PHARMACOKINETICS IN THE MEDICALLY ILL

Pharmacokinetics describes the absorption, distribution, metabolism, and

excretion of drugs,
pharmacodynamics refers to the effects of drugs, primarily in the brain.
1. Absorption
Orally administered drugs absorbed through the gastrointestinal tract may be
extensively altered by first-pass hepatic metabolism before entering the
systemic circulation. Sublingual and topical administration of drugs minimizes this
first-pass effect, and rectal administration may reduce the first-pass effect by
50%.
Drug formulation, drug interactions, gas- tric motility, and the characteristics of
the absorptive sur- face all influence the rate of absorption, a key factor when
rapid onset is desired. The extent of drug absorption, however, is more important
with chronic administration. The bioavailability of a drug describes the rate and
extent to which the drug ingredient is absorbed from the drug product and
available for drug action. Intravenous drug delivery has 100% bioavailability.
2. Distribution
Systemic drug distribution is influenced by serum pH, blood flow, protein binding,
lipid solubility, and the de- gree of ionization.
In general, acidic drugs (e.g., valproic acid, barbitu- rates) bind mostly to
albumin, and more basic drugs (e.g., phenothiazines, tricyclic antidepressants
[TCAs], am- phetamines, most benzodiazepines) bind to globulins. In general,
only free (unbound to plasma proteins) drug is pharmacologically active.
Decreases in protein binding increase availability of the free drug to
pharmacological action, metabolism, and excretion.
Volume of distribution is a function of a drugs lipid sol- ubility and plasma- and
tissue-binding properties. Most psychotropic drugs are lipophilic but are also
extensively bound to plasma proteins.

3.Metabolism (or Biotransformation) and Elimination of Drugs

Biotransformation occurs throughout the body, with the greatest activity in the
liver and gut wall. Most psychotro- pic drugs are eliminated by hepatic
metabolism and renal excretion.
The hepatic clearance of drugs may be limited by either the rate of delivery (i.e.,
hepatic blood flow) of the drug to the hepatic metabolizing enzymes or the
intrinsic capacity of the enzymes to metabolize the substrate. Clinically significant decreases in hepatic blood flow occur only in severe cirrhosis, and when

possible, parenteral administration of drugs is preferred.

The kidneys primary pharmacokinetic role is drug elimination. However, renal
disease may affect absorp- tion, distribution, and metabolism of drugs. Creatinine
clearance is a more useful indicator of renal function than serum creatinine.
DRUG-DRUG INTERACTIONS
Drugdrug interactions are pharmacodynamic or pharmacokinetic in nature.
Pharmacodynamic interactions in- volve alterations in the pharmacological
response to a drug, which may be additive, synergistic or antagonistic.
Pharmacokinetic interactions include altered absorption, distribution, metabolism,
or excretion and can result in changing the drug concentration in tis- sues.
SUBSTRATE
A substrate is an agent or a drug that is metabolized by an enzyme.
INDUCER
An inducer is an agent or a drug that increases the activity of the metabolic
enzyme, allowing for an in- creased rate of metabolism. Induction may lead to
de- creases in the amount of circulating parent drug and increases in the number
and amount of metabolites pro- duced. The clinical effect may be a loss or
decrease in therapeutic efficacy or an increase in toxicity from metab- olites.
An inhibitor has the opposite effect, decreasing or blocking enzyme activity
needed for the metabolism of other drugs. This results in increased levels of any
drug dependent on that enzyme for biotransformation, thereby producing
prolonged pharmacological effect or increased toxicity.
General Principles
In medically ill patients, polypharmacy is usually the norm and requires vigilance
regarding the many potential drugdrug interactions.
Cozza et al. (2003) advised that physicians prescribing in a polypharmacy
environment should, whenever possible, avoid medications that significantly
inhibit or induce cytochrome P450 enzymes and prefer those that are eliminated
by multiple pathways and have a wide safety margin.

Identification of Potential Pharmacokinetic Interactions

Most pharmacokinetic drugdrug interactions involve the effects of an interacting
drug on the cytochrome P450 mediated metabolism of a substrate drug. The

interacting drug may be either an inhibitor or an inducer of the crit- ical P450
isozymes involved in the substrate drugs metab- olism.
Metabolic drug interactions are most likely to occur in three situations: addition of
an interacting drug (inhibitor or inducer) to an existing critical substrate drug;
with- drawal of an interacting drug from a dosing regimen con- taining a substrate
drug; or addition of a substrate drug to an existing regimen containing an
interacting drug.
The addition of an interacting drug to a medication regimen containing a
substrate drug at steady-state levels will dramatically alter the concentration of
the substrate drug. If the interacting drug is an inhibitor, substrate drug
concentrations will rise as its elimination is reduced. This rise in substrate levels
may result in toxicity because of the drugs narrow therapeutic index. Conversely,
addition of an enzyme inducer will increase elimination of the sub- strate, thereby
lowering its concentration and therapeutic effect.
Withdrawal of an interacting drug from a drug regi- men containing a critical
substrate drug can also result in a drug interaction. The dosage of substrate drug
will have been titrated, in the presence of the interacting drug, to optimize
therapeutic effect and minimize adverse effects. Withdrawal of an enzyme
inhibitor will allow metabolism to return (increase) to normal levels. This
increased me- tabolism of the substrate drug will lower its levels and de- crease
therapeutic effect. In contrast, removal of an en- zyme inducer will result in an
increase in substrate drug levels and drug toxicity as metabolism of the substrate
de- creases to a normal rate.

The addition of a critical substrate drug to a drug reg- imen containing an

interacting drug can result in a clini- cally significant interaction if the substrate is
dosed ac- cording to established guidelines. Dosing guidelines do not account for
the presence of a metabolic inhibitor or inducer and thus may lead to substrate
concentrations that are, respectively, toxic or subtherapeutic.

Drug interactions that affect renal drug elimination are clinically significant only if
the parent drug or its ac- tive metabolite undergoes appreciable renal elimination.

