CLINICAL
PHARMACOLOGY OF DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM. CLINICAL
PHARMACOLOGY OF GASTROINTESTINAL AGENTS
The central
nervous system directs the functions of all tissues of the body. The peripheral
nervous system receives thousands of sensory inputs and transmits them to the
brain via the spinal cord. The brain processes this incoming information and
discards 99% as unimportant. After sensory information has been evaluated,
selected areas of the central nervous system initiate nerve impulses to organs
or tissue to make an appropriate response.
Chemical
influences are capable of producing a myriad of effects on the activity and
function of the central nervous system. Since our knowledge of different
regions of brain function and the neurotransmitters in the brain is limited,
the explanations for the mechanisms of drug action may be vague. The known
neurotransmitters are: acetylcholine which is involved with memory and
learning; norepinephrine which is involved with mania-depression and emotions;
and serotonin which is involved with biological rhythms, sleep, emotion, and
pain.
Central Nervous System
Stimulants:
Stimulants
are drugs that exert their action through excitation of the central nervous
system. Psychic stimulants include caffeine, cocaine, and various amphetamines.
These drugs are used to enhance mental alertness and reduce drowsiness and
fatigue. However, increasing the dosage of caffeine above 200 mg (about 2 cups
of coffee) does not increase mental performance but may increase nervousness,
irritability, tremors, and headache. Heavy coffee drinkers become psychically
dependent upon caffeine. If caffeine is withheld, a person may experience mild
withdrawal symptoms characterized by irritability, nervousness, and headache.
Stimulants
increase alertness, attention, and energy, which are accompanied by increases
in blood pressure, heart rate, and respiration.
Historically, stimulants were used to
treat asthma and other respiratory problems, obesity, neurological disorders,
and a variety of other ailments. As their potential for abuse and addiction
became apparent, the use of stimulants began to wane. Now, stimulants are
prescribed for treating only a few health conditions, including narcolepsy,
attention-deficit hyperactivity disorder (ADHD), and depression that has not
responded to other treatments. Stimulants may also be used for short-term
treatment of obesity and for patients with asthma.
Caffeine and the
chemically related xanthines, theophylline and theobromine, decrease in the
order given in their stimulatory action. They may be included in some
over-the-counter drugs.
The
action of caffeine is to block adenosine receptors as an antagonist. As
caffeine has a similar structure to the adenosine group. This means that
caffeine will fit adenosine receptors as well as adenosine itself. It inhibits
the release of neurotransmitters from presynaptic sites but works in concert
with norepinephrine or angiotensin to augment their actions. Antagonism of
adenosine receptors by caffeine would appear to promote neurotransmitter
release, thus explaining the stimulatory effects of caffeine.
Amphetamines:
The stimulation
caused by amphetamines is caused by excessive release of norepinephrine from
storage sites in the peripheral nervous system. It is not known whether the
same action occurs in the central nervous system. Two other theories for their
action are that they are degraded slower than norepinephrine or that they could
act on serotonin receptor sites.
Therapeutic doses
of amphetamine elevate mood, reduce feelings of fatigue and hunger, facilitate
powers of concentration, and increase the desire and capacity to carry out
work. They induce exhilarating feelings of power, strength, energy,
self-assertion, focus and enhanced motivation. The need to sleep or eat is
diminished.
Levoamphetamine
(Benzedrine), dextroamphetamine (Dexedrine), and methamphetamine (Methedrine)
are collectively referred to as amphetamines.
Benzedrine is a
mixture of both the dextro and levoamphetamine isomers. The dextro isomer is
several times more potent than the levo isomer.
The
misuse and abuse of amphetamines is a significant problem which may include the
house wife taking diet pills, athletes desiring an improved performance, the
truck driver driving non-stop coast to-coast, or a student cramming all night
for an exam.
Dextroamphetamine
Pharmacological Class: Amphetamine.
Contraindications:
Advanced
arteriosclerosis. Cardiovascular disease. Moderate to severe hypertension.
Hyperthyroidism. Glaucoma. Drug or alcohol abuse. Agitation. During or within
14 days of MAOIs. Hypersensitivity to sympathomimetics.
Warnings/Precautions:
Tourette's syndrome. Psychosis. Mild
hypertension. Seizure disorders. Monitor growth in children. Reevaluate need
for therapy after drug-free interval. Prescribe limited quantity. Pregnancy
(Cat.C). Nursing mothers: not recommended.
Interactions:
Hypertensive crisis with MAOIs: see
Contraindications. Potentiated by urinary alkalinizers (e.g., some thiazides),
tricyclic antidepressants, propoxyphene. Potentiates meperidine,
norepinephrine, phenobarbital, phenytoin. Antagonized by acidifiers,
psychotropics, lithium. Antagonizes adrenergic blockers, sedatives,
antihypertensives. Monitor phenytoin, ethosuximide, phenobarbital. Convulsions
with propoxyphene overdose and amphetamines. May interfere with urinary steroid
tests.
Adverse Reactions:
Hypertension, tachycardia, CNS
overstimulation, dry mouth, GI disorders, anorexia, urticaria.
Methamphetamine
CLINICAL
PHARMACOLOGY
Methamphetamine
is a sympathomimetic amine with CNS stimulant activity. Peripheral actions
include elevation of systolic and diastolic blood pressures and weak
bronchodilator and respiratory stimulant action. Drugs of this class used in
obesity are commonly known as "anorectics" or
"anorexigenics". It has not been established, however, that the
action of such drugs in treating obesity is primarily one of appetite
suppression. Other central nervous system actions, or metabolic effects, may be
involved, for example.
Adult obese subjects instructed in dietary
management and treated with "anorectic" drugs, lose more weight on
the average than those treated with placebo and diet, as determined in
relatively short-term clinical trials.
The magnitude of increased weight loss of
drug-treated patients over placebo-treated patients is only a fraction of a
pound a week. The rate of weight loss is greatest in the first weeks of therapy
for both drug and placebo subjects and tends to decrease in succeeding weeks.
The origins of the increased weight loss due to the various possible drug
effects are not established. The amount of weight loss associated with the use
of an "anorectic" drug varies from trial to trial, and the increased
weight loss appears to be related in part to variables other than the drug
prescribed, such as the physician-investigator, the population treated, and the
diet prescribed. Studies do not permit conclusions as to the relative
importance of the drug and non-drug factors on weight loss.
The natural history of obesity is measured
in years, whereas the studies cited are restricted to a few weeks duration;
thus, the total impact of drug-induced weight loss over that of diet alone must
be considered clinically limited.
The mechanism of action involved in producing
the beneficial behavioral changes seen in hyperkinetic children receiving
methamphetamine is unknown.
In humans, methamphetamine is rapidly
absorbed from the gastrointestinal tract. The primary site of metabolism is in
the liver by aromatic hydroxylation, N-dealkylation and deamination. At least
seven metabolites have been identified in the urine. The biological half-life
has been reported in the range of 4 to 5 hours. Excretion occurs primarily in
the urine and is dependent on urine pH. Alkaline urine will significantly
increase the drug half-life. Approximately 62% of an oral dose is eliminated in
the urine within the first 24 hours with about one-third as intact drug and the
remainder as metabolites.
INDICATIONS
Attention Deficit Disorder
with Hyperactivity
Methamphetamine
hydrochloride tablets are indicated as an integral part of a total treatment
program which typically includes other remedial measures (psychological,
educational, social) for a stabilizing effect in children over 6 years of age with
a behavioral syndrome characterized by the following group of developmentally
inappropriate symptoms: moderate to severe distractibility, short attention
span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this
syndrome should not be made with finality when these symptoms are only of
comparatively recent origin. Nonlocalizing (soft) neurological signs, learning
disability, and abnormal EEG may or may not be present, and a diagnosis of
central nervous system dysfunction may or may not be warranted.
CONTRAINDICATIONS
Methamphetamine hydrochloride tablets are contraindicated during or
within 14 days following the administration of monoamine oxidase inhibitors;
hypertensive crisis may result. It is also contraindicated in patients with
glaucoma, advanced arteriosclerosis, symptomatic cardiovascular disease,
moderate to severe hypertension, hyperthyroidism or known hypersensitivity or
idiosyncrasy to sympathomimetic amines. Methamphetamine should not be given to
patients who are in an agitated state or who have a history of drug abuse.
ADVERSE REACTIONS
The following are adverse reactions in decreasing order of severity
within each category that have been reported:
Cardiovascular:
Elevation of blood pressure, tachycardia and palpitation. Fatal
cardiorespiratory arrest has been reported, mostly in the context of
abuse/misuse.
Central
Nervous System: Psychotic episodes have been rarely reported at recommended
doses. Dizziness, dysphoria, overstimulation, euphoria, insomnia, tremor,
restlessness and headache. Exacerbation of motor and phonic tics and Tourette's
syndrome.
Gastrointestinal:
Diarrhea, constipation, dryness of mouth, unpleasant taste and
other gastrointestinal disturbances.
Hypersensitivity: Urticaria.
Endocrine:
Impotence and changes in libido.
Miscellaneous:
Suppression of growth has been reported with the long-term use of
stimulants in children.
DRUG ABUSE AND
DEPENDENCE
Controlled
Substance
Methamphetamine
hydrochloride tablets are subject to control under DEA schedule II.
Abuse
Methamphetamine
has been extensively abused. Tolerance, extreme psychological dependence, and
severe social disability have occurred. There are reports of patients who have
increased the dosage to many times that recommended. Abrupt cessation following
prolonged high dosage administration results in extreme fatigue and mental
depression; changes are also noted on the sleep EEG. Manifestations of chronic
intoxication with methamphetamine include severe dermatoses, marked insomnia,
irritability, hyperactivity, and personality changes. The most severe
manifestation of chronic intoxication is psychosis often clinically
indistinguishable from schizophrenia. Abuse and/or misuse of methamphetamine
have resulted in death. Fatal cardiorespiratory arrest has been reported in the
context of abuse and/or misuse of methamphetamine.
OVERDOSAGE
Manifestations
of acute overdosage with methamphetamine include restlessness, tremor,
hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations,
panic states, hyperpyrexia, and rhabdomyolysis. Fatigue and depression usually
follow the central stimulation. Cardiovascular effects include arrhythmias,
hypertension or hypotension, and circulatory collapse. Gastrointestinal
symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal
poisoning usually terminates in convulsions and coma.
Consult with a Certified Poison Control
Center regarding treatment for up to date guidance and advice. Management of
acute methamphetamine intoxication is largely symptomatic and includes gastric
evacuation, administration of activated charcoal, and sedation. Experience with
hemodialysis or peritoneal dialysis is inadequate to permit recommendations in
this regard.
Acidification of urine increases
methamphetamine excretion, but is believed to increase risk of acute renal
failure if myoglobinuria is present. Intravenous phentolamine (Regitine1) has been suggested for possible acute, severe
hypertension, if this complicates methamphetamine overdosage. Usually a gradual
drop in blood pressure will result when sufficient sedation has been achieved.
Chlorpromazine has been reported to be useful in decreasing CNS stimulation and
sympathomimetic effects.
DOSAGE AND ADMINISTRATION
Methamphetamine
hydrochloride tablets are given orally.
Methamphetamine should be administered at
the lowest effective dosage, and dosage should be individually adjusted. Late
evening medication should be avoided because of the resulting insomnia.
Attention Deficit Disorder
with Hyperactivity
For treatment of children 6 years or older with a behavioral syndrome
characterized by moderate to severe distractibility, short attention span,
hyperactivity, emotional lability and impulsivity: an initial dose of 5 mg methamphetamine hydrochloride tablets once or
twice a day is recommended. Daily dosage may be raised in increments of 5 mg at
weekly intervals until an optimum clinical response is achieved. The usual
effective dose is 20 to 25 mg daily. The total daily dose may be given in two
divided doses daily.
Where possible, drug administration should
be interrupted occasionally to determine if there is a recurrence of behavioral
symptoms sufficient to require continued therapy.
For
Obesity
One
5 mg tablet should be taken one-half hour before each meal. Treatment should
not exceed a few weeks in duration. Methamphetamine is not recommended for use
as an anorectic agent in children under 12 years of age.
Regular use of
amphetamines induces tolerance to some effects, which means that more
and more of the drug is required to produce the desired effects. Tolerance does
not develop to all effects at the same rate, however; indeed, there may be
increased sensitivity to some of them.
Chronic users may
also become psychologically dependent on amphetamines. Psychological
dependence exists when a drug is so central to a person's thoughts,
emotions, and activities that the need to continue its use becomes a craving or
compulsion. Experiments have shown that animals, when given a free choice, will
readily operate pumps that inject them with cocaine or amphetamine. Animals
dependent on amphetamines will work hard to get more of the drug.
