
Toxicity: Cough,
hyperkalemia,
angioneurotic edema
Interactions: Additive
with other angiotensin
antagonists
Subclass
Mechanism Effects
of Action
Clinical
Applicatio
ns
Pharmacokinetic
s, Toxicities,
Interactions
Angiotensin
receptor
blockers
(ARBs):
Antagonize AII
effects at AT1
receptors
Like ACE
inhibitors used
in patients
intolerant to
ACE inhibitors
Oral duration 68 h
Toxicity: Hyperkalemia;
angioneurotic edema
with other angiotensin
antagonists
Chronic heart
failure: To slow
progression
reduce mortality
in moderate and
severe heart
failure many
other indications
in Chapter 10.
Oral duration 1012 h

Toxicity:
Bronchospasm,
bradycardia,
atrioventricular block,
acute cardiac
decompensation see
Chapter 10 for other
toxicities and
interactions
Like ACE inhibitors
Losartan
Enalapril, many other ACE inhibitors: Like captopril
Candesartan, many other ARBs: Like losartan
Beta blockers
Carvedilol
Competitively
blocks 1
receptors (see
Chapter 10)
Slows heart rate

reduces blood
pressure poorly
understood effects
reduces heart
failure mortality
Metoprolol, bisoprolol: Select group of blockers that reduce heart failure mortality
Cardiac Glycoside
Digoxin
Na+,K+ ATPase
inhibition results
in reduced Ca2+
expulsion and
increased Ca2+
stored in
sarcoplasmic
reticulum
Increases cardiac
contractility
cardiac
parasympathomime
tic effect (slowed
sinus heart rate,
slowed
atrioventricular
conduction)
Chronic
symptomatic
heart failure
rapid ventricular
rate in atrial
fibrillation
Oral, parenteral
duration 3640 h
Toxicity: Nausea,
vomiting, diarrhea
cardiac arrhythmias
Releases nitric
oxide (NO)
activates
guanylyl cyclase
(see Chapter
12)
Venodilation
reduces preload
and ventricular
stretch
Acute and
chronic heart
failure angina
Oral 46 h duration
Toxicity: Postural
hypotension,
tachycardia, headache
with other vasodilators
and synergistic with
Vasodilators
Venodilators:
Isosorbide
dinitrate
Subclass
Mechanism Effects
of Action
Clinical
Applicatio
ns
Pharmacokinetic
s, Toxicities,
Interactions
phosphodiesterase type
5 inhibitors
Arteriolar
dilators:
Hydralazine
Combined
arteriolar and
venodilator:
Nitroprusside
Beta-adrenoceptor agonists
Dobutamine
Beta1selective
agonist
increases cAMP
synthesis
Increases cardiac
Acute
contractility, output decompensated
heart failure
intermittent
therapy in
chronic failure
reduces
symptoms
IV only duration a few

minutes Toxicity:
Arrhythmias.
with other
sympathomimetics
Dopamine
Dopamine
receptor agonist
higher doses
activate and
adrenoceptors
Increases renal
blood flow higher
doses increase
cardiac force and
blood pressure
Acute
decompensated
heart failure
shock
IV only duration a few

minutes Toxicity:
Arrhythmias
with sympathomimetics
Phosphodiestera
se type 3
inhibitors
decrease cAMP
breakdown
Vasodilators lower
peripheral vascular
resistance also
increase cardiac
contractility
Acute
IV only duration 36 h
decompensated
Toxicity: Arrhythmias
heart failure
with other
arrhythmogenic agents
Vasodilation
diuresis
Acute
IV only duration 18
decompensated minutes Toxicity: Renal
failure
damage, hypotension
Bipyridines
Inamrinone,
milrinone
Natriuretic Peptide
Nesiritide
Activates BNP
receptors,
increases cGMP
ANTIARRHYTHMIC DRUGS
Antiarrhythmic Drugs
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Class IA
Procainamide INa (primary) and Slows
IKr (secondary)
conduction
blockade
velocity and
pacemaker rate
prolongs action
potential
duration and
dissociates from
INa channel with
intermediate
kinetics direct
depressant
effects on
sinoatrial (SA)
and
atrioventricular
(AV) nodes
Most atrial and

ventricular
arrhythmias drug
of second choice
for most sustained
ventricular
arrhythmias
associated with
acute myocardial
infarction
Oral, IV, IM eliminated by

hepatic metabolism to Nacetylprocainamide (NAPA;
see text) and renal
elimination NAPA implicated
in torsade de pointes in
patients with renal failure
Toxicity: Hypotension longterm therapy produces
reversible lupus-related
symptoms
Disopyramide: Similar to procainamide but significant antimuscarinic effects; may precipitate heart
failure
Quinidine: Similar to procainamide but more toxic (cinchonism, torsade); rarely used
Class 1B
Lidocaine
Sodium channel
(INa) blockade
Blocks activated
and inactivated
channels with
fast kinetics
does not prolong
and may shorten
action potential
Terminate
ventricular
tachycardias and
prevent ventricular
fibrillation after
cardioversion
IV first-pass hepatic
metabolism reduce dose in
patients with heart failure or
liver disease Toxicity:
Neurologic symptoms
Mexiletine: Orally active congener of lidocaine; used in ventricular arrhythmias, chronic pain
syndromes
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Sodium channel
(INa) blockade
Supraventricular
Oral hepatic, and kidney
arrhythmias in
metabolism half life ~ 20 h
patients with
Toxicity: Proarrhythmic
normal heart do
not use in ischemic
conditions (postmyocardial
infarction)
Class 1C
Flecainide
Dissociates from
channel with
slow kinetics no
change in action
potential
duration
Propafenone: Orally active, weak -blocking activity; supraventricular arrhythmias; hepatic