A. Side Effects and Toxicity

1. Selective Serotonin Reuptake Inhibitors and Novel/Mixed-Action Agents

Adverse effects of selective serotonin reuptake inhibitors (SSRIs) and
novel/mixed-action agents are common, but they are usually mild, dose related,
and abate over time. However, serotonergic agents, especially when used in
combination, can induce the potentially fatal serotonin syndrome
Common short-term side effects with SSRIs and venlafaxine include nausea,
vomiting, anxiety, headache, se- dation, tremors, and anorexia. Common longterm side effects include sexual dysfunction, dry mouth, sweating, impaired
sleep, and potential weight gain.
Mirtazapine is associated with a high incidence of sedation, increased appetite,
and weight gain (Nelson 1997). Common ad- verse effects of bupropion include
agitation, insomnia, anxiety, dry mouth, constipation, postural hypotension,
tachycardia, and cardiac arrhythmias. Nausea and vomiting are much less
common with bupropion than with SSRIs
Central nervous system. An association between SSRI use and increased
suicidal ideation was proposed by Teicher in 1990 on the basis of case reports
(Teicher et al. 1990). Unfortunately, because of lack of definitive data, the existence of an association and the magnitude of effect re- main unanswered.
In June 2003, the United Kingdom Department of Health concluded that the rate
of self-harm and potentially suicidal behavior is increased in children and
adolescents receiving paroxetine for treat- ment of depression.
In March of 2004, the FDA asked manufacturers of antidepressant drugs (including fluoxetine, sertraline, paroxetine, fluvoxamine, citalo- pram, escitalopram,
bupropion, venlafaxine, nefazodone, and mirtazapine) to include in their labeling
a warning statement that recommends close observation of adult and pediatric
patients treated with these agents for wors- ening depression or the emergence
of suicidality, The FDA has not concluded that these drugs cause worsening
depression or suicidality.
The seizure risk reported for other antidepressants ranges from 0.04% for
mirtazapine to 15.6% (n=32) for mapro- tiline (Harden and Goldstein 2002;
Jabbari et al. 1985). Given that the annual incidence of first unprovoked sei- zure
is 0.06% in the general population, seizure risk for patients taking most
antidepressants is not elevated.
Serotonin syndrome. Serotonin syndrome is an uncom- mon but potentially lifethreatening complication of treatment with serotonergic agents.

The incidence of the syndrome is unknown, partly due to the lack of uniform
diagnostic criteria. Virtually all medica- tions that potentiate serotonergic
neurotransmission in the CNS have been reported in association with serotonin
syndrome. The antidepressant combinations most com- monly implicated have
been monoamine oxidase inhibitors (MAOIs; reversible and irreversible) and
TCAs, MAOIs and SSRIs, and MAOIs and venlafaxine.
Thus, the differential diagnosis for serotonin syndrome is similar to that for
neuroleptic malignant syn- drome (NMS) (see Neuroleptic Malignant Syndrome
subsection later in the chapter). Differentiating serotonin syndrome from NMS
can be very difficult in patients receiving both serotonergic and antipsychotic
medications.
Serotonin syndrome is often self-limited and usually resolves quickly after
discontinuation of serotonergic agents. Management includes the following basic
princi- ples: 1) provide necessary supportive care, 2) discontinue all serotonergic
agents, 3) anticipate potential complica- tions, 4) consider administering
antiserotonergic agents, and 5) reassess the need for psychopharmacological
therapy before reinstituting drug therapy (Keck and Arnold 2000). Some patients will
require admission to an inten- sive care unit, but most will show some
improvement within 24 hours with supportive care alone. There are no specific
antidotes available for the treatment of serotonin syndrome. The antihistamine
cyproheptadine is the most consistently effective serotonin antagonist reported.
The recommended adult dose is 48 mg and may be repeated every 14 hours
up to a maximum daily dose of 32 mg.
Autonomic and cardiovascular. The SSRIs and the novel/ mixed-action
antidepressants have a much safer cardio- vascular profile than the TCAs and
MAOIs. In general,
Bupropion is reported to cause hy- pertension without affecting heart rate in
some patients. In patients using transdermal nicotine, bupropion is asso- ciated
with a 6.1% incidence of hypertension (Khawaja and Feinstein 2003). Reboxetine
has also been associated with an increase in heart rate of 811 beats/minute
(Flei- shaker et al. 2001), but without any significant effect on
electrocardiography (Andreoli et al. 2002).
Gastrointestinal. Nausea is the most common adverse effect associated with the

serotonergic antidepressants.
Weight gain/loss. Weight gain is a relatively common problem during both acute
and long-term treatment with antidepressants. TCAs and MAOIs are more likely
to cause weight gain than other antidepressants, with the exception of
mirtazapine. Paroxetine may be more likely than other SSRIs to cause weight
gain during long-term treatment. Bupropion rarely causes weight gain (Fava
2000).
Abrupt discontinuation of SSRIs, especially those with short half-lives, may give
rise to a discontinuation syndrome characterized by a wide variety of symptoms,
including gastrointestinal, psychiatric, neurological, and flulike symptoms; sleep
disturbances; and headache (Had- dad 1998), usually resolving within 3 weeks.
Antidepres- sants, like all psychoactive medications, should be grad- ually
withdrawn. Discontinuation symptoms can cause misdiagnosis and inappropriate
treatment, particularly in a patient with an active medical illness, as well as erode
fu- ture compliance.
TCAs are now viewed as second-line treatments for depression because their
adverse effect profile is less benign than that of SSRIs.
TCAs are antagonists at histamine H1, adrenergic alpha1, and muscarinic
receptors and have type-1A antiarrhythmic (quinidine-like) effects as a result of
their blockade of voltage-dependent Na+-channels.
Adverse effects of the TCAs include sedation, anticholinergic effects (dry mouth,
dry eyes, constipation, urinary retention, decreased sweating, confusion, memory
impairment, tachycardia, blurred vision), and postural hypotension. Tolerance to
these effects usually develops over time.
TCAs can cause heart block, arrhythmias, palpitations, tachycardia, syncope,
and heart failure and should be used with caution in pa- tients with preexisting
cardiovascular disease or at risk of suicide.
Drug interactions. The combination of TCAs and other drugs with sedating,
hypotensive, antiarrhythmic, or sei- zure thresholdlowering properties may lead
to additive toxicity.

