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‫بسمه تعالی‬
‫عوارض داروهای‬
‫‪Antidepressants‬‬
‫‪Antipsychotics‬‬
‫‪Analgesics‬‬
‫دکتر دولتی‬
‫گروه فارماکولوژی‬
‫دانشکده پزشکی‬
‫عوارض داروهای ضد افسردگی‬
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‫تقسیم بندی‬
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‫عوارض داروهای ضد افسردگی‬
‫تقسیم بندی‬
‫‪SECOND-GENERATION‬‬
‫تقسیم بندی‬
third generation
‫تقسیم بندی‬
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS)
MONOAMINE OXIDASE (MAO) INHIBITORS
10
= none; + = slight; ++ = moderate; +++ = high; ? = uncertain.
2Significant
α2antagonism.
Adverse Effects
Adverse Effects
Adverse Effects
Adverse Effects
Drug Choice
No special indications for particular types of depression have been
found for SSRIs or other newer antidepressants
roughly equivalent in efficacy
Although this may be true for groups of patients, individual
patients may respond better to one drug than to another
Meta-analyses of outpatient studies also show a greater efficacy of
tricyclics over SSRIs in patients who complete trials.
Tricyclics and the second- and third-generation agents differ
mainly in the degree of sedation they produce (greatest with
amitriptyline, doxepin, trazodone, and mirtazapine)
Tricyclics and the second- and third-generation agent
antimuscarinic effects (greatest with amitriptyline and doxepin
SSRIs are generally free of sedative effects and safe in
overdose.
Drug Choice
A provocative clinical report that fluoxetine use increased suicidal
or aggressive ideation was not supported by subsequent analyses of
massive databases. In 2004, however, because of an apparent increase
in suicidal thoughts and behaviors in children on SSRIs, the FDA
issued a general warning about increased risk of suicide with newer
antidepressants.
Studies of concurrent epidemiologic data involving much larger
numbers than the trials cited by the FDA came to the opposite
conclusion— any increase in suicide risk is seen only with older
antidepressants (primarily tricyclics).
MAO inhibitors remain helpful despite their adverse effects but
are reserved for patients who have failed to respond to at least two
courses of monotherapy or combination treatment with different
classes of antidepressants.
‫موارد کاربرد‬
‫تقسیم بندی‬
‫‪ANTIPSYCHOTIC AGENTS‬‬
‫تقسیم بندی‬
Antipsychotic Drugs: Relation of Chemical Structure to Potency and
Toxicitie
Adverse Pharmacologic Effects of Antipsychotic Drugs.
PSYCHOLOGICAL EFFECTS
cause unpleasant subjective effects in nonpsychotic individuals; the
combination of sleepiness, restlessness, and autonomic effects creates
experiences unlike those associated with more familiar sedatives or
hypnotics
Nonpsychotic persons also experience impaired
performance as judged
ELECTROENCEPHALOGRAPHIC EFFECTS
usually slowing them and increasing their synchronization. The
slowing (hypersynchrony) is sometimes focal or unilatera
Some of the neuroleptic agents lower the seizure threshold and
induce EEG patterns typical of seizure disorders
ENDOCRINE EFFECTS
Older antipsychotic drugs produce striking adverse effects on the
reproductive system. Amenorrhea-galactorrhea, false-positive
pregnancy tests, and increased libido have been reported in women,
whereas men have experienced decreased libido and gynecomastia
blockade of dopamine's tonic inhibition of prolactin secretion; others
may be due to increased peripheral conversion of androgens to estrogens
Absent or minimal increases of prolactin after some of the newer
antipsychotics such as olanzapine, quetiapine, and aripiprazole may be a
marker of diminished D2 antagonism and hence reduced risks of
extrapyramidal system dysfunction and tardive dyskinesia as well as
endocrine dysfunction.
CARDIOVASCULAR EFFECTS
Orthostatic hypotension and high resting heart rates frequently result
from use of the low-potency phenothiazines. Mean arterial pressure,
peripheral resistance, and stroke volume are decreased, and heart rate
is increased.
Abnormal ECGs have been recorded, especially with
thioridazine. Changes include prolongation of QT interval and
abnormal configurations of the ST segment and T waves. These
changes are readily reversed by withdrawing the drug.
prolongation of the QT or QTc interval—with increased risk of
dangerous arrhythmias—has been of such concern that the
atypical drug sertindole was withdrawn shortly after being
marketed
Ziprasidone carries a warning about the risk of significant QTc
prolongation.