Physical
dependence occurs when the body has adapted to the presence of the drug, and
withdrawal symptoms occur if its use is stopped abruptly. The most common
symptoms of withdrawal among heavy amphetamine users are fatigue, long but
troubled sleep, irritability, intense hunger, and moderate to severe
depression, which may lead to suicidal behavior. Fits of violence may also
occur. These disturbances can be temporarily reversed if the drug is taken
again.
Stimulants such
as dextroamphetamine (Dexedrine) and methylphenidate (Ritalin) have chemical
structures that are similar to key brain neurotransmitters called monoamines,
which include norepinephrine and dopamine. Stimulants increase the levels of
these chemicals in the brain and body. This, in turn, increases blood pressure
and heart rate, constricts blood vessels, increases blood glucose, and opens up
the pathways of the respiratory system. In addition, the increase in dopamine
is associated with a sense of euphoria that can accompany the use of
stimulants.
Research
indicates that people with ADHD do not become addicted to stimulant
medications, such as Ritalin, when taken in the form and dosage prescribed.1
However, when misused, stimulants can be addictive.
The consequences
of stimulant abuse can be extremely dangerous. Taking high doses of a stimulant
can result in an irregular heartbeat, dangerously high body temperatures,
and/or the potential for cardiovascular failure or seizures. Taking high doses
of some stimulants repeatedly over a short period of time can lead to hostility
or feelings of paranoia in some individuals.
Stimulants should
not be mixed with antidepressants or over-the-counter cold medicines containing
decongestants. Antidepressants may enhance the effects of a stimulant, and
stimulants in combination with decongestants may cause blood pressure to become
dangerously high or lead to irregular heart rhythms.
Treatment of
addiction to prescription stimulants, such as methylphenidate and amphetamines,
is based on behavioral therapies proven effective for treating cocaine or
methamphetamine addiction. At this time, there are no proven medications for
the treatment of stimulant addiction. Antidepressants, however, may be used to
manage the symptoms of depression that can accompany early abstinence from
stimulants.
Depending on the
patient’s situation, the first step in treating prescription stimulant
addiction may be to slowly decrease the drug’s dose and attempt to treat
withdrawal symptoms. This process of detoxification could then be followed with
one of many behavioral therapies. Contingency management, for example, improves
treatment outcomes by enabling patients to earn vouchers for drug-free urine
tests; the vouchers can be exchanged for items that promote healthy living.
Cognitive-behavioral therapies, which teach patients skills to recognize risky
situations, avoid drug use, and cope more effectively with problems, are
proving beneficial. Recovery support groups may also be effective in
conjunction with a behavioral therapy.
Antidepressant
Antidepressant
drugs are used to restore mentally depressed patients to an improved mental
status. Depression results from a deficiency of norepinephrine at receptors in
the brain. Mechanisms that increase their effective concentration at the
receptor sites should alleviate depression. Antidepressant drugs act by one or
more of the following stimulation type mechanisms:
a) Increase release of norepinephrine:
Amphetamines and
electroconvulsive therapy act by this mechanism. Amphetamines mimic
norepinephrine.
b) Prevent inactivation of norepinephrine:
Monoamine oxidase
(MAO) inhibitors are thought to act as antidepressant agents in part by
preventing the breakdown and inactivation of norepinephrine.
c) Prevent the re uptake of
norepinephrine:
The
action of norepinephrine at the receptor site is terminated by the re uptake of
norepinephrine by the neuron from which it was originally released.
General
characteristics of antidepressants include the following:
• All are effective in relieving
depression, but they differ in their adverse effects.
• All must be taken for 2 to 4 weeks
before depressive symptoms improve.
• They are given orally, absorbed from the
small bowel, enter the portal circulation, and circulate through the liver,
where they undergo extensive first-pass metabolism before reaching the systemic
circulation.
• They are metabolized by the cytochrome
P450 enzymes in the liver. Many antidepressants and other drugs are metabolized
by the 2D6 or 3A4 subgroup of the enzymes.
Thus,
antidepressants may interact with each other and with a wide variety of drugs
that are normally metabolized by the same subgroups of enzymes.
Tricyclic
Antidepressants: (TCA)
The
tricyclic antidepressants are the most effective drugs presently available for
the treatment of depression. These act by increasing the release of
norepinephrine. Amphetamine and cocaine can also act in this manner.
Tricyclic
Antidepressants:
Imipramine,
amitriptylin, and other closely related drugs are among the drugs currently
most widely used for the treatment of major depression.
Imipramine (Tofranil)
Trade
Names: Tofranil, Apo-Imipramine, Imipramine Pamoate
Pharmacokinetics
Absorption: T max is 2 to 4 h. Steady state is reached in 2 to 5 days.
Distribution: More than 90% is protein bound. Lipid soluble.
Metabolism: Significant first pass effect. Metabolism occurs in liver. Active
metabolite is desipramine.
Elimination: The t ½ is 11 to 25 h.
Peak: 2 to 4 weeks.
Indications
and Usage: Relief of symptoms of depression; treatment of enuresis in children 6 yr
and older.
Unlabeled Uses: Treatment of chronic pain, panic disorder, eating disorders (bulimia
nervosa), and facilitation of cocaine withdrawal.
Contraindications: Hypersensitivity to any tricyclic antidepressant. Generally not to be
given in combination with or within 14 days of treatment with MAO inhibitor or
during acute recovery phase of MI; cross-sensitivity may occur among the
dibenzazepines.
Dosage
and Administration
Depression: Use parenterally only in patients who are not
able or not willing to take oral medication. Give via IM route. Do not
administer IV. Up to 100 mg/day in divided doses may be given IM. Switch to
oral as soon as possible.
Adults: PO 100 to 300 mg/day, in divided doses or once
daily at bedtime.
Elderly
& Adolescents: PO 30 to 40 mg/day; may increase up to 100 mg/day.
Children: PO 1.5 mg/kg/day in divided doses; up to maximum of 5 mg/kg/day.
Childhood
Enuresis (6 yr): PO 25 mg/day
given 1 h before bedtime; if response unsatisfactory after 1 wk, may increase
to 50 mg in children younger than 12 yr of age. Children older than 12 yr of
age may receive 75 mg/night. Do not exceed 2.5 mg/kg/day.
Drug
Interactions
Carbamazepine: Carbamazepine levels may increase; imipramine levels may decrease.
Cimetidine,
fluoxetine: May cause increased imipramine blood
levels and effects.
Clonidine; May result in hypertensive crisis.
CNS
depressants: Depressant effects may be additive.
Dicumarol: Anticoagulant actions may increase.
Guanethidine: Hypotensive action may be inhibited.
MAO
inhibitors: May cause
hyperpyretic crises, severe convulsions, and death when given with imipramine.
Sympathomimetics: Pressor response may be decreased by
indirect-acting sympathomimetics and increased by direct-acting ones.
Adverse
Reactions Cardiovascular: Orthostatic hypotension; hypertension; tachycardia; palpitations;
arrhythmias; ECG changes; stroke; heartblock; CHF.
CNS: Confusion; hallucinations; delusions; nervousness; restlessness;
agitation; panic; insomnia; nightmares; mania; exacerbation of psychosis;
drowsiness; dizziness; weakness; numbness; extrapyramidal symptoms; emotional
lability; seizures; tremors.
Dermatologic: Rash; pruritus; photosensitivity reaction; dry skin; acne; itching.
EENT: Nasal congestion; tinnitus; conjunctivitis; mydriasis; blurred vision;
increased IOP.
GI: Nausea; vomiting; anorexia; GI distress; diarrhea; flatulence; peculiar
taste in mouth; dry mouth; constipation.
Genitourinary: Impotence; sexual dysfunction; nocturia; urinary frequency; UTI;
vaginitis; cystitis; dysmenorrhea; amenorrhea; urinary retention and hesitancy.
Hematologic: Bone marrow depression including agranulocytosis; eosinophilia; purpura;
thrombocytopenia; leukopenia.
Hepatic; Hepatitis; jaundice.
Metabolic: Elevation or depression of blood sugar.
Respiratory: Pharyngitis; rhinitis; sinusitis; laryngitis; coughing.
Miscellaneous: Breast enlargement.
Desipramine (Norpramin)
DRUG CLASS AND MECHANISM:
Desipramine
is an oral antidepressant, a member of the tricyclic antidepressant (TCA)
family which also includes amitriptyline (Elavil, Endep), and imipramine (Tofranil). Depression is an all-pervasive sense of sadness
and gloom. It is believed that in some patients with depression, abnormal
levels of neurotransmitters (chemicals that nerves use to communicate with each
other) may be the cause of their depression. Desipramine elevates mood by
raising the level of neurotransmitters in nerves of the brain. Desipramine also
is responsible for the antidepressant effects of imipramine because imipramine
is converted by the body to desipramine. The FDA approved desipramine in 1964.
PREPARATIONS: Tablets: 10, 25,
50, 75, 100, and 150 mg.
PRESCRIBED FOR: Desipramine is
used to elevate the mood of patients with depression. Non-FDA approved
(off-label) uses include anxiety, attention-deficit hyperactivity disorder, bulimia nervosa, cataplexy syndrome, chronic itching, depression caused by traumatic brain injury, neuropathic pain (due to injury of nerves), and panic disorder. Desipramine also has sedative
properties although less than most other TCAs. Therefore, it is useful in
depressed patients with insomnia, restlessness, and nervousness.
DOSING: The usual adult
dose is 100-200 mg daily. The maximum dose is 300 mg daily.
DRUG INTERACTIONS: Desipramine
interacts with other medications and drugs that slow the brain's function, such
as alcohol, barbiturates, benzodiazepines, for example, lorazepam (Ativan), diazepam (Valium), temazepam (Restoril), oxazepam (Serax), clonazepam (Klonopin) as well as zolpidem (Ambien) and narcotics. Reserpine has a
stimulatory effect on patients taking TCAs.
Desipramine and other TCAs should not be
used with monoamine oxidase inhibiting drugs, for example, isocarboxazid
(Marplan), phenelzine (Nardil), tranylcypromine (Parnate), and procarbazine (Matulane)
since high fever, convulsions and even death can occur when
these drugs are used together.
Cimetidine (Tagamet) can increase desipramine
blood levels, possibly causing side effects. Other drugs which share this
effect include propafenone (Rythmol), flecainide (Tonocard), quinidine (Quinidex, Quinaglute), and fluoxetine (Prozac).
TCAs may inhibit the antihypertensive effect
of clonidine (Catapres). Therefore, combining TCAs
with clonidine may lead to dangerous elevations in blood pressure.
PREGNANCY: There are no
adequate studies in pregnant women.
NURSING MOTHERS: It is not known
if desipramine is secreted in breast milk.
SIDE EFFECTS: The most
commonly encountered side effects associated with desipramine include fast
heart rate, blurred vision, urinary retention (difficulty
urinating), dry mouth, constipation, weight gain or loss, and low blood pressure upon arising that may cause
light-headedness. Rash, hives, seizures, and hepatitis are rare side effects.
Desipramine also causes elevated pressure in the eyes of some patients with glaucoma. Overdoses of desipramine can cause
life-threatening abnormal heart rhythms or seizures. Sexual
dysfunction also has been associated with desipramine.
The activity of
the tricyclic drugs depends on the central ring of seven or eight atoms which
confers an angled or twisted conformation. The side chain must have at least 2
carbons although 3 appear to be better. The amine group may be either tertiary
or secondary.
All tricyclic
antidepressants block the re-uptake of norepinephrine at nerve terminals.
However, the potency and selectivity for the inhibition of the uptake of norepinephrine,
serotonin, and dopamine vary greatly among the agents. The tertiary amine
tricyclics seem to inhibit the serotonin uptake pump, whereas the secondary
amine ones seem better in switching off the NE pump. For instance, imipramine
is a potent and selective blocker of serotonin transport, while desipramine
inhibits the uptake of norepinephrine.
Serotonin:
Serotonin
(5-hydroxytryptamine or 5-HT) is a monoamine neurotransmitter found in
cardiovascular tissue, in endothelial cells, in blood cells, and in the central
nervous system. The role of serotonin in neurological function is diverse, and
there is little doubt that serotonin is an important CNS neurotransmitter.
Although some of
the serotonin is metabolized by monoamine oxidase, most of the serotonin
released into the post-synaptic space is removed by the neuron through a re
uptake mechanism inhibited by the tricyclic antidepressants and the newer, more
selective antidepressant re uptake inhibitors such as fluoxetine and
sertraline.