metabolism
Moricizine: Phenothiazine derivative, orally active; ventricular arrhythmias, proarrhythmic.
Withdrawn in USA.
Class 2
Propranolol
-Adrenoceptor
blockade
Direct
membrane
effects (sodium
channel block)
and prolongation
of action
potential
duration slows
SA node
automaticity and
AV nodal
conduction
velocity
Atrial arrhythmias Oral, parenteral duration 4

and prevention of 6 h Toxicity: Asthma, AV
recurrent infarction blockade, acute heart failure
and sudden death
cardiac depressants and
hypotensive drugs
Esmolol: Short-acting, IV only; used for intraoperative and other acute arrhythmias
Class 3
Amiodarone
Blocks IKr, INa,

ICa-L channels,
adrenoceptors
Prolongs action
potential
duration and QT
interval slows
heart rate and
AV node
conduction low
incidence of
torsade de
pointes
Serious ventricular
arrhythmias and
supraventricular
arrhythmias
Oral, IV variable absorption

and tissue accumulation
hepatic metabolism,
elimination complex and slow
Toxicity: Bradycardia and
heart block in diseased heart,
peripheral vasodilation,
pulmonary and hepatic
toxicity hyper- or
hypothyroidism.
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
Interactions: Many, based on
CYP metabolism
Dofetilide
IKr block
Prolongs action
potential,
effective
refractory period
Maintenance or
restoration of sinus
rhythm in atrial
fibrillation
Oral renal excretion

Toxicity: Torsade de pointes
(initiate in hospital)
other QT-prolonging drugs
Sotalol: -Adrenergic blocker, direct action potential prolongation properties, use for ventricular
arrhythmias, atrial fibrillation
Ibutilide: Potassium channel blocker, may activate inward current; IV use for conversion in atrial
flutter and fibrillation
Dronedarone: Investigational amiodarone derivative; multichannel actions, reduces mortality in
patients with atrial fibrillation
Vernakalant: Investigational, multichannel actions in atria, prolongs atrial refractoriness, effective in
atrial fibrillation
Class 4
Verapamil
Calcium channel Slows SA node

Supraventricular
(ICa-L type)
automaticity and tachycardias
blockade
AV nodal
conduction
velocity
decreases
cardiac
contractility
reduces blood
pressure
Oral, IV hepatic metabolism

caution in patients with
hepatic dysfunction Toxicity
&Interactions: See Chapter
12
Diltiazem: Equivalent to verapamil

Miscellaneous
Adenosine
Activates inward Very brief,

Paroxysmal
rectifier IK
usually complete supraventricular
blocks ICa
AV blockade
tachycardias
Magnesium
Poorly
understood
interacts with
Na+,K+ ATPase,
Normalizes or
increases
plasma Mg2+
IV only duration 1015

Toxicity: Flushing, chest
tightness, dizziness
Torsade de pointes IV duration dependent on

digitalis-induced
dosage Toxicity: Muscle
arrhythmias
weakness in overdose
Subclass
Mechanism Effects
of Action
Clinical
Pharmacokinetics,
Interactions
K+ and Ca2+
channels
Potassium
Increases K+
permeability, K+
currents
Slows ectopic
pacemakers
slows conduction
velocity in heart
Digitalis-induced
arrhythmias
arrhythmias
associated with
hypokalemia
Oral, IV Toxicity: Reentrant

arrhythmias, fibrillation or
arrest in overdose
DIURETIC AGENTS
Diuretic Agents
Subclass
Mechanis
m of
Action
Effects
Clinical
Pharmacokinetics
s
Interactions
Reduces
reabsorption of
HCO3 in the
kidney,
causing selflimited diuresis
hyperchloremi
c metabolic
acidosis
reduces body
pH, reduces
intraocular
pressure
Glaucoma,
mountain
sickness, edema
with alkalosis
Oral and topical

preparations available
duration of action ~ 812
h Toxicity: Metabolic
acidosis, renal stones,
hyperammonemia in
cirrhotics
Pulmonary
edema,
peripheral
edema,
Oral and parenteral

preparations duration of
action 24 h Toxicitiy:
Carbonic anhydrase inhibitors

Acetazolamide,
others
Inhibition of the
enzyme
prevents
dehydration of
H2CO3 and
hydration of CO2
Brinzolamide, dorzolamide: Topical for glaucoma

Loop diuretics
Furosemide
Inhibition of the
Na/K/2Cl
transporter in
the ascending
Marked
increase in
NaCl
excretion,
Subclass
Mechanis
m of
Action
Effects
Clinical
Pharmacokinetics
s
Interactions
limb of Henle's
loop
some K
wasting,
hypokalemic
metabolic
alkalosis,
increased
urine Ca and
Mg
hypertension,
acute
hypercalcemia or
hyperkalemia,
acute renal
failure, anion
overdose
Ototoxicity, hypovolemia,
K wasting, hyperuricemia,
hypomagnesemia
Bumetanide, torsemide: Sulfonamide loop agents like furosemide

Ethacrynic acid: Not a sulfonamide but has typical loop activity and some uricosuric action
Thiazides
Hydrochlorothiazid
e
Inhibition of the
Na/Cl
transporter in
the distal
convoluted
tubule
Modest
increase in
NaCl excretion
some K
wasting
hypokalemic
metabolic
alkalosis
decreased
urine Ca
Hypertension,
mild heart failure,
nephrolithiasis,
nephrogenic
diabetes insipidus
Oral duration 812 h