Some Representative Antipsychotic Drugs
1Other
aliphatic phenothiazines: promazine, triflupromazine.
piperidine phenothiazines: piperacetazine, mesoridazine.
3Other piperazine phenothiazines: acetophenazine, perphenazine, carphenazine, prochlorperazine, trifluoperazine.
2Other
Dose Relationships of Antipsychotics.
Adverse Reactions
Most of the unwanted effects of antipsychotics are
extensions of their known pharmacologic actions
but a few effects are allergic and some are
idiosyncratic.
BEHAVIORAL EFFECTS
The older typical antipsychotic drugs are unpleasant to ta
Many patients stop taking these drugs because of the adverse
effects, which may be mitigated by giving small doses during the day
and the major portion at bedtime.
A "pseudodepression" that may be due to drug-induced
akinesia usually responds to treatment with antiparkinsonism
drugs
Toxic-confusional states may occur with very high doses of
drugs that have prominent antimuscarinic actions.
Adverse Reactions
NEUROLOGIC EFFECTS
Extrapyramidal reactions occurring early during treatment with older agents
include typical Parkinson's syndrome, akathisia (uncontrollable restlessness),
and acute dystonic reactions (spastic retrocollis or torticollis).
Parkinsonism can be treated, when necessary, with conventional antiparkinsonism
drugs of the antimuscarinic type
(Levodopa should never be used in these patients.)
Akathisia and dystonic reactions also respond to such treatment, but many prefer
to use a sedative antihistamine with anticholinergic properties, eg, diphenhydramine
Tardive dyskinesia, as the name implies, is a late-occurring syndrome of abnormal
choreoathetoid movements
Seizures, though recognized as a complication of chlorpromazine treatment
de novo seizures may occur in 2–5% of patients treated with clozapine.
Adverse Reactions
AUTONOMIC NERVOUS SYSTEM EFFECTS
Most patients are able to tolerate the antimuscarinic
adverse effects of antipsychotic drugs. Those who are made
too uncomfortable or who develop urinary retention or other
severe symptoms can be switched to an agent without
significant antimuscarinic action
Orthostatic hypotension or impaired ejaculation—
common chlorpromazine or mesoridazin
switching to drugs with less marked adrenoceptorblocking actions.
Adverse Reactions
METABOLIC AND ENDOCRINE EFFECTS
Weight gain is very common, especially
with clozapine and olanzapine,
Hyperprolactinemia in women results in the
amenorrhea-galactorrhea syndrome and infertility;
in men, loss of libido, impotence, and infertility
may result.
Adverse Reactions
TOXIC OR ALLERGIC REACTIONS
Agranulocytosis, cholestatic jaundice, and skin eruptions
occur rarely with the high-potency antipsychotic drugs
currently used.
In contrast to other antipsychotic agents, clozapine
causes agranulocytosis in a small but significant number
of patients—approximately 1–2% of those treated
be reversible upon discontinuance of the drug
Because of the risk of agranulocytosis, patients receiving
clozapine must have weekly blood counts for the first 6
months of treatment and every 3 weeks thereafter.
Adverse Reactions
OCULAR COMPLICATIONS
Deposits in the anterior portions of the eye (cornea and lens)
are a common complication of chlorpromazine therapy.
 They may accentuate the normal processes of aging of the
lens.
Thioridazine is the only antipsychotic drug that causes
retinal deposits, which in advanced cases may resemble
retinitis pigmentosa. The deposits are usually associated with
"browning" of vision.
The maximum daily dose of thioridazine has been limited to
800 mg/d to reduce the possibility of this complication.
Adverse Reactions
CARDIAC TOXICITY
Thioridazine in doses exceeding 300 mg daily is almost always
associated with minor abnormalities of T waves that are easily
reversible. Overdoses of thioridazine are associated with major
ventricular arrhythmias, cardiac conduction block, and sudden
death; it is not certain whether thioridazine can cause these same
disorders when used in therapeutic doses.
In view of possible additive antimuscarinic and quinidine-like
actions with various tricyclic antidepressants, thioridazine should
be combined with the latter drugs only with great care.
Among the atypical agents, ziprasidone carries the greatest risk
of QT prolongation and therefore should not be combined with
other drugs that prolong the QT interval, including thioridazine,
pimozide, and quinidine.