Toxicity/overdose. TCA overdose carries a risk of death from cardiac conduction

abnormalities that result in malignant ventricular arrhythmias. Initial symptoms of overdose involve CNS

stimulation, in part due to anti- cholinergic effects, and include hyperpyrexia,

delirium, hypertension, hallucinations, seizure, agitation, hyperre- flexia, and
parkinsonian symptoms.
Treatment for overdose includes removal of any unab- sorbed medication from
the stomach (gastric lavage or emesis with aspiration precautions and then
activated charcoal to reduce absorption), followed by supportive therapy and
close monitoring. Cardiac conduction abnor- malities, arrhythmias, and
hypotension may be treated with administration of intravenous sodium
bicarbonate to produce a serum pH of 7.47.5.
Abrupt discontinuation of TCAs may give rise to a discontinuation syndrome
characterized by dizziness, lethargy, headache, nightmares, and symptoms of
anti- cholinergic rebound, including gastrointestinal upset, nausea, vomiting,
diarrhea, excessive salivation, sweating, anxiety, restlessness, piloerection, and
delirium
3. Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs), with the possible exception of
moclobemide (not available in the United States), are seen as third-line
antidepressants because of their significant drug interactions and the dietary
restric- tions that accompany their use.
Common adverse effects of MAOIs include orthostatic hypotension, dizziness,
head- ache, sedation, insomnia or hypersomnia, tremor, and hyperreflexia.
Interactions between MAOIs and direct- or indirect-acting sympathomimetics or
dopaminergic agonists may cause a hypertensive crisis. MAOIs may trigger
serotonin syndrome when combined with other medications
Toxicity/overdose. Symptoms of MAOI overdose are an extension of the normal
adverse-effect profile. Treatment for overdose includes removal of any
unabsorbed medica- tion from the stomach and supportive measures.
Treatment for hypertensive crisis involves discontinuing the MAOI and slowly
administering intravenous phen- tolamine (typical adult dose = 5 mg). Betablockers should never be used; beta-blockade allows unrestrained alphaadrenergic stimulation, which further exacerbates the hyperten- sion.
Mood stabilizers are used in the medically ill to treat pri- mary and secondary
mood disorders as well as for symp- toms such as headache and chronic pain.
Valproic acid, carbamazepine, and oxcarbazepine are the most commonly used

anticonvulsant mood stabilizers.

A. Side Effects and Toxicity
1. Lithium
Most patients using lithium experience some side effects, both acute
(gastrointestinal distress and tremor) and long- term (polyuria and polydipsia,
hypothyroidism, weight gain, impaired cognition, sedation, impaired coordination,
edema, acne, and hair loss), most of which are mild and dose related (Peet and
Pratt 1993). Adverse effects of lith- ium can be minimized by reducing the dose
or decreasing the rate of absorption from the gut by administering the drug either
in divided doses with meals or in a slow-release form.
Central nervous system. Headache, fatigue, hand tremor, and mild cognitive
impairment are reported by up to 50% of patients beginning lithium treatment.
Hand tremor is usually a benign, fine, rapid intention tremor that resolves over
time or can be managed by dose reduction or low- dose beta-blockers. Mild
cognitive impairment may be experienced during the first 68 months of
treatment; although rarely progressive, this impairment is the most common
reason for noncompliance
Autonomic and cardiovascular. Lithium causes benign reversible repolarization
electrocardiographic changes in 20%30% of patients (Mitchell and Mackenzie
1982), in- cluding T-wave depression and inversion. Other cardio- vascular
effects of lithium include decreased heart rate and, rarely, cardiac conduction
abnormalities and arrhyth- mias (Burggraf 1997).
Renal. Lithium reduces renal response to antidiuretic hormone, resulting in
polyuria and/or polydipsia initially in 30%50% of patients and persisting in 10%
25%. Stopping lithium usually reverses this nephrogenic diabetes insipidus
(McEvoy 2003). Apart from dry mouth, patients do not generally exhibit signs of
dehydration. Management of polyuria may include changing to a single daily
bedtime dose of lithium, decreasing dosage, and/or administering thiazide
diuretics or amiloride. If thiazide diuretics are added, lithium dosage typically will
have to be reduced by 50% to compensate for thiazide-induced reduction of
lithium excretion (Jefferson et al. 1987).
Most investigators continue to agree that the risk of renal dysfunction during
chronic use is far less than the risk of psychiatric morbidity (Perry 1996).
Endocrine and metabolic. The prevalence of overt hypo- thyroidism has been

reported to be as high as 8%19% for

patients taking lithium, compared with a prevalence of 0.5%1.8% in the general
population.
Elevated thyroid-stimulating hormone is present in approximately 30% of patients
tak- ing lithium for 6 months or more, and progression to overt hypothyroidism
(elevated thyroid-stimulating hormone and low free T4) may occur in as many as
5%10% of pa- tients per year (Kleiner et al. 1999). Thyroid function should be
assessed before lithium is started and periodi- cally during therapy.
Hypothyroidism can be treated with L-thyroxine and is not a contraindication to
continuing lithium
Weight gain is the second most common reason cited by patients for lithium
noncompliance (Gitlin et al. 1989). Weight gain is a consequence of increased
caloric intake in part due to consumption of high-calorie fluids in re- sponse to
increased thirst
Dermatological. Dermatological adverse effects include dry skin and acne.
Occurring in about 1% of patients tak- ing lithium (Jefferson et al. 1987), these
effects usually re- spond to standard treatment and rarely require lithium
discontinuation. Alopecia and exacerbation of psoriasis occur less frequently
Drug interactions. Lithium is almost entirely renally ex- creted, and most lithium
filtered by the glomeruli is reab- sorbed with sodium in the proximal tubule.
Serum lith- ium levels are increased by thiazide diuretics, NSAIDs, angiotensinconverting enzyme inhibitors, sodium deple- tion, and dehydration
Toxicity/overdose. Toxicity increases markedly as serum lithium levels exceed 1.5
mEq/L, and serum levels greater than 2.0 mEq/L are dangerous. However, some
patients experience toxicity at therapeutic levels. Initial symp- toms of toxicity
include marked tremor, nausea, diarrhea, blurred vision, vertigo, confusion, and
increased deep tendon reflexes, progressing to seizures, coma, cardiac arrhythmia, and possibly permanent neurological impair- ment as lithium levels
increase.
Treatment for lithium toxicity includes gastric lavage or emesis followed by
supportive measures. These mea- sures include volume resuscitation with
isotonic or one- half isotonic sodium chloride solution to enhance renal
elimination of lithium in individuals with mild-to-moderate toxicity, or hemodialysis
for patients with severe toxicity and/or lithium levels of 3.5 mEq/L or higher
2. Anticonvulsants
The anticonvulsants valproate, carbamazepine, gabapentin, lamotrigine,
oxcarbazepine, topiramate, tiagabine, zonisamide, and levetiracetam share a