Toxicity: Hypokalemic
metabolic alkalosis,
hyperuricemia,
hyperglycemia,
hyponatremia
Metolazone: Popular for use with loop agents for synergistic effects
Chlorothiazide: Only parenteral thiazide available (IV)
Potassium-sparing diuretics
Spironolactone
Pharmacologic
antagonist of
aldosterone
weak
antagonism of
androgen
receptors
Reduces Na
retention and
K wasting in
kidney poorly
understood
antagonism of
aldosterone in
heart and
vessels
Aldosteronism
from any cause
hypokalemia due
to other diuretics
postmyocardial
infarction
Slow onset and offset of

effect duration 2448 h
gynecomastia
(spironolactone, not
eplerenone) additive
interaction with other Kretaining drugs
Amiloride
Blocks epithelial
sodium
channels in
collecting
tubules
Reduces Na
retention and
K wasting
increases
lithium
Hypokalemia
Orally active duration 24
from other
h Toxicity: Hyperkalemic
diuretics reduces metabolic acidosis
lithium-induced
polyuria
Subclass
Mechanis
m of
Action
Effects
Clinical
Pharmacokinetics
s
Interactions
clearance
Eplerenone: Like spironolactone, more selective for aldosterone receptor
Triamterene: Mechanism like amiloride, much less potent, more toxic
Osmotic diuretics
Mannitol
Physical osmotic
effect on tissue
water
distribution
because it is
retained in the
vascular
compartment
Marked
increase in
urine flow,
reduced brain
volume,
decreased
intraocular
pressure,
initial
hyponatremia,
then
hypernatremia
Renal failure due IV administration

to increased
Toxicity: Nausea,
solute load
vomiting, headache
(rhabdomyolysis,
chemotherapy),
increased
intracranial
pressure,
glaucoma
Antagonist at
V1a and V2
ADH receptors
Reduces water Hyponatremia

reabsorption,
increases
plasma Na
concentration
Other Agents
Conivaptan
IV Only Toxicity: Infusion

site reactions
DRUGS USED IN ASTHMA

Drugs Used in Asthma
Subclass
Mechanism
of Action
Effects
Clinical
Pharmacokinetics,
Selective
agonist
Prompt,
efficacious
bronchodilation
Asthma, chronic
obstructive
pulmonary
disease (COPD)
drug of choice in
acute asthmatic
Beta agonists
Albuterol
Aerosol inhalation duration

several hours also
available for nebulizer and
parenteral use Toxicity:
Tremor, tachycardia
overdose: arrhythmias
Subclass
Mechanism
of Action
Effects
Clinical
Pharmacokinetics,
bronchospasm
Salmeterol
Selective
agonist
Slow onset,
primarily
preventive
action;
potentiates
corticosteroid
effects
Asthma
prophylaxis
Aerosol inhalation duration

1224 h Toxicity: Tremor,
tachycardia, overdose:
arrhythmias
Metaproterenol, terbutaline: Similar to albuterol; terbutaline available as an oral drug

Formoterol: Similar to salmeterol
Epinephrine
Isoproterenol
Nonselective and Bronchodilation

agonist
plus all other
sympathomimetic
effects on
cardiovascular
and other organ
systems (see
Chapter 9)
1
and
agonist
Anaphylaxis,
asthma, others
(see Chapter 9)
rarely used for
asthma ( 2selective agents
preferred)
Aerosol, nebulizer, or
parenteral see Chapter 9
Bronchodilation
plus powerful
cardiovascular
effects
Asthma, but 2selective agents

preferred
Aerosol, nebulizer, or
parenteral see Chapter 9
Reduces
mediators of
inflammation
powerful
prophylaxis of
exacerbations
Asthma adjunct
in COPD
Aerosol duration hours

Toxicity: Limited by aerosol
application candidal
infection, vocal cord
changes
Corticosteroids, inhaled
Fluticasone
Alters gene
expression
Beclomethasone, budesonide, flunisolide, others: Similar to fluticasone

Corticosteroids, systemic
Prednisone
Like fluticasone
Like fluticasone
Methylprednisolone: Parenteral agent like prednisone

Stabilizers of mast and other cells
Asthma adjunct
in COPD
Oral duration 1224 hours

Toxicity: Multiple see
Chapter 39
Subclass
Mechanism
of Action
Effects
Clinical
Pharmacokinetics,
Cromolyn,
nedocromil
Alters function of
delayed chloride
channels inhibits
inflammatory cell
activation
Prevents acute
bronchospasm
Asthma (other
routes used for
ocular, nasal, and
gastrointestinal
allergy)
Aerosol duration 68 h
Toxicity: Cough not
absorbed so other toxicities
are minimal
Methylxanthines
Theophylline
Uncertain
phosphodiesterase
inhibition
adenosine
receptor
antagonist
Bronchodilation, Asthma, COPD

cardiac
stimulation,
increased skeletal
muscle strength
(diaphragm)
Oral duration 812 h but

extended-release
preparations often used
Toxicity: Multiple (see
text)
Leukotriene antagonists
Montelukast, Block leukotriene
zafirlukast
D4 receptors
Block airway
response to
exercise and
antigen challenge
Prophylaxis of
Oral duration hours
asthma, especially Toxicity: Minimal
in children and in
aspirin-induced
asthma
Zileuton: Inhibits lipoxygenase, reduces synthesis of leukotrienes

