Jean E. Horn
The antipsychotic medication
Haloperidol (Haldol) and its drug interactions.
Haloperidol (Systemic) is sold under the U.S. brand names
Haldol and Haldol Decanoate (Mayoclinic.com). The Canadian brand
names for Haloperidol are: Apo Haloperidol, Haldol, Haldol LA,
Novo Peridol, Peridol, and PMS Haloperidol. In Mexico
Haldolperidol is sold under the brand name Haloperil (University
of Maryland Medical Center). Haloperidol is obtainable through
a doctor's prescription. In the U.S. and Canada Haloperidol
prescriptions may come in the following dosage types: Oral
(solution or tablets) and Parenteral (IM injection). Haldol
Decanoate 50 (Haloperidol) and Haldol Decanoate 100
(Haloperidol) are used for intramuscular injections only and are
manufactured by Ortho Mc Neil Pharmaceutical, Inc. U.S.A
(Physicians' Desk Reference, 2005).
Description of Haloperidol (Haldol)
Quoting the definition of Haldol Decanoate (Haloperidol) in
the (Physicians' Desk Reference, 2005): Haloperidol Decanoate is
the decanoate ester of the butyrophenone, Haldol (Haloperidol).
Haloperidol Decanoate is packaged in sterile sesame oil for
intramuscular (IM) injection. The medication comes in two forms:
Haldol Decanoate 50 (Haloperidol) and Haldol Decanoate
100(Haloperidol).
Prescription Haloperidol (generic) tablets are made by Mylan
Pharmaceuticals (Physicians' Desk Reference, 2005). The orange
tablets are described as: Haloperidol USP, 0.5mg MYLAN
351/Scored, Haloperidol USP, 1mg MYLAN 257/Scored, Haloperidol
USP, 2mg MYLAN 214/Scored and Haloperidol USP, 5mg MYLAN
327/Scored. The brand name Haldol tablets are described as:
Haldol 0.5mg a white round tablet with a cut out H on one side
of the tablet. Haldol 1mg is a yellow round tablet with a cut
out H on one side. Haldol 2mg is a pink round tablet with a cut
out H on one side. Haldol 5mg is a green round tablet with a cut
out H on one side. Haldol 10mg is an aqua round tablet with a
cut out H on one side. Haldol 20mg is a salmon colored round
tablet with a cut out H on one side (Yale New Haven Health).
Haldol and generic Haloperidol may come in other forms as well,
depending on the manufacture of the tablets.
Chemical Structure
The chemical structure for Haloperidol Decanoate is 4(4
chlorophenyl) 1[4(4 fluorophenyl) 4 oxobutyl] 4 piperidinyl
decanoate (Physicians' Desk Reference, 2005). In the nonliquid
form, Haloperidol is an odorless white to yellow crystalline
powder (encyclopedia.laborlawtalk.com). The chemical structure
for the nonliquid Haloperidol is 4[4(p chlorophenyl) 4
hydroxypiperidino] 4' fluorobutyrophenone and the empirical
formula is C21 H23 CIFNO2.
Treatment uses.
Haloperidol is used in the treatment of Schizophrenia.
Additionally, Haloperidol is used to treat Tourette's Disorder
(90% of suffers are treated with Haloperidol) and Huntington's
chorea (University of Maryland Medical Center; Palfai and
Jankiewicz, 2001). Mania, Hyperactivity (ADHD), Conduct
disorder, Chronic brain disorder, Motion sickness (in small
dosages), and Infantile Autism are treated with
Haloperidol(HealthyPlace.com;drugdigest.org; MedlinePlus;
mentalhealth.com/drug;Healthfinder.gov).In the emergency room,
Haloperidol is used as a treatment for amphetamine, LSD, and PCP
drug overdoses as the antipsychotic medication aids in the
control of intense agitation, aggression and psychotic thinking
(encyclopedia.laborlawtalk.com; mayoclinic.com). Although an off
label usage, Haloperidol has been used to treat severe nausea
and vomiting in cancer chemotherapy patients. The medulla is the
area of the brain stem that controls vomiting (Palfai and
Jankiewicz, 2001). When Haloperidol is used as an antivomiting
(antiemetic) medication, the dopamine neurotransmitters are
inhibited (blocked) in the medulla.
Clinical Pharmacology
Haldol Decanoate 50 (Haloperidol) and Haldol Decanoate 100
(Haloperidol) have a long duration of effect, as they are
intramuscular injections (Physicians' Desk Reference, 2005). The
only difference between Haloperidol Decanoate and oral
Haloperidol (Haldol) is the duration of action. Long lasting
Intramuscular injections may last up to six weeks
(mayoclinic.com). When taken orally, the peak plasma levels for
Haloperidol takes place within two to six hours after dosage and
for intramuscular injection (IM) the peak plasma level is within
twenty minutes (HealthyPlace.com). Haloperidol is 92% bound to
plasma proteins (electronic Medicines Compendium, p.9). The
medication is quickly dispersed to the liver and adipose
tissues. Haloperidol (Haldol) seems to manifest an increase in
the striatum (Basal ganglia), nucleus accumbens, and the septum
(Schatzberg and Nemeroff, 2001, p.135).
Dopamine Neurotransmitter
Haloperidol Decanoate and Haldol block dopamine
neurotransmitters in the Central Nervous System (CNS)
(Physicians' Desk Reference, 2005). It has been reported that
Haloperidol occupies 90% of the D2 receptors in the putamen
(Schatzberg and Nemeroff, 2001, p.127). The medication also has
an effect on dopamine receptors in the periphery, as well
(electronic Medicines Compendium). The dopamineric neurons begin
in the midbrain and the substantia nigra (mesencephalon) (Palfai
and Jankiewicz, 2001, p.144; Rivas Vazquez, 2003). Then the
neurotransmitter ventures from the substantia nigra to the
ventral tegmental area to the cortical regions (mesocortical
pathways connect the midbrain to the prefrontal cortex). From
the cortical regions the neurotransmitter is sent to the limbic
system (mesolimbic pathways connect the midbrain to the ventral
tegmental, the medial forebrain bundle, and the nucleus
accumbens (Palfai and Jankiewicz, 2001, p.144; Rivas Vazquez,
2003). It has been reported that pleasure, reward, and the
reinforcing effects of drugs are linked to the mesolimbic area
of the brain. The dopamine neurotransmitters then venture to the
nigrostriatal pathway, which extends from the substantia nigra
to the corpus striatum and the Basal ganglia (the region of the
brain where motor control and initiation are mediated) (Rivas
Vazquez, 2003). During its final leg of the journey, the
dopamine neurotransmitter ventures to the tuberoinfundibular
pathway which is connected to the hypothalamus, and from there,
the dopamine neurotransmitter ventures to the pituitary gland,
where the hormone prolactin is regulated and released.
Other neurotransmitter sites
Haloperidol (Haldol) binds to Central Nervous System (CNS)
opiate (Sigma) neurotransmitters (electronic Medicines
Compendium; home.caregroup.org.). The biological activities
connected to the Sigma neurotransmitter are hallucinations,
dysphoria, increased psychomotor activity, and respiratory
activity (Doweiko, 2002, p.166). Haloperidol has some
anticholinergic activity, as a result of the blocking of
cholinergic neurotransmitters (Palfai and Jankiewicz, 2001). As
previously stated, Haloperidol is among the category of
Butyrophenones. Antipsychotic Butyropherones are low blockers of
acetylcholine (Ach), resulting in a high acetylcholine to
dopamine ratio in the Basal ganglia, and therefore significant
extrapyramidal side effects are exhibited. The antipsychotic
drug has weak alpha adrenolytic properties, as well. The alpha
adrenolytic transmitters are a category of the neurotransmitter
norepinephrine (NE), which is blocked by the Butyrophenones
(Haloperidol/Haldol). Alpha neurotransmitters display a high to
low affinity in the arrangement of norepinephrine (NE),
epinephrine (E), and isoproterenol (ISO) (HealthyPlace.com;
Palfai and Jankiewicz, 2001). Blood Pressure is raised when
alpha transmitters on the blood vessels in the periphery are
stimulated by NE.
What are drug interactions?