similar profile of CNS adverse effects. Sedation, ataxia, dizziness, muscle

weakness, fatigue, and vision dis- turbances such as nystagmus and diplopia are
common and often resolve with time, dosage reduction, or discon- tinuation.
Cognitive impairment is a com- mon complication of anticonvulsant use. Among
anti- convulsants used in psychiatry, the ranking of cognitive profile is (best to
worst) gabapentin, lamotrigine, val- proate and carbamazepine, and topiramate
Gastrointestinal. Symptoms of gastrointestinal distress, including nausea,
vomiting, dyspepsia, diarrhea, and an- orexia, are the most frequent adverse
effects experienced with most anticonvulsants. These effects are often dose
related and transient, and can be minimized by giving the drug in divided doses,
with meals, or with slow titration. Gastrointestinal effects appear less often with
dival- proex sodium than with valproic acid or sodium val- proate.
Hematological. Carbamazepine is frequently associated with transient leukopenia
and rarely may cause aplastic anemia. Carbamazepine should be discontinued in
pa- tients with white blood cell counts less than 3.0 109/L or neutrophil counts
less than 1.0 109/L, and patients must be educated to report early signs of
anemia, infec- tion, or bleeding (Sobotka et al. 1990).
Mild, asymptomatic leukopenia and thrombocytope- nia have been observed with
valproate and are generally reversible with dosage reduction or discontinuation.
More severe cases of thrombocytopenia and agranulocytosis have also been
reported (Finsterer et al. 2001)
.
Renal. Carbamazepine and oxcarbazepine frequently cause the syndrome of
inappropriate antidiuretic hor- mone secretion (SIADH), leading to hyponatremia
and water intoxication.
Endocrine and metabolic. Transient elevations in liver enzymes occur commonly
with anticonvulsants. Signifi- cant changes in hepatic function are usually
reversible with dosage reduction or discontinuation.
Weight gain is a common factor in noncompliance (Mendlewicz et al. 1999).
Weight gain is especially a prob- lem with valproate, with 25% of patients gaining
up to 20 kg (Pijl and Meinders 1996). Gabapentin is reported to result in about
10% gain of body weight in 25% of pa- tients (DeToledo et al. 1997). Although
carbamazepine is also reported to cause weight gain, the incidence is less than
with valproate
Immune system. Benign skin rashes occur in 5%20% of patients receiving
anticonvulsants, including valproate, carbamazepine, and lamotrigine. However,
serious and potentially fatal immune reactions to anticonvulsants are not

uncommon. Severe and often fatal hypersensitivity cutaneous reactions include

StevensJohnson syndrome and toxic epidermal necrolysis. Mor- tality occurs in about
5%10% of patients with Stevens- Johnson syndrome and in up to 45% of those
with toxic epidermal necrolysis. In comparison with general medical patients, the
risk of developing Stevens-Johnson syn- drome or toxic epidermal necrolysis
during the first 2 months of anticonvulsant therapy is increased by 120-fold for
carbamazepine, 25-fold for lamotrigine, and 24-fold for valproate
The presence of an anti- convulsant-induced rash should prompt drug discontinuation (Hebert and Ralston 2001).
Drug interactions. Significant cytochrome P450 enzyme induction occurs with
carbamazepine (CYP1A2, CYP2C, and CYP3A4), oxcarbazepine (CYP3A4), and
valproate (CYP2C)
Side Effects and Toxicity
1. Central Nervous System
Acute EPSakathisia, akinesia, and dystoniaoccur in as many as 50%75%
of patients who take typical antipsychotics (Collaborative Working Group on
Clinical Trial Evaluations 1998). High- potency typical antipsychotics are
associated with higher rates of EPS than are low-potency agents. Among the currently available atypical antipsychotics, the hierarchy of
EPS risk (greater to lesser) is risperidone > olanzapine = ziprasidone =
aripiprazole (estimated) > quetiapine > clo- zapine (Tandon 2002).
It is also im- portant to exclude other causes of restlessness that may mimic
akathisia in medically ill patients, such as hypogly- cemia, hypoxia, drug
withdrawal, pain, electrolyte distur- bances, iron deficiency, and restless legs
syndrome.
Seizures. At higher doses, there appears to be an in- creased risk of seizures
associated with antipsychotics.
Most of the early case reports were of sei- zures with chlorpromazine. Although
there are no con- trolled comparative studies to allow an accurate assess- ment
of relative seizure risk, it appears that high-potency typical antipsychotics and
risperidone have the lowest rate of seizures; olanzapine, quetiapine, and lowpotency typical antipsychotics have an intermediate risk; and clo- zapine has the
highest risk
Sedation. Sedation is the most common single side ef- fect, especially with the
low-potency typical antipsychot- ics. Among the atypical antipsychotics, the
hierarchy of potential for sedation (greater to lesser) is clozapine > quetiapine >

olanzapine > risperidone > ziprasidone = aripiprazole (estimated) (Tandon 2002).