IgE antibody
Omalizumab
Humanized IgE
antibody reduces
circulating IgE
Reduces
frequency of
asthma
exacerbations
Severe asthma
inadequately
controlled by
above agents
Parenteral duration 24 d
Toxicity: Injection site
reactions (anaphylaxis
extremely rare)
APPENDIX: VACCINES, IMMUNE

GLOBULINS, & OTHER COMPLEX
BIOLOGIC PRODUCTS:
INTRODUCTION
Vaccines and related biologic products constitute an important group of agents that bridge the
disciplines of microbiology, infectious diseases, immunology, and immunopharmacology. A list of the
most important preparations is provided here. The reader who requires more complete information is
referred to the sources listed at the end of this appendix.
ACTIVE IMMUNIZATION
Active immunization consists of the administration of antigen to the host to induce formation of
antibodies and cell-mediated immunity. Immunization is practiced to induce protection against many
infectious agents and may utilize either inactivated (killed) materials or live attenuated agents (Table
A1). Desirable features of the ideal immunogen include complete prevention of disease, prevention of
the carrier state, production of prolonged immunity with a minimum of immunizations, absence of
toxicity, and suitability for mass immunization (eg, cheap and easy to administer). Active
immunization is generally preferable to passive immunizationin most cases because higher antibody
levels are sustained for longer periods of time, requiring less frequent immunization, and in some
cases because of the development of concurrent cell-mediated immunity. However, active
immunization requires time to develop and is therefore generally inactive at the time of a specific
exposure (eg, for parenteral exposure to hepatitis B, concurrent hepatitis B IgG [passive antibodies]
and active immunization are given to prevent illness).
Table A1 Materials Commonly Used for Active Immunization in the United

States.1
Vaccine
Type of
Agent
Route of
Primary
Booster2 Indication
Administratio Immunizatio
s
n
n
Diphtheriatetanus
acellular
pertussis
(DTaP)
Toxoids and
inactivated
bacterial
components
Intramuscular
See Table A2
None
Haemophilus
influenzae
type b
conjugate
(Hib)
Bacterial
polysaccharid
e conjugated
to protein
Intramuscular
One dose (see

Table A2 for
childhood
schedule)
Not
1. For all
recommende children
d
2. Asplenia and
other at-risk
conditions
Hepatitis A
Inactivated
virus
Intramuscular
One dose
(administer at
least 24 weeks
before travel to
endemic areas)
At 612
months for
long-term
immunity
For all children
1. Travelers to
hepatitis A
endemic areas
2. Homosexual
and bisexual
men
3. Illicit drug
users
4. Chronic liver
disease or
clotting factor
disorders
5. Persons with
occupational
risk for
infection
6. Persons
living in, or
relocating to,
endemic areas
7. Household
and sexual
contacts of
individuals with
acute hepatitis
A
Hepatitis B
Inactive viral
Intramuscular
Three doses at 0,
Not routinely 1. For all
Vaccine
Type of
Agent
Route of
Primary
Booster2 Indication
s
n
n
antigen,
recombinant
(subcutaneous
injection is
acceptable in
individuals with
bleeding disorders)
1, and 6 months
(see Table A2 for
childhood
schedule)
recommende infants
d
2.
Preadolescents,
adolescents,
and young
adults
3. Persons with
occupational,
lifestyle, or
environmental
risk
4.
Hemophiliacs
5. Persons with
end-stage renal
disease or
chronic liver
disease
6.
Postexposure
prophylaxis
Human
Virus-like
Intramuscular
papillomaviru particles of
s (HPV)
the major
capsid protein
Three doses at 0,
2, and 6 months
Influenza,
inactivated
One dose (Children Yearly with

< 9 years who are current
receiving influenza vaccine
vaccine for the first
time should
receive two doses
administered at
least 1 month
apart.)
Inactivated
virus or viral
components
Intramuscular
None
All females
between 9 and
26 years of age
1. Adults 50
years
2. Persons with
high-risk
conditions (eg,
asthma)
3. Health care
workers and
others in
contact with
high-risk
groups
Vaccine
Type of
Agent
Route of
Primary
Booster2 Indication
s
n
n
4. Residents of
nursing homes
and other
residential
chronic care
facilities
5. All children
aged 6 months
to 18 years
6. Healthy
persons age
1949 who
desire
protection
against
influenza
7. Women who
will be
pregnant
during the
influenza
season
Influenza,
live
attenuated
Live virus
Intranasal
Split dose in each Yearly with

nostril. Children
current
age 58 who are
vaccine
receiving influenza
vaccine for the first
time should
receive two doses
administered 610
weeks apart
Healthy
persons age
1949 who
desire
protection
against
influenza. May
be substituted
for inactivated
vaccine in
healthy
children 218
years
Measles
Live virus
Subcutaneous
Two doses at least