Selective Serotonin
Reuptake Inhibitors: (SSRI)
In recent years,
selective serotonin re uptake inhibitors have been introduced for the treatment
of depression. Prozac is the most famous drug in this class. Clomiprimine,
fluoxetine (Prozac), sertraline and paroxetine selectively block the re uptake
of serotonin, thereby increasing the levels of serotonin in the central nervous
system. Note the similarities and differences between the tricyclic
antidepressants and the selective serotonin re uptake inhibitors. Clomipramine has
been useful in the treatment of obsessive-compulsive disorders.
Monoamine Oxidase (MAO)
Inhibitors:
Monoamine oxidase
(MAO) causes the oxidative deamination of norephinephrine, serotonin, and other
amines. This oxidation is the method of reducing the concentration of the
neurotransmitter after it has sent the signal at the receptor site. A drug
which inhibits this enzyme has the effect of increasing the concentration of
the norepinephrine which in turn causes a stimulation effect.
Most MAO inhibitors
are hydrazine derivatives. Hydrazine is highly reactive and may form a strong
covalent bond with MAO with consequent inhibition for up to 5 days.
These drugs are
less effective and produce more side effects than the tricyclic
antidepressants. For example, they lower blood pressure and were at one time
used to treat hypertension. Their use in psychiatry has also become very
limited as the tricyclic antidepressants have come to dominate the treatment of
depression and allied conditions. Thus, MAOIs are used most often when
tricyclic antidepressants give unsatisfactory results.
MAO Inhibitors:
Phenelzine is the
hydrazine analog of phenylethylamine, a substrate of MAO. This and several
other MAOIs, such as isocarboxazide, are structurally related to amphetamine
and were synthesized in an attempt to enhance central stimulant properties.
phenelzine (Nardil)
isocarboxazid (Marplan)
INDICATIONS FOR USE
Antidepressant
drug therapy may be indicated if depressive symptoms persist at least 2 weeks,
impair social relationships or work performance, and occur independently of
life events. In addition, antidepressants are increasingly being used for treatment
of anxiety disorders. TCAs may be used in children and adolescents in the
management of enuresis (bedwetting or involuntary urination resulting from a
physical or psychological disorder). In this setting, a TCA may be given after physical
causes (eg, urethral irritation, excessive intake of fluids) have been ruled
out. TCAs are also commonly used in the treatment of neuropathic pain. MAOIs
are considered third-line drugs, largely because of their potential for serious
interactions with certain foods and other drugs.
Contraindications to Use
Antidepressant
drugs are contraindicated or must be used with caution in clients with acute
schizophrenia; mixed mania and depression; suicidal tendencies; severe renal, hepatic,
or cardiovascular disease; narrow-angle glaucoma; and seizure disorders.
MISCELLANEOUS
ANTIDEPRESSANTS
Bupropion (Wellbutrin,
Zyban) inhibits the reuptake of dopamine, norepinephrine, and serotonin. It was
marketed with warnings related to seizure activity. Seizures are most
likely to occur with doses above 450 mg/day and in clients known
to have a seizure disorder. After an oral dose, peak plasma levels are reached
in about 2 hours. The average drug half-life is about 14 hours. The drug is
metabolized in the liver and excreted primarily in the urine. Several
metabolites are pharmacologically active. Dosage should be reduced with
impaired hepatic or renal function. Acute episodes of depression usually
require several months of drug therapy. Bupropion is also used as a smoking
cessation aid.
Bupropion has few adverse effects on cardiac function and
does not cause orthostatic hypotension or sexual dysfunction. In addition to
seizures, however, the drug has CNS stimulant effects (agitation, anxiety,
excitement, increased motor activity, insomnia, restlessness) that may require
a sedative during the first few days of administration. These effects may
increase the risk of abuse. Other common adverse effects include dry mouth,
headache, nausea and vomiting, and constipation.
Maprotiline is similar to the
TCAs in therapeutic and adverse effects.
Mirtazapine (Remeron) blocks
presynaptic alpha2-adrenergic receptors (which increases the release of
norepinephrine), serotonin receptors, and histamine H1 receptors. Consequently,
the drug decreases anxiety, agitation, insomnia, and migraine headache as well
as depression. The drug is well absorbed after oral administration, and peak
plasma levels occur within 2 hours after an oral dose. It is metabolized in the
liver, mainly to inactive metabolites.
Common adverse effects
include drowsiness (with accompanying cognitive and motor impairment),
increased appetite, weight gain, dizziness, dry mouth, and constipation. It
does not cause sexual dysfunction. Mirtazapine should not be taken concurrently
with other CNS depressants (eg, alcohol or benzodiazepine antianxiety or hypnotic
agents) because of additive sedation. In addition, it should not be taken
concurrently with an MAOI or for 14 days after stopping an MAOI. An MAOI should
not be started until at least 14 days after stopping mirtazapine.
Nefazodone (Serzone)
inhibits the neuronal reuptake of serotonin and norepinephrine, thereby
increasing the amount of these neurotransmitters in the brain. It is
contraindicated in pregnancy and liver damage and should be used with caution in
people with cardiovascular or cerebrovascular disorders, dehydration, hypovolemia,
mania, hypomania, suicidal ideation, hepatic cirrhosis, electroconvulsive
therapy, debilitation, and lactation. It has a long half-life (2 to 3 days) and
crosses the placenta. It is metabolized in the liver and produces two active metabolites.
It is excreted in breast milk, urine, and feces.
Adverse effects resemble
those of SSRIs and TCAs, including agitation, confusion, dizziness, GI symptoms
(nausea, vomiting, diarrhea), headache, insomnia, orthostatic hypotension, sedation,
and skin rash. Because of its association with liver failure, serum levels of
liver enzymes (eg, aspartate and alanine aminotransferases [AST and ALT])
should be measured before starting nefazodone therapy, periodically during therapy,
and immediately when symptoms of liver dysfunction (eg, anorexia, nausea,
vomiting, dark urine) develop.
Nefazodone should not be
taken with an MAOI because of the risk of severe toxic effects. If a client on
nefazodone is to be transferred to an MAOI, the nefazodone should be
discontinued at least 7 days before starting the MAOI; if a client on an MAOI
is to be transferred to nefazodone, the MAOI should be discontinued at least 14
days before starting nefazodone. Other potentially serious drug interactions
include increased CNS depression with general anesthetics and decreased
metabolism of drugs metabolized by the cytochrome P450 3A4 enzymes, which are
inhibited by nefazodone.
Trazodone (Desyrel) is used
more often for sedation and sleep than for depression because high doses
(>300 mg/day) are required for antidepressant effects and these amounts
cause excessive sedation for many clients. It is often given concurrently with
a stimulating antidepressant, such as bupropion, fluoxetine, sertraline, or
venlafaxine.
Trazodone is well
absorbed with oral administration, and peak plasma concentrations are obtained
within 30 minutes to 2 hours. It is metabolized by the liver and excreted
primarily by the kidneys. Adverse effects include sedation, dizziness, edema,
cardiac dysrhythmias, and priapism (prolonged and painful penile erection).
Venlafaxine (Effexor)
inhibits the reuptake of norepinephrine, serotonin, and dopamine, thereby
increasing the activity of these neurotransmitters in the brain. The drug
crosses the placenta and may enter breast milk. It is metabolized in the liver
and excreted in urine. It is contraindicated during pregnancy, and women should
use effective birth control methods while taking this drug. Adverse effects
include CNS (anxiety, dizziness, dreams, insomnia, nervousness, somnolence, tremors),
GI (anorexia, nausea, vomiting, constipation, diarrhea), cardiovascular
(hypertension, tachycardia, vasodilation), genitourinary (abnormal ejaculation,
impotence, urinary frequency), and dermatologic (sweating, rash, pruritus)
symptoms.
Venlafaxine does not
interact with drugs metabolized by the
cytochrome P450 system, but it should not be taken concurrently with MAOIs
because of increased serum levels and risks of toxicity. If a client on
venlafaxine is to be transferred to an MAOI, the venlafaxine should be discontinued
at least 7 days before starting the MAOI; if a client on an MAOI is to be
transferred to venlafaxine, the MAOI should be discontinued at least 14 days
before starting venlafaxine.
Mood-Stabilizing Agents
Lithium carbonate (Eskalith) is a
naturally occurring metallic salt that is used in bipolar disorder, mainly to
treat and prevent manic episodes. It is well absorbed after oral
administration, with peak serum levels in 1 to 3 hours after a dose and
steadystate concentrations in 5 to 7 days. Serum lithium concentrations should
be monitored frequently because they vary widely among clients taking similar
doses and because of the narrow range between therapeutic and toxic levels.
Lithium is not
metabolized by the body; it is entirely excreted by the kidneys, so adequate
renal function is a prerequisite for lithium therapy. Approximately 80% of a
lithium dose is reabsorbed in the proximal renal tubules. The amount of
reabsorption depends on the concentration of sodium in the proximal renal
tubules. A deficiency of sodium causes more lithium to be reabsorbed and
increases the risk of lithium toxicity; excessive sodium intake causes more
lithium to be excreted (ie, lithium diuresis) and may lower serum lithium levels
to nontherapeutic ranges.
Before lithium therapy is
begun, baseline studies of renal, cardiac, and thyroid status should be
obtained because adverse drug effects involve these organ systems. Baseline
electrolyte studies are also necessary.
Anticonvulsants are also used as mood stabilizing agents in
bipolar disorder, because they modify nerve cell function. Carbamazepine
(Tegretol) and valproate (Depakene) are commonly used. Newer drugs (eg,
gabapentin, lamotrigine, topiramate, oxcarbazepine) are being used and studied
regarding their effects in bipolar disorder, but none are FDA-approved for this
purpose. Thus far, most of the drugs seem to have some beneficial effects but
additional studies are 
needed.
DRUG SELECTION
Because the available
drugs seem similarly effective, the choice of an antidepressant depends on the
client’s age, medical conditions, previous history of drug response, if any,
and the specific drug’s adverse effects. Cost also needs to be considered. The
newer drugs are much more expensive than the TCAs. However, they may be more cost
effective overall because TCAs are more likely to cause serious adverse
effects, they require monitoring of plasma drug levels and ECGs, and clients
are more likely to stop taking them. Additional guidelines for choosing a drug
include the following:
1. The SSRIs are the drugs of first choice. These drugs are effective
and usually produce fewer and milder adverse effects than other drugs.
Guidelines for choosing one SSRI over another have not been established.
2. With TCAs, initial selection may be based on the client’s
previous response or susceptibility to adverse effects. For example, if a
client (or a close family member) responded well to a particular drug in the
past, that is probably the drug of choice for repeated episodes of depression.
The response of family members to individual drugs may be significant because
there is a strong genetic component to depression and drug response. If therapeutic
effects do not occur within 4 weeks, the TCA probably should be discontinued or
changed, because some clients tolerate or respond better to one TCA than to
another. For a potentially suicidal client, an SSRI or another newer drug is
preferred over a TCA because the TCAs are much more toxic in overdoses.
3. MAOIs are third-line drugs for the treatment of depression
because of their potential interactions with other drugs and certain foods. An
MAOI is most likely to be prescribed when the client does not respond to other
antidepressant drugs or when electroconvulsive therapy is refused or
contraindicated.
4. Criteria for choosing bupropion, mirtazapine, nefazodone, and
venlafaxine are not clearly defined. Bupropion does not cause orthostatic
hypotension or sexual dysfunction. Mirtazapine decreases anxiety, agitation, migraines,
and insomnia, as well as depression. In addition, it does not cause sexual
dysfunction or clinically significant drug–drug interactions. Nefazodone has
sedating and anxiolytic properties that may be useful for clients with severe
insomnia, anxiety, and agitation. However, it has been associated with liver failure
and probably should not be given to clients with significant liver impairment.
In addition, serum nefazodone levels are increased in clients with cirrhosis, and
the drug inhibits cytochrome P450 3A4 enzymes that metabolize many drugs.
Venlafaxine has stimulant effects, increases blood pressure, and causes sexual
dysfunction, but does not cause significant drug–drug interactions
5. For clients with cardiovascular disorders, most
antidepressants can cause hypotension, but the SSRIs, bupropion, nefazodone,
and venlafaxine are rarely associated with cardiac dysrhythmias. Venlafaxine
and MAOIs can increase blood pressure.
6. For clients with seizure disorders, bupropion,
clomipramine, and maprotiline should be avoided; SSRIs, MAOIs, and desipramine
are less likely to cause seizures.