Sedation is most prominent in the early stages of therapy, with some de- gree of
tolerance developing over time.
Neuroleptic malignant syndrome. NMS is a rare, poten- tially fatal, idiosyncratic
reaction to antipsychotics.
NMS is not specific to any neuropsychiatric diagnosis and has been reported in
nonpsychiatrically ill individuals who were treated with other dopamine
antagonists such as metoclo- pramide and prochlorperazine (
Malnutrition, dehydration, and iron deficiency all appear to increase risk for NMS.
NMS generally develops over a 13 day period and lasts for 510 days after a
nondepot antipsychotic is dis- continued. Mortality is high, often quoted at 20%
30% but probably lower now because of earlier recognition. The main clinical
features of NMS include hyperthermia (>37C), generalized muscle rigidity,
mental status changes and autonomic instability. Temperature in hyper- thermia
is greater than 38C in the majority of cases and can exceed 40C, which
predisposes the patient to severe complications, including irreversible CNS and
other or- gan damage. Muscle rigidity is often heterogeneous and can be leadpipe or cogwheeling. Autonomic dysfunc- tion in NMS may include hypertension,
orthostatic hypo- tension, labile blood pressure, tachycardia, tachypnea,
sialorrhea, diaphoresis, skin pallor, and urinary inconti- nence. Neurological
dysfunction may consist of tremor, myoclonus, focal dystonias, dysphagia,
dysarthria, opistho- tonus, oculogyric crisis, and dyskinesias. Altered level of
consciousness may range from decreased awareness to coma. CPK levels are
often elevated in NMS secondary to muscle necrosis from rigidity, hyperthermia,
and ische- mia. Elevated CPK levels are not proof of NMS, because they may
result from agitation, use of physical restraints, and intramuscular injections.
Extreme elevation of CPK (>100,000 U/L) constitutes rhabdomyolysis, which may
be a consequence of NMS and/or other causes in the medically ill (e.g., sepsis,
shock, alcohol). Serial CPK monitoring in NMS will typically show declining levels
with the resolution of the syndrome.
The differential diagnosis of NMS is large (Table 376). Although the vast
majority of patients receiving antipsychot- ics who develop fever and rigidity will
be found to have other conditions, the possibility of NMS should be considered
be- cause of the importance of promptly withholding antipsy- chotics.
The main interventions in NMS are early diagnosis, rapid cessation of the
antipsychotic treatment, and intensive supportive care. Lithium, antipsychotics, and all other dopamine-blocking
agents (including antiemetics and droperidol) should be discontinued. Most
cases of NMS require initial treatment in a medical intensive care unit and should

be transferred back to a psychiatric service only after the patient is med- ically
stable. Among patients who recover from NMS, there may be a 30% risk of
recurrent episodes following subse- quent antipsychotic rechallenge, but the
majority of pa- tients who require antipsychotic therapy can be cautiously retreated.
Autonomic and cardiovascular.
Among the atypical agents, the hierarchy for producing hypotension (from
greatest risk to least risk) is clozapine > quetiapine > risperidone > olanzapine =
ziprasidone = aripiprazole (estimated)
Other cardiac side effects. Potentially fatal myocarditis, cardiomyopathy, and
heart failure have been reported with clozapine.
2. Endocrinological and MetabolicGlucose tolerance.
Pharmacoepidemiological studies and case reports reveal an association
between the use of various atypical antipsychotics with hyperglycemia, newonset type 2 diabetes
Current limited data report that hyper- glycemia has been associated with all
marketed atypical antipsychotics.
Diabetic ketoacidosis has been reported in association with all atypical antipsychotics except for ziprasidone
Lipids. More recent studies with atypical antipsychotics have demonstrated
elevated serum triglyceride levels in patients taking clozapine, olanzapine, and
quetiapine (Domon and Cargile 2002; Gaulin et al. 1999; Meyer 2001b), usually
peaking in the first year of therapy.
Hyperprolactinemia. Hyperprolactinemia is relatively common, especially with
high-potency typical antipsy- chotics and risperidone, and can result in
amenorrhea or irregular menses, galactorrhea, gynecomastia, sexual dysfunction, and osteoporosis.
Weight gain. All currently marketed antipsychotics (with the possible exception of
molindone, ziprasidone, and aripiprazole) are associated with weight gain, which
may increase health risks (hypertension, atherosclerosis, type 2 diabetes,
cardiovascular disease, and stroke), stig- matization, noncompliance, impairment
in quality of life, and social withdrawal. The relative propensity to cause weight
gain among the atypical antipsychotics (from greatest to least) is clozapine >
olanzapine > risperidone = quetiapine = aripiprazole (estimated) > ziprasidone
(Tan- don 2002).
Syndrome of inappropriate antidiuretic hormone secre- tion. SIADH can occur

with typical as well as atypical antipsychotics (and some antidepressants and

anticonvul- sants). SIADH is characterized by a reduced ability to excrete water,
resulting in extracellular dilution and hypo- natremia.
Common symptoms include weakness, lethargy, headache, anorexia, and weight
gain and may progress to confusion, convulsions, coma, and death.
Hematological. Hematological side effects of antipsychotics include
agranulocytosis, aplastic anemia, neutropenia, eosinophilia, and
thrombocytopenia
Agranulocytosis is the most common serious hematological side effect with
typical antipsychotics (<0.1%) and occurs more frequently with low-potency
agents. Clozapine-associated agranulocytosis occurs in about 1%2% of
patients, with highest risk in the first 6 months. A white blood count less than
2,000/mm3 or an absolute neutrophil count less than 1,000/mm3 is an indication
for immediate cessation of clozapine.
Allergic, dermatological, and ophthalmological. Derma- tological adverse
reactions include early allergic rashes, photosensitivity, and skin
hyperpigmentation, especially with chlorpromazine.
Sexual. Antipsychotics may cause sexual dysfunction
Drug interactions. Most antipsychotic drugs have sedat- ing, hypotensive,
anticholinergic, antiarrhythmic, and sei- zure thresholdlowering properties.
antipsychotics may strongly potentiate the sedative effects of other CNS
depressants, and anticholinergic anti- psychotics will have additive adverse
effects with other anticholinergic drugs.
Antipsychotics may greatly enhance the hypotensive effects of antihypertensive
agents
Anxiolytics and Sedative-Hypnotics
Side Effects and Toxicity
1. Benzodiazepines
Benzodiazepines have long been considered the corner- stone of
pharmacotherapy for anxiety and insomnia. Al- ternatives include buspirone for
anxiety and the nonben- zodiazepine hypnotics zolpidem, zopiclone, and
zaleplon. These newer agents appear to have much less tolerance and abuse
potential and fewer adverse effects than benzo- diazepines. Chloral hydrate has
been used as a sedative- hypnotic since 1869, but dependence occurs rapidly

and withdrawal can be fatal.