1 month apart
1. Adults and
adolescents
born after 1956
without a
history of
measles or live
virus
None
Vaccine
Type of
Agent
Route of
Primary
Booster2 Indication
s
n
n
vaccination on
or after their
first birthday
2.
Postexposure
prophylaxis in
unimmunized
persons
Measlesmumpsrubella
(MMR)
Live virus
Meningococc
al conjugate
vaccine
Bacterial
Intramuscular
polysaccharid
es conjugated
to diphtheria
toxoid
One dose
Bacterial
polysaccharid
es of
serotypes
A/C/Y/W-135
One dose
Meningococc
al
polysaccharid
e vaccine
Subcutaneous
See Table A2
None
1. For all
children
2. Adults born
after 1956
Subcutaneous
Unknown
1. All
adolescents
2. Preferred
over
polysaccharide
vaccine in
persons age
1155 years
Every 35
years if
there is
continuing
high risk of
exposure
1. Military
recruits
2. Travelers to
areas with
hyperendemic
or epidemic
meningococcal
disease
3. Individuals
with asplenia,
complement
deficiency, or
properdin
deficiency
4. Control of
outbreaks in
closed or
semiclosed
Vaccine
Type of
Agent
Route of
Primary
Booster2 Indication
s
n
n
populations
5. College
freshmen who
live in
dormitories
6.
Microbiologists
who are
routinely
exposed to
isolates of
Neisseria
meningitidis
Mumps
Live virus
Subcutaneous
One dose
None
Adults born
after 1956
without a
history of
mumps or live
virus
vaccination on
or after their
first birthday
Pneumococca Bacterial
Intramuscular or
l conjugate
polysaccharid subcutaneous
vaccine
es conjugated
to protein
See Table A2
None
For all children
Pneumococca
l
polysaccharid
e vaccine
Bacterial
polysaccharid
es of 23
serotypes
Intramuscular or
subcutaneous
One dose
Repeat after 1. Adults 65

5 years in
years
patients at
2. Persons at
high risk
increased risk
for
pneumococcal
disease or its
complications
Poliovirus
vaccine,
inactivated
(IPV)
Inactivated
viruses of all
three
serotypes
Subcutaneous
See Table A2 for

childhood
schedule. Adults:
Two doses 48
weeks apart, and a
third dose 612
One-time
booster dose
for adults at
increased
risk of
1. For all
children
2. Previously
unvaccinated
adults at
Vaccine
Rabies
Type of
Agent
Inactivated
virus
Route of
Primary
Booster2 Indication
s
n
n
Intramuscular (IM)
months after the

second
exposure
Preexposure:
Three doses at
days 0, 7, and 21
or 28
Serologic
testing every
6 months to
2 years in
persons at
high risk
Postexposure:
Five-doses at days
0, 3, 7, 14, and
28
increased risk
for
occupational or
travel exposure
to polioviruses
1.
Preexposure
prophylaxis in
persons at risk
for contact with
rabies virus
2.
Postexposure
prophylaxis
(administer
with rabies
immune
globulin)
Rotavirus
Live virus
Oral
See Table A2
None
For all infants.

The series of 3
doses should
be initiated by
age 12 weeks
and completed
by age 32
weeks
Rubella
Live virus
Subcutaneous
One or two doses

(at least 28 days
apart)
None
Adults born
after 1956
without a
history of
rubella or live
virus
vaccination on
or after their
first birthday
Tetanusdiphtheria
(Td or DT)3
Toxoids
Intramuscular
Two doses 48
Every 10
weeks apart, and a years or a
third dose 612
single
months after the
booster at
second
age 50
1. All adults
2.
Postexposure
prophylaxis if >
5 years has
passed since
Vaccine
Type of
Agent
Route of
Primary
Booster2 Indication
s
n
n
last dose
Tetanus,
diphtheria,
pertussis
(Tdap)
Toxoids and
inactivated
bacterial
components
Intramuscular
Substitute 1 dose
of Tdap for Td in
patients 1964
years of age
Typhoid,
Ty21a oral
Live bacteria
Oral
Four doses
Four doses
administered every every 5
other day
years
Risk of
exposure to
typhoid fever
Typhoid, Vi
Bacterial
capsular
polysaccharid
polysaccharid e
e
Intramuscular
One dose
Risk of
exposure to
typhoid fever
Varicella
Subcutaneous
Two doses 48
Unknown
weeks apart in
persons past their
13th birthday (see
Table A2 for
childhood
schedule)
Live virus
None
Every 2
years
All adults < 65

years
1. For all
children
2. Persons past
their 13th
birthday
without a
history of
varicella
infection or
immunization
3.
Postexposure
prophylaxis in
susceptible
persons
Yellow fever
Live virus
Subcutaneous
One dose 10 years Every 10

to 10 days before years
travel
1. Laboratory
personnel who
may be
exposed to
yellow fever
virus
2. Travelers to
areas where
yellow fever
occurs
Zoster
Live virus
Subcutaneous
One dose
None
All adults 60
Vaccine
Type of
Agent
Route of
Primary
Booster2 Indication
s
n
n
years of age
Dosages for the specific product, including variations for age, are best obtained from the
manufacturer's package insert.
1
One dose unless otherwise indicated.
Td is tetanus and diphtheria toxoids for use in persons <7 years of age (contains less diphtheria
toxoid than DPT and DT). DT is tetanus and diphtheria toxoids for use in persons < 7 years of age
(contains the same amount of diphtheria toxoid as DPT).
3
Current recommendations for routine active immunization of children are given in Table A2.
Table A2 Recommended Routine Childhood Immunization Schedule.
Age
Immunization
Comments
Birth to
2
months
Hepatitis B vaccine (HBV)
Infants born to seronegative mothers:

Administration should begin at birth, with
the second dose administered at least 4
weeks after the first dose.
Infants born to seropositive mothers:
Should receive the first dose within 12
hours after birth (with hepatitis B immune
globulin), the second dose at 12 months of
age, and the third dose at 6 months of age.
2
months
Diphtheria and tetanus toxoids and acellular

pertussis vaccine (DTaP), inactivated
poliovirus vaccine (IPV), Haemophilus
influenzae type b conjugate vaccine (Hib),1
pneumococcal conjugate vaccine (PCV),
rotavirus vaccine (Rota)
14
months
HBV
4
months
DTaP, Hib,1 IPV, PCV, Rota
6
months
DTaP, Hib,1 PCV, Rota
618
months
HBV, IPV, influenza
The second dose should be given at least 4

weeks after the first dose.
The third dose of HBV should be given at

least 16 weeks after the first dose and at
Age
Immunization
Comments
least 8 weeks after the second dose, but not
before age 6 months. Influenza vaccine
should be administered annually to children
aged 6 months to 18 years.
1215
months
Measles-mumps-rubella vaccine (MMR), Hib,1