7. For clients with diabetes mellitus, SSRIs may have a hypoglycemic
effect and bupropion and venlafaxine have little effect on blood sugar levels.
8. Lithium is the drug of choice for clients with bipolar disorder.
When used therapeutically, lithium is effective in controlling mania in 65% to
80% of clients. When used prophylactically, the drug decreases the frequency
and intensity of manic cycles. Carbamazepine (Tegretol), an anticonvulsant, may
be as effective as lithium as a mood-stabilizing agent. It is often used in
clients who do not respond to lithium, although it is not FDA approved for that
purpose.
Tranquilizers
Tranquilizers are
depressant drugs that slow down the central nervous system (CNS), and thus are
similar to such other CNS depressants as alcohol and barbituates.
The term
"major tranquilizer" was formerly applied to drugs used to treat
severe mental illnesses, such as schizophrenia. However, these drugs are now
more commonly called neuroleptics; their action specifically relieves the
symptoms of mental illness, and they are rarely misused for other purposes.
This paper therefore deals with the anti-anxiety agents, or anxiolytics
(formerly called "minor" tranquilizers).
Anti-anxiety agents share
many similiarities with barbituates; both are classified as sedative/hypnotics.
These newer agents were introduced under the term "tranquilizer"
because, it was claimed, they provided a calming effect without sleepiness.
Today, tranquilizers have largely replaced barbiturates in the treatment of
both anxiety and insomnia because they are safer and more effective. The degree
of sleepiness induced depends on the dosage. Tranquilizers are also used as
sedatives before some surgical and medical procedures, and they are sometimes
used medically during alcohol withdrawal.
Although tranquilizers do
not exhibit the serious dependence characteristics of barbiturates, they
nevertheless can produce tolerance and dependence. They may also be misused and
abused.
The first drug to be
labelled a tranquilizer was meprobamate - under the trade name Miltown - in
1954. Today, however, the most popular anti-anxiety agents are the
benzodiazepines (e.g. Valium, Halcion, and Ativan). (NOTE that where a drug
name is capitalized, it is a registered trade name of the manufacturer.) Since
the early 1960s, the benzodiazepines have accounted for more than half the
total world sales of tranquilizers. They are currently the most commonly
prescribed class of psychotropic (mood-altering) drugs in Canada.
The first benzodiazepine
developed was chlordiazepoxide, which is sold under such trade names as Librium
and Novopoxide. The next was diazepam; it is marketed, among other brand names,
as Valium, E-Pam, and Vivol. In the early 1970s diazepam was the most widely
prescribed drug in North America. Now Halcion and Ativan - drugs from the same
family as diazepam but eliminated more rapidly from the body - account for most
benzodiazepine prescriptions. There are 14 different benzodiazepines currently
available in Canada. Some are prescribed as anti-anxiety drugs (e.g. Valium,
Librium); others are recommended as sleeping medications (e.g. Dalmane, Somnol,
Novoflupam, and Halcion).
Effects
The effects of any
drug depend on several factors:
- the amount taken at one time.
- the user's past drug experience.
- the manner in which the drug is taken.
- the circumstances under which the drug is taken (the place, the
user's psychological and emotional stability, the presence of other
people, the simultaneous use of alcohol or other drugs, etc.).
With tranquilizers, a
therapeutic dose (i.e. what is medically prescribed) relieves anxiety and may,
in some people, induce a loss of inhibition and a feeling of well-being.
Responses vary, however. Some people report lethargy, drowsiness, or dizziness.
Tranquilizers, though, have very few side effects.
As the dose of a
tranquilizer is increased, so is sedation and impairment of mental acuity and
physical coordination. Lower doses are recommended for older people or for those
with certain chronic diseases, since their bodies tend to metabolize these
drugs more slowly.
Studies show that
anti-anxiety agents, even at the usually recommended and prescribed doses, may
disrupt the user's ability to perform certain physical, intellectual, and
perceptual functions. For these reasons, users should not operate a motor
vehicle or engage in tasks calling for concentration and coordination. Such
activities are particularly hazardous if tranquilizers are used together with
alcohol and/or barbiturates (i.e. other sedative/hypnotics) or antihistamines
(in cold, cough, and allergy remedies). These effects occur early in therapy,
however, and wane over time with increased tolerance (when more of the drug is
needed to produce the same effect).
Because some
tranquilizers (such as diazepam) are metabolized quite slowly, residue can
accumulate in body tissues with long- term use and can heighten such effects as
lethargy and sluggishness.
Toxic Effects
Tranquilizer overdose,
particularly with benzodiazepines, has become increasingly common since the
1960s. While these drugs are usually safe even when an overdose is taken (death
rarely results from benzodiazepine use alone), they can be fatal in combination
with alcohol and other drugs that depress the central nervous system.
In Canada, as elsewhere,
tranquilizer-related poisonings and overdoses have kept pace with the drug's
availability. It is a fact that the drugs used in suicide attempts are those
most widely prescribed and available. (The majority of these drug-related
suicide attempts are by women under 30.)
Tolerance and Dependence
Because tolerance
to the mood-altering effects of tranquilizers can develop with regular use,
higher daily doses become necessary to maintain the desired effects. Tolerance
may occur even at prescribed doses.
Chronic users may become
both psychologically and physically dependent on tranquilizers.
Psychological dependence exists when a
drug is so central to a person's thoughts, emotions, and activities that the
need to continue its use becomes a craving or compulsion.
With chronic use,
especially at higher doses, physical dependence can also occur. The
user's body has adapted to the presence of the drug and suffers withdrawal
symptoms when use is stopped. The frequency and severity of the withdrawal
syndrome depends on the dose, duration of use, and whether use is stopped
abruptly or tapered off. Symptoms range in intensity from progressive anxiety,
restlessness, insomnia, and irritability in mild cases to delirium and convulsions
in severe cases.
Dependence may also occur
following long-term therapeutic use, but withdrawal symptoms in such cases are
mild. Patients complain of gastrointestinal problems, loss of appetite, sleep
disturbances, sweating, trembling, weakness, anxiety, and changes in perception
(e.g. increased sensitivity to light, sound, and smells).
Risk of dependency
increases if tranquilizers are taken regularly for more than a few months,
although problems have been reported within shorter periods. The onset and
severity of withdrawal differ between the benzodiazepines that are rapidly
eliminated from the body (e.g. Halcion) and those that are slowly eliminated
(e.g. Valium). In the former case, symptoms appear within a few hours after
stopping the drug and may be more severe. In the latter case, symptoms usually
take a few days to appear.
CENTRAL NERVOUS SYSTEM
DEPRESSANTS - SEDATIVE - HYPNOTIC AGENTS
CNS depressants slow normal brain function. In higher doses,
some CNS depressants can become general anesthetics. Tranquilizers and
sedatives are examples of CNS depressants. CNS depressants can be divided into
two groups, based on their chemistry and pharmacology:
Barbiturates, such as
mephobarbital (Mebaral) and pentobarbitalsodium (Nembutal), which are used to
treat anxiety, tension, and sleep disorders.
Benzodiazepines, such as
diazepam (Valium), chlordiazepoxide HCl (Librium), and alprazolam (Xanax),
which can be prescribed to treat anxiety, acute stress reactions, and panic
attacks. Benzodiazepines that have a more sedating effect, such as estazolam
(ProSom), can be prescribed for short-term treatment of sleep disorders.
Hypnotic
and sedative drugs are non-selective, general depressants of the central
nervous system. If the dose is relatively low, a sedative action results in a
reduction in restlessness and emotional tension. A larger dose of the same drug
produces a hypnotic sleep inducing effect. As the dosage is increased further,
the result is anesthesia or death if the dosage is sufficiently high.
There are many
CNS depressants, and most act on the brain similarly—they affect the
neurotransmitter gamma-aminobutyric acid (GABA). Neurotransmitters are brain
chemicals that facilitate communication between brain cells. GABA works by
decreasing brain activity. Although different classes of CNS depressants work
in unique ways, ultimately it is their ability to increase GABA activity that
produces a drowsy or calming effect. Despite these beneficial effects for
people suffering from anxiety or sleep disorders, barbiturates and
benzodiazepines can be addictive and should be used only as prescribed.
CNS depressants
should not be combined with any medication or substance that causes sleepiness,
including prescription pain medicines, certain over-the-counter cold and
allergy medications, or alcohol. If combined, they can slow breathing, or slow
both the heart and respiration, which can be fatal.
Discontinuing
prolonged use of high doses of CNS depressants can lead to withdrawal. Because
they work by slowing the brain’s activity, a potential consequence of abuse is
that when one stops taking a CNS depressant, the brain’s activity can rebound
to the point that seizures can occur. Someone thinking about ending their use
of a CNS depressant, or who has stopped and is suffering withdrawal, should
speak with a physician and seek medical treatment.
In addition to
medical supervision, counseling in an in-patient or out-patient setting can
help people who are overcoming addiction to CNS depressants. For example, cognitive-behavioral
therapy has been used successfully to help individuals in treatment for abuse
of benzodiazepines. This type of therapy focuses on modifying a patient’s
thinking, expectations, and behaviors while simultaneously increasing their
skills for coping with various life stressors.
Often the abuse
of CNS depressants occurs in conjunction with the abuse of another substance or
drug, such as alcohol or cocaine. In these cases of polydrug abuse, the
treatment approach should address the multiple addictions.
Barbiturates:
The barbiturates
once enjoyed a long period of extensive use as sedative-hypnotic drugs;
however, except for a few specialized uses, they have been largely replaced by
the much safer benzodiazepines.
Barbiturates are
CNS depressants and are similar, in many ways, to the depressant effects of
alcohol. To date, there are about 2,500 derivatives of barbituric acid of which
only 15 are used medically. The first barbiturate was synthesized from
barbituric acid in 1864. The original use of barbiturates was to replace drugs
such as opiates, bromides, and alcohol to induce sleep.
The hyponotic and
sedative effects produced by barbiturates are usually ascribed to their
interference of nerve transmission to the cortex. Various theories for the action
of barbiturates include: changes in ion movements across the cell membrane;
interactions with cholinergic and non cholinergic receptor sites; impairment of
biochemical reactions which provide energy; and depression of selected areas of
the brain.
The structures of
the barbiturates can be related to the duration of effective action. Although
over 2000 derivatives of barbituric acid have been synthesized only about a
dozen are currently used. All of the barbiturates are related to the structure
of barbituric acid shown below.
The duration of
effect depends mainly on the alkyl groups attached to carbon # 5 which confer
lipid solubility to the drug. The duration of effective action decreases as the
total number of carbons at C # 5 increases. To be more specific, a long effect
is achieved by a short chain and/or phenyl group. A short duration effect
occurs when there are the most carbons and branches in the alkyl chains.
Benzodiazepines:
The term
benzodiazepine refers to the portion of the structure composed of a benzene
ring (A) fused to a seven-membered diazepine ring (B). However, since all of
the important benzodiazepines contain a aryl substituent ring C) and a 1,
4-diazepine ring, the term has come to mean the aryl-1,4-benzodiazepines. There
are several useful benzodiazepines available: chlordiazepoxide (Librium) and
diazapam (Valium).
The actions of
benzodiazepines are a result of increased activation of receptors by
gamma-aminobutyric acid (GABA). Benzodiazepine receptors are located on the
alpha subunit of the GABA receptor located almost exclusively on postsynaptic
nerve endings in the CNS (especially cerebral cortex). Benzodiazepines enhance
the GABA transmitter in the opening of postsynaptic chloride channels which leads
to hyperpolarization of cell membranes. That is, they "bend" the
receptor slightly so that GABA molecules attach to and activate their receptors
more effectively and more often.
Narcotic Analgesic Drugs
Introduction:
Narcotic agents are potent analgesics
which are effective for the relief of severe pain. Analgesics are selective
central nervous system depressants used to relieve pain. The term analgesic
means "without pain". Even in therapeutic doses, narcotic analgesics
can cause respiratory depression, nausea, and drowsiness. Long term
administration produces tolerance, psychic, and physical dependence called
addiction.
Narcotic agents may be classified into
four categories:
1)
Morphine and codeine – natural
alkaloids of opium.
2) Synthetic derivatives of morphine such as heroin.
3) Synthetic agents which resemble the morphine structure.
4) Narcotic antagonists which are used as antidotes for overdoses of narcotic
analgesics.
The main pharmacological action of
analgesics is on the cerebrum and medulla of the central nervous system.
Another effect is on the smooth muscle and glandular secretions of the
respiratory and gastro-intestinal tract. The precise mechanism of action is
unknown although the narcotics appear to interact with specific receptor sites
to interfere with pain impulses.