Central nervous system. Acute adverse CNS effects, in- cluding sedation, fatigue
and weakness, ataxia, slurred speech, confusion, and memory impairment, are
com- mon, especially in older individuals and the medically ill. When used for the
treatment of insomnia, long-half-life benzodiazepines are more likely to cause
daytime seda- tion and cognitive impairment than short-half-life drugs.
A study of the cognitive effects of long-term benzodiazepine use in the elderly
demonstrated that the impairment of memory, at- tention, and psychomotor
speed evident with acute ben- zodiazepine use reverts to predrug levels over 6
months of therapy
Respiratory.
The respiratory depressant ef- fects of benzodiazepines may become clinically
signifi- cant in those with preexisting respiratory disorders, such as chronic
obstructive pulmonary disease (COPD) (Clarke and Lyons 1977; Model 1973) or
sleep apnea (Mendelson et al. 1981), or those with seizure disorders (which also
can cause respiratory depression).
The incidence of respiratory depression associated with benzodiazepine
treatment of seizure disorder ranges from 10.6% for lorazepam in adults
(Alldredge et al. 2001) to 14% in children treated mainly with lorazepam (Stewart
et al. 2002) and 9%20% for children treated with diazepam
Drug interactions. Additive CNS depressant effects, in- cluding respiratory
depression, result from the combina- tion of benzodiazepines and other CNS
depressants, in- cluding alcohol.
Toxicity/Overdose.
Benzodiazepines have a wide margin of safety;
Overdose may result in sedation, ataxia, slurred speech, confusion, seizures,
respiratory depres- sion, and coma. Treatment includes removal of any unabsorbed drug from the stomach (gastric lavage or emesis) followed by supportive
therapy. The benzodiazepine antagonist flumazenil can also be used but may
cause seizures.
Sudden discontinuation of benzodiazepines may result in severe withdrawal
symptoms, including anxiety, agita- tion, dysphoria, anorexia, insomnia,
sweating, vomiting, diarrhea, abdominal cramps, ataxia, psychosis, and seizures.

Anxiolytics and Sedative-Hypnotics

2. Nonbenzodiazepine Sedatives (Zolpidem, Zopiclone, and Zaleplon)
Zolpidem, zopiclone, and zaleplon are very well tolerated short-half-life hypnotics
with very few dose-related ad- verse effects. Zolpidems adverse effects include
CNS (dizziness, drowsiness, and headache) and gastrointestinal effects (nausea
and dyspepsia) (Hajak and Bandelow 1998). Zopiclones adverse effects include
bitter taste, dry mouth, difficulty arising in the morning, sleepiness, nau- sea, and
nightmares (Allain et al. 1991).
Respiratory. Zolpidem has been reported to cause respi- ratory depression at
high doses (Cirignotta et al. 1988). Zopiclone dose not appear to have significant
effects on respiratory function. The respiratory effects of zaleplon are unknown.
Toxicity/overdose.
Symptoms of intentional overdose of zolpidem include drowsiness, vomiting,
coma, and respiratory failure. Treatment is generally limited to supportive
measures and/or gastric lavage. Symptoms of toxicity rapidly subside in most cases (Garnier et al. 1994).
Fatal overdose with zopiclone has been reported but,
as with zolpidem, appears rare
3. Chloral Hydrate
4. Buspirone
Psychostimulants

Side Effects and Toxicity

Methylphenidate, Amphetamines, and Pemoline

Modafinil and Atomoxetine

Cognitive Enhancers

Side Effects and Toxicity

Cholinesterase Inhibitors

NMDA Receptor Antagonists

Alternative Routes of Administration

Antidepressants

Anxiolytics and Sedative-Hypnotics

Antipsychotics

Psychostimulants

Mood Stabilizers

Cholinesterase Inhibitors

Complementary Medicines
Patients with chronic disease may be especially vulnerable to adverse effects
from herbal medicines because of compromised organ function and
polypharmacy with conventional agents.
Herbal preparations may contain several plant species used under a sin- gle
name (Chandler 2000) and may be adulterated with unlisted pharmacological
agents, pesticides, and heavy metals, including cadmium, lead, mercury, or
arsenic (Crone and Wise 1998). Drugs such as anti-inflammatory agents,

steroids, diuretics, antihistamines, sildenafil-like compounds (Wooltorton 2003),

and benzodiazepines may be intentionally added to the herbal product for
therapeutic effect.
Selected Herbal Medicines
1. Black Cohosh
Purported use.
Menopausal symptoms
Black co- hosh binds to estrogen receptors and lowers levels of lu- teinizing
hormone. It is contraindicated in pregnancy and lactation and should be avoided
by women with estrogendependent tumors.
2. Feverfew
Purported use. Migraine prophylaxis, anti-inflammatory
Pharmacological effects and drug interactions. Used as an abortifacient in
animals, feverfew is contraindicated in pregnancy in humans. It inhibits platelet
activation factor and may prolong bleeding time. Use caution with drugs known to
increase bleeding times, such as anticoagulants, NSAIDs, and platelet inhibitors.
Allergic reactions are common. Withdrawal syndrome (anxiety, fatigue, joint
ache) may occur on sudden discontinuation.
3. Ginger
Purported use. Antispasmodic, antiemetic
Ginger is a possible mutagen and abortifacient; avoid use in preg- nancy. It
inhibits thromboxane synthesis and thus may prolong bleeding time. Use caution
with drugs known to increase bleeding times, such as anticoagulants, NSAIDs,
and platelet inhibitors. These cautions do not apply to typical culinary doses.
4.Ginkgo Biloba
>Purported Use:Ginkgo biloba improves peripheral and CNS blood flow and is
used as a treatment for ischemia associated with peripheral artery disease and
vascular dementia.
>may cause palpitations. Seizures have been reported in children, and efficacy of
anticonvulsants may be reduced. The ginkgo biloba fruit, including the seeds, is
poisonous and very allergenic. Ingestion of the fruit has resulted in loss of
consciousness, seizures, and death, with a mortality rate of 27%. Ingestion of
fruit also causes con- tact dermatitis of mucous membranes. Discontinue use at
least 2 days before surgery.