PCV
1218
months
DTaP at 1518 months, varicella vaccine
DTaP may be given as early as age 12

months. Varicella vaccine is recommended
at any visit after the first birthday for
susceptible children. The second dose
should be administered at age 46 years.
1223
months
Hepatitis A vaccine
Two doses 6 months apart.
46
years
DTaP IPV, MMR, varicella vaccine
The second dose of MMR should be routinely

administered at 46 years of age but may
be given during any visit if at least 4 weeks
have elapsed since administration of the
first dose. The second dose should be given
no later than age 1112 years.
1112
years
Tetanus, diphtheria, pertussis (Tdap) vaccine, Three doses of HPV should be administered
human papillomavirus vaccine (HPV),
to females at 0, 2, and 6 months.
meningococcal conjugate vaccine
Three Hib conjugate vaccines are available for use: (a) oligosaccharide conjugate Hib vaccine (HbOC),
(b) polyribosylribitol phosphate-tetanus toxoid conjugate (PRP-T), and (c) Haemophilus influenzae
type b conjugate vaccine (meningococcal protein conjugate) (PRP-OMP). Children immunized with
PRP-OMP at 2 and 4 months of age do not require a dose at 6 months of age.
1
Adapted from MMWR Morb Mortal Wkly Rep 2008;57:Q-1.
PASSIVE IMMUNIZATION
Passive immunization consists of transfer of immunity to a host using preformed immunologic
products. From a practical standpoint, only immunoglobulins have been used for passive
immunization, since passive administration of cellular components of the immune system has been
technically difficult and associated with graft-versus-host reactions. Products of the cellular immune
system (eg, interferons) have also been used in the therapy of a wide variety of hematologic and
infectious diseases (see Chapter 56).
Passive immunization with antibodies may be accomplished with either animal or human
immunoglobulins in varying degrees of purity. These may contain relatively high titers of antibodies
directed against a specific antigen or, as is true for pooled immune globulin, may simply contain
antibodies found in most of the population. Passive immunization is useful for (1) individuals unable to
form antibodies (eg, congenital agammaglobulinemia); (2) prevention of disease when time does not
permit active immunization (eg, postexposure); (3) for treatment of certain diseases normally
prevented by immunization (eg, tetanus); and (4) for treatment of conditions for which active
immunization is unavailable or impractical (eg, snakebite).
Complications from administration of human immunoglobulins are rare. The injections may be
moderately painful and rarely a sterile abscess may occur at the injection site. Transient hypotension
and pruritus occasionally occur with the administration of intravenous immune globulin (IVIG)
products, but generally are mild. Individuals with certain immunoglobulin deficiency states (IgA
deficiency, etc) may occasionally develop hypersensitivity reactions to immune globulin that may limit
therapy. Conventional immune globulin contains aggregates of IgG; it will cause severe reactions if
given intravenously. However, if the passively administered antibodies are derived from animal sera,
hypersensitivity reactions ranging from anaphylaxis to serum sickness may occur. Highly purified
immunoglobulins, especially from rodents or lagomorphs, are the least likely to cause reactions. To
avoid anaphylactic reactions, tests for hypersensitivity to the animal serum must be performed. If an
alternative preparation is not available and administration of the specific antibody is deemed essential,
desensitization can be carried out.
Antibodies derived from human serum not only avoid the risk of hypersensitivity reactions but also
have a much longer half-life in humans (about 23 days for IgG antibodies) than those from animal
sources (57 days or less). Consequently, much smaller doses of human antibody can be administered
to provide therapeutic concentrations for several weeks. These advantages point to the desirability of
using human antibodies for passive protection whenever possible. Materials available for passive
immunization are summarized in Table A3.
Table A3 Materials Available for Passive Immunization.1
Indication
Product
Dosage
Comments
Black widow
spider bite
Antivenin (Latrodectus One vial (6000 units) IV or

mactans), equine
IM.
For persons with

hypertensive cardiovascular
disease or age < 16 or > 60
years.
Bone marrow
transplantation
Immune globulin
(intravenous [IV])2
500 mg/kg IV on days 7

and 2 prior to
transplantation and then
once weekly through day
90 after transplantation.
Prophylaxis to decrease the

risk of infection, interstitial
pneumonia, and acute graftversus-host disease in adults
undergoing bone marrow
transplantation.
Botulism
Botulism antitoxin,
equine
Consult the CDC.3
Treatment and prophylaxis

of botulism. Available from
the CDC.3 Ten to 20 percent
incidence of serum
reactions.
Chronic
Immune globulin (IV)2 400 mg/kg IV every 34
CLL patients with
Indication
Product
lymphocytic
leukemia (CLL)
Dosage
Comments
weeks. Dosage should be

hypogammaglobulinemia
adjusted upward if bacterial and a history of at least one
infections occur.
serious bacterial infection.
Cytomegalovirus
(CMV)
Cytomegalovirus
immune globulin (IV)
Consult the manufacturer's

dosing recommendations.
Prophylaxis of CMV infection

in bone marrow, kidney,
liver, lung, pancreas, heart
transplant recipients.
Diphtheria
Diphtheria antitoxin,
equine
20,000120,000 units IV or Early treatment of