All types of Adverse Drug Reactions (ADRs) contribute
significantly to the number of hospital admissions and ER visits
(fda.gov/cder/drug/drugReactions). ADRs represent 3 to 5% of
preventable drug interactions. Adverse Drug Reactions are the
fourth leading cause of death ahead of pulmonary disease,
diabetes, AIDS, pneumonia, accidents and vehicle deaths
(fda.gov/cder/drug/drugReactions, 2002, p.5). Drug interactions
occur when two or more separate drugs are absorbed into the body
and each of the drugs effect the others. When the drugs effects
are increased a synergistic response occurs, and when the drugs
are inhibited there is a reduced effect of the drug. A
metabolite is formed when the drugs produce a new effect that is
unlike either of the parent drugs (dictionary laborlawtalk.com;
Doweiko, 2002)
The Cytochrome P450 is a liver enzyme that biotransforms
barbiturates, alcohol, and numerous additional substances
(Palfai and Jankiewicz, 2001). The enzyme is responsible for
drug and alcohol tolerance and for the majority of drug
interactions. The Cytochrome P450 enzyme is the primary cause of
the majority of drug & drug, drug & diet, and drug & herb
interactions (fda.gov/cder/drug/drugReactions). The principle
Cytochrome P450 Isoforms are as follows: CYP1A2, CYP3A (which is
responsible for metabolizing the majority of marketed
medications followed by CYP2D6), CYP2C9, CYP2C19, and CYP2D6.
Enzyme categories are defined and named by their relationship to
amino acid sequences.
Drug interactions may be avoided by knowing the three
properties of the Cytochrome P450 enzyme Isoforms
(fda.gov/cder/drug/drugReactions). Some individuals have genetic
mutations in one or more of the nucleic acids in their DNA
sequence expression of the Cytochrome P450 Isozyme
(fda.gov/cder/drug/drugReactions, 2002, p.23). As a
consequence, the Cytochrome P450 enzyme may be missing or have
low, or no metabolizing activity for drugs that are metabolized
by the Cytochrome P450 enzyme
(fda.gov/cder/drug/drugReactions, 2002, p.23). If the genetic
trait is common (more than 1%) a polymorphism is produced. The
Cytochrome P450 enzyme has three enzymes that are polymorphic
and they are 2D6, 2C19, and 2C9. Those individuals expressing a
polymorphism will metabolize drugs at a different rate than
others in the population.
Some individuals are poor metabolizers (PM) of drugs. The
Cytochrome P450 enzyme CYP2D6 is absent in some livers. About 7%
of Caucasians and from 1 to 2% of other ethnic groups in the
U.S. population have a genetic defect in CYP2D6 which results in
poor metabolization (fda.gov/cder/drug/drugReactions, 2002,
p.23). The normal or typical phenotype can be seen in people
without this genetic defect, who are called extensive
metabolizers (EM) of drugs. Individuals who are ultra
metabolizers (UR) metabolize drugs more quickly, and drugs will
clear their systems faster than other individuals in the
population. As a consequence ultra metabolizers (UR) will have
lower blood levels of drugs and may also have a lower
therapeutic effect. Ultra metabolizers (UR) have a higher rate
of metabolizism, because they have multiple copies of the CYP2D6
gene, for which thirteen subtypes have been reported. The second
property of the Cytochrome P450 enzyme Isoforms is that
individuals who are extensive metabolizers (EM) may become poor
metabolizers (PM) when given a food or drug which inhibits the
enzyme (fda.gov/cder/drug/drugReactions, 2002, p.24). Therefore,
if two drugs are taken at the same time, one drug may inhibit
the enzyme while the second drug may be stored in the body, thus
resulting in higher and potentially toxic concentrations. The
final property of the Cytochrome P450 enzyme Isoforms is that
they may be induced to produce higher levels of activity. When
this happens, any drug which is a substrate for that Isozyme
will be metabolized faster and will result in lower plasma
concentrations for that drug (fda.gov/cder/drug/drugReactions,
2002, p.24). These lower plasma concentrations may then reduce
the effectiveness of the drug. Furthermore, if the drug is
metabolized to a toxic substance, the toxic metabolite may well
build up to a higher intensity
(fda.gov/cder/drug/drugReactions, 2002, p.24).
Some frequently used drugs are inhibitors of CYP2D6 enzymes
(fda.gov/cder/drug/drugReactions, 2002). The CYP2D6 inhibitors
include Quinidine (used to treat heart disorders and malaria)
and Haloperidol (Haldol) as well as a number of other
antipsychotic drugs. Pharmacokinetic interactions between the
Tricyclic antidepressants and the selective serotonin reuptake
inhibitor (SSRI) antidepressants seems to be due to Fluoxetine
(Prozac & Sarafem) and Paroxetine (Paxil) as both are potent
inhibitors of the enzyme CYP2D6, and these (SSRI) antidepressant
drugs leave patients metabolically equal to individuals who lack
the CYP2D6 enzyme (fda.gov/cder/drug/drugReactions, 2002, p.27;
Preston and Johnson, 2004, p.7). As a result there is an
increase in plasma levels for the Tricyclic antidepressants and
the possibility for side effects is increased.
Increased plasma levels of Haloperidol have been reported
when Haloperidol is combined with the following drugs:
Quinidine, Fluoxetine, and Buspirone (electronic Medicines
Compendium). When Tricyclic antidepressants and Haloperidol are
combined together there is an increased chance of low blood
pressure (hypotension) and CNS effects, as well as other
depressant effects (mayoclinic.com). For this reason it is
suggested that Haloperidol (Haldol), SSRIs, and Tricyclic
antidepressants are not to be coadministered.
Other reasons for drug interactions
Drug interactions may be caused by several different
methods. The conditions that lead to a drug interaction may
begin before or after a drug is administered.
(fda.gov/cder/drug/drugReactions, 2002). For example Haloperidol
(Haldol) should be stored away from direct light and away from
heat; the manufacturer suggests storage between 59 and 86
degrees F or 15 and 30 degrees C (Mayoclinic.com;
drugdigest.org; Physicians'desk Reference, 2005). Do not store
Haloperidol in the bathroom medicine cabinet or near the kitchen
sink or other damp areas as heat or moisture breaks down
Haloperidol. Do not store liquid or Haloperidol Decanoate 50 or
Haloperidol Decanoate 100 in the refrigerator or allow
Haloperidol to freeze. Do not take liquid Haloperidol with tea
or coffee, because they cause Haloperidol to separate out of
solution (MedlinePlus). Additionally, some researchers recommend
that patients should not drink tea or coffee one hour before or
two hours after taking Haloperidol (home.caregroup.org). Alcohol
should not be consumed when one is taking Haloperidol as the
drug will potentiate the effects of drowsiness and decreased
coordination (home.caregroup.org; mayoclinic.com;
HealthPlace.com).
Pharmacokinetic interactions may occur in other areas
besides the liver, such as in the plasma, kidneys and GI tract
(fda.gov/cder/drug/drugReactions, 2002). Medications may bind to
each other in the GI tract and as a result absorption may be
prevented and a reduction of systematic availability may occur.
Thus the rate of metabolism may be altered as some drugs are
inhibitors or inducers of drug metabolism.
Other miscellaneous drug interactions may happen through the
competition of drug transporters. And some interactions may
occur at the point of drug action for example when using a beta
blocker drug and calcium channel blocker drug together
(fda.gov/cder/drug/drugReactions, 2002). Finally pharmacodynamic
drug interactions may occur at target organs.
Haloperidol and Lithium drug interaction
Lithium is sold under the brand names Eskalith, Lithium
CARB, Lithiun Cit, Lithobid, Lithonate, and Lithotab
(rxlist.com). The generic forms of Lithium are Lithium Carbonate
and Lithium Cit. Lithium is used in the treatment of acute Mania
and in the treatment of Bipolar Disorder (Hellwig, Heblinger,
and Walden, 1996; Harkness, 1991).
A neurotoxic drug interaction may occur when Haloperidol and
Lithium are combined (Harkness, 1991). The combination of drugs
may result in an encephalopathic syndrome (Physicians' Desk
Reference, 2005). The typical symptoms are: weakness, fever,
lethargy, confusion, tremors, extrapyramidal symptoms,
leukocytosis, elevated serum enzymes, FBS, and BUN which is
followed by irreversible brain damage (Physicians' Desk
Reference, 2005, p.2500).