5. Ginseng
Purported use:Ginseng is promoted as a physical, men- tal, and sexual tonic,
immunostimulant, and mood enhancer.
Pharmacological effects and drug interactions: Ginseng possesses estrogenic
activity; it is contraindicated in pa- tients with estrogen receptorpositive breast
cancer. It may cause estrogen-related bleeding disorders (vaginal bleeding) and
breast nodules. Sympathomimetic activity may cause tachycardia, hypertension,
nervousness, agita- tion, mania, and headache.
Avoid use in patients with diabetes, hypertension, anxiety disor- ders, and bipolar
disorder or those using estrogen therapy, antiestrogen therapy, or anticoagulants.
Avoid long-term use, which may be associated with ginseng abuse syn- drome;
symptoms include hypertension, nervousness, in- somnia, skin eruptions,
diarrhea, and tremor. A with- drawal syndrome (hypotension, weakness, tremor)
may occur on discontinuation. Discontinue at least 7 days before surgery.
6. Kava Kava
Purported use. Anxiolytic; sedative
Kava kava is also hallucinogenic. Sale of kava has been banned in many
jurisdictions because of
several incidents of fatal hepatotoxicity. Discontinue at least 24 hours before
surgery.
7.Ma Huang (Ephedra)
Purported use. Weight loss, stimulant
Excessive sympathetic stimulation can lead to dizziness, headache, decreased
appetite, gastro- intestinal distress, irregular heartbeat, tachycardia, hypertension, insomnia, flushing, seizures, stroke, and death.
Discontinue at least 24 hours before surgery.
8. St. Johns Wort
Purported Use: Antidepressant for mild to moderate depression, sedative
Pharmacological effects and drug interactions.
St. Johns wort increases serotonin and norepinephrine activity, which may cause
sinus tachycardia and gastrointestinal distress and may exacerbate bipolar
disorder, causing ma- nia.
Discontinue at least 5 days before surgery.

9. Valerian
Purported use.
Sedative, short-term treatment of in-somnia, anxiolytic
Pharmacological effects and drug interactions.
Withdrawal effects are similar to benzodiazepine with- drawal and can be
managed with benzodiazepines.
10. Yohimbe, Yohimbine
Purported use. Aphrodisiac, stimulant
Adverse effects include insomnia, anxiety, panic attacks, hallucinations,
hypertension, tachycardia, nausea, and vomiting. It should be avoided in patients
with hyper- tension, sleep disorders, anxiety disorders, and psychosis.
Selected Nonherbal Nutritional Supplements
DHEA (Dehydroepiandrosterone)
Purported use. Depression, postmenopausal osteoporo- sis, systemic lupus
erythematosus, erectile dysfunction, multiple sclerosis, dementia
Pharmacological effects and drug interactions.
DHEA may cause weight gain, voice change, hirsutism, and menstrual
irregularities in females and gynecomastia and prostatic hypertrophy in males.
DHEA is contraindi- cated in patients who have liver dysfunction, prostate cancer, or hormone-dependent diseases such as estrogen- dependent breast
cancer.

Gamma-Hydroxybutyrate (GHB), Gamma-Butyrolactone, and 1,4-Butanediol

Purported use. Narcolepsy, recreational fast-acting hyp- notic
Adverse effects include nystagmus, ataxia, apnea, sedation, dizziness, and
respira- tory depression. Coma, bradycardia, and death can result. Psychiatric
side effects of GHB include hallucinations, delusions, agitation, confusion, and
euphoria. GHB is a banned drug in many juris- dictions, but its precursors,
gamma-butyrolactone and 1,4-butanediol, are industrial solvents and are
available as street drugs.

S-Adenosyl-L-Methionine (SAMe)
Purported use. Depression, osteoarthritis, chronic liver

disease
Pharmacological effects and drug interactions.Adverse effects include nausea,
vomiting, and diarrhea. SAMe may increase anxiety and restlessness in patients
with depression and mania and hypomania in pa- tients with bipolar disorder.
Psychotropic Drug Use in the Medically Ill
A. Gastrointestinal Disease
1. Hepatic Disease
The dosage of psychotropics in patients with chronic hepatitis may need to be
modified depending on the severity of liver dysfunction.
When psychotropic medication is being pre- scribed for patients with impaired
hepatic function, it is prudent to reduce the initial dose and titrate more slowly for
any drug primarily metabolized by the liver, to care- fully monitor for clinical
response and side effects, and to choose drugs with a wide therapeutic index.
a. Antidepressants. Citalopram, paroxetine, sertraline, and fluoxetine have all
been used safely in patients with hepa- titis C, usually in the context of interferon treatment.
Hepatotoxicity is a known rare side effect of many an- tidepressants, but
nefazodone has a higher reported inci- dence than other current antidepressants
and thus should be avoided in patients with preexisting hepatic disease.
Elevation of aspartate transaminase (AST) or alanine transaminase (ALT) levels
of two to three times baseline or two times normal is significant, and any elevation of alkaline phosphatase (ALP) or bilirubin may be significant.
b. Antipsychotics. haloperidol remains the most commonly chosen antipsychotic
for patients with hepatic disease. Chlorpro- mazine should be avoided because
of its greater risk for hepatotoxicity. Low-potency typical antipsychotics, which are
more anticholinergic than high-potency typi- cals, may precipitate hepatic
encephalopathy in patients with cirrhosis (as described for TCAs).
c. Anxiolytics and sedative-hypnotics.
All benzodiazepines should be avoided in patients at risk for developing he- patic
encephalopathy because they may precipitate its on- set. When their use cannot
be avoided (e.g., alcohol withdrawal in a patient with cirrhosis), the benzodiazepines just mentioned are
preferred,d.
d. Mood stabilizers.
Because of the risk of hepatotoxicity, carbamazepine and valproic acid are
relatively contraindi- cated in patients with preexisting liver disease. If either of
these agents is used, reduce dose and monitor liver func- tion regularly,
especially during the first 6 months of ther- apy.
Lith- ium, although renally excreted, may require dose adjust- ment and close