Adverse Reactions
NEUROLEPTIC MALIGNANT SYNDROME
This life-threatening disorder occurs in patients who are extremely sensitive
to the extrapyramidal effects of antipsychotic agents (see also Chapter 16).
The initial symptom is marked muscle rigidity. If sweating is impaired, as it
often is during treatment with anticholinergic drugs, fever may ensue, often
reaching dangerous levels. The stress leukocytosis and high fever associated
with this syndrome may erroneously suggest an infectious process.
Autonomic instability, with altered blood pressure and pulse rate, is often
present. Creatine kinase isozymes are usually elevated, reflecting muscle
damage. This syndrome is believed to result from an excessively rapid
blockade of postsynaptic dopamine receptors. A severe form of
extrapyramidal syndrome follows. Early in the course, vigorous treatment of
the extrapyramidal syndrome with antiparkinsonism drugs is worthwhile.
Muscle relaxants, particularly diazepam, are often useful. Other muscle
relaxants, such as dantrolene, or dopamine agonists, such as bromocriptine,
have been reported to be helpful. If fever is present, cooling by physical
measures should be tried. Various minor forms of this syndrome are now
recognized.
Overdoses
Poisonings with antipsychotics (unlike tricyclic antidepressants)
are rarely fatal, with the exception of those due to mesoridazine
and thioridazine. In general, drowsiness proceeds to coma, with
an intervening period of agitation. Neuromuscular excitability
may be increased and proceed to convulsions. Pupils are miotic,
and deep tendon reflexes are decreased. Hypotension and
hypothermia are the rule, though fever may be present later in the
course.
The lethal effects of mesoridazine and thioridazine are related to
induction of ventricular tachyarrhythmias. Patients should be
given the usual "ABCD" treatment for poisonings (see Chapter
59) and treated supportively.
Management of overdoses of thioridazine and mesoridazine,
which are complicated by cardiac arrhythmias, is similar to that
for tricyclic antidepressants (see Chapter 30).
LITHIUM & OTHER MOOD-STABILIZING DRUGS
Lithium carbonate Adverse Effects & Complications
NEUROLOGIC AND PSYCHIATRIC
ADVERSE EFFECTS
DECREASED THYROID FUNCTION
EDEMA
NEPHROGENIC DIABETES
INSIPIDUS AND OTHER RENAL
ADVERSE EFFECTS
CARDIAC ADVERSE EFFECTS
Overdoses
Therapeutic overdoses of lithium are more common than
those due to deliberate or accidental ingestion of the drug.
Therapeutic overdoses are usually due to accumulation of
lithium resulting from some change in the patient's status,
such as diminished serum sodium, use of diuretics, or
fluctuating renal function. Since the tissues will have
already equilibrated with the blood, the plasma
concentrations of lithium may not be excessively high in
proportion to the degree of toxicity; any value over 2 mEq/L
must be considered as indicating likely toxicity. Because
lithium is a small ion, it is dialyzed readily. Both peritoneal
dialysis and hemodialysis are effective, though the latter is
preferred. Dialysis should be continued until the plasma
concentration falls below the usual therapeutic range.
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
NONSELECTIVE COX INHIBITORS
COX-2 Selective Inhibitors
COX-2 Selective Inhibitors
Celecoxib
Meloxicam
Etoricoxib
Valdecoxib
COX-2 inhibitors have analgesic, antipyretic, and
anti-inflammatory
approximate halving of gastrointestinal
adverse effects
COX-2 inhibitors at usual doses have been shown to
have no impact on platelet
COX-2 inhibitors do not offer the cardioprotective
effects of traditional nonselective NSAIDs
a higher incidence of cardiovascular thrombotic events
associated with COX-2 inhibitors such as rofecoxib and
valdecoxib
Celecoxib
Probably because it is a sulfonamide, celecoxib
may cause rashes. It does not affect platelet
aggregation at usual doses
Although celecoxib is associated with about half
the gastrointestinal side effects of nonselective
NSAIDs, the frequency of other adverse effects
approximates that of other NSAIDs. Celecoxib
causes no more edema or renal effects than other
members of the NSAID group, but edema and
hypertension have been documented.
Etoricoxib
has a gastrointestinal safety profile similar
to that of other coxibs.
Since etoricoxib has structural
similarities to diclofenac, it is
appropriate to monitor hepatic
function carefully in patients
using this drug.
Meloxicam
Meloxicam is an enolcarboxamide related to piroxicam
that has been shown to preferentially inhibit COX-2 over COX-1,
particularly at its lowest therapeutic dose of 7.5 mg/d.