A case study was conducted by Hellwig et al. (1996). They
report on a 34 year old male with a diagnosis of schizoaffective
disorder who had been admitted into the hospital, because of
acute manic syndrome. After the withdrawal of clozapine and the
combined administering of Lithium and Haloperidol the patient
developed acute brain syndrome. The symptoms were described as
illusionary misconceptions and a confused state. After three
days of clozapine therapy and seven days after the beginning of
the combination of Haloperidol the patient lapsed into a pre
coma. At the time of the pre coma his Lithium Carbonate levels
were 1350/mg/d, Valproic acid levels were 2100 mg/d, and the
Haloperidol levels were 15mg/d at which time all medication was
then stopped. The patient's Lithium serum level was 1.47mmol/1
at the time of the pre coma. The researchers reported that the
patient's Lithium level had dropped the next day to 1.15 mmol/1
when recorded in the morning and in the evening the Lithium
level had dropped to 0.85 mmol/1. The patient showed an
improvement the following day with a Lithium level of 0.4
mmol/1. The researchers reported that the patient finally became
completely coherent and showed no further signs of
disorientation.
Other studies have reported confused states in patients with
schizoaffective psychosis with Lithium levels in the 1 to 2
mmol/1 range (Hellwig et al. 1996). The combination of
Haloperidol and Lithium is moderately safe when the Lithium
levels are kept below 1.0 mm0l/1 (Batchelor and Lowe, 2004).
Nevertheless, patients should be monitored by their physician
when they are taking a combination of Haloperidol and Lithium.
The physician should be on the lookout for the symptoms of
neurotoxicity and treatment should be discontinued if symptoms
appear (Physicians' Desk Reference, 2005).
A limitation to the Hellwig et al. (1996) study is that
Valproic acid may have also contributed to the patient's
illness, as well. Valproic acid (aka.Valproate) (Depakene and
Depakote brand names) is used to treat epilepsy, convulsions,
and seizures (Rosenthal, 1996). Valproate is highly protein
bound and is widely metabolized by the liver and as a result
other drug and drug interactions may well happen when other
protein bound drugs or other metabolized drugs are combined
(Schatzberg and Nemeroff, 2001). Also Valproic acid is not to be
used with Haloperidol (Haldol) as it produces a drug interaction
(rxlist.com).
Haloperidol and Carbamazepine drug interaction
Carbamazepine (Tegretol and Epitol brand name) is used in
the treatment of Epilepsy and other seizure disorders (Cooper,
1991). Carbamazepine is also used in the treatment of Trigeminal
Neuralgia a severe and painful facial nerve disorder. Trigeminal
Neuralgia is also known as Tic Doulourex.
When the drugs Haloperidol and Carbamazepine are combined
they cause a significant lowering of Haloperidol plasma levels
(mentalhealth.com/drug). It has been further reported that
Carbamazepine changes certain features of the Cytochrome P450
enzyme (Arana, Goff, Friedman, Ornsteen, Greenblatt, Black, and
Shader, 1986). The drug Carbamazepine generates its own
metabolism and the metabolism of other compounds, as well (Arana
et al. 1986). For example, Carbamazepine is a potent inducer of
the catabolic enzyme; the enzyme accelerates the metabolism and
lowers the plasma level of Haloperidol (Schatzberg and Nemeroff,
2001, p. 246).
In one study seven male hospital patients (aged 24 to 68
years) were given both Carbamazepine (400 to 2000 mg/day) and
Haloperidol (10 to 40 mg/day) (Arana et al. 1986). When
measuring the patient's Haloperidol plasma levels with gas
liquid chromatography it was found that their Haloperidol plasma
levels were reduced on an average of 60%. Two of the patients
symptoms had worsened when given the combination of Haloperidol
and Carbamazepine as their Haloperidol plasma levels were
undetectable. The researchers suggested that when Haloperidol
and Carbamazepine are combined the patient's Haloperidol plasma
levels should be monitored. Other researchers have suggested
that when the combination of Carbamazepine and Haloperidol is
used, the Haloperidol dosage should be increased as needed; in
addition, when the drug Carbamazepine is discontinued the
Haloperidol dosage should be lowered (Harkness, 1991;
mentalhealth.com/drug).
Haloperidol and Glycine Amino Acid drug interaction
Glycine is an amino acid and a major inhibitory transmitter
in the nervous system, and like other amino acids it has
multiple functions (Palfai and Jankiewicz, 2001). The amino acid
Glycine has been shown to have excitatory activity at some
nervous system sites. Glycine makes up 1 to 5 % of the protein
in the average diet (Palfai and Jankiewicz, 2001, p.153).
It is believed that Glycine hyperpolarizes neurons by acting
on ion channels which affect CL- (Chlorine) movement (Palfai and
Jankiewicz, 2001). As reported by Palfai and Jankiewicz (2001,
p.153) deactivation takes place through reuptake. The
dissemination of Glycine is chiefly in the spinal cord, in the
medulla, the pons, and the retina (Palfai and Jankiewicz, 2001,
p. 153).
The NMDA receptor (N methyl d aspartate acid) includes an
agonist (Glutamate) and Glycine, and it has an adequate amount
of depolarization to eliminate a magnesium ion block in the ion
channel (Palfai and Jankiewicz, 2001, p. 154). Additionally, the
ion channel includes a binding site for the psychoactive drug
Phencyclidine (PCP) which generates psychotic states similar to
Schizophrenia by inhibiting the ion channel gated by NMDA
Glutamate receptor (Palfai and Jankiewicz, 2001, p. 154; Javitt,
Zylberman, Zukin, Heresco Levy, & Lindenmayer, 1994). A PCP
induced psychosis will have features which look like
Schizophrenia: The positive symptoms are hallucinations,
delusions and thought disorders. The negative symptoms are
poverty of speech, lack of or inappropriate emotion, and a lack
of motivation. Included are cognitive dysfunctions (Heresco
Levy, Javitt, Ermilov, Mordel, Horowitz, and Kelly, 1996;
encyclopedia.
laborlawtalk.com).
It has been reported by some researchers that Schizophrenia
is linked to an underactivity of brain glutamatergic
neurotransmission, particularly at the NMDA subtype of the
Glutamate receptor (Heresco et al. 1996). Glutamate is one of
the main excitatory transmitters in the brain as it is used by
more than 60% of cortical neurons. The authors further report
that the theory is supported by a number of findings in
Schizophrenia, which include lower Glutamate intensity and
abnormalities in Glutamate neurotransmitter metabolism,
function, and density.
It has been found that chronic antipsychotic treatment can
change Glutamatergic activity (Schatzberg and Nemeroff, 2001).
The administration of Haloperidol increases NMDAR1 subunit
immunoreactivity in the stratum (Basal ganglia) (Schatzberg and
Nemeroff, 2001, p.135). And Haloperidol has been shown to
increase GluR1 immunoreactivity in the Prefrontal Cortex.
A double blind study was conducted with eleven chronic
Schizophrenia patients who were drug treatment resistant
(Heresco Levy et al.1986). The study lasted for six weeks;
patients were randomly assigned to receive a drug or a placebo.
The crossover treatment trial consisted of their prior
antipsychotic treatment (Haloperidol) and the addition of 0.8
g/kg body/weight of Glycine. It was noted by the researchers
that Glycine reaches peak blood levels within 60 minutes of
intravenous administration (Heresco Levy et al.1986).
The researchers found that the patients were able to
tolerate Glycine with out any side effects. This was done by
monitoring the patient's liver and kidney functions, hematology,
and blood chemistry in the lab (Heresco Levy et al.1986). It was
also found that the patient's serum Glycine levels increased.
The researchers further reported that the patient's negative
symptoms were reduced by a mean of 36 (7%) (p < 0.0001). There
was also an improvement in the patient's cognitive and
depressive symptoms. The improvement in the patient's negative
symptoms and cognitive dysfunction was not accompanied by a
worsening of their positive symptoms (Heresco Levy et al.1986).
The researchers stated that the combination of the patient's
antipsychotic medication and high doses of Glycine in the diet
may lower symptom severity in Schizophrenic patients who are
treatment resistant. It was found that the patients with the
lowest baseline serum Glycine levels seemed to have the most
improvement in their negative symptoms.