monitoring secondary to fluctuating fluid balance in patients with liver disease

accompanied by as- cites (secondary hyperaldosteronism).
e. Cholinesterase inhibitors.
Donepezil clearance may be reduced in cirrhosis, but there are no specific
dosing rec- ommendations for hepatic insufficiency.
Rivastig- mine clearance may be reduced by 60%65% in patients with mild to
moderate hepatic insufficiency, and dosing should be guided by monitoring
efficacy and tolerability.
f. Psychostimulants.
There are no specific dosing recom- mendations for methylphenidate. Modafinil
clearance is reduced in hepatic insufficiency, and its dosage should be reduced
by 50% in patients with severe hepatic insuffi- ciency.

2. Gastrointestinal Bleeding
Antidepressants. Recent reports have raised concern re- garding SSRIs and the
risk of gastrointestinal bleeding (Dalton et al. 2003; de Abajo et al. 1999).
Serotonin plays a role in hemostasis, and there have been cases of pro- longed
bleeding time, ecchymosis, purpura, and epistaxis, as well as gastrointestinal,
genitourinary, and intracranial bleeding, in patients receiving SSRIs.
3. Other Gastrointestinal Disorders
In general, however, orally administered drugs may be poorly absorbed in the
presence of malabsorption syndromes. In patients with delayed gastric emptying
(due to diabetes mellitus, atrophic gastritis, gastric cancer, pyloric stenosis,
pancreatitis, or gastric ulcer or drug induced), the pharmacokinetic effect may be
to slow ab- sorption rate and delay time to onset of the medication.
For non-enteric-coated preparations, increased gastric emptying is likely to
increase the rate of drug absorp- tion, and conversely, delayed gastric emptying
will slow the rate of drug absorption.
For enteric-coated preparations, however, reduced gastric acidity increases the
rate of drug absorp- tion because dissolution of the preparation will occur in the
stomach.

B. Renal Disease
most psychotropics do not require drastic dosage adjustment in renal failure
with end-stage renal disease (ESRD): many problems associated with use of

psychotropics in patients are related to comorbid illnesses rather than to the

renal failure
>rule of two- thirds: patients with renal insufficiency, use two-thirds of the dose
(except for lithium and gabapentin) used for patients with normal renal function
>not dialyzable: most psychotropics=lipophilic compounds with large volumes of
distribution
>removed by dialysis: only lithium, gabapentin, valproate, topiramate, and
levetiracetam are a.Antidepressants

b. Antipsychotics

c.Anxiolytics and Sedative-Hypnotics

d. Mood Stabilizers

e.Cholinesterase Inhibitors

f. Psychostimulants
Antipsychotics
Pregnancy: Typical agentsNot associated with any evidence of
teratogenic, behavioral, emotional, or cognitive abnormalities. Low-potency drugsCan cause neonatal tachycardia,
gastrointestinal dysfunction, sedation, and hypoten- sion for a few days after
birth. Best avoided so as to minimize anticholinergic, hypotensive, and antihistaminic effects.
High-potency drugsPreferred despite the risk of fetal EPS. Incidence of fetal
EPS (hyperactivity, hy- perreflexia, abnormal movements, tremor, hand flapping,
and crying that may persist for several months) is dose related.

 Atypical agentsInsufficient human data for recom- mendation.

Depot preparationsAvoid because of long duration of action.

Breast-feeding: _____________________

Antidepressants

Pregnancy:
TCAsNot associated with evidence of teratogenic effects.
Avoid maprotiline because of increased ma- ternal seizure risk.
Neonatal TCA withdrawal symp- toms include seizures, irritability,
abdominal cramps, insomnia, tachycardia, tachypnea, and
cyanosis.
SSRIsFluoxetine not associated with teratogenic effects. Other
SSRIs do not appear to be teratogenic from limited human data.
MAOIsAvoid because of hypotensive effects and potential for
drug and food interactions.

Breast-feeding: __________________

NOT YET FINISHED================

General Guidelines for Psychotropic Drug Use in Pregnancy and Breast-Feeding
1. For any woman of childbearing age, carefully select all drugs for their safety in
pregnancy and breast- feeding.
2. Remember that the benefit of any medication to the mother must outweigh
the risk to the fetus.
3. Discuss with the mother the risks and benefits of us- ing psychotropic
medications while pregnant or breast- feeding.
4. Avoid all drugs during pregnancy and breast-feeding if possible, including
over-the-counter and herbal medicines.
5. Use the lowest effective dose of a short-half-life agent.

6.

Prefer monotherapy to combination therapy.

7.Select established drugs with known effects in pregnancy and breast-feeding

8.Select medications for minimum teratogenic and behavioral toxicity

9.during pregnancy: monitor clinical response and drug levels where possible
slowly return drug dose to prepregnancy levels: at delivery
10. Minimize drug exposure for the nursing infant

11.treatment of depression:consider electroconvulsive therapy

Rapid developments in medical care in general, and psychopharmacology in
particular, challenge clinicians to remain current with new agents, new indications
for established agents, and potential pharmacokinetic and pharmacodynamic
interactions in a polypharmacy envi- ronment, which also includes over-thecounter and herbal preparations.