IM depending on the
respiratory diphtheria.
severity and duration of
Available from the CDC.3
illness.
Anaphylactic reactions in
7% of adults and serum
reactions in 510% of
adults.
Hepatitis A
Immune globulin
(intramuscular [IM])
Preexposure
prophylaxis: 0.02 mL/ kg
IM for anticipated risk of 3
months, 0.06 mL/kg for
anticipated risk of > 3
months, repeated every 4
6 months for continued
exposure.
Preexposure and
postexposure hepatitis A
prophylaxis. The availability
of hepatitis A vaccine has
greatly reduced the need for
preexposure prophylaxis.
Postexposure: 0.02
mL/kg IM as soon as
possible after exposure up
to 2 weeks.
Hepatitis B
Hepatitis B immune
globulin (HBIG)
0.06 mL/kg IM as soon as

possible after exposure up
to 1 week for percutaneous
exposure or 2 weeks for
sexual exposure. 0.5 mL IM
within 12 hours after birth
for perinatal exposure.
Postexposure prophylaxis in
nonimmune persons
following percutaneous,
mucosal, sexual, or perinatal
exposure. Hepatitis B
vaccine should also be
administered.
HIV-infected
children
Immune globulin (IV)2 400 mg/kg IV every 28

days.
HIV-infected children with

recurrent serious bacterial
infections or
hypogammaglobulinemia.
Kawasaki disease
Immune globulin (IV)2 400 mg/kg IV daily for 4

consecutive days within 4
days after the onset of
illness. A single dose of 2
Effective in the prevention of

coronary aneurysms. For use
in patients who meet strict
criteria for Kawasaki
Indication
Measles
Product
Immune globulin (IM)
Dosage
Comments
g/kg IV over 10 hours is

also effective.
disease.
Normal hosts: 0.25 mL/kg Postexposure prophylaxis

IM.
(within 6 days after
exposure) in nonimmune
Immunocompromised
contacts of acute cases.
hosts: 0.5 mL/kg IM
(maximum 15 mL for all
patients).
Idiopathic
Immune globulin (IV)2 Consult the manufacturer's
thrombocytopenic
dosing recommendations
purpura (ITP)
for the specific product
being used.
Response in children with

ITP is greater than in adults.
Corticosteroids are the
treatment of choice in
adults, except for severe
pregnancy-associated ITP.
Primary
Immune globulin (IV)2 Consult the manufacturer's
immunodeficiency
dosing recommendations
disorders
for the specific product
being used.
Primary immunodeficiency
disorders include specific
antibody deficiencies (eg, Xlinked agammaglobulinemia)
and combined deficiencies
(eg, severe combined
immunodeficiencies).
Rabies
Rabies immune
globulin
20 IU/kg. The full dose

should be infiltrated around
the wound and any
remaining volume should
be given IM at an anatomic
site distant from vaccine
administration.
Postexposure rabies
prophylaxis in persons not
previously immunized with
rabies vaccine. Must be
combined with rabies
vaccine.
Respiratory
syncytial virus
(RSV)
Palivizumab
15 mg/kg IM once prior to

the beginning of the RSV
season and once monthly
until the end of the season.
For use in infants and

children younger than 24
months with chronic lung
disease or a history of
premature birth ( 35 weeks'
gestation).
Rubella
Immune globulin (IM)
0.55 mL/kg IM.
Nonimmune pregnant
women exposed to rubella
who will not consider
therapeutic abortion.
Administration does not
prevent rubella in the fetus
of an exposed mother.
Indication
Product
Dosage
Comments
Snake bite (coral

snake)
Antivenin (Micrurus
fulvius), equine
At least 35 vials (3050

mL) IV initially within 4
hours after the bite.
Additional doses may be
required.
Neutralizes venom of
eastern coral snake and
Texas coral snake. Serum
sickness occurs in almost all
patients who receive > 7
vials.
Snake bite (pit

vipers)
Antivenin (Crotalidae)
polyvalent, equine
The entire dose should be

given within 4 hours after
the bite by the IV or IM
route (1 vial = 10 mL):
Minimal envenomation: 24
vials Moderate
envenomation: 59 vials
Severe envenomation: 10
15 vials Additional doses
may be required.
Neutralizes the venom of

rattlesnakes, copperheads,
cottonmouths, water
moccasins, and tropical and
Asiatic crotalids. Serum
sickness occurs in almost all
patients who receive > 7
vials.
Antivenin (Crotalidae)
polyvalent immune
Fab, ovine
An initial dose of 46 vials

should be infused
intravenously over 1 hour.
The dose should be
repeated if initial control is
not achieved. After initial
control, 2 vials should be
given every 6 hours for up
to 3 doses.
For the management of

minimal to moderate North
American crotalid
envenomation.
Tetanus immune
globulin
Postexposure
prophylaxis: 250 units IM.
For severe wounds or when
there has been a delay in
administration, 500 units is
recommended.
Treatment of tetanus and

postexposure prophylaxis of
nonclean, nonminor wounds
in inadequately immunized
persons (less than two doses
of tetanus toxoid or less
than three doses if wound is
more than 24 hours old).
Tetanus
Treatment: 30006000
units IM.
Vaccinia
Vaccinia immune
globulin
Consult the CDC.3
Treatment of severe
reactions to vaccinia
vaccination, including
eczema vaccinatum, vaccinia
necrosum, and ocular
vaccinia. Available from the
CDC.3
Varicella
Varicella-zoster
immune globulin
Weight
(kg)
Postexposure prophylaxis
(preferably within 48 hours
Dose
(units)
Indication
Product
Dosage
10
Comments
125 IM
10.120
250 IM
20.130
375 IM
30.140
500 IM
40
but no later than within 96