In a second study fourteen male patients with chronic
Schizophrenia were treated with Glycine (Javitt et al.1994). For
eight weeks one group was given the Glycine treatment and the
other group was given the placebo. The therapy started with
doses of 2 g/day and gradually rose to a dose of 0.4 g/day body
weight (about 30 g/day) during the first 2 weeks (Javitt et
al.1994, p. 1234). After the double blind study all of the
patients were offered the Glycine treatment for an added eight
weeks. The following measurements were used: The Positive and
Negative System Scale, which was given every two weeks during
the double blind study; and which was given every four weeks
during the Glycine open label therapy. The Abnormal Involuntary
Movement Scale (AIMS) and the Extrapyramidal Rating Scale were
used to measure tardive dyskinesia and extrapyramidal side
effects.
The results were that all seven of the patients who were
given Glycine had a decrease in their negative symptoms (using
Fisher's exact test) (Javitt et al.1994). The researchers stated
that the daily doseage of Glycine was from 10 to 15 times
greater than the daily average Glycine intake of 2.1 g/day
(Javitt et al.1994). Suggesting, a synergistic action between
the combination of the amino acid Glycine and the antipsychotic
drug Haloperidol (Yale New Haven Health).
There are many other drugs that have an interaction with
Haloperidol. To find more information you may check the web
sites which will be given in the references. Some of the
Alternative Medications are beneficial drug interactions with
Haloperidol. Patients who are taking Haloperidol should tell
their Doctor or Dentist that they are taking Haloperidol; as
Haloperidol has drug interactions with some Opiates and
Anesthetics (Physicians' Desk Reference, 2005). When taking an
eye exam the Ophthalmologist should be advised that the patient
is taking Haloperidol. Atropine is used to widen the pupils of
the eye when taking the eye exam (Palfai and Jankiewicz, 2001,
p. 431). Atropine has an adverse drug interaction with
Haloperidol. Advise your patients not to take any medications or
discontinue any medications before checking with their Doctor.
PLEASE INSERT FIGURES: 1., 2., AND 3 HERE.
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Rivas Vazquez, R.A. (2003). Aripiprazole: A novel
antipsychotic with dopamine stabilizing properties
[Clinical Psychopharmacology update]. Psychology:
Research and Practice. 34 (1). 108 to 111. Retrieved
from 2/8/05 http://gateway.ut.ovid.com/gw2/ovidweb.cgi
Rosenthal, M. E. (1996). Talking your medications safely.
(p. 167). Springhouse, PA: Springhouse Corporation.
Schatzberg, A. F., and Nemeroff, C. B. (2001). Essentials
of Psychopharmacology. (pp. 127, 135, 246, 253, 618)
Washington, D. C., U.S.A.: American Psychiatric
Publishing, Inc.
http://dictionary.larborlawtalk.com/index.php
http://www.drugdigest.org/DD/DVH/Uses/0,3915,312%
7CHaloperidol+Tablets,00.html
http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.
asp?documentid=6750
http://encyclopedia.laborlawtalk.com/haloperidol
Figures 1. and 2. Retrieved 4/19/05. (pp. 1 to 2).
http://encyclopedia.laborlawtalk.com/index.php
http://www.fda.gov/cder/drug/drugReactions/default.htm
http://www.healthfinder.gov/news/newsstory.asp?docid=520474
http://www.HealthyPlace.com/medications/haloperidol.asp
http://www.home.caregroup.org/clinical/altmed/interactions/
Drugs/Haloperidol.htm
http://www.mayoclinic.com/invoke.cfm?objectid=BAAEE91B-
6ABE-4CDE-8B454E817C…
http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202278.
Html
http://www.mentalhealth.com/drug/p30-h02.html
http://www.rxlist.com/cgi/rxlist.cgi?drug=Lithium&x=10&y=9
http://www.umm.edu/altmed/ConsDrugs/Haloperidolcd.html
University of Maryland Medical Center.
http://yalenewhavenhealth.org/library/healthguide/en-
us/Cam/topic.asp?hwid=hn-1137008
Yale New Haven Health.
http://yalenewhavenhealth.org/library/healthguide/en-us/
drugguide/topic.asp?hwid=d0002…
Yale New Haven Health
Brian Lok
Dextroamphetamine and Amphetamine Interactions
The amphetamine molecule exists in two mirror-image forms,
called isomers. Dextroamphetamine, also known as d-amphetamine,
dextroamphetamine or Dexedrine; a trade name here in the States,
is the right-handed (dextro – right) version of the amphetamine
molecule.
Dexedrine comes in two forms; tablets and Spansule capsules.
Spansule is a registered trademark for a timed release capsule
where the initial dose is released quickly and the remaining is
released gradually.
The only FDA approved usages of Dexedrine are for Narcolepsy and
Attention Deficit Hyperactivity Disorder (ADDH)
(GlaxoSmithKline, 2001.) Another use is for obesity, although
apparently this is off-label since it doesn't show up on the
package insert. One problem is that obesity involves an
increased chance of cardiovascular disease (Palfai, T., And
Jankiewicz, H.,2001.) and symptomatic cardiovascular disease is
one of the listed contraindications (i.e., makes it's use
inadvisable)
It is a central nervous system (CNS) stimulant, which functions
basically by causing the release of large quantities of dopamine
and norepinephrine (DA and NE, respectively.) DA and NE,
closely related in both synthesis and structure, are referred to
as catecholamines (Palfai, T., And Jankiewicz, H.,2001).
Amphetamines have physical similarity to the catecholamines,
which allows them to enter nerve endings through reuptake
channels and stimulate the release of DA and NE. The exact
mechanism of how this takes place is not known (GlaxoSmithKline,
2001). The amount of catecholamines released from amphetamine
stimulation is more than the usual amount and on top of that the
reuptake channel is blocked. This increases the effectiveness
of the amphetamine molecule is through the amount of time it
stays in the synapse via the blocked reuptake.
D-amphetamines have numerous drug interactions; some
dangerous, some (arguably) simply annoying. They can be classed
under four general effects:
1. Substances that decrease the effectiveness of d-
amphetamine
2. Substances that increase the effectiveness of d-
amphetamine
3. Substances that are decreased in effectiveness from d-
amphetamine
4. Substances that are increased in effectiveness from d-
amphetamine
1. Haldol (haloperidol) and Thorazine (chlorpromazine) are
both neuroleptics aka antipsychotics. Both block DA and NE
reuptake and result in the inhibition of amphetamine CNS
stimulation. Chlorpromazine is effective in amphetamine
poisoning because it antagonizes many effects (Palfai, T.,
And Jankiewicz, H.,2001.) Reserpine, a drug used to
produce depression in lab animals, nullifies the activity
of d-amphetamines by forcing the release of DA into the
synapse where it is then destroyed by the enzymatic actions
of monoamine oxidase (MAO.) With the vesicles now emptied,
the d-amphetamine, which would normally dump the DA into
the synapse, will not be as effective. D-amphetamine
effectiveness is decreased when taken with vitamin C, fruit
juices (presumably because of the vitamin C contained
within them), glutamic acid hydrochloride or urinary
acidifiers because of decreased absorption and a general
increase in elimination (toxnet.nlm.nih.gov.)
2. Conversely, urinary alkalizers such as calcium/magnesium
containing antacids, carbonic anhydrase inhibitors and
sodium bicarbonate (baking soda) increase the effects of
amphetamines because of increased absorption and decreased
elimination (toxnet.nlm.nih.gov.) Since MAO destroys both DA
and NE, it follows that MAO inhibitors (MAOI) will further
potentiate the effects of amphetamines. MAOIs increase the
amounts neurotransmitters in the vesicles by irreversibly
binding to MAO (which destroy NE and DA); so when
amphetamines are taken after this occurs there is much more
NE and DA available, and thus the effects are increased.
3. Antihistamines like Benadryl can be less effective when
taken with d-amphetamine. Phenytoin (Dilantin) is an anti-
epileptic drug prescribed for seizures; it's intestinal
absorption may be delayed from amphetamines. With
coadministration of amphetamines it may produce a
synergistic anticonvulsant action. Amphetamine inhibits the
hypotensive (low blood pressure) effect of veratrum
alkaloids
4. Meperidine, otherwise known as Demerol, is a narcotic
analgesic (pain-reducer). Although it's effects may be
potentiated by d-amphetamine, this is not recommended
because of the possibility of resulting hypotension, severe
respiratory depression, coma, convulsions, hyperpyrexia
(extreme fever), vascular collapse, and death in some
patients due to the monoamine oxidase inhibition properties
of amphetamines.