Natural Peptide
Analgesics - Enkephalins:
Recently investigators have discovered two
compounds in the brain called enkephalins which resemble morphine in structure.
Each one is a peptide composed of 5 amino acids and differ only in the last
amino acid. The peptide sequences are: tyr-gly-gly-phe-leu and
tyr-gly-gly-phe-met. Molecular models show that the structures of the
enkephalins has some similarities with morphine. The main feature in common
appears to be the aromatic ring with the -OH group attached (tyr). Methadone
and other similar analgesics have 2 aromatic rings which would be similar to
the enkephalins (tyr and phe).
Analgesics may relieve
pain by preventing the release of acetylcholine. Enkephalin molecules are
released from a nerve cell and bind to analgesic receptor sites on the nerve
cell sending the impulse. The binding of enkephalin or morphine-like drugs
changes the shape of the nerve sending the impulse in such a fashion as to
prevent the cell from releasing acetylcholine. As a result, the pain impulse
cannot be transmitted and the brain does not preceive pain.
Synthetic narcotic
analgesics may include the following:
Meperidine is the most common subsitute
for morphine. It exerts several pharmacological effects: analgesic, local
anesthetic, and mild antihistamine. This multiple activity may be explained by
its structural resemblance to morphine, atropine, and histamine.
Methadone:
Methadone is more active and more toxic
than morphine. It can be used for the relief of may types of pain. In addition
it is used as a narcotic substitute in addiction treatment because it prevents
morphine abstinence syndrome.
Methadone was synthesized by German
chemists during Wold War II when the United States and our allies cut off their
opium supply. And it is difficult to fight a war without analgesics so the
Germans went to work and synthesized a number of medications in use today,
including demerol and darvon which is structurally simular to methadone. And
before we go further lets clear up another myth. Methadone, or dolophine was
not named after Adolf Hitler. The "dol" in dolophine comes from the
latin root "dolor." The female name Dolores is derived from it and the
term dol is used in pain research to measure pain e.g., one dol is 1 unit of
pain.
Even methadone, which looks strikingly
different from other opioid agonists, has steric forces which produce a
configuration that closely resembles that of other opiates. See the graphic on
the left and the top graphic on this page. In other words, steric forces bend
the molecule of methadone into the correct configuration to fit into the opiate
receptor.
When you take methadone it first must be
metabolized in the liver to a product that your body can use. Excess methadone
is also stored in the liver and blood stream and this is how methadone works
its 'time release trick' and last for 24 hours or more. Once in the blood
stream metabolized methadone is slowly passed to the brain when it is needed to
fill opiate receptors. Methadone is the only effective treatment for heroin
addiction. It works to smooth the ups and down of heroin craving and allows the
person to function nomrally.
Narcotic Antagonists:
Narcotic Antagonists prevent or abolish
excessive respiratory depression caused by the administration of morphine or
related compounds. They act by competing for the same analgesic receptor sites.
They are structurally related to morphine with the exception of the group attached
to nitrogen.
Nalorphine precipitates withdrawal
symptoms and produces behavioral disturbances in addition to the antogonism
action. Naloxane is a pure antagonist with no morphine like effects. It blocks
the euphoric effect of heroin when given before heroin.
Naltrexone became clinically available in
1985 as a new narcotic antagonist. Its actions resemble those of naloxone, but
naltrexone is well is well absorbed orally and is long acting, necessitating
only a dose of 50 to 100 mg. Therefore, it is useful in narcotic treatment
programs where it is desired to maintain an individual on chronic therapy with
a narcotic antagonist. In individuals taking naltrexone, subsequent injection
of an opiate will produce little or no effect. Naltrexone appears to be particularly
effective for the treatment of narcotic dependence in addicts who have more to
gain by being drug-free rather than drug dependant.
General Anesthesia
General anesthesia can be
used for almost any surgical, diagnostic, or therapeutic procedure. If a
medical disorder of a vital organ system (cardiovascular, respiratory, renal)
is present, it should be corrected before anesthesia, when possible. General anesthesia
and major surgical procedures have profound effects on normal body functioning.
When alterations due to other disorders are also involved, the risks of
anesthesia and surgery are greatly increased. Because of the risks, general anesthetics
and neuromuscular blocking agents should be given only by people with
special training in correct usage and only in locations where staff,
equipment, and drugs are available for emergency use or cardiopulmonary
resuscitation.
Regional and Local Anesthesia
Unlike other
drugs which act in the region of the synapse, local anesthetics are agents that
reversibly block the generation and conduction of nerve impulses along a nerve
fiber. They depress impulses from sensory nerves of the skin, surfaces of
mucosa, and muscles to the central nervous system. These agents are widely used
in surgery, dentistry, and ophthalmology to block transmission of impulses in
peripheral nerve endings.
Most local
anesthetics can be represented by the following general formula. In both the
official chemical name and the proprietary name, a local anesthetic drug can be
recognized by the "-caine" ending.
The ester linkage
can also be an amide linkage. The most recent research indicates that the local
anesthetic binds to a phospholipid in the nerve membrane and inhibits the
ability of the phospholipid to bind Ca+2 ions.
Practically all of the
free-base forms of the drugs are liquids. For this reason most of these drugs
are used as salts (chloride, sulfate, etc.) which are water soluble, odorless,
and crystalline solids. As esters these drugs are easily hydrolyzed with
consequent loss of activity. The amide form of the drug is more stable and
resistant to hydrolysis
Regional or local
anesthesia is usually safer than general anesthesia because it produces fewer
systemic effects. Forexample, spinal anesthesia is often the anesthesia of choice
for surgery involving the lower abdomen and lower extremities, especially in
people who are elderly or have chronic lung disease. A major advantage of
spinal anesthesia is that it causes less CNS and respiratory depression.
Guidelines for injections
of local anesthetic agents include the following:
1. Local anesthetics should be injected only by people
with special training in correct usage and only in locations where
staff, equipment, and drugs are available for emergency use or cardiopulmonary
resuscitation.
2. Choice of a local anesthetic depends mainly on the reason for
use or the type of regional anesthesia desired. Lidocaine, one of the most
widely used, is available in topical and injectable forms.
3. Except with IV lidocaine for cardiac dysrhythmias, local
anesthetic solutions must not be injected into blood vessels because of the
high risk of serious adverse reactions involving the cardiovascular system and
CNS. To prevent accidental injection into a blood vessel, needle placement must
be verified by aspirating before injecting the local anesthetic solution. If blood
is aspirated into the syringe, another injection site must be selected.
4. Local anesthetics given during labor cross the placenta and
may depress muscle strength, muscle tone, and rooting behavior in the newborn.
Apgar scores are usually normal. If excessive amounts are used (eg, in
paracervical block), local anesthetics may cause fetal bradycardia, increased
movement, and expulsion of meconium before birth and marked depression after
birth. Dosage used for spinal anesthesia during labor is too small to depress
the fetus or the newborn.
5. For spinal or epidural anesthesia, use only local
anesthetic solutions that have been specifically prepared for spinal anesthesia
and are in single-dose containers. Multiple-dose containers are not used
because of the risk of injecting contaminated solutions.
6. Epinephrine is often added to local anesthetic solutions to
prolong anesthetic effects. Such solutions require special safety precautions,
such as the following:
a. This combination of drugs should not be used for nerve
blocks in areas supplied by end arteries (fingers, ears, nose, toes, penis)
because it may produce ischemia and gangrene.
b. This combination should not be given IV or in excessive dosage
because the local anesthetic and epinephrine can cause serious systemic
toxicity, including cardiac dysrhythmias.
c. This combination should not be used with inhalation anesthetic
agents that increase myocardial sensitivity to catecholamines. Severe
ventricular dysrhythmias may result.
d. These drugs should not be used in clients with severe cardiovascular
disease or hyperthyroidism.
e. If used in obstetrics, the concentration of epinephrine should
be no greater than 1:200,000 because of the danger of producing
vasoconstriction in uterine blood vessels. Such vasoconstriction may cause
decreased placental circulation, decreased intensity of
uterine contractions, and prolonged labor.
Valerian is a
central nervous system relaxer, and as such has been used as a calming sleep
aid for over 1,000 years. When taken in the proper dosage, Valerian can
induce restful sleep without grogginess the next morning, unlike prescription
drugs that mimic it's properties, such as Valium. It is also much safer
when used with alcohol, as it doesn't magnify the effects of alcohol as do it's
prescription counterparts. It is widely used in Europe, and is rapidly
gaining popularity in the United States as more people discover it's beneficial
properties.
Valerian root is
the part of the plant that is used for medicinal purposes. The root can
be distilled into oils and ointments, or dried and used in teas or
capsules. Please see the links below for specifics on how to make fresh
or dried root into homemade medications. Obviously, you can also buy
prepared Valerian online or at any health food store.
Valerian has a
fairly wide range of uses in the home medicine cabinet. It is an
effective stress reducer, and has benefit in cases of nervous tension,
depression, irritability, hysteria, panic, anxiety, fear, stomach cramping,
indigestion due to nervousness, delusions, exhaustion, and, of course, nervous
sleeplessness. It also appears to have real benefits in cases of
sciatica, multiple sclerosis, epilepsy, shingles, and peripheral neuropathy,
including numbness, tingling, muscle weakness, and pain in the
extremities. Testing has also revealed that it eases muscle cramping,
rheumatic pain, migraines, uterine cramps, intestinal colic, and stress-related
heart problems and hypertension. It has shown some benefit in behavioral
problems in both adults and children, and is used to treat attention deficit
disorders, hyperactivity, anxiety headaches, and bedwetting, and it has shown
some promise in helping reduce thumb sucking and nail biting in children.
It has a stabilizing effect on blood pressure and can help regulate
arrhythmias.
Lastly, Valerian
is useful as a digestive aid, is helpful in cases of gas, diarrhea, and cramps,
and alleviates the pain of ulcers. In the respiratory tract, it is
believed to be of benefit in reducing the discomfort of asthma
attacks.
Valerian is
contraindicated in pregnant and breast feeding women, but otherwise is a safe
herb to use intermittently when needed for stress or sleep related problems.
It is not recommended that you use it every day, however. Overdose is
unlikely, so experiment with dosages that work best for you. The usual
dose with an oil is 1 teaspoon as needed, and with a tea or capsule, 1-2
cups or tablets as needed.
CLINICAL PHARMACOLOGY OF DRUGS FOR GASTROINTESTINAL
DISORDERS
Drugs used in digestive
disorders primarily alter GI secretion, absorption, or
motility. They may act systemically or locally in the GI
tract. The drug groups included in this section are drugs used
for acid-peptic disorders, laxatives, antidiarrheals, and antiemetics.
Other drug groups used in GI disorders include
cholinergics, anticholinergics, corticosteroids, and antiinfective drugs.
Drugs used in Dyspepsia and Peptic Ulcer Disease
There are three
major landmarks in the management of peptic ulcer disease. The first was the
introduction of the H2 receptor antagonists
(H2RA) of which the first was cimetidine. This gave
effective acid suppression for the first time.