hours after exposure) in
susceptible
immunocompromised hosts,
selected pregnant women,
and perinatally exposed
newborns.
625 IM
Passive immunotherapy or immunoprophylaxis should always be administered as soon as possible

after exposure. Prior to the administration of animal sera, patients should be questioned and tested for
hypersensitivity.
1
See the following references for an analysis of additional uses of intravenously administered immune
globulin: Ratko TA et al: Recommendations for off-label use of intravenously administered
immunoglobulin preparations. JAMA 1995;273:1865; and Feasby T et al: Guidelines on the use of
intravenous immune globulin for neurologic conditions. Transfus Med Rev 2007;21(2 Suppl 1)S57.
2
Centers for Disease Control and Prevention, 404-639-3670 during weekday business hours; 770-4887100 during nights, weekends, and holidays (emergency requests only).
3
LEGAL LIABILITY FOR UNTOWARD REACTIONS

It is the physician's responsibility to inform the patient of the risk of immunization and to use vaccines
and antisera in an appropriate manner. This may require skin testing to assess the risk of an untoward
reaction. Some of the risks previously described are, however, currently unavoidable; on the balance,
the patient and society are clearly better off accepting the risks for routinely administered
immunogens (eg, influenza and tetanus vaccines).
Manufacturers should be held legally accountable for failure to adhere to existing standards for
production of biologicals. However, in the present litigious atmosphere of the USA, the filing of large
liability claims by the statistically inevitable victims of good public health practice has caused many
manufacturers to abandon efforts to develop and produce low-profit but medically valuable
therapeutic agents such as vaccines. Since the use and sale of these products are subject to careful
review and approval by government bodies such as the Surgeon General's Advisory Committee on
Immunization Practices and the FDA, "strict product liability" (liability without fault) may be an
inappropriate legal standard to apply when rare reactions to biologicals, produced and administered
according to government guidelines, are involved.
RECOMMENDED IMMUNIZATION OF ADULTS FOR TRAVEL

Every adult, whether traveling or not, should be immunized with tetanus toxoid and should also be
fully immunized against poliomyelitis, measles (for those born after 1956), and diphtheria. In addition,
every traveler must fulfill the immunization requirements of the health authorities of the countries to
be visited. These are listed in Health Information for International Travel , available from the
Superintendent of Documents, United States Government Printing Office, Washington, DC 20402. A
useful website is http://wwwn.cdc.gov/travel/contentVaccinations.aspx. The Medical Letter on Drugs
and Therapeutics also offers periodically updated recommendations for international travelers (see
Treatment Guidelines from The Medical Letter , 2006;4:25). Immunizations received in preparation for
travel should be recorded on the International Certificate of Immunization. Note: Smallpox
vaccination is not recommended or required for travel in any country.

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DRUGS THAT ACT IN THE CENTRAL

Selective serotonin reuptake inhibitors (SSRIs)

Half-lives from 1575 h

Fluvoxamine: Similar to above but approved only for obsessive-compulsive behavior

DRUGS USED FOR MOVEMENT DISORDERS

Levodopa and combinations

Levodopa + carbidopa (Sinemet): Carbidopa inhibits peripheral metabolism of levodopa to

Direct agonist at Reduces

Ropinirole: Similar to pramipexole; nonergot; relatively pure D 2 agonist

Apomorphine: Nonergot; subcutaneous route useful for rescue treatment in levodopa-induced

Monoamine oxidase (MAO) inhibitors

Oral Toxicity &

Oral Toxicity: Increased

Reduces tremor Parkinson's

Oral Toxicity: Typical

Biperiden, orphenadrine, procyclidine, trihexyphenidyl: Similar antimuscarinic agents with CNS

Oral Toxicity: Hypotension,

Oral Toxicity: Parkinsonism,

Haloperidol, other neuroleptics: Sometimes helpful

Blocks central D2 Reduces vocal

and motor tic

other dyskinesias sedation

Clonidine: Effective in ~ 50% of patients; see Chapter 11 for basic pharmacology

Half-lives from 240 h

IV, short half-life Toxicity:

Half-lives from 460 h oral

Oral activity short halflives CYP substrates

Slow onset (12 Generalized

Oral activity forms active

ANTIPSYCHOTIC DRUGS & LITHIUM

Oral and parenteral forms,

Oral and parenteral forms

Oral absorption, renal

Newer agents for bipolar disorder

DRUGS USED SKELETAL MUSCLE RELAXANTS

Depolarizing neuromuscular blocking agent

Nondepolarizing neuromuscular blocking agents

Renal excretion duration,

Not dependent on renal or

Oral, intrathecal Toxicities:

Chlorphenesin, methocarbamol, orphenadrine, others: Like cyclobenzaprine with varying degrees of

Renal and hepatic

IV, oral duration, 46 h

Direct-acting muscle relaxants

Mechanis Pharmacokineti Clinical

Well absorbed orally

Mechanis Pharmacokineti Clinical

plasma proteins peak

Ethosuximide Reduces low

Well absorbed orally,

Absence seizures Toxicity: Nausea,

Well absorbed orally,

Mechanis Pharmacokineti Clinical

Well absorbed orally

Lorazepam: Similar to diazepam

Well absorbed orally

Mechanis Pharmacokineti Clinical

Well absorbed from

Toxicity: Nausea, tremor,

Well absorbed orally no

Well absorbed orally

Well absorbed highly