References
Palfai, T., & Jankiewicz, H. (2001). Drugs and human behavior.
McGraw Hill Primis:New York.
Pendell, Dale. (2002). Pharmako/Dynamis: Stimulating Plants,
Potions and Herbcraft. Mercury House Books, San Francisco, CA.
Psychiatry Drug Database (5-2-05). From
http://www.spisdemo.com/RX/RXDisplay.aspx?qsRXID=RXPS054&qsSecti
on=6
GlaxoSmithKline. (2001). Prescribing Information for Dexedrine
brand of dextroamphetamine sulfate, Research Triangle Park, NC.
Hazardous Substances Data Bank (HSDB) (5-02-05). Retrieved from
http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~0MdZ6m:1
PDRHealth.com (5-02-05). Retrieved from
http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/dex1129.
shtml
Eileen Klima
Drug Interactions of Anxiolytics:
Benzodiazepines (Valium and Ativan) and Buspirone (Buspar)
The anxiety disorders are the most common form of mental
illness found in the United States. Between 7% and 23% of the
general population are thought to be suffering from anxiety in
one form or another. Approximately, one-third of all adults
will experience at least transient periods of anxiety intense
enough to interfere with their daily lives (Doweiko, 2002). For
thousands of years, alcohol was the only agent that could reduce
an individual's anxiety level until the discovery of
barbiturates in the late 19th century. More recent, the
benzodiazepines were developed in the 1960's, and Valium
(diazepam) still is the most popular anti-anxiety agent
prescribed in Humboldt County (according to local pharmacists)
followed by Ativan (lorazepam) and BuSpar (buspirone).
Buspirone is chemically different from the benzodiazipines
(diazepam and lorazepam), and is a member of a new class of
medications called the azapirones.
The benzodiapine molecule is thought to bind to one of the
Gamma Aminobutyric Acid (GABA) receptor sites, and also to a
chloride channel on the neuron surface, making the cell more
sensitive to the GABA that already exists. Neurons that that
utilize GABA are especially common in the locus ceruleus of the
brain. Nerve fibers from the other parts of the brain thought
to be involved in fear and panic reactions. Animal research has
suggested that stimulation of the locus ceruleus causes behavior
similar to those seen in humans who are having a "panic attack".
It is thought by enhancing the effects of GABA, the
benzodiazepines reduce the level of neurological activity in the
locus ceruleus, reducing the individual's anxiety level. The
benzodiazepines act by binding specific receptor site located on
the GABAA macromolecular complex (Palfai & Jankiewicz, 2001).
A key site for the modulation of anxiety, this is where the
barbituate binding site is found as well. Whereas the
barbiturates, upon binding, increase the amount of time that the
ion channel remains open while GABA is acting, the
benzodiazepines augment the GABAergic action by increasing the
frequency of the channel opening. In both cases, chlorine ions
enter through the post-synaptic membrane, making the cell
interior more negative and raising the threshold for excitation.
This hyperpolarizes and inhibit's the neuron, with a net effect
of reducing excitability in the central nervous system. The
benzodiazepines' action also increases the binding of GABA
molecules to the receptor. The tranquillizing action of
anxiolytics correlates with their affinity for the GABAA
receptor. The GABA imbalances in the normal functioning of the
receptor may be a factor in anxiety disorders. It has been
hypothesized that acquired or inherited dysfunctions in the
receptor may serve as a biological basis for anxiety disorders.
The number of benzodiazepine appears to correlate negatively to
anxiety levels (the more receptors the less anxiety).
The anxiolytic effects of the benzodiazepines are most
likely mediated by circuits in the neocortex, where the
concentration of of benzodiazepine receptors are the highest.
The brainstem concentrations are low, circuits involving GABA
there effect fear and the acoustic startle reflex. The limbic
structure is also implicated, such as the hippocampus and the
amygdala (reduction of aggression and conflict seen in animal
studies).
Buspirone (BuSpar) is a newer, nonbenzodiazepine anxiolytic
and its effect are through the serotonergic rather than the
GABAergic systems. The role of serotonin (5-HT) in anxiety is
known, because benzodiazepines inhibit the firing 5H-T neurons
in the raphe nucleus and the destruction of raphe neurons is
considered the alleviation of anxiety symptoms. Buspirone is a
serotonergic agonist that shows a high affinity for 5-HT1A
receptors, found in parts of the brain that project from the
midbrain raphe nucleus.
Valium (diazepam):
Valium is a schedule IV classification drug. It is used in
the treatment of anxiety. Valium is rapidly absorbed from the
General Intestine (GI) tract when taken orally and is slowly
absorbed (unpredictable) when injected (Davis, 2005). Valium is
widely distributed throughout the body and crosses the blood
brain barrier. It can cross the placenta and enter into breast
milk. Diazepam is highly metabolized by the liver. Some
products of metabolism are active Central Nervous System (CNS)
depressants. Valium has a 20 to 70 hour half life and up to 200
hours for metabolites.
Contraindications and precautions to be aware of with
diazepam are hypersensitivity, cross sensitivity with other
benzodiazepines may occur, comatose patients, pre existing CNS
depression, uncontrolled severe pain, narrow angle glaucoma,
pregnancy or lactation, some products contain alcohol, propylene
glycol, or terrain and should be avoided in patients with known
hypersensivity or intolerance. Use cautiously in hepatic
dysfunction, severe renal impairment, history of suicide attempt
or drug dependency, geriatric or debilitated patients (dosage
reduction required) and children (dosage should not exceed 0.25
mg/kg).
Adverse reactions and side effects can result as dizziness,
drowsiness, lethargy, depression, hangover, headache,
paradoxical excitation in the CNS. Respiration depression and
in the GI tract is the potential for constipation, diarrhea,
nausea and vomiting. Patients are at risk for physical
dependence, psychological dependence and tolerance.
Drug to drug interactions with alcohol, antidepressants,
antihistamines, and opioid analgesics concurrent use results in
additive CNS depression. Cimetidine, hormonal contraceptives,
disulfiram, fluoxetine, isoniazid, ketoconazole, metoprolol,
propoxyphene, propranolol, or valporic acid may decrease the
metabolism of diazepam, enhancing its actions. May decrease the
efficacy of levodopa. Rifampin or barbiturates may increase
the metabolism and decrease effectiveness of diazepam. Sedative
effects may be decreased by theophylline. Drug to natural
products (herbal) concomitant use of kava, valerian, skullcap,
chamomile, or hops can increase CNS depression.
In the treatment of anxiety, assess degree of anxiety and
level of sedation (ataxia, dizziness, slurred speech) prior to
and periodically throughout therapy. If Valium is used in the
treatment of alcohol withdrawal, assess patient for tremors,
agitation, delirium, and hallucinations. Protect the patient
from injury.
Effectiveness of therapy can be demonstrated by a decrease
in anxiety level. Full therapeutic antianxiety effects occur
after1 to 2 weeks of therapy. Decreased tremulousness and more
rational ideation when used for alcohol withdrawal.
Ativan (lorazepam)
Ativan is a schedule IV classification of drug. It is used
in the treatment of anxiety (PDR, 2002). Lorazepam is well
absorbed following oral administration and well distributed
throughout the body. It crosses the blood brain barrier, the
placenta and can enter into breast milk. Ativan is highly
metabolized by the liver and has a half life of 10 to 20 hours.
Contraindications and precautions with lorazepam for
patient use are hypersensitivity, cross sensitivity with other
benzodiazepines, comatose patients or those with pre existing
CNS depression. Also patients with severe uncontrolled pain,
narrow angle glaucoma, pregnancy and lactation. Use cautiously
with patients who have severe hepatic/renal/pulmonary
impairment, myasthenia gravis, history of suicide attempt or
drug abuse, geriatric or debilitated patients (dosage reduction
recommended).
The adverse reactions and side effects of Ativan are
dizziness, drowsiness, lethargy, hangover, headache, mental
depression, paradoxical excitation in the CNS. Respiratory
depression, constipation, diarrhea, nausea, vomiting and skin
rashes. Also physical dependence, psychological dependence and
tolerance.
Drug to drug interactions of increased CNS depression with
alcohol , antihistamines, antidepressants, opioid analgesics,
and other sedative/hypnotics including other benzodiazepines.