Drug Category: H2-receptor
antagonists
Inhibit the action of histamine on the parietal
cell, which inhibits acid secretion. The 4 drugs in this class are all equally
effective and are available over the counter in half prescription strength for
heartburn treatment. Although the IV administration of H2 blockers may be used
to treat acute complications (eg, GI bleeding), the benefits are yet to be
proven.
|
Drug Name |
Cimetidine (Tagamet) |
|
Description |
Inhibits histamine at
H2 receptors of the gastric parietal cells, resulting in reduced gastric acid
secretion, gastric volume, and hydrogen ion concentrations. |
|
Adult Dose |
150 mg PO qid; not to
exceed 600 mg/d |
|
Pediatric Dose |
Not established |
|
Contraindications |
Documented
hypersensitivity |
|
Interactions |
Can increase blood
levels of theophylline, warfarin, tricyclic antidepressants, triamterene,
phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine |
|
Pregnancy |
B - Usually safe but
benefits must outweigh the risks. |
|
Precautions |
Elderly patients may
experience confusional states; may cause impotence and gynecomastia in young
males; may increase levels of many drugs; adjust dose or discontinue
treatment if changes in renal function occur |
|
Drug Name |
Famotidine (Pepcid) |
|
Description |
Competitively inhibits
histamine at the H2 receptor of the gastric parietal cells, resulting in
reduced gastric acid secretion, gastric volume, and reduced hydrogen
concentrations. |
|
Adult Dose |
40 mg PO qhs |
|
Pediatric Dose |
Not established |
|
Contraindications |
Documented
hypersensitivity |
|
Interactions |
May decrease effects of
ketoconazole and itraconazole |
|
Pregnancy |
B - Usually safe but
benefits must outweigh the risks. |
|
Precautions |
If changes in renal
function occur during therapy, consider adjusting dose or discontinuing
treatment |
|
Drug Name |
Nizatidine (Axid) |
|
Description |
Competitively inhibits
histamine at H2 receptors of gastric parietal cells, resulting in reduced
gastric acid secretion, gastric volume, and reduced hydrogen concentrations. |
|
Adult Dose |
300 mg PO hs or 150 mg
PO bid |
|
Pediatric Dose |
Not established |
|
Contraindications |
Documented
hypersensitivity |
|
Interactions |
None reported |
|
Pregnancy |
B - Usually safe but
benefits must outweigh the risks. |
|
Precautions |
Caution in renal or
liver impairment; if changes in renal function occur during therapy, consider
adjusting dose or discontinuing treatment |
|
Drug Name |
Ranitidine (Zantac) |
|
Description |
Competitively inhibits
histamine at the H2 receptors of gastric parietal cells, resulting in reduced
gastric acid secretion, gastric volume, and reduced hydrogen concentrations. |
|
Adult Dose |
150 mg PO bid or 300 mg
PO qhs; not to exceed 300 mg/d |
|
Pediatric Dose |
<12 years: Not
established |
|
Contraindications |
Documented
hypersensitivity |
|
Interactions |
May decrease effects of
ketoconazole and itraconazole; may alter serum levels of ferrous sulfate,
diazepam, nondepolarizing muscle relaxants, and oxaprozin |
|
Pregnancy |
B - Usually safe but
benefits must outweigh the risks. |
|
Precautions |
Caution in renal or liver
impairment; if changes in renal function occur during therapy, consider
adjusting dose or discontinuing treatment |
The second was the
introduction of the proton pump inhibitors
(PPI) of which omeprazole was the first.
This gave more profound and more prolonged suppression of gastric acid.
Drug Category: Proton
pump inhibitors
Bind to the proton pump of parietal cell,
inhibiting secretion of hydrogen ions into gastric lumen. Proton pump
inhibitors relieve pain and heal peptic ulcers more rapidly than H2 antagonists
do. Drugs in this class are equally effective. They all decrease serum
concentrations of drugs that require gastric acidity for absorption, such as
ketoconazole or itraconazole. Five drugs are now FDA approved in this category.
Omeprazole will soon go off patent and be available as a generic.
|
Drug Name |
Lansoprazole (Prevacid) |
|
Description |
Decreases gastric acid
secretion by inhibiting the parietal cell H+/K+ ATP
pump. |
|
Adult Dose |
30 mg PO qd for 4-8 wk |
|
Pediatric Dose |
Not established |
|
Contraindications |
Documented
hypersensitivity |
|
Interactions |
May decrease effects of
ketoconazole and itraconazole; may increase theophylline clearance |
|
Pregnancy |
B - Usually safe but
benefits must outweigh the risks. |
|
Precautions |
Adjust dose in liver
impairment |
|
Drug Name |
Omeprazole (Prilosec) |
|
Description |
Decreases gastric acid
secretion by inhibiting the parietal cell H+/K+ ATP
pump. |
|
Adult Dose |
20 mg PO qd for 4-8 wk |
|
Pediatric Dose |
Not established |
|
Contraindications |
Documented
hypersensitivity |
|
Interactions |
May decrease effects of
itraconazole and ketoconazole; may increase toxicity of warfarin, digoxin,
and phenytoin |
|
Pregnancy |
C - Safety for use
during pregnancy has not been established. |
|
Precautions |
Bioavailability may be
increased in elderly patients |
|
Drug Name |
Esomeprazole (Nexium) |
|
Description |
S-isomer of omeprazole.
Decreases gastric acid secretion by inhibiting the parietal cell H+/K+
ATP pump. |
|
Adult Dose |
20-40 mg PO qd |
|
Pediatric Dose |
Not established |
|
Contraindications |
Documented
hypersensitivity |
|
Interactions |
Amoxicillin or
clarithromycin may increase plasma levels of esomeprazole when used
concurrently; may reduce absorption of dapsone; may increase levels of
diazepam and GI absorption of digoxin; may decrease absorption of iron,
ketoconazole and itraconazole |
|
Pregnancy |
C - Safety for use
during pregnancy has not been established. |
|
Precautions |
Symptomatic relief with
proton pump inhibitors may mask symptoms of gastric malignancy |
|
Drug Name |
Rabeprazole (Aciphex) |
|
Description |
Decreases gastric acid
secretion by inhibiting the parietal cell H+/K+ ATP
pump. For short-term (4-8 wk) treatment and symptomatic relief of gastritis. |
|
Adult Dose |
20 mg tab PO qd 4-8 wk |
|
Pediatric Dose |
Not established |
|
Contraindications |
Documented
hypersensitivity |
|
Interactions |
May decrease effects of
itraconazole and ketoconazole; may increase toxicity of warfarin, digoxin,
and phenytoin |
|
Pregnancy |
B - Usually safe but
benefits must outweigh the risks. |
|
Precautions |
Symptomatic relief with
proton pump inhibitors may mask symptoms of gastric malignancy |
|
Drug Name |
Pantoprazole (Protonix) |
|
Description |
Decreases gastric acid
secretion by inhibiting the parietal cell H+/K+ ATP
pump. For short-term (4-8 wk) treatment and symptomatic relief of gastritis. |
|
Adult Dose |
40 mg PO qd |
|
Pediatric Dose |
Not established |
|
Contraindications |
Documented
hypersensitivity |
|
Interactions |
May decrease effects of
itraconazole and ketoconazole; may increase toxicity of warfarin, digoxin,
and phenytoin |
|
Pregnancy |
C - Safety for use
during pregnancy has not been established. |
|
Precautions |
Symptomatic relief with
proton pump inhibitors may mask symptoms of gastric malignancy |
The third was the
discovery that Helicobacter pylori is associated with much peptic ulcer
disease, and with this came the rationale for eradication of the organism. As a
result of these innovations, the need for surgery for peptic ulcer has been
dramatically reduced. H pylori infection is associated with about 95% of duodenal ulcers
and 80% of gastric ulcers.
The remainder are mainly related to NSAIDs. Biphosphonates and corticosteroids may also be
implicated.
Indications
· Symptomatic
management of ulcer dyspepsia and non-ulcer dyspepsia
· Healing of
gastric or duodenal ulcers
· Eradication of
Helicobacter pylori
· Healing of ulcers
related to drugs. This is usually the NSAIDs and in some cases it may be
desirable to continue the drug and to give something to heal the ulcers.
Contraindications
· Many of the drugs
used in the management of peptic ulcer disease carry a warning that they should
not be used in pregnancy or whilst breast feeding. This is usually because of
lack of information about safety in pregnancy rather than evidence of adverse
effects in pregnancy.
· The exception is misoprostol, a
prostaglandin analogue, that should be avoided in pregnancy as it may cause
abortion. Indeed, gynaecologists sometimes use it for that end.
· If H pylori
eradication is used, it may be necessary to avoid a certain antibiotic if the
patient is allergic. For example, amoxicillin may be replaced
by either metronidazole or
tetracycline.
Caution
·
Beware of the possibility of failing to diagnose
gastric malignancy.
·
PPIs are metabolised mostly in the liver. In
liver disease, do not exceed the following doses:
o
20mg daily for omeprazole, pantoprazole, and esomeprazole;
o
30mg daily for lansoprazole
o
There are no data on the use of rabeprazole in people with
severe hepatic impairment so the manufacturer advises caution.
·
Omeprazole and esomeprazole may interfere with warfarin monitoring.
·
If metronidazole is used, remember to warn the
patient to avoid alcohol.
The article on peptic ulcer disease
includes a list of warning signs that may suggest that the patient has a
gastric malignancy rather than a peptic ulcer. Malignancy needs to be diagnosed
and treated accordingly. Acid suppression will ease the pain of gastric carcinoma and in
doing so may delay diagnosis. Acid suppression in malignancy is not
contraindicated. It can give in relief in palliative care. Care is
required so as not to miss the diagnosis.
Initiation
of treatment
Management is not just
pharmacological but should include attention to lifestyle. This may include stopping
smoking, more regular meals, ceasing excessive alcohol consumption and possibly
stopping drugs that may be contributing to the problem. There may be times that
it is necessary to continue these drugs but treatment may be given to heal
ulcers and to prevent recurrence.
Choice
of treatment
·
Antacids are cheap, simple and may be all that is
required for relief of occasional symptoms. Most antacids contain a mixture of
aluminium hydroxide that tends to cause constipation and magnesium hydroxide
that tends to cause diarrhoea. The balance between the two cannot be assured
and there may be disturbance of bowel function. If a large amount of antacid is
being consumed, consider acid suppression. The BNF advises that complexes such
as hydrotalcite confer no special advantage.
·
The H2RAs provide a swift and effective means of
acid suppression and can be used intermittently to achieve control of symptoms.
The PPIs are more prolonged in action, produce more profound acid suppression
and are more expensive. Their greater efficacy may still provide value for
money.
·
Attempts should be made to eradicate Helicobacter
pylori whenever it is found, whether the diagnosis is duodenal ulcer, gastric
ulcer, NSAID induced ulcer or even non-ulcer dyspepsia.
·
Only chelated bismuth should be used. It
is rather unpleasant to take but it is effective at helping to eradicate H
pylori and may have a place in second line treatment after previous failure of
eradication.
·
Misoprostol tends to be used to heal NSAID
associated ulcers. Using a prostaglandin analogue to heal ulcers caused by
prostaglandin antagonism is logical but it does tend to cause diarrhoea too and
may be unacceptable. Proprietary combinations of NSAID with misoprostol are
available.
·
Prokinetic agents have fallen from favour. NICE
says that cisapride is no longer licenced whilst the evidence for
metoclopramide and domperidone is limited.1
Symptomatic relief
Simple antacids will usually give symptomatic relief of fairly
short duration. However, such relief is very non-specific and should not be
taken as indicative of peptic ulcer disease. Heartburn may also occur in this
condition although it is more typical of gastro-oesophageal reflux disease.
An antacid alginate mixture is usually
preferred for reflux.
More profound and prolonged acid suppression may be achieved with a H2RA or,
better still, a PPI. The problem is that if the patient is due for endoscopy,
the ulcer may heal before the investigation is performed. It may also interfere
with the diagnosis of H pylori infection.2
Ulcer healing
Both H2RAs and PPIs are usually produced at a standard dose and a
lower (half) dose. Some may also be produced at a higher dose that is usually
reserved for gastro-oesophageal reflux disease. To a considerable extent, the
PPIs have superseded the H2RAs as they are more potent and have a longer
effect, although the H2RAs are cheaper.
Clinical Knowledge Summaries recommend that if an ulcer is proven but H pylori
testing is negative, then acid suppression at full dose should be offered for 1
or 2 months. A lower maintainance dose may be continued after. The full course
should be taken as there is little correlation between the relief of symptoms
and the healing of ulcers and if medication is stopped too soon the ulcer will
relapse.
Helicobacter pylori eradication
The article on
Helicobacter pylori gives much more detail about the diagnosis and treatment of
the infection, including follow up. If the infection is suspected or
demonstrated, then eradication is the logical course of action. NICE suggests
that eradication should be offered if a test is positive1 and they give grade A level of
evidence. Clinical Evidence suggests that even in the absence of a
history of ulceration, that the finding of the infection should lead to
eradication. It is effective in non-ulcer dyspepsia. There are several regimes that are available. They usually consist of
high dose acid suppression with a PPI and two antibiotics, also at quite high
dose. The usual recommended duration of treatment is 7 days and it is said to
give eradication in about 90% of cases. A 14 days course may produce a higher
rate of eradication but the incidence of adverse effects may make compliance
poor. Diarrhoea is common with two antibiotics at high dose. The BNF states
that 2 week regimens using a proton pump inhibitor and a single antibacterial
are licensed, but produce low rates of eradication and are not recommended.