It is not as selective as the other coxibs and may be considered
"preferentially" selective rather than "highly" selective. The drug is
popular in Europe and many other countries for most rheumatic
diseases and has recently been approved for treatment of osteoarthritis
in the USA. Its efficacy in this condition and rheumatoid arthritis is
comparable to that of other NSAIDs.
It is associated with fewer clinical gastrointestinal symptoms and
complications than piroxicam, diclofenac, and naproxen.
Similarly, while meloxicam is known to inhibit synthesis of
thromboxane A2, it appears that even at supratherapeutic doses its
blockade of thromboxane A2 does not reach levels that result in
decreased in vivo platelet function.
Other toxicities are similar to those of other NSAIDs.
Valdecoxib
Valdecoxib, a diaryl-substituted isoxazole, is a new
highly selective COX-2 inhibitor. The analgesic dose for
valdecoxib is 20 mg twice daily. Gastrointestinal and other
toxicities are similar to those of the other coxibs.
Valdecoxib has no effect on platelet aggregation or
bleeding time.
Serious reactions have been reported in sulfonamidesensitive individuals. Valdecoxib was withdrawn from the
market in the USA in early 2005 in response to FDA
concerns about cardiovascular risks and Stevens-Johnson
syndrome, but the drug is still available in other countries.
Diclofenac
Diclofenac is a phenylacetic acid derivative that is relatively
nonselective as a COX inhibitor.
Adverse effects occur in approximately 20% of patients and
include gastrointestinal distress, occult gastrointestinal
bleeding, and gastric ulceration, though ulceration may occur
less frequently than with some other NSAIDs. A preparation
combining diclofenac and misoprostol decreases upper
gastrointestinal ulceration but may result in diarrhea. Another
combination of diclofenac and omeprazole was also effective
with respect to the prevention of recurrent bleeding, but renal
adverse effects were common in high-risk patients. Diclofenac
at a dosage of 150 mg/d appears to impair renal blood flow
and glomerular filtration rate. Elevation of serum
aminotransferases may occur more commonly with this drug
than with other NSAIDs.
Diflunisal
Although diflunisal is derived from salicylic acid, it is
not metabolized to salicylic acid or salicylate.
effective for cancer pain with bone metastases and for
pain control in dental (third molar) surgery. A 2%
diflunisal oral ointment is a clinically useful analgesic
for painful oral lesions.
Because its clearance depends on renal function as
well as hepatic metabolism, diflunisal's dosage should
be limited in patients with significant renal
impairment.
Its adverse event profile is similar to those of other
NSAIDs; pseudoporphyria has also been reported.
Etodolac
Etodolac is a racemic acetic acid derivative with an
intermediate half-life (Table 36–1). It is slightly more COX2-selective than most other NSAIDs, with a COX-2:COX-1
activity ratio of about 10. Unlike many other racemic
NSAIDs, etodolac does not undergo chiral inversion in the
body. The dosage of etodolac is 200–400 mg three to four
times daily. Etodolac provides good postoperative pain
relief after coronary artery bypass operations, although
transient impairment of renal function has been reported.
There are no data to suggest that etodolac differs
significantly from other NSAIDs except in its
pharmacokinetic parameters, though it has been claimed to
cause less gastric toxicity in terms of ulcer disease than
other nonselective NSAIDs.
Naproxen
Naproxen is a naphthylpropionic acid derivative. It is the only
NSAID presently marketed as a single enantiomer, and it is a
nonselective COX inhibitor. Naproxen's free fraction is significantly
higher in women than in men, although albumin binding is very high in
both sexes (Table 36–1). Naproxen is effective for the usual
rheumatologic indications and is available both in a slow-release
formulation and as an oral suspension. A topical preparation and an
ophthalmic solution are also available.
The incidence of upper gastrointestinal bleeding in over-the-
counter use is low but still double that of over-the-counter
ibuprofen (perhaps due to a dose effect). Rare cases of allergic
pneumonitis, leukocytoclastic vasculitis, and pseudoporphyria
Tolmetin
Tolmetin is a nonselective COX inhibitor
with a short half-life (1–2 hours) and is not
often used. Its efficacy and toxicity profiles
are similar to those of other NSAIDs with
the following exceptions: it is ineffective
(for unknown reasons) in the treatment of
gout,
and it may cause (rarely) thrombocytopenic
purpura.
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