It may decrease the efficacy of levodopa. Smoking may increase
metabolism and decrease effectiveness. Probenecid may decrease
metabolism of lorazepam, enhancing its actions. Drug to
natural products (herbal) concomitant use of kava, valerian,
skullcap, chamomile, or hops can increase CNS depression.
Assess degree and manifestations of anxiety prior to and
periodically throughout therapy. Prolonged high dose therapy
may lead to psychological or physical dependence. Restrict drug
amount available to patient. Patients on high dose therapy
should receive routine evaluation of renal hepatic, and
hematologic function.
Evaluation of effectiveness of therapy can be demonstrated
by increase in sense of well being and decrease in subjective
feelings of anxiety without excessive sedation. Need for
continued therapy should be re evaluated regularly. Minimum
effective dose should be used.
BuSpar (buspirone)
BuSpar is a medication used in the treatment of anxiety
(Preston & Johnson, 2002). Busiprone is rapidly absorbed by the
human body, it has a half life of 2 to 3 hours and it is
extensively metabolized by the liver. Contraindications and
precautions of BuSpar are hypersensitivity, severe hepatic or
renal impairment, concurrent use of MAO inhibiters and ingestion
of large amounts of grapefruit juice. Use cautiously in
patients receiving other anti anxiety medications (other agents
should be withdrawn to prevent withdrawl or a rebound effect)
and other psychotropic medication. Safe use has not been
established with pregnancy, lactation and with children.
Adverse reactions and side effects are dizziness,
drowsiness, excitement, fatigue, headache, insomnia,
nervousness, weakness, and personality changes. Other reactions
are blurred vision, nasal congestion, sore throat, tinnitus,
altered taste or smell and conjunctivitis. Respiratory
reactions are chest congestion, hyperventilation and shortness
of breath. Cardiovascular reactions are chest pain,
palpitations, tachycardia, hypertension, hypotension.
Additional side effects are nausea, abdominal pain,
constipation, diarrhea, dry mouth, vomiting, changes in libido,
urinary frequency, urinary hesitation, skin rashes, edema,
irregular menses, incoordination, tremor, sweating and fever.
Drug to drug interactions with MAO inhibiters result in
hypertension and is not recommended. Erythromycin, nefezadone,
ketoconazole, itraconazole and other inhibiters of CYP 3A4
increases blood levels and effects of buspirone, dose reduction
is recommended. Rifampin, dexamethasone, phenytoin,
phenobarbital, carbamazepine, and other inducers of CYP 3A4
decrease blood levels and the effects of buspirone. Avoid
concurrent use with alcohol. Drug to natural products (herbal)
concomitant use with kava, valerian or chamomile can increase
CNS depression. Grapefruit juice increases serum levels and
effect. Drinking large amounts of grapefruit juice is not
recommended.
Effectiveness of BuSpar can be demonstrated by increase in
the sense of well being, decrease in subjective feelings of
anxiety. Some improvement may be seen in 7 to 10 days. Optimal
results take 3 to 4 weeks of therapy. BuSpar is usually used
for short term therapy (3 to 4 weeks), however, long term use is
also recommended.
Benzodiazepines and buspirone appear to be effective in the
treatment of anxiety disorders. Valium, Ativan and BuSpar are
considered by local pharmacists to be the most often prescribed
by doctors who practice in Humboldt County. Caution should be
used when taking any medication, especially when more than just
one is recommended.
References:
Davis, F.A. Company (2005) Davis's Drug Guide For Nurses (9th
edition). Philadelphia, PA.
Davis, F.A. Company (2005). Taber's Cyclopedic Medical
Dictionary. Philadelphia, PA.
Doweiko, H. E., (2002). Concepts of Chemical Dependency (5th
edition). Brooks/Cole Thomson Learning. Pacific Grove, CA.
Palfai, T. & Jankiewicz, H. (2001). Drugs and Human Behavior (2nd
edition).New York: McGraw Hill.
Physicians Desk Reference (2002). Medical Economics Company,
Inc.. Montvale, New Jersey.
Preston, J., & Johnson, J., (2004). Clinical Psychopharmacology
Made Ridiculously Simple (5th edition). MedMaster,Inc.. Miami,
FL.
Anti-Psychotic Medications and Interactions
By Eric Dick
Medications have help millions of people the world over and have
saved innumerable lives, however medications have also been
found to be a deadly concoction for many when the drug interacts
with any other substance in a negative way. The drug
interactions often referred to contraindications have to be
monitored closely and with a good knowledge of what hey are when
taking any medication or dietary supplement.
The following paper takes a look at several popular
antipsychotic medications and their most common and severe
interactions. The following however are not a comprehensive lit
of all interactions and should not be used solely in educating
yourself about dangerous interactions and effects. If you are
taking any of these medications please research the
possibilities of interactions fully using many of the resource
sited in this paper.
Given that many antipsychotic medications are used in
combination with other medicinal treatments for depressive
disorders, it is essential to understand the potential
interactions in combination with both antidepressants and mood
stabilizers. "For mood stabilizers such as lithium, valproate
and carbamazepine, the interaction with antipsychotic drugs at
the metabolic level is generally insignificant except for
carbamazepine. In a number of studies, carbamazepine has been
shown to lower the levels of antipsychotic drugs present given a
certain dose thus making it important to consider raising the
dose of the antipsychotic if there is no effect if used in
conjunction with carbamazepine." (www.psychdirect) Lithium,
however, at high doses may lead to potentially dangerous
reactions with conventional antipsychotic medications. This
requires the patient to use extreme caution when using these
medications together. "Antidepressants of the SSRI type may
interact with enzyme systems within the liver to cause varying
degrees of elevation of antipsychotic drugs for a given dose."
(www.psychdirect) These interactions are too complicated to
discuss in detail in this presentation. Of the newer
antipsychotic drugs in the novel classification, olanzepine is
the only one without known significant interactions with SSRI's.
Ziprasidone (Geodon) is an antipsychotic used to treat mental
and emotional disorders such as schizophrenia. Ziprasidone
(Geodon) interacts with other drugs that may prolong the QT
interval such as amiodarone, procainamide, quinidine, dofetilide,
pimozide, sotalol, bepridil, certain other antipsychotics (e.g.,
thioridazine), certain quinolones (e.g., moxifloxacin,
sparfloxacin); or certain diuretics. Caution should be used and
changes to dosage may be recommended if you are taking
carbamazepine, or ketoconazole for high blood pressure or
Parkinson's disease. Because Ziprasidone (Geodon) has a direct
effect on the central nervous system, people taking this drug
should be cautious when taking other drugs that affect the
central nervous system. Alcohol should never be consumed while
taking Geodon. The avoidance of ginko biloba while taking any
anti-psychotic medications is also recommended as the combination
has been correlated with seizures and hallucinations.
Phenothiazines such as chlorpromazine are a complicated matter
when it comes to interactions as many substances can change the
effectiveness of phenothiazines. The development of extra
pyramidal symptoms and dystonia has been seen in a few patients
taking fluoxetine alone or with haloperidol, fluphenazine,
maprotiline, metoclopramide, perphenazine, pericyazine, pimozide,
risperidone, sulpiride, thiothixene or trifluoperazine. The
antipsychotic effects and extra pyramidal side-effects of the
phenothiazines can be opposed by levodopa while phenothiazines
and butyrophenones can also oppose the effects of levodopa
One of the promising features of most atypical antipsychotic
medications is their overall lack of other drug interactions.
Most antipsychotic drug interactions are found in relation to the
conventional types of antipsychotic medications. This bodes well
for the future of psychopharmacology as many patients are now
being switched over to these newer less dangerous and often more
effective atypical designs. Drug interactions will always be a
critical component to keep an eye on as new drugs are developed
and new possibilities emerge however the pharmaceutical industry
is paying more attention to the possibilities of interaction when
designing many of these new drugs.
References
http://www.healthyplace.com/Communities/Thought_Disorders/schizo
/medications/geodon.htm
http://www.psychdirect.com/depression/d-meds.htm
http://www.medicinenet.com/risperidone/article.htm
http://www.rxlist.com/cgi/generic2/ziprasidone_ad.htm
Joseph Waters
Alcohol Interactions with Other Drugs
When speaking of drugs it is commonly heard "drugs and alcohol".
This term is a misnomer because alcohol is a drug also. The
major difference is that alcohol is legal. Alcohol is a poison
that has direct toxic effects on nerve and muscle cells.
Depending on which nerve and muscle pathways are involved,
alcohol contributes to effects such as memory loss,
incoordination, seizures, weakness, and sensory deficits. Other
side effects include confusion, dizziness; impaired judgment,
memory, intellectual performance, and motor coordination.
Alcohol (Etoh) is a depressant of the central nervous system
(CNS); in fact it is the most widely used depressant. The
definition of a central nervous system depressant is any drug
that can be used to slow down brain activity, or the sympathetic
impulses of the central nervous system (i.e. respiratory rate,
heart rate). CNS depressants can be physically and
psychologically addictive and alcohol is no exception. As the
body takes in depressants it build a tolerance, making the body
require more of the drug to provide the desired effect.
Alcohol is known to be linked with diseases such as liver
disease, heart disease, pancreatitis, certain forms of cancer,
and alcoholism. Pregnant women who consume alcohol can cause a
range of birth defects and the child could possibly have
lifelong learning and behavioral problems. The most serious
problem caused by drinking during pregnancy is fetal alcohol
syndrome (FAS). This is characterized by a child having severe
mental, physical, and behavioral problems. It is unknown exactly
how much alcohol is needed to result in FAS, but it is best to
refrain from drinking while pregnant. Being that alcohol is a
very widely used drug it has a dangerously high potential of
being mixed with other drugs and medications.
Reactions From Previous/Current Users of Alcohol With Other
Drugs
In a survey of 12 people who had experience with mixing alcohol
with other drugs there was a great range of experiences.
Although there have been a great range of experiences they all
have reported that there was some degree of danger.
Alcohol mixed with "downers"
This is by far the most dangerous mixture that was reported.
"Downers" are depressants of the CNS, as is alcohol. Any drug
depressing the CNS in combination with alcohol can be fatal.
There is an increased risk for overdose when mixing a depressant
with alcohol. Among the "downers" are GHB, heroin, morphine,
opium, and barbiturates. Additional depressants are some
sleep/anti-anxiety medications such as xanax, amytal, librium,
valium, and traxene to name a few. The drug used by most of the
people interviewed mixed alcohol with heroin. Luckily the ones
who did this lived to tell about it. The second most depressant
mixed with alcohol is valium. The biggest complaint with the
combination of the downers with alcohol was that their breathing
felt "weird". Their breathing felt weird because the downer
interferes with normal breathing patterns by decreasing them. In
many cases this could result in a coma. Everyone who experienced
this interaction between two dangerous drugs stated that their
experience encouraged them to become more educated about drug
interactions.
Alcohol Mixed With Methamphetamines
Alcohol and "speed" is another dangerous combination. It is
dangerous in the sense the effect of the alcohol is masking the
high of speed. This inhibits the user's ability to experience
how the speed is influencing their body and they won't know when
to stop. However, upon talking to experienced individuals it was
reported that the speed masks the effects of the alcohol. When
taking speed, it allowed them the ability to drink more because
they didn't feel drunk so they kept drinking more and more. This
is dangerous because it is very easy to get alcohol poisoning by
continuing to consume alcohol well past the normal limit. So as
one can see, the drugs are opposites, methamphetamines speed up
the metabolism, and the central nervous system, thus it is a
stimulant. Each drug allows the other to be consumed at an
unusually high dosage leading to an overdose of either drug,
which can be fatal. The crash from speed is very hard and can
throw one into a depression; this sort of depression paired with
alcohol has been reported to exacerbate the depression.
Alcohol Mixed with Cocaine/Crack
Cocaine alone increases heart rate, and blocks the reuptake of
dopamine; paired with alcohol the heart rate is increased about
4 times which can lead to heart failure and heart attacks. It
gives the user the feeling of exhilaration and is described by
users as "an extremely good feeling, everything is light and
floaty, can do anything-invincible, super-high confidence".
Alcohol, described by many as "liquid courage", gives people the
courage to do what they normally wouldn't do, say things they
wouldn't normally say, and just plain act on impulse. This
paired with cocaine is said to give the user "liquid courage"
and "powder courage". This combination can have a person
believing they can do impossible things that can be fatal (i.e.
stopping a speeding bus at will, flying off of a building,
fighting multiple opponents simultaneously, etc.). Users have
also stated that the crash from cocaine is hard like the crash
from speed and the result of consuming alcohol during this time
will yield the same result. This crash in most cases encourages
the person to crave the drug again in order to be in that
euphoric state again. There is debate as to whether the drugs
take away the ability to feel pleasure, thus making the body
dependent on the drug to feel pleasure.
Alcohol Mixed With Ecstasy
Ecstasy interferes with the body's ability to maintain body
temperature causing a sharp increase in temperature. This can
lead to liver, kidney, and cardiovascular system failure.
Alcohol alone has the ability to raise body temperature. This
increases the chance of death by hypertension. Users have
reported feeling happiness within, empathy, and friendliness
toward others; the further state that the drug opens up their
mind to ideas and thoughts that they never experienced before.
Some of the users have been warned about mixing alcohol with
ecstasy, others didn't want to "mess up their high", and decided
when using ecstasy they would not use alcohol. A large
percentage of deaths and hospitalizations associated with
Ecstasy have involved a combination with alcohol.
References:
www.free.freespeech.org
www.ecstasy.org
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www.nida.nih.gov
Debra Pizzuto
SSRI interactions in treatment of depression
Whether or not neurotransmitters are abnormal in depression,
the neurotransmitter hypothesis of antidepressant action
suggests that initial reaction of antidepressants result in
eventual down regulation of key neurotransmitter receptors in a
time course consistent with the delayed onset of antidepressant
action of these drugs (Schatzberg & Nemeroff 1998 ). According
to Stahl (1996) it is possible that the serotonin neuron is
normal but that events triggered by SSRIs compensate for
neurochemical deficiencies elsewhere in the brain. This action
may also be responsible for the development of tolerance to the
acute side effects of antidepressants. The delayed drug action
may also explain why some patients fail to respond to
antidepressants. It may also explain side effects of acute
actions of serotonin at undesirable receptors in undesirable
pathways.
The pharmacodynamic (time course intensity) actions,
antidepressant efficacy, and adverse effect profiles of
selective serotonine reuptake inhibitors (SSRIs) are remarkably
similar (Catterson & Preskorn 1996). Although SSRIs share a
common mechanism of action, they differ substantially in their
respective chemical structure, metabolism, and pharmacokinetics
(drug concentration changes in plasma over time). The basis of
commonality between SSRIs is that they share more potent
selective inhibition of serotonin reuptake over other
antidepressants (TCAs) as well as less undesirable side effects.
Perhaps the most important difference between the SSRIs is their
potential to cause drug-drug interactions through the inhibition
of cytochrome P450 isoforms (Hemeryck & Belpaire 2002). The
available evidence indicates that individual SSRIs display a
distinct profile of cytochrome P450 inhibition(Catterson &
Preskorn 1996).
There are five important enzymes for antidepressant drug
metabolism. However, not all individuals have the same CYP450
enzymes. According to (Stahl 1996) there are differences in
metabolisms via certain enzymes between individuals and between
cultures (i.e. Caucasian, Black, Asian).
Fluvoxamine (Luvox) is a potent CYP1A2 and CYP2C19 inhibitor,
and moderate CYP2C9, CYP2D6, and CYP3A4 inhibitor.
Fluoxetine(Prozac) and paroxetine(paxil) are both potent CYP2D6
inhibitors. Sertraline(zoloft)is a moderate CYP2D6 inhibitor.
Fluoxetine has the longest half life after discontinuation.
Drug combinations with SSRIs should be assessed on an individual
basis. Knowledge of the CYP isoforms involved in co-
administered therapies may help clinicians avoid potentially
dangerous drug-drug interactions.
Individual drug interactions including those for antidepressants
(SSRIs) can take place at five different levels-
gastrointestinal absorption, serum protein binding, hepatic
metabolism, renal excretion, and competition for receptor sites
(Tollefson 1981) in Shen (1997). Any one of these processes
can determine therapeutic or toxic concentrations. The
variability of three main dose-effect relationships (i.e.
presence of pharmacologically active metabolites,
pharmacogenetic differences between patients, and interactions
of concurrent medications administered) is important in an
individual regime pertaining to antidepressant drugs (SSRIs).