The following is based on the recommendations of Helicobacter pylori eradication
:
|
·
omeprazole 20mg ·
amoxicillin 1000mg ·
clarithromycin 500mg, all
twice daily for 7 days. An alternative regimen with a similar eradication rate of around
90% is: ·
omeprazole 20mg ·
clarithromycin 250mg ·
metronidazole 400mg, again all twice daily for
7 days. |
There is probably no difference between the various PPIs
available, provided that they are used at equivalent dose and this is a matter
of personal choice. It would be reasonable to have local protocols based upon
local patterns of antibiotic resistance. Resistance to metronidazole, in
particular, is highly variable.If there is failure of treatment, this is
usually due to poor compliance or antibiotic resistance. The latter can even
develop during treatment, especially with a single antibiotic. A further
attempt at eradication may be made. The regimen should be adjusted according to
the nature of the problem. If it was poor compliance, a more tolerable regimen
may be required. If there is antibiotic resistance and the organism has been
cultured after endoscopy, it may be possible to obtain sensitivities. It is
common practice to use 4 drugs for a repeated attempt. The antibiotics can be
changed and chelated bismuth may be used. A
typical quadruple therapy would be:
· a PPI twice a day
· bismuth 120 mg
four times a day
· metronidazole 400
mg three times a day
· oxytetracycline 500 mg four
times a day, all for 7 days.
Reinforce the importance of compliance as it is not easy to take
so many tablets so many times a day, even for just a week.
Ulcers associated with NSAIDs
If a drug is thought to be the cause
of peptic ulceration, it is sensible to stop the drug or change it to another
with a lower risk. There may be times when it is desirable to continue that
drug. An old person may need treatment for arthritis to maintain mobility or aspirin may be required in
cardiovascular disease. It is often possible to heal the ulcer without stopping
the offending drug and a maintenance dose is continued to prevent relapse.
· Clinical
Knowledge Summaries recommend that omeprazole 20mg daily is preferable to ranitidine 150mg twice
daily as the respective rates of healing are 80% and 63%.
· H2RAs are slow to
heal the ulcers if the offending drug is not stopped and so, under these
conditions, a PPI is preferred.
· H pylori
eradication is no more effective than omeprazole alone to heal ulcers, but if
the infection is present, then eradication will reduce the rate of relapse.
· H pylori is not
associated with an increased risk of ulcer with NSAIDs in the elderly but there
is an increased risk of bleeding.
Drug Category: Prostaglandins
Can prevent peptic ulcers in patients taking
NSAIDs and may be used with NSAIDs in patients at a high risk of complications.
|
Drug Name |
Misoprostol (Cytotec) |
|
Description |
A prostaglandin analog
that protects the lining of the GI tract by replacing depleted prostaglandin
E1 in prostaglandin inhibiting therapies. |
|
Adult Dose |
200 mcg PO qid with
food; if not tolerated, decrease to 100 mcg qid or 200 mcg bid with food |
|
Pediatric Dose |
Not established |
|
Contraindications |
Documented
hypersensitivity |
|
Interactions |
None reported |
|
Pregnancy |
X - Contraindicated in
pregnancy |
|
Precautions |
Caution with elderly
patients and in renal impairment |
Misoprostol is a prostaglandin analogue that is both an
antisecretory and a protective agent for the healing of both gastric and
duodenal ulcers. Its use is limited as diarrhoea is a common adverse effect and
acid suppression tends to be better tolerated. Only the higher doses of
misoprostol match acid suppression for efficacy.
Monitoring
Patients should be reviewed at the end of a course of treatment,
especially H pylori eradication, to confirm a satisfactory outcome.
|
Repeat endoscopy may be
required for: ·
Failure to eradicate symptoms in a duodenal
ulcer. ·
Failure to have eradicated H pylori. ·
Follow up of a gastric ulcer requires repeat
endoscopy to confirm healing at 6 to 8 weeks along with confirmation of
eradication of H pylori. ·
NSAID induced ulcers should be treated
according to whether they are gastric or duodenal. If a gastric ulcer persists, referral to secondary care is
required. If it is healed but symptoms persist, a course of acid suppression
for a limited duration may be in order but if symptoms persist, referral is
necessary. |
If simple acid suppression is given, review after 1 or 2 months is required to
ascertain that the end is being achieved and there are no warning signs such as
weight loss to suggest malignancy.
Complications
and reasons to discontinue drug
It may be necessary to stop treatment if adverse effects become
intolerable or are of a serious nature.
· During H pylori
eradication, abdominal discomfort and diarrhoea are very common but the patient
should be encouraged to persist to achieve eradication and to heal the ulcer
permanently. Lactobacilli, usually ingested
in the form of natural unpasteurised yoghurt, may be of value in replacing the
natural flora of the gut and they may also have a suppressive effect on H
pylori.8
· Adverse reactions
to PPIs and H2RAs are usually rare and mild but severe problems can arise. Rare
but not serious problems may include taste disturbance, peripheral oedema,
photosensitivity, fever, arthralgia, myalgia and sweating. Serious problems
include liver dysfunction, hypersensitivity reactions (including urticaria, angioedema, bronchospasm, anaphylaxis), depression, interstitial nephritis,
blood disorders (including leucopenia, leucocytosis, pancytopenia,
thrombocytopenia), and skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis,
bullous eruption).
· Misoprostol often
causes diarrhoea and abdominal pain, especially at higher doses.
Treatment goals are the
relief of discomfort and protection of the gastric mucosal barrier to promote
healing. Eradication of H pylori infection is a prolonged and complicated
process requiring confirmation of the presence of the organism, which is beyond
the scope of practice in the ED. Cessation of the causative agent and antacids
may be sufficient outpatient therapy in mild cases. Most patients require an
H2-receptor antagonist or a proton pump inhibitor, which has been proven to
provide faster and more reliable healing than antacids. Either an H2-receptor
blocker or a proton pump inhibitor can be used as a first-line agent. With
continued symptoms, they may be used together. In refractory cases, sucralfate
also may be indicated.
Drug Category: Antacids
Aluminum-containing and magnesium-containing
antacids can be helpful in relieving symptoms of gastritis by neutralizing
gastric acids. These agents are inexpensive and safe.
|
Drug Name |
Aluminum and magnesium
hydroxide (Maalox, Mylanta) |
|
Description |
Neutralizes gastric
acidity, resulting in increase in stomach and duodenal bulb pH. Aluminum ions
inhibit smooth muscle contraction, thus inhibiting gastric emptying. Magnesium
and aluminum antacid mixtures are used to avoid bowel function changes. |
|
Adult Dose |
2-4 tsp PO qid prn |
|
Pediatric Dose |
0.5 mL/kg PO qid prn |
|
Contraindications |
Documented
hypersensitivity |
|
Interactions |
Both drugs reduce
efficacy of fluoroquinolones, corticosteroids, benzodiazepines, and
phenothiazines; aluminum and magnesium potentiate effects of valproic acid,
sulfonylureas, quinidine, and levodopa |
|
Pregnancy |
C - Safety for use
during pregnancy has not been established. |
|
Precautions |
Use aluminum containing
antacids with caution in patients who have recently suffered a massive upper
GI hemorrhage |
Drug Category: Gastrointestinal
agents
Are effective in the treatment of peptic ulcers
and in preventing relapse. Their mechanism of action is not clear. Multiple
doses are required, and they are not as effective as the other options.
|
Drug Name |
Sucralfate (Carafate) |
|
Description |
Binds with positively
charged proteins in exudates and forms a viscous adhesive substance that
protects the GI lining against pepsin, peptic acid, and bile salts. Used for
short-term management of ulcers. |
|
Adult Dose |
|
|
Pediatric Dose |
Not established |
|
Contraindications |
Documented
hypersensitivity |
|
Interactions |
May decrease effects of
ketoconazole, ciprofloxacin, tetracycline, phenytoin, warfarin, quinidine,
theophylline, and norfloxacin |
|
Pregnancy |
B - Usually safe but
benefits must outweigh the risks. |
|
Precautions |
Caution in renal
failure and impaired excretion of absorbed aluminum |
LAXATIVES AND CATHARTICS
Laxatives and
cathartics are somewhat arbitrarily classified as bulk-forming
laxatives, surfactant laxatives or stool softeners, saline
cathartics, stimulant cathartics, lubricant or emollient laxatives, and
miscellaneous. Individual drugs are listed in Drugs at a
Glance: Laxatives and Cathartics.
Bulk-Forming Laxatives
Bulk-forming laxatives
(eg, polycarbophil, psyllium seed) are substances that are
largely unabsorbed from the intestine. When water is
added, these substances swell and become gellike. The added bulk or
size of the fecal mass stimulates peristalsis and defecation.
The substances also may act by pulling water into the
intestinal lumen. Bulk-forming laxatives are the most
physiologic laxatives because their effect is similar to that of
increased intake of dietary fiber. They usually act within 12 to 24
hours, but may take as long as 2 to 3 days to exert their full
effects.
Surfactant Laxatives
(Stool Softeners)
Surfactant laxatives (eg,
docusate calcium, potassium, or sodium) decrease the
surface tension of the fecal mass to allow water to penetrate
into the stool. They also act as a detergent to facilitate
admixing of fat and water in the stool. As a result, stools
are softer and easier to expel. These agents have little if
any laxative effect. Their main value is to prevent straining while
expelling stool. They usually act within 1 to 3 days and
should be taken daily.
Saline Laxatives
Saline laxatives (eg,
magnesium citrate, milk of magnesia) are not well absorbed
from the intestine. Consequently, they increase osmotic
pressure in the intestinal lumen and cause water to be
retained. Distention of the bowel leads to increased peristalsis and
decreased intestinal transit time for the fecal mass. The
resultant stool is semifluid. These laxatives are used when
rapid bowel evacuation is needed. With oral magnesium
preparations, effects occur within 0.5 to 6 hours; with sodium
phosphate–containing rectal enemas, effects occur within 15
minutes.
Saline laxatives are
generally useful and safe for shortterm treatment of
constipation, cleansing the bowel prior to endoscopic
examinations, and treating fecal impaction. However, they are not safe
for frequent or prolonged usage or for certain patients
because they may produce fluid and electrolyte imbalances. For
example, patients with impaired renal function are at
risk of developing hypermagnesemia with magnesium-containing
laxatives because some of the magnesium is absorbed
systemically. Patients with congestive heart failure are
at risk of fluid retention and edema with sodium-containing
laxatives.
Polyethylene
glycol–electrolyte solution (eg, NuLytely) is a
nonabsorbable oral solution that induces diarrhea within 30 to 60 minutes
and rapidly evacuates the bowel, usually within 4 hours.
It is a prescription drug used for bowel cleansing before
GI examination (eg, colonoscopy) and is contraindicated
with GI obstruction, gastric retention, colitis, or bowel
perforation.
Polyethylene glycol
solution (MiraLax) is an oral laxative that may be used
to treat occasional constipation. Effects may require 2 to 4
days. It is a prescription drug and should not be taken longer than
2 weeks.
Stimulant Cathartics
The stimulant cathartics
are the strongest and most abused laxative products. These
drugs act by irritating the GI mucosa and pulling water
into the bowel lumen. As a result, feces are moved through the
bowel too rapidly to allow colonic absorption of fecal water,
so a watery stool is eliminated. These drugs should not
be used frequently or longer than 1 week because they may produce
serum electrolyte and acid–base imbalances (eg,
hypocalcemia, hypokalemia, metabolic acidosisbor alkalosis). Oral stimulant cathartics include bisacodyl, cascara sagrada, castor oil, and senna products. These products produce laxative effects in 6 to 12 hours. As a result, a single bedtime dose usually produces a morning bowel movement. Rectal suppository products include bisacodyl, which produces effectsbwithin 15 minutes to 2 hours, and glycerin. In addition to
irritant, stimulant effects, glycerin exerts
hyperosmotic effects in the colon. It usually
acts within 30 minutes. Glycerin is not given orally for
laxative effects.
Lubricant Laxative
Mineral oil is the only
lubricant laxative used clinically. It lubricates the fecal mass
and slows colonic absorption of water from the fecal
mass, but the exact mechanism of action is unknown. Effects usually
occur in 6 to 8 hours. Oral mineral oil may cause several
adverse effects and is not recommended for long-term
use. Mineral oil enemas are sometimes used to soften fecal
impactions and aid their removal.
Miscellaneous Laxatives
Lactulose is a disaccharide
that is not absorbed from the GI tract. It exerts laxative
effects by pulling water into the intestinal lumen. It is used
to treat constipation and hepatic encephalopathy. The
latter condition usually results from alcoholic liver disease in
which ammonia accumulates and causes stupor or coma. Ammonia
is produced by metabolism of dietary protein and intestinal
bacteria. Lactulose decreases production of ammonia in the
intestine. The goal of treatment is usually to maintain two to
three soft stools daily; effects usually occur within 24 to 48
hours. The drug should be used cautiously because it may produce
electrolyte imbalances and dehydration.