Almost all psychoactive drugs are highly fat soluable, requiring
metabolism by cytochrome P450- dependent monooxygenases as part
of phase one of two biotransformations. Specifically, the
CYP450 enzyme in the gut wall or liver converts the drug into a
biotransformed product in the bloodstream. From there the drug
exists as a partly transformed product in the bloodstream. The
SSRIs are predominately eliminated via oxidation in the liver.
Cytochrome P-450 is found in liver cells. It is the key enzyme
in mixed function oxidases (Palfai & Jankiewicz 2001).
Two major mechanisms of drug interactions involve an alteration
of metabolism by either induction or inhibition of cytochrome
P450 enzymes. Further, drug therapies are frequently co-
administered to achieve therapeutic effects from combined
actions at effect sites or to treat adverse effects caused by
one drug with another. The SSRIs have the potential for
inhibiting P450 enzymes, with each of the five types of SSRIs
differing with regard to specific enzyme type inhibition. For
example, Fluvoxamine (luvox), is the only SSRI that inhibits
CYP1A2. This is the mechanism that appears to interact also
with caffeine, amitriptyline, clomioramine, imipramine,
clozipine. There are clinically important interactions with
standard doses of tricyclic antidepressants, some neuroleptics,
and some anti arrhythmics likely to occur in even lowest
recommended
doses of fluoxetine and setraline in vulnerable patients.
According to Stahl (1996) one of the most important drug
interactions through the inhibition of 2D6 is to raise plasma
levels of tricyclic antidepressants (TCAs) given concomitantly
with SSRIs. A second important interaction is with respect to
any switching between TCAs and SSRIs. Because TCAs are
substrates for 2D6, results could be toxic. The CYP450 2D6 also
interacts with atypical antidepressants. Co-administrated
psychotropic with nonpsychotropic drugs that inhibit CYP450 3A4
such as cisapride, terfenidine, and astemazole must be
metabolized to avoid toxic accumulation resulting in
cardiovascular consequences and sudden death.
Inducers of CYP450 increase activity (make more copies) of the
enzyme overtime. One example of this is cigarette smoking,
which induces CYP450 1A2. Antidepressant medications may need
to be increased over time to compensate. Interestingly, if one
stops smoking, 1A2 levels will rise. Many drug interactions
require dosage adjustment of one of the drugs. A few
combinations (MAOs and SSRIs) should be strictly avoided (Stahl
1996).
Much of the marketing of the new antidepressants has relied
heavily on the fact that they inhibit the enzymatic activity of
cytochrome subfamilies. One reason for this may relate to the
timing of the development of SSRIs and the discovery of the drug
metabolizing cytochrome P450 system. Subsequent lab
investigations have shown that several SSRIs are potent
inhibitors of P450 enzymes (Hemeryck & Belpaire 2002). The
property of the enzymatic inhibition is sometimes exploited for
clinical advantages as a marketing mechanism.
According to Stahl (1996) it should not seem surprising to find
different therapeutic actions of SSRIs. He suggests there may
be need to differentiate between therapeutic profiles of SSRIs
from one therapeutic indication to another. Individuals react
very differently to one SSRI verses another (Stahl 1996).
Whether these secondary binding profiles can account for the
differences in drug efficacy and tolerability on an individual
treatment basis requires further investigative efforts.
Treatment resistant depression represents an important challenge
for pharmacotherapy. Again, the strategy is to improve response
through combinations of SSRIs with other drugs. However the
research has emphasized that combination treatments be applied
under careful supervision and through regular controls of serum
levels.
Reboxine is thought to be one of the newer logical
pharmacological compliments to the SSRIs. This compounds
selective noradrenergic reuptake action increases serotonergic
neurotransmission without the adverse side effects of earlier
TCAs. Reboxine, a selective noradrenaline reuptake inhibitor
(SNRI) may be useful in cases of severe depression unresponsive
to other antidepressants and also as an adjunct to treat more
difficult cases (Stahl 1996). Empirical analyses assessing the
efficacy as a combination strategy (from different
pharmacological families) on patients who failed to respond to
SSRI therapy alone, or did so partially, look promising.
Further controlled trials are needed to evaluate the
effectiveness of this apparently well-tolerated low side-effect
combination (Rubio et al 2003). According to Rubio and
collegues, there is a lack of consensus on the conceptualization
of treatment resistant depression. Selectivity in monotherapies
may be less desired than multiple drug therapies in treating
resistant to selective serotonergic mechanisms. According to
Rubio and others, the results of open studies are
methodologically questionable. However, the use of placebo in
this type of patient would be unethical, given that risk of
suicide would be markedly higher.
Behavioral issues including substance abuse and compliance
issues account for a substantial percentage of problematic
treatment efficacies. Substance abuse and individual
comorbitity or "dual diagnosis" in the general population is
indicated to be as much as 40% by recent estimates (Helgason &
Tomasson 1996). The most prevalent diagnoses for substance
abuse and compliance issues are anxiety, affective, and
personality disorders.
Compliance issues with respect to client-practitioner
relationships result form patient inability or unwillingness to
follow a drug regime related to drug-drug interactions that may
be often unrecognized. They can however present in many ways.
Pharmacodymanic (i.e.the time course intensity of
pharmacological effects) interactions occur qualitatively when
the mechanism of one drug amplifies or diminishes the effect
produced by the mechanism of action of another drug (Preskorn
1996) in (Roose 2003). Pharmacokinetic(i.e. study of
description of concentration changes in plasma over
time)interactions often present as quantitative change in
response (magnitude of response). This type of interaction
occurs when one drug affects the pharmacokinetics of another
drug changing concentration at the site of action. Clinically,
the patient may appear sensitive or non-responsive. This type
of reaction can be mislabeled as an idiosyncratic reaction
particular to that patient. Roose (2003) references the
importance of knowing all medication a patient is taking,
including non-prescription substances in evaluation of potential
drug-drug interactions. Low propensity for pharmacokinetic
interactions is an important feature of any antidepressant drug.
Many treatment guidelines recommend continued dosage therapy for
6-9 months after resolution of depressive symptoms as a
prevention of relapse according to APA guides for 2000 in (Roose
2003). However, depending on the antidepressant and the
population studied, up to 68% of patients will discontinue
antidepressant treatment after three months due to adverse
events. According to Roose, patient physician communication
across a wide range of topics, including short and long term
side-effects, and treatment duration is essential for optimal
treatment and sustained compliance.
References
Bosker, G. (1999) Pharmatecture: minimizing medications to
maximize results. St. Louis
Mo. Facts and Comparisons publisher.
Catterson, M., & Preskorn, S. (1996) Pharmacokinetics of
selective serotonin reuptake inhibitors: clinical
relevance Pharmacology & toxicology (78) 4. Retrieved
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Helgason, T. & Tomasson, K. (1996) Substance use disorders:
epidemiological overview of psychiatric comorbidity.
European psychiatry (11) 4. Retrieved 04/20/05 from
http://www.sciencedirect.com
Hemeryck, A. & Belpaire, F. (2002) Selective serotonin
reuptake inhibitor and cytochrome P450 mediated drug-
drug interactions: an update. Current drug metabolism
(3)1. Retrieved 04/20/05 from
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Palfori, T. & Jankiewicz, H. (2001) Drugs and Human
Behavior. New York: McGraw Hill.
Roose, S. (2003) Compliance: the impact of adverse events
and tolerability on the physician's treatment decisions.
European Neuropsychopharmacology (13) 3. Retrieved 04/23/05
from http://www.sciencedirect.com
Rubio, G., San, L. Lopez-Munez, F.& Almano, C. (2004)
Reboxetine adjunct for partial or nonresponders to
antidepressant treatment. Journal of affective
disorders (81) 1. Retrieved 05/01/05 from
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Schatzberg, A. & Nemeroff, C.(1998) the Textbook of
Psychopharmacology 2nd.ed. Washington, DC. American
Psychiatric Press.
Shen W. (1997) The metabolism of psychoactive drugs: a
review of enzymatic biotransformation and inhibition.
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Stahl, S. (1996) Essential Psychopharmacology:
Neuroscientific Basis and Practical Applications.
Boston: Cambridge University Press.
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