Sorbitol is a
monosaccharide that pulls water into the intestinal lumen and has
laxative effects. It is often given with sodium
polystyrene sulfonate (Kayexalate), a potassiumremoving resin used to
treat hyperkalemia, to prevent constipation and aid expulsion
of the potassium–resin complex.
Laxative Abuse
Laxatives and cathartics
are widely available on a nonprescription basis and are
among the most frequently abused drugs. One reason for
overuse is the common misconception that a daily bowel
movement is necessary for health and wellbeing, even with little
intake of food or fluids. This notion may lead to a
vicious cycle of events in which a person fails to have a bowel
movement, takes a strong laxative, again fails to have a bowel
movement, and takes another laxative before the fecal column
has had time to become reestablished (2 to 3 days with
normal food intake). Thus, a pattern of laxative dependence and
abuse is established.
Laxatives are also abused
for weight control, probably most often by people with
eating disorders and those who must meet strict weight
requirements (eg, some athletes). This is a very dangerous
practice because it may lead to lifethreatening fluid and
electrolyte imbalances.
Indications for Use
Despite widespread abuse
of laxatives and cathartics, there are several rational
indications for use:
1. To relieve constipation in pregnant
women, elderly clients whose abdominal and perineal
muscles have become weak and atrophied, children with
megacolon, and clients receiving drugs that decrease
intestinal motility (eg, opioid analgesics, drugs
with anticholinergic effects)
2. To prevent straining at stool in
clients with coronary artery disease (eg,
postmyocardial infarction), hypertension, cerebrovascular
disease, and hemorrhoids and other rectal conditions
3. To empty the bowel in preparation for
bowel surgery or diagnostic procedures (eg, colonoscopy,
barium enema)
4. To accelerate elimination of
potentially toxic substances from the GI tract (eg,
orally ingested drugs or toxic compounds)
5. To prevent absorption of intestinal
ammonia in clients with hepatic
encephalopathy
6. To obtain a stool specimen for
parasitologic examination
7. To accelerate excretion of parasites
after anthelmintic drugs have been
administered
8. To reduce serum cholesterol levels
(psyllium products)
Contraindications to Use
Laxatives and
cathartics should not be used in the presence of undiagnosed
abdominal pain. The danger is that the drugs may cause an
inflamed organ (eg, the appendix) to rupture and spill GI
contents into the abdominal cavity with subsequent peritonitis, a
life-threatening condition. Oral drugs also are
contraindicated with intestinal obstruction and fecal impaction.
Drug Selection
Choice of a laxative or
cathartic depends on the reason for use and the client’s
condition.
1. For long-term use of laxatives or cathartics in clients who are elderly, unable or unwilling to eat an adequate diet, or debilitated, bulk-forming laxatives (eg, Metamucil)
usually are preferred. However, because obstruction may occur, these
agents should not be given to clients with
difficulty in swallowing or adhesions or strictures in the
GI tract, or to those who are unable or unwilling to drink
adequate fluids.
2. For clients in whom straining is potentially harmful or painful, stool softeners (eg, docusate sodium) are the agents of choice.
3. For occasional use to cleanse the bowel for endoscopic or radiologic examinations, saline or stimulant cathartics are acceptable (eg, magnesium citrate, polyethylene glycol–electrolyte solution, bisacodyl). These drugs should not be used more than once per week. Frequent use is likely to produce laxative abuse.
4. Oral use of mineral oil may cause potentially serious adverse effects (decreased absorption of fat-soluble vitamins and some drugs, lipid pneumonia if aspirated into the lungs).
Thus, mineral oil is not an oral laxative of choice in any
condition, although occasional use in the alert client
is unlikely to be harmful. It should not be used
regularly. Mineral oil is probably most useful as a retention
enema to soften hard, dry feces and aid
in their expulsion.
6. Saline cathartics containing magnesium, phosphate, or potassium salts are contraindicated in clients with renal failure because hypermagnesemia, hyperphosphatemia, or hyperkalemia may occur.
7. Saline cathartics containing sodium salts are
contraindicated in clients with edema or congestive heart
failure because enough sodium may be absorbed to
cause further fluid retention and edema. They also
should not be used in clients with impaired renal
function or those following a sodium-restricted diet for
hypertension.
8. Polyethylene glycol–electrolyte solution is formulated for rapid and effective bowel cleansing without significant changes in water or electrolyte balance.
Antidiarrheals
Antidiarrheal drugs are
used to treat diarrhea, defined as the frequent
expulsion of liquid or semiliquid stools. Diarrhea is a symptom of
numerous conditions that increase bowel motility, cause secretion
or retention of fluids in the intestinal lumen, and cause
inflammation or irritation of the gastrointestinal (GI) tract. As a
result, bowel contents are rapidly propelled toward the rectum, and
absorption of fluids and electrolytes is limited.
Some causes of diarrhea
include the following:
1. Excessive use of laxatives
2. Intestinal infections with viruses, bacteria, or protozoa. A common source of infection is ingestion of food or fluid
contaminated by Salmonella, Shigella, or Staphylococcus microorganisms.
So-called travelers’ diarrhea is usually caused
by an enteropathogenic
strain of Escherichia coli.
3. Undigested, coarse, or highly spiced food in the GI tract. The food acts as an irritant and attracts fluids in a defensive attempt to dilute the irritating agent. This may result from inadequate chewing of food or lack of digestive enzymes.
4. Lack of digestive enzymes. Deficiency of pancreatic enzymes inhibits digestion and absorption of carbohydrates, proteins, and fats. Deficiency of lactase, which breaks down lactose to simple sugars (ie, glucose and galactose) that can be absorbed by GI mucosa, inhibits digestion of milk and milk products. Lactase deficiency commonly occurs among people of African and Asian descent.
5. Inflammatory bowel disorders, such as gastroenteritis, diverticulitis, ulcerative colitis, and Crohn’s disease. In these disorders, the inflamed mucous membrane secretes large amounts of fluids into the intestinal lumen, along with mucus, proteins, and blood, and absorption of water and electrolytes is impaired. In addition, when the ileum is diseased or a portion is surgically excised, large amounts of bile salts reach the colon, where they act as cathartics and cause diarrhea. Bile salts are normally reabsorbed from the ileum.
6. Drug therapy. Many
oral drugs irritate the GI tract and may cause diarrhea,
including acarbose, antacids that contain magnesium,
antibacterials, antineoplastic agents, colchicine,
laxatives, metformin, metoclopramide, misoprostol,
serotonin reuptake inhibitors, tacrine, and tacrolimus.
Antibacterial drugs are commonly used offenders that also
may cause diarrhea by altering the normal
bacterial flora in the intestine. Antibiotic-associated
colitis (also called pseudomembranous colitis and Clostridium
difficile colitis) is a serious condition
that results from oral or parenteral antibiotic therapy. By
suppressing normal flora, antibiotics allow
gram-positive, anaerobic C. difficile organisms to proliferate.
The organisms produce a toxin that causes fever,
abdominal pain, inflammatory lesions of the colon, and severe
diarrhea with stools containing mucus, pus,
and sometimes blood. Symptoms may develop within a few
days or several weeks after the causative
antibiotic is discontinued. Antibiotic-associated colitis is more often
associated with ampicillin, cephalosporins, and
clindamycin, but may occur with any antibiotic
or combination of antibiotics that alters intestinal
microbial flora.
7. Intestinal neoplasms.
Tumors may increase intestinal motility by occupying
space and stretching the intestinal wall. Diarrhea sometimes
alternates with constipation in colon cancer.
8. Functional disorders. Diarrhea may be a symptom of stress or anxiety in some clients. No organic disease process can be found in such circumstances.
9. Hyperthyroidism. This condition increases bowel motility.
10. Surgical excision of portions of the intestine,
especially the small intestine. Such procedures
decrease the absorptive area and increase fluidity
of stools.
11. Human immunodeficiency virus (HIV) infection/acquired
immunodeficiency syndrome (AIDS). Diarrhea occurs in most
clients with HIV infection, often as a chronic condition that
contributes to malnutrition and weight loss. It may be
caused by drug therapy, infection with a variety of
microorganisms, or other factors. Diarrhea may be acute or
chronic and mild or severe. Most episodes of acute
diarrhea are defensive mechanisms by which the body tries to
rid itself of irritants, toxins, and infectious agents. These are
usually self-limiting and subside within 24 to 48 hours
without serious consequences. If severe or prolonged,
acute diarrhea may lead to serious fluid and electrolyte
depletion, especially in young children and older adults. Chronic
diarrhea may cause malnutrition and anemia and is often
characterized by remissions and exacerbations.
Antidiarrheal drugs
include a variety of agents. When used for treatment of diarrhea, the
drugs may be given to relieve the symptom (nonspecific therapy)
or the underlying cause of the symptom (specific
therapy). Individual drugs are listed in Drugs at a
Glance: Antidiarrheal Drugs.
Nonspecific Therapy
A major element of
nonspecific therapy is adequate fluid and electrolyte
replacement. When drug therapy is required, nonprescription antidiarrheal drugs (eg, loperamide) may be effective. Loperamide
(Imodium) is a synthetic derivative of meperidine that
decreases GI motility by its effect on intestinal muscles. Because
loperamide does not penetrate the central nervous system
(CNS) well, it does not cause the CNS effects
associated with opioid use and lacks potential for abuse. Although
adverse effects are generally few and mild, loperamide can
cause abdominal pain, constipation, drowsiness, fatigue, nausea,
and vomiting. For nonprescription use, dosages for
adults should not exceed 8 mg/day; with supervision by a health care
provider, maximum daily dosage is 16 mg/day. In general,
loperamide should be discontinued after 48 hours if
clinical improvement has not occurred. Overall, opiates
and opiate derivatives are the most effective agents for
symptomatic treatment of diarrhea. These drugs decrease
diarrhea by slowing propulsive movements in the small and
large intestines. Morphine, codeine, and
related drugs are effective in relieving diarrhea but are
rarely used for this purpose because of their adverse
effects. Opiates have largely been replaced by the
synthetic drugs diphenoxylate, loperamide, and
difenoxin, which are used only for treatment of diarrhea and
do not cause morphine-like adverse effects in recommended
doses. Diphenoxylate and difenoxin require a prescription.
Bismuth salts have
antibacterial and antiviral activity; bismuth
subsalicylate (Pepto-Bismol, a commonly used overthe- counter drug) also
has antisecretory and possibly antiinflammatory effects because
of its salicylate component.
Octreotide acetate is a
synthetic form of somatostatin, a hormone produced in the
anterior pituitary gland and in the pancreas. The drug may be
effective in diarrhea because it decreases GI secretion and
motility. It is used for diarrhea associated with carcinoid
syndrome, intestinal tumors, HIV/AIDS, and diarrhea that
does not respond to other antidiarrheal drugs.
Other nonspecific agents
sometimes used in diarrhea areanticholinergics
and polycarbophil and psyllium preparations.
Anticholinergic drugs, of which atropine is the
prototype, are infrequently used because doses large
enough to decrease intestinal motility and secretions cause
intolerable adverse effects. The drugs are occasionally used
to decrease abdominal cramping and pain (antispasmodic
effects) associated with acute nonspecific diarrhea and
chronic diarrhea associated with inflammatory bowel disease. Polycarbophil (eg, FiberCon) and psyllium preparations (eg, Metamucil) are most often used as bulk-forming laxatives. They are occasionally used in diarrhea to decrease fluidity of
stools. The preparations absorb large amounts of water and produce
stools of gelatin-like consistency. They may cause abdominal
discomfort and bloating.
Indications for Use
Despite the
limitations of drug therapy in prevention and treatment of
diarrhea, antidiarrheal drugs are indicated in the following
circumstances:
1. Severe or prolonged diarrhea (>2 to
3 days), to prevent severe fluid and
electrolyte loss
2. Relatively severe diarrhea in young
children and older adults. These groups are
less able to adapt to fluid and electrolyte losses.
5. HIV/AIDS-associated diarrhea
6. When specific causes of diarrhea have
been determined
Contraindications to Use
Contraindications
to the use of antidiarrheal drugs include diarrhea caused by toxic
materials, microorganisms that penetrate intestinal mucosa
(eg, pathogenic E. coli, Salmonella, Shigella), or
antibiotic-associated colitis. In these circumstances, antidiarrheal
agents that slow peristalsis may aggravate and prolong
diarrhea. Opiates (morphine, codeine) usually are
contraindicated in chronic diarrhea because of possible opiate dependence. Difenoxin, diphenoxylate, and loperamide are contraindicated in children younger than 2 years of